Treatments for seizures in catamenial (menstrual-related) epilepsy

Background

Catamenial (menstrual) epilepsy describes a worsening of seizures in relation to the menstrual cycle and may affect around 40% of women with epilepsy. There are specific times within the menstrual cycle when women are most at risk: in the days leading up to a menstrual period and during a menstrual period (perimenstrual or catamenial type 1 pattern); at the time of ovulation (catamenial type 2 pattern); and in the second half of their cycle (luteal phase or catamenial type 3 pattern). The reason for this increased risk may relate to changes in the levels of progesterone around the time of a menstrual period and oestrogen surge around ovulation. Studies in animals have demonstrated that lower progesterone may affect how the brain reacts to the brain chemical gamma-Aminobutyric acid (GABA), which is important in preventing seizures. The link between high levels of oestrogen and risk of seizures remains unclear.

At present, catamenial epilepsy is treated depending on whether a woman has regular or irregular menstrual periods. If a woman has regular periods, hormonal (e.g. progesterone supplements) and non-hormonal treatments (e.g. clobazam or acetazolamide) taken prior to and during a period may be used. In women who do not have regular periods, and therefore cannot predict their period days, stopping periods using synthetic hormones (e.g. medroxyprogesterone (Depo-Provera) or gonadotropin‐releasing hormone (GnRH) analogues (triptorelin and goserelin)) are treatment options.

Catamenial epilepsy 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 catamenial seizures. There is uncertainty regarding which treatment works best and when in the menstrual cycle treatments should be taken. There are also concerns about 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

The aim of the review was to examine the effectiveness of hormonal and non-hormonal treatments in stopping seizures in women with catamenial epilepsy.

Methods

Our latest search for trials was in January 2019. We searched the electronic databases to find relevant randomised and quasi-randomised controlled trials (RCTs) (studies in which participants are assigned to one of two or more treatment groups using a random method) in which treatment was continued for at least 12 weeks. Our outcomes of interest were: average change in seizures, percentage of women achieving a reduction in seizures by at least 50%, and percentage of women who became seizure-free. We also examined the reasons why women dropped out of the studies and the reported side effects.

Results

Out of 62 records found in our searches, we were able to include four RCTs of hormonal treatments: two trials evaluating progesterone, and two evaluating norethisterone. In all of these RCTs, the treatment was compared to a placebo (a harmless sugar pill). We did not find any studies testing non-hormonal treatments or any studies in women with irregular periods. The four RCTs included 192 participants aged between 13 and 45 years experiencing catamenial epilepsy. The RCTs did not demonstrate any significant differences when comparing progesterone or norethisterone to placebo for seizure outcomes. The RCTs reported limited information on side effects, but women taking progesterone were no more likely to withdraw from the study due to side effects than those on placebo.

Certainty of the evidence

We judged the certainty of the evidence from this review to be very low to moderate, as the RCTs provided unclear information on methods of blinding, recruited small numbers of participants, and were inconsistent in reporting treatment outcomes.

Conclusions

We found very limited, mostly low-certainty evidence, of no difference in seizure outcomes for norethisterone and progesterone versus placebo in women with catamenial epilepsy. Our review highlights an overall lack of information on the effectiveness of a wide range of other hormonal and non-hormonal treatments currently being used. Further clinical studies are needed in this area.

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.

Read the full abstract...
Background: 

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 strategy: 

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), ClinicalTrials.gov, 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.

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