Historically epilepsy, or recurring seizures, is a common illness in both genders. Showing no predilection for male or female, recurring seizures occur in between 0.8 and 1.2% of the American public. A frequent problem is that research excludes women as research candidates, limiting the information available concerning epilepsy in women. In years past, such presentations on women's issues with respect to epilepsy would have been restricted to pregnancy alone. It has become increasingly clear that many additional elements in epilepsy require specific attention when dealing with the female patient.
Epilepsy and reproduction
Puberty and the onset of the menstrual cycle is potentially one of the least studied portions of reproductive life. This stage involves predominantly children and few publications actually exist addressing whether or not the relationship between epilepsy and the onset of the menstrual cycle exists. It is very common to hear that the onset of their seizures occurred around the time of the onset of their menstrual cycle in women. No study has been performed looking at the relationship between these two events, but authors have looked at girls with epilepsy and not identified an effect of epilepsy on the onset of the menstrual cycle. Two publications do address if epilepsy affects menarche. One author strongly recommends eliminating medications before menarche if possible. An additional study of a large number of children sees no effect of epilepsy on the puberty development cycle. They strongly recommend that any child who is not experiencing normal development of sexual differentiation be evaluated for a cause. Epilepsy has never been shown to produce a delay or acceleration of this process.
Much more study has gone into the period known as perimenopause and menopause. Menopause is the stage of the reproductive life when hormones that control reproduction decrease with fewer menstrual cycles. The onset of menopause is not immediate, and the period immediately prior to menopause with many menstrual irregularities is perimenopause. Perimenopause is associated with cycles that are of irregular length and decreasing hormonal levels. Perimenopause is also associated with instability in the blood vessel system that individuals experience a phenomenon referred to as hot flashes where perceptions of body temperature are markedly altered.
Recently there has been significant interest in perimenopause and menopause with respect to their effect on epilepsy. No effect of epilepsy on perimenopause and menopause has been discovered. Significant studies of the effects of perimenopause and menopause on the seizure frequency are available. One study reported by Dr. Harden of Cornell University suggests that the period of perimenopause is significantly associated with an increase in seizure frequency in a group of patients followed by Dr. Harden. Women patients experienced an increase in their seizures compared to the earlier portions of their life. Menopause was associated with a significant reduction in seizures. Approximately one half of patients during the menopausal period reported that their seizures were significantly less than earlier in their life.
This study reported that women experiencing an increase during their perimenopausal stage were the same group of individuals experiencing a reduction during their menopause. This group also had increases in their seizures during their menstrual cycle earlier in life. This group appeared to have seizure increases when exposed to hormone replacement therapy. Hormone replacement therapy involves the taking of Estrogens to attempt to replace the normal secretion of Estrogen in the body to diminish some of the side effects and symptoms that are associated with the onset of perimenopause. Hormones are generally known to be Estrogen-like substances and the traditional treatment is the medication Premarin.
Women also experience seizures associated with their regular menstrual cycles. The menstrual cycle is associated with an increasing frequency of seizures. Between 15 - 70% of women have increased seizures during their menstrual flow. Originally referred to as catamenial epilepsy, it is now obvious this increase is not as unique a condition as was once anticipated. Depending on how rigidly one defines catamenial epilepsy, as having all seizures occur three days prior to or three days following the menstrual flow vs. having a majority of seizures occur during this time, the frequency of catamenial epilepsy is estimated to be as high as 70%. So, the majority of women report the majority of their seizures occurred during their menstrual flow. Research that has been done has suggested that the hormone associated with the menstrual flow known as Estrogen has an important role in the seizure process. Estrogen balances with a second hormone known as Progesterone. The variations of these hormones produce the menstrual cycle and a cycle of seizure frequency.
Estrogen is a well-known proconvulsant substance which can be used to actually induce seizures when placed directly on the surface of the brain. Progesterone serves in an opposite function to actually reduce the tendency of the brain to experience seizures. Several studies have been done looking at compounds which affect these hormones and the affect that they may have on seizures. A well known agent used to increase the fertility of women, Clomiphene was described by a physician at Harvard University, Dr. Herzog, as improving seizure frequency. With that experience, additional attempts at modifying the relationship between hormones involved in the menstrual cycle was made.
Dr. Herzog looked at the administration of Progesterone as a treatment for epilepsy. He used a 200mg tablet of Progesterone three times a day and was able to see significant reductions in seizures in nearly 70% of the patients who attempted the use of the medicine. No significant side effects were seen, and Dr. Herzog reported that the majority of patients remained on the medication for periods of up to three years experiencing more than 50% reductions in their seizures while on the Progesterone. Further study of Progesterone is ongoing. While progesterone is an uncommon treatment in general for the treatment of epilepsy, some epilepsy centers are involved in clinical testing of this process, and there is one federally funded, large study which is only a portion of the way completed, with investigators such as Dr. Hertzog and Harden.
The addition of extra medications during the menstrual cycle is used in catamenial seizures. Systematic studies of this approach have not been completed, but antecedotal attempts at increasing of patient's current medication while adding a second medication have been undertaken. Historically the use of Acetazolamide has been considered a treatment for women who experience this form of seizure. Significant studies do not exist and no controlled trials of this approach exist as well.
Epilepsy, bone health and sexuality
Bone health is important in the health of women because women appear to have a predisposition to develop osteoporosis. Osteoporosis, or thinning of the density of the bone, can be associated with an increased chance of breakage of bone and can lead to significant disability from broken bones in the back and limbs. The effects of epilepsy on sexuality appear to reduce general satisfaction and produce negative emotional and physical effects on women who have epilepsy.
For a long time bone health has been an issue in the treatment of epilepsy. Some medications haven been identified historically as being associated with poor bone maintenance and it was assumed seizure medications blocked the vitamins that are responsible for bone health such as Vitamin D. Recently it appears that there is a more complex relationship that may exist. It is identified that several anticonvulsants such as Tegretol, Depakote, and Dilantin have been associated with reduced bone development, and additional studies have shown that Vitamin D levels do not appear to be fundamentally involved in the process of bone strength. While it is yet unproven, it has been suggested that the effects of anticonvulsants may be to modify the influence which Estrogen has on the bones. Areas of research in this problem are currently underway.
Sexuality has been reported to be influenced by epilepsy and by the medications potentially that are used in the treatment of epilepsy. Women were originally noted to have a lower fertility rate when experiencing seizures. This phenomenon was also noted in men but appeared to become normal in men who married while in women fertility rates remained low. Dr. Morrell investigated the nature of sexual satisfaction in women who were experiencing epilepsy. Using a questionnaire, she gathered significant information to suggest that there were elevations in anxiety and discomfort associated with the sexual act in women with epilepsy when compared to a control group.
Surveys are easily criticized as being reflective of an individual's perception of their situation, and Dr. Morrell was able to similarly study physical effects associated with sexuality and epilepsy. Dr. Morrell measured increases in blood flow in the genital area associated with viewing erotic material. She was able to show that individuals with epilepsy experienced significant reductions in physiological changes associated with sexual stimulation which occurred in both men and women. While the specific causes of this phenomenon are unclear, it is definitely an area of some considerable interest and potentially plays a role in a higher infertility rate in women who experience seizures.
Conception and contraception
The third area which is unique in women with epilepsy is issues that revolve around conception and contraception. Contraception is the attempt regulate the time of conception. Contraception can definitely be affected as many seizure medications lowering the effect of birth control pills (BCP). Medications that potentially can effect birth control pills include Phenobarbital, Dilantin, Tegretol, Carbatrol, Gabitril, and Topamax. Drugs which are not associated with these effects include Depakote, Neurontin, and Lamictal. This interaction between BCPs and seizure drugs is not one that is well appreciated by many medical practitioners. A survey conducted by Dr. Krauss at John Hopkins University attempted to identify what knowledge physicians had concerning the effects of seizure medications on BCPs. He determined there was a very low knowledge about interactions between seizure drugs and BCPs. Unplanned pregnancies occur if BCPs are impaired by seizure medications. His study showed that no obstetricians and only 4% of neurologists surveyed knew the effects of the most commonly used seizure medications on BCPs.
Conception is also significantly impacted by epilepsy. The effects are different with different types of epilepsy. The presence of lower conception rates in epilepsies of the temporal lobe have been described. Effects from of epilepsy are a likely altering of the secretion of hormones regulating fertility. Further research is necessary in this area to further show these effects.
In addition, there appears to be an increased frequency of a condition known as Polycystic Ovary Syndrome. This condition involves the formation of fluid filled cysts in the ovaries. These fluid-filled cysts are the remnants of normal cystic growth in the ovaries, but if they enlarge and stay enlarged, they can hamper the ability of the ovary to secrete eggs and produce fertility. Polycystic Ovary Syndrome can lead to infertility. It has been associated with some forms of epilepsy and has been suggested to be related to an antiseizure drug, Depakote. While these effects are still under study, physicians are carefully, currently considering the use of and effects of Depakote on women's fertility.
Finally pregnancy is potentially modified by epilepsy and epilepsy modified by pregnancy. Studies have suggested that epilepsy itself does not appear to be significantly modified, although some women do experience increases in their seizures, others experience decreases and overall change in seizure frequency for women during pregnancy is stable.
Several issues come up regarding pregnancy and epilepsy. These include the safe use of seizure medications by women during pregnancy and precautions during pregnancy with respect to women with epilepsy.
Probably the most common of these concerns is seizure medication use during pregnancy. This issue has always been studied in ways that fail in providing important information. That important information, of course, being the safety of seizure medications for the developing fetus. Several medications have been both historically and repeatedly shown to have negative effects on the fetus. Medications such as Dilantin, Carbatrol, or Depakote have been associated with an increase in major malformations and carry a warning that they should only be used when absolutely necessary. The remainder of seizure medications carry a warning of potential harm but no clear studied effects that recommend that they not be used.
Currently a large scale study is underway in attempts to document how safe seizure medications are is being conducted at Harvard University and has been underway for many years. Unfortunately this study does not have significant numbers of women whose pregnancy was exposed to specifically new seizure medications, so it leaves great holes in our knowledge about the safe use of seizure medications. Some pregnancy registries exist outside of the Harvard registry undertaken by governments; for instance in Europe or by the pharmaceutical sponsors themselves. Lamictal has a significant number of patients (greater than 400) exposed to their medication and no pattern of specific seizure malformation has been seen. Additional, careful registries of all pregnancies reported are available for medications including Neurontin, Topamax, and Trileptal, but all of the numbers of exposures are below what is believed to be an important threshold number of 400 patients and hopefully in the years to follow these reports will be completed and these medications safety profiles can be established.
Seizures themselves appear to have an effect on the developing fetus but few studies have been able to identify how many seizures produce a specific risk. When studied in a specific Chinese population, women experiencing more frequent seizures tended to have more fetal abnormalities, but this same group of women were also exposed to more seizure medications. The more medications that a woman takes, the more likely they are to experience a fetal malformation as a result of their pregnancy.
These gloomy reports of increased fetal abnormalities need to be taken into context. While no negative outcome is acceptable, the normal population experiences human malformations at a rate of approximately 1/2 %. An overall increase in this frequency occurs on the order of between 3 and 5 times. This, in context, means that 95 - 97% of pregnancies in women on anticonvulsant agents happen without major malformations. Importantly, this risk to human development must be put in perspective.
Finally the period of delivery and the management of seizure medications can be of some additional difficulty. Seizure medications often change the body's ability to eliminate them. As pregnancies advance, both kidney and liver functions are altered. Women experience increases in the quantity of blood within their blood stream, as well as increases in the activities of their livers. Some medications such as Tegretol and Lamictal can have dramatic swings in blood concentrations during pregnancy. These seizure medications generally need to be monitored much more frequently, anywhere from monthly to weekly when these changes occur. At the time of delivery, supplementation with Vitamin K to avoid bleeding difficulties is also often necessary.
All women need to have Folate supplementation during pregnancy. Women with epilepsy have been described as benefiting from on-going Folate supplementation, so as to provide a good Folate level prior to conception. This assures that fetuses do not experience an undo risk from relative Folate deficiency.
These issues cover many areas pertaining to women and epilepsy and what makes their situation unique. There are potentially many others that may come up, but these cover many of the traditionally identified areas. If they apply, these should be part of the discussion that each woman has with the physician treating her epilepsy.