Figure 46.1. Three patterns of catamenial epilepsy: perimenstrual (C1) and periovulatory (C2) exacerbations during normal ovulatory cycles and entire second half of the cycle (C3) exacerbation during ILP cycles. F, follicular phase; L, luteal phase; M, menstruation; O, ovulation. (From Herzog AG. Catamenial epilepsy: definition, prevalence, pathophysiology and treatment. Seizure. 2008;17:151–159.)

A third pattern of catamenial seizures (C3) is seen in patients with inadequate luteal phase (ILP) cycles and occurs less frequently than the other two catamenial seizure patterns. Women with abnormal FSH secretion have decreased progesterone production secondary to poor development of the follicle and a poorly developed and functioning corpus luteum. This is known as ILP. Although ILP cycles can occasionally occur in normal women, they may also be caused by problems with the hypothalamic pituitary axis, ovarian defects, or defects in luteal cell steroidogenesis (30). ILP cycles have been shown to occur more in women with epilepsy than in healthy controls (31), which is likely related to dysfunction of inputs to the hypothalamus from ictal and interictal discharges. Estrogen levels are not affected, creating an increased estradiol/progesterone ratio and increased seizure occurrence from days 10 to 3 of the menstrual cycle (29). These findings are illustrated in Figure 46.1.

Effect of Menstrual Cyclic Antiepileptic Drug Levels on Seizure Occurrence

In addition to the pharmacodynamic effects of endogenous reproductive steroids on seizure occurrence, it has also been postulated that the pharmacokinetic effects of neurosteroids can alter the metabolism of AEDs. One study reported that phenytoin levels on day 28 in women with catamenial seizures were significantly lower than in women without cyclic exacerbations (32). However, it has also been shown in other studies that there is no relationship between neurosteroid levels and serum AED levels (32,33). In general, alterations in AED levels do not account for catamenial seizure exacerbations, while endogenous hormonal cycling has more influence.

Treatment of Catamenial Epilepsy

The first-line treatment for all patients with epilepsy is a first-line AED. However, adjunctive therapy with acetazolamide, benzodiazepines, and hormonal therapy may prove beneficial in managing patients with catamenial epilepsy. Most of the treatment interventions for women with catamenial epilepsy have been aimed at treating the premenstrual seizure exacerbations in women with regular menstrual periods (Fig. 46.2). Treatments are usually started during the second half of the menstrual cycle (days 14 to 26), starting treatment a prescribed number of days after menstrual bleeding.

Although never studied in randomized trials, acetazolamide has been used in the treatment of catamenial epilepsy for over 50 years. It must be used over short periods during the menstrual cycle, since tolerance can rapidly develop to its anticonvulsant properties. It has been shown to be most effective at doses of 250 to 500 mg daily from 3 to 7 days prior to menses until day 1 of the menstrual cycle (34,35).

Benzodiazepines have also been used in women with epilepsy, with clobazam being the only formally studied treatment for catamenial seizures. Clobazam, at 20 to 30 mg/day for 10 days, starting 2 to 4 days premenstrually has been shown to reduce seizure frequency as compared to placebo (36).

In addition to the medications above, it is also reasonable to temporarily increase the dose of the patient’s regular antiepileptic medication at specific times during the menstrual cycle. However, this should be avoided with phenytoin since there is a risk of toxicity associated with its nonlinear kinetics.

Since progesterone has mainly been shown to have anticonvulsant properties, it can be hypothesized that progesterone and its metabolites may be used in conjunction with current antiepileptic medications to treat women with catamenial epilepsy. Medroxyprogesterone acetate (MPA) is a synthetic progestin-only contraceptive agent that is administered every 10 to 12 weeks intramuscularly and stops the regular menstrual cycle. In patients with catamenial epilepsy, it has been shown to decrease seizure frequency by 39% at 1-year follow-up (37). However, this agent has been shown to have adverse side effects of slow return to normal fertility and increased risk of osteoporosis. Therefore, it should be considered only if catamenial exacerbations are severe and intractable to other interventions.

Although natural progesterone is not yet approved for use in the treatment of seizures, it is clear that natural progesterone could play an important role in the treatment of women with catamenial epilepsy. A small open-label study with long-term follow-up of women with catamenial seizures taking progesterone lozenges showed a significant reduction in seizure frequency when progesterone was taken during the exacerbation phase of the cycle (38). A recent randomized, double-blind, placebo-controlled multicenter clinical trial concluded that when all patients with catamenial epilepsy were grouped together, there was no overall benefit of natural progesterone as compared to placebo (39). However, further analysis showed that progesterone was much more effective in women with at least three times or greater increase in seizure frequency during the perimenstrual phase (3 days prior to menses to 3 days after onset of menses) as compared to other days in the month (39). The degree of perimenstrual seizure exacerbation was found to be a significant predictor of response to progesterone treatment when progesterone was given as 200 mg oral lozenges twice daily on days 14 to 28, with possible taper days 26 to 28 (39). A proposed treatment algorithm of patients with seizure clustering during the perimenstrual phase is shown in Figure 46.2.

ORAL CONTRACEPTIVE AGENTS IN WOMEN WITH EPILEPSY

Oral contraceptive pills have been found in case reports to decrease seizure frequency but have not yet been systemically studied. They are, however, often used in women with epilepsy to prevent unwanted high-risk pregnancies. When these agents are used, it must be noted that they are inducers of the P450 system and may decrease the effectiveness of AEDs, which are hepatically metabolized. Furthermore, a noninducing AED should be used in combination with oral contraceptive pills when possible, to prevent increased metabolism and decreased efficacy of the contraceptive agent.

SEXUAL DYSFUNCTION AND REPRODUCTIVE HEALTH IN EPILEPSY

Sexual Dysfunction

It is important to take a detailed sexual history in all patients with a history of epilepsy. It has been shown that patients with epilepsy have a higher incidence of sexual dysfunction, mainly manifested by decreased sexual desire and potency, as compared to patients with other neurologic diseases (40). As previously discussed, there are AEDs that interact with endogenous hormones, and seizures have the ability to alter the hypothalamic–pituitary–gonadal axis. These findings, in combination with living with a perceived stigma (41) and the adverse influences of depressed mood and poor self-esteem (42), create a multifactorial etiology for sexual dysfunction in patients with epilepsy.

It is also important for the physician to bring up the topic of sexual dysfunction, since the frequency with which sexual complaints are volunteered is largely dependent on the attitude of the physician (43). When discussing sexual dysfunction, social factors, mood, hormone levels, and the effect of AEDs must all be assessed. The patient’s somatic, psychological, and social well-being, as well as the dynamics of the couple and family, must all be explored (43). It must also be remembered that the sexual dysfunction may not always be secondary to epilepsy, and a full medical workup is often required as well. In addition to a complete physical and neurologic examination, patients with sexual dysfunction should undergo laboratory evaluation looking at the following serum levels: testosterone, sex hormone–binding globulin, FSH, LH, prolactin, hemoglobin A1C, and TSH. If a clear cause of sexual dysfunction cannot be elicited, urologic or gynecologic consultation may be necessary.

Vaginal dryness and dyspareunia may be treated with over-the-counter moisturizing and lubrication products in addition to prolongation of foreplay. Phosphodiesterase inhibitors have been used in men to treat erectile dysfunction but have no effect on libido or sexual desire, which are controlled mainly by testosterone. A combination of testosterone and an aromatase inhibitor may hypothetically be beneficial in treating men with epilepsy having sexual dysfunction by increasing free serum testosterone levels and decreasing serum estradiol levels. Aromatase inhibitors in men with epilepsy have been shown to increase testosterone levels and possibly decrease seizure frequency, increase mood, and improve sexual functioning, but this combination needs to be further studies before making any definite judgments about their role in clinical practice (44,45).

Birth Rates

Population-based studies have shown that both men and women with epilepsy have lower birth rates than the general population and that adults with active epilepsy have lower birth rates in comparison to those who no longer have seizures after childhood (46,47). Decreased birth rates may be in part secondary psychosocial factors affecting patients with epilepsy such as choosing not to enter into romantic relationships or deciding not to have children. Additionally, patients with epilepsy have been shown to have decreased fertility, defined as the absence of contraception after 1 year of unprotected intercourse.

Fertility in Men with Epilepsy

Abnormal spermatogenesis may be a cause of infertility in men with epilepsy. A study of 60 men with epilepsy and 41 controls found the frequency of morphologically abnormal sperm to be significantly higher among men treated with carbamazepine, oxcarbazepine, and valproate compared the control group. Poor sperm motility was found in men taking valproate or carbamazepine, and the frequency of abnormally low sperm concentration was highest in men taking carbamazepine (22). Men treated with phenytoin have also been found to have morphologically abnormal sperm in addition to lower seminal volume, spermatozoa concentration, and total sperm count (48). However, temporal lobe epilepsy itself has also been documented to cause testicular failure independent of AED use (49). These findings indicate that both seizures and AEDs have effects on the hypothalamic–pituitary–gonadal axis in men that can impair fertility.

Fertility in Women with Epilepsy

Disturbances in the hypothalamic–pituitary–gonadal axis secondary to seizures or AEDs make women with epilepsy more likely to have early perimenopause and menopause, increased rates of anovulatory cycles, and a frequent occurrence of PCOS all of which are associated with decreased fertility (50,51). PCOS is defined as the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders (52). It is currently thought that PCOS is multigenic in etiology and susceptible to a variety of environmental triggers, which are as of yet unclear (53). Secondary to likely hypothalamic and pituitary dysregulation, there is elevated LH secretion and an increased ratio of LH to FSH, with produces polycystic follicles that are premature and deficient in aromatase, leading to increased serum androgen levels. The androgen is converted to estrogen by aromatase in the periphery, which feeds back to the pituitary to dysregulate normal LH secretion (54).

In addition to the effect of seizures on the hypothalamic–pituitary–gonadal axis creating an increased risk for PCOS, it has also been shown that patients on valproate are at increased risk for the symptoms associated with PCOS (55). A recent study of women with epilepsy found that the incidence of PCOS was twice that of the general population (56). Taking valproate and younger age of seizure onset were risk factors for getting PCOS. Taking these findings into account, physicians must assess for abnormal menstrual cycles, hirsutism, acne, male pattern balding, and weight gain at each visit in women with epilepsy. Women with an early age of seizure onset, and women on valproate, should have a higher index of suspicion. If PCOS features are present, patients should be referred to an endocrinologist, gynecologist, or both for further evaluation and possible treatment. In addition, it is reasonable to consider alternative agents if valproate is part of the AED regimen.

Women with epilepsy, in addition to an increased occurrence of PCOS, also are at risk of early perimenopause and menopause, often in the late fourth decade or early fifth decade of life. A negative correlation has been reported between the age at menopause and seizure frequency, with women having frequent seizures experiencing earlier menopause (51). As in PCOS, the mechanism for this finding is likely related to hypothalamic–pituitary–gonadal axis dysfunction producing dysregulation of maturation of ovarian follicles, which leads to early loss of follicles available for ovulation.

Perimenopause and Menopause

No prospective information exists on the course of epilepsy as women progress through the transition to menopause. However, a cross-sectional study evaluated the effect of menopause and perimenopause on the course of epilepsy (57). The perimenopausal group consisted of 39 women with a history of epilepsy. Nearly two-thirds of the women reported an increase in seizure frequency during perimenopause, with those women having a history of catamenial epilepsy more likely to have increased seizures. The increase in seizure frequency during perimenopause is likely secondary to the elevation of the estrogen/progesterone ratio during this period. Evaluation of the postmenopausal women with epilepsy showed no overall direction change in seizure frequency (57). However, a history of catamenial epilepsy was significantly associated with a decrease in seizures after menopause.

Hormone Replacement Therapy

In the cross-sectional study listed above, postmenopausal was found to have an increase in seizure frequency after starting hormone replacement therapy (HRT), which usually consisted of an estrogen in combination with a synthetic progestin (57). These results prompted further investigation in the form of a double-blind, randomized, placebo-controlled trial using three study groups: women taking single-dose combination HRT (0.625 mg of conjugated equine estrogens [CEEs] plus 2.5 mg of MPA, or CEE/MPA) daily, double-dose CEE/MPA, or placebo (58). Increased seizure frequency was associated with increasing the CEE/MPA dose, suggesting that this regimen should not be used in postmenopausal women with epilepsy. Perhaps a regimen combining natural progesterone with estrogen may be alternatively considered in women requiring HRT.

BONE HEALTH IN EPILEPSY

Both men and women with epilepsy have an increased propensity to fractures due to medication side effects (e.g., ataxia and dizziness), coexisting neurologic deficits (e.g., cerebral palsy), and seizure-related falls (59

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