Approximately 40% of women with epilepsy experience increased seizure activity associated with certain points in the menstrual cycle, including just before and during menstruation, at the time of ovulation, and during the luteal phase. This condition is known as catamenial epilepsy. Mechanisms proposed include fluctuations in progesterone levels in the perimenstrual and luteal phases and an increase in estrogen levels before ovulation, although more work is needed to elucidate the underlying pathophysiology
In suspected cases, the diagnostic process includes recording seizures and menstrual cycles for at least two 28-day cycles. A 2-fold or greater increase in the frequency of seizures during one of the 3 points in time in the cycle is positive for the diagnosis of catamenial epilepsy.2,3
Because standard anti-epileptic drugs generally do not affect seizure activity in catamenial epilepsy, it is important for clinicians to understand the range of therapies used to treat these patients.3 So far, studies of the effectiveness of various drugs in treating this condition have shown mixed results overall
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“Current treatment strategies include natural progesterone; However, a randomized controlled trial of prometrium in pregnancy was discontinued because it was unsuccessful, “said Jaqueline A. French, MD, professor in the Department of Neurology at NYU Grossman School of Medicine and founder and director of the Epilepsy Study Consortium.4 Post-hoc Analysis suggested that a subset of women with certain catamenial patterns might benefit, but a recent Cochrane review concluded that there was no evidence of an effect. ”4.1
The review authors indicated that their conclusions were based on low to moderate certainty due to the risk of bias, and noted the lack of literature on the subject. French explained that catamenial epilepsy is due to its highly complex and variable nature.
In addition, there was “a major discovery recently – that both men and women tend to have a cycle of seizures that often revolves around a 25-30 day cycle, and that multidien cycle is equally common in men and women, “she said.5” This raises the question of whether some women who believe epilepsy is linked to their menstrual cycle may only experience multidien cycles and therefore hormone therapy would not be effective. “Among the many research gaps in this area, this possibility warrants further investigation.
For an in-depth discussion of current treatment strategies and other clinical considerations for catamenial epilepsy, we interviewed Andrew G. Herzog, MD, MSc, Professor of Neurology at Harvard Medical School and Director of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Boston. (Part 2 of this series will include an interview with an obstetrician and gynecologist.)
What are the underlying mechanisms of catamenial epilepsy?
Dr. Duke: A number of reproductive hormones, including the two main regulators of the menstrual cycle, estradiol and progesterone, are neuroactive steroids that modulate neuronal excitability, seizure thresholds, and the occurrence of seizures. Estradiol generally has a neuro-excitatory effect, while progesterone, which acts mainly through its reduced metabolite allopregnanolone, has a neuro-inhibiting effect.
Allopregnanolone is a potent positive allosteric modulator of the GABAA receptor. Current theory suggests that the rapid premenstrual withdrawal of progesterone, and therefore allopregnanolone, may be a major factor in worsening premenstrual seizures, while the preovulatory surge in estradiol may be a trigger for an increase in mid-cycle seizures.
The rapid premenstrual withdrawal of progesterone not only leads to the rapid withdrawal of the potent GABAergic ligand allopregnanolone, but also changes the subunit composition of the GABAA receptor in a form that is insensitive to benzodiazepines and less sensitive to GABA itself.
The proconvulsive effects of estradiol on seizures and epileptogenesis are less precisely defined and can include both short latency effects (seconds to minutes) on synaptic neurotransmission and long latency effects (hours to days) on the dendritic and synaptic structure in the limbic system.
What are the Patterns of Catamenial Epilepsy?
Dr. Duke: There are 3 patterns of catamenial epilepsy: C1 pattern with exacerbation of perimenstrual seizures (day -3 to +3, with day 1 being the first day of menstrual flow), C2 pattern with exacerbation in the middle of the cycle (day 10 to – 13, with day -14 being ovulation day for most women) and C3 pattern (day 10 to day 3 occurring primarily in anovulatory cycles that have high estradiol / progesterone serum concentration ratios during the days of the second half of the menstrual cycle 6.7
Oral synthetic progestins have not been found to reduce seizures. However, there is evidence from Phase III clinical trials that additional bioidentical progesterone supplementation during the second half of the menstrual cycle with gradual tapering premenstrually in the subgroup of women with the C1 pattern of. Catamenial Epilepsy may be more effective than adding placebo. Efficacy has been demonstrated in terms of both the proportion of women with epilepsy who had seizure frequency reduced by 50% or more and the overall reduction in seizure frequency.8,6
What are the current treatment strategies and are there new treatment methods?
Dr. Duke: For new treatment modalities, synthetic analogues of allopregnanolone have not been shown to be superior to placebo in phase III studies in women with epilepsy of childbearing potential in general (ganaxolone) or in superrefractory status epilepticus (brexanolone). However, these studies did not include any sub-analyzes demonstrating effectiveness in a subset of hormonally susceptible individuals such as women with epilepsy with perimenstrually exacerbated seizures.
Cycle suppression therapy with depomedroxyprogesterone or depot GnRH analog plus stable, balanced bioidentical HRT may provide a strategy for the management of mid-cycle exacerbations and perimenstrual seizures, but further studies are required
On the non-hormonal side, there is a small study (n = 18) that suggests a possible benefit of cyclical 10-day perimenstrual treatment with clobazam. 9
What are some recommendations for clinicians regarding balancing treatment against its effects on fertility, menstrual cycle, bone health, and cardiovascular health?
Dr. Duke: Cyclic bioidentical progesterone supplement has no negative effects on fertility, menstrual cycle, or bone health. In fact, progesterone cycling is a recognized method of regulating the menstrual cycle and can improve fertility in women with inadequate luteal phase cycles. It is not known to affect bone health because dosing progesterone in the cyclical physiological range does not suppress estradiol levels.
Although “drug supplements” for commercially available bioidentical progesterone supplements typically cite the same potential cardiovascular side effects as with oral contraceptive and synthetic progestogen use, there is very little supporting evidence of these effects.
Why is research on this topic so sparse?
Dr. Duke: Research on this topic can be scanty for a number of reasons: Neurologists often have limited knowledge, experience, and comfort with reproductive endocrine problems related to menstrual disorders, menstrual cycle regulation, and hormone treatment. Second, gynecologists are generally unfamiliar and unexperienced with the effects of hormones on seizures in women with epilepsy (which can constitute a very small part of gynecological practice) and with some interactions with anti-epileptic drugs. Finally, previous research on catamenial epilepsy produced conflicting results that were quite confusing. There was no single definition of what term catamenial epilepsy was or how to identify its various patterns.
What can help improve the standard of care for catamenial epilepsy?
Dr. Duke: The standard of care could benefit from including the day of menstruation on seizure calendars to identify catamenial patterns of seizure occurrence, along with recognizing the role of menstrual disorders in seizures. Irregular cycles, heavy menstrual bleeding, or irregular bleeding may indicate estrogen-dominant or inadequate luteal phase cycles, which may play a role in the seizure exacerbation.
In addition, routine hormone tests are performed on women with epilepsy and menstrual disorders, which are indicated for signs of hypothyroidism, increased testosterone (indicated on Polycystic Ovarian Syndrome) or any other endocrine finding that may make seizures worse would be helpful, as would further studies on the role of bioidentical progesterone and synthetic allopregnanolone analogues in the management of persistent seizures in the subgroup of hormonally susceptible women with epilepsy.
References
1. Maguire MJ, Nevitt SJ. Treatments for seizures in catamenial (menstrual) epilepsy. Cochrane Database Syst Rev. Published online September 16, 2021. doi: 10.1002 / 14651858.CD013225.pub3
2. Epilepsy Foundation. Basics of catamenial epilepsy. Accessed online December 1, 2021.
3. Frank S., Tyson NA. A clinical approach to catamenial epilepsy: A Review. Perm J. Published online December 2, 2020. doi: 10.7812 / TPP / 19.145
4. French YES. Treatment for catamenial epilepsy is still up in the air. Epilepsy curr. Published online March 1, 2013. doi: 10.5698 / 1535-7597-13.2.71
5. Karoly PJ, Freestone DR, Eden D, et al. Epileptic seizure cycles: six common clinical misconceptions. Front Neurol. Published online on August 4, 2021. doi: 10.3389 / fneur.2021.720328
6. Herzog AG. Catamenial Epilepsy: Update on Prevalence, Pathophysiology, and Treatment from Results of the NIH Progesterone Treatment Study. Seizure. Publish online February 23, 2015. doi: 10.1016 / j.seizure.2015.02.024
7. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsy. Published online August 3, 2005. doi: 10.1111 / j.1528-1157.1997.tb01197.x.
8. Herzog AG, Fowler KM, Smithson SD, et al .; Study group for progesterone studies. Progesterone vs. Placebo Therapy for Women with Epilepsy: A Randomized Clinical Trial. Neurology. Published online May 30, 2012. doi: 10.1212 / WNL.0b013e318259e1f9
9. Feely M, Calvert R, Gibson J. Clobazam in catamenial epilepsy. A model for evaluating anticonvulsants. Lancet. Published online July 10, 1982. doi: 10.1016 / s0140-6736 (82) 91691-9
