 |
|
Updates on the Treatment of Epilepsy in Women
William O. Tatum IV, DO;
Joyce Liporace, MD;
Selim R. Benbadis, MD;
Peter W. Kaplan, MB, FRCP
Arch Intern Med. 2004;164:137-145.
ABSTRACT
| |
Epilepsy is a condition of the central nervous system that is characterized by recurrent seizures. The goal of management is to make patients seizure free without intolerable adverse effects from treatment. Men and women differ in their physiologic makeup and therefore have different needs that must be considered when attempting to attain this goal. There are special concerns for women of child-bearing years with regard to contraception, pregnancy, and teratogenicity that should be consided during counseling and selection of appropriate treatment. There are also emerging concerns about the interaction of antiepileptic drugs and endocrine function that can affect ovarian function, induce polycystic ovary (PCO)-like syndrome, and threaten fertility. Systemic adverse effects can have a negative impact on weight, cosmetic appearance, sexual function, and bone health. Individualized treatment coupling antiepileptic drug use and the specific phase of impact of the reproductive cycle must be considered in treatment selection. Important concerns regarding long-term therapy are being raised as there are more treatment options to consider because of the plethora of new antiepileptic drugs that are available, often with more favorable pharmacokinetics and different adverse event profiles. Also, sex hormone fluctuations during maturation may exacerbate seizures at particular points during the life cycle for women, including menarche, during menses, during pregnancy, or later in the perimenopausal years, often presenting a uniquely challenging aspect to treatment. As the number of available treatment options for epilepsy increases, the optimal goal for primary care physicians is to work as a team with obstetricians, gynecologists, and neurologists in an effort to ensure the best treatment of women with epilepsy.
INTRODUCTION
Seizures are one of the most common neurologic conditions in clinical practice. Up to 3% of the population will be diagnosed with epilepsy by 75 years of age.1 In the United States, there are approximately 2.8 million persons with epilepsy.2 While the incidence of epilepsy is slightly higher in men, there is a trend of female predominance during the first 5 years of life.1 Overall, there are more than 1.1 million women of childbearing age with epilepsy.2 Physiologic and hormonal differences between women and men pose unique challenges for the physicians who are treating women with epilepsy (WWE). Adrenal and gonadal sex hormones, as well as antiepileptic drugs (AEDs), may influence and be altered by seizures.3 When the use of AEDs is considered, the relationship to pregnancy, catamenial seizures, and menopause present practical problems for treating WWE. Treating WWE throughout the reproductive cycle warrants the prophylactic use of folic acid, with attention to potential preg nancy, inactivation of contraception by AEDs, and a heightened awareness of the possibility of birth defects should pregnancy occur. The potential for anomaly, teratogenicity, and heightened risk of a poor outcome exists, and creates a formidable obstacle for any physician and WWE who is considering becoming a mother when they are choosing therapy for epilepsy. National registries have been formed to track the outcome of women who were exposed to AEDs during pregnancy. The effect of hormonal influence on seizure frequency presents unique management challenges for women with catamenial seizures. Unique gender-based comprehensive health care involves sexual dysfunction, menstrual cycle irregularities, contraception, and pregnancy, which are special issues that are critical for the optimal treatment of WWE. Seizures may be triggered during menarche, with effects lasting through the perimenopausal period of life.4
Today, there is a greater focus on the potential for adverse cosmetic effects of treatment, such as coarsening of facial features, excessive hair growth, gingival hyperplasia, weight gain, and tremor, which can visibly alter body image and which for some patients are worse than the original condition. General health issues include maintaining ideal body weight and the integrity of bone mass, both of which are capable of being adversely affected by AED treatment. Practice parameters for treating WWE are now available to guide management.5-6 It is critical that certain practices are adhered to and supported by appropriate patient instruction. For primary care providers, an understanding of the principles of treatment is essential to the optimal treatment of WWE.
THE BALANCE OF HORMONES
A major difference between men and women is the genetically determined influence of sex hormones on biologic systems. Male and female sex steroids have profound effects on normal maturation and development and determine human sexual phenotype. The distribution of estrogen receptors in the brain changes through the process of maturation during female development.7 Animal studies have demonstrated that estrogen receptors are present in the neocortex of the brain during development and that they later redistribute within the limbic cortex and decrease in the neocortex after puberty.3 Estrogen and progesterone may influence abnormally functioning cortical neurons by altering the seizure threshold.2-3 Also, normal levels of circulating sex hormones may be altered by the AEDs used to treat seizures.
At the cellular level, estrogens bind to the  -aminobutyric acid (GABA) type A (GABAA) receptor site on the cell membrane and promote neuronal excitability though direct membrane and genomic effects.3 Altered transcription of messenger RNA–encoding cellular enzymes that regulate GABA synthesis also occurs. Synthesis of GABA, as well as of the GABAAreceptor, is reduced, thereby decreasing neuronal inhibition and facilitating seizures.3 Estrogen also activates the N-methyl-D-aspartate excitatory neurotransmitter receptors in the hippocampus to stimulate excitation3, 7 and has been found to regulate dendritic spine density in rat hippocampi.8 The overall effect of estrogen on cortical neurons is to promote seizures (proconvulsant effect). Progesterone has the opposite effect on GABAA, N-methyl-D-aspartate response, and both GABA and GABAAreceptor synthesis.3, 7 Therefore, progesterone increases inhibition, decreases excitation, and reduces seizures (anticonvulsant effect).
PRIMARY ENDOCRINE FUNCTION
Epilepsy influences hormonal release.9 The hormonal cycling that normally occurs often plays a role in significantly altering seizure frequency,10-14 and the influence on seizure has frequently been observed by WWE. The monthly menstrual cycle is regulated by the hypothalamic-pituitary-ovarian axis.2-3,6 Gonadotropin-releasing hormones are released in a pulsatile fashion from the hypothalamus to effect pituitary production of follicle-stimulating hormone and luteinizing hormone. Increased development of the ovarian follicles during the first portion of the cycle occurs as a result of the release of follicle-stimulating hormone. The follicle secretes estrogen in the form of estradiol-promoting endometrial proliferation to augment implantation of a fertilized ovum. A feedback system within the axis allows greater release of follicle-stimulating hormone as well as luteinizing hormone when the follicle develops to the point of rupture with ovum release. The corpus luteum then forms, producing progesterone. When implantation of a fertilized ovum does not occur, after 2 weeks the endometrium is sloughed, resulting in menses.
Complex partial seizures are the most common seizure type and usually arise from medial temporal lobe structures. Epileptic activity may propagate to the hypothalamus, altering normal pituitary gonadotropic hormone release, which in turn alters sex steroid release. Anovulatory cycles, infertility, and irregular menses subsequently occur. Interictal alteration in the release of luteinizing hormone from the pituitary gland can occur in women with partial epilepsy,15 as well as in those with primary generalized epilepsy.16 The manifestations ultimately depend on the type of epilepsy and the AED used, as well as on a woman's baseline general medical health. Elevated circadian serum prolactin levels and sex hormone–binding globulin levels are increased in women with partial epilepsy.9 Also, the levels of thyrotropin, luteinizing hormone, estradiol, and dehydroepiandosterone are reduced and affected by the choice of the AED.10 Seizures themselves may induce further changes in the secretion of pituitary hormones. For example, prolactin levels often increase after seizures. The measurement of this hormone concentration has been used clinically to differentiate epileptic seizures by demonstrating an increase from baseline levels as opposed to nonepileptic seizures that do not show the increase.17 Postictal increases of cortisol and growth hormone may be measured as well.11
THE EFFECT ON SEIZURE OCCURRENCE
Seizures appear to be influenced by the relationship between the proconvulsant effects of estrogen and the anticonvulsant effects of progesterone. Some WWE experience an increase in frequency or severity of seizures before or during menses.2-3,6, 18-23 Catamenial epilepsy occurs when seizures are exacerbated primarily or exclusively during the perimenstrual period. Overall, approximately one third of WWE have seizures that increase 2-fold around menses; however, a wide range has been described because of inconsistencies in the definition of catamenial.18-22,24 Although definitions have varied, a greater than 2-fold increase in seizures has been suggested.22 Women with catamenial seizures are most vulnerable to seizure increases when estrogen levels are high, and when the corpus luteum that normally secretes progesterone does not form at ovulation, the effects of estrogen go unchallenged. Three common patterns of increased seizure have been described24: immediately before menses, during the second half of menses, and at ovulation.24-25 Seizure exacerbation may occur, especially when the cycles are anovulatory.24-25 During the cycles when ovulation is absent, physiologic progesterone peaks do not occur and the estrogen-progesterone ratio remains constantly elevated. Subsequently, seizures are more frequent than when ovulation occurs. When patients have an anovulatory cycle or inadequate luteal phase, progesterone may be supplemented with exogenous progesterone to provide antiepileptic properties. A basal body temperature that increases less than 0.7°F (-17.4°C) for at least 10 days during the second half of the menstrual cycle, a serum progesterone level of less than 5.0 ng/mL during days 20 through 22, or a biopsy specimen with evidence of underdeveloped secretory endometrium 8 to 10 days after ovulation indicates that there is an insufficient progesterone response.22 Progesterone therapy (taken as 100- to 200-mg lozenges 3 times a day) during days 15 to 25 to produce luteal progesterone levels of 5 to 25 ng/mL (1-5 nmol/L), with subsequent tapering of the dosage over days 26 to 28, has effectively decreased complex partial seizures by 65% and generalized tonic-clonic seizures by 74% during a 3-year follow-up period in 1 uncontrolled study.26 Suppression of the hormone fluctuations associated with the menstrual cycle has also been evaluated using synthetic gonadotropin-releasing hormone analogues.27 Hormone therapy has been used in patients with hormone-sensitive seizures, although the risk of treatment should be discussed with the patient and with a gynecologist.
ANTIEPILEPTIC DRUG IMPACT ON ENDOCRINE FUNCTION
The impact of drug treatment may have ramifications on endocrine function beyond the influence on seizure frequency alone. Antiepileptic drugs may affect the function of neurotransmitters, including GABA and glutamate, the major inhibitory and excitatory neurotransmitters in the brain.3 Women taking AEDs are more likely to have hormonal abnormalities of the endocrine system than those who are not, especially AEDs that are metabolized by the cytochrome P450 hepatic enzyme systems. Furthermore, AEDs may affect pituitary hormone function via a direct effect on cortical input to the hypothalamic-pituitary-ovarian axis or alter gonadal hormonal feedback, which could affect gonadal and adrenal sex steroid output.3, 7 Also, enzyme-inducing AEDs (EIAEDs), such as carbamazepine-oxcarbazepine, phenytoin, phenobarbital-primidone, and topiramate, may reduce levels of circulating estrogen and progesterone in the body and alter protein binding.2-3 As a result, higher levels of steroid hormone–binding globulin and subsequently reduced unbound steroid hormones that are biologically active are available for normal function. Sex steroids appear to be neuroactive proteins. In essence, estrogen creates the cellular effect of neuronal excitability, and progesterone promotes neuronal stabilization. Enzyme induction is important not only for sex steroid availability but also for maintaining the efficacy of synthetic oral contraceptive pills.2-3,28
REPRODUCTIVE FUNCTION
As recently as the 1980s, WWE were said to be "unfit parents" and were banned from marriage and legally prevented from bearing children in some states in the United States!29 Social stigma has diminished with increasing awareness that patients with epilepsy can lead normal lives.
THE EFFECT ON OVARIAN FUNCTION
Epilepsy may be associated with a greater risk of ovarian dysfunction, leading to premature ovulatory failure, PCOs, and reduced fertility.28 Seizures or interictal epileptiform discharges can disrupt the hypothalamic-pituitary-ovarian axis, thus altering hormone secretion. The menstrual cycle may become irregular, prolonged, oligomenorrheic, or even amenorrheic.2 Fertility may also be compromised, with a greater risk of miscarriages and pregnancy-related complications when conception does occur.30-31 Polycystic ovary–like syndrome should be suspected when irregular or anovulatory menstrual cycles develop in WWE who are obese or hirsute. The syndrome is characterized by multiple cysts (at least 8), with ovarian enlargement and thickened stroma, and may be visualized on pelvic ultrasound. Altered endocrine function, including elevated androgen levels, may cause acne, excess growth of body and facial hair, weight gain, irregular menses, ovulatory failure, and infertility. Hyperinsulinemia due to insulin resistance, with PCOs, promotes androgen production. A higher incidence of PCOs32 and higher androgen concentrations33 have been noted in WWE. The cause-and-effect relationship between specific AEDs, such as valproate,33-34 that has been described, however, is controversial and requires further validation. It has been suggested that PCOs and/or hyperandrogenism often occurs in obese women who have been exposed to valproate,32-34 although this theory has not been validated by other studies and is at odds with reported clinical experience.35 Nevertheless, if women who have been treated with valproate develop symptoms of PCO-like syndrome, their physicians should consider changing their AEDs or prescribing adjunct hormone therapy. Enzyme-inducing AEDs, such as carbamazepine, phenytoin, phenobarbital, topiramate, tiagabine, and oxcarbazepine, decrease the circulating sex steroid effect by inducing cytochrome P450 hepatic enzymatic degradation. Increases in steroid hormone–binding globulin levels reduce the unbound hormone concentrations that are available to exert the desired antiepileptic effect.
MENARCHE TO MENOPAUSE: THE EFFECT ON SEIZURES
Seizure patterns can change with menses, but they may also change during evolution of the female reproductive cycle from menarche through menopause. The expression of epilepsy may change over an individual's lifetime as hormonal balance changes.36 Puberty, menarche, menses, and menopause are times when the reproductive hormones may have a profound impact on seizures. An increase in generalized tonic-clonic seizures has been noted during puberty.12 Furthermore, juvenile myoclonic epilepsy often begins during puberty. Conversely, other primary generalized epilepsies and benign partial epilepsies of childhood can enter remission. The hormonal underpinnings in these situations are incompletely understood.
Menarche and menses may herald or continue to exacerbate seizures. Gonadotropin-releasing hormone secretion in children is extremely low and slowly increases for several years prior to menarche.2 Hormonal influences remain important in women through menopause, although information regarding these influences is limited.4, 37-38 Menopause typically begins between the ages of 48 and 55 years, as women enter the latter third of their lifespan.4 Seizures may begin during menopause independent of a known symptomatic cause.4 Often, seizure patterns may change. Catamenial epilepsy has been associated with improvement in menopause as estrogen concentrations decline.13 Hormone therapy can provide a beneficial effect against the risk of osteoporosis or possibly dementia of the Alzheimer type developing.37 Hormone therapy consisting only of estrogen-containing preparations may worsen seizure activity, as noted by patient survey evaluation, although information is limited4, 38-39 and the response appears to be mixed.4, 16 Patients who were also taking progesterone as part of their hormone therapy were more likely to report improvement rather than worsening of their seizures.4 Therefore, combination therapy appears to be useful even if women have previously undergone a hysterectomy.37
SEXUALITY
Most WWE appear to have normal sex lives, although approximately 33% to 50% of them may experience some degree of sexual dysfunction.2, 24, 40-41 Greater levels of anxiety and apathy related to sexual performance as well as reduced vaginal lubrication and genital blood flow and increased dyspareunia and anorgasmia during intercourse have been reported.3, 40 A multifactorial cause appears operational. Important regions of cerebral cortical dysfunction, the effect of recurrent seizures and AED treatments on normal hormonal function, and the psychosocial implications of having epilepsy are involved. Sexual dysfunction is best defined for localization-related epilepsy associated with recurrent partial seizures.3-6,13, 31, 36, 40 Seizures arising from limbic structures disrupt function in the neighboring hypothalamus and medial frontal lobe, which are important in regulating expression of libido and arousal.40-41 Also, seizures electrically alter hormonal function14 via pituitary secretion, creating sexual dysfunction.40 It has been reported that AEDs can interfere with circulating sex steroid concentrations2-3,6 and directly influence mood and behavior, thereby affecting sexual desire. Despite the problems encountered in WWE, evaluation is required to exclude other systemic or gynecologic causes for appropriate treatment, and counseling is also necessary.
CONTRACEPTION
|
