Seizures and the Menstrual Cycle
Nancy E. Noldy-MacLean, Ph.D.
A relationship between the menstrual cycle and seizures has been noticed for over 100 years. Despite the length of time that this has been recognized, inconsistencies in the definition, prevalence, underlying physiology and treatment of these types of seizures abound in the literature.
What is catamenial epilepsy?
In 1956, Laidlaw first used the term catamenial epilepsy to describe seizures around menstruation. Since then, there has been little agreement regarding the definition of catamenial epilepsy in the research literature. Gastaut defined a catamenial seizure as "an epileptic seizure that occurs either during menstruation or several days preceding or following", and catamenial epilepsy as "a type of epilepsy characterized mainly or exclusively by catamenial epileptic seizures." Thus, for some authors, catamenial epilepsy is defined in the strictest sense, in that seizures must occur primarily during the few days prior to and the first few days of menses before the diagnosis of catamenial epilepsy is applied.
By contrast, another author includes in his descriptions of catamenial epilepsy, a seizure pattern in which fewer seizures are seen between day 8 of one cycle and day 2 of the next, relative to days 2 to 8. Still others have described a number of patterns of seizure activity which are observed during different phases of the menstrual cycle and call them all catamenial. The number of seizures which constitute an increase or most seizures occurring during a certain range of days also varies between authors. The question of which seizure patterns can be considered catamenial has not been answered consistently and remains debatable.
How common is catamenial epilepsy?
Because this condition has been defined so differently by different authors, figures relating to its commonness are also very variable. Prevalence data vary from 12.5% to 72% of women with epilepsy having catamenial seizures. Generally, studies that use a very restrictive definition of catamenial epilepsy (seizures primarily occurring from 4 days preceding to 6 days following the onset of menstruation, excluding women whose seizures occur during ovulation), report very low prevalence. Studies allowing a more flexible definition report a higher incidence. One study of 69 women with epilepsy and a total of more than 1,237 menstrual cycles found that 2/3 of these women had seizures that were related to their menstrual cycle. There was an increase in seizure frequency in the second phase of the cycle, which was at it's highest on the first day of menstruation. However, no woman had seizures exclusively connected with her menstrual cycle.
Hormone Levels and Seizures
What might cause these changes in seizure frequency during the menstrual cycle?
In many animal models of epilepsy, estrogens have been found to excite brain activity. In human studies, hormones also directly change electroencephalographic (EEG) activity. For example, in one study, an intravenous (IV) injection of estrogen resulted in clinical seizures in 4 of 16 women with epilepsy and activated EEG epileptic-type activity in 11. An IV infusion of progesterone decreased this type of activity temporarily in 4 of 7 women with partial epilepsy.
During the normal menstrual cycle, regular fluctuations in the hormones estrogen and progesterone occur. Estrogen levels are higher than progesterone levels just before ovulation (at mid-cycle), at the end of the cycle just before menstruation, and for the first few days of menstruation. Research indicates that seizure frequency is maximal when progesterone levels are low compared to estrogen levels. Seizures are most common when estrogen rises and less common when progesterone levels are highest. Thus, in general, seizure activity seems to increase during the few days prior to menstruation as well as the first few days of menstruation, and again near mid-cycle, prior to ovulation, between days 8 and 14 (where the first day of the cycle is the first day of menstruation).
Reproductive disorders
Disorders related to hormone regulation during the menstrual cycle appear to occur more frequently in women with epilepsy and also seem to cause increased seizure frequency. Two of these types of disorders are described below. Each affects a phase of the menstrual cycle in which seizures become worse in some women with epilepsy.
Anovulatory cycles are menstrual cycles in which ovulation does not occur. This condition is associated with constant estrogen levels which are not balanced during the cycle by progesterone. A report on women with partial temporal lobe epilepsy (TLE) indicated that 35.3% had anovulatory cycles when observed for 3 consecutive months. The incidence in healthy women without epilepsy was only 8.3%.
While some studies have indicated that anovulatory cycles are associated with increased seizure frequency, others have not found a relationship. Other investigators studied women with epilepsy in whom steroid hormone levels were tested in 4 stages of the menstrual cycle. They found that seizure frequency is significantly greater at menstruation and is much greater for cycles in which the woman did not ovulate, compared to cycles in which the women did ovulate.
An inadequate luteal phase is a disorder characterized by decreased progesterone secretion in the second half of the cycle. Thus, the amount of estrogen exceeds that of progesterone at levels higher than normal when this condition is present, and seizure frequencies also tend to be higher.
Seizures and menopause
Little is known about the effects of menopause on epilepsy. As early as 1907, Turner observed that menopause did not generally affect seizures, but in some cases seizures ceased, while another study described seizure exacerbation at during menopause. Given that menopause is a process occurring over many months and is experienced differently among individuals, assessment of seizure frequency at any one time may reflect very different processes in different women. Anovulatory cycles associated with increased estrogen levels may develop early in menopause, while decreased estrogen production may occur later in menopause. Some other sex hormones, which are continually produced throughout menopause, may also be converted to estrogen and may thereby also affect seizure activity.
Seizure patterns and endocrine disorders in men
Men with epilepsy frequently complain of sexual dysfunction, especially impotence and loss of libido. The reported occurrence of hyposexuality and impotence in men with epilepsy ranges from 38% to 71%. In a study of 37 men with epilepsy who had been seizure-free for 5 years, impotence was diagnosed in 8 patients. Several investigators have reported increased occurrence of impotence and decreased libido in patients with active temporal lobe epilepsy (TLE). Others have not found a significant difference in sexual dysfunction between men with different types of epilepsy.
Stress and Seizures
Several studies indicate that seizures increase following times of stress, and that this effect is independent of the stage of menstrual cycle. Therefore, it may be unreasonable in the life of any woman with a disorder as potentially disruptive as epilepsy to expect to see seizures only in a certain phase of menstrual cycle. The factors contributing to seizure onset are likely more complex than fluctuations strictly associated with menstrual cycle. Hormonal change may be a common underlying element, but effects of stress on seizure activity can occur during any phase of menstrual cycle. Thus, when we look at definitions of catamenial epilepsy, it is important to remember that stress may cause a seizure at any point during the menstrual cycle.
Treatment Strategies
Detecting hormone-related fluctuations in seizure frequency
Schachter recommends evaluations of women with epilepsy should include menstrual changes, fertility and cyclical seizure exacerbation, preferably documented by daily recording of basal body temperature, onset of menses and seizure occurrence. These investigations, plus tests of hormone levels, may indicate neuroendocrine profiles which themselves require treatment, or point to an appropriate treatment strategy for seizure reduction.
Natural and Synthetic Hormone Therapies
Hormone therapies have been found to benefit some women. However, at this point in their development, they appear to be most appropriate for women who also have existing endocrine abnormalities, and for women who are not anticipating pregnancy and are taking adequate birth control precautions. Synthetic progestin therapy has been found to relieve some women with complex partial seizures, but it seems to work only in doses large enough to cause amenorrhea (complete lack of menstruation). Side effects include depression, sedation, hot flashes, breakthrough bleeding, and regular ovulatory cycles may take up to a year to return.
By contrast, natural progesterone does appear to be effective cyclically in some women. Suppositories were given to 8 women with temporal epileptiform discharges and seizure exacerbation either before or during menstruation, at midcycle or in the entire second half of the menstrual cycle. These women also had reproductive disorders (anovulatory cycles or inadequate luteal phase). Progesterone was given during the phase of menstrual cycle in which seizure frequency was highest. Of 8 women with hormone therapy, 6 had fewer seizures and none experienced an increase. Half of the women described tiredness and depression. The author admits that in this preliminary investigation, alterations in antiepileptic medications associated with the influx of progesterone could not be ruled out. While further investigation is necessary, this small study presents promising results indicating that natural progesterone therapy may be useful, particularly in women with existing endocrine dysfunctions.
Add-on AED therapy
Some researchers have investigated the possibility of adding extra anti-epileptic medication during the times of the cycle when seizures tend to increase. Add-on clobazam has been attempted in women whose seizures consistently occurred during a 10-day period prior to menstruation. Of 24 patients who received this therapy, 2 "defaulted", 2 withdrew because of adverse events, and 2 did not comply with the regimen. Of the remaining 18, 4 described sedation, 2 complained of mild depression and 2 "felt better" on clobazam. After 10 days on each treatment, 8 patients reported decreases in seizure frequency on clobazam compared to placebo.
As with other benzodiazepines, the risk of tolerance must always be addressed. The effectiveness of add-on AEDs in reducing seizure frequency associated with predictable cyclical increases in seizures is a matter for future research.
Research at Toronto Hospital - Western Division
A study investigating the relationship between hormones and seizures is ongoing at Toronto Hospital - Western Division, Epilepsy Clinic. Dr. Carlen (Director of the Epilepsy Clinic), Drs. McLusky and Edwards (University of Toronto) and I are carefully examining seizure diaries and hormone levels in women with intractable epilepsy in the clinic. We are comparing the relationship between hormone levels and seizure frequency during different phases of the menstrual cycle in women with regular and irregular menstrual cycles.
Our preliminary analysis of the diaries indicates that even in women with irregular cycles, whose seizure pattern does not appear to be catamenial by the current definitions, there may be hormonal influence on seizure occurrence.
Dr. Nancy Noldy-MacLean obtained her Ph.D. in psychology at the University of Ottawa and is currently a researcher for the Bloorview Epilepsy Research Program of the University of Toronto. Her research on women and hormones has been supported by donations through Epilepsy Ontario. She may be contacted at noldy@playfair.utoronto.ca
