Drugs Aging DOI 10.1007/s40266-014-0201-5
CURRENT OPINION
Epilepsy and Menopause: Potential Implications for Pharmacotherapy Olafur Sveinsson • Torbjo¨rn Tomson
Springer International Publishing Switzerland 2014
Abstract Being a woman with epilepsy is not the same as being a man with the disease. There is a complex multidirectional interaction between sex hormones, seizures and antiepileptic drugs (AEDs) with gender-specific implications. Estrogen can be a potent proconvulsant, whereas progesterone is an anticonvulsant in experimental models. It is well established that women with epilepsy can have changes in seizure propensity related to their menstrual cycle (catamenial epilepsy). There is good evidence that the gonadotropin-releasing hormone cell population in the hypothalamus can be affected by seizures originating in the limbic system, possibly leading to anovulatory menses, possibly contributing to lower fertility, and earlier menopause among women with epilepsy. Data on the effects of menopause on epilepsy are scarce. In general, menopause appears to have limited effects on seizure control, with the possible exception of women with catamenial epilepsy who may experience an increase in seizure frequency during perimenopause and a decrease after menopause. Hormone replacement therapy has the potential to increase seizure frequency and thus cannot be recommended for women with epilepsy. Of particular relevance for menopause is the adverse effect on bone mineral density caused by enzyme inducers and other AEDs. In general, there is a remarkable shortage of studies on the impact of menopause on epilepsy and on its implications for epilepsy treatment.
O. Sveinsson T. Tomson Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden T. Tomson (&) Department of Neurology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden e-mail: [email protected]
Key Points There is a complex multidirectional interaction between sex hormones, seizures and antiepileptic drugs with gender-specific implications Estrogen can be a potent proconvulsant, whereas progesterone is an anticonvulsant in experimental models Menopause appears to have limited impact on seizure frequency
1 Introduction Epilepsy is characterized by recurrent unprovoked epileptic seizures of different types and causes. It is a major public health problem worldwide and at least 50 million people are thought to be affected, with particularly high prevalence and incidence among the elderly [1, 2]. Being a woman with epilepsy is different from being a man with the disease [3]. Regions of the limbic cortex, particularly the amygdala, have extensive reciprocal connections with the hypothalamus and can modulate the hypothalamicpituitarygonadal axis [4], and the gonadotropin-releasing hormone (GnRH) cell population in the hypothalamus can be affected by seizures [5]. Hence, disrupted release of pituitary hormones is seen in women with epilepsy and has been suggested to cause earlier menopause and anovulatory menses, and contribute to lower fertility [6]. Additionally, sex hormones may have an effect on epilepsy. Sex hormone receptors are abundant in the limbic system and regions of the limbic cortex [4]. Estrogen can be a potent
O. Sveinsson, T. Tomson
proconvulsant, whereas progesterone is an anticonvulsant in experimental models [7–9]. Given this potential of sex hormones, it is not surprising that women with epilepsy can have changes in the seizure threshold related to their menstrual cycle (catamenial epilepsy), and it is also reasonable to consider that alterations can occur perimenopausally and after menopause, which will be discussed in the following review. Furthermore, some antiepileptic drugs (AEDs) can affect the hormonal system. Many of the AEDs are enzyme inducers (carbamazepine, oxcarbazepine, eslicarbazepine acetate, phenobarbital, phenytoin, primidone, felbamate, rufinamide, and topiramate) and can cause a lowering of sex hormones. On the other hand, valproic acid is an enzyme inhibitor and can increase testosterone. Adding to the complexity, the metabolism of some AEDs, in particular lamotrigine, is influenced by synthetic estrogen (increases glucuronidation of lamotrigine). Given these multiple interactions between sex hormones, epilepsy and AEDs, it is reasonable to consider the possibility of an effect of menopause on epilepsy and its treatment. In this article we will review the evidence for an impact of menopause and perimenopause on epilepsy and in what ways this might affect the management of women with epilepsy, particularly in terms of pharmacotherapy.
2 The Hormonal Influence on Epilepsy For some women with epilepsy, seizures appear to occur in a fixed relation to the phases of their menstrual cycle (catamenial epilepsy), with an increase in frequency just before or during menses being the most common pattern [10, 11]. Seizures thus tend to occur during the phase of the cycle when estradiol levels are at their peak [12]. Small open-label clinical trials suggest that progestogens might reduce seizure frequency in women with catamenial epilepsy [13, 14]. Progesterone is converted in the brain to allopregnanolone, which has been suggested as being responsible for decreased seizure susceptibility [15]. However, a well-controlled, randomized study failed to demonstrate improved seizure control with adjunctive progesterone therapy in women with epilepsy [16]. Moreover, a post hoc secondary analysis of the data suggested that progesterone might be useful for a subset of women with prominent perimenstrual seizure exacerbation.
3 Impact of Epilepsy on Menopause Menopause is defined as the permanent cessation of menses resulting from loss of ovarian follicular function [17]. The defining event for natural menopause is the final menstrual period, but strictly speaking it can be identified only
retrospectively after a 12-month period of amenorrhea. In the general population, the average age at menopause is 51 years, with a range of approximately 42–58 years. Ovarian estrogen production begins to decline 1 or 2 years before the final menstrual period and reaches a low stable value about 2 years after menopause. With menopause, estradiol and progesterone are no longer synthesized by the ovaries, and menstruation ceases. Levels of follicularstimulating hormone are increased. Otherwise, there are no specific hormonal or biochemical markers of menopause [18]. The term ‘menopausal transition’ refers to the time before menopause when menstrual cycles begin to show variation in cycle length, and the perimenopause encompasses the menopausal transition plus the first 12 months after the final menstrual period [17]. Women with epilepsy have a tendency to enter perimenopause, and subsequently menopause, earlier (by about 2–3 years) [19]. Menopause occurs about 3 years earlier for women with frequent seizures compared with women with infrequent seizures [19– 21]. The reasons for this are not entirely clear but may be caused by disruption of hypothalamic and pituitary function by the seizures.
4 Effect of Menopause/Perimenopause on Epilepsy and Seizure Control Unfortunately there are little data about the impact of perimenopause, menopause and postmenopause on the different types of epilepsy. From a physiological point of view, one could expect that under perimenopause the epilepsy might destabilize due to decreased progesterone secretion by the ovaries and high and variable secretion of estrogen until late perimenopause [22]. Sleep disturbance is also common during the climacteric period and could affect seizure control. As stated above, there are a few studies on the effect of perimenopause and menopause on epilepsy. Most are retrospective based on questionnaires with a low response rate, or telephone interviews, which are all marked by limitations [23–25]. These studies do not have statistical power to analyze a number of confounding factors, such as age, body mass index, type of menopause (surgical, premature, natural), type of epilepsy, types and doses of AEDs or hormone replacement therapy (HRT) [25]. In one postal survey of perimenopausal and postmenopausal women with epilepsy, 13 of 42 respondents linked menopause to increased seizure frequency, and 17 of 42 reported that frequency had decreased [23]. The small number of participants makes interpretation difficult. Interestingly, women reporting decreased seizure frequency in this study also reported a catamenial pattern to
Epilepsy and Menopause
their seizures prior to menopause. Notably, 10 of 16 HRT users, but only 3 of 26 non-users, reported increased seizure frequency. In another survey, the reported seizure frequency was compared between 61 perimenopausal or postmenopausal women and 46 premenopausal women. No difference was found between the groups [24]. Hence, there does not seem to be much difference in seizure frequency before and after menopause for women with epilepsy, with the possible exception of women with catamenial epilepsy who may experience an increase in seizure frequency during perimenopause and a decrease after menopause, in accordance with the fluctuating, sometimes high, estrogen levels during perimenopause, contrary to low estrogen levels during postmenopause [23].
5 Effect of Menopause on the Kinetics of Antiepileptic Drugs (AEDs) Not only are the data on the effect of menopause on the kinetics of AEDs very limited but it is also conflicting. In a retrospective analysis of data from a Swedish therapeutic drug monitoring database [26], the dose/plasma concentration (D/C) ratios of carbamazepine were very similar among men and women in all age groups under study. In contrast, lamotrigine D/C ratios seemed to decline in women 51–55 years of age, being significantly lower among women than among men. This suggested that there may be a decline in clearance of lamotrigine in conjunction with presumed menopause. Interestingly, a small Dutch study showed the opposite [27]. A non-significant trend towards higher mean lamotrigine clearance was noted in postmenopausal women (n = 7) compared with premenopausal women (n = 7). A subsequent larger retrospective study from the same Dutch group, based on data from a therapeutic monitoring database, found no effect of perimenopausal age on lamotrigine or oxcarbazepine clearance [28].
6 Effect of Hormone Replacement Therapy on Epilepsy and the Kinetics of AEDs A small, randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy has been conducted [29]. Women taking stable doses of AEDs within 10 years of their last menses were randomized to placebo, 0.625 mg of conjugated equine estrogens (CEE) plus 2.5 mg of medroxyprogesterone acetate (MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period. Five (71 %) of seven subjects taking the higher CEE/MPA dose had an increased frequency of at least one seizure type
compared with four (50 %) of eight taking the lower CEE/ MPA dose and one (17 %) of six taking placebo. Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25–30 % while taking CEE/MPA. Therefore, it was concluded that CEE/MPA was associated with a doserelated increase in seizure frequency in postmenopausal women with epilepsy and, furthermore, that CEE/MPA may decrease lamotrigine levels [29]. Although this particular study has some limitations, such as the small number of women with epilepsy in each treatment arm, short-term use of HRT, and one particular type of HRT, it is the first and only study in this field. Another concern is that the progesterone used in this study (MPA) is not metabolized to the active neurosteroid allopregnanolone, which is thought to have anticonvulsant properties [16]. However, given these data, one can hardly recommend HRT in the abovementioned combination, for women with epilepsy. It remains to be investigated if another regimen, such as natural progesterone, should be considered. If HRT is considered, one needs to take into account the possible interaction between enzyme-inducing AEDs (see above) and the prescribed hormones so that dose adjustment of the HRT might be needed.
7 Impact of Menopause on AED-Related Adverse Effects Bone health is of special relevance for women, particularly after menopause. Multiple studies have found a two- to sixfold increased risk of fractures in persons with epilepsy treated with AEDs [30]. Case-control studies have shown that the risk of fractures is higher among women with epilepsy compared with men [31]. Women with epilepsy have an increased risk of fracture secondary to decreased bone mineral density (BMD), altered bone quality, and a propensity to fall because of either seizures or side effects of medication. This has mostly been linked to the use of enzyme-inducing AEDs [31]. The main mechanism postulated to explain these changes is accelerated metabolism of vitamin D secondary to enzyme induction. However, similar observations have been made in patients treated with the non enzyme-inducing AED valproic acid [31]. However, results are somewhat conflicting regarding valproic acid. A number of studies have not shown a negative effect of valproic acid on bone health [32, 33]. BMD and other markers of bone health have been analyzed in epilepsy patients receiving different AEDs in cross-sectional studies. One such study reported less adverse effects of lamotrigine compared with phenytoin but the results were difficult to interpret since treatment duration was much longer with phenytoin. In a prospective study of young women followed up for only 1 year, those treated with
O. Sveinsson, T. Tomson
phenytoin developed femoral neck bone loss, whereas those treated with carbamazepine, lamotrigine and valproic acid did not show detectable alterations [34]. Again, longitudinal studies are much needed and further data in relation to use of the newer generation AEDs are necessary. In postmenopausal women with prolonged exposure to AEDs commonly associated with abnormalities in bone (particularly phenytoin), BMD screening should be performed, particularly if other risk factors are present. It is recommended that all persons obtain adequate amounts of calcium and vitamin D. In support of this, a randomized, double-blind trial study of epilepsy patients comparing low-dose (400 IU/day) and high-dose (4000 IU/day) vitamin D supplementation showed increases in BMD at all skeletal sites, in those receiving high-dose but not low-dose vitamin D [35]. Bisphosphonates are known to increase BMD and reduce the risk of fracture but are not routinely recommended in premenopausal women, particularly as the teratogenic potential is unknown. However, in postmenopausal women with epilepsy and low BMD, they can be considered. In postmenopausal women with epilepsy, reduced BMD, and other risk factors for fractures, enzymeinducing AEDs are probably best avoided when possible and other AEDs devoid of such properties are to be preferred, such as lamotrigine.
8 Implications for Treatment of Epilepsy Wherever possible, one should probably avoid enzymeinducing AEDs in postmenopausal women with other risk factors for osteopenia and fractures. It seems as though perimenopause or menopause has no significant effect on the disposition of AEDs in general, although a minor effect on lamotrigine cannot be excluded. It also seems that women with a history of catamenial epilepsy risk deterioration in seizure control in the pre- and perimenopausal period, which might warrant closer monitoring during this period of life.
9 Implications for the Treatment and Management of Menopause Systemic HRT can hardly be recommended for women with epilepsy due to the risk of increased seizure frequency, at least not CEE plus medroxyprogesterone. Particular caution is called for if the woman is receiving treatment with lamotrigine (estrogen lowers the concentration of lamotrigine). Meta-analyses have shown that low-dose, local estrogen therapy is just as effective as systemic therapy for symptoms of vaginal atrophy [36], and unlikely to affect the epilepsy or
AEDs, and this route of administration is therefore preferred in women with epilepsy. For women with difficult-to-treat postmenopausal symptoms, a combination of a single estrogenic compound such as 17-b-estradiol along with natural progesterone can be considered [37].
10 Conclusions and Recommendations Data on the effects of menopause on epilepsy and the therapeutic implications of this phase of life for women with epilepsy are scarce. There is an obvious need for more research in order to facilitate a rational management of epilepsy for the many women of this age who suffer from epilepsy. The following conclusions and recommendations are thus not based on high-level evidence. •
• • •
The effects from perimenopause on epilepsy is difficult to predict but likely to be insignificant in the majority of cases. Increased vigilance might be justified for women with a history of catamenial epilepsy. Under perimenopause, consider checking serum levels of AEDs, particularly lamotrigine. Generally speaking, oral HRT can, at present, not be recommended for women with epilepsy, but for women with difficult-to-treat postmenopausal symptoms a combination of a single estrogenic compound such as 17-b-estradiol along with natural progesterone can be considered.
Acknowledgments Torbjo¨rn Tomson has received grants from Stockholm County Council, AFA Insurance, CURE, GSK, Eisai, UCB, Sanofi-Aventis, Novartis, Bial. He has received speaker’s or consultancy fees from Eisai, GSK, UCB, and Sun Pharma. Olafur Sveinsson has no conflicts of interest to declare. No funding was received for the preparation of this article.
References 1. World Health Organisation. Epilepsy. http://www.who.int/topics/ epilepsy. Accessed 13 Dec 2013. 2. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34(3):453–68. 3. Taubøll E, Luef G. Gender issues in epilepsy—the science of why it is special. Seizure. 2008;17:99–100. 4. Harden CL, Pennell PB. Neuroendocrine considerations in the treatment of men and women with epilepsy. Lancet Neurol. 2013;12(1):72–83. 5. Friedman MN, Geula C, Holmes GL, Herzog AG. GnRHimmunoreactive fiber changes with unilateral amygdala-kindled seizures. Epilepsy Res. 2002;52:73–7. 6. Quigg M, Kiely JM, Johnson ML, et al. Interictal and postictal circadian and ultradian luteinizing hormone secretion in men with temporal lobe epilepsy. Epilepsia. 2006;47:1452–9.
Epilepsy and Menopause 7. Luef G. Female issues in epilepsy: a critical review. Epilepsy Behav. 2009;15:78–82. 8. Cramer JA, Gordon J, Schachter S, et al. Women with epilepsy: hormonal issues from menarche through menopause. Epilepsy Behav. 2007;11:160–78. 9. Frye CA. Hormonal influences on seizures: basic neurobiology. Int Rev Neurobiol. 2008;83:27–77. 10. Logothetis J, Harner R, Morrell F, et al. The role of estrogens in catamenial exacerbation of epilepsy. Neurology. 1959;9:352–60. 11. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia. 1997;38:1082–8. 12. Terasawa E, Timiras PS. Electrical activity during the estrous cycle of the rat: cyclic changes in limbic structures. Endocrinology. 1968;83:207–16. 13. Mattson RH, Cramer JA, Caldwell BV, et al. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology. 1984;34:1255–8. 14. Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology. 1997;52:1917–8. 15. Scharfman HE, MacLusky NJ. The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female. Epilepsia. 2006;47:1423–30. 16. Herzog AG, Fowler KM, Smithson SD, et al. Progesterone vs placebo therapy for women with epilepsy: a randomized clinical trial. Neurology. 2012;78:1959–66. 17. North American Menopause Society. Menopause Core Curriculum Study Guide. 2nd ed. Cleveland: North American Menopause Society; 2002. 18. Soules MR, Sherman S, Parrott E, et al. Executive summary: stages of reproductive aging workshop (STRAW). Fertil Steril. 2001;76:874–8. 19. Harden CL, Koppel BS, Herzog AG, et al. Seizure frequency is associated with age at menopause in women with epilepsy. Neurology. 2003;61:451–5. 20. McAuley JW, Koshy SJ, Moore JL, et al. Characterization and health risk assessment of postmenopausal women with epilepsy. Epilepsy Behav. 2000;1:353–5. 21. Klein P, Serje A, Pezzulo JC. Premature ovarian failure in women with epilepsy. Epilepsia. 2001;42:1584–9. 22. Burger HG, Dudley EC, Robertson DM, et al. Hormonal changes in the menopause transition. Recent Prog Horm Res. 2002;57:257–75.
23. Harden CL, Pulver MC, Ravdin L, et al. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. 1999;40:1402–7. 24. Abbasi F, Krumholz A, Kittner SJ, et al. Effects of menopause on seizures in women with epilepsy. Epilepsia. 1999;40:205–10. 25. McAuley JW, Sapna SJ, Moore JL, et al. Characterization and health risk assessment of postmenopausal women with epilepsy. Epilepsy Behav. 2000;1(353–355):23. 26. Tomson T, Lukic S, Ohman I. Are lamotrigine kinetics altered in menopause? Observations from a drug monitoring database. Epilepsy Behav. 2010;19:86–8. 27. Wegner I, Edelbroek PM, Bulk S, et al. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology. 2009;73:1388–93. 28. Wegner I, Wilhelm AJ, Sander JW, et al. The impact of age on lamotrigine and oxcarbazepine kinetics: a historical cohort study. Epilepsy Behav. 2013;29:217–21. 29. Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, doubleblind, placebo-controlled study. Epilepsia. 2006;47:1447–51. 30. Mattson RH, Gidal BE. Fractures, epilepsy, and antiepileptic drugs. Epilepsy Behav. 2004;5(Suppl. 2):S36–40. 31. Pack A. Bone health in people with epilepsy: is it impaired and what are the risk factors? Seizure. 2008;17(2):181–6. 32. Zare M, Ghazvini MR, Dashti M, et al. Bone turnover markers in epileptic patients under chronic valproate therapy. J Res Med Sci. 2013;18:338–40. 33. Jette´ N, Lix LM, Metge CJ, et al. Association of antiepileptic drugs with nontraumatic fractures: a population-based analysis. Arch Neurol. 2011;68:107–12. 34. Pack AM, Morrell MJ, Randall A, et al. Bone health in young women with epilepsy after 1 year of antiepileptic drug monotherapy. Neurology. 2008;70(18):1586–93. 35. Mikati MA, Dib L, Yamout B, et al. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: impact on bone. Neurology. 2006;67(11):2005–14. 36. Cardozo L, Bachmann G, McClish D, et al. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1998;92:722–7. 37. Erel T, Guralp O. Epilepsy and menopause. Arch Gynecol Obstet. 2011;283(4):755–9.
CURRENT OPINION
Epilepsy and Menopause: Potential Implications for Pharmacotherapy Olafur Sveinsson • Torbjo¨rn Tomson
Springer International Publishing Switzerland 2014
Abstract Being a woman with epilepsy is not the same as being a man with the disease. There is a complex multidirectional interaction between sex hormones, seizures and antiepileptic drugs (AEDs) with gender-specific implications. Estrogen can be a potent proconvulsant, whereas progesterone is an anticonvulsant in experimental models. It is well established that women with epilepsy can have changes in seizure propensity related to their menstrual cycle (catamenial epilepsy). There is good evidence that the gonadotropin-releasing hormone cell population in the hypothalamus can be affected by seizures originating in the limbic system, possibly leading to anovulatory menses, possibly contributing to lower fertility, and earlier menopause among women with epilepsy. Data on the effects of menopause on epilepsy are scarce. In general, menopause appears to have limited effects on seizure control, with the possible exception of women with catamenial epilepsy who may experience an increase in seizure frequency during perimenopause and a decrease after menopause. Hormone replacement therapy has the potential to increase seizure frequency and thus cannot be recommended for women with epilepsy. Of particular relevance for menopause is the adverse effect on bone mineral density caused by enzyme inducers and other AEDs. In general, there is a remarkable shortage of studies on the impact of menopause on epilepsy and on its implications for epilepsy treatment.
O. Sveinsson T. Tomson Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden T. Tomson (&) Department of Neurology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden e-mail: [email protected]
Key Points There is a complex multidirectional interaction between sex hormones, seizures and antiepileptic drugs with gender-specific implications Estrogen can be a potent proconvulsant, whereas progesterone is an anticonvulsant in experimental models Menopause appears to have limited impact on seizure frequency
1 Introduction Epilepsy is characterized by recurrent unprovoked epileptic seizures of different types and causes. It is a major public health problem worldwide and at least 50 million people are thought to be affected, with particularly high prevalence and incidence among the elderly [1, 2]. Being a woman with epilepsy is different from being a man with the disease [3]. Regions of the limbic cortex, particularly the amygdala, have extensive reciprocal connections with the hypothalamus and can modulate the hypothalamicpituitarygonadal axis [4], and the gonadotropin-releasing hormone (GnRH) cell population in the hypothalamus can be affected by seizures [5]. Hence, disrupted release of pituitary hormones is seen in women with epilepsy and has been suggested to cause earlier menopause and anovulatory menses, and contribute to lower fertility [6]. Additionally, sex hormones may have an effect on epilepsy. Sex hormone receptors are abundant in the limbic system and regions of the limbic cortex [4]. Estrogen can be a potent
O. Sveinsson, T. Tomson
proconvulsant, whereas progesterone is an anticonvulsant in experimental models [7–9]. Given this potential of sex hormones, it is not surprising that women with epilepsy can have changes in the seizure threshold related to their menstrual cycle (catamenial epilepsy), and it is also reasonable to consider that alterations can occur perimenopausally and after menopause, which will be discussed in the following review. Furthermore, some antiepileptic drugs (AEDs) can affect the hormonal system. Many of the AEDs are enzyme inducers (carbamazepine, oxcarbazepine, eslicarbazepine acetate, phenobarbital, phenytoin, primidone, felbamate, rufinamide, and topiramate) and can cause a lowering of sex hormones. On the other hand, valproic acid is an enzyme inhibitor and can increase testosterone. Adding to the complexity, the metabolism of some AEDs, in particular lamotrigine, is influenced by synthetic estrogen (increases glucuronidation of lamotrigine). Given these multiple interactions between sex hormones, epilepsy and AEDs, it is reasonable to consider the possibility of an effect of menopause on epilepsy and its treatment. In this article we will review the evidence for an impact of menopause and perimenopause on epilepsy and in what ways this might affect the management of women with epilepsy, particularly in terms of pharmacotherapy.
2 The Hormonal Influence on Epilepsy For some women with epilepsy, seizures appear to occur in a fixed relation to the phases of their menstrual cycle (catamenial epilepsy), with an increase in frequency just before or during menses being the most common pattern [10, 11]. Seizures thus tend to occur during the phase of the cycle when estradiol levels are at their peak [12]. Small open-label clinical trials suggest that progestogens might reduce seizure frequency in women with catamenial epilepsy [13, 14]. Progesterone is converted in the brain to allopregnanolone, which has been suggested as being responsible for decreased seizure susceptibility [15]. However, a well-controlled, randomized study failed to demonstrate improved seizure control with adjunctive progesterone therapy in women with epilepsy [16]. Moreover, a post hoc secondary analysis of the data suggested that progesterone might be useful for a subset of women with prominent perimenstrual seizure exacerbation.
3 Impact of Epilepsy on Menopause Menopause is defined as the permanent cessation of menses resulting from loss of ovarian follicular function [17]. The defining event for natural menopause is the final menstrual period, but strictly speaking it can be identified only
retrospectively after a 12-month period of amenorrhea. In the general population, the average age at menopause is 51 years, with a range of approximately 42–58 years. Ovarian estrogen production begins to decline 1 or 2 years before the final menstrual period and reaches a low stable value about 2 years after menopause. With menopause, estradiol and progesterone are no longer synthesized by the ovaries, and menstruation ceases. Levels of follicularstimulating hormone are increased. Otherwise, there are no specific hormonal or biochemical markers of menopause [18]. The term ‘menopausal transition’ refers to the time before menopause when menstrual cycles begin to show variation in cycle length, and the perimenopause encompasses the menopausal transition plus the first 12 months after the final menstrual period [17]. Women with epilepsy have a tendency to enter perimenopause, and subsequently menopause, earlier (by about 2–3 years) [19]. Menopause occurs about 3 years earlier for women with frequent seizures compared with women with infrequent seizures [19– 21]. The reasons for this are not entirely clear but may be caused by disruption of hypothalamic and pituitary function by the seizures.
4 Effect of Menopause/Perimenopause on Epilepsy and Seizure Control Unfortunately there are little data about the impact of perimenopause, menopause and postmenopause on the different types of epilepsy. From a physiological point of view, one could expect that under perimenopause the epilepsy might destabilize due to decreased progesterone secretion by the ovaries and high and variable secretion of estrogen until late perimenopause [22]. Sleep disturbance is also common during the climacteric period and could affect seizure control. As stated above, there are a few studies on the effect of perimenopause and menopause on epilepsy. Most are retrospective based on questionnaires with a low response rate, or telephone interviews, which are all marked by limitations [23–25]. These studies do not have statistical power to analyze a number of confounding factors, such as age, body mass index, type of menopause (surgical, premature, natural), type of epilepsy, types and doses of AEDs or hormone replacement therapy (HRT) [25]. In one postal survey of perimenopausal and postmenopausal women with epilepsy, 13 of 42 respondents linked menopause to increased seizure frequency, and 17 of 42 reported that frequency had decreased [23]. The small number of participants makes interpretation difficult. Interestingly, women reporting decreased seizure frequency in this study also reported a catamenial pattern to
Epilepsy and Menopause
their seizures prior to menopause. Notably, 10 of 16 HRT users, but only 3 of 26 non-users, reported increased seizure frequency. In another survey, the reported seizure frequency was compared between 61 perimenopausal or postmenopausal women and 46 premenopausal women. No difference was found between the groups [24]. Hence, there does not seem to be much difference in seizure frequency before and after menopause for women with epilepsy, with the possible exception of women with catamenial epilepsy who may experience an increase in seizure frequency during perimenopause and a decrease after menopause, in accordance with the fluctuating, sometimes high, estrogen levels during perimenopause, contrary to low estrogen levels during postmenopause [23].
5 Effect of Menopause on the Kinetics of Antiepileptic Drugs (AEDs) Not only are the data on the effect of menopause on the kinetics of AEDs very limited but it is also conflicting. In a retrospective analysis of data from a Swedish therapeutic drug monitoring database [26], the dose/plasma concentration (D/C) ratios of carbamazepine were very similar among men and women in all age groups under study. In contrast, lamotrigine D/C ratios seemed to decline in women 51–55 years of age, being significantly lower among women than among men. This suggested that there may be a decline in clearance of lamotrigine in conjunction with presumed menopause. Interestingly, a small Dutch study showed the opposite [27]. A non-significant trend towards higher mean lamotrigine clearance was noted in postmenopausal women (n = 7) compared with premenopausal women (n = 7). A subsequent larger retrospective study from the same Dutch group, based on data from a therapeutic monitoring database, found no effect of perimenopausal age on lamotrigine or oxcarbazepine clearance [28].
6 Effect of Hormone Replacement Therapy on Epilepsy and the Kinetics of AEDs A small, randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy has been conducted [29]. Women taking stable doses of AEDs within 10 years of their last menses were randomized to placebo, 0.625 mg of conjugated equine estrogens (CEE) plus 2.5 mg of medroxyprogesterone acetate (MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period. Five (71 %) of seven subjects taking the higher CEE/MPA dose had an increased frequency of at least one seizure type
compared with four (50 %) of eight taking the lower CEE/ MPA dose and one (17 %) of six taking placebo. Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25–30 % while taking CEE/MPA. Therefore, it was concluded that CEE/MPA was associated with a doserelated increase in seizure frequency in postmenopausal women with epilepsy and, furthermore, that CEE/MPA may decrease lamotrigine levels [29]. Although this particular study has some limitations, such as the small number of women with epilepsy in each treatment arm, short-term use of HRT, and one particular type of HRT, it is the first and only study in this field. Another concern is that the progesterone used in this study (MPA) is not metabolized to the active neurosteroid allopregnanolone, which is thought to have anticonvulsant properties [16]. However, given these data, one can hardly recommend HRT in the abovementioned combination, for women with epilepsy. It remains to be investigated if another regimen, such as natural progesterone, should be considered. If HRT is considered, one needs to take into account the possible interaction between enzyme-inducing AEDs (see above) and the prescribed hormones so that dose adjustment of the HRT might be needed.
7 Impact of Menopause on AED-Related Adverse Effects Bone health is of special relevance for women, particularly after menopause. Multiple studies have found a two- to sixfold increased risk of fractures in persons with epilepsy treated with AEDs [30]. Case-control studies have shown that the risk of fractures is higher among women with epilepsy compared with men [31]. Women with epilepsy have an increased risk of fracture secondary to decreased bone mineral density (BMD), altered bone quality, and a propensity to fall because of either seizures or side effects of medication. This has mostly been linked to the use of enzyme-inducing AEDs [31]. The main mechanism postulated to explain these changes is accelerated metabolism of vitamin D secondary to enzyme induction. However, similar observations have been made in patients treated with the non enzyme-inducing AED valproic acid [31]. However, results are somewhat conflicting regarding valproic acid. A number of studies have not shown a negative effect of valproic acid on bone health [32, 33]. BMD and other markers of bone health have been analyzed in epilepsy patients receiving different AEDs in cross-sectional studies. One such study reported less adverse effects of lamotrigine compared with phenytoin but the results were difficult to interpret since treatment duration was much longer with phenytoin. In a prospective study of young women followed up for only 1 year, those treated with
O. Sveinsson, T. Tomson
phenytoin developed femoral neck bone loss, whereas those treated with carbamazepine, lamotrigine and valproic acid did not show detectable alterations [34]. Again, longitudinal studies are much needed and further data in relation to use of the newer generation AEDs are necessary. In postmenopausal women with prolonged exposure to AEDs commonly associated with abnormalities in bone (particularly phenytoin), BMD screening should be performed, particularly if other risk factors are present. It is recommended that all persons obtain adequate amounts of calcium and vitamin D. In support of this, a randomized, double-blind trial study of epilepsy patients comparing low-dose (400 IU/day) and high-dose (4000 IU/day) vitamin D supplementation showed increases in BMD at all skeletal sites, in those receiving high-dose but not low-dose vitamin D [35]. Bisphosphonates are known to increase BMD and reduce the risk of fracture but are not routinely recommended in premenopausal women, particularly as the teratogenic potential is unknown. However, in postmenopausal women with epilepsy and low BMD, they can be considered. In postmenopausal women with epilepsy, reduced BMD, and other risk factors for fractures, enzymeinducing AEDs are probably best avoided when possible and other AEDs devoid of such properties are to be preferred, such as lamotrigine.
8 Implications for Treatment of Epilepsy Wherever possible, one should probably avoid enzymeinducing AEDs in postmenopausal women with other risk factors for osteopenia and fractures. It seems as though perimenopause or menopause has no significant effect on the disposition of AEDs in general, although a minor effect on lamotrigine cannot be excluded. It also seems that women with a history of catamenial epilepsy risk deterioration in seizure control in the pre- and perimenopausal period, which might warrant closer monitoring during this period of life.
9 Implications for the Treatment and Management of Menopause Systemic HRT can hardly be recommended for women with epilepsy due to the risk of increased seizure frequency, at least not CEE plus medroxyprogesterone. Particular caution is called for if the woman is receiving treatment with lamotrigine (estrogen lowers the concentration of lamotrigine). Meta-analyses have shown that low-dose, local estrogen therapy is just as effective as systemic therapy for symptoms of vaginal atrophy [36], and unlikely to affect the epilepsy or
AEDs, and this route of administration is therefore preferred in women with epilepsy. For women with difficult-to-treat postmenopausal symptoms, a combination of a single estrogenic compound such as 17-b-estradiol along with natural progesterone can be considered [37].
10 Conclusions and Recommendations Data on the effects of menopause on epilepsy and the therapeutic implications of this phase of life for women with epilepsy are scarce. There is an obvious need for more research in order to facilitate a rational management of epilepsy for the many women of this age who suffer from epilepsy. The following conclusions and recommendations are thus not based on high-level evidence. •
• • •
The effects from perimenopause on epilepsy is difficult to predict but likely to be insignificant in the majority of cases. Increased vigilance might be justified for women with a history of catamenial epilepsy. Under perimenopause, consider checking serum levels of AEDs, particularly lamotrigine. Generally speaking, oral HRT can, at present, not be recommended for women with epilepsy, but for women with difficult-to-treat postmenopausal symptoms a combination of a single estrogenic compound such as 17-b-estradiol along with natural progesterone can be considered.
Acknowledgments Torbjo¨rn Tomson has received grants from Stockholm County Council, AFA Insurance, CURE, GSK, Eisai, UCB, Sanofi-Aventis, Novartis, Bial. He has received speaker’s or consultancy fees from Eisai, GSK, UCB, and Sun Pharma. Olafur Sveinsson has no conflicts of interest to declare. No funding was received for the preparation of this article.
References 1. World Health Organisation. Epilepsy. http://www.who.int/topics/ epilepsy. Accessed 13 Dec 2013. 2. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34(3):453–68. 3. Taubøll E, Luef G. Gender issues in epilepsy—the science of why it is special. Seizure. 2008;17:99–100. 4. Harden CL, Pennell PB. Neuroendocrine considerations in the treatment of men and women with epilepsy. Lancet Neurol. 2013;12(1):72–83. 5. Friedman MN, Geula C, Holmes GL, Herzog AG. GnRHimmunoreactive fiber changes with unilateral amygdala-kindled seizures. Epilepsy Res. 2002;52:73–7. 6. Quigg M, Kiely JM, Johnson ML, et al. Interictal and postictal circadian and ultradian luteinizing hormone secretion in men with temporal lobe epilepsy. Epilepsia. 2006;47:1452–9.
Epilepsy and Menopause 7. Luef G. Female issues in epilepsy: a critical review. Epilepsy Behav. 2009;15:78–82. 8. Cramer JA, Gordon J, Schachter S, et al. Women with epilepsy: hormonal issues from menarche through menopause. Epilepsy Behav. 2007;11:160–78. 9. Frye CA. Hormonal influences on seizures: basic neurobiology. Int Rev Neurobiol. 2008;83:27–77. 10. Logothetis J, Harner R, Morrell F, et al. The role of estrogens in catamenial exacerbation of epilepsy. Neurology. 1959;9:352–60. 11. Herzog AG, Klein P, Ransil BJ. Three patterns of catamenial epilepsy. Epilepsia. 1997;38:1082–8. 12. Terasawa E, Timiras PS. Electrical activity during the estrous cycle of the rat: cyclic changes in limbic structures. Endocrinology. 1968;83:207–16. 13. Mattson RH, Cramer JA, Caldwell BV, et al. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology. 1984;34:1255–8. 14. Herzog AG. Progesterone therapy in women with epilepsy: a 3-year follow-up. Neurology. 1997;52:1917–8. 15. Scharfman HE, MacLusky NJ. The influence of gonadal hormones on neuronal excitability, seizures, and epilepsy in the female. Epilepsia. 2006;47:1423–30. 16. Herzog AG, Fowler KM, Smithson SD, et al. Progesterone vs placebo therapy for women with epilepsy: a randomized clinical trial. Neurology. 2012;78:1959–66. 17. North American Menopause Society. Menopause Core Curriculum Study Guide. 2nd ed. Cleveland: North American Menopause Society; 2002. 18. Soules MR, Sherman S, Parrott E, et al. Executive summary: stages of reproductive aging workshop (STRAW). Fertil Steril. 2001;76:874–8. 19. Harden CL, Koppel BS, Herzog AG, et al. Seizure frequency is associated with age at menopause in women with epilepsy. Neurology. 2003;61:451–5. 20. McAuley JW, Koshy SJ, Moore JL, et al. Characterization and health risk assessment of postmenopausal women with epilepsy. Epilepsy Behav. 2000;1:353–5. 21. Klein P, Serje A, Pezzulo JC. Premature ovarian failure in women with epilepsy. Epilepsia. 2001;42:1584–9. 22. Burger HG, Dudley EC, Robertson DM, et al. Hormonal changes in the menopause transition. Recent Prog Horm Res. 2002;57:257–75.
23. Harden CL, Pulver MC, Ravdin L, et al. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia. 1999;40:1402–7. 24. Abbasi F, Krumholz A, Kittner SJ, et al. Effects of menopause on seizures in women with epilepsy. Epilepsia. 1999;40:205–10. 25. McAuley JW, Sapna SJ, Moore JL, et al. Characterization and health risk assessment of postmenopausal women with epilepsy. Epilepsy Behav. 2000;1(353–355):23. 26. Tomson T, Lukic S, Ohman I. Are lamotrigine kinetics altered in menopause? Observations from a drug monitoring database. Epilepsy Behav. 2010;19:86–8. 27. Wegner I, Edelbroek PM, Bulk S, et al. Lamotrigine kinetics within the menstrual cycle, after menopause, and with oral contraceptives. Neurology. 2009;73:1388–93. 28. Wegner I, Wilhelm AJ, Sander JW, et al. The impact of age on lamotrigine and oxcarbazepine kinetics: a historical cohort study. Epilepsy Behav. 2013;29:217–21. 29. Harden CL, Herzog AG, Nikolov BG, et al. Hormone replacement therapy in women with epilepsy: a randomized, doubleblind, placebo-controlled study. Epilepsia. 2006;47:1447–51. 30. Mattson RH, Gidal BE. Fractures, epilepsy, and antiepileptic drugs. Epilepsy Behav. 2004;5(Suppl. 2):S36–40. 31. Pack A. Bone health in people with epilepsy: is it impaired and what are the risk factors? Seizure. 2008;17(2):181–6. 32. Zare M, Ghazvini MR, Dashti M, et al. Bone turnover markers in epileptic patients under chronic valproate therapy. J Res Med Sci. 2013;18:338–40. 33. Jette´ N, Lix LM, Metge CJ, et al. Association of antiepileptic drugs with nontraumatic fractures: a population-based analysis. Arch Neurol. 2011;68:107–12. 34. Pack AM, Morrell MJ, Randall A, et al. Bone health in young women with epilepsy after 1 year of antiepileptic drug monotherapy. Neurology. 2008;70(18):1586–93. 35. Mikati MA, Dib L, Yamout B, et al. Two randomized vitamin D trials in ambulatory patients on anticonvulsants: impact on bone. Neurology. 2006;67(11):2005–14. 36. Cardozo L, Bachmann G, McClish D, et al. Meta-analysis of estrogen therapy in the management of urogenital atrophy in postmenopausal women: second report of the Hormones and Urogenital Therapy Committee. Obstet Gynecol. 1998;92:722–7. 37. Erel T, Guralp O. Epilepsy and menopause. Arch Gynecol Obstet. 2011;283(4):755–9.
