Differential effects of antiepileptic drugs on neonatal outcomes.

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial.

OBJECTIVE: To assess progesterone treatment of intractable seizures in women with partial epilepsy. METHODS: This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles. RESULTS: There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3. CONCLUSION: There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.

Effects of fetal antiepileptic drug exposure: outcomes at age 4.5 years.

OBJECTIVE: To examine outcomes at age 4.5 years and compare to earlier ages in children with fetal antiepileptic drug (AED) exposure. METHODS: The NEAD Study is an ongoing prospective observational multicenter study, which enrolled pregnant women with epilepsy on AED monotherapy (1999-2004) to determine if differential long-term neurodevelopmental effects exist across 4 commonly used AEDs (carbamazepine, lamotrigine, phenytoin, or valproate). The primary outcome is IQ at 6 years of age. Planned analyses were conducted using Bayley Scales of Infant Development (BSID at age 2) and Differential Ability Scale (IQ at ages 3 and 4.5). RESULTS: Multivariate intent-to-treat (n = 310) and completer (n = 209) analyses of age 4.5 IQ revealed significant effects for AED group. IQ for children exposed to valproate was lower than each other AED. Adjusted means (95% confidence intervals) were carbamazepine 106 (102-109), lamotrigine 106 (102-109), phenytoin 105 (102-109), valproate 96 (91-100). IQ was negatively associated with valproate dose, but not other AEDs. Maternal IQ correlated with child IQ for children exposed to the other AEDs, but not valproate. Age 4.5 IQ correlated with age 2 BSID and age 3 IQ. Frequency of marked intellectual impairment diminished with age except for valproate (10% with IQ <70 at 4.5 years). Verbal abilities were impaired for all 4 AED groups compared to nonverbal skills. CONCLUSIONS: Adverse cognitive effects of fetal valproate exposure persist to 4.5 years and are related to performances at earlier ages. Verbal abilities may be impaired by commonly used AEDs. Additional research is needed.

Effects of breastfeeding in children of women taking antiepileptic drugs.

BACKGROUND: Breastfeeding is known to have beneficial effects, but there is concern that breastfeeding during antiepileptic drug (AED) therapy may be harmful to cognitive development. Animal and human studies have demonstrated that some AEDs can adversely affect the immature brain. However, no investigation has examined effects of breastfeeding during AED therapy on subsequent cognitive abilities in children. METHODS: The Neurodevelopmental Effects of Antiepileptic Drugs Study is an ongoing prospective multicenter observational investigation of long-term effects of in utero AED exposure on cognition. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single AED (carbamazepine, lamotrigine, phenytoin, or valproate). We recently reported on differential AED effects on age 3 year cognitive outcomes. In this report, we focus on the effects of breastfeeding during AED therapy on age 3 cognitive outcomes in 199 children. RESULTS: A total of 42% of children were breastfed. IQs for breastfed children did not differ from nonbreastfed children for all AEDs combined and for each of the 4 individual AED groups. Mean adjusted IQ scores (95% confidence intervals) across all AEDs were breastfed = 99 (96-103) and nonbreastfed = 98 (95-101). Power was 95% to detect a half SD IQ effect in the combined AED analysis, but was inadequate within groups. CONCLUSIONS: This preliminary analysis fails to demonstrate deleterious effects of breastfeeding during AED therapy on cognitive outcomes in children previously exposed in utero. However, caution is advised due to study limitations. Additional research is needed to confirm this observation and extend investigations to other AEDs and polytherapy.

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.

Seizure control and mortality in epilepsy.

Mortality rates are increased among people with epilepsy, and may be highest in those with uncontrolled seizures. Because epilepsy surgery eliminates seizures in some people, we used an epilepsy surgery population to examine how seizure control influences mortality. We tested the hypothesis that patients with complete seizure relief after surgery would have a lower mortality rate than those who had persistent seizures. Three hundred ninety-three patients who had epilepsy surgery between January 1986 and January 1996 were followed after surgery to assess long-term survival; 347 had focal resection or transection, and 46 had anterior or complete corpus callosotomy. A multivariate survival analysis was performed, contrasting survival in those who had seizure recurrence with survival of those who remained seizure free. Standardized mortality ratios and 95% confidence intervals were calculated. Overall, seizure-free patients had a lower mortality rate than those with persistent seizures. This was true for the subset of patients with localized resection or multiple subpial transection. No patients died among 199 with no seizure recurrence, whereas of 194 patients with seizure recurrence, 11 died. Six of the deaths were sudden and unexplained. Most patients who died had a substantial reduction in postoperative seizure frequency. The standardized mortality ratio for patients with recurrent seizures was 4.69, and the risk of death in these patients was 1.37 in 100 person-years, whereas among patients who became seizure free, there was no difference in mortality rate compared with the age- and sex-matched population of the United States. Elimination of seizures after surgery reduces mortality rates in people with epilepsy to a level indistinguishable from that of the general population, whereas patients with recurrent seizures continue to suffer from high mortality rates. This suggests that uncontrolled seizures are a major risk factor for excess mortality in epilepsy. Achieving complete seizure control with epilepsy surgery in refractory patients reduces the risk of death, so the long-term risk of continuing medical treatment appears to be higher than the risk of epilepsy surgery in suitable candidates.

Outcome after temporal lobectomy in bilateral temporal lobe epilepsy.

We determined how noninvasive presurgical data relate to prognosis after temporal lobectomy in patients with independent bilateral temporal lobe (IBTL) complex partial seizures on the intracranial electroencephalogram (EEG). Between 1986 and 1994, 28 patients had IBTL seizures on intracranial EEG. Fifteen of these 28 patients underwent temporal lobectomy and 13 were not offered surgery. Of the 15 patients who had surgery, 10 patients became seizure-free. Magnetic resonance imaging (MRI) and the Wada test were the only variables associated with a seizure-free outcome. Seven of 10 seizure-free patients had a lateralized Wada result or the presence of unilateral hippocampal sclerosis, whereas none of the patients with persistent seizures had either of these findings. Variables not found to be predictive of a seizure-free outcome included location of scalp interictal spikes, degree of seizure-onset laterality, presence of early epilepsy risk factor, duration of epilepsy, and full-scale intelligence quotient. We conclude that MRI and the Wada test provide information of prognostic value in patients with bilateral temporal seizures independent of intracranial EEG data.

New antiepileptic drugs. Overcoming the limitations of traditional therapy.

Several new antiepileptic drugs have become available recently. Since seizures and epilepsy are common, primary care physicians are likely to encounter a patient who is taking one of these new medications. Successful medical management of epilepsy requires a proper understanding of medication half-life, indications, and side effects. Felbamate has a broad spectrum of efficacy but is limited by side effects and idiosyncratic reactions. Fosphenytoin has the efficacy of phenytoin and offers the advantage of intramuscular and intravenous dosing without the significant adverse effects associated with intravenous phenytoin; however, it is expensive. Gabapentin has minimal side effects and drug interactions yet has limited efficacy for seizures. Lamotrigine has broad seizure efficacy but requires a slow adjustment to therapeutic levels. Topiramate has minimal drug interactions, but therapy must be initiated slowly to avoid side effects. All of the new antiepileptics hold great promise in the management of patients with recurrent seizures.

Women's issues in epilepsy. Menses, childbearing, and more.

A variety of special issues arise in caring for women with epilepsy. Seizures related to the menstrual cycle (catamenial epilepsy) can be controlled by several treatment strategies. Oral contraceptives are not contraindicated, but higher-dose agents are needed if enzyme-inducing antiepileptic medications are given concomitantly. Sexual and reproductive dysfunctions are common but often go unrecognized. In the past, many people with epilepsy were wrongly advised against reproduction. With appropriate management, most women with epilepsy deliver healthy children. A better understanding of these concerns will allow physicians to improve the lives of women with epilepsy.

Seizures in temporal lobe epilepsy: I. Reliability of scalp/sphenoidal ictal recording.

We determined both (1) the reliability (reproducibility) of seizure onset location in patients with temporal lobe recorded with extracranial EEG and (2) if interictal spike (IIS) location influences that reliability. EEGs were recorded with the 10-20 system and sphenoidal electrodes. Between 1985 and 1993, 166 patients with suspected temporal lobe epilepsy were eligible for inclusion with a total of 734 seizures recorded. Each seizure onset was classified as either localized, lateralized, or nonlocalized. Individual patients were then grouped according to interictal spike location (i.e., unilateral, bilateral, or none) as well as by ictal onset reproducibility patterns (i.e., concordant, semiconcordant, conflicting, or nonlocalized) based on each patient's monitoring session. Seizure onset location was reproducible in 68% of the cases and variable patterns of seizure onset were seen in 32% of patients. Patients with unilateral IIS (68%) were more likely to have consistent ictal onset patterns than patients with bilateral IIS (27%). The first seizure more often predicted subsequent seizure onset patterns when it was localized than when it was nonlocalized. Of 18 patients with conflicting temporal lobe seizures, up to four seizures were necessary to detect independent bilateral temporal lobe seizures.

Absence seizures and carbamazepine in adults.

Carbamazepine (CBZ) therapy was associated with development of absence seizures in 4 adults with generalized epilepsy. Two patients had new appearance of absence seizures and 2 patients had recrudescence of remote absence seizures. The seizures abated after discontinuation of CBZ therapy or addition of ethosuximide (ESM) in 1 patient intolerant of valproate (VPA).

Polyclonal B cell stimulation and interleukin 1 induction by the mucoid exopolysaccharide of Pseudomonas aeruginosa associated with cystic fibrosis.

Mucoid exopolysaccharide isolated from Pseudomonas aeruginosa obtained from colonized cystic fibrosis patients was found to be a potent mitogen for mouse lymphocytes. The responding lymphocyte was a B cell, and we found no evidence that T cell could proliferate or synergize with B cells in response to the mucoid exopolysaccharide. Proliferation was not inhibitable by polymyxin B, which blocks lipopolysaccharide (LPS)-induced proliferation, indicating that a minor LPS contaminant in the purified exopolysaccharide was not the mitogenic component. Mucoid exopolysaccharide induced secretion of IgG, suggesting that it is polyclonal mitogen. It also induced splenic adherent cells (macrophages) to produce interleukin 1. We propose that mucoid exopolysaccharide produced by P. aeruginosa present in the lungs of cystic fibrosis patients may have potent in vivo consequences resulting in aberrant immunoregulation and inhibition of effective immune elimination of P. aeruginosa.