Researchers identifies a link between women with catamenial epilepsy and drug-resistant epilepsy


More frequent seizures during the menstrual cycle in women with genetic generalized epilepsy have been linked for the first time to drug-resistant epilepsy, when anti-seizure medications don’t work, according to a Rutgers coauthored study that may help lead to tailored treatments.

Women with a form of genetic generalized epilepsy called catamenial epilepsy – when seizure frequency increases during their menstrual cycle – were nearly four times more likely to have drug-resistant epilepsy than women who experience no changes in frequency, according to the study in the journal Neurology.

This association was found in two independent samples.

“Typically, genetic generalized epilepsy is thought to respond better to anti-seizure medications than focal epilepsy.

However, previous studies suggest a minority of individuals, between 18 percent and 36 percent, with genetic generalized epilepsy do not respond well to these medications,” said senior author Gary A. Heiman, an associate professor in the Department of Genetics in the School of Arts and Sciences at Rutgers University-New Brunswick.

“It is unclear why seizures in these individuals do not respond well, and we sought to investigate why.

We found a surprising association between women’s menstrual cycle and those with drug-resistant genetic generalized epilepsy. Understanding the reasons for this association could lead to alternative, personalized treatment options for at least some patients.”

In generalized epilepsy, seizures begin on both sides of the brain, while focal epilepsy seizures start in only one part of the brain.

In 2015, about 3.4 million people, including 470,000 children, had epilepsy in the United States, according to the U.S. Centers for Disease Control and Prevention.

Anti-seizure drugs limit the spread of seizures in the brain and work for about two-thirds of people with epilepsy. Other options include surgery.

The study included 589 patients with or without drug-resistant genetic generalized epilepsy at Columbia Comprehensive Epilepsy Center and 66 patients at Yale Comprehensive Epilepsy Center. The goal was to develop and validate a model for predicting generalized epilepsy that resists drug treatment.

Such models may allow healthcare professionals to identify patients who may benefit from more aggressive or different kinds of treatment.

This shows a brain
A computer-generated multi-color image of a brain based on data from magnetic resonance imaging. In generalized epilepsy, seizures begin on both sides of the brain. Image is credited to National Institute of Mental Health, National Institutes of Health.

“Women whose seizures increase during their menstrual cycle and have drug-resistant genetic generalized epilepsy may represent a homogeneous group with a specific cause,” Heiman said.

“Genetic and treatment studies of these women could uncover the reason, and tailored treatment could be developed. Although our study sample is one of the largest to date and found in two independent samples, further investigation using larger sample sizes is required.”

Suzanne Thornton, who earned a doctorate at Rutgers and is now at Swarthmore University, contributed to the study. Coauthors include scientists at Columbia University Medical Center, University of Miami, Yale University, University of Oxford, Free University of Brussels, Monash University, The Royal Melbourne Hospital, The University of Melbourne and Alfred Health.

Catamenial epilepsy describes a worsening of seizures in relation to the menstrual cycle and may affect around 40% of women with epilepsy. Vulnerable days of the menstrual cycle for seizures are perimenstrually (C1 pattern), at ovulation (C2 pattern), and during the luteal phase (C3 pattern).

A reduction in progesterone levels premenstrually and reduced secretion during the luteal phase is implicated in catamenial C1 and C3 patterns. A reduction in progesterone has been demonstrated to reduce sensitivity to the inhibitory neurotransmitter in preclinical studies, hence increasing risk of seizures.

A pre-ovulatory surge in oestrogen has been implicated in the C2 pattern of seizure exacerbation, although the exact mechanism by which this surge increases risk is uncertain.

Current treatment practices include the use of pulsed hormonal (e.g. progesterone) and non-hormonal treatments (e.g. clobazam or acetazolamide) in women with regular menses, and complete cessation of menstruation using synthetic hormones (e.g. medroxyprogesterone (Depo-Provera) or gonadotropin-releasing hormone (GnRH) analogues (triptorelin and goserelin)) in women with irregular menses.Catamenial epilepsy and seizure exacerbation is common in women with epilepsy, and may have a significant negative impact on quality of life.

Women may not be receiving appropriate treatment for their seizures because of uncertainty regarding which treatment works best and when in the menstrual cycle treatment should be taken, as well as the possible impact on fertility, the menstrual cycle, bone health, and cardiovascular health. This review aimed to address these issues in order to inform clinical practice and future research.

Objectives: To evaluate the efficacy and tolerability of hormonal and non-hormonal treatments for seizures exacerbated by the menstrual cycle in women with regular or irregular menses. We synthesised the evidence from randomised controlled trials of hormonal and non-hormonal treatments in women with catamenial epilepsy of any pattern.

Search methods: We searched the following databases to 10 January 2019: Cochrane Register of Studies (CRS Web; includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL)), MEDLINE (Ovid: 1946 to 9 January 2019),, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We used no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies.

Selection criteria: We included randomised and quasi-randomised controlled trials (RCTs) of blinded or opeṉlabel design that randomised participants individually (i.e. cluster-randomised trials were excluded). We included cross-over trials if each treatment period was at least 12 weeks in length and the trial had a suitable wash-out period.

Types of interventions included: women with any pattern of catamenial epilepsy who received a hormonal or non-hormonal drug intervention in addition to an existing antiepileptic drug regimen for a minimum treatment duration of 12 weeks.

Data collection and analysis: We extracted data on study design factors and participant demographics for the included studies. The primary outcomes of interest were: proportion seizure-free, proportion of responders (at least 50% decrease in seizure frequency from baseline), and mean change in seizure frequency.

Secondary outcomes included: number of withdrawals, number of women experiencing adverse events of interest (seizure exacerbation, cardiac events, thromboembolic events, osteoporosis and bone health, mood disorders, sedation, menstrual cycle disorders, and fertility issues), and quality of life outcomes.

Main results: We identified 62 records from the databases and search strategies. Following title, abstract, and full-text screening, we included eight full-text articles reporting on four double-blind, placebo-controlled RCTs. We included two cross-over RCTs of pulsed norethisterone and two parallel RCTs of pulsed progesterone recruiting a total of 192 women aged between 13 and 45 years with catamenial epilepsy.

We found no RCTs for non-hormonal treatments of catamenial epilepsy or for women with irregular menses.Meta-analysis was not possible for the primary outcomes, therefore we undertook a narrative synthesis. For the two RCTs evaluating norethisterone versus placebo (24 participants), there were no reported treatment differences for mean change in seizure frequency.

Outcomes for the proportion seizure-free and 50% responders were not reported. For the RCTs evaluating progesterone versus placebo (168 participants), the studies reported conflicting results on the primary outcomes.

One progesterone RCT reported no significant difference between progesterone 600 mg/day taken on day 14 to 28 and placebo with respect to 50% responders, seizure freedom rates, and change in seizure frequency for any seizure type.

The other progesterone RCT reported that the decrease in seizure frequency from baseline in the progesterone group was significantly higher than the decrease in seizure frequency from baseline in the placebo group.Results of secondary efficacy outcomes showed no significant difference in terms of treatment withdrawal for any reason in the pooled progesterone RCTs when compared to placebo (pooled risk ratio (RR) 1.56, 95% confidence interval (CI) 0.81 to 3.00, P = 0.18, I2 = 0%) or for treatment withdrawals due to adverse events (pooled RR 2.91, 95% CI 0.53 to 16.17, P = 0.22, I2 = 0%).

No treatment withdrawals from the norethisterone RCTs were reported. The RCTs reported limited information on adverse events, although one progesterone RCT reported no significant difference in the number of women experiencing adverse events (diarrhoea, dyspepsia, nausea, vomiting, fatigue, nasopharyngitis, dizziness, headache, and depression).

No studies reported on quality of life.We judged the evidence from the included progesterone RCTs to be of low to moderate certainty due to risk of bias and from the included norethisterone RCTs to be of very low certainty due to serious imprecision and risk of bias.

Authors’ conclusions: This review provides very low-certainty evidence of no treatment difference between norethisterone and placebo, and moderate- to low-certainty evidence of no treatment difference between progesterone and placebo for catamenial epilepsy. However, as all the included studies were underpowered, important clinical effects cannot be ruled out.Our review highlighted an overall deficiency in the literature base on the effectiveness of a wide range of other hormonal and non-hormonal interventions currently being used in practice, particularly for those patients who do not have regular menses. Further clinical trials are needed in this area.

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Rutgers University


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