Global Perspectives

Epilepsy is a common neurologic condition, which is seen in all age groups. The prevalence of this disease is believed to be 6.8 per 1000 population [1]. Management of this disease poses several challenges – this is largely so because of the nature of the disease itself, which presents in various forms. Also, the pathogenesis is uncertain. There are several classes of anti epileptic drugs (AEDs) that are available for its treatment – but none of them are without serious side effects. Newer drugs such as gabapentin, felbamate, lamotrigine, tiagabine, topiramate and vigabatrin have done away with several of them, but not completely.

In such a scenario, management of women with epilepsy (WWE) poses several more challenges. Gender specific issues span the entire length of WWE and hence guidelines are required to manage them. These guidelines are difficult to lay down because of certain confounding factors. Primary care physicians are the primary contact point for epileptic patients: however, experienced personnel are required to pre-empt intervention and provide necessary specialty consultation for WWE. A literature survey indicates several attempts at unraveling these numerous questions posed, however, we are still largely groping in the dark. This is because of the paucity of studies and because of the large variations in the study methods and patterns in those that have been conducted. This article summarizes existing knowledge.

Management of WWE during reproductive years

1) Seizure variations during the menstrual cycle

Ovarian hormones are known to influence seizure frequency. Estrogens lower seizure threshold and progesterones raise it [1][2]. In the light of this knowledge, it is easy to understand why seizure exacerbations, or catamenial seizures as they also termed, occur during various phases of the menstrual cycle. Seizure frequency was found to be higher around the time of ovulation and peri-menstrually – both these phases correspond to relatively high estrogen and low progesterone levels. One study documented a catamenial rise of upto 78%. Some workers have thus tried a combination of anti epileptic drugs and hormonal manipulation: however, these studies are far too small to draw conclusions from [1].

2) Seizures and their effects on fertility

Various hormones of the neuroendocrine system influence fertility -this has been documented to be as low as two thirds of that in the general population [1][2]. This is especially true in women with temporal lobe and other partial epilepsies as compared to those with generalized seizures.
Epileptic discharges and AEDs may alter hormone surges in the hypothalamus and the pituitary and thus result in abnormalities of gonadotropins and other sex steroid hormones[1][2]. These hormone imbalances lead to menstrual irregularities (amenorrhea, oligomenorrhea, metrorrhagia, menorrhagia and abnormal cycle length) and gynaecologic syndromes (anovulatory cycles, polycystic ovaries and polycystic ovary syndrome). All these, in turn, reflect as impaired fertility.

Abnormalities in sexual arousal, too can lead to infertility [1]. In those WWE who happen to conceive, increased incidence of obstetric complications are known to occur[1]. WWE are known to have a higher incidence of vaginal bleeding, hyperemesis gravidarum, abruption placenta, ectopic and premature abortions, cesarean sections, stillbirths and neonatal deaths. Existing data are not sufficient to provide specific recommendations regarding management strategies for prevention of obstetric complications in WWE.

3) Seizures, AEDs and contraception

Ovarian hormones have the potential to influence seizure frequency – it follows that hormonal contraception too can influence seizure frequency adversely. However, no studies report such an adverse outcome [1] [2].
Instead, cases of failed hormonal contraception have been reported [1][2]. This is easy to understand in view of the fact that conventional AEDs such as phenobarbital, primidone, phenytoin, carbamazepine and the newer AED topiramate are inducers of hepatic cytochrome P450 of mixed function oxidases. This result in an increase of protein bound fraction and consequently, decrease in free estrogen and progesterone levels. It also results in increased clearance of these hormones. Both these events result in failure of contraception. Valproic acid and felbamate inhibit the hepatic microsomal enzyme system. The other newer AEDs such as gabapentin, lamotrigine, tiagabine and vigabatrin have no significant effect. Progesterone only contraceptives have no advantage over oral contraceptives although an exhaustive study is yet to be conducted.

Management of pregnancy related issues for WWE

Management of this class of patients begins with pre pregnancy counseling. The woman should be made aware of the possibility of a rise in seizure frequency, the teratogenic potential of AEDs, the importance of compliance, folic acid and vitamin K supplementation and the pros and cons of breast feeding.

1) Folate supplementation

Folic acid must be present in within the first 25 days post-conception to prevent neural tube defects in the fetus [2]. Considering the fact that pregnancy might not be detected this early and also the fact that not all women consult physicians before planning a pregnancy, the Centres for Disease Control and Prevention recommend that all women of child bearing age be supplemented with 0.4 mg/ day of folic acid [1][2].

AEDs are known to interfere with absorption, uptake and metabolism of folic acid. This then is the biologic basis for recommending folic acid supplementation very strongly in WWE. Whether such women require a dose of more than 0.4 mg/day is not known. Prenatal ultrasound along with evaluation of maternal alfa fetoprotein can detect early neural tube defects.

2) Seizure control during pregnancy

The goal of anti epileptic therapy in a WWE should be to confer adequate protection with minimal harm to the fetus. Seizure frequency is known to alter during pregnancy. However, several studies have failed to correlate the relation between seizure frequency, serum AED level and clinical effects [1][2]. This is largely due to multiple changes during pregnancy such as hypoalbuminemia and increased renal and hepatic clearance, which contribute to alterations in protein bound and free drug levels. Because of these pharmacokinetic changes (which are commonly seen with carbamazepin, phenytoin and valproate), serum levels should be monitored every 3 months during pregnancy.

A woman who is contemplating pregnancy should be carefully withdrawn from AED therapy along the same lines as that for the general population provided she is seizure free for at least 2 years. She should be followed closely throughout pregnancy because the risk of relapse is greatest in the first 6 months after withdrawal [2].

If a woman has already conceived, withdrawal may be attempted, but with extreme caution [2]. If a woman presents after conceiving and is on a single drug and is well controlled, no change should be made [2]. Conversely, serious attempts should be made in a woman who has conceived and is on polytherapy to reduce the number of drugs [2].

Physiologic changes in pregnancy are reversed quickly post partum – this must be borne in mind and dosage changes reversed so as to minimize toxicity during this period [2].