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.

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.

Exploring diazoxide and continuous glucose monitoring as treatment for Glut1 deficiency syndrome.

Glut1 deficiency syndrome is caused by SLC2A1 mutations on chromosome 1p34.2 that impairs glucose transport across the blood-brain barrier resulting in hypoglycorrhachia and decreased fuel for brain metabolism. Neuroglycopenia causes a drug-resistant metabolic epilepsy due to energy deficiency. Standard treatment for Glut1 deficiency syndrome is the ketogenic diet that decreases the demand for brain glucose by supplying ketones as alternative fuel. Treatment options are limited if patients fail the ketogenic diet. We present a case of successful diazoxide use with continuous glucose monitoring in a patient with Glut1 deficiency syndrome who did not respond to the ketogenic diet.

Ventriculoperitoneal Shunt Drainage Increases With Gravity and Cerebrospinal Fluid Pressure Pulsations: Benchtop Model.

BACKGROUND: There have been few improvements in cerebrospinal fluid (CSF) shunt technology since John Holter introduced the silicon valve, with overdrainage remaining a major source of complications. OBJECTIVE: To better understand why valves are afflicted by supra-normal CSF flow rates. We present in Vitro benchtop analyses of flow through a differential pressure valve under simulated physiological conditions. METHODS: The pseudo-ventricle benchtop valve testing platform that comprises a rigid pseudo-ventricle, compliance chamber, pulsation generator, and pressure sensors was used to measure flow rates through a differential pressure shunt valve under the following simulated physiological conditions: orientation (horizontal/vertical), compliance (low/medium/high), and pulsation generator force (low/medium/high). RESULTS: Our data show that pulse pressures are faithfully transmitted from the ventricle to the valve, that lower compliance and higher pulse generator forces lead to higher pulse pressures in the pseudo-ventricle, and that both gravity and higher pulse pressure lead to higher flow rates. The presence of a valve mitigates but does not eliminate these higher flow rates. CONCLUSION: Shunt valves are prone to gravity-dependent overdrainage, which has motivated the development of gravitational valves and antisiphon devices. This study shows that overdrainage is not limited to the vertical position but that pulse pressures that simulate rhythmic (eg, cardiac) and provoked (eg, Valsalva) physiological CSF pulsations increase outflow in both the horizontal and vertical positions and are dependent on compliance. A deeper understanding of the physiological parameters that affect intracranial pressure and flow through shunt systems is prerequisite to the development of novel valves.

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.

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.

The Timing, Nature, and Range of Neurobehavioral Comorbidities in Juvenile Myoclonic Epilepsy.

BACKGROUND: Accumulating evidence suggests that considerable cognitive and psychiatric comorbidity is associated with juvenile myoclonic epilepsy, for which the etiology remains controversial. Our goal was to comprehensively characterize the status of multiple neurobehavioral comorbidities in youth with new- or recent-onset juvenile myoclonic epilepsy, before effects of chronic seizures and medications. METHODS: A total of 111 children aged eight to 18 years (41 new- or recent-onset juvenile myoclonic epilepsy and 70 first-degree cousin controls) underwent neuropsychological assessment (attention, executive, verbal, perceptual, speed), structured review of need for supportive academic services, parent reports of behavior and executive function (Child Behavior Checklist and Behavior Rating Inventory of Executive Function), and formal structured psychiatric interview and diagnosis (Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version). RESULTS: Children with juvenile myoclonic epilepsy performed worse than controls across all tested cognitive domains (F(1,105) = 3.85, P < 0.01), utilized more academic services (47% versus 19%, P = 0.002), had more parent-reported behavioral problems and dysexecutive function with lower competence (P < 0.001), and had a higher prevalence of current Axis I diagnoses (attention-deficit/hyperactivity disorder, depression, and anxiety; 54% versus 23%, P = 0.001). Academic and psychiatric problems occurred antecedent to epilepsy onset compared with comparable timeline in controls. CONCLUSION: Comprehensive assessment of cognitive, academic, behavioral, and psychiatric comorbidities in youth with new- or recent-onset juvenile myoclonic epilepsy reveals a pattern of significantly increased neurobehavioral comorbidities across a broad spectrum of areas. These early evident comorbidities are of clear clinical importance with worrisome implications for future cognitive, behavioral, and social function. It is important for health care providers to avoid delays in intervention by assessing potential comorbidities early in the course of the disorder to optimize their patients' social, academic and behavioral progress.

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.

Overdrainage-related ependymal bands: a postulated cause of proximal shunt obstruction.

OBJECTIVEVentricular shunts have an unacceptably high failure rate, which approaches 50% of patients at 2 years. Most shunt failures are related to ventricular catheter obstruction. The literature suggests that obstructions are caused by in-growth of choroid plexus and/or reactive cellular aggregation. The authors report endoscopic evidence of overdrainage-related ventricular tissue protrusions ("ependymal bands") that cause partial or complete obstruction of the ventricular catheter.METHODSA retrospective review was completed on patients undergoing shunt revision surgery between 2008 and 2015, identifying all cases in which the senior author reported endoscopic evidence of ependymal tissue in-growth into ventricular catheters. Detailed clinical, radiological, and surgical findings are described.RESULTSFifty patients underwent 83 endoscopic shunt revision procedures that revealed in-growth of ventricular wall tissue into the catheter tip orifices (ependymal bands), producing partial, complete, or intermittent shunt obstructions. Endoscopic ventricular explorations revealed ependymal bands at various stages of development, which appear to form secondarily to siphoning. Ependymal bands are associated with small ventricles when the shunt is functional, but may dilate at the time of obstruction.CONCLUSIONSVentricular wall protrusions are a significant cause of proximal shunt obstruction, and they appear to be caused by siphoning of surrounding tissue into the ventricular catheter orifices.

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.

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.

Correlation of EEG with neuropsychological status in children with epilepsy.

OBJECTIVE: To determine correlations of the EEG frequency spectrum with neuropsychological status in children with idiopathic epilepsy. METHODS: Forty-six children ages 8-18 years old with idiopathic epilepsy were retrospectively identified and analyzed for correlations between EEG spectra and neuropsychological status using multivariate linear regression. In addition, the theta/beta ratio, which has been suggested as a clinically useful EEG marker of attention-deficit hyperactivity disorder (ADHD), and an EEG spike count were calculated for each subject. RESULTS: Neuropsychological status was highly correlated with posterior alpha (8-15 Hz) EEG activity in a complex way, with both positive and negative correlations at lower and higher alpha frequency sub-bands for each cognitive task in a pattern that depends on the specific cognitive task. In addition, the theta/beta ratio was a specific but insensitive indicator of ADHD status in children with epilepsy; most children both with and without epilepsy have normal theta/beta ratios. The spike count showed no correlations with neuropsychological status. CONCLUSIONS: (1) The alpha rhythm may have at least two sub-bands which serve different purposes. (2) The theta/beta ratio is not a sensitive indicator of ADHD status in children with epilepsy. (3) The EEG frequency spectrum correlates more robustly with neuropsychological status than spike count analysis in children with idiopathic epilepsy. SIGNIFICANCE: (1) The role of posterior alpha rhythms in cognition is complex and can be overlooked if EEG spectral resolution is too coarse or if neuropsychological status is assessed too narrowly. (2) ADHD in children with idiopathic epilepsy may involve different mechanisms from those in children without epilepsy. (3) Reliable correlations with neuropsychological status require longer EEG samples when using spike count analysis than when using frequency spectra.

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.

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.

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.

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.

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.