Page B. Pennell

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.

Epileptic Seizures May Begin Hours in Advance of Clinical Onset: A Report of Five Patients*

Mechanisms underlying seizure generation are traditionally thought to act over seconds to minutes before clinical seizure onset. We analyzed continuous 3- to 14-day intracranial EEG recordings from five patients with mesial temporal lobe epilepsy obtained during evaluation for epilepsy surgery. We found localized quantitative EEG changes identifying prolonged bursts of complex epileptiform discharges that became more prevalent 7 hr before seizures and highly localized subclinical seizure-like activity that became more frequent 2 hr prior to seizure onset. Accumulated energy increased in the 50 min before seizure onset, compared to baseline. These observations, from a small number of patients, suggest that epileptic seizures may begin as a cascade of electrophysiological events that evolve over hours and that quantitative measures of preseizure electrical activity could possibly be used to predict seizures far in advance of clinical onset.

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.

Brain Blood Flow Alterations Induced by Therapeutic Vagus Nerve Stimulation in Partial Epilepsy: I. Acute Effects at High and Low Levels of Stimulation

Summary: Purpose: Left cervical vagus nerve stimulation (VNS) decreases complex partial seizures (CPS) by unknown mechanisms of action. We hypothesized that therapeutic VNS alters synaptic activities at vagal afferent terminations and in sites that receive polysynaptic projections from these medullary nuclei.

Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Teratogenesis and perinatal outcomes Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and American Epilepsy Society

Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy. Methods: Systematic review of relevant articles published between January 1985 and June 2007. 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 <7. 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 <7 (Level C).

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.

Acute blood flow changes and efficacy of vagus nerve stimulation in partial epilepsy

Objective: To determine possible sites of therapeutic action of vagus nerve stimulation (VNS), by correlating acute VNS-induced regional cerebral blood flow (rCBF) alterations and chronic therapeutic responses. Background: We previously found that VNS acutely induces rCBF alterations at sites that receive vagal afferents and higher-order projections, including dorsal medulla, somatosensory cortex (contralateral to stimulation), thalamus and cerebellum bilaterally, and several limbic structures (including hippocampus and amygdala bilaterally). Methods: VNS-induced rCBF changes were measured by subtracting resting rCBF from rCBF during VNS, using [O-15]water and PET, immediately before ongoing VNS began, in 11 partial epilepsy patients. T-statistical mapping established relative rCBF increases and decreases for each patient. Percent changes in frequency of complex partial seizures (with or without secondary generalization) during three months of VNS compared with pre-VNS baseline, and T-thresholded rCBF changes (for each of the 25 regions of previously observed significant CBF change), were rank ordered across patients. Spearman rank correlation coefficients assessed associations of seizure-frequency change and t-thresholded rCBF change. Results: Seizure-frequency changes ranged from 71% decrease to 12% increase during VNS. Only the right and left thalami showed significant associations of rCBF change with seizure-frequency change. Increased right and left thalamic CBF correlated with decreased seizures (p < 0.001). Conclusions: Increased thalamic synaptic activities probably mediate some antiseizure effects of VNS. Future studies should examine neurotransmitter-receptor alterations in reticular and specific thalamic nuclei during VNS.

The impact of pregnancy and childbirth on the metabolism of lamotrigine

This study was performed to clarify alterations in lamotrigine (LTG) clearance during pregnancy and childbirth. Fourteen women on LTG monotherapy had LTG concentration samples obtained before conception and monthly. LTG apparent clearance, weight-adjusted relative clearance, and percentages of baseline clearance significantly differed between preconception baseline and each trimester and between trimesters. LTG clearance progressively increased until 32 weeks’ gestational age, reaching a peak of >330% of baseline, and then began to decline.

Lamotrigine in pregnancy : Clearance, therapeutic drug monitoring, and seizure frequency

Objective: To characterize the magnitude and course of alterations in total and free lamotrigine (LTG) clearance (Cl) during pregnancy and the postpartum period, to assess the impact of therapeutic drug monitoring (TDM) on seizure frequency, to determine the ratio to individual target LTG concentration that is associated with increased seizure risk, and to evaluate maternal postpartum toxicity. Methods: A cohort of women were enrolled before conception or during pregnancy in this prospective, observational study. Visits occurred every 1 to 3 months with review of seizure and medication diaries, examination, and blood sampling. Total and free LTG Cls were calculated. Individualized target concentrations were used for TDM. The ratio to target concentration (RTC) was compared between patients with and without increased seizures. A receiver operating characteristic curve determined the threshold RTC that best predicts increased seizure frequency. Results: Analysis of 305 samples in 53 pregnancies demonstrated increased total and free LTG Cl in all trimesters above nonpregnant baseline (p < 0.001), with peak increases of 94% and 89% in the third trimester. Free LTG Cl was higher in white compared with black women (p < 0.05). Increased seizure frequency (n = 36 women with epilepsy) in the second trimester was associated with a lower RTC (p < 0.001), and RTC < 0.65 was a significant predictor of seizure worsening. An empiric postpartum taper reduced the likelihood of maternal LTG toxicity (p < 0.05) (n = 27). Newborn outcomes were similar to the general population (n = 52). Conclusions: These novel data contribute to a rational treatment plan and dosing paradigm for lamotrigine use during pregnancy, parturition, and the postpartum period.

Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): II. Teratogenesis and perinatal outcomes Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first‐trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) 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 <7. If possible, avoidance of VPA and AED polytherapy during the first trimester of pregnancy should be considered to decrease the risk of MCMs. If possible, avoidance of VPA and AED polytherapy throughout pregnancy should be considered and avoidance of PHT and PB throughout pregnancy may be considered to prevent reduced cognitive outcomes.