Effects of Menopause on Seizures in Women with Epilepsy

Summary: Purpose: Although important associations between epilepsy and women's hormonal phases are described, the relation of menopause to epilepsy has received little attention. Methods: By using a structured interview, we studied menopausal women with epilepsy seen at the University of Maryland Epilepsy Center over a 1-year period from 1994 to 1995. We analyzed the characteristics and temporal relation of the seizures to menopause and compared the frequency and severity of the seizures with those in a similar group of premenopausal women. Results: We identified 61 menopausal women (46 who were postmenopausal and 15 perimenopausal) and compared them with 46 premenopausal women. No statistically significant differences were noted in either the frequency or the severity of seizures comparing all menopausal or only postmenopausal with premenopausal women. However, 12 (20%) of the 61 menopausal women noted that their seizures first began during or after menopause, with eight having no proven cause for their seizures. Many individual women described changes in their seizures with menopause. Among the 61 menopausal women, 49 had established epilepsy before the onset of menopause, and 20 (41%) reported worsening of their seizures with menopause, 13 (27%) noted improvement, and 16 (33%) described no changes. These observations were similar for peri- and post-menopausal women. Of the 15 menopausal women taking hormone replacement therapy, the six taking progestin were significantly less likely to report worsening of their seizures. Conclusions: These findings support the view that hormonal influences are important in women with seizures. Although, in aggregate, menopausal (combined perimenopausal and post-menopausal) and postmenopausal women's seizures were similar in frequency and severity to those of other women, menopause was associated with changes in seizures for some women. Moreover, menopause may be a previously unrecognized factor for some new-onset seizures. The relations between menopause and epilepsy deserve to be more fully investigated.     

Three Patterns of Catamenial Epilepsy

Summary: Purpose: On the basis of the neuroactive properties of estradiol and progesterone and the menstrually related cyclic variations of their serum concentrations, we propose the existence of three hormonally based patterns of seizure exacerbation. Because previous reports both support and refute the concept of catamenial epilepsy, we test the hypothesis by charting seizures and menses and measuring midluteal serum progesterone levels to estimate the frequency of epileptic women with catamenial seizure exacerbation. Methods: One hundred eighty-four women with intractable complex partial seizures (CPS) charted their seizure occurrence and onset of menstruation on a calendar for one cycle during which they had a midluteal blood sample taken for serum progesterone determination on day 22. Levels >5 ng/ml were considered ovulatory. The cycle was divided into four phases with onset of menstruation being day 1: menstrual (M) = -3 to +3, follicular (F) = 4 to 9, ovulatory (O) = 10 to -13, and luteal (L) =?12 to ?4. Average daily seizure frequency for each phase was calculated and compared among phases by repeated-measures analysis of variance (ANOVA) and the Student-Newman-Keul's test, separately for ovulatory and anovulatory cycles. Results: The 1,324 seizures recorded during 98 ovulatory cycles occurred with significantly greater (p < 0.001) average daily frequency during the M (0.59) and O (0.50) phases than during the F (0.41) and L (0.40) phases, offering support for perimenstrual (catamenial 1) and preovulatory (catamenial 2) patterns of seizure exacerbation. The 1,523 seizures recorded during 86 anovulatory cycles occurred with significantly lower (p < 0.001) average daily frequency during the F phase (0.49) than during all other phases (M = 0.78, O = 0.74, L = 0.74), offering support for seizure exacerbation throughout the second half of inadequate luteal phase cycles (catamenial pattern 3). Although 71.4% of the women with ovulatory cycles and 77.9% with inadequate luteal phase cycles had seizure exacerbation in relation to one of the three patterns of catamenial epilepsy, approximately one third of the women showed at least a twofold increase in average daily seizure frequency. We propose a twofold or greater increase as a reasonable definition of catamenial epilepsy. Conclusions: Charting of seizures and menses and determination of day 22 progesterone levels during each cycle may be sufficient to establish the existence of three distinct patterns of catamenial epilepsy. Approximately one third of women with intractable CPS may have catamenial epilepsy.     

Interactions Between Hormones and Epilepsy in Female Patients

Summary: Epilepsy and epileptic seizures may influence the release of hormones from the hypothalamus and the pituitary. After complex-partial seizures or generalized tonic–clonic seizures, serum prolactin increases in about two thirds of cases. Apart from this transient effect, interictal epileptic discharges from the temporal lobe may exert a prolonged influence on hormone release. Changes in luteinizing hormone (LH) pulse frequency and increased prolactin levels have been reported. As a consequence, menstrual cycles may be disturbed. The cyclic change of sex serum hormones during the ovulatory menstrual cycle may have an impact on seizure occurrence during the days of ovulation and/or menstruation (e.g., catamenial seizures). By a supplementation of progesterone during the second half of anovulatory cycles, a decrease of seizure frequency can be achieved.     

2005 AES Annual Course: Evidence Used to Treat Women with Epilepsy

Summary:  Although most female-specific considerations for treatment of epilepsy cannot be answered by Class I evidence, significant progress in our knowledge base has occurred in the past few years. Open-label studies of progesterone supplementation showed promising results; an ongoing randomized trial may provide definitive evidence for therapeutic use of progesterone in women. A randomized trial of hormone replacement therapy demonstrated a dose-related increase in seizure frequency in postmenopausal women with epilepsy. The use of different AED regimens during pregnancy cannot be explored with randomized, controlled trials; we must rely on the best available evidence from ongoing observational studies. The consistent findings of large prospective pregnancy registries reveal a consistent pattern of amplified risk for major congenital malformations in pregnancies exposed to valproate. These registries have also highlighted the concern for the effect of shifting hormones on AED concentrations. An increased frequency of seizures during pregnancy has been noted with lamotrigine (LTG) and oxcarabazepine, both of which undergo glucuronidation. Other studies have demonstrated an increased clearance of LTG during pregnancy and with exogenous estrogen use. It may be prudent to closely monitor serum concentrations of these AEDs with hormonal changes. An increased risk for neurodevelopmental consequences has been demonstrated for the fetus exposed to AED polytherapy, valproic acid, or frequent maternal convulsive seizures. Preliminary information about breastfeeding with LTG and levetiracetam is available. These newly released findings provide the tools to begin to practice evidence-based medicine when treating our female patients during their reproductive and postmenopausal years.     

Hormonal Effects on Epilepsy in Women

Summary: Some female gonadal and adrenal steroid hor-mones and their related pituitary peptides have neuroactive effects that can influence seizures. These effects may play a significant role in the pathophysiology of epilepsy, the pattern of seizure occurrence, therapeutic interventions using naturally occurring hormones, and the development of hormone-based neuroactive synthetic analogues with potent antiepileptic properties.     

From menarche to menopause: exploring the underlying biology of depression in women experiencing hormonal changes

Epidemiologic data consistently report an elevated prevalence of major depressive disorder (MDD) in women. This increase begins during adolescence and continues through the menopausal transition. Population-based clinical studies report an increase in the incidence of MDD during perimenopause compared to either the premenopausal or postmenopausal period. Evidence suggests that fluctuations and decline of hormonal levels are correlated with this observed increase in risk for MDD. A strong predictor of depression in the perimenopausal period is a previous history of MDD. However, recent studies revealed an increased risk of new onset depression in perimenopausal women without a history of MDD. Additionally, recent reports have indicated that the presence of vasomotor symptoms may be associated with an increased the risk for MDD. The objective of this paper is to review evidence that would support our hypothesis that neurotransmitter systems are affected by changes in hormonal status over the course of a woman's life, leading to increase vulnerability to perimenopausal depression. Relevant data from nonclinical experiments will be discussed in the context of observed clinical evidence of the risk for MDD before, during, and after the menopausal transition. A testable hypothesis will be proposed to advance our understanding of hormonal effects on mood.     

Effects of Epilepsy on Women's Reproductive Health

Summary: Reproductive dysfunctions are common and wide-ranging in women with epilepsy. Menstrual cycle disruption, anovulatory cycles, disturbances in hypothalamic andor pituitary hormones, and disturbances in gonadal steroids are more common among women with epilepsy. Sexual dysfunction can present as either disorders of desire or physiologic arousal, but the most common dysfunction appears to be an inadequate initial physiologic arousal response. Reproductive dysfunctions may be due to psychologic, pharmacologic, or physiologic factors. Physicians should routinely question all women with epilepsy regarding their reproductive and sexual health. A full history, a complete physical, and laboratory evaluations with endocrinologic work-up should be performed in any woman who reports a reproductive dysfunction. Treatment and or referral to a gynecologist or endocrinologist should be initiated as appropriate.     

Menopause, hormone replacement and RR and QT modulation during sleep

BACKGROUND AND PURPOSE: Sleep affects the RR interval in electrocardiogram (ECG) recordings and ventricular repolarization differentially in men and women. Compared to men, pre-menopausal women have a more pronounced shortening of RR interval and prolongation of QT and QT corrected (QTc, by Bazett's formula) ECG waves during rapid eye movement (REM) sleep. The aim of the present study was to evaluate sleep-related RR and QT changes: (1) with the physiological decline in female hormones occurring with menopause, and (2) after hormone replacement therapy with estrogen and progesterone (HRT). PATIENTS AND METHODS: We analyzed ECG recordings from 14 post-menopausal women (48-61 years old) who underwent polysomnography before HRT (T1) and after 6 months of HRT (T2) with estrogen and progesterone. Eight of the post-menopausal women (48-54 years) were also compared to eight age-matched pre-menopausal women. In all subjects, mean RR interval, mean QT interval and QTc, were obtained from 1-min recordings selected from wakefulness, stage 2 and REM sleep. RESULTS: Pre-menopausal and post-menopausal women showed similar changes in RR, QT and QTc intervals from wakefulness through sleep. Specifically, in both pre-menopausal and post-menopausal women the RR interval was shorter during REM sleep compared to wakefulness (P=0.009) and stage 2 sleep (P=0.001); the QT interval was more prolonged during stage 2 (P=0.002) and REM (P=0.006); and the QTc interval was significantly prolonged during stage 2 (P=0.01) and REM (P=0.0003) sleep compared to wakefulness. Among post-menopausal women, both before and after HRT (T1 and T2), RR interval shortened significantly during REM compared to wakefulness (P=0.03) and to stage 2 (P=0.002); the absolute QT interval was longer during stage 2, compared to both wakefulness (P<0.001) and REM (P<0.001); the QTc interval was increased during REM sleep compared to wakefulness (P=0.003). CONCLUSIONS: Sleep-related RR and QT changes in women are not altered by menopausal status nor by post-menopausal hormonal replacement with estrogen and progesterone.     

Hormones and Epilepsy Through the Lifetime

Summary: Hormones influence brain function from gestation throughout life and may affect the seizure threshold by altering neuronal excitability. Estrogen enhances and progesterone diminishes neuronal excitability experimentally, whereas testosterone and corticosteroids have less consistent effects. Hormonal effects in the CNS also depend on the region of brain in which the hormone acts. Sites of action for most steroid hormones include the hypothalamus and limbic cortex, providing a mechanism for modulating behavior and endocrine function. Seizure patterns may change at certain life stages, perhaps as a result of alterations in hormones. At puberty, epilepsy and benign rolandic epilepsy often remit, while juvenile myoclonic and photosensitive epilepsy may arise. Other types of epilepsy do not respond predictably to events in the reproductive life or to advancing age. In some women, fluctuations in hormones over the menstrual cycle appear to increase seizure vulnerability, probably reflecting changes in relative amounts of estrogen and progesterone. Seizure patterns can be altered, for better or worse, during pregnancy. Whether this reflects the effects of hormones or changes in levels of antiepileptic drugs is not resolved. More information is needed about changes in established epilepsy at menopause and in the elderly. Better understanding of endocrine effects on seizures over a lifetime should lead to more effective epilepsy therapies.     

Phenytoin-Induced Elevation of Serum Estradiol and Reproductive Dysfunction in Men with Epilepsy

Reproductive and sexual dysfunction in men with epilepsy has been attributed to androgen deficiency. Low serum free testosterone (FT) levels occur in both hypogonadotropic and hypergonadotropic hypogonadism. Antiepileptic drugs (AEDs) have been implicated. Proposed mechanisms include induction of increased sex hormone binding globulin (SHBG) resulting in decreased FT, as well as dysfunction or premature aging of the hypothalamopituitary-gonadal axis. In an investigation comparing serum reproductive steroid levels among 20 men receiving phenytoin (PHT) monotherapy for complex partial seizures, 21 untreated men with complex partial seizures, and 20 age-matched normal controls, total estradiol levels were significantly higher in the PHT group (56.3 +/- 29.4 pg/ml, mean +/- SD) than in the untreated (32.4 +/- 27.4 pg/ml, p less than 0.01) and normal control (34.3 +/- 12.7 pg/ml, p less than 0.05) groups. The physiologically active non-SHBG-bound serum estradiol levels were also significantly higher in the medicated group (45.1 +/- 21.7 pg/ml) than in the untreated (29.9 +/- 17.2 pg/ml, p less than 0.01) and normal control (31.1 +/- 11.4 pg/ml, p = 0.05) groups. These findings suggest that PHT may lower FT by induction of aromatase, enhancing FT conversion to estradiol, as well as SHBG synthetase. Estradiol exerts a potent inhibitory influence on luteinizing hormone secretion and has been suggested to play a major role in negative feedback in men as well as women. Suppression of LH secretion results in hypogonadotropic hypogonadism. Chronically low FT leads to testicular failure and hypergonadotropic hypogonadism. Finally, estradiol has been shown to produce premature aging of the hypothalamic arcuate nucleus, which secretes gonadotropin-releasing hormone.     

Obstetric and Gynecologic Care of Women with Epilepsy

Summary: Optimal gynecologic and obstetric care for women with epilepsy requires a multidisciplinary approach throughout the various life stages. Epilepsy has important effects on puberty, contraceptive efficacy, pregnancy and fetal development, and menopause. This article discusses these effects and makes recommendations for gynecologic and obstetric care of patients with epilepsy, with particular focus on pregnancy. Despite very real risks to both the developing fetus and the mother, the majority of women with epilepsy—with appropriate pregnancy planning and management—have good pregnancy outcomes.     

Prognosis of Epilepsy in Newly Referred Patients: A Multicenter Prospective Study of the Effects of Monotherapy on the Long-Term Course of Epilepsy

Summary: A cohort of 280 previously untreated epilepsy subjects (159 men and 121 women aged 2–81 years) recruited in 14 Italian centers were treated with antiepileptic drug (AED) monotherapy and followed for a median period of 48 months to investigate the rates of seizure remission (i.e., complete control), in general and with reference to various prognostic factors. The cumulative probability of achieving 1-year remission was 62% by 1 year after onset of treatment, 81% by 2 years, 92% by 3 years, and 98% by 5 years. The corresponding figures for 2- and 3-year remission at 5 years were 92 and 78%, respectively. Sixty-two patients (22.1%) had no remission period with monotherapy. Remission rates were significantly lower among patients with two or more seizure types and were inversely correlated to the number of seizures before treatment. The rate of seizure relapses during the first year of follow-up appear to correlate to the risk of developing refractory epilepsy (i.e., with no remission).     

Reproductive Function in Epilepsy

Summary: : The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.     

A Child with Epilepsy: Initial Presentation and Subsequent Course

Summary:  Presented is the case of a child with epilepsy with dramatic evolution between the ages of 18 months and 3 years. Initially, the case is one of treatment-responsive focal epilepsy, but then evolves to treatment-resistant focal epilepsy with an epileptic encephalopathy. The case demonstrates the poorly understood entities of age-related changes in seizure suspectibility, seizure types, and drug responsiveness.     

Is Cognitive Reserve Applicable to Epilepsy? The Effect of Educational Level on the Cognitive Decline After Onset of Epilepsy

Summary:  Purpose: The aim of this study was to know the effect of education level (EL) on the cognitive change after onset of epilepsy. The rationale is that people with high EL may have more cognitive reserve and show resistance to damage brought about by epilepsy.
Methods: Patients were from an outpatient epilepsy clinic of a national university hospital. All received initial and repeated neuropsychological tests and the Cognitive Ability Screening Instrument (CASI), at an interval of 12 months. CASI consists of nine items, with a total score of 100. We compared the differences between the two tests, in terms of z-scores. The EL was divided into high and low with a cut-off at 12 years, and age at entry was divided with a cut-off at 38 years. Epilepsy severity was divided into intractable and nonintractable.
Results: A total of 64 patients completed the study, including 31 with high EL and 33 with low EL, with no differences in gender and epilepsy severity between groups. In general, patients had cognitive impairment in multiple domains. At the baseline, the effect of EL was found for all items except remote memory and orientation, whereas the effect of age was observed for remote and recent memory. At the 12-month follow-up, subjects with high EL showed deterioration in mental manipulation, whereas subjects with low EL showed improvement in verbal fluency but deterioration in attention.
Conclusions: Patients with high EL have better cognitive functioning than those with low EL after epilepsy has developed, which supports the cognitive reserve theory. However, 1-year follow-up might be too short to see significant changes between groups.