Folate fortification of food: Insufficient for women with epilepsy.

OBJECTIVE: Folic acid supplementation during the periconceptual period has been shown to improve cognitive outcomes in children of women with epilepsy taking anti-seizure medications (ASMs). The dose of folic acid necessary to provide positive cognitive outcomes is unclear. In many countries including the United States, food is fortified with folic acid, but no data exist on how food fortification may affect cognition in children with fetal-ASM exposure. This study evaluated the effect of dietary folate from natural folates plus folic acid fortification, separate from folic acid vitamin supplements, on age-6 year IQ in children with fetal-ASM exposure. METHODS: Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study were retrospectively analyzed for this investigation. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98. The primary outcome of the present study was to assess association of maternal prepregnancy nutrient levels to child age-6 IQ. RESULTS: Folate from food alone without supplement was not associated with improvement of age-6 IQ in children with fetal ASM exposure (95% CI: -11.7-2.3, p = 0.187). Periconceptual folate supplement use was associated with a 10.1-point higher age-6 IQ (95% CI: 5.2-15.0, p < .001). Total combined folate from food plus supplement also showed that higher intake of folate was associated with higher age-6 IQ (Coefficient: 4.5, 95% CI: 2.0-6.9, p < .001). Six other nutrients from food and supplements were analyzed (Vitamin C, Vitamin D, Vitamin E, Omega 3, Gamma Tocopherol, and Vitamin B12) and had no significant association with age 6-IQ. SIGNIFICANCE: Dietary content of folate, even in a country where food is fortified with folic acid, is not sufficient to provide improved cognitive outcomes for children of women taking ASMs during pregnancy. Folate supplementation is needed for significant improvement in cognitive outcomes, specifically age-6 IQ.

Management of epilepsy during pregnancy: evidence-based strategies.

Child-bearing years are often the most precarious management period in the life of a woman with epilepsy. This article reviews the results of many different studies with findings that enable the healthcare team to make confident decisions and recommendations during these critical periods. Preconceptional planning, effective contraception and folic acid supplementation are important fundamentals in preparation for pregnancy. There is growing evidence to avoid valproic acid use during the child-bearing years. Emerging data on congenital malformations and neurocognitive outcomes are available for some of the second-generation antiepileptic drugs and appear reassuring for lamotrigine and levetiracetam. Also reviewed are the benefits of postpartum drug tapers and favorable breastfeeding facts. Counseling the mother and her family on medication choices enables the healthcare team to implement informed decisions that are beneficial for the mother and child.

Management issues for women with epilepsy--focus on pregnancy (an evidence-based review): III. Vitamin K, folic acid, blood levels, and breast-feeding: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment 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 preconceptional folic acid and prenatal vitamin K use and the clinical implications of placental and breast-milk transfer of antiepileptic drugs (AEDs). The committee evaluated the available evidence based on a structured literature review and classification of relevant articles. Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in clinically important amounts. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentrations of lamotrigine, phenytoin, and, to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative (MHD). Supplementing WWE with at least 0.4 mg of folic acid before pregnancy may be considered. Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered, and monitoring of levetiracetam and oxcarbazepine (as MHD) levels may be considered. A paucity of evidence limited the strength of many recommendations.

Using current evidence in selecting antiepileptic drugs for use during pregnancy.

Children born to mothers taking antiepileptic drugs (AEDs) are at increased risk for findings of fetal anticonvulsant syndrome. Accepted treatment paradigms to minimize fetal risks include use of AED monotherapy and folic acid supplementation. However, as data are acquired from several ongoing pregnancy registries, differential risks among the various AED monotherapy regimens are being defined, further improving fetal outcomes.

Pregnancy in women who have epilepsy.

Ideal, comprehensive care of women who have epilepsy during the reproductive years must include effective preconceptional counseling and preparation. The importance of planned pregnancies with effective birth control should be emphasized, with consideration of the effects of the enzyme-inducing AEDs on lowering efficacy of hormonal contraceptive medications and the need for back-up barrier methods. Before pregnancy occurs, the patient's diagnosis and treatment regimen should be reassessed. Once the diagnosis of epilepsy is confirmed, it is important to verify if the individual patient continues to need medications and if she is taking the most appropriate AED to balance control of her seizures with teratogenic risks. For most women who have epilepsy, withdrawal of all AEDs before pregnancy is not a realistic option. A decision to undergo a trial while not taking AEDs before a planned pregnancy should be based on the same principles used for AED withdrawal in any person who has epilepsy. The taper should be completed at least 6 months before planned conception to provide some reassurance that seizures are not going to recur. If a woman who has epilepsy is in the more prevalent category of needing AEDs for seizure control, then monotherapy at the lowest effective dosage should be used. If large daily doses are needed, then frequent smaller doses or extended-release formulations may be helpful to avoid high peak levels. Some of the newest information about differential risks between AEDs also should be considered. The woman's AED regimen should be optimized and folate supplementation should begin before pregnancy. Given that 50% of pregnancies are unplanned in the United States, folate supplementation should be encouraged in all women of childbearing age who are taking any AED for any indication. Dosing recommendations vary from 0.4 mg/d to 5 mg/d. It is not uncommon for a physician to consider changing AED regimens when the patient first reports that she is pregnant. In many cases, she already is in or past the critical period of organogenesis (Table 3). If a woman who has epilepsy presents after conception and is taking a single AED that is effective, her medication usually should not be changed. Exposing the fetus to a second agent during a crossover period of AEDs only increases the teratogenic risk, and seizures are more likely to occur with any abrupt medication changes. If a woman is on polytherapy, it may be possible to switch to monotherapy safely. Seizure control remains an important goal during pregnancy. In particular, convulsive seizures place the mother and fetus at risk. Nonconvulsive seizures also may be harmful, especially if they involve falling or other forms of trauma. Monitoring serum AED levels during pregnancy can be helpful in optimizing seizure control. Prenatal screening can detect major malformations in the first and second trimesters. Vitamin K1 is given 10 mg/d orally during the last month of pregnancy followed by 1 mg intramuscularly or intravenously to the new-born. Although women who have epilepsy and women who are taking AEDs for other indications do have increased risks for maternal and fetal complications, these risks can be reduced considerably with effective preconceptional planning and careful management during pregnancy and the postpartum period.

Brain blood-flow alterations induced by therapeutic vagus nerve stimulation in partial epilepsy: II. prolonged effects at high and low levels of stimulation.

PURPOSE: To measure vagus nerve stimulation (VNS)-induced cerebral blood flow (CBF) effects after prolonged VNS and to compare these effects with immediate VNS effects on CBF. METHODS: Ten consenting partial epilepsy patients had positron emission tomography (PET) with intravenous [15O]H2O. Each had three control scans without VNS and three scans during 30 s of VNS, within 20 h after VNS began (immediate-effect study), and repeated after 3 months of VNS (prolonged study). After intrasubject subtraction of control from stimulation scans, images were anatomically transformed for intersubject averaging and superimposed on magnetic resonance imaging (MRI) for anatomic localization. Changes on t-statistical maps were considered significant at p < 0.05 (corrected for multiple comparisons). RESULTS: During prolonged studies, CBF changes were not observed in any regions that did not have CBF changes during immediate-effect studies. During both types of studies, VNS-induced CBF increases were similarly located in the bilateral thalami, hypothalami, inferior cerebellar hemispheres, and right postcentral gyrus. During immediate-effect studies, VNS decreased bilateral hippocampal, amygdalar, and cingulate CBF and increased bilateral insular CBF; no significant CBF changes were observed in these regions during prolonged studies. Mean seizure frequency decreased by 25% over a 3-month period between immediate and prolonged PET studies, compared with 3 months before VNS began. CONCLUSIONS: Seizure control improved during a period over which some immediate VNS-induced CBF changes declined (mainly over cortical regions), whereas other VNS-induced CBF changes persisted (mainly over subcortical regions). Altered synaptic activities at sites of persisting VNS-induced CBF changes may reflect antiseizure actions.

The importance of monotherapy in pregnancy.

The great majority of women with epilepsy who become pregnant have normal pregnancies and healthy infants. However, in utero exposure to antiepileptic drugs (AEDs) can put infants of women with epilepsy at increased risk for a variety of abnormalities, including intrauterine growth retardation, minor anomalies, major congenital malformations, microcephaly, and cognitive dysfunction. Various combinations of these findings can occur in an individual infant and are referred to as the fetal anticonvulsant syndrome (FAS). The most common major malformations are cleft lip/palate, heart defects, neural tube defects, and urogenital defects. Although AEDs have teratogenic risks, withdrawal of all AEDs before pregnancy is not a realistic option for many women with epilepsy. The results of several studies indicate that AED monotherapy reduces the risk for development of FAS compared with polytherapy exposure in utero. Current treatment guidelines advise use of AED monotherapy when possible and folate supplementation beginning before and continuing throughout pregnancy. Prenatal screening for major malformations should be offered. Careful planning and management of any pregnancy in women with epilepsy is essential to increase the likelihood of a healthy outcome for mother and infant.

Pregnancy in the woman with epilepsy: maternal and fetal outcomes.

Pregnancy in women with epilepsy is associated with increased obstetric risks and increased adverse neonatal outcomes. Prior to conception, folic acid should be administered and the antiepileptic drug (AED) regimen should be optimized. Effective control of maternal seizures with the least risk to the fetus is the goal, preferably using AED monotherapy. Periodic monitoring of total and free AED levels is recommended. The "fetal anticonvulsant syndrome" has been described with all of the AEDs and includes major malformations, minor anomalies, microcephaly, cognitive impairment, intrauterine growth retardation, and infant mortality. The most common major malformations are cleft lip/palate, heart defects, and neural tube defects. Prenatal screening should be offered. Supplemental vitamin K(1) should be given to the mother and newborn to prevent neonatal hemorrhagic disorder. Careful planning and management of any pregnancy in women with epilepsy are essential to increase the likelihood of a healthy outcome for the mother and infant.