Summary 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. Funding US National Institutes of Health, UK Epilepsy Research Found...

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Results of this systematic literature review suggest that the overall incidence of CMs in children born of WWE is approximately threefold that of healthy women. The risk is elevated for all AED monotherapy and further elevated for AED polytherapy compared to women without epilepsy. The risk was significantly higher for children exposed to valproate monotherapy and to polytherapy of 2 or more drugs when the polytherapy combination included phenobarital, phenytoin, or valproate. Further research is needed to delineate the specific risk for each individual AED and to determine underlying mechanisms including genetic risk factors.

Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. Results: It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine and possible compared to phenytoin or lamotrigine. Compared to untreated WWE, it is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. It is probable that antiepileptic drug (AED) polytherapy as compared to monotherapy regimens contributes to the development of MCMs and to reduced cognitive outcomes. For monotherapy, intrauterine exposure to VPA probably reduces cognitive outcomes. Further, monotherapy exposure to phenytoin or phenobarbital possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of Ͻ7. Methods: Recommendations:If possible, avoidance of valproate (VPA) and antiepileptic drug (AED) polytherapy during the first trimester of pregnancy should be considered to decrease the risk of major congenital malformations (Level B). If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered to prevent reduced cognitive outcomes (Level B). If possible, avoidance of phenytoin and phenobarbital during pregnancy may be considered to prevent reduced cognitive outcomes (Level C). Pregnancy risk stratification should reflect that the offspring of women with epilepsy taking AEDs are probably at increased risk for being small for gestational age (Level B) and possibly at increased risk of 1-minute Apgar scores of Ͻ7 (Level C). Neurology ® 2009;73:133-141 GLOSSARY AAN ϭ Academy of Neurology; AED ϭ antiepileptic drug; CBZ ϭ carbamazepine; CI ϭ confidence interval; LTG ϭ lamotrigine; MCM ϭ major congenital malformation; OR ϭ odds ratio; PB ϭ phenobarbital; PHT ϭ phenytoin; RR ϭ relative risk; SGA ϭ small for gestational age; VPA ϭ valproate; WWE ϭ women with epilepsy.

SUMMARY OBJECTIVES Temporal lobe epilepsy (TLE) patients experience significant deficits in category-related object recognition and naming following standard surgical approaches. These deficits may result from a decoupling of core processing modules (e.g., language, visual processing, semantic memory), due to “collateral damage” to temporal regions outside the hippocampus following open surgical approaches. We predicted stereotactic laser amygdalohippocampotomy (SLAH) would minimize such deficits because it preserves white matter pathways and neocortical regions critical for these cognitive processes. METHODS Tests of naming and recognition of common nouns (Boston Naming Test) and famous persons were compared with nonparametric analyses using exact tests between a group of nineteen patients with medically-intractable mesial TLE undergoing SLAH (10 dominant, 9 nondominant), and a comparable series of TLE patients undergoing standard surgical approaches (n=39) using a prospective, non-randomized, non-blinded, parallel group design. RESULTS Performance declines were significantly greater for the dominant TLE patients undergoing open resection versus SLAH for naming famous faces and common nouns (F=24.3, p<.0001, η2=.57, & F=11.2, p<.001, η2=.39, respectively), and for the nondominant TLE patients undergoing open resection versus SLAH for recognizing famous faces (F=3.9, p<.02, η2=.19). When examined on an individual subject basis, no SLAH patients experienced any performance declines on these measures. In contrast, 32 of the 39 undergoing standard surgical approaches declined on one or more measures for both object types (p<.001, Fisher’s exact test). Twenty-one of 22 left (dominant) TLE patients declined on one or both naming tasks after open resection, while 11 of 17 right (non-dominant) TLE patients declined on face recognition. SIGNIFICANCE Preliminary results suggest 1) naming and recognition functions can be spared in TLE patients undergoing SLAH, and 2) the hippocampus does not appear to be an essential component of neural networks underlying name retrieval or recognition of common objects or famous faces.