David W. Loring

Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs

BACKGROUND Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. METHODS Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. RESULTS At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Childrens IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. CONCLUSIONS In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.

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.

Functional MRI cerebral activation and deactivation during finger movement

Objective: To examine interhemispheric interactions of motor processes by using functional MRI (fMRI). Background: Despite evidence of interhemispheric inhibition from animal, clinical, and transcranial magnetic stimulation (TMS) studies, fMRI has not been used to explore activation and deactivation during unilateral motor tasks. fMRI changes associated with motor activity have traditionally been described by comparing cerebral activation during motor tasks relative to a “resting state.” In addition to this standard comparison, we examined fMRI changes in the resting state relative to a motor task. Methods: Thirteen healthy volunteers performed self-paced sequential finger/thumb tapping for each hand. During fMRI data acquisition, four epochs were obtained; each comprised of 30 seconds of rest, 30 seconds of right hand activity, and 30 seconds of left hand activity. Resultant echoplanar images were spatially normalized and spatially and temporally smoothed. Results: As expected, hand movements produced activation in the contralateral sensorimotor cortex and adjacent subcortical regions and, when present, the ipsilateral cerebellum. However, hand movement also produced a significant deactivation (i.e., decreased blood flow) in the ipsilateral sensorimotor cortex and subcortical regions, and when present, the contralateral cerebellum. Conjunction analysis demonstrated regions that are activated by one hand and deactivated by the contralateral hand. Conclusion: Unilateral hand movements are associated with contralateral cerebral activation and ipsilateral cerebral deactivation, which we hypothesize result from transcallosal inhibition.

Unilateral cerebral inactivation produces differential left/right heart rate responses

We studied heart rate following unilateral hemispheric inactivation by intracarotid amobarbital in 25 patients undergoing preoperative evaluation for epilepsy surgery. Heart rate increased after left hemisphere inactivation, but decreased following right hemisphere inactivation. The results are consistent with differential left/right cerebral hemispheric effects on autonomic function, and appear related to functional and anatomic asymmetries in both the central and peripheral nervous systems.

Cognitive side effects of antiepileptic drugs in children

Cognitive impairment associated with antiepileptic drug (AED) therapy in children is an important concern given the potential negative effects of treatment on school learning and performance. Unfortunately, there have been few studies examining the cognitive effects of AEDs in this population and no adequate studies of newer AEDs. This article will discuss the effects of the traditional and newer AEDs on neuropsychological function in children. Because of various limitations in the designs of these studies, however, many of the studies report inconclusive findings. Although it will be necessary to overcome many programmatic and procedural hurdles, well-designed randomized prospective studies that are of adequate length to determine how AEDs ultimately relate to school performance and social adjustment are needed to firmly establish the cognitive and behavioral effects of AEDs in children.

In utero antiepileptic drug exposure Fetal death and malformations

Background: Pregnancy outcomes following in utero exposure to antiepileptic drugs (AEDs) are uncertain, limiting an evidenced-based approach. Objective: To determine if fetal outcomes vary as a function of different in utero AED exposures. Methods: This ongoing prospective observational study across 25 epilepsy centers in the USA and UK enrolled pregnant women with epilepsy from October 1999 to February 2004 to determine if differential long-term cognitive and behavioral neurodevelopmental effects exist across the four most commonly used AEDs. This initial report focuses on the incidence of serious adverse outcomes including major congenital malformations (which could be attributable to AEDs) or fetal death. A total of 333 mother/child pairs were analyzed for monotherapy exposures: carbamazepine (n = 110), lamotrigine (n = 98), phenytoin (n = 56), and valproate (n = 69). Results: Response frequencies of pregnancies resulting in serious adverse outcomes for each AED were as follows: carbamazepine 8.2%, lamotrigine 1.0%, phenytoin 10.7%, and valproate 20.3%. Distribution of serious adverse outcomes differed significantly across AEDs and was not explained by factors other than in utero AED exposure. Valproate exhibited a dose-dependent effect. Conclusions: More adverse outcomes were observed in pregnancies with in utero valproate exposure vs the other antiepileptic drugs (AEDs). These results combined with several recent studies provide strong evidence that valproate poses the highest risk to the fetus. For women who fail other AEDs and require valproate, the dose should be limited if possible.

Cerebral language lateralization : evidence from intracarotid amobarbital testing

Cerebral language lateralization was investigated in 103 patients undergoing intracarotid amobarbital testing as part of their diagnostic work-up for epilepsy surgery. Inclusion criteria included adequate bilateral intracarotid amobarbital studies and no radiologic lesion in areas other than the temporal lobe. Language was evaluated with respect to strict presence or absence of language representation, in which a patient was considered to have bilateral language despite potentially having asymmetric language representation, and with respect to forced relative hemispheric dominance, in which a single side could be considered dominant despite bilateral language representation. Seventy-nine patients displayed exclusive left hemisphere language representation, two patients showed exclusive right hemisphere language representation, and 22 patients had language represented in each hemisphere. In the 22 patients with bilateral language, an asymmetry was present in 17 cases (13 L greater than R, 4 R greater than L). These data indicate that language restricted only to the right hemisphere is rare, and that in the absence of purely left hemisphere language, most patients exhibit bilateral representation. Previously reported incidence of exclusive right hemisphere language may be an artifact of dichotomizing a continuous variable.

Comparative cognitive effects of anticonvulsants

We investigated the neuropsychological effects of carbamazepine, phenobarbital, and phenytoin in 15 partial complex epilepsy patients treated with each drug for 3 months, using a randomized double-blind, triple crossover design. Neuropsychological evaluation at the end of each treatment period included Digit Span, Selective Reminding Test, Digit Symbol, Finger Tapping, Grooved Pegboard, Choice Reaction Time, P3 evoked potential, and Profile of Mood States. Employing anticonvulsant blood levels and seizure frequencies as covariates, the only significant difference was for Digit Symbol. Performance with phenobarbital was significantly worse than with the other 2 anticonvulsants despite phenobarbitals having had the lowest overall blood levels. Our data show that patients receiving carbamazepine, phenobarbital, and phenytoin have comparable neuropsychological performance on most measures. The results suggest that the differential cognitive effects of anticonvulsants may be subtle.

A Comparison of Magnetoencephalography, MRI, and V-EEG in Patients Evaluated for Epilepsy Surgery

Summary: Purpose: To determine the efficacy and relative contribution of several diagnostic methods [ictal and interictal scalp and intracranial EEG, magnetic resonance imaging (MRI), and magnetoencephalography (MEG)] in identifying the epileptogenic zone for resection.

Determinants of quality of life in epilepsy.

Although depression is associated with diminished quality of life (QOL) in epilepsy patients, the relative contributions of epilepsy-specific concerns, as well as clinical and cognitive variables of QOL, have not been simultaneously investigated. A comprehensive neuropsychological test battery including the Beck Depression Inventory (BDI), Epilepsy Foundation of Americas (EFA) Concerns Index, MMPI-2, QOLIE-89, WAIS-III, and Selective Reminding was administered to 115 epilepsy surgery candidates with normal Full Scale IQs. Linear regression analyses were performed to identify significant predictor combinations of QOLIE-89 total score. Regression analysis demonstrated that depressive symptomatology, whether reflected by the BDI (R2=0.45) or Depression scale of the MMPI-2 (R2=0.36), was a robust individual QOL predictor. Seizure Worry from the EFA Concerns Index was nearly as effective as the BDI in predicting QOLIE-89 (R2=0.42). When the BDI and EFA Concerns Index were combined into the same regression, both factors continued to contribute significantly to the QOLIE-89 total score, with both variables accounting for 61% of the variance. Although patients who developed their seizures at an older age had poorer QOL and patients with higher educational levels reported higher QOL, neither factor was related to QOL after accounting for the effects of psychological variables and epilepsy-related concerns. Although quality of life has multiple determinants, symptoms of depression and seizure worry are the most important factors affecting QOL in patients with intractable epilepsy.