A comparison of statistical versus clinical classifiers of seizure clustering in women with catamenial and noncatamenial epilepsy.

OBJECTIVE: We assessed whether (1) women with statistical clustering of daily seizure counts (DSCs) or seizure intervals (SIs) also showed clinical clustering, defined separately by ≥2 (≥2-SC) and ≥3 (≥3-SC) seizures on any single day; and (2) how these classifiers might apply to catamenial epilepsy. METHODS: This is a retrospective case-control analysis of data from 50 women with epilepsy (WWE). We assessed the relationships of the four classifiers to each other and to catamenial versus noncatamenial epilepsy using chi-squared, correlation, logistic regression, and receiver operating characteristic (ROC) analyses. RESULTS: ≥3-SC, not ≥2-SC, was more frequent in WWE who had statistical DSC clustering versus those who did not (21/25 [84.0%] vs. 11/25 [44.0%], p = .007). Logistic regression (p = .006) and ROC (p = .015) identified ≥3-SC, not ≥2-SC, as a predictor of statistical DSC clustering, but ≥4-SC was more accurate. ≥3-SC correlated with the average daily seizure frequencies (ADSFs) of the subjects (p = .01). ROC optimal sensitivity-specificity cut-point for ADSF prediction of ≥3-SC (.372) was 64.6% higher than for ≥2-SC (.226). SI clustering was more common in WWE who had catamenial versus noncatamenial epilepsy (p = .013). Logistic regression identified statistical SI clustering as the only significant classifier (p = .043). ROC analysis offered only marginal support (p = .056), because specificity was low (42.1%). SIGNIFICANCE: The findings lend statistical support for (1) the utility of clinical ≥3-SC as a predictor of convulsive status epilepticus, (2) consideration of ADSFs in defining clustering, and (3) ≥4-SC as a more accurate clinical predictor of statistical DSC clustering. Statistical SI clustering occurred more frequently in women with catamenial than noncatamenial epilepsy (90.3% vs. 57.9%, p = .013). Although sensitivity was high (90.3%, 28/31), specificity was only 42.1% (8/19). Algorithms that test patterns and periodicities of clusters are more applicable.

Association between family history of alcohol use disorder and catamenial epilepsy.

The purpose of this investigation was to determine whether a family history of alcohol use disorder (AUD) might be a risk factor and possible clinical biomarker for catamenial epilepsy. The retrospective case-control data came from 119 women, aged 13-48 years, with intractable seizures. We report the relative risk for positive family history of AUD among women with catamenial epilepsy (Group 1) relative to women with noncatamenial epilepsy (Group 2). The risk ratio (RR) for positive AUD history for Group 1 (n = 59) relative to Group 2 (n = 60) was 3.46 (95% confidence interval = 1.36-8.76, p = .009). The RRs were significant for women who had the (C1) perimenstrual (p = .009) and (C3) entire luteal phase (p = .003) patterns but not the (C2) preovulatory pattern. AUD history had a high specificity of 91.7% (55/60) but relatively low sensitivity of 28.8% (17/59) for the prediction of catamenial epilepsy. The positive predictive value was 77.3% (17/22), whereas the negative predictive value was 56.7% (55/97). AUD history is a highly specific biomarker for catamenial epilepsy but has relatively low sensitivity for its detection. Further investigation may identify additional biomarkers that are more efficient than seizure-menses calendars.

Differential risks of changes in seizure frequency with transitions between hormonal and non-hormonal contraception in women with epilepsy: A prospective cohort study.

This prospective, observational, cohort study of 101 women with epilepsy (WWE) assesses the seizure safety of systemic hormonal contraception (HC) versus non-HC (NHC). It reports risks of changes in seizure frequency associated with transition from NHC to HC relative to HC to NHC for (1) proportions of WWE with ≥50% increase and decrease in seizure frequency, (2) changes in seizure frequency, (3) changes in seizure severity, and 4) changes in AED regimen during the study. In comparing NHC to HC versus HC to NHC, NHC to HC had greater risk of ≥50% increase in seizure frequency: RR = 1.98 (1.07-3.64), p = 0.03 and lower risk of ≥50% decrease in seizure frequency: RR = 0.42 (0.22 = 0.83), p = 0.01. These risks were particularly notable for oral contraceptive pill: RR = 2.91 (1.26-6.72), p = 0.01 and RR = 0.54 (0.30-0.97), p = 0.04, respectively. Median monthly seizure frequency (MMSF) increased 302.0% (p = 0.0019) with transition from NHC to HC. MMSF decreased 81.9% with change from HC to NHC (p = 0.001). RR for change in seizure type from milder to more severe type was greater for NHC to HC: RR = 3.32 (1.07-10.27), p = 0.04. Change in AED regimen was not a significant factor. The findings suggest further prospective study to assess whether HC, especially oral contraceptive pill, poses a greater risk of increased seizures than NHC.

Infertility, impaired fecundity, and live birth/pregnancy ratio in women with epilepsy in the USA: Findings of the Epilepsy Birth Control Registry.

OBJECTIVE: To determine the current risks of infertility and impaired fecundity as well as the live birth/pregnancy ratio among women with epilepsy (WWE) in the USA and whether antiepileptic drug (AED) use is a factor. METHODS: These retrospective survey data come from the 2010-2014 Epilepsy Birth Control Registry (EBCR) Web-based survey of 1000 WWE in the USA, aged 18-47 years, who provided demographic, epilepsy, AED, reproductive, and contraceptive data. We report risks of infertility and impaired fecundity, live birth/pregnancy ratio, and whether outcomes differ by AED use or category versus No AED. RESULTS: A total of 978 of the 1000 USA WWE reported reproductive data; 373 WWE had 724 pregnancies and 445 births. An additional 38 WWE (9.2%, 95% confidence interval [CI] = 6.7-12.4%) tried to conceive but were infertile. A total of 72.5% had a live birth outcome for their first pregnancy, 89.0% had at least one live birth for their first two pregnancies, and 61.6% had two live births for their first two pregnancies. Eighty-four of 406 WWE (20.7%, 95% CI = 17.0-2.9%) had impaired fecundity. The risk of impaired fecundity trended higher on AED polytherapy than on No AED (risk ratio [RR] = 1.79, 95% CI = 0.94-3.11, P = .08). The ratio of live birth/unaborted pregnancy (445/594, 74.9%) was similar among WWE on No AED (71.3%), AED monotherapy (71.8%), and polytherapy (69.7%). None of the AED categories differed significantly from No AED. Note that glucuronidated AED (lamotrigine), which had the highest ratio of live birth/pregnancy (89.1%), compared favorably to enzyme-inhibiting AED (valproate), which had the lowest (63.3%; RR = 1.41, 95% CI = 1.05-1.88, P = .02). SIGNIFICANCE: The EBCR finds 9.2% infertility risk and 20.7% impaired fecundity risk among WWE in the USA. Impaired fecundity trended higher on AED polytherapy than on No AED. Live birth/pregnancy ratio was higher with the use of lamotrigine than valproate. These findings may provide WWE a more objective basis for pregnancy planning.

Reasons for discontinuation of reversible contraceptive methods by women with epilepsy.

OBJECTIVE: To report the reasons for discontinuation of contraceptive methods by women with epilepsy (WWE). METHODS: These retrospective data come from a web-based survey regarding the contraceptive practices of 1,144 WWE in the community, ages 18-47 years. We determined the frequencies of contraceptive discontinuations and the reasons for discontinuation. We compared risk ratios for rates of discontinuation among contraceptive methods and categories. We used chi-square analysis to test the independence of discontinuation reasons among the various contraceptive methods and categories and when stratified by antiepileptic drug (AED) categories. RESULTS: Nine hundred fifty-nine of 2,393 (40.6%) individual, reversible contraceptive methods were discontinued. One-half (51.8%) of the WWE who discontinued a method discontinued at least two methods. Hormonal contraception was discontinued most often (553/1,091, 50.7%) with a risk ratio of 1.94 (1.54-2.45, p < 0.0001) compared to intrauterine devices (IUDs), the category that was discontinued the least (57/227, 25.1%). Among all individual methods, the contraceptive patch was stopped most often (79.7%) and the progestin-IUD was stopped the least (20.1%). The top three reasons for discontinuation among all methods were reliability concerns (13.9%), menstrual problems (13.5%), and increased seizures (8.6%). There were significant differences among discontinuation rates and reasons when stratified by AED category for hormonal contraception but not for any other contraceptive category. SIGNIFICANCE: Contraception counseling for WWE should consider the special experience profiles that are unique to this special population on systemic hormonal contraception.

Folic acid use by women with epilepsy: Findings of the Epilepsy Birth Control Registry.

PURPOSE: To determine the prevalence and predictors of folic acid (FA) use by women with epilepsy (WWE) at risk of unintended pregnancy. METHODS: These retrospective data come from the Epilepsy Birth Control Registry (EBCR) web-based survey of 1144 WWE in the community, 18-47years, who provided demographic, epilepsy, AED, contraception, pregnancy, healthcare visits and FA data. We report prevalence and predictors of FA use in relation to risk of pregnancy (not at risk, at risk, seeking pregnancy, pregnant), demographics, seizure types and AED and contraception categories. RESULTS: 368 (47.6%) of the 773 WWE at risk of unintended pregnancy in the EBCR took FA supplement. Being at risk was a significant predictor in comparison to WWE not at risk (OR=1.464 [1.103-1.944], p=0.008). In comparison to WWE at risk, FA use trended greater for WWE actively seeking pregnancy (29/47, 61.7% v 368/773, 47.6%; p=0.0605) and was greater for pregnant WWE (17/19, 89.5% v 368/773, 47.6%; p=0.0007). Demographic predictors for WWE at risk were race (p=0.003), education (p=0.012) and income (0.043) with significantly greater FA use by Caucasians than minorities and direct correlations between FA use and levels of education and household income. Seizure type, AED use, category and dosage, polytherapy and contraceptive category were not predictors. A healthcare provider visit during the year prior to the survey was not a predictor. Prevalence of FA use was similar following visits with gynecologists - 51.7%, neurologists - 48.7% and primary care - 48.6%. FA supplementation by prescription was greater for WWE at risk on AED versus no AED (190/355, 53.5% v 3/13, 23.1%; p=0.045). CONCLUSION: Low prevalence of preconception FA use may reflect a need for more education. In addition, further research is needed to provide definitive evidence that FA reduces congenital malformations in the offspring of WWE.

Contraceptive practices of women with epilepsy: Findings of the epilepsy birth control registry.

OBJECTIVE: To report the contraceptive practices of women with epilepsy (WWE) in the community, predictors of highly effective contraception use, and reasons WWE provide for the selection of a particular method. METHODS: These cross-sectional data come from the Epilepsy Birth Control Registry (EBCR) web-based survey regarding the contraceptive practices of 1,144 WWE in the community, ages 18-47 years. We report demographic, epilepsy, and antiepileptic drug (AED) characteristics as well as contraceptive use. We determined the frequency of use of highly effective contraception use, that is, methods with failure rate <10%/year, and conducted binary logistic regression analysis to determine predictors of highly effective contraception use. We report frequencies of WWE who consult various health care providers regarding the selection of a method and the reasons cited for selection. RESULTS: Of the 796 WWE at risk of unintended pregnancy, 69.7% use what is generally considered to be highly effective contraception (hormonal, intrauterine device [IUD], tubal, vasectomy). Efficacy in WWE, especially for the 46.6% who use hormonal contraception, remains to be proven. Significant predictors of highly effective contraception use are insurance (insured 71.6% vs. noninsured 56.0%), race/ethnicity (Caucasian 71.3% vs. minority 51.0%), and age (38-47, 77.5%; 28-37, 71.8%; 18-27, 67.0%). Of the 87.2% who have a neurologist, only 25.4% consult them regarding selection of a method, although AED interaction is cited as the top reason for selection. SIGNIFICANCE: The EBCR web-based survey is the first large-scale study of the contraceptive practices of WWE in the community. The findings suggest a need for the development of evidence-based guidelines that address the efficacy and safety of contraceptive methods in this special population, and for greater discourse between neurologists and WWE regarding contraception.

Differential impact of contraceptive methods on seizures varies by antiepileptic drug category: Findings of the Epilepsy Birth Control Registry.

PURPOSE: The aim of this study was to determine whether categories of contraception differ in their impact on seizures in women with epilepsy and whether the impact varies by antiepileptic drug category. METHODS: Retrospective survey data came from 2712 contraceptive experiences reported by 1144 women with epilepsy. We compared risk ratios for reports of increase and decrease in seizure frequency on hormonal versus nonhormonal contraception, stratified by antiepileptic drug categories. RESULTS: More women with epilepsy reported a change in seizures on hormonal (28.2%) than on nonhormonal contraception (9.7%) (p<0.0001). The risk ratio for seizure increase on hormonal (18.7%) versus nonhormonal contraception (4.2%) was 4.47 (p<0.0001). The risk ratio for seizure decrease on hormonal (9.5%) versus nonhormonal contraception (5.5%) was 1.71, p<0.0001. On hormonal contraception, the risk ratio for seizure increase was greater than for decrease (1.98, p<0.0001). In comparison to combined pills, both hormonal patch and progestin-only pills had greater risk ratios for seizure increase. Depomedroxyprogesterone was the only hormonal method with a greater risk ratio for seizure decrease than combined pills. Seizure increase was greater for hormonal than nonhormonal contraception for each antiepileptic drug category (p<0.001). On hormonal contraception, relative to the non-enzyme-inducing antiepileptic drug category which had the lowest rate, each of the other categories had significantly greater risks for seizure increase, especially the enzyme-inhibiting (valproate) category (risk ratio=2.53, p=0.0002). CONCLUSION: The findings provide community-based, epidemiological survey evidence that contraceptive methods may differ in their impact on seizures and that this impact may vary by antiepileptic drug category.

Distribution of seizures across the menstrual cycle in women with epilepsy.

The purpose of this study was to determine whether seizure frequency and cycle days with seizure occurrence vary across the menstrual cycle. The subjects were the first 100 women with intractable focal onset seizures, 13-45 years old, who completed the baseline phase of the National Institutes of Health (NIH) Progesterone Trial. Each subject recorded seizures and menses during a 3-month baseline phase. Data consisted of (1) seizure numbers for each cycle day and (2) cycle days with seizure occurrence. Statistical comparisons of seizure frequency and days with seizures were performed using generalized estimating equation one-way analysis of variance (ANOVA) and logistic regression followed by pairwise multiple comparisons of days based on the least square means. Seizure numbers and cycle days with seizure occurrence varied across the menstrual cycle. There was an approximately twofold difference between the highest (day 1) and lowest (day -8) values for both seizure frequency and days with occurrence. The demonstration of variation in seizure frequency and cycle days with seizure occurrence across the menstrual cycle, as well as identification of specific days that have substantially higher or lower frequencies than other days, supports the existence of catamenial epilepsy.

Variation of seizure frequency with ovulatory status of menstrual cycles.

PURPOSE: To determine if seizure frequency differs between anovulatory and ovulatory cycles. METHODS: The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic-clonic seizures - 2°GTCS, complex partial seizures - CPS, simple partial seizures - SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis. KEY FINDINGS: ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only. SIGNIFICANCE: Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.

Neuroendocrinological aspects of epilepsy: important issues and trends in future research.

Neuroendocrine research in epilepsy focuses on the interface among neurology, endocrinology, gynecology/andrology and psychiatry as it pertains to epilepsy. There are clinically important reciprocal interactions between hormones and the brain such that neuroactive hormones can modulate neuronal excitability and seizure occurrence while epileptiform discharges can disrupt hormonal secretion and promote the development of reproductive disorders. An understanding of these interactions and their mechanisms is important to the comprehensive management of individuals with epilepsy. The interactions are relevant not only to the management of seizure disorder but also epilepsy comorbidities such as reproductive dysfunction, hyposexuality and emotional disorders. This review focuses on some of the established biological underpinnings of the relationship and their clinical relevance. It identifies gaps in our knowledge and areas of promising research. The research has led to ongoing clinical trials to develop hormonal therapies for the treatment of epilepsy. The review also focuses on complications of epilepsy treatment with antiepileptic drugs. Although antiepileptic drugs have been the mainstay of epilepsy treatment, they can also have some adverse effects on sexual and reproductive function as well as bone density. As longevity increases, the prevention, diagnosis and treatment of osteoporosis becomes an increasingly more important topic, especially for individuals with epilepsy. The differential effects of antiepileptic drugs on bone density and their various mechanisms of action are reviewed and some guidelines and future directions for prevention of osteoporosis and treatment are presented.

Premenstrual dysphoric disorder in women with epilepsy: relationships to potential epileptic, antiepileptic drug, and reproductive endocrine factors.

The purpose of this prospective observational investigation was to determine whether the frequency of premenstrual dysphoric disorder (PMDD) and the severity of PMDD symptoms differ between women with epilepsy and controls without epilepsy and whether there exists a relationship between the severity of PMDD symptoms and some epileptic, antiepileptic drug, and reproductive endocrine features. The results suggest that epilepsy, antiepileptic drug levels, ovulatory status, and hormone levels and ratios may all influence PMDD in women with epilepsy. PMDD severity scores may be greater in people with right-sided than in those with left-sided epilepsy, and in people with temporal than in those with nontemporal epileptic foci. PMDD severity scores may be greater with anovulatory cycles, and scores may correlate negatively with midluteal serum progesterone levels and positively with midluteal estradiol/progesterone ratios. Mood score may vary with particular antiepileptic drugs, favoring carbamazepine and lamotrigine over levetiracetam. PMDD severity scores may correlate directly with carbamazepine levels, whereas they correlate inversely with lamotrigine levels.

The interactions between reproductive hormones and epilepsy.

There are complex interactions between hormones, epilepsy, and antiepileptic drugs (AEDs). While there is ample evidence that hormones influence epilepsy, it is also apparent that epileptic activity influences hormones in both women and men. In addition, AEDs may disturb endocrine function. The clinical importance of these interactions is primarily related to the effects on reproductive hormones, which is the focus of this article. Reproductive endocrine dysfunction is common among women and men with epilepsy. Menstrual disorders, polycystic ovaries, and infertility have been described among women with epilepsy, while reduced potency and sperm abnormalities have been found in men. Sexual problems and endocrine changes have been frequently described in both sexes. Epilepsy and AEDs can target a number of substrates to impact hormone levels. These include the limbic system, hypothalamus, pituitary, peripheral endocrine glands, liver, and adipose tissue. AEDs may also alter the synthesis of steroids and binding proteins, as well as hormone metabolism, and produce direct gonadal effects.

A comparison of anastrozole and testosterone versus placebo and testosterone for treatment of sexual dysfunction in men with epilepsy and hypogonadism.

Hyposexuality is commonly associated with low bioavailable testosterone (BAT) and relative estradiol elevation in men with epilepsy. This prospective, randomized, double-blind trial compared the effects of depotestosterone+the aromatase inhibitor anastrozole (T-A) versus depotestosterone+placebo (T-P) on sexual function, hormone levels, mood, and seizure frequency in men with epilepsy. Forty men with focal epilepsy, hyposexuality, and hypogonadism were randomized 1:1 to two groups (T-A or T-P) for a 3-month treatment trial of depotestosterone+either anastrozole or matching placebo. Outcomes included both efficacy and safety measures. Normalization of sexual function (S-score) occurred with greater frequency in the T-A (72.2%) than in the T-P (47.4%) group, but the difference was not statistically significant. T-A resulted in significantly lower estradiol levels and S-scores correlated inversely with estradiol levels at baseline and during treatment. Beck Depression Inventory II (BDI-II) scores improved significantly in both groups and changes in S-score correlated inversely with changes in BDI-II score. Changes in seizure frequency correlated with changes in BDI-II score. Seizure frequency decreased with both treatments and showed significant correlations with estradiol levels. Triglyceride levels increased with T-P and decreased with T-A. The difference in triglyceride changes between the two treatments was significant and correlated with changes in estradiol levels. Significant correlations between estradiol levels and S-scores, as well as seizure outcomes and triglyceride levels, suggest further study regarding a potential role for anastrozole in the treatment of men with epilepsy who have hyposexuality and hypogonadism.

Association of Unintended Pregnancy With Spontaneous Fetal Loss in Women With Epilepsy: Findings of the Epilepsy Birth Control Registry.

Importance: If unintended pregnancy is common among women with epilepsy and is associated with increased risk of spontaneous fetal loss (SFL), it is important to develop guidelines for safe and effective contraception for this community. Objective: To assess whether planned pregnancy is a determinant of SFL in women with epilepsy. Design, Setting, and Participants: The Epilepsy Birth Control Registry conducted this web-based, retrospective survey between 2010 and 2014. It gathered demographic, epilepsy, antiepileptic drug (AED), contraceptive, and reproductive data from 1144 women with epilepsy in the community between ages 18 and 47 years. Data were analyzed between March 2018 and May 2018. Main Outcomes and Measures: The primary outcome was the risk ratio (RR) with 95% confidence intervals for SFL in unplanned vs planned pregnancies. The secondary outcome was the identification of some potentially modifiable variables (maternal age, pregnancy spacing, and AED category) of SFL vs live birth using binary logistic regression. Results: The participants were proportionally younger (mean [SD] age, 28.5 [6.8] years), and 39.8% had household incomes of $25 000 or less. Minority women represented only 8.7% of the participants. There were 530 of 794 unplanned pregnancies (66.8%) and 264 of 794 planned pregnancies (33.2%). The risk for SFL in 653 unaborted pregnancies in women with epilepsy was greater for unplanned (n = 137 of 391; 35.0%) than planned (n = 43 of 262; 16.4%) pregnancies (RR, 2.14; 95% CI, 1.59-2.90; P < .001). Regression analysis found that the risk for SFL was greater when planning was entered alone (odds ratio [OR], 2.75; 95% CI, 1.87-4.05; P < .001) and more so when adjusted for maternal age, interpregnancy interval, and AED category (OR, 3.57; 95% CI, 1.54-8.78; P = .003). Interpregnancy interval (OR, 2.878; 95% CI, 1.8094-4.5801; P = .008) and maternal age (OR, 0.957; 95% CI, 0.928-0.986 for each year from 18 to 47 years; P = .02), but not AED category, were also associated. The risk was greater when interpregnancy interval was less than 1 year (n = 56 of 122; 45.9%) vs greater than 1 year (n = 56 of 246; 22.8%) (RR, 2.02; 95% CI, 1.49-2.72; P < .001). Relative to the younger than 18 years cohort (n = 15 of 29; 51.7%), the risks were lower for the intermediate older cohort aged 18 to 27 years (n = 118 of 400; 29.5%; RR, 0.57; 95% CI, 0.39-0.84; P < .004) and the cohort aged 28 to 37 years (n = 44 of 212; 20.8%; RR, 0.40; 95% CI, 0.26-0.62; P < .001) but not significantly different for the small number of participants in the aged 38 to 47 years cohort (n = 3 of 12; 25.0%). No individual AED category's SFL frequency differed significantly from the no AED category. Conclusions and relevance: The Epilepsy Birth Control Registry retrospective survey finding that unplanned pregnancy in women with epilepsy may double the risk for SFL warrants prospective investigation with outcome verification.

Does the age of seizure onset relate to menarche and does it matter?

PURPOSE: To determine whether there is a relationship between the age of seizure onset and the age of menarche. METHODS: 1144 women with epilepsy (WWE) in the community, ages 18-47 years, provided web-based survey data. We compared the frequencies of the individual differences between their ages of seizure onset and menarche to each other and chance. We determined whether the age of menarche is a predictor of the age of seizure onset and the percentage of the variance that menarche explains. We used two-step cluster analysis to auto-identify a cluster of years relative to the age of menarche that showed the greatest predilection for seizure onset. RESULTS: Average age of menarche was 12.55 [95% CI: 12.45-12.65]. It was greater in WWE who developed seizures before versus after menarche (12.70 [12.54-12.86] v 12.42 [12.30-12.54], p = 0.006). More WWE had seizure onset during the year of menarche than during any other year (8.3% v expected 2.1%; p < 0.0001). Menarche, however, explained only 1% of the variance. Seizure onset frequencies were greatest for an auto-identified cluster that spanned 2 years before to 6 years after menarche and subsumed 49.3% of seizure onset. CONCLUSION: Although the results indicate a significant relationship between the age of seizure onset and the age of menarche, the broader auto-identified perimenarchal cluster that subsumes 49.3% of seizure onset suggests that research target the potential role of the great increase in adrenarchal, as well as gonadarchal, neuroactive steroids that modulate neuronal excitability and seizures during that span.

Prevalence of highly effective contraception use by women with epilepsy.

OBJECTIVE: To determine (1) the proportion of women with epilepsy (WWE) at risk of unintended pregnancy who use highly effective contraception, (2) demographic predictors, and (3) folic acid (FA) use. METHODS: These cross-sectional data come from 311 US WWE, 18-47 years, who participated in the Epilepsy Birth Control Registry (EBCR) web-based survey in 2017. They provided demographic, epilepsy, antiepileptic drug (AED), contraceptive, and FA data. We report frequencies of highly effective contraception use and use logistic regression to determine demographic predictors. We report the proportion who take FA. RESULTS: A total of 186 (59.8%) of the 311 WWE were at risk of unintended pregnancy. A total of 131 (70.4%) used a highly effective contraceptive category; 55 (29.6%) did not. An additional 13 (7.0%) used a combination of generally effective hormonal contraception with an enzyme-inducing AED, which poses increased risk of unintended pregnancy. Overall, 68 (36.6%) of the 186 WWE at risk did not use highly effective contraception. Increasing income (p = 0.004) and having insurance (p = 0.048) were predictors of highly effective contraception. A total of 50.0% took FA supplement. There was no significant difference in relation to the use or lack of use of highly effective contraception. CONCLUSION: A total of 36.6% of WWE in the EBCR did not use highly effective contraception and 50.0% did not take FA in 2017 despite the important negative consequences of unintended pregnancy on pregnancy outcomes. There is a need for more readily available information and counseling on safe and effective contraception and FA use for this community.

Circalunar and ultralunar periodicities in women with partial seizures.

PURPOSE: Little consensus exists for the definition of catamenial epilepsy. Few studies have evaluated the periodicity of seizures to test the hypothesis that seizures in women have periodic patterns of occurrence independent of a priori hormonal considerations. In the present study, we determined seizure periodicity according to a "menstrual clock" provided by a common phase marker of the onset of menses. METHODS: Seizure and menstrual diaries of approximately 3 months duration were obtained from women enrolled in a trial of hormonal therapy for localization-related epilepsy. Midluteal progesterone levels identified ovulatory (>or=5 ng/ml, OC) from anovulatory cycles (AC). Individual cycles were normalized to a common phase and period (day 0 = menses onset, intervening days = 28 bins). Periodicity of combined data was estimated with cosinor-nonlinear least squares analysis. Best-fit rhythms were estimated with 95% confidence limits. RESULTS: 100 patients provided 3344 seizures within 293 cycles (77% OC, 20% AC, indeterminate 3%). OC seizures displayed a circalunar rhythm with peak phase of occurrence at onset of menses. AC seizures also featured a circalunar rhythm that peaked at menses onset but also had ultralunar rhythms of approximately 14 and approximately 9 days. DISCUSSION: Seizures in women with epilepsy occur in circalunar rhythms. OC and AC seizures differ in seizure timing with the latter occurring in ultralunar rhythms in addition to the predominant circalunar rhythm. This finding supports the existence of catamenial epilepsy and differences in patterns of seizure occurrence between OC and AC.

Disorders of reproduction in patients with epilepsy: primary neurological mechanisms.

Reproductive disorders are unusually common among women and men with epilepsy. They are generally associated with and may be the consequence of reproductive endocrine disorders. Both epilepsy itself and antiepileptic drug use have been implicated in their pathophysiology. This review focuses on how temporolimbic dysfunction in epilepsy may disrupt normal neuroendocrine regulation and promote the development of reproductive endocrine disorders. The particular nature of the dysregulation may relate to the laterality and focality of the epilepsy and some hormonal changes may develop in close temporal relation to the occurrence of epileptiform discharges. In women, reproductive endocrine disorders include polycystic ovary syndrome, hypothalamic amenorrhea, functional hyperprolactinemia, and premature menopause. In men, hypogonadism may be hypogonadotropic, hypergonadotropic or related to hyperprolactinemia. The significance of these reproductive endocrine disorders is that they may contribute not only to sexual dysfunction and infertility but may also have an adverse impact on seizure control.

Catamenial epilepsy: definition, prevalence pathophysiology and treatment.

Seizures do not occur randomly. They tend to cluster in the majority of men and women with epilepsy. Seizure clusters, in turn, often show a periodicity. When the periodicity of seizure exacerbation aligns itself with that of the menstrual cycle, it is designated as catamenial epilepsy. The neuroactive properties of reproductive steroids and the cyclic variation in their serum concentrations are important pathophysiologic factors. Recent investigations have demonstrated and confirmed the existence of at least three patterns of catamenial seizure exacerbation: perimenstrual and periovulatory in ovulatory cycles and entire luteal phase in anovulatory cycles. A rational mathematical basis for the categorization of seizure exacerbation as catamenial epilepsy has been developed. It identifies approximately one third of women as having catamenial epilepsy. If seizures show hormonal sensitivity in their occurrence, they may also respond to hormonal treatment. Successful open label trials using cyclic natural progesterone supplement, depomedroxyprogesterone and gonadotropin-releasing hormone analogues in women and using testosterone with or without aromatase inhibitor in men have been reported. Prospective, randomized, placebo-controlled, double-blind investigations are warranted and under way.