Abstracts

Rationale: In a previous report (Meador et al., Brain 2011), we noted greater impairment of verbal vs. non-verbal abilities at age 3 in children exposed in utero to antiepileptic drugs (AEDs). We postulated that this performance discrepancy might be due to AED effects on cerebral lateralization during neurodevelopment. Here, we test this hypothesis by examining handedness and verbal/non-verbal functions in our cohort at age 6 years. Methods: The NEAD Study is a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on AED monotherapy from 1999 to 2004. The purpose of the investigation is to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). 225 children were assessed at age 6, and handedness information was available for 215 of them. Verbal and Non-verbal Indexes were derived from subscores of the Differential Abilities Scales (DAS) and the Developmental Neuropsychological Assessment (NEPSY), and also the Expressive One-Word Picture Vocabulary Test, and the Developmental Test of Visual Motor Integration (DTVMI). Handedness was assessed in 167 children by a 7-item modification of the Edinburgh Handedness Inventory. Hand performance was assessed for writing, drawing, ball throwing, scissor cutting, brushing teeth, eating with a spoon, and opening a box. A handedness index was calculated using ((R - L) / (R + L) X 100. In another 48 children, handedness was determined by hand use on the Grooved Pegboard or DTVMI. Handedness results were compared to handedness information from 187 normal six year old children in the standardization sample of the Wechsler Intelligence Scale for Children (WISC-4). Results: The Verbal Index score was less than the Non-verbal Index score across all AEDs combined (p<.017) and for lamotrigine (p<.028) and valproate (p<.006) groups. In the WISC sample, 93% of children are right-handed. Compared to this normative sample using a logistic regression analysis, right-handedness is reduced in the NEAD children overall (86% right-handed, p=.04) and for lamotrigine (83%, p=.03) and for valproate (79%, p=.009) groups. Right-handedness was reduced for valproate compared to carbamazepine (p=.028) and a trend compared to phenytoin (p=.064). NEAD children exhibited an overall AED dose (p=.033) effect for reduced right-handedness. Conclusions: The reduced frequency of right-handedness and the relatively greater impairment of verbal vs. non-verbal abilities for some AEDs are observations consistent with reduced cerebral lateralization. We postulate that an adverse impact of fetal AED exposure on immature neurons alter normal cerebral lateralization during development. Further research is needed to confirm these findings and delineate the mechanisms.