Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy.

We evaluated the occurrence and distribution of patterns of catamenial epilepsy in a heterogenous cohort of women with epilepsy on no hormonal therapies, enrolled in a prospective, observational study. The primary aim of the study was pregnancy rate in women with epilepsy with no prior reproductive problems. In this analysis, we included women who recorded one or more menstrual cycles with one or more seizures. We measured progesterone concentrations for one to three cycles. We defined catamenial patterns as twofold or greater average daily seizure frequency around menstruation (C1), ovulation (C2), and for anovulatory cycles, from midcycle through menstruation (C3). Twenty-three of the 89 enrolled women with epilepsy were eligible for this analysis; 12 of 23 met criteria for catamenial epilepsy; five of 23 demonstrated only a C1 pattern, two of 23 only a C2 pattern, five of 23 a combined C1/C2 pattern, and the one woman with anovulatory cycles did not demonstrate a C3 pattern. There were no differences in likelihood of demonstrating a catamenial pattern between those who reported a prior catamenial pattern and those who did not (p = .855). This analysis demonstrates the utility of app-based tracking to determine a catamenial pattern. Larger prospective studies could confirm these findings and inform potential therapeutic trial designs for catamenial epilepsy.

Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age.

OBJECTIVE: To determine how early lamotrigine clearance (LTG-CL/F) increases during early pregnancy in women with epilepsy and to quantify the relationship of LTG-CL/F to estradiol concentrations and gestational week. METHODS: This was a multicenter, observational study of pregnant women with epilepsy on lamotrigine and no interacting concomitant medications, employing frequent blood sampling prior to and early in pregnancy. A population mixed-effects modeling approach was used to describe the relationship between LTG-CL/F and gestational week and between LTG-CL/F and estradiol. Akaike information criterion (AIC) compared goodness of fit between final models and a generalized estimating equation to compare differences between low and high percentage LTG-CL/F change groups (p < 0.05). RESULTS: Twenty-five pregnancies (22 participants) were available. Increases in LTG-CL/F were present at 5 weeks gestational age. Both estradiol and gestational week were highly correlated with LTG-CL/F changes; LTG-CL/F increased at the rate of 0.115l/h for every gestational week and 0.844l/h for every 1ng/ml of estradiol, with women in the high LTG-CL/F percentage change group changing at a faster rate (p < 0.001). Models using gestational week performed better than models using estradiol. INTERPRETATION: Gestational week was a better predictor of changes in LTG-CL/F than estradiol concentration and may reflect additional factors, although neither was robust enough to use clinically due to substantial interpatient variability. Changes in LTG-CL/F begin as early as the 5th gestational week, often before women know they are pregnant, emphasizing the importance of planning and early detection of pregnancy and consideration of early implementation of therapeutic drug monitoring. Ann Neurol 2018;84:556-563.

Fertility and Birth Outcomes in Women With Epilepsy Seeking Pregnancy.

Importance: Prior studies report lower birth rates for women with epilepsy (WWE) but have been unable to differentiate between biological and social contributions. To our knowledge, we do not have data to inform WWE seeking pregnancy if their likelihood of achieving pregnancy is biologically reduced compared with their peers. Objective: To determine if WWE without a prior diagnosis of infertility or related disorders are as likely to achieve pregnancy within 12 months as their peers without epilepsy. Design, Setting, and Participants: The Women With Epilepsy: Pregnancy Outcomes and Deliveries study is an observational cohort study comparing fertility in WWE with fertility in control women (CW) without epilepsy. Participants were enrolled at 4 academic medical centers and observed up to 21 months from November 2010 to May 2015. Women seeking pregnancy aged 18 to 40 years were enrolled within 6 months of discontinuing contraception. Exclusion criteria included tobacco use and a prior diagnosis of infertility or disorders that lower fertility. Eighteen WWE and 47 CW declined the study, and 40 WWE and 170 CW did not meet study criteria. The Women With Epilepsy: Pregnancy Outcomes and Deliveries electronic diary app was used to capture data on medications, seizures, sexual activity, and menses. Data were analyzed from November 2015 to June 2017. Main Outcomes and Measures: The primary outcome was proportion of women who achieved pregnancy within 12 months after enrollment. Secondary outcomes were time to pregnancy using a proportional hazard model, pregnancy outcomes, sexual activity, ovulatory rates, and analysis of epilepsy factors in WWE. All outcomes were planned prior to data collection except for time to pregnancy. Results: Of the 197 women included in the study, 142 (72.1%) were white, and the mean (SD) age was 31.9 (3.5) years among the 89 WWE and 31.1 (4.2) among the 108 CW. Among 89 WWE, 54 (60.7%) achieved pregnancy vs 65 (60.2%) among 108 CW. Median time to pregnancy was no different between the groups after controlling for key covariates (WWE: median, 6.0 months; 95% CI, 3.8-10.1; CW: median, 9.0 months; 95% CI, 6.5-11.2; P = .30). Sexual activity and ovulatory rates were similar in WWE and CW. Forty-four of 54 pregnancies (81.5%) in WWE and 53 of 65 pregnancies (81.5%) in CW resulted in live births. No epilepsy factors were significant. Conclusions and Relevance: Women with epilepsy seeking pregnancy without prior known infertility or related disorders have similar likelihood of achieving pregnancy, time to pregnancy, and live birth rates compared with their peers without epilepsy.

Medication adherence in women with epilepsy who are planning pregnancy.

OBJECTIVE: This study examines medication adherence among women with epilepsy via use of an electronic diary, as part of a prospective multicenter observational study designed to evaluate fertility in women with epilepsy (WWE) versus age-matched controls. METHODS: WWE and healthy age-matched controls, seeking pregnancy, were given an iPod Touch using a customized mobile application (the WEPOD App) for daily data tracking. Eighty-six WWE tracked seizures and antiepileptic drugs (AEDs). Tracking of nonepilepsy medications was optional. Diary data were counted from enrollment date until date of delivery, or up to 12 months if pregnancy was not achieved. Each day that subjects reported missing one or more AED was counted as nonadherence. Because adherence can only be determined in women who track consistently, we elected to include adherence data only for women who tracked >80% of days in the study. RESULTS: Approximately 75% of WWE tracked >80% of days and were included in medication adherence data analysis. In this group, medication adherence rate was 97.71%; 44% of women admitted to missing an AED on at least 1 day. Among the subgroup of WWE who recorded nonepilepsy medications, AED adherence rate was 98.56%, versus 93.91% for non-AEDs. SIGNIFICANCE: The 75% compliance rate with an electronic diary suggests that it may be useful to track medication adherence in future studies and in the clinical setting. In those who tracked, the observed medication adherence rate was considerably higher than the 75% adherence rate seen in previous epilepsy studies. This might be explained in part by selection bias, but may also result from properties of the diary itself (daily reminders, real time feedback given to the provider). Women reported a higher rate of adherence to AEDs than to other prescribed medications and supplements, suggesting that perceived importance of medications likely influences medication adherence, and warrants future study.

Anti-mullerian hormone is higher in seizure-free women with epilepsy compared to those with ongoing seizures.

OBJECTIVE: To determine if anti-mullerian hormone (AMH), a neuroactive peptide hormone and a measure of ovarian reserve, is different between women with epilepsy (WWE) and healthy controls (HC) seeking pregnancy and to evaluate epilepsy-related factors associated with AMH concentrations. METHODS: Subjects were participants in Women with Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD), a multi-center prospective, observational cohort study evaluating fecundity in WWE compared to HC, ages 18-40 years. WWE were divided into a Sz+ group or a Sz- group, dependent on whether they had seizures within the 9 months prior to enrollment. Serum was collected, and AMH concentrations were measured as an exploratory analysis. Linear and logistic regression models were used to assess associations and control for covariates. RESULTS: Serum AMH concentrations were measured in 72 out of 90 enrolled WWE and 97 out of 109 HC; the remaining subjects became pregnant before serum was obtained. Thirty WWE were in the Sz+ group and 40 in the Sz- group (retrospective seizure information was missing for two). All AMH concentrations were within the range, however, the normal inverse correlation between age and AMH was present in the HC and in the Sz- groups, but was lacking in the Sz+ group. Mean AMH concentration was higher in the Sz- group (3982pg/ml (SD+/-2452)) compared to the Sz+ group of WWE (2776pg/ml (SD+/-2308)) and HCs (3241 (SD±2647)). All values were within the expected range for age. In WWE, by linear regression, after controlling for age and BMI, seizure occurrence remained associated with AMH (p=0.025). In the prospective phase of the study, AMH concentrations were also associated with seizure occurrence during the menstrual cycle in which the serum sample was obtained (p=0.012). Antiepileptic drugs and other epilepsy factors were not associated with AMH concentrations. When analyzing the Sz- WWE group and the HC group by linear regression with AMH as the dependent variable, after controlling for age and BMI, the association with AMH was also present (p=0.017). AMH concentrations of the Sz+ group and HCs did not differ. SIGNIFICANCE: In this exploratory analysis, seizure freedom was associated with higher AMH concentrations compared to women with ongoing seizures and to HCs. Future studies should further investigate the mechanism of the association of AMH with seizure occurrence, whether AMH could have a direct seizure-protective neuroactive hormone effect, as well as implications of AMH concentrations as a biomarker for ovarian reserve in women with epilepsy.

Do mood instability symptoms in epilepsy represent formal bipolar disorder?

We aimed to assess rates of bipolar symptoms versus bipolar disorder in epilepsy, and the effect of bipolar symptoms on quality of life (QOL) in epilepsy. Bipolar, disability, and QOL instruments were administered to 99 tertiary epilepsy center patients. Patients who scored positive on the Mood Disorder Questionnaire (MDQ) also completed depression scales and a structured psychiatric interview. Results indicated MDQ+ patients (10.1%) had worse QOL and more work, social, and family life disruptions. Most MDQ+ patients did not have bipolar disorder. There was close overlap between depressive and bipolar symptomatology. Based on results of this study, bipolar symptom is not synonymous with bipolar disorder. Symptoms picked up by the MDQ may be epilepsy-related depressive symptoms. Bipolar symptoms are associated with more disability, worse QOL, and may have treatment implications.