Abstract
Seizure Course During Pregnancy in Catamenial Epilepsy.
Cagnetti C, Lattanzi S, Foschi N, Provinciali L, Silvestrini M. Neurology 2014;83:339–344.
OBJECTIVE: Our aim was to evaluate seizure course in catamenial epilepsy (CE) and noncatamenial epilepsy (NCE) during pregnancy. METHODS: We prospectively followed women referred to our Epilepsy Center for pregnancy planning to the end of the pregnancy. According to their seizure frequency variations across the menstrual cycle, all patients were divided into either the CE or the NCE group. Data on seizure frequency during pregnancy were collected for each patient and compared with seizure frequency during the pregestational 9 months. RESULTS: Fifty-nine women with CE and 215 with NCE were included. Forty-seven subjects (79.7%) with CE and 48 subjects (22.3%) with NCE remained seizure-free throughout pregnancy (odds ratio [OR] = 2.612, 95% confidence interval [CI] 1.901–3.323, p < 0.001), whereas 30 (50.8%) in the CE group and 18 (8.4%) in the NCE group had reduced seizure frequency during pregnancy (OR = 2.427, 95% CI 1.724–3.129, p < 0.001). Decreases in seizures ≥50% occurred in 26 women (44.1%) with CE and 14 women (6.5%) with NCE (OR = 2.426, 95% CI 1.679–3.173, p < 0.001). Multiple logistic regression models confirmed the significant role of catamenial pattern as predictor for better outcomes. CONCLUSIONS: Better seizure control during pregnancy in the catamenial group may be attributable to the absence of cyclical hormone variations and the increase in circulating progesterone levels. These data may have practical implications for therapeutic management of patients with CE during pregnancy.
Commentary
Pregnancy offers many challenges for the woman with epilepsy. Will she have a harder time getting pregnant? Which antiepileptic drugs (AEDs) are best? Will her seizures get worse? Can she have a vaginal delivery? Can she breastfeed? Will her baby be OK? In the past decade, we as a community have, through observational studies, advanced our understanding of these and other questions. Regarding seizure frequency, studies find that women who have good seizure control prior to getting pregnant are more likely to remain seizure free (1). We now know that closely following AED concentrations, particularly of some AEDs such as lamotrigine, is important for seizure control. Besides AED concentrations, are there other factors that can help us to understand how seizure frequency may change during pregnancy? Sleep deprivation, compliance, hormonal changes, and stressors associated with pregnancy have all been postulated to affect seizure control in pregnancy but have received limited systematic study.
Catamenial epilepsy is a common subtype occurring in approximately one-third of women with epilepsy and is defined as increased seizure susceptibility in relation to a woman's menstrual cycle (2). Women with catamenial epilepsy have a 2-fold or greater increase in seizure frequency in one of three of the following vulnerable time periods: 1) perimenstrual period (days −3 to 3) in a normal menstrual cycle, 2) periovulatory period (days 10 to −13) in normal cycle, and 3) luteal phase (days 10 to 3) in inadequate phase cycles (3). Day 1 is considered the first day of menstrual flow and day −14 the day of ovulation. Much study has focused on why some women are more likely to seize during these periods. Basic science and clinical work find that estrogen is a proconvulsant agent, whereas progesterone and its metabolites, mainly allopregnanolone, have antiepileptic properties. Fluctuating concentrations of these hormones may mediate both short- and long-term effects on neuronal excitability either directly on neuronal membranes or by modulating specific receptor isoforms. For example, estrogens exert excitatory effects at the neuronal membranes, and progesterones act as positive allosteric modulators of the γ-aminobutyric acid type A receptor isoforms. During pregnancy, reproductive hormones are significantly elevated for sustained periods of time. By understanding how seizure frequency changes during pregnancy among women with catamenial epilepsy, we may learn more about both the course of pregnancy as it relates to women with epilepsy and the effects of hormones on seizures.
Despite catamenial epilepsy being common, and the potential impact of pregnancy-related hormonal changes on seizure frequency, the effects of pregnancy in women with catamenial epilepsy are not well understood. Cagnetti and colleagues present findings from the first well-defined study on seizure frequency in women with catamenial epilepsy compared with women with noncatamenial epilepsy. Women with epilepsy who had been referred to a single Italian epilepsy center for pregnancy planning were enrolled and observed prospectively. Using established definitions, women were categorized as having either catamenial or noncatamenial epilepsy. Women with catamenial epilepsy were further subdivided into one of the three groups discussed above. Groups two and three would have required that a midluteal-phase serum progesterone level be drawn in order to be fully defined, and therefore only women classified as being in group one were followed. We therefore continue to have limited understanding of the effects of pregnancy on these subtypes of catamenial epilepsy. In order to be included, women had to be followed for at least 24 months prior to pregnancy; this inclusion criteria provided a well-defined baseline seizure frequency. In addition, only pregnancies registered within 8 weeks of the start of gestation were included. Commensurate with recent study findings that folic acid supplementation reduces the risk of major congenital malformations as well as its association with better cognitive outcomes (4, 5), all women were prescribed prophylactic folic acid (5 mg/d). Fifty-nine women with catamenial epilepsy and 215 with noncatamenial epilepsy were followed (from the original enrollment, 62 were not included because of either being lost to follow-up or premature ending of pregnancy). After enrollment, women had a clinical evaluation every 3 months that included data collection on drug toxicity, treatment compliance, and seizure occurrence. Data frequency data were collected and compared with recorded seizure frequency in the 9 months prior to a woman becoming pregnant.
As a whole group, seizure freedom was less than has been reported in other published reports. Approximately 35% were seizure free throughout the pregnancy. In another large prospective study of over 3,000 pregnancies, 66.6% remained seizure free throughout pregnancy (6). Seizure frequency decreased in 17.5%, decreased by ≥50% in 9.1%, increased in 23.4%, and increased by ≥50% in 9.1%. It is unclear from the study design and presentation as to whether AED levels were followed routinely; this could potentially explain the reduced seizure freedom.
Of interest, women with catamenial epilepsy had better seizure control during pregnancy. Approximately 80% of women with catamenial epilepsy remained seizure free throughout pregnancy, which was significantly better when compared with the 22.3% of women with noncatamenial epilepsy who were seizure free (p < 0.001). When looking at the other percentages, women with catamenial epilepsy consistently did better: reduced seizure frequency (50.8% in the catamenial epilepsy group compared with 8.4% in the noncatamenial epilepsy group, p < 0.001), decrease in seizures of ≥50% (44.1% in catamenial epilepsy group compared with 6.5% in the noncatamenial epilepsy group, p < 0.001). These findings were supported by the catamenial pattern being a predictor of better outcomes in analyses using multiple regression models.
Cagnetti and colleagues nicely demonstrate that women with premenstrual epilepsy have better seizure control when compared with women who do not have catamenial epilepsy. These findings help us counsel pregnant women with epilepsy. In my anecdotal experience, many women with catamenial epilepsy worry that they actually may have more seizures during pregnancy. We can now inform them otherwise. Similar to reported in clinical and basic science studies, these findings suggest that reproductive sex steroid hormones do effect seizure susceptibility and presentation among women with catamenial epilepsy. These women provide a model for us to better understand the dynamic effects of reproductive sex steroid hormones on seizures. Future studies will hopefully elucidate this further.