Catamenial epilepsy refers to seizure exacerbation in relation to the menstrual cycle. In its purest form, a woman with catamenial epilepsy may have seizures only at the time of menstruation, but this form is not very common. More typically, the woman may tend to have more seizures at particular times during her menstrual cycle, usually just before or during the onset of menstruation or at the time of ovulation.
Patterns of catamenial epilepsy
Three patterns of catamenial seizure exacerbation may be observed:
The three patterns of catamenial exacerbation of epilepsy in relation to serum estradiol (E2) and progesterone (P) levels. C1 = perimenstrual; C2 = preovulatory; C3 = luteal phase.
- at the time of ovulation
- throughout the second half of the menstrual cycle
Seizure exacerbation around the time of menstruation or ovulation occurs in women with normal menstrual cycles.
Women with abnormal menstrual cycles may have exacerbation in the second half (luteal phase) of the cycle. This pattern is the most difficult one to distinguish because the time of seizure exacerbation is prolonged rather than focused. These women have anovulatory cycles and inadequate luteal phase syndrome. Because they do not ovulate, no corpus luteum (derived from the egg leaving the ovary) is formed during the second (luteal) half of the menstrual cycle and no progesterone is secreted.
Causes of catamenial epilepsy
Menstrually related hormonal fluctuations in estrogen and progesterone underlie the patterns of catamenial seizure exacerbation. Estrogens facilitate seizures, whereas progesterone protects against seizures. During the menstrual cycle, serum levels of estradiol and progesterone fluctuate.
Estrogens (in particular estradiol, the most important of the different estrogen forms) have potent proconvulsant properties. They exert an excitatory effect on neurons by stimulating the N-methyl-D-aspartate (NMDA)- type glutamate receptor. In women with epilepsy, intravenous administration of conjugated estrogens activates epileptiform discharges and may result in seizures.
Progesterone hyperpolarizes neurons, acting via one of its natural endogenous metabolites, allopregnanolone, as an agonist at the γ- aminobutyric acid (GABA)-a receptor with a potency almost a thousandfold greater than that of pentobarbital and greater than the most potent benzodiazepine, nitroflurazepam. In women with partial seizures, intravenous infusion of progesterone, resulting in luteal phase plasma levels, suppresses interictal epileptiform discharges.
In a normally menstruating woman, the surge of serum estrogen levels at the time of ovulation may be associated with increased seizure tendency; as may the fall in serum progesterone levels just before and during menstruation.
In a woman with an anovulatory cycle, estrogen levels rise at the end of the follicular phase and stay elevated throughout the luteal phase until premenstrually, as in normally menstruating women. Little or no progesterone is secreted, however, creating an estrogen:progesterone (E/P) imbalance with a relative excess of estrogen (or deficiency of progesterone) throughout the whole second (luteal) half of the menstrual cycle. Seizure exacerbation results.
A number of studies have suggested that both progesterone deficiency and estrogen excess relative to progesterone contribute to the catamenial pattern of seizure exacerbation in both normal women and in women with menstrual irregularities. The E/P ratio appears to determine the overall reproductive hormonal effect upon seizure frequency.
In addition, premenstrual exacerbation of seizures may also be related to a decline in anticonvulsant medication levels. In women with catamenial epilepsy, phenytoin levels decline premenstrually by up to one-third. This decline may be due to an increased rate of clearance at the beginning of menstruation, with an associated reduction in the half-life of phenytoin from 19 to 13 hours. Hepatic microsomal enzymes metabolize both gonadal steroids and anticonvulsants such as phenytoin, with competition between the two. The premenstrual decline in gonadal steroid secretion may therefore permit increased metabolism of AEDs, resulting in lower serum levels. It is not certain whether all AEDs are affected. Phenobarbital is not, and catamenial fluctuation in serum levels of other AEDs has not been studied.
The best way of establishing whether the patient's seizures tend to worsen at certain points of the menstrual cycle is to have her keep a careful seizure diary in relation to her menstrual cycle. Using the first day of menstrual bleeding as the first day of the cycle, the menstrual cycle is divided into four phases:
- menstrual, days -3 to +3
- follicular, days +4 to +9
- ovulatory, days +10 to +16
- luteal, days +17 to -4
The number of seizures in each phase is counted. The average daily number of seizures for each menstrual phase is then compared with the average daily number of seizures for the rest of the cycle to look for a pattern of exacerbation or remission at certain phases of the menstrual cycle. A useful definition of seizure exacerbation is a twofold or greater increase in average daily seizure frequency during the affected part of the cycle in comparison to the remainder of the cycle.
If a catamenial pattern of seizure exacerbation is established from this record, additional steps in the evaluation will help to guide treatment:
- Establish the menstrual pattern: normal or abnormal menstrual cycles.
- Check midluteal serum progesterone levels (for example, on day 22 of a 28-day menstrual cycle) to see whether the luteal phase is inadequate.
- If the woman has perimenstrual (type I) catamenial seizure exacerbation, check trough AED levels on day 22 (when estradiol and progesterone levels are high and the AED level should be "normal") and day 1 (when estradiol and progesterone levels are low). Low AED levels at this time (perhaps related to increased drug metabolism) could be the cause of perimenstrual seizure exacerbation.
Endocrine treatment of seizures may rationally be aimed at those endocrinologic aspects of seizures that act either to exacerbate or to ameliorate them. Because progesterone has anticonvulsant effects and estrogen has proconvulsant effects, treatment with progesterone or estrogen antagonists may prove to be useful adjunctive treatments in appropriate patients.
Low progesterone levels or rapid withdrawal of progesterone may be a factor in the increased seizure frequency seen during the premenstrual and early follicular phase of women with catamenial epilepsy and normal ovulatory cycles, and during the entire luteal phase of women with anovulatory cycles. Progesterone may be expected to be beneficial in these women.
Synthetic progestin therapy may be considered. Little or no benefit has been noted with oral forms in a number of studies although occasional benefits have been described in single case reports.
In one study of women with refractory partial seizures and normal ovulatory cycles, a medroxyprogesterone dose large enough to induce amenorrhea (120 to 150 mg every 6 to 12 weeks intramuscularly or 20 to 40 mg orally daily) resulted in a 40% average seizure reduction. Weekly doses of 400 mg of intramuscular depo medroxyprogesterone may be more effective.
Potential side effects include depression, sedation, and breakthrough vaginal bleeding. The use of depo medroxyprogesterone also may delay the return of regular menstrual cycles.
Natural progesterone may be a more effective treatment. In a study of 25 women with catamenial exacerbation of complex partial seizures of temporal lobe origin, 72% of the women improved. The average decline in seizure frequency was 55%. Of the 25 women in the study, 14 had anovulatory cycles or an inadequate luteal phase. These women took progesterone lozenges (200 mg tid) on days 15 through 25 of each menstrual cycle, with taper over days 26 through 28. The 11 women with normal cycles and perimenstrual seizure exacerbation took the same type and dose of progesterone on days 23 through 25 of each menstrual cycle.
The natural and synthetic progestins are not equivalent because natural progesterone is metabolized to allopregnanolone, which has very potent GABA-a mimetic and anticonvulsant action, whereas synthetic progestins are not metabolized in this way.
Potential side effects of progesterone treatment may include:
- weight gain
- breast tenderness
- breakthrough vaginal bleeding
All of these effects are readily reversed if the hormone is stopped or the dose is lowered.
If low AED levels are found during certain phases of the woman's menstrual cycle, it may be helpful to increase the dose slightly around that time, or in some cases to add a low dose of another AED, such as a benzodiazepine.
Adapted from Klein P and Herzog AG. Endocrine aspects of partial seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 207-232. With permission from Elsevier (www.elsevier.com).