Although epilepsy is more prevalent in men than in women, there are special challenges that women with the condition face during their reproductive lives, according to Martha J. Morrell, MD, Director of the Comprehensive Epilepsy Center at New York Presbyterian Hospital. “Women with epilepsy are more likely to have cycles in which they do not ovulate, and in certain groups of women taking anti-epilepsy drugs, more than 50 percent of their cycles are anovulatory. A number of investigators are trying to understand the cause of these disruptions,” she said.
Indeed, to gain a better understanding about optimal therapy regimens for women with epilepsy, researchers have been exploring hormonal influences on seizure activity; interactions between seizures, epilepsy drugs, and reproductive health; and the potential for drug-associated teratogenicity.
Most gains in research and treatment have come about in the last 20 years. Before then, much of the reproductive dysfunction was attributed – legitimately, Dr. Morrell said – to the social disability associated with epilepsy. Proscriptive laws meant that women with epilepsy were much less likely to be married. The state of Missouri, for example, did not repeal its ban against performing marriages of people with epilepsy until 1980, according to the Epilepsy Foundation.
“Until the 1980s, there were laws in the United States that made it illegal for women with epilepsy to have children, and it was not uncommon for women to be counseled that they weren't fit to be parents,” Dr. Morrell said. “It wasn't until society became more informed about epilepsy, and people with epilepsy had more equal social opportunities – such as those afforded under the Americans with Disabilities Act passed in 1992 – that we started to notice that birth rates were down, even though marriage rates now began to match those of women without epilepsy. This social progress made it obvious that we couldn't attribute what we were seeing, in terms of the fertility deficit, to social causes alone.”
In the mid 1980s, Jouko I.T. Isojarvi, MD, PhD, Assistant Professor of Neurology, and his colleagues at the University of Oulu in Finland, began investigating the endocrine effects of the anti-epilepsy drug, carbamazepine, in both men and women. “We knew that these drugs, especially carbamazepine, have endocrine effects, but little was known about reproductive endocrine disorders in women with epilepsy and especially about the role of anti-epilepsy drugs in the development of these disorders,” Dr. Isojarvi said.
In 1991, his research team initiated a large scale study to look at reproductive endocrine disorders in women with epilepsy taking anti-epilepsy drugs. Their results, published in the New England Journal of Medicine in 1993 (329: 1383-8) found that women taking valproate had a high frequency of related reproductive endocrine disorders, characterized by polycystic ovaries, hyperandrogenism, and menstrual disorders.
Despite these findings, neither Dr. Morrell nor Dr. Isojarvi advise neurologists to abandon the prescription of valproate.“We should not jump to premature and possibly inaccurate conclusions,” cautioned Dr. Morrell. “At least 50 percent of the women receiving valproate do not have these problems. And, we do not know with complete confidence how many of these effects are strictly due to the valproate and how many are related to the type of epilepsy that valproate is most often used to treat.
“It's important to remember,” she emphasized, “that if women on valproate develop these symptoms, appropriate interventions – changing drugs or prescribing hormonal therapy in concert with a gynecologist – can be implemented, reversing symptoms and restoring reproductive health.
“The work [on the effects of valproate and other anti-epilepsy drugs] is by no means definitive,” Dr. Morrell continued. “Neurologists should have heightened sensitivity to signs of reproductive dysfunction.”
In fact, phenobarbital, primidone, phenytoin, and carbamazepine can also have endocrine effects in women. Carbamazepine, for example, reduces levels of estrogen and progesterone in the body by inducing the hepatic cytochrome P-450 enzyme system. It also may increase steroid hormone-binding globulins, which also decreases levels of free hormones in the body. Either action, according to the AAN's practice parameters, can result in the failure of hormonal contraceptive methods.
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, and topiramate are known to reduce the efficacy of oral contraceptives, while felbamate, gabapentin, lamotrigine, valproate, and vigabatrin have no effect on oral contraceptives.
Women receiving valproate should be monitored for certain basic indicators, such as body weight and menstrual cycles, Dr. Isojarvi advised. “If there is weight gain or irregular menstruation [cycles shorter than 23 days or longer than 35 or mid-cycle bleeding], one can suspect a reproductive endocrine disorder induced by valproate.”
Dr. Morrell added that hirsutism or acne can also indicate disruptions in ovarian hormones, and that these signs can easily be detected during routine office visits. High serum testosterone concentrations and possible polycystic changes seen on ultrasonography of the ovaries can confirm a valproate-related endocrine disorder, Dr. Isojarvi explained. Confirmation of an endocrine disorder may warrant switching to an alternative medication, especially in adolescent girls whose epilepsy appears to dictate the necessity of long-term medication, he said.
HORMONES AND SEIZURES
Women with epilepsy have often asserted that there is an association between their menstrual cycles and seizure patterns, but there was a period – from the 1940s to 1970s – when physicians said there was no connection between the two. Dr. Morrell recalled that her own training textbooks reflected this disconnection.
Dr. Morrell cited the pioneering work of Dr. Isojarvi and Andrew G. Herzog, MD, Associate Professor of Neurology at Beth Israel-Deaconess Medical Center in Boston, among others, for debunking the notion that ovarian steroids do not alter neuronal activity. Approximately 30 to 50 percent of women with epilepsy have menstrual-associated seizure patterns (so-called catamenial seizures), she said.
Although the mechanisms for these seizure patterns are not yet fully understood, most research suggests that sex hormones are neuroactive, Dr. Morell said. Estrogen acts at the cellular level to “excite” neuronal activity, affecting seiure frequency. Progesterone, on the other hand, appears to dampen seizure activity.
According to Dr. Herzog, women with catamenial seizures are most vulnerable to exacerbations of their epilepsy when estrogen levels are high – just before and during menstrual flow and at ovulation. But in women whose ovaries do not release egg follicles, the corpus luteum does not form and thus secretion of progesterone does not occur to counterbalance estrogen levels. So anovulatory women may be vulnerable to more seizures during the entire two-week time period up through the beginning of menstrual flow.
Dr. Herzog, whose research was published in the journal Psychosomatics (1999; 40(2):102-8), is continuing investigations of adjunctive progesterone therapy in hormone-sensitive seizure disorders.
GAPS IN KNOWLEDGE
At epilepsy centers nationwide, where patients often have access to a multidisciplinary care team, neurologists continue to fine-tune their treatment of women with epilepsy. In the broader medical community, however, practitioners are often unaware of newer treatment standards.
A survey of 3535 health care professionals conducted by the Epilepsy Foundation from March to November 1998 found that most respondents did not know the specific effects of estrogen and progesterone on the seizure threshold. Moreover, they were not aware of menstrual-associated seizure patterns, and could not identify the anti-epileptic drugs that interfere with oral contraceptives.
In addition, the majority of those completing the survey did not know that women with epilepsy have higher rates of infertility and sexual dysfunction. The study, by Dr. Morrell and others, was published last year in the Journal of Women's Health and Gender-Based Medicine (9: 959-965).
Patricia Osborne Shafer, MN, RN, an Epilepsy Nurse Specialist at the Comprehensive Epilepsy Center at Beth Israel-Deaconess Hospital in Boston, co-authored the health care professional survey. Ms. Shafer, who is Chair of the Professional Advisory Board of the Epilepsy Foundation, said it is“striking” that so many professionals failed to appreciate how gender-specific changes might be manifested in epilepsy.
“When they did appreciate differences, it was a very general level of awareness,” she said. “The specifics, which really impact the care that women get, were lacking.” Not surprisingly, neurologists were the most knowledgeable about issues pertaining to women with epilepsy (scoring an average 8.1 out of a maximum score of 15), followed by endocrinologists (with an average score of 7.1), obstetrician/gynecologists (5.5) and internists(5.0).
MISPERCEPTIONS ON AEDS
Mark S. Yerby, MD, Director of North Pacific Epilepsy Research, and Associate Clinical Professor of Neurology, Public Health, and Obstetrics and Gynecology at Oregon Health Sciences University in Portland, finds that many non-neurologists lack an appreciation for the hazards of seizures themselves.
“Physicians are very concerned about medications and the problems medications can cause – and they can. But we cannot completely ignore the fact that we're using the medications to treat seizures which are hazardous in and of themselves.”
In addition, Dr. Yerby said, “primary care physicians sometimes assume that the older the medication is, the safer it is – and that the newer the medication is, the more dangerous it is. This is not supported by the data.”
Dr. Yerby said he had heard from one woman whose doctor had taken her off phenytoin and put her on phenobarbital because it was“safer.” There is no evidence to suggest that phenobarbital is safer; in fact, some evidence suggests that it may be even worse, he said.
Another misperception, said Dr. Yerby, is that “all medicines are created to be equal and all epilepsy is the same. People often don't understand that there are different types of epilepsy and that they may respond differently to individual medications.”
“Epilepsy is not just a ‘one size fits all’ diagnosis,” agrees Marc R. Nuwer, MD, PhD, Professor of Neurology in the Department of Neurology at UCLA Medical Center and co-director of the UCLA Seizure Disorders Center in Los Angeles. “There are so many nuances, types of seizures, risk factors, and other things to take into account [when treating women with epilepsy]. It's really hard for a generalist like an ob/gyn, internist, or family practitioner to tailor all that information to the particular patient.”
One way to address the complexity and misperceptions about management of women with epilepsy is for the neurologist to take the lead in managing the treatment plan. The AAN's own practice parameter summary statement, in fact, supports this.
PREGNANCY AND EPILEPSY
Coordinating epilepsy management becomes even more critical in women with epilepsy who are of childbearing age. Resources are available to help manage pregnancy in women with epilepsy, and experts maintain that over 90 percent of women with epilepsy can successfully carry pregnancies to term.
Proper management of pregnancy in women with epilepsy should ideally be instituted well before conception, experts maintain. But since 40 percent of all pregnancies in the US are unplanned, folic acid supplementation (at least one to four milligrams a day to help prevent neural tube defects) is recommended in women of childbearing age.
One chief concern among women (and their physicians) is the potential teratogenicity from epilepsy drugs. This risk often obscures the greater risk of uncontrolled seizures during the pregnancy, which can cause direct damage to the fetus by reducing placental blood flow and impairing fetal oxygenation.
Kimford J. Meador, MD, Professor of Neurology and Pharmacology/Toxicology at the Medical College of Georgia in Augusta, noted that there is a small group of women with extremely mild epilepsy who may be able to discontinue medications before conceiving. “By the time most women with epilepsy find out they're pregnant, it is too late to prevent possible anatomical defects. All that happens in the first six weeks.”
Dr. Meader cited reports that some women, upon discovering they are pregnant, discontinue medication on their own, or their doctors take them off the medicines, only to experience reoccurrence of their seizures. “That is not a very wise idea at all,” he said.
“While the effects of these anti-epilepsy drugs cause concern,” Dr. Meador continued, “the vast majority of babies are still normal, anatomically and in terms of their general IQ. We don't want to make women feel like they can't have babies, or that they can't take their medication. At this point, we do know the risks of seizures. Those risks outweigh the risks of taking the drugs. So we are trying to fine-tune this so we can make the best choices for women and give them more information. But it does need to be a balanced message: the vast majority of these babies are normal.”
AAN's practice parameters and recommendations by others strongly support taking the anti-epilepsy drugs throughout the pregnancy. (Parameters for trial withdrawal of AEDs in select women are also outlined.) Monotherapy, rather than polytherapy, is also recommended during pregnancy, as is vitamin K supplementation, to compensate for vitamin K deficiencies and help prevent hemorrhage in neonates exposed in utero to anti-epilepsy drugs.
AREAS OF INVESTIGATION
The risk of major malformations in babies born to women with epilepsy ranges from four to eight percent. The major birth defects associated with the older drugs, such as carbamazepine, phenobarbital, or phenytoin, include facial clefts and congenital heart disease. Carbamazepine and valproate are also associated with neural tube defects.
Researchers are currently seeking more information about women taking newer anti-epileptic drugs and the risk of birth defects, as well as the potential for later development of cognitive difficulties in these children.
Neurologists interviewed for this article strongly encouraged physicians to enroll their pregnant patients in two ongoing observational database studies – one based at Harvard Medical School, and the other at the Medical College of Georgia.
The Antiepileptic Drug Pregnancy Registry, based at Massachusetts General Hospital of Harvard Medical School, is particularly interested in women taking any of the newer drugs introduced after 1993.
“We have not been enrolling as many patients with the newer drugs as we would like,” Dr. Yerby said, “and therefore we're not getting the kind of data that we really need to help clinicians and their patients.”
Dr. Yerby speculated that lagging enrollment may reflect patients' concerns about confidentiality issues. The safeguards for protecting participants' privacy, as mandated by the study's institutional review board, dictate that the patients must be the ones to call in to register. “Once the pregnancy is completed and the data is collected, the person's name is purged and their data is entered into the database with the study number only. There's no way to trace any individual person.”
The Medical College of Georgia is the lead institution in a longitudinal observational study, Neurodevelopmental Effects of Anti-epileptic Drugs, which will follow for three years the children born to women with epilepsy taking carbamazepine, phenytoin or valproate monotherapy throughout their pregnancies.
According to Dr. Meador, the study's principal investigator, the 21-center NIH-funded study aims to determine the prevalence of diminished IQ and mental retardation in the children of women taking monotherapy, and to establish dosages at which these effects might be seen.
“When you look at the animal studies, it is clear that some of the older drugs have behavioral teratogenicity at dosages that are below those that induce anatomical birth defects, and at dosages that produce blood levels that are in the general range of what we use to treat women,” Dr. Meador said.
Moving into human data, the observations are less clear. One problem is that most studies on humans, to date, rely on retrospective data, and none of these have ever controlled for the mother's IQ as a covariant. Dr. Meador hopes to follow the children for up to six years, since predictive cognitive behavioral assessments can be conducted when children enter school.
Also planned is a parallel pilot study, with separate informed consent, to collect blood work from both mother and baby at the time of birth to ferret out some of the underlying mechanisms of anti-epilepsy drug behavioral teratogenicity.
“The major mechanisms that have been proposed,” explained Dr. Meador,“are reactive intermediates that include hypoxide hydrolase– about which there has been controversy, since the baby does not have the enzymes to form hypoxides – or free radicals. Now, free radicals can be formed in the baby, and that may be a possible mechanism. Another theory has to do with the interference of folate metabolism. We hope to get a parallel grant to look at these underlying mechanisms.”
Meanwhile, at Columbia Presbyterian Hospital, Dr. Morrell's colleague Alison M. Pack, MD, Assistant Professor of Clinical Neurology, is currently collaborating on a study following women aged 18 to 40 who take enzyme-inducing anti-epilepsy drugs to measure the effects on bone health.
Comparing participants' bone density scans at entry and one year, as well as urine and serum markers for calcium, the researchers now have preliminary data suggesting that women on carbamazepine have decreased bone density at the hip, and that women on phenytoin have high percentages of osteopenia.
“Ultimately, our goal is to establish research-based guidelines for following bone health,” said Dr. Pack. “Women on epilepsy drugs, especially the enzyme-inducers, should be aware of the long-term effects on bone health. They can follow this with a bone density screening test, specifically the DEXA (dual x-ray absorptiometry), and I would recommend supplementation with calcium: 1,000 mg for premenopausal women and 1,200 mg for pregnant and postmenopausal women, as well as 200-400 I.U. of vitamin D.”
Evidence of osteopenia on follow up DEXA studies might warrant intervention with a bisphosphonate. Dr. Pack's group also plans another study to compare the effects of carbamazepine and oxcarbazepine in both men and women to examine the mechanisms for effecting bone turnover.
Ms. Shafer, who, with Dr. Morrell, was instrumental in developing fact sheets as part of the Epilepsy Foundation's Women and Epilepsy Initiative, said it is crucial for women to be proactive. The Foundation launched its initia-tive in direct response to patients' needs, and has received enthusiastic feedback on their fact sheets, designed for both consumers and healthcare providers.“The ideal end result is that you're going to create a team, with the woman at the center and all her other caregivers working together.
“It is very sad that we still had laws recommending sterilization of women or prohibiting their getting married as recently as 20 years ago. Just removing those laws doesn't mean that the stigma's gone and that the misperceptions are gone. There's still a lot of work that needs to be done.”
ADDITIONAL RESOURCES ON TREATMENT FOR WOMEN WITH EPILEPSY
* The Summary Statement of the AAN Quality Standards Subcommittee's Practice Parameter on Management Issues for Women with Epilepsy is available online at:http://aan.com/public/practiceguidelines/wwe.pdf.
* “Seizure Disorders in Pregnancy,” an American College of Obstetricians and Gynecologists (ACOG) Physicians Educational Bulletin (1996:231:1-13) is available online at www.acog.org.
* The Epilepsy Foundation provides fact sheets written for women patients, with companion provider fact sheets, on a complete range of issues facing women with epilepsy throughout their life cycles. These topics include: hormone-sensitive seizures, hormonal contraception, adolescence, sexuality, pregnancy, postpartum issues, breastfeeding, and menopause. These are available from the Epilepsy Foundation, 4351 Garden City Drive, Landover, MD 20785; (800) 332-1000;www.epilepsyfoundation.org.
* “Guidelines for the Care of Women with Epilepsy,” by Martha J. Morrell, MD,– (Neurology 51(suppl4) 1998; 21-27), and“Seizures and Epilepsy in Women,” Chapter 14, Neurological Diseases in Women (Demos Publishing), pp. 189-206 are excellent supplements to professional practice guidelines.
* The Web site maintained by Dr. Yerby's North Pacific Epilepsy Research contains overview articles and resources for women with epilepsy, with an emphasis on issues related to pregnancy: www.seizures.net.
* “Early Hormonal Changes During Valproate or Carbamazepine Treatment: A Three Month Study,” a study by Dr. Iojarvi and others, appeared in the August 14th issue of Neurology. The study analyzed the effects of both drugs during the first three months of medication in men and women with recently diagnosed epilepsy.