Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy.

Importance: The association of fetal exposure to antiseizure medications (ASMs) with outcomes in childhood are not well delineated. Objective: To examine the association of fetal ASM exposure with subsequent adaptive, behavioral or emotional, and neurodevelopmental disorder outcomes at 2, 3, and 4.5 years of age. Design, Setting, and Participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational cohort study conducted at 20 epilepsy centers in the US. A total of 456 pregnant women with epilepsy or without epilepsy were enrolled from December 19, 2012, to January 13, 2016. Children of enrolled women were followed up with formal assessments at 2, 3, 4.5, and 6 years of age. Statistical analysis took place from August 2022 to May 2023. Exposures: Exposures included mother's epilepsy status as well as mother's ASM blood concentration in the third trimester (for children of women with epilepsy). Women with epilepsy were enrolled regardless of ASM regimen. Main Outcomes and Measures: The primary outcome was the Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) score among children at 4.5 years of age. Children of women with epilepsy and children of women without epilepsy were compared, and the associations of ASM exposures with outcomes among exposed children were assessed. Secondary outcomes involved similar analyses of other related measures. Results: Primary analysis included 302 children of women with epilepsy (143 boys [47.4%]) and 84 children of women without epilepsy (45 boys [53.6%]). Overall adaptive functioning (ABAS-3 GAC score at 4.5 years) did not significantly differ between children of women with epilepsy and children of women without epilepsy (parameter estimate [PE], 0.4 [95% CI, -2.5 to 3.4]; P = .77). However, in adjusted analyses, a significant decrease in functioning was seen with increasing third-trimester maximum ASM blood concentrations (PE, -7.8 [95% CI, -12.6 to -3.1]; P = .001). This decrease in functioning was evident for levetiracetam (PE, -18.9 [95% CI, -26.8 to -10.9]; P < .001) and lamotrigine (PE, -12.0 [95% CI, -23.7 to -0.3]; P = .04), the ASMs with sample sizes large enough for analysis. Results were similar with third-trimester maximum daily dose. Conclusions and Relevance: This study suggests that adaptive functioning of children of women with epilepsy taking commonly used ASMs did not significantly differ from that of children of women without epilepsy, but there was an exposure-dependent association of ASMs with functioning. Thus, psychiatric or psychological screening and referral of women with epilepsy and their offspring are recommended when appropriate. Additional research is needed to confirm these findings.

Cognitive outcomes at age 3 years in children with fetal exposure to antiseizure medications (MONEAD study) in the USA: a prospective, observational cohort study.

BACKGROUND: The neurodevelopmental effects of fetal exposure to most antiseizure medications are unclear. We aimed to investigate the effects of fetal exposure to commonly used antiseizure medications on neuropsychological outcomes at age 3 years. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicentre cohort study at 20 specialty epilepsy centres in the USA. We have investigated pregnancy outcomes in women (aged 14-45 years) with and without epilepsy who were enrolled during pregnancy (≤20 weeks' gestational age), and their children. The primary outcome for children at age 3 years was a blindly assessed Verbal Index score, which was calculated by averaging scores on the Naming Vocabulary and Verbal Comprehension subtests of Differential Ability Scales-II, Expressive Communication and Auditory Comprehension subscales of Preschool Language Scale-5, and Peabody Picture Vocabulary Test-4. Children of women with and without epilepsy were compared, and the associations of medication exposures to outcomes in exposed children were assessed. The MONEAD study is registered with ClinicalTrials.gov, NCT0730170, and is ongoing. FINDINGS: Between Dec 19, 2012, and Jan 13, 2016, 456 pregnant women (351 with epilepsy and 105 without epilepsy) were enrolled into the study. 345 children were born to women with epilepsy and 106 children were born to women without epilepsy. Verbal Index scores at age 3 years did not differ for children of women with epilepsy (n=284; adjusted least-square mean 102·7, 95% CI 101·4 to 103·9) versus those without epilepsy (n=87; 102·3, 99·8 to 104·7). Significant risk factors for reduced Verbal Index scores included maternal intelligence quotient, maternal education, post-birth anxiety, gestational age at enrolment, child's sex, and child's ethnicity. For Verbal Index scores, antiseizure medication exposure effects were not seen for maximum third trimester blood concentrations (n=258; adjusted parameter estimate -2·9, 95% CI -6·7 to 1·0). However, in secondary analyses, exposure-dependent effects were present on multiple cognitive measures, which varied by medication. INTERPRETATION: We found no difference in neurodevelopmental outcomes between children with fetal exposure to newer antiseizure medications compared with unexposed children. However, some exposure-dependent antiseizure medication effects were seen in secondary analyses. The adverse effects of maternal post-birth anxiety emphasise the importance of screening mothers during pregnancy and postpartum and implementing interventions. Additional studies are needed to clarify the exposure-dependent effects. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institute of Child Health and Development.

Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.

Importance: The neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs). Objective: To compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE. Design, Setting, and Participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020. Main Outcomes and Measures: Language domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed. Results: The BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (-0.5; 95% CI, -4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (-5.6; 95% CI, -10.7 to -0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (-1.4; 95% CI, -2.8 to -0.05). Conclusions and Relevance: Outcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women. Trial Registration: ClinicalTrials.gov Identifier: NCT01730170.

Folate fortification of food: Insufficient for women with epilepsy.

OBJECTIVE: Folic acid supplementation during the periconceptual period has been shown to improve cognitive outcomes in children of women with epilepsy taking anti-seizure medications (ASMs). The dose of folic acid necessary to provide positive cognitive outcomes is unclear. In many countries including the United States, food is fortified with folic acid, but no data exist on how food fortification may affect cognition in children with fetal-ASM exposure. This study evaluated the effect of dietary folate from natural folates plus folic acid fortification, separate from folic acid vitamin supplements, on age-6 year IQ in children with fetal-ASM exposure. METHODS: Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study were retrospectively analyzed for this investigation. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98. The primary outcome of the present study was to assess association of maternal prepregnancy nutrient levels to child age-6 IQ. RESULTS: Folate from food alone without supplement was not associated with improvement of age-6 IQ in children with fetal ASM exposure (95% CI: -11.7-2.3, p = 0.187). Periconceptual folate supplement use was associated with a 10.1-point higher age-6 IQ (95% CI: 5.2-15.0, p < .001). Total combined folate from food plus supplement also showed that higher intake of folate was associated with higher age-6 IQ (Coefficient: 4.5, 95% CI: 2.0-6.9, p < .001). Six other nutrients from food and supplements were analyzed (Vitamin C, Vitamin D, Vitamin E, Omega 3, Gamma Tocopherol, and Vitamin B12) and had no significant association with age 6-IQ. SIGNIFICANCE: Dietary content of folate, even in a country where food is fortified with folic acid, is not sufficient to provide improved cognitive outcomes for children of women taking ASMs during pregnancy. Folate supplementation is needed for significant improvement in cognitive outcomes, specifically age-6 IQ.

Effects of periconceptional folate on cognition in children of women with epilepsy: NEAD study.

OBJECTIVE: Emerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study. METHODS: The NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age). RESULTS: Periconceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function-Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age. CONCLUSIONS: Use of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development. CLINICALTRIALSGOV IDENTIFIER: NCT00021866.

Are frontal and temporal lobe epilepsy dissociable in their memory functioning?

There is controversy in the literature as to how dissociable frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE) are in terms of memory deficits. Some researchers have demonstrated that FLE is associated with greater executive dysfunction including working memory, whereas TLE is associated with greater memory impairment. Others have found the two groups to be comparable in memory functioning. Hence, we examined this question in children with FLE and TLE versus typically developing controls. We found most of the expected effects when the groups with focal onset epilepsy were compared to controls. Specifically, children with left TLE performed worse on verbal short-term memory/learning and long-term memory measures. In contrast, children with right TLE exhibited a more global pattern of difficulty on short-term memory/learning measures but performed worse than controls on long-term memory for faces. Children with FLE performed worse than controls on verbal working memory. Nevertheless, laterality effects were mild, as children with right and left TLE did not differ significantly from each other. Further, children with FLE did not differ from those with TLE on most measures except delayed facial recognition, where children with right TLE performed worse. In addition, attention problems and poor behavioral regulation were related to encoding problems in both the total epilepsy sample and in children with TLE specifically. Hence, our findings overall are consistent with prior studies indicating that children with TLE and FLE are commensurate in most aspects of memory impairment when compared to each other, likely related to rapid propagation between the frontal and temporal lobes, as would be expected with an excitatory lesion.

Fetal antiepileptic drug exposure and learning and memory functioning at 6 years of age: The NEAD prospective observational study.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study was a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on learning and memory functions in 221 six-year-old children (including four sets of twins) whose mothers took one of these AEDs during pregnancy. Their performance was compared with that of a national sample of normally developing six year olds from the standardization sample of the Children's Memory Scale (CMS). The major results of this study indicate that the mean performance levels of children exposed to valproate were significantly below that of the children in the normal comparison group across all seven of the CMS Indexes. With one exception, this finding held up at the subtest level as well. These findings taken together with nonsignificant verbal and nonverbal forgetting scores appear to indicate that, as a group, children exposed to valproate experienced significant difficulty in their ability to process, encode, and learn both auditory/verbal as well as visual/nonverbal material. In addition, they exhibited significant difficulty holding and manipulating information in immediate auditory working memory. However, once the information was learned and stored, the valproate-exposed children appeared to be able to retrieve the information they did learn at normal levels. Finally, the processing, working memory, and learning deficits demonstrated by the valproate-exposed children are dose-related. In contrast to valproate, the findings pertaining to the children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy are less clear. Therefore, further research will be required to delineate the potential risks to learning and memory functions in children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy during pregnancy. Additional research employing larger prospective studies will be required to confirm the long-term cognitive and behavioral risks to children of mothers who are prescribed these four AEDs during pregnancy as well as to delineate any potential risks of newer AEDs and to understand the underlying mechanisms of adverse AED effects on the immature brain.

Neurocognitive and behavioral profiles of children with Landau-Kleffner syndrome.

This is a retrospective study of 14 cases of children with Landau-Kleffner syndrome (LKS), the most prominent feature of which is acquired aphasia. These children were followed at a tertiary care pediatric epilepsy center. From the research data base, all LKS cases with neuropsychological evaluation were extracted. Children ranged in age from 6 to 13 years (M = 9.12; SD = 2.19) at the time of assessment (1 to 10 years post-onset). The majority of the children were white males, and all but one continued to experience seizure activity. Global intellectual functioning ranged from 59 to 101 (M = 82.07; SD = 12.14). Across the 14 cases reviewed, the neuropsychological profiles are considered in the context of neurological and syndrome-related factors. For these cases, 86% demonstrated continued expressive, and 50% had receptive language problems with 57% exhibiting poor auditory processing. Furthermore, 50 to 57% had deficits in auditory working memory and verbal memory. Academically, the majority had poor reading fluency and comprehension; 50% exhibited difficulty with mathematics. Finally, 57% evidenced attentional or other behavioral problems. Better understanding of LKS can assist in targeted assessment and intervention planning.

[Formula: see text]Differences in memory functioning between children with attention-deficit/hyperactivity disorder and/or focal epilepsy.

Prior research has shown that attention-deficit/hyperactivity disorder (ADHD) and epilepsy are frequently comorbid and that both disorders are associated with various attention and memory problems. Nonetheless, limited research has been conducted comparing the two disorders in one sample to determine unique versus shared deficits. Hence, we investigated differences in working memory (WM) and short-term and delayed recall between children with ADHD, focal epilepsy of mixed foci, comorbid ADHD/epilepsy and controls. Participants were compared on the Core subtests and the Picture Locations subtest of the Children's Memory Scale (CMS). Results indicated that children with ADHD displayed intact verbal WM and long-term memory (LTM), as well as intact performance on most aspects of short-term memory (STM). They performed worse than controls on Numbers Forward and Picture Locations, suggesting problems with focused attention and simple span for visual-spatial material. Conversely, children with epilepsy displayed poor focused attention and STM regardless of the modality assessed, which affected encoding into LTM. The only loss over time was found for passages (Stories). WM was intact. Children with comorbid ADHD/epilepsy displayed focused attention and STM/LTM problems consistent with both disorders, having the lowest scores across the four groups. Hence, focused attention and visual-spatial span appear to be affected in both disorders, whereas additional STM/encoding problems are specific to epilepsy. Children with comorbid ADHD/epilepsy have deficits consistent with both disorders, with slight additive effects. This study suggests that attention and memory testing should be a regular part of the evaluation of children with epilepsy and ADHD.

Spectrum of Mathematical Weaknesses: Related Neuropsychological Correlates.

Math disorders have been recognized for as long as language disorders yet have received far less research. Mathematics is a complex construct and its development may be dependent on multiple cognitive abilities. Several studies have shown that short-term memory, working memory, visuospatial skills, processing speed, and various language skills relate to and may facilitate math development and performance. The hypotheses explored in this research were that children who performed worse on math achievement than on Full-Scale IQ would exhibit weaknesses in executive functions, memory, and visuoperceptual skills. Participants included 436 children (27% girls, 73% boys; age range = 5-17 years, M(age) = 9.45 years) who were referred for neuropsychological evaluations due to academic and/or behavioral problems. This article specifically focuses on the spectrum of math weakness rather than clinical disability, which has yet to be investigated in the literature. Results suggest that children with relative weakness to impairments in math were significantly more likely to have cognitive weaknesses to impairments on neuropsychological variables, as compared with children without math weaknesses. Specifically, the math-weak children exhibit a weakness to impairment on measures involving attention, language, visuoperceptual skills, memory, reading, and spelling. Overall, our results suggest that math development is multifaceted.

IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study.

OBJECTIVE: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. METHODS: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. RESULTS: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] -4.9 to -14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5-19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (-5.6, 95% CI -11.1 to -0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4-18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (-4.2, 95% CI -0.6 to -7.8; p = 0.02) and increased frequency of IQ <85. CONCLUSIONS: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

Executive Function Performance for Children With Epilepsy Localized to the Frontal or Temporal Lobes.

Research with adults with epilepsy consistently indicates deficits in executive function (EF). There is less research specific to children with epilepsy and EF. The purpose of this study was to consider EF deficits in children with complex partial epilepsy and complex partial with secondary generalization epilepsy with onset localized to the frontal or temporal lobes. This was a retrospective study of 28 children followed in an outpatient pediatric epilepsy clinic who were consecutively referred for neuropsychological assessment, which included measures of EF. The sample was predominantly White and male, with a mean age of 12.88 years (SD = 1.64) and mean cognitive ability of 89.39 (SD = 13.41). Comparison of right-temporal, left-temporal, and frontal groups yielded significant differences (p = .01) between the left-temporal and frontal groups on the Wisconsin Card-Sorting Test (WCST) Categories with the frontal group demonstrating the greatest deficits. Although mean differences were not significant, the frequency of impaired performance by the frontal group on the Attention/Concentration Index was greater than in the temporal groups. Results indicate that for children with complex partial and complex partial with secondary generalized seizures localized to the frontal and temporal lobes, there is an increased likelihood for impaired EF evident on the WCST, but not on others. Implications of these findings for prevention and intervention are discussed.

There are laterality effects in memory functioning in children/adolescents with focal epilepsy.

In a sample of individuals with childhood focal epilepsy, children/adolescents with left hemisphere foci outperformed those with right foci on both measures of nonverbal learning. Participants with left foci performed worse than controls on paired associate delayed recall and semantic memory, and they had greater laterality effects in IQ. Participants with right foci performed worse than controls on delayed facial recognition. Both groups displayed reduced focused attention and poor passage retention over time. Although participants with bilateral foci displayed poor learning and lower IQ than controls, they did not have worse impairment than those with a unilateral focus.

Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years.

IMPORTANCE: Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES: To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES: Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS: In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P < .001 [adjusted IQ worse by 7-13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, -0.1; 95% CI, -0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2-10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0-8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0-7] points higher for breastfed children, P = .03). CONCLUSIONS AND RELEVANCE: No adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021866.

Adaptive skills and somatization in children with epilepsy.

Objective. Children with epilepsy are at risk for less than optimum long-term outcomes. The type and severity of their epilepsy may contribute to educational, psychological, and social outcomes. The objective of this study was to determine the relation between somatization and adaptive skills based on seizure type that could impact on those outcomes. Methods. This study examined adaptive functioning and somatization in 87 children with epilepsy using archival data from a tertiary care facility. Results. No significant differences in adaptive skills emerged between groups of children diagnosed with complex partial (CP) as compared to CP-secondary generalized (SG) seizures; however, deficits in adaptive behavior were found for both groups. The number of medications, possibly reflecting the severity of the epilepsy, was highly correlated to adaptive function. Conclusions. Identification of deficits in adaptive behavior may represent an opportunity for tailored prevention and intervention programming for children with epilepsy. Addressing functional deficits may lead to improved outcomes for these children.

Fetal antiepileptic drug exposure: Adaptive and emotional/behavioral functioning at age 6years.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on adaptive and emotional/behavioral functioning at 6years of age in 195 children (including three sets of twins) whose parent (in most cases, the mother) completed at least one of the rating scales. Adjusted mean scores for the four AED groups were in the low average to average range for parent ratings of adaptive functioning on the Adaptive Behavior Assessment System-Second Edition (ABAS-II) and for parent and teacher ratings of emotional/behavioral functioning on the Behavior Assessment System for Children (BASC). However, children whose mothers took valproate during pregnancy had significantly lower General Adaptive Composite scores than the lamotrigine and phenytoin groups. Further, a significant dose-related performance decline in parental ratings of adaptive functioning was seen for both valproate and phenytoin. Children whose mothers took valproate were also rated by their parents as exhibiting significantly more atypical behaviors and inattention than those in the lamotrigine and phenytoin groups. Based upon BASC parent and teacher ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy were at a significantly greater risk for a diagnosis of ADHD. The increased likelihood of difficulty with adaptive functioning and ADHD with fetal valproate exposure should be communicated to women with epilepsy who require antiepileptic medication. Finally, additional research is needed to confirm these findings in larger prospective study samples, examine potential risks associated with other AEDs, better define the risks to the neonate that are associated with AEDs for treatment of seizures, and understand the underlying mechanisms of adverse AED effects on the immature brain.

Does Rey Complex Figure copy performance measure executive function in children?

The Rey Complex Figure Task (RCFT) is currently utilized with both adult and child clinical populations. In addition to the measurement of visual-constructional ability and memory, the RCFT has also been suggested as a measure of executive function (EF), specifically requiring planning and organizing skills. The purpose of the current study was to determine the extent to which the RCFT Copy task, using the scoring system developed by Meyers and Meyers (1995), tapped components of EF. The participants in this study were 108 children (M(age) = 12.61 years; SD = 2.27) who were administered a battery of neuropsychological measures including the RCFT Copy, NEPSY Tower and Arrows subtests, Clock Face Drawing, and a measure of verbal fluency, in addition to other measures of visual-motor integration and cognitive ability. Overall, in this clinically mixed population, scores on the RCFT Copy correlated significantly only with overall cognitive ability, Block Design, and visual-motor integration scores. Implications of these results are discussed.

Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study.

BACKGROUND: Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic drugs on cognitive outcomes in children up to 6 years of age. METHODS: In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov, number NCT00021866. FINDINGS: We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94-101) than to carbamazepine (105, 102-108; p=0·0015), lamotrigine (108, 105-110; p=0·0003), or phenytoin (108, 104-112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ (r=-0·56, p<0·0001), verbal ability (r=-0·40, p=0·0045), non-verbal ability (r=-0·42, p=0·0028), memory (r=-0·30, p=0·0434), and executive function (r=-0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 [93%] of 187 children), right-handedness was less frequent in children in our study overall (185 [86%] of 215; p=0·0404) and in the lamotrigine (59 [83%] of 71; p=0·0287) and valproate (38 [79%] of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106-111) than they were in unexposed children (101, 98-104; p=0·0009). INTERPRETATION: Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal (vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies.

Posterior quadrant epilepsy surgery: predictors of outcome.

PURPOSE: To identify predictors of seizure recurrence following posterior quadrant epilepsy surgery. METHODS: Between 1983 and 2008, 43 medically refractory epilepsy patients underwent posterior quadrant epilepsy surgery. Epilepsy surgery involved the occipital lobe in all cases; some cases also included resection of the adjacent parietal or temporal cortex. Using a logistic regression model, we evaluated the relationship between outcome (Engel class I-IV) and 5 outcome predictors: absence of a visual aura, a temporal lobe type aura, versive head movement unaccompanied by a visual aura, non-focal interictal scalp EEG, and surgical pathology other than low grade tumor or cortical dysplasia. We also determined the relative risk for significant post-operative cognitive decline of Wechsler intelligence test score among those receiving complete lobectomies compared to those receiving partial lobectomies. RESULTS: Overall, outcome was favorable at 1 year following surgery: 22 (51.2%) patients Engel class I, 10 (24%) patients Engel class II, 5 (12%) patients Engel class III, and 6 (14%) patients Engel class IV. The 3 best univariate predictors of seizure recurrence were versive head movement unaccompanied by visual aura, non-focal interictal scalp EEG, and pathology other than low grade tumor or cortical dysplasia. A multivariate predictor combining temporal lobe type aura, versive head movement unaccompanied by visual aura, non-focal interictal scalp EEG, and pathology other than low grade tumor or cortical dysplasia was optimum. Complete lobectomy significantly increased the risk of post-operative decline of Wechsler intelligence score. CONCLUSIONS: These findings indicate that posterior quadrant epilepsy surgery may provide sustained seizure control. A multivariate model combining temporal lobe type aura, versive head movement unaccompanied by a visual aura, non-focal interictal scalp EEG, and pathology other than low grade tumor or cortical dysplasia may contribute to predicting seizure recurrence following posterior quadrant epilepsy surgery. The extent of cortical resection may predict significant cognitive decline in post-operative Wechsler intelligence score.

Fetal antiepileptic drug exposure: motor, adaptive, and emotional/behavioral functioning at age 3 years.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3 years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain.