Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303
Mark S. Yerby M.D., M.P.H.
Clinical Associate Professor of Neurology, Public Health and Ob-Gyn
Oregon Health Sciences University
ABSTRACT
Women with epilepsy present their health care providers with unique problems and hence opportunities for advancement of care. The fundamentals of epileptic pathophysiology are similar in men and women. In the management of women however, one must take into account the significant differences between the sexes. Cosmetic effects of antiepileptic drugs (AED) may have different implications for women than men. A subset of women has seizures that are associated with their menstrual cycle or catamenial epilepsy. Such patients may need special attention to their cyclic hormone changes as well as to their AED selection.
Antiepileptic drugs may reduce the effectiveness of hormonal contraception resulting in unplanned pregnancies. Women with epilepsy have higher than expected rates of infertility and an increased prevalence of reproductive and endocrine disorders. The majority of women with epilepsy have normal healthy children, but their pregnancies are considered high risk due to an increase in seizure frequency, metabolic alterations of AED which complicate management, and an increased risk of adverse pregnancy outcomes. This report reviews these issues and suggests an approach to optimize the management of women with epilepsy.
INTRODUCTION
Fundamental Principles
The management of all persons with epilepsy is based on certain fundamental principles: An accurate diagnosis and characterization of seizure type; choosing the most effective antiepileptic drug (AED), for the seizure type; pushing the dose to effect or until unacceptable side effects occur; exhausting monotherapy prior to using polytherapy of non medical therapies. These principles obviously apply to women as well as to men with epilepsy. The significant social and physiological differences between these groups require one to modify the approach to women patients.
Epilepsy is one of the most common neurological disorders, affecting approximately 1.0 % of the population (1). In the United States there are approximately 2.8 million persons with epilepsy of whom 1.1 million are women of childbearing age. There is unfortunately a great deal of prejudice directed toward persons with epilepsy. Most persons take marriage and raising children for granted; however childbearing for women with epilepsy has not always been acceptable. The many social and cultural taboos surrounding seizures have often lead to ostracism. Misperceptions that epilepsy was a psychiatric condition lead many people to believe that such persons were unfit to have children. The possibility that it could be inherited reinforced those beliefs, (2).
At one time virtually every state in this nation had discriminatory legislation directed at persons with epilepsy. It was only in 1982 that the state of Missouri finally repealed legislation, which made it illegal for persons with epilepsy to marry. As late as 1986 women with epilepsy (WWE) in the state of South Carolina could still be involuntarily sterilized. Although social attitudes have changed, a great deal of prejudice still exists.
With the advent of more effective (AED) about 80 % of persons with epilepsy can have their seizures controlled. Dispute these advances the management of WWE still presents physicians with unique problems. Cosmetic side effects of medication may effect drug selection and compliance. Many women have seizures that are effected by their menstrual cycle and are notoriously difficult to control. AED may interfere with the effectiveness of hormonal contraceptives resulting in unplanned pregnancies. Infertility rates for WWE are significantly higher than for controls. Pregnancies in WWE are considered high risk. This is because during pregnancy the metabolism of AED changes making their management more difficult. Approximately one third of these women will have an increase in their seizure frequency. They have higher rates of complications of pregnancy, labor and delivery, and their children have higher rates of adverse pregnancy outcomes.
COSMETIC CONSEQUENCES OF EPILEPSY THERAPY
All medications have potential side effects. The choice of a drug requires a consideration of effectiveness and the risks of adverse experiences. Thankfully most AED are quite safe, but several compounds have side effects which may effect the physical appearance of patients and result in resistance to their use.
Weight gain has been described as a non-dose related side effect of valproate more commonly seen in women than men (3). Other compounds such as felbamate and topiramate have been associated with significant weight loss occasionally requiring discontinuation of the AED (4, 5).
Hair loss has also been described with valproate, as has hair regrowth with a change in color and texture (6). Phenytoin has been demonstrated to cause excessive hair growth particularly of the face and arms, and facial acne and coarsening. Gingival hypertrophy has been reported in 13% of persons taking this medication (7).
In choosing an AED primary consideration must be given to effectiveness for seizure control. The potential cosmetic side effects should however be considered and plans for their management developed. Otherwise compliance may suffer as women struggle with unwanted modifications of their appearance by reducing doseage.
CATAMENIAL EPILEPSY
Definition
The term catamenial is a derivation of the Greek katamenia and means monthly. It has become synonymous with seizures associated with the menstrual cycle. For as long as this phenomenon has been recognized it is surprisingly poorly understood. Ancient writings associated epileptic attacks to phases of the moon-giving rise to the term "lunatic," a theory still popular in the 19th century (8,9). Gowers was the first to clearly characterize the cyclic nature of seizures with menses (10), but it was Dickerson who performed the first systematic prospective study of seizures and menses. In an institutionalized population of 480 women with epilepsy followed for one year, 10% had a clear association of their seizures with their menstrual period (11).
Normal Ovarian Function
A woman's menstrual cycle is the result of a complex interaction of hypothalamic, pituitary and ovarian hormones. Gonadotropin releasing hormone (GnRH) is secreted from the hypothalamus in a pulsatile fashion. Its origin is neurons in the arcuate nucleus. These neurons are inhibited by dopamine, and facilitated by norepinephrine.
The GnRH travels to the pituitary through the portal system where it binds to specific receptors stimulating the production of follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Luteininzing hormone is released from the pituitary in a pulsatile fashion reflecting the pulses of GnRH. In men the LH pulses vary little. In women LH pulses are of low amplitude 5-7 mIU/ml every 60 - 90 minutes during the follicular phase. The pulses accelerate just prior to ovulation. During the luteal phase the amplitude is higher 8-12 mIU/ml and the frequency lower every 3 - 4 hours. In childhood there is minimal secretion of GnRH. For 3 - 4 years prior to the development of menses GnRH secretion increases.
Follicle stimulating hormone increases prior to ovulation and stimulates the development of a group of ovarian follicles. As one of these follicles predominates it secretes estradiol which exerts a positive feedback on the pituitary, and more FSH and LH are produced. As more LH is secreted a follicle will rupture and the corpus luteum forms.
Estrogen secretion by the ovary stimulates endometrial proliferation during the first half or follicular phase of the menstrual cycle. During the second half or luteal phase, the corpus luteum produces progesterone. The combined effects of both of these ovarian hormones change the endometrium from proliferative to secretory and after approximately 2 weeks without fertilization the concentrations of estrogen and progesterone fall and the endometrium is shed resulting in menses.
Neuronal Effects of Estrogen and Progesterone
Sex hormones effect cortical excitability. Estrogens placed on the cortex can activate a new seizure focus. They reduce the threshold needed to induce seizures with electroshock. Intravenous estrogen infusion increases interictal epileptiform discharges. A proposed mechanism for these actions is a reduction in gamma-amino-butyric-acid (GABA) (12, 13). Progestens appear to depress the kindling response. They increase the threshold needed to induce electroshock. Intravenous infusions of progesterone reduce interictal epileptiform discharges. Increasing GABA is the proposed mechanism. ). Progesterone in contrast, reduces epileptiform activity on EEG and protects mice against pentylenetetrazol induced seizures. Testosterone by comparison has no consistent effect on electroshock threshold or kindling (14, 15).
Prevalence of Catamenial Epilepsy
The reported prevalence of catamenial epilepsy varies from 10 to 72 % (TABLE 1.) The marked variation is due to the lack of a consistent definition. Some authors required that all, others most, others 75% of seizures be associated with menses. In some series seizures occurring a few days before the actual menstrual flow are also counted, and in others seizures during ovulation are also considered catamenial.
Three investigators have attempted to describe specific patterns associated with catamenial epilepsy. Backstrom followed 7 WWE and demonstrated 2 peaks of catamenial seizure activity: at the beginning of the menstrual cycle, and at ovulation (22). Herkes and co-workers also found 2 peaks of seizure increase in a group of 12 women followed over 44 cycles. The first was from 2 days before and throughout the period of menstrual flow. The second occurred at midcycle (ovulation) (23). Herzog and colleagues describe 3 patterns. Ovulating patients had their seizures during menses or ovulation. Anovulatory patients had more seizures during the second half of the luteal phase. All three groups found that most seizure exacerbation occurred during menses (24).
These studies and the preponderance of the literature support a working definition of catamenial epilepsy as that in which all or most of a womanís seizures occur during a 7 day period from 3 days before through the early phase of the menstrual cycle (25).
Mechanism
Catamenial epilepsy appears to be related to a relative lack of progesterone during the luteal phase of the cycle. Backstrom and co-workers initial studies suggested an elevated ratio of estrogen to progesterone (E/P), in women with catamenial epilepsy (22). Subsequent investigators have demonstrated that it is a relative progesterone lack, not estrogen excess that accounts for the altered E/P ratio (26,27).
Other studies have suggested that AED concentrations are altered during menses. Shavit et al (28) demonstrated a mean 4.1 ug/ml decrease in phenytoin levels during menses in 17 women and a 50% increase in clearance rate of the drug during that same interval. A similar decline in phenytoin concentration during menses was described in 8 women with catamenial seizures, a mean of 3.44 ug/ml compared to 0.91 ug/ml in controls (29).
Sixty three percent of women on valproate have been shown to have lower progesterone concentrations in the luteal phase compared to women treated with carbamazepine or phenobarbital. Such patients were more likely to be anovulatory. It has been suggested that medications which alter GABA transmission may also effect noradrenergic regulation of gonadotropic pulsatile release and hence ovulation (30).
Significance
Though there is lack of agreement on the prevalence, and the definition may be fairly loose, there can be no doubt that some WWE do have seizures related to their menstrual periods. The importance of this is that such women are rather difficult to control with conventional AED.
A number of researchers have attempted to improve control with the addition of progesterone to the AED regimen. The induction of amenorrhea with medroxyprogesterone acetate orally or intramuscularly reduced seizure frequency by 30% from a mean of 8.3 to 5.1 seizures per month (31). Similar improvement using medroxyprogesterone acetate was found by Zimmerman et al. (32). Intermittent treatment with progesterone in the form of vaginal suppositories of oral lozenges (200-mg. tid) has been pioneered by Herzog et al. (33). For women with perimenstrual seizure exacerbations the hormone was given during days 23-25. For women with anovulatory cycles the treatment was extended to days 15-25. A reduction of seizures of 72% was demonstrated.
In addition to progesterone medications with anti-estrogen effects have been used to treat catamenial epilepsy in women with abnormal menstrual cycles with some success. Clomiphene resulted in an 87% decline in seizures and a normalization of menstrual cycles (34).
Management
The effective management of catamenial epilepsy requires a precise diagnosis. Initial therapy involves maximizing conventional AED therapy. Once this has been done if a woman continues to complain of seizures associated with her menses a careful compilation of her seizures and menstrual cycle on a calendar will demonstrate an association if it exists. Seizures are random events and when systematically monitored some will fall within the first 7 days of the cycle. In order for the diagnosis of catamenial epilepsy to be made a preponderance of seizures must occur during that interval.
Once a diagnosis of catamenial epilepsy has been established one needs to demonstrate a progesterone deficiency prior to supplementing a patient. Differentiating inadequate luteal phase and anovulatory cycles is important in planning further investigations. A progesterone level measured during the mid luteal phase day 20-22 of a 28 day cycle should be higher than 5.0 ng/ml. Failure to do so implies inadequate progesterone production and suggests that supplementation with progesterone may be helpful.
Determining ovulation is a bit more tedious. The failure of the basal body temperature to rise by 0.7 degrees F. for at least 10 days during the second half of the cycle implies failure of ovulation. If this occurs further investigation is required to rule out polycystic ovarian disorder with ultrasound.
A variety of approaches are available for progesterone supplementation. Progesterone creams are available, but their progesterone concentration and absorption are quite variable and so is their effectiveness. A natural progesterone lozenge is available. Herzog (33) recommends 100 to 200 mg. three to four times a day. The target progesterone levels are 5 - 25 ng/ml. Many women unfortunately suffer form side effects of progesterone limiting its utility. Sedation, depression, breast tenderness, weight gain, and vaginal spotting have frequently been reported.
Synthetic progestational agents such as medroxyprogesterone may be administered intramuscularly 120 - 150 mg. every 6 - 12 weeks. Cessation of menses can occur, as can hot flashes, vaginal bleeding, and breast tenderness. Such an approach limits one's ability to adjust the doseage quickly (31, 32). Most authors have not found oral synthetic progesterone effective (35, 36). I have had some success with the continuous use of oral contraceptives such as Nordette Æ, (levonorgestrel 0.15 mg/ethinyl estradiol 0.03 mg.) given continuously.
Clomiphene, an estrogen antagonist, has been used intermittently 25 - 100 mg. a day from days 5 - 9 of the cycle. One half of patients in the only reported series, had significant side effects of breast tenderness, abdominal cramping and pain, the development of ovarian cysts (34).
ANTIEPILEPTIC DRUGS AND HORMONAL CONTRACEPTIVES
Oral contraceptives have not been associated with exacerbation of epilepsy (37). The effectiveness of hormonal contraceptives can however, be reduced by enzyme inducing AED (carbamazepine, phenytoin, phenobarbital, felbamate, topiramate). Hormonal contraceptives come in three formulations: oral (estrogen-progesterone combinations, or progesterone only); subcutaneous, (levonorgestrel) or intrauterine, (progestasert) implants; and injectable (depoprovera). All three forms can be adversely impacted by enzyme inducing AED.
AEDs may lower concentrations of estrogens by 40 to 50 %. They also increase sex hormone binding globulen (SHBG) which increases the binding of progesterone and reducing the unbound fraction. The result is that hormonal contraception is less reliable with enzyme inducing AED.
The low or mini dose oral contraceptives are therefore to be used with caution. Oral contraceptives should have at least 50ug. of estrogen. The more rapid clearance of the estrogens when used in conjunction with an enzyme inducing AED will reduce the likelihood of unwanted side effects from higher dose tablets.
Failure of implantable hormonal contraceptives have also occured. Midcycle spotting or bleeding is a sign that ovulation is not suppressed. If this occurs alternative or supplementary methods of contraception are required. Contraceptive failure may not always be predicable, even when midcycle spotting does not occur. Failure of basal body temperature to rise at midcycle can be used to document ovulatory suppression. Alternatively non enzyme inducing AED may need to be considered (valproate, lamotrigine, gabapentine).
INFERTILITY
Epidemiological studies have demonstrated that women with epilepsy have only 1/4 to 1/3 as many children as women in the general population (38, 39). A variety of hypotheses have been developed to explain this phenomenon. A direct effect of seizures or epileptiform discharges on pituitary and hypothalamus could disrupt ovulation. Electroconvulsive therapy increase prolactin concentrations over five fold within 15 to 20 minutes, and in premenopausal women there is an acute increase in LH and FSH. Generalized seizures also increase prolactin serum concentrations within 15 to 20 minutes by a factor 3 fold. This fact has been used to assist physicians in differentiating epileptic from non-epileptic seizures (40). Partial seizures however do not increase serum prolactin and they account for the majority ( 60% ) of the epilepsies.
Strong social pressures on women with epilepsy to refrain from reproducing could also be a factor (41), have demonstrated that unmarried WWE have fertility rates 0nly 36 % of their non-epileptic siblings. When WWE marry however that rate increases to only 42 %. Social pressures may contribute but even among married WWE infertility is common.
Women with epilepsy have higher rates of reproductive and endocrine disorders (RED) than expected. Libido is significantly reduced in 1/3 of men and women with epilepsy (42). Herzog and co-workers (35) was among the first to demonstrate RED in women with temporal lobe epilepsy. Nineteen of 50 women had significant reproductive problems. Seven had polycystic ovarian disease, 7 had hypergonadotropic hypogonadism, and 6 hypogonadotrophic hypogonadism. Women with primary generalized epilepsies also have RED. Five of 20 women studied by Bilo and colleagues (43) had RED, 3 with polycystic ovarian disease, and 2 with hypogonadotropic hypogonadism. Ascertainment bias may account for the high proportion of WWE with RED in these studies, nonetheless clinicians should be aware of these potential problems.
MANAGEMENT of the PREGNANT WOMAN with EPILEPSY
Those who care for WWE face a dilemma. On the one hand, seizures need to be prevented; on the other hand, fetal exposure to anticonvulsant drugs needs to be minimized. The ideal situation would be to withdraw the patient from anticonvulsants prior to conception. For most women this is not a realistic option. Women today are more likely to be employed and the potential disruption of their lifestyle by seizures, such as the risk of loss of driver's license, makes elimination of anticonvulsants impractical.
The major organ systems have formed by late in the first trimester. The posterior neuropore closes by day 27 and the palate by the 47th day of gestation. By the time most women realize they are pregnant, malformations already may have developed. WWE of childbearing age need to be informed of the risks of pregnancy associated with anticonvulsant use prior to conception if at all possible (TABLE 2). They also need to know that seizures can be harmful to mother and fetus, and that risks can be reduced with proper care.
Other risk factors for adverse pregnancy outcomes should also be assessed and minimized. These include nutritional status (obese and underweight women have increased risks, vegetarians may not obtain enough Vitamin B12); other intercurrent illnesses (diabetes, phenolketonuria carriers, hypertension) may also increase the risk of adverse outcomes. Other medications may be much more teratogenic than AED. Gold, lithium, Iso-retinoin, folate-antagonists, and warfarin are all teratogenic and should be avoided. Active maternal infections such as hepatitis B, or a history of rubella exposure need to be established or ruled out. Toxoplasmosis titers taken prior to conception may help to determine whether elevated titers are secondary to a primary infection or an old exposure. Genetic risk factors such as Tay Sachs, thalessemia, sickle cell disease, and cystic fibrosis should also be ruled out.
Risks can be minimized by the preconceptual use of multivitamins with folate, and using AED in monotherapy with the lowest effective dose. Monitoring free drug levels both prior to and during pregnancy will permit accurate assessment of concentrations in a situation where plasma protein binding is in flux. Dose adjustment, however, should be made on a clinical basis. Plasma anticonvulsant drug concentrations will fall in pregnant women, but only one-third of them will have an increase in seizures. We tend to keep dosage as low as possible during conception and organogenesis, but will often raise dosage during the third trimester to reduce the risk of seizures during labor.
Supplementation with 0.4 mg/day of folate is recommended by the Center for Disease Control for all women of child-bearing age whether or not they have epilepsy. A number of observational and interventional studies have demonstrated a reduction in the risk of malformations in general and neural tube defects specifically in women taking folate prior to conception (107 - 111). The doses used ranged from 0.8 to 5.0 mg/day. All Western European and North American nations except Norway have similar 0.4 mg/day recommendations. The exception is for those women in which there is a family history of a neural tube defect. For these women 4.0 mg/day is the recommended dose.
Vitamin K1, 10 mg per day, should be initiated late in the third trimester to prevent neonatal hemorrhage. We usually prescribe it during the final month of gestation.
Trimethadione is absolutely contraindicated in women who might become pregnant. Pregnant women taking valproate and or carbamazepine should have a level II ultrasonogram, and, if negative, amniocentesis at approximately 18 weeks of gestation to exclude neural tube defects. Breast-feeding should be done cautiously by women receiving phenobarbital or primidone due to the risk of infant sedation, withdrawal symptoms, or both.
A number of relatively new AEDs have been marketed in the last two years. Gabapentin, felbamate, lamotrigine, tiagabine and topiramate are all readily available. The numbers of exposed pregnancies with these drugs is very low, seven with felbamate, 25 with gabapentin, 136 with lamotrigine, and 29 with gabapentine. These numbers are not large enough for one to determine if there is an increased risk of adverse outcome with fetal exposure to these compounds. We expect that they will act like other AEDs during pregnancy with declining levels until delivery.
FDA assignment of risk factors of a medication ís safety in pregnancy has been done for all drugs marketed in the United States. Five categories have been established (A, B, C, D, X), based on the level of risk the drug poses to the fetus. The interpretation of the categories is as follows:
Category A: Controlled studies have failed to demonstrate a risk to the fetus in the first trimester and the possibility of fetal harm is remote.Category B: Either animal-reproduction studies have not demonstrated a fetal risk; or such studies have shown an adverse effect not confirmed in controlled studies in women.
Category C: Either animal-reproductive studies have revealed adverse effects on the fetus and there are no controlled studies in women; or studies in women and animals are not available. Such medications should be used only if the potential benefit outweighs the risk to the fetus.
Category D: There is a positive evidence of human fetal risk, but the benefits from the use in pregnant women may be acceptable.
Category X: Studies in animals or humans have demonstrated fetal abnormalities, and the risk of the use clearly outweighs any possible benefit. Such drugs are contraindicated in women who may become pregnant (112).
All commonly use AED are currently listed as category C except: phenobarbital, phenytoin, primidone, trimethadione, and valproate which are category D. Thus all AED can be used in pregnancy if the potential benefit outweighs the risk (113). The risk of generalized seizures is considered by most neurologists a hazard of similar risk to that of AED.
Seizures during labor and delivery are best managed with a parenteral benzodiazepine, although we have observed decreased fetal heart rates after intravenous lorazepam. During prolonged labor, a pregnant woman may not be able to continue taking her oral medications. Since medication withdrawal alone can precipitate seizures, loading with parenteral phenytoin may be necessary, especially in women with frequent generalized tonic-clonic attacks. Meperidine used as a post-cesarean section analgesic clearly exacerbated the myoclonic seizures of two of our patients. It lowers seizure threshold and should be used cautiously in patients with seizure disorders including pregnant women.
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Mark S. Yerby M.D., M.P.H.
North Pacific Epilepsy Research
Mother Joseph Plaza
9427 SW Barnes Road - Suite 595
Phone: 503-291-5300
Fax: 503-291-5303
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