Epilepsy in women

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    07-May-2015

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<p>Seizures in Pregnancy</p> <p>Dr Parth Sarthi Deb MD, DM</p> <p>Epilepsy in WomenEpilepsy 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 510 cases per 1000 persons and a lifetime prevalence of between 25% of the population.Premature death is 23 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.</p> <p>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.</p> <p>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</p> <p>1Epilepsy in womenMany 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.</p> <p>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.</p> <p>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.</p> <p>2OutlineMenarcheMenstrual cycleFertilityWeight gainPoly Cystic Ovarian SyndromeOral contraceptivePregnancyFetusBreast feedingMenopauseCalcium and bones</p> <p>MenarcheFew seizure appear during this age like JME, JAE 25%Few childhood seizure change patternSporadic seizure may become cyclicalBenign rolandic , Absence seizure may remit </p> <p>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 Juvinile Myoclonic E) will presentaround puberty, while some nongenetic partial epilepsies may worsencausing them tocome 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 timein part due to this increase in estrogen, cyclic increases in estrogen relative to progesterone appear as alikelytrigger for breakthrough seizures.[9 ]Different seizure types maybe exacerbated bydifferent 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.[4Menstrual CycleMenorrhagiaOligomenorrheaMetrorrhagiaSimple partialComplex partialVAL+-CBZPCODWt. gainSigns 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.</p> <p>5Catamenial epilepsy10-70% of epilepsy in womenType-I (Perimenstrual)Type-II (Periovulatory)Type-III (Second half of MC in anovlulatory cycle )Estrogen is pro-convulsant andProgesterone is anticonvulsantCyclical use of AnticonvulsantClobazam has show to be most effective (60-80%)Natural progesteron 200mg tid is effective used intermittentlyClomifen also has shown effective</p> <p>Catamenial epilepsyCatamenial epilepsy is a general term applied to any exacerbation in seizures with the menstrual cycle.True catamenial epilepsy requires reproducible and consistent increaseor change in character of seizures at the same point in a regular menstrual cycle.Anovulatory cycles can make therelationship of seizure to hormones difficult to discern.</p> <p>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, orwas confirmed by physiologichormonallevel changes.[9 ]The breadth of the reportedrange itself indicates that seizure exacerbations are influenced by multiplefactors, 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.</p> <p>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 seizuresand menses for several cycles can suggest a cyclic pattern of seizures.This can be confirmed by physiologic measuresincluding 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.</p> <p>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 ofadjunctive therapy such as acetazolamide or benzodiazepines has anecdotally been advocated, but with no prospective supportive evidence.Management strategies using exogenoushormones have not been consistently successful.If improved control is incidentally noted withhormonal 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.</p> <p>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 ]</p> <p>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.</p> <p>6Effect of AEDs on WeightDrugWeight gainValproate&gt;50%Carbamazepine15-25%Gabapentin15%LamotrigineNoLevetiracetamNoTopiramateLoss in 45-85%</p> <p>Effects of Commonly Used AEDs on WeightAnother effect of these antiepileptic drugs is on metabolism. The most obvious clinical manifestation of changes in metabolism i...</p>