Both female patients with epilepsy and their treating physicians have observed a tendency for seizures to cluster in relationship to the menstrual cycle during the reproductive years. This phenomen has been the source of much investigation in humans with epilepsy and in animal studies. It has been attributed to the neuroactive properties of sex steroid hormones and the cyclic variation of their serum levels. Results of animal studies of the effects of 17beta-estradiol (estradiol) and progesterone are compelling. Estradiol has been shown to increase seizure activity, while progesterone has been shown to have anticonvulosant properties [20
]. Many cellular and molecular mechanisms have been identified contributing to the changes in brain excitability mediated by these hormones.
In animal studies, estrogen is generally proconvulsant [70
]. Estradiol can create new cortical seizure foci when applied topically, activate preexisting cortical foci, increase the severity of pentylenetetrazol-induced seizures, lower the electroshock seizure threshold, and increase the number of dendritic spines and excitatory synapses on hippocampal CA1 pyramidal cells. Mechanisms are complex and likely include estrogen receptor-mediated effects, and action at glutamate and NMDA receptors. Progesterone, conversely, generally has an anticonvulsant effect [70
]. Animal studies demonstrate that progesterone (PROG) elevates the seizure threshold, suppresses kindling, and decreases interictal spikes caused by cortically-applied penicillin. Potential mechanisms include action at the progesterone receptor, but also through metabolism to GABAA
receptor modulating neuroactive steroids. Several studies suggest that allopregnanolone (ALLO) is the primary compound responsible for decreased seizure susceptibility when PROG is elevated and the anticonvulsant actions of PROG administration [79
]. Putative steroid binding sites have been described on the GABAA
Although many NAS can be synthesized in the brain from precursors such as PROG, experimental evidence demonstrates that blood levels correlate with seizure frequency and that administration of neuroactive steroids systemically can provoke or protect against seizures or the development of epilepsy }[72
Even natural fluctuations in sex steroid hormone levels during the menstrual cycle can affect not only epilepsy, but other neuropsychiatric symptoms including premenstrual syndrome, perimenstrual migraines, and dysphoria. Withdrawal from progesterone after chronic administration to rats via subcutaneous route results in increased seizure susceptibility [71
Androgens can also worsen seizures and some are felt to be proconvulsant in experimental models [76
], but given that major fluctuations do not occur except during puberty and gradually with aging, a regulatory role on seizure control is harder to demonstrate in men with epilepsy.
A) Catamenial Epilepsy during the Reproductive Years
In women with epilepsy during the reproductive years, a correlation has been observed between the cyclic monthly levels of estrogen and progesterone and seizure frequency [3
]. Catamenial epilepsy is the term applied when the pattern of seizure occurrence in a woman fluctuates with the menstrual cycle. The reported prevalence of a catamenial epilepsy among women varies due to differing definitions and few formal studies, with reports that it affects between 20–70% of women with epilepsy [15
]. Work by Herzog et al. has led to a more uniform acceptance of the definition of catamenial epilepsy as a two-fold increase in daily seizure frequency during specific phases of the menstrual cycle [30
Herzog et al. [40
] studied a cohort of 184 women with medically-refractory localization-related epilepsy and were able to define three distinct patterns of catamenial epilepsy based on statistical evaluation of seizure frequency in women during their reproductive years. The definitions are based on Day 1 as the first day of menstrual flow and ovulation is presumed to occur 14 days before the subsequent onset of menses (Day −14). Seizures and menses were charted and midluteal serum progesterone levels were obtained on day 22. Progesterone concentrations >5 ng/ml were considered ovulatory. Cycles were divided into four phases: menstrual (M) = −3 to +3, follicular (F) = 4 to 9, ovulatory (O) = 10 to −13, and luteal (L) = −12 to −4 (). Average daily seizure frequency for each phase was calculated and compared among phases, separately for ovulatory and anovulatory cycles. The seizures recorded during ovulatory cycles occurred with significantly greater average daily frequency during the menstrual and ovulatory phases than during the follicular and luteal phases, in patterns labeled perimenstrual (catamenial 1) and periovulatory (catamenial 2). For the anovulatory cycles, seizures occurred with lower frequency during the follicular phase than during all other phases, in a pattern labeled catamenial 3 by the authors (). The authors went on to plot of the percentage of women with greater seizure frequency according the three patterns of catamenial epilepsy and evaluated points of inflection of the S-shaped distribution curves for optimal distinction between women with high and low susceptibility to hormonal influence. Based on these findings, these authors proposed a twofold increase in average daily seizure frequency during these phases in one of the three patters for the designation of catamenial epilepsy. In their patient cohort, one-third of women showed at least one of the three patterns of catamenial epilepsy.
Schematic diagram of allopregnanolone and its neuroactive steroid binding site on the GABAA-BDZ receptor
A follow-up study by Herzog et al. [39
] in 87 women found that 39% of women enrolling in a progesterone treatment trial demonstrated a catamenial pattern. This study assessed 87 women over a few menstrual cycles rather than just one cycle. Catamenial epilepsy designation was made if two of three cycles showed at least one of the three catamenial patterns. Another study by El-Khayat et al [16
] of 42 Egyptian women with epilepsy (and 21 controls) evaluated the pattern of seizure occurrence and hormone levels. Additionally, pelvic ultrasound was performed near the time of ovulation. A catamenial pattern of seizures occurred in 31% of patients (53.8% C1 pattern; 46.15% C3 pattern). Patients with C3 pattern showed lower progesterone levels in the midluteal phase compared to patients with noncatamenial pattern, to those with C1 pattern or to controls. Patients with the C1 pattern had lower progesterone levels than controls in the menstrual phase. The patients with a catamenial pattern also had higher estradiol/progesterone ratios.
Although approximately one-third of women with localization-related epilepsy have a catamenial pattern, this cyclic pattern is often under-recognized or under-acknowledged by physicians treating women with epilepsy. Often the woman is the one to bring it up to her physician, but still too often her concerns are met by indifference or even doubt [58
]. Perhaps one of the reasons is the perceived lack of treatment options. No similarly rigorous studies have been performed in women with idiopathic generalized epilepsy, but would be more difficulty given that seizures are often more readily controlled. Patients will often report, however, that their rare seizures only occur during the perimenstrual phase.
B) Epilepsy during other Reproductive Life Stages
Alterations in seizure patterns can occur with other major hormonal shifts, such as during puberty, pregnancy, and perimenopause. Some epilepsy syndromes are first expressed or worsen during puberty [11
]. Perimenopause is marked by erratic and frequently high estrogen levels, while postmenopause is characterized by stable, low estrogen levels. A retrospective questionnaire study suggested that seizure frequency can increase with perimenopause and can improve once the menopausal transition is complete [28
]. This alteration in seizure pattern was more likely to occur in women who experienced a catamenial pattern during their reproductive years. In the postmenopausal group, hormone replacement therapy (HRT) was significantly associated with an increase in seizures.
The latter finding led to design and implementation of a multicenter, double-blind, randomized, placebo-controlled trial of the effects of two doses of Prempro (CEE/MPA) (0.625mg of conjugated equine estrogens, plus medroxyprogesterone acetate, 2.5 mg) on seizure control [25
]. Subjects received either placebo, single dose CEE/MPA, or double dose CEE/MPA. Twenty-one subjects were randomized after completing baseline. Five out of seven subjects (71%) on double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared to 4/8 (50%) on single dose CEE/MPA and 1/6 (17%) on placebo (p=0.05). Increasing CEE/MPA dose was also associated with an increase in the frequency of the subject s most severe seizure type (p=0.008) and of complex partial seizures (p=0.05). Despite the limited enrollment of this study, the conclusion could still be made that CEE/MPA was associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy.
This study in postmenopausal women with epilepsy was halted early due to findings from the Women’s Health Initiative (WHI) study: overall health risks after five years of follow-up clearly exceeded benefits from use of single dose CEE/MPA in healthy postmenopausal US women [77
]. Although the released findings from the WHI study has resulted in decreased long-term HRT use for preventive health measures, HRT is still frequently used as treatment for perimenopausal symptom relief. The findings from study by Harden, et al. [25
] raise caution even for the short-term use of CEE/MPA in women with epilepsy. However, synthetic progestins such as medroxyprogesterone acetate are not metabolized to the active neurosteroid allopregnanolone. Future studies of whether an estrogen with natural progesterone could circumvent the risk for increased seizures would be beneficial for women with epilepsy.