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Epilepsy in women
 

Epilepsy in women

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  • Epilepsy is the most common serious neurological condition and is no longer considered to be benign. In the UK it affects more than 300,000 people, with an overall incidence of about 5–10 cases per 1000 persons and a lifetime prevalence of between 2–5% of the population.Premature death is 2–3 times higher in people with epilepsy, and 1000 die each year as a direct result of their seizures. Sudden unexpected death in epilepsy (SUDEP) is the principle cause of death, and seizure control is key to minimizing this risk. Women of childbearing years account for 25% of all people with epilepsy and most of these women will require long-term treatment with antiepileptic drugs (AEDs). It is estimated that 3-4 pregnancies in every 1000 occur to women with epilepsy: in the UK alone, around 1800-2400 infants are born every year to women with epilepsy.Reassuringly, once the diagnosis has been made, some 70-80% of patients will have their seizures well controlled with one of the increasing number of AEDs available.If we think about the goals in treating women with epilepsy, we can develop an algorithm, with the first node, or the first decision point, being: which medication is going to be most likely to protect my patient from seizures? But, given that, there are special concerns if that patient is a child or an adolescent. If it is a reproductive-age woman, we are particularly concerned about maintaining normal physiology -- maintaining metabolic and endocrine health -- leading to normal fertility and normal sexual drive. We want to avoid unplanned pregnancies, by ensuring that our choice of contraception is going to be effective. We also want, in the woman planning to become pregnant, to ensure that her pregnancy outcome is successful. For all women and men with epilepsy, we want to ensure that this brain disorder is not accompanied by depression or other affective disorders, and that the individual is able to think clearly and maintain optimal intellectual functioning. Finally, I would suggest -- again at all ages and for women, as well as men -- that maintaining normal bone health is essential and an area where we have data suggesting that this patient population may be at risk.Protection from seizureHealthy childhood and adolescenceAvoidance of excessive weight gainHealthy reproductive and sexual lifeEffective use of contraceptivesHealthy and successful pregnancyAvoidance of mood disturbanceNo impairment of cognitive functionMaintain bone health
  • Many of our antiepileptic drugs have effects on metabolism that lead to disturbances in reproductive and metabolic health. They do so by altering levels of physiologic steroid hormones; this can affect fertility. They also can affect lipid and carbohydrate metabolism; the end effect of that may be glucose intolerance and obesity, as well as lipid metabolism disturbances. These medications also may affect bone mineral metabolism by multiple mechanisms, including calcium and vitamin D homeostasis, and alter the metabolism of the bone cells themselves.First, let me suggest that the choice of antiepileptic drugs should consider these effects on the body because we want to find the medication that is most likely to achieve effectiveness the first go-around. Second, I am going to show you data supporting this statement.Some AEDs Alter Steroid Hormone MetabolismFirst, some antiepileptic drugs affect the metabolism of the ovarian sex steroid hormones -- the estrogens, and the progesterones, as well as the androgens, all produced by the ovary. Data from our own group, as well as others, show that the effect of these medications is related to their impact on cytochrome P450 enzymes, or the liver mixed-function oxidase enzymes. We can classify these medications as the inducers; carbamazepine and phenytoin are the most commonly used enzyme inducers and the best studied. The antiepileptic drug that inhibits cytochrome P450 enzymes is represented by valproate. The best-studied medications that have no effect on these enzymes are lamotrigine and gabapentin. There is a great deal of data now showing that women who are taking the inducing antiepileptic drugs have reductions in sex steroid hormones, both the estrogens and androgens. This is not only an effect on the metabolism of these sex steroid hormones, but on the binding because these enzymeinducers increase the levels of sex hormone-binding globulin, which binds to these sex steroid hormones and renders them biologically inactive.Is this relevant to the woman with epilepsy? There are suggestions from our own group that women who have disorders of sexual desire or sexual arousal are those with reductions in androgens and estrogens, those women who are on these enzyme inducers. Similar data have been presented by Herzog showing the same phenomenon with men; that is, that use of these inducers associated with reductions in androgens is associated with erectile dysfunction and reductions in libido in men.Valproate, as an enzyme inhibitor, is associated with elevations in androgens. Dr. Strauss at the University of Pennsylvania has recently shown that valproate induces synthesis of androgens from ovarian thecal cells; so, there is an effect both on synthesis and on metabolism that acts to increase androgen levels. We will speak about what the implications of elevated androgens might be for the woman with epilepsy. In our own study, looking at women with epilepsy receiving lamotrigine and gabapentin, we found no difference between these women and nonepileptic, medically normal controls in any of the parameters of sex steroid hormone levels. So, we must recognize that, based on the antiepileptic drug we are selecting, we may be altering physiologic concentrations of hormones. This may have clinical consequences.Clinical Implications of Weight GainIs this benign? I think that weight gain in the 50% in whom this develops is not benign. It leads to a number of consequences; one of them is noncompliance with medication. It also leads to longer-term health effects, including elevations in insulin and glucose intolerance. Again, those women who gain weight on valproate are those women who show elevations in fasting and postprandial insulin almost immediately after starting valproate therapy. This can lead to, not only immediate problems with glucose intolerance, but longer term, with diabetes. There also may be psychologic effects associated with the weight gain, and also sleep disturbances, including sleep apnea. The changes in lipid metabolism may predispose to cardiovascular disease. Obesity also is associated with increased risk of certain gynecological malignancies, including endometrial and breast cancer.
  • Many women report cyclic exacerbations of seizures, and patients with childhood-onset epilepsy may note that seizures that occurred sporadically before menarche become somewhat more predictable after puberty. Reviews have identified 25% of women had their first seizure in association with menarche.[5 ] Certain genetically determined epilepsies (ie, Juvinile Absence E and JuvinileMyoclonic E) will present around puberty, while some nongenetic partial epilepsies may worsen causing them to come to medical attention at this time. Childhood absence[6 ]and benign rolandic epilepsy[7 ]may remit at puberty. Other researchers have noted that if epilepsy presents within the year after menarche, it is common for seizures to maintain variability with cyclic hormone changes.[8 ]  At menarche, pituitary gonadotropins (FSH and LH) and ovarian steroids (estrogen and progesterone) increase in overall concentration. Although epilepsy may be expressed at this time in part due to this increase in estrogen, cyclic increases in estrogen relative to progesterone appear as a likely trigger for breakthrough seizures.[9 ]Different seizure types may be exacerbated by different hormonal patterns of exacerbation. For example, partial seizures more commonly worsen in the follicular phase, whereas absence seizures more likely increase in the luteal phase.[
  • Signs and Symptoms of Reproductive Health DysfunctionWhat do we do as clinicians? We must stop being complacent about weight gain. A woman who demonstrates weight gain when we begin an antiepileptic drug or any woman whose BMI is more than 25 requires some type of therapeutic intervention. We also must be more concerned about hirsutism; which means we must ask about facial hair, which will likely have been cosmetically removed; and we must ask about pubic hair distribution. We have to look over the scalp. We have to have our patients keep menstrual diaries. If her cycle is shorter than 23 days or longer than 35 days, then she falls more than 2 standard deviations outside the mean for a normal cycle; her cycle is almost overwhelmingly likely to be anovulatory. Anovulatory cycles often are characterized by midcycle menstrual spotting. Finally, ask about interest in sexual activities and the ability to have a normal sexual arousal response. In your patients who have these problems, it may be worth asking whether this could be associated with reductions in sex steroid hormones, as a consequence of their antiepileptic drug. I would suggest that these aspects of reproductive health are very important considerations when thinking about which antiepileptic drug to select.
  • Catamenial epilepsy Catamenial epilepsy is a general term applied to any exacerbation in seizures with the menstrual cycle. True catamenial epilepsy requires reproducible and consistent increase or change in character of seizures at the same point in a regular menstrual cycle. Anovulatory cycles can make the relationship of seizure to hormones difficult to discern.Perceived rates of catamenial epilepsy tend to be much higher than true catamenial epilepsy. Although 10-75% of women have noted a cyclic variation in seizure frequency, it was not reported whether this occurred during regular, ovulatory cycles, or was confirmed by physiologic hormonal level changes.[9 ]The breadth of the reported range itself indicates that seizure exacerbations are influenced by multiple factors, rather than exclusively hormonal changes. The physiologic processes of menstruation and ovulation can transiently worsen many medical conditions, and it is likely that, for some women, physical effects that are only secondarily related to hormones will increase seizures. Nonetheless, between one third and one half of women report increased cyclic seizures related primarily to hormonal factors.[11 ]  Three patterns of hormonally based catamenial epilepsy have been described.[12 ]Significantly higher numbers of seizures were found when estrogen increased faster than progesterone: perimenstrually (catamenial type 1), and preovulatory (catamenial type 2). In patients with anovulatory cycles, seizures more commonly occurred in the second half of the cycle (catamenial type 3) when progesterone was lower than normal due to failure to develop a corpus luteum. Management of patients with catamenial exacerbations must begin with a clear definition of the clinical situation. An accurate diagnosis of epilepsy is necessary, and may indicate a need for video-EEG monitoring. Paroxysmal events mimicking epilepsy (ie, nonepileptic events, or "pseudoseizures") may also worsen at cyclic intervals. Clear identification of ovulation at regular intervals is helpful in determining whether there is any specific higher risk time in the menstrual cycle. A scrupulously maintained calendar listing seizures and menses for several cycles can suggest a cyclic pattern of seizures. This can be confirmed by physiologic measures including basal body temperature and serum hormone levels. Other factors that may contribute to poor seizure control such as sleep deprivation, suboptimal medication for epilepsy type, and simple noncompliance must be eliminated, if possible. Optimization of AED dosing is often helpful and increasing doses each cycle for the duration of time of expected exacerbation may be the best tolerated option. Some AEDs, however, are poorly suited to this strategy, particularly if they exhibit nonlinear pharmacokinetics or extensive enzyme induction. Temporary use of adjunctive therapy such as acetazolamide or benzodiazepines has anecdotally been advocated, but with no prospective supportive evidence. Management strategies using exogenous hormones have not been consistently successful. If improved control is incidentally noted with hormonal contraceptives, and pregnancy is not desired, then longer-acting contraceptive agents, such as Depo-Provera, may be helpful in seizure control. Persistent menstrual irregularity or other suggestions of spontaneous anovulatory cycles warrants evaluation by an endocrinologist. Some researchers have had limited success with progesterone to control true catamenial epilepsy. Continuous progestational supplements reduced catamenial seizures as they suppressed cycles,[13 ]and intermittent progesterone suppositories reduced seizures up to 60%, but half of these discontinued treatment due to intolerable side effects.[14 ]Adverse effects of synthetic and, to a lesser degree, natural progesterones include sedation, breast tenderness, depression, increased appetite and weight, and breakthrough menstrual bleeding. In addition, unopposed progesterone has been implicated in breast cancer, lipid elevations, and hypercoagulability.[15 ]Synthesized novel neurosteroids devoid of hormonal side effects (eg, ganaxolone) have proven promising but have prohibitive production costs.[16 ]Overall, natural progesterones are better tolerated than synthetic agents, but no evidence substantiates efficacy of one over the other. Further evidence is needed before any hormonal agent can be recommended for epilepsy management.
  • Effects of Commonly Used AEDs on WeightAnother effect of these antiepileptic drugs is on metabolism. The most obvious clinical manifestation of changes in metabolism is weight. Here we have classified the antiepileptic drugs as those that are associated with weight gain, those that are weight neutral, and those that are associated with weight loss. They are not all equivalent. Valproate is the medication that we most often think about when we think about weight gain on an antiepileptic drug; this may affect up to 50% of women receiving this medication. Conversely, 50% of women do not gain weight. We will discuss the difference between those who have a disturbance in carbohydrate metabolism and those who do not. We see more modest weight gains with carbamazepine and with gabapentin. Lamatrogine, levetiracetam, and oxcarbazepine have been shown to be weight neutral in the pre- and postmarketing trials. Topiramate is the antiepileptic drug that we recognize as most often associated with weight loss. Depending on the study,this has been reported in anywhere between half and three quarters of the women receiving this medication and in men as well. Zonisamide is associated with weight loss. Clinically we recognize this, although the numbers are not firm as to how often this affects our patients.
  • Potential Mechanisms for AED Induced Change in WeightIt should not be surprising that the antiepileptic drugs are associated with changes in weight, based on our understanding of the metabolic underpinnings of weight. We can appreciate that the antiepileptic drugs affect many of the systems that control appetite and metabolism. Appetite is very much mediated by GABA, the inhibitory neurotransmitter, and also by serotonin -- both neurochemicals that we recognize are very much affected by essentially all of our antiepileptic drugs. Weight is also affected by lipids. Some of our antiepileptic drugs, particularly valproate, alter lipid metabolism -- valproate doing so probably because it is a fatty acid. We recognize that some of the antiepileptic drugs, especially valproate and topiramate, alter insulin concentrations. Thyroid hormone may be affected or reduced by some of our antiepileptic drugs. Leptin, a compound or neurochemical very much associated with regulation of appetite and metabolism, also is altered by some of ourantiepileptic drugs.
  • Clinical Implications of Weight GainIs this benign? I think that weight gain in the 50% in whom this develops is not benign. It leads to a number of consequences; one of them is noncompliance with medication. It also leads to longer-term health effects, including elevations in insulin and glucose intolerance. Again, those women who gain weight on valproate are those women who show elevations in fasting and postprandial insulin almost immediately after starting valproate therapy. This can lead to, not only immediate problems with glucose intolerance, but longer term, with diabetes. There also may be psychologic effects associated with the weight gain, and also sleep disturbances, including sleep apnea. The changes in lipid metabolism may predispose to cardiovascular disease. Obesity also is associated with increased risk of certain gynecological malignancies, including endometrial and breast cancer.
  • Polycystic ovary syndrome Polycystic ovary syndrome (PCOS) and polycystic ovaries (PCOs) have received much attention in the epilepsy literature. Polycystic ovary morphology has been found by ultrasonography in 20-30% of healthy premenopausal women.[25 ] In contrast, using National Institutes of Health (NIH) diagnostic criteria (ovulatory dysfunction, clinical manifestation of hyperandrogenism, exclusion of other endocrinopathies), the cumulative prevalence of PCOS is only 6.6%.[26 ]Long-term effects of PCOS include infertility, insulin resistance, obesity, dyslipidemia, hirsutism, and increased risk for endometrial cancer. PCOS may have similar cardiovascular risks of metabolic syndrome, since the 2 disorders are both associated with abdominal obesity, insulin resistance, and dyslipidemia. PCOS has been found to be more prevalent in women with epilepsy than in the general population.[27 ] PCOs were found in 41% of women with idiopathic generalized epilepsy, and 26% of women with localization-related epilepsy.[28 ]Because this seizure type has often been treated with valproate, whether this medication or the seizure type (or perhaps a combined effect) is the critical trigger for development of PCO is controversial. Treatment of PCOS includes the antiestrogenic agent clomiphene, which is also used as a fertility-enhancing agent. Use if this agent in PCOS patients with epilepsy has been anecdotally reported to be associated with a reduction in seizures, but no evidence supports this agent as a primary antiepileptic agent.[29 ] A retrospective series found multiple cysts by ultrasonography on the ovaries of 43% of women taking valproate for epilepsy,[30 ]adding to the ongoing controversy of the relative contributions of valproate, weight gain, and epilepsy itself to the development of PCOS. Harden's extensive review of this literature concluded PCOS has multiple etiologies, but because valproate is often a confounding variable, "it seems prudent that clinicians educate themselves on the prevalence of PCOS in epilepsy before recommending the use of valproate, or any AED to female patients."[31 ]For related information, see eMedicine article Polycystic Ovarian Syndrome.Polycystic Ovary Syndrome (PCOS)One phenomenon that we are concerned may be over-represented in women with epilepsy is a syndrome called polycystic ovary syndrome (PCOS). This is a gynecologic syndrome that affects approximately 10% of reproductive-aged women. It is misnamed, because polycystic ovaries are not required. The syndrome presents as a specific phenotype, the most prevalent feature being elevated androgen sensitivity or increased androgens leading to a picture of hyperandrogenism.Antiepileptic drugs may be associated with a predilection for this syndrome. These data, that Betts published last year, show that 30% of women receiving valproate had PCOS. In his study, he included women on lamotrigine or carbamazepine and found that there was no difference in the prevalence of this syndrome in these women compared to healthy controls. Not all investigators have found this; other investigators have found that the risk of PCOS for women with epilepsy on other antiepileptic drugs may be as high as 20%. But, all studies have found that receiving valproate predisposes to, or is more often associated with, this syndrome.Effect of AEDS and OCs on PCOSOf interest is the ability of oral contraceptives to treat this syndrome. Reproductive endocrinologists and gynecologists treat the syndrome with oral contraceptives, particularly those with antiandrogenic properties. For women with this syndrome who are on antiepileptic drugs, this phenomenon holds true: the prevalence of PCOS drops with treatment with oral contraceptives for women receiving valproate to 20%. We see the same lower rate of PCOS -- at least in Betts' study -- for women receiving lamotrigine and carbamazepine. This suggests that, for women displaying this phenotype or this syndrome, one approach would be to treat with an oral contraceptive.
  • Infertility Women with epilepsy overall have lowered fertility compared with women in the general population.[17 ]Menstrual disorders are estimated to occur in 1 of 3 women with epilepsy compared with 1 in 7 in the general population.[18 ]Oligomenorrhea and abnormal cycle length (35 d) occur in up to one third of women with epilepsy. At least one third of menstrual cycles in women with generalized seizures are anovulatory.[19 ] Seizures themselves can result in abnormal reproductive hormone variations. Fluctuations of luteinizing hormone and pulsatile release of prolactin and sex steroids have been observed in temporal relation to some seizures.[20 ] Although some clinicians use a failure of elevation of serum prolactin level to diagnose nonepileptic events, the American Academy of Neurology Guideline for the use of serum prolactin level documents that this is not a consistent enough relationship for diagnostic purposes.[21 ]The type of epilepsy may also have a significant influence on reproductive hormones and function. The reciprocal feedback of the temporal and limbic structures with the hypothalamus can alter secretion of hypothalamic, pituitary, and gonadal hormones. A structural neurologic abnormality of the amygdala or mesial temporal lobe may cause both epilepsy and altered hypothalamic hormonal function. Different hypothalamic gonadotropins responses result from right versus left temporal lobe seizure activity have been observed.[22 ]Observed lower birth rates in women with epilepsy may be due to social inhibitions. There may be fear of rejection due to seizures during social occasions, development of relationships, or intercourse. Some studies have indicated that reproduction rates in married women with epilepsy are not less than those in married women without epilepsy, although marriage rates are lower and occur at older ages, when fertility may be less for other reasons.[23 ]Others have reported that the reduced fertility rate in married women with epilepsy is only partly explained by these social factors.[17 ]Fear of effects of epilepsy or its treatments on a pregnancy may cause women with epilepsy to seek contraception, abortions, and even sterilization. Recent attention has been focused on historical state sterilization programs for reproductive age women with mental handicaps, often including those with epilepsy. Such programs are no longer enforced, though caregivers of women with epilepsy not infrequently request health care providers perform surgical sterilization or prescribe long-acting contraception. The American College of Obstetrics and Gynecology has recently issued a committee opinion that mental capacity in itself does not justify sterilization, and that any such plan must be agreed upon with the appropriate caregivers or agents to preserve the patient's best interests and, to the maximum extent possible, her autonomy.[24 ]For related information, see eMedicine article Infertility.Reproductive Dysfunction in Women With EpilepsyThese antiepileptic drugs are associated with disruptions in reproductive physiology. Clinically, this is evident as reduced birth rates. One of my colleagues has been conducting a study in northern Manhattan, the Columbia Family Epilepsy Project. She finds that women with epilepsy are only 30% as likely to give birth to a child as their nonepileptic sibling. Some of this may be choice, and some of it may reflect the slightly lower marriage rates that are still evident for women and men with epilepsy. We believe that most of the basis is related to disturbances in physiology that can cause sexual dysfunction, disturbances in hypothalamic and pituitary hormones regulating the ovarian cycle, as well as ovarian sex steroid hormones, and perhaps can alter ovarian function itself.
  • Contraception Issues in EpilepsyWomen taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.[34 ]These AEDs increase hepatic metabolism of steroid hormones and increase their binding to sex hormone binding globulin and other serum proteins, both effects that reduce the availability of hormonal contraception. The more potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) are the most likely to interfere with contraception. Milder inducers (oxcarbazepine, topiramate) appear not to alter contraceptive efficacy significantly when administered at low doses. Lamotrigine, which has one of the most complex interactions with hormones, also potentially reduces the efficacy of contraception.In addition, progesterone and its derivatives have been shown to significantly reduce lamotrigine levels, potentially increasing the risk of seizures. This effect is easily seen during pregnancy with a more than 50% drop in lamotrigine levels due to normal gestational increased progesterone.[35 ] Contraceptives with low doses of estrogen (eg, ethinylestradiol) or progesterone (eg, norgestrel, norethindrone) may be poorly effective with these AEDs. Triphasic contraceptives, which contain 1 week of very low-dose estrogen immediately following the placebo week, effectively provides no contraceptive benefit until day 14 of the cycle. Such contraceptive regimens may also be particularly ineffective in women taking enzyme-inducing AEDs or lamotrigine. Alternative contraception or adjunctive methods should be considered in these patients.Although neurologists and obstetricians should be familiar with these interactions, a 1996 survey indicates that both specialties are predominantly unaware of these effects and thus unable to provide appropriate contraception counseling to women with epilepsy. Krauss et al found that 27% of neurologists and 21% of obstetricians reported oral contraceptive failures in their patients taking AEDs, but only 4% of neurologists and none of the obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36 ]  Subdermallevonorgestrel implants (Norplant) have also been shown to have reduced efficacy in women taking enzyme-inducing AEDs.[37 ]It is likely that other forms of hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced efficacy with these drugs, but no literature supports this conjecture. Although the American Academy of Neurology Practice Parameter for Management Issues for Women with Epilepsy states that increasing the estrogenic component of a contraceptive to at least 50 mcg will improve contraceptive effect, reproductive specialists disagree, arguing that the progestin component has a greater effect in preventing ovulation than the estrogen component.[38 ] The literature is not consistent in identifying whether the estrogen or progestin is clinically more important in pregnancy prevention.[39 ] Whether GnRH analogs and other nonovarian hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception by nonhormonal methods or changing antiepileptic therapy to those without hormonal interactions are both reasonable considerations. No impairment of hormonal contraception has been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin, tiagabine, valproate, or zonisamide.[39 ] No adverse effect on contraception has been reported with implantable stimulators for epilepsy or with epilepsy surgery.
  • Epilepsy and Pregnancy IssuesAll of us deal with patients with epilepsy; 50% of the patients we deal with are women, and at least half of that subgroup are women in the childbearing years. Pregnancy issues are a problem to all of us -- how best to advise women from as early as possible to minimize the risks to themselves and to their unborn child. About 3 or 4 of every 1000 pregnancies occurs in women with epilepsy; that is, perhaps slightly less given the prevalence of epilepsy in the population, but that is because women with epilepsy are sometimes worried, or frightened, about becoming pregnant. They have lower rates of getting married, lower rates of having children. The most common reason for this is psychosocial; but there also are, perhaps, difficulties in conceiving, because of infertility issues, issues that surround polycystic ovaries, etc. But, there is this fear that the drugs they take, or the epilepsy that they have, may affect their unborn child. I want to examine this and show how we have been looking at this from our own perspective and from other parts of the world.
  • Contraception Issues in EpilepsyWomen taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.[34 ]These AEDs increase hepatic metabolism of steroid hormones and increase their binding to sex hormone binding globulin and other serum proteins, both effects that reduce the availability of hormonal contraception. The more potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) are the most likely to interfere with contraception. Milder inducers (oxcarbazepine, topiramate) appear not to alter contraceptive efficacy significantly when administered at low doses. Lamotrigine, which has one of the most complex interactions with hormones, also potentially reduces the efficacy of contraception.In addition, progesterone and its derivatives have been shown to significantly reduce lamotrigine levels, potentially increasing the risk of seizures. This effect is easily seen during pregnancy with a more than 50% drop in lamotrigine levels due to normal gestational increased progesterone.[35 ] Contraceptives with low doses of estrogen (eg, ethinylestradiol) or progesterone (eg, norgestrel, norethindrone) may be poorly effective with these AEDs. Triphasic contraceptives, which contain 1 week of very low-dose estrogen immediately following the placebo week, effectively provides no contraceptive benefit until day 14 of the cycle. Such contraceptive regimens may also be particularly ineffective in women taking enzyme-inducing AEDs or lamotrigine. Alternative contraception or adjunctive methods should be considered in these patients.Although neurologists and obstetricians should be familiar with these interactions, a 1996 survey indicates that both specialties are predominantly unaware of these effects and thus unable to provide appropriate contraception counseling to women with epilepsy. Krauss et al found that 27% of neurologists and 21% of obstetricians reported oral contraceptive failures in their patients taking AEDs, but only 4% of neurologists and none of the obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36 ]  Subdermallevonorgestrel implants (Norplant) have also been shown to have reduced efficacy in women taking enzyme-inducing AEDs.[37 ]It is likely that other forms of hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced efficacy with these drugs, but no literature supports this conjecture. Although the American Academy of Neurology Practice Parameter for Management Issues for Women with Epilepsy states that increasing the estrogenic component of a contraceptive to at least 50 mcg will improve contraceptive effect, reproductive specialists disagree, arguing that the progestin component has a greater effect in preventing ovulation than the estrogen component.[38 ] The literature is not consistent in identifying whether the estrogen or progestin is clinically more important in pregnancy prevention.[39 ] Whether GnRH analogs and other nonovarian hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception by nonhormonal methods or changing antiepileptic therapy to those without hormonal interactions are both reasonable considerations. No impairment of hormonal contraception has been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin, tiagabine, valproate, or zonisamide.[39 ] No adverse effect on contraception has been reported with implantable stimulators for epilepsy or with epilepsy surgery.
  • Contraception Issues in EpilepsyWomen taking cytochrome P450 enzyme-inducing antiepileptic drugs (AEDs) have a potential 6% failure rate per year for oral contraceptive pills.[34 ]These AEDs increase hepatic metabolism of steroid hormones and increase their binding to sex hormone binding globulin and other serum proteins, both effects that reduce the availability of hormonal contraception. The more potent enzyme inducers (carbamazepine, phenytoin, phenobarbital, primidone) are the most likely to interfere with contraception. Milder inducers (oxcarbazepine, topiramate) appear not to alter contraceptive efficacy significantly when administered at low doses. Lamotrigine, which has one of the most complex interactions with hormones, also potentially reduces the efficacy of contraception.In addition, progesterone and its derivatives have been shown to significantly reduce lamotrigine levels, potentially increasing the risk of seizures. This effect is easily seen during pregnancy with a more than 50% drop in lamotrigine levels due to normal gestational increased progesterone.[35 ] Contraceptives with low doses of estrogen (eg, ethinylestradiol) or progesterone (eg, norgestrel, norethindrone) may be poorly effective with these AEDs. Triphasic contraceptives, which contain 1 week of very low-dose estrogen immediately following the placebo week, effectively provides no contraceptive benefit until day 14 of the cycle. Such contraceptive regimens may also be particularly ineffective in women taking enzyme-inducing AEDs or lamotrigine. Alternative contraception or adjunctive methods should be considered in these patients.Although neurologists and obstetricians should be familiar with these interactions, a 1996 survey indicates that both specialties are predominantly unaware of these effects and thus unable to provide appropriate contraception counseling to women with epilepsy. Krauss et al found that 27% of neurologists and 21% of obstetricians reported oral contraceptive failures in their patients taking AEDs, but only 4% of neurologists and none of the obstetricians knew the effects of the 6 most common AEDs on oral contraceptives.[36 ]  Subdermallevonorgestrel implants (Norplant) have also been shown to have reduced efficacy in women taking enzyme-inducing AEDs.[37 ]It is likely that other forms of hormonal contraception (eg, transdermal patch, Depo-Provera) have potentially reduced efficacy with these drugs, but no literature supports this conjecture. Although the American Academy of Neurology Practice Parameter for Management Issues for Women with Epilepsy states that increasing the estrogenic component of a contraceptive to at least 50 mcg will improve contraceptive effect, reproductive specialists disagree, arguing that the progestin component has a greater effect in preventing ovulation than the estrogen component.[38 ] The literature is not consistent in identifying whether the estrogen or progestin is clinically more important in pregnancy prevention.[39 ] Whether GnRH analogs and other nonovarian hormones have altered efficacy in epilepsy is unknown. Adjunctive contraception by nonhormonal methods or changing antiepileptic therapy to those without hormonal interactions are both reasonable considerations. No impairment of hormonal contraception has been reported with ethosuximide, felbamate, gabapentin, levetiracetam, pregabalin, tiagabine, valproate, or zonisamide.[39 ] No adverse effect on contraception has been reported with implantable stimulators for epilepsy or with epilepsy surgery.
  • Neural Tube DefectsOne of the worries is that the drugs these people take to control the epilepsy may be teratogenic. The currently perceived wisdom is that women with epilepsy taking antiepileptic drugs have a 2-3 times greater risk of having a child with a major congenital malformation. Background risk in the United Kingdom is about 1% to 3%. That means that women with epilepsy taking antiepileptic drugs have a 3% to 9% risk of having a child with a major malformation. One would like to try to withdraw antiepileptic drugs, if possible; but in many cases, that is not possible either because the epilepsy is still active or because of other reasons, such as effects on driving license, or women not wishing to take the risk. Seizures may increase during pregnancy and in the United Kingdom, epilepsy is now the second most common cause of maternal death due to nonobstetric causes. I do not know why that is -- and it is not disclosed in statistics -- but I suspect it is probably because women may be withdrawing from antiepileptic drugs precipitously.What are we good at? When we are giving women preconceptual advice, we are probably all very good at warning of the risks of major structural abnormalities, such as neural tube defects. We recognize, from previous studies, that there is an increased risk, particularly with valproate, and also perhaps with carbamazepine at a level maybe about 1% or 2%. We are probably not so good at recognizing that the neural tube defects in women taking valproate, in particular, are not the same as the neural tube defects in the general population. They tend to be skin covered; they tend not to be with the other abnormalities, such as anencephaly; they tend to be a lower defect, more sacral, lumbosacral; and it may affect canalization. That might be relevant, because we give folic acid, preconceptually, to all women with epilepsy to protect them from this defect. But, that is because we correlate our women with women in the general population in whom folic acid has been shown to reduce the risk of neural tube defects. But, this neural tube defect is slightly different. We are perhaps not so good at knowing about the other major congenital abnormalities that occur, such as facial clefts, hypospadias; how often do they occur, what type of defects occur; and are they associated with any particular drug. We have not got the information about that.
  • Fetal Valproate Syndrome: Facial FeaturesWe are probably getting a bit better at knowing about some of the minor anomalies that occur. We have become aware, over the last number of years, that some children maybe have dysmorphic features. This has been associated, particularly, with valproate. The point of these dysmorphic features is not so much that the child has these particular features, but rather, is there some association with behavior, or learning, or cognitive delay?
  • Is the diagnosis of epilepsy well established? In some patients, routine EEG recordings or continuous video/EEG monitoring may be warranted to confirm the diagnosisDoes the patient require AEDs and if so, is she on the most appropriate medications and the minimum dose to maintain seizure controlMany physicians will consider withdrawal of AEDs after a period of two years without seizures. The frequency of seizure recurrence within six and twelve months of discontinuing therapy is 12 and 32 percent, respectively. Thus, if a woman has been seizure-free for a satisfactory period, a taper and withdrawal of AEDs at least six months prior to becoming pregnant is suggestedReproductive counseling All physicians treating women of reproductive potential must discuss pregnancy with these patients, and when appropriate, their caregivers. There are few medical conditions in which pregnancy and childbirth do not complicate management. It always is preferable to discuss epilepsy management options before conception occurs. A candid discussion of whether or when pregnancy is desired can help determine the timing of diagnostic tests and medication changes. The Physician's Discussion Checklist for Women with Epilepsy contains helpful clinical printable practice aids for physicians of women with epilepsy in their reproductive years. There are several ways to optimize therapy prior to consideration of pregnancy. First, establish whether the female patient requires antiepileptic therapy at all. Review of history and EEG may show that the diagnosis is unsubstantiated (due to lack of historical documentation or inadequate diagnostic testing) or that the patient is now seizure free for several years. Second, determine if the current regimen is appropriate for the epilepsy syndrome or seizure type. If drug choice or dosing is in question, referral to a comprehensive epilepsy center for a second opinion should be considered. Third, advocate simplification of treatment to monotherapy, or consider whether epilepsy surgery may be beneficial. EEGs and video-EEGs, scrupulously conducted by qualified laboratories and interpreted by qualified epileptologists, may be helpful. 
  • Folic acid Low serum or red blood cell folate levels have been associated with spontaneous abortion and developmental anomalies in animals and humans, especially neural tube defects.[40,41 ]All women of reproductive age, with or without epilepsy, should be on folate supplementation, even if pregnancy is not planned in the near future. Blood folate levels decline in women taking older AEDs. Although folate levels have not been shown to decrease in all AEDs, folate supplementation is recommended for all patients with epilepsy, both men and women. A recently described association with the MTHFR (a polymorphism of methylenetetrahydrofolatereductase) genotype appears to confer increased susceptibility to development of malformations when AED exposure occurs in utero.[42 ]The American Academy of Neurology (AAN) guidelines addressing the care of women with epilepsy (currently in the process of being updated), recommends use of folate supplementation at a dosage of no less than 0.4 mg daily for all reproductive-aged women before conception and throughout gestation. Prenatal multivitamins contain at least 0.8 mg of folate, and individual folate tablets are available as 1-mg doses. Folate in doses up to 15 mg daily is safe and usually well-tolerated.[28 ] Higher doses likely offer more protection against development of neural-tube defects (NTD), and most epileptologists recommend between 1 and 5 mg daily. The AAN states women who have personal or family history of NTD births should receive 4 mg daily.[43 ] This is supported by the recommendation of the American College of Obstetrics and Gynecology that women with "health risks, including epilepsy" should take 5 mg folate from 3 months before conception through 3 months after conception, followed by 0.4-1.0 mg folate daily through lactation[44 ]. Note, however, that supplementation with as little as 1 mg daily can be expected to decrease phenytoin serum concentration and anticonvulsant effect[45 ], so increased dosing of this AED may be necessary to maintain therapeutic effect.Animal studies have shown that valproate and phenytoin decrease the concentration of certain forms of folate and are associated with neural tube defectsIt has not yet been conclusively determined if folic acid supplementation prevents neural tube defects in women receiving AEDs. Once a woman with epilepsy who is taking AEDs becomes pregnant, serum and red cell folate levels can be monitored (goal is concentration about 4 mg/ml).
  • The ideal AED serum free level must be established for each patient before conception, and should be the level at which seizure control is the best possible for that patient without debilitating side effects. Levels should be repeated at the beginning of each trimester and again in the last 4 weeks of pregnancy. Monitoring should continue until the 6th to 8th week postpartum. In doing so, one may be able to avoid symptoms of toxicity that result from the changes in pharmacokinetics postpartum.Some authors recommend monthly monitoring, given the possibility of rapid and unpredictable decreases in AED levels in an individual patient. The frequency with which levels are monitored must be tailored to each situation, including increased monitoring for worsening seizure control, adverse effects, and compliance issues. Transvaginal U/S can be performed at 18-20 weeks to diagnose the most severe defets (face - heart). However, sensitivity is better, for cleft palate and lips, if U/S is repeated between 24-28 weeks.Screening for NTD: by combination of Maternal serum α –fetoprotein at 15-22 weeks and Level II,structural Ultrasound, at 16-20 weeks. If results are equivocal, proceed with amniocentesis with measurements of amniotic fluid α -fetoprotein and acetylcholine-esterase
  • The majority of women who have epilepsy have a safe vaginal delivery without seizure occurrence; provided, the AED is taken before and throughout labor. Generalized tonic clonic Seizures GTCSs needs aggressive interference because of the high risk for the mother and fetus, especially if they progress to status epilepticus. Oxygen should be administered to the patient and she should be placed on her left side to increase uterine blood flow and decrease the risk for maternal aspiration. Emergency C.S. should be performed when repeated GTCSs cannot be controlled during labor or when the mother is unable to cooperate.Any lady having a seizure during labour must be observed closely for the next 72 hours.Obstetric analgesia may be used to allow for rest before delivery. Pethidine should never be used because it is metabolised to norpethidine, which is epileptogenic. Diamorphine is an option. Few cases of postpartum seizures were reported following epidural analgesia.During labor, oral absorption of AEDs may be inappropriate and any vomiting might complicate the situation. PB, PHT, and VPA can be given IV at the same maintenance dosage. Convulsive seizures and repeated seizures during labor should be treated promptly with parenteralLorazepamor MidazolamBenzodiazepines, in large doses, can cause neonatal cardiac and respiratory depression; therefore, close monitoring for these neonates is mandatory.
  • Many AEDs induce the hepatic cytochrome P-450 system, which is the primary metabolic pathway of the sex steroid hormones. This leads to rapid clearance of steroid hormones and allow ovulation in women taking OCPs or other hormonal forms of birth control. In 1998, the American Academy of Neurology recommended the use of an E2 dose of 50 μg or its equivalent for 21 days of each cycle when using OCPs with the enzyme-inducing AEDs. More recently, however, it is recognized that this still is inadequate protection, and a backup barrier method was recommended. Women on low dose pills or minipills and AED may get pregnant. Patients on hormonal contraception need to be warned that midcycle bleeding indicates possible birth control failure, but its absence does not indicate adequate birth control efficacy. The newer transdermal patch formulation have a higher failure rate with these AEDs. IM medroxyprogesterone provides higher dosages of progestin but still may require dosing at 8- to 10-week intervals rather than 12-week intervals.
  • Bone healthAEDs may decrease bone mineral density and result in osteopenia, osteoporosis, and fractures. Although these risks are present in both men and women treated with AEDs for more than several years, postmenopausal women are especially susceptible due to the added risk factor of hormonal depletion. A prospective study of women older than 65 years found that those taking AEDs were twice as likely to develop hip fractures.[66 ]Patients with epilepsy have been reported to suffer osteopenic fractures due to falls and tonic events associated with convulsions.Several mechanisms have been proposed for bone loss with AED treatment. Cytochrome p-450 enzyme-inducing agents (phenytoin, phenobarbital, primidone, carbamazepine) increase vitamin-D metabolism, leading to decreased calcium absorption in the intestine, and increased parathyroid hormone, causing bone calcium stores to be mobilized. Reports suggest that non-enzyme-inducing AEDs, such as valproate, may also result in decreased bone mineral density, though to a lesser degree.[67 ]Little information is available about the effects of agents approved since 1993.Testing for bone loss can be performed by using chemical or structural methods. Measuring biochemical serum levels for low calcium and phosphate, reduced vitamin D and its metabolites, and elevated serum alkaline phosphatase and parathyroid hormone levels may provide insight into risks for bone loss. However, such testing should not be used as the sole measure of bone health because structural integrity and fracture resistance may be impaired even when laboratory tests are in the normal range. Markers of bone formation and resorption can also be monitored. Severity of these abnormalities can correlate with duration of AED exposure as well as the number and types of AEDs used.[68 ] Bone mineral density (BMD) testing is the preferred method to quantify risk of osteoporosis.  Dual energy x-ray absorptiometry (DXA or DEXA) can be performed centrally (hip, spine) or peripherally (finger, wrist, heel, tibia) and are not always directly comparable, due to the different normal composition of these bones. The test defines a T-score with zero or greater defining normal bone mass, and negative numbers defining osteopenia (T score between -1 and -2.5) or osteoporosis (T <-2.5). Testing bone structure by BMD should be conducted in all patients taking AEDs more than 5 years and repeated at biannual intervals to assess adequacy of therapy.[69 ]Therapy to prevent bone loss should begin well before menopause and is a consideration for any patient (male or female) treated with AEDs. Calcium supplements are most helpful when used in conjunction with vitamin C (which promotes absorption of calcium) and vitamin D. The recommended daily allowance of calcium varies from 1000-1500 mg in adults and increased doses for those with evidence or risk of bone loss. The recommended daily intake of vitamin D is 400-800 IU, but doses up to 15,000 IU may be necessary in patients with evidence of bone loss.[70 ]Judicious sunlight exposure to the skin helps provide vitamin D for calcium metabolism. Weight-bearing exercise (even walking) also significantly reduces the risk of bone loss in the general population. Pharmacologic intervention with bisphosphonates or other agents is recommended for T scores of -2 or less. Such therapy should usually be managed by an internist or endocrinologist.Bone Health in Women With Epilepsy Receiving Antiepileptic DrugsThe last topic is bone health. We know from the literature, which goes back to the 1940s, that women and men with epilepsy are at higher risk for bone disease. Most of this literature suggests that the likelihood of having bone disease is related to the burden of exposure of the skeleton to antiepileptic drugs -- whether that is taking antiepileptic drugs for a longer period of time, taking multiple antiepileptic drugs, or taking higher doses. The data also suggest that the risk for bone disease is highest in individuals taking enzyme-inducing antiepileptic drugs -- that includes carbamazepine, phenytoin, or phenobarbital. This is another essential consideration I would suggest when selecting an antiepileptic drug.Bone Disease in Persons With Epilepsy on AEDsThe manifestation of bone disease in these patients is primarily one of bone loss, with these individuals displaying osteopenia or osteoporosis. The bone loss is most evident in trabecular bone -- the trabecular bone being measured in the femoral neck of the hip and in the spine, particularly lumbar spine, as well as in the ribs. Changes in bone density easily are detectable by dual X-ray absorptiometry (DXA) scan. Ultrasound, a less precise measure of bone density, also has been used to show that you can pick up this bone loss even in the hand. This is a concern for women with epilepsy, but a recent prospective study has shown that young men are similarly affected. If we look at epidemiologic studies identifying variables predicting risk for bone disease in the general population, individuals with epilepsy who are receiving antiepileptic drugs always emerge as a population at risk. In these population-based studies, this population is 4 times more likely to have a hip fracture and2 times more likely to have a fracture at any location in the skeleton.Incidence of Fractures Among Women With or Without EpilepsyFor women with epilepsy, there are data suggesting that this risk of hip fracture may be evident even at an early age. In these data, the rate for hip fracture really starts to escalate in the reproductive years, being significantly higher than the general population by the years after menopause, 50 plus. We also would be concerned that children are similarly at risk. Although there are fewer data for children, there is a deviation toward lower bone density even in the first 2 decades of life. If we look at hips, we see that, although the risk for hip fracture remains lower during the reproductive life, it is still higher than for the general population. After menopause, there is a marked and quite concerning increase in likelihood of hip fracture in women receiving antiepileptic drugs.Possible Mechanisms of OsteoporosisWhat do we see in individuals with epilepsy? We see mechanisms that are multiple. We can presume that induction of cytochrome P450 enzymes is leading to increased catabolism of vitamin D and reducing the bioactive metabolites of this vitamin. We also see impaired absorption of calcium with many of the antiepileptic drugs, in fact all of the older agents. These medications may inhibit the bones' response to parathyroid hormone and may reduce the levels of calcitonin. Recent data also suggest that these medications may directly affect the activity of osteoblasts and osteoclasts.In treatment of bone disease, we have to know better which antiepileptic drugs are bone sparing; but in all of our patients -- particularly those on enzyme-inducing antiepileptic drugs -- we must monitor bone disease with bone density scans, and that should start earlier, rather than later, in life. There are multiple therapies for bone disease, although we have no studies showing that any of these are effective for antiepileptic-drug associated bone disease. Nevertheless, it seems prudent to provide prophylactic calcium and vitamin D supplementation to all individuals receiving antiepileptic drugs, especially those on the enzyme inducers. For those with bone density loss, those individuals may be candidates for treatment with the bisphosphonates, with hormone replacement, or with a new group of compounds called selective estrogen receptor modulators. These agents may not have the same long-term health consequences of estrogen therapy and progesterone therapy, but they have afavorable effect on bone.

Epilepsy in women Epilepsy in women Presentation Transcript