Catamenial epilepsy is a specific type of epilepsy where seizure frequency is exacerbated during certain phases of the menstrual cycle, affecting a significant proportion of women with epilepsy. This condition is characterized by the influence of menstrual cycle hormonal fluctuations on seizure patterns. Vulnerable days of the menstrual cycle for seizures are perimenstrually (C1 pattern), at ovulation (C2 pattern), and during the luteal phase (C3 pattern).
Understanding Catamenial Epilepsy
Catamenial epilepsy describes a worsening of seizures in relation to the menstrual cycle and may affect around 40% of women with epilepsy. Some studies estimate that upwards of 50 percent of women with epilepsy experience seizure patterns influenced by their menstrual cycle. Close to one in three women with epilepsy self-report an increase in seizure frequency during specific phases of their menstrual cycle. Women with focal epilepsy are more likely to experience catamenial patterns compared to those with generalized epilepsy.
Hormonal Influence on Seizures
Estrogen and progesterone, steroid hormones that circulate throughout the brain, have been shown to affect neuronal excitability. Estrogen generally increases neuronal excitability and has proconvulsant properties, while progesterone has anticonvulsant effects, enhancing GABA-mediated inhibition. Thus, changes in the serum estradiol/progesterone ratio throughout a normal reproductive cycle can increase or decrease the risk of seizure occurrence. The higher ratio of serum estradiol/ progesterone during the premenstrual period has been shown to lead to the clustering of seizures in ovulatory cycles.
Patterns of Catamenial Epilepsy
Catamenial epilepsy is diagnosed by evaluating a menstrual and seizure diary, noting seizures during each phase of the menstrual cycle for at least two cycles. The three recognized patterns of catamenial epilepsy, defined in the late 1990s, include:
- C1 Pattern (Perimenstrual): Seizures worsen in the days leading up to and during menstruation, when progesterone levels drop in ovulatory cycles. This is the most common seizure pattern.
- C2 Pattern (Periovulatory): Seizures are exacerbated around ovulation due to the midcycle surge of estrogen, which is relatively unopposed by progesterone.
- C3 Pattern (Anovulatory): Seizure frequency increases during anovulatory cycles, where the luteal phase is characterized by low progesterone levels. The midcycle surge in estrogen still occurs, but without a significant increase in progesterone levels.
Notably, the same individuals may have multiple types of CE. Interestingly, some studies have shown that catamenial epilepsy is substantially and statistically significantly more common among women with left temporal foci than among those with right temporal foci. Furthermore, age affects overall seizure rate: youth increases seizure occurrence across the 28-day cycle.
Read also: Epilepsy medication and its impact on weight
Pathophysiology of Catamenial Epilepsy
The pathophysiology of catamenial epilepsy is complex and incompletely understood. The increased risk of seizures may relate to changes in the levels of progesterone (a hormone released by the ovaries) around the time of a menstrual period and oestrogen (a female sex hormone) surge around ovulation.
Progesterone and GABA Receptors
A reduction in progesterone levels premenstrually and reduced secretion during the luteal phase is implicated in catamenial C1 and C3 patterns. 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. Progesterone is converted into metabolites called neuro-steroids (e.g., allopregnanalone and tetrahydrocortiosterone). These neurosteroids suppress seizures through unique interactions with GABA receptors (GABA-R). Altered GABA-R subunit populations have been implicated in several seizure models, including CE. High progesterone levels are associated with high expressions of GABA-Rs with a δ subunit and decreased overall seizure susceptibility.
Estrogen and Neuronal Excitability
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. Estradiol-triggered convulsions in people with epilepsy who menstruate have been reported. Studies in rodents have even demonstrated cyclic epileptiform activity that correlates to fluctuating estrogen levels. The exact mechanism of estrogen-triggered seizures remains unclear, however, because numerous studies also show that estrogen can suppress seizures. Some reasons for these paradoxical actions of estrogen include variable distribution of estrogen receptor subtypes in different brain regions and the broad effects of estrogen, which binds to glutamate, norpinephrine, and dopamine receptors, among others.
Treatment Strategies for Catamenial Epilepsy
To date, there are no specific drug treatments approved by the Food and Drug Administration (FDA) for catamenial epilepsy; however, both non-hormonal and hormonal therapies have been proposed. 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. The choice of hormonal therapy is dependent on the regularity of an individual’s menstrual cycles.
Non-Hormonal Treatments
- Intermittent Benzodiazepines: Benzodiazepines, particularly clobazam, are frequently used to treat intractable epilepsies including CE. Clobazam is initiated 2 to 4 days before the expected menstruation phase in which seizure exacerbation occurs and continued for 10 days. This monthly dosing strategy is believed to help prevent benzodiazepine tolerance. Suitable treatment candidates are those with C1 and C2 subtypes.
- Acetazolamide: A carbonic anhydrase inhibitor, acetazolamide (AZM) has a long history of use in the treatment of refractory epilepsies. All CE subtypes are potential candidates for treatment with AZM because it can be administered intermittently (during periods of seizure exacerbation) or continuously.
Hormonal Treatments
- Natural Progesterone: Adjunctive natural progesterone lozenges can be considered for use in people with C1. Supplemental progesterone is thought to help prevent the perimenstrual progesterone withdrawal implicated in C1 seizure exacerbation.
- Ganaxolone: A synthetic analog of allopregnanolone, ganaxolone is a neurosteroid metabolite of progesterone. Ganaxolone may provide an effective approach for catamenial epilepsy therapy that is reliable, and that does not expose patients to the risk of hormonal side effects.
- Clomiphene: The selective estrogen receptor modulator clomiphene is typically used to treat hypogonadism and has been used to regulate menstrual cycles. People with C3 are potential candidates for clomiphene citrate for seizure treatment.
- GnRH Analogs: GnRH analogs (e.g., goserelin and triptorelin) cause the suppression of pituitary gonadotropins and prevent monthly menstruation. Evidence for GnRH analogs for CE is strongest for the C1 subtype but considering that GnRH analogs work to stop menstrual cycles entirely, those with C2 and C3 may potentially benefit as well.
- DMPA: A progesterone-only contraceptive, DMPA is injected intramuscularly every 3 months and reduces seizures when used in doses that produce amenorrhea. DMPA is therefore thought to reduce CE by suppressing the menstrual cycle. All catamenial subtypes potentially benefit from this treatment.
Additional Considerations for Women with Epilepsy
Women with epilepsy may not receive 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. Some women with epilepsy appear to be at increased risk of ovulatory dysfunction.
Read also: Diet for Seizures in Dogs
Contraceptive Considerations
Adolescents with seizure disorders require ongoing education about potential adverse pregnancy outcomes and the most effective contraceptive options. There is no conclusive evidence that combination hormonal contraception increases epileptic seizures, and epilepsy itself poses no increased risk of an adverse outcome for those using combined OCPs, the contraceptive patch, or a contraceptive ring. Because many antiepileptic drugs are teratogenic, discussing sexual health with and providing effective contraceptive choices to this population is critical.
Review of Clinical Trials
This is an updated version of a Cochrane Review previously published in 2019. A review of relevant studies included four randomized controlled trials (studies in which participants are randomly assigned to one of two or more treatment groups) of hormonal treatments, two trials evaluating progesterone and two evaluating norethisterone. The four included studies involved a total of 192 women aged between 13 and 45 years experiencing catamenial epilepsy. The included studies did not demonstrate any significant differences between groups when comparing progesterone or norethisterone to placebo for seizure outcomes. The included studies 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 receiving placebo. The evidence is current to July 2021.
Norethisterone vs. Placebo
For the two RCTs evaluating norethisterone versus placebo (24 participants), there were no reported treatment differences for change in seizure frequency. Outcomes for the proportion seizure‐free and 50% responders were not reported.
Progesterone vs. Placebo
For the two RCTs evaluating progesterone versus placebo (168 participants), the studies reported conflicting results for 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 a decrease in seizure frequency from baseline in the progesterone group that was significantly higher than the decrease in seizure frequency from baseline in the placebo group.
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. This review highlights 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 women who do not have regular menses. Further clinical trials are needed in this area.
Read also: Ketogenic Recipes for Epilepsy
The Need for Further Research
The limited evidence base and conflicting results underscore the need for further research into effective treatments for catamenial epilepsy. Studies should focus on:
- Evaluating a wider range of hormonal and non-hormonal interventions.
- Including women with irregular menses in clinical trials.
- Utilizing larger sample sizes to increase statistical power.
- Standardizing the definition and classification of catamenial epilepsy subtypes.
- Investigating the long-term effects of different treatment strategies on seizure control, hormone levels, and quality of life.
Living with Catamenial Epilepsy
Living with catamenial epilepsy can be challenging, but effective management strategies can significantly improve the quality of life for affected women. Key aspects of managing this condition include:
- Accurate Diagnosis: Maintaining detailed menstrual and seizure diaries to identify patterns and triggers.
- Personalized Treatment Plan: Working closely with a healthcare team to develop a tailored treatment approach based on individual needs and seizure patterns.
- Lifestyle Modifications: Implementing lifestyle changes to minimize seizure triggers, such as stress management, adequate sleep, and regular exercise.
- Contraceptive Counseling: Discussing contraceptive options and potential interactions with antiepileptic medications with a healthcare provider.
- Ongoing Support: Seeking support from family, friends, and epilepsy support groups to cope with the emotional and social challenges of living with epilepsy.
tags: #catamenial #epilepsy #management