Seizures that occur around the menstrual cycle are called catamenial epilepsy. Studies show that changes in seizures are most often in the. Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein. Epilepsy is a chronic neurological condition characterized by recurrent seizures. Catamenial epilepsy is a subset of epilepsy, which includes women whose.
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Catamenial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual cycle, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition. To date, there are no specific drug treatments for catamenial epilepsy however, non-hormonal and hormonal therapies have been proposed.
The aim of this review is to report preclinical and clinical evidences about the relationship between female reproductive steroids and epileptic seizures, and to describe treatment approaches for catamenial epilepsy.
Women with epilepsy may have seizure patterns associated with changes in estrogen and progesterone levels. In catamenial epilepsy seizures tend to cluster in relation to the menstrual cycle; 4 this may be construed as a greater increase in seizure frequency during a particular phase of the menstrual cycle.
Knowledge of the effects of sex hormones on epilepsy may open new therapeutic approaches, in addition to antiepileptic drugs, for women with catamenial seizures pattern. Catamenial epilepsy is believed to occur secondarily to the neuroactive properties of endogenous steroid hormones and the natural cyclic variation in their serum levels throughout the menstrual cycle. Herzog 4 distinguished three patterns of catamenial seizure exacerbation, relating to the ctamenial seizure occurrence during the specific phases of the menstrual cycle: Probably, the sudden withdrawal of progesterone, analogous to a benzodiazepine withdrawal, could be the cause of the premenstrual rise in seizure epilepdy, while, during the days catmaenial ovulation, the rapid and steep rise in serum estradiol concentration is believed to be responsible for the increase of seizures at that time.
In women with anovulatory cycle, in which luteal phase is characterized by low levels of progesterone, seizure frequency increases in the premenstrual phase because the mid cycle surge in estrogen still occurs, without a significant increase in progesterone levels. Interestingly, some studies have shown that catamenial epilepsy is substantially and statistically significantly more common among women with left temporal foci than among those with right temporal foci.
Furthermore, Quigg et al 19 also reported that age affects overall seizure rate: Because this factor is phase-independent, the modulatory effect of age may arise from factors outside the cyclic effects of the hypothalamic-pituitary- gonadal axis. It is known that estrogen and progesterone have important effects on neuronal catameniak and plasticity in widespread cerebral and brainstem regions, 20 through their capacity to regulate synthesis, release, and transport of neurotransmitters.
Estrogens have proconvulsant and epileptogenic properties in animals and humans. There are also studies that support protective effects of estrogen and that suggest that it may also be anticonvulsant under some circumstances.
In cayamenial models, the thresholds of limbic seizures in female rats are inversely related to estradiol levels, 22 and intravenous or topical administration of estradiol in rabbits increases spontaneous electrically recorded paroxysmal spike discharges.
The mechanism by which estradiol increases neuronal excitability is not clearly understood; however, in experimental studies, there are many factors influencing effects of estrogen on seizure susceptibility, such as sex, age, the hormone species natural or syntheticregional epiepsy of hormone receptors, treatment duration, time interval for initiation of hormonal treatment following gonadal removal, route of administration, as well as the dose.
NMDA-mediated calcium entry increases with a larger amount of excitatory inputs to the pyramidal cells. Logothetis et al 28 have demonstrated that intravenous infusions of estrogen were associated cagamenial rapid interictal epileptiform activity in women with epilepsy, and that seizures catmaenial exacerbated when estrogen was given premenstrually. Therefore, it is hypothesized that estrogens may facilitate some forms of catamenial seizures observed during these phases.
The periovulatory catamenial exacerbation has been attributed to the midcycle surge of estrogen that is relatively unopposed by progesterone until early luteal phase. They also reported that in many patients with catamenial epilepsy, a marked increase in spike and wave discharges are observed during menstruation.
In contrast, there are several studies of chronic estrogen administration in females that show either anticonvulsant or no effect of estrogen on seizures. The neuroprotective activity of estrogens was then confirmed by several subsequent studies. Animal and humans studies 3839 clearly indicate that catamenial seizures are associated with a rapid decline in progesterone immediately before, during, and after menstruation. In animal models, progesterone has been found to reduce neuronal firing and decrease spontaneous and induced epileptiform discharges.
In clinical studies, progesterone has been found to reduce seizures. A recent study used transcranial magnetic stimulation to investigate the changes in cortical excitability during anovulatory and ovulatory cycles: The rise in progesterone levels during the luteal phase of the ovulatory cycles and the progesterone withdrawal during menstruation did not induce significant changes in any of the transcranial magnetic stimulation parameters.
Furthermore, there was no correlation between progesterone levels and intracortical inhibition. Physiological actions of progesterone are mediated by progesterone receptors PRa member of the nuclear receptor superfamily of transcription factors. However, there is strong evidence that the antiseizure effects of progesterone are not related to interactions with classical PR; in fact, the antiseizure activity of progesterone was undiminished in PR knockout mice, 1 which are generated by a null mutation of the PR gene.
Thus, the role of the PR in seizure susceptibility has not been fully explained. To date, a rapid effect of progesterone has been reported in the hippocampus slice excitability, that was blocked by the PR antagonist RU It causes a transient increase in dendritic spines over the first 6 hours of exposure, followed by a decrease in the number of CA1 dendritic spines and excitatory synapses.
Progesterone also antagonizes estrogen actions, lowering estrogen receptor number. The marked hormonal changes that occur in the menopausal transition seem to have an effect on seizure susceptibility. Women with catamenial epilepsy may experience an increase in seizure frequency in perimenopause and a decrease after menopause, which is consistent with the high estrogen levels in perimenopause, and low estrogen levels in postmenopause.
In experimental studies on ovariectomized animals where hormonal changes are abrupt, in contrast to the gradual hormonal changes found in the menopausal transition, the concerted lack of estradiol and progesterone may facilitate the seizure susceptibility. In fact, both estradiol and progesterone affect the GABA function; therefore, the simultaneous decrease of estrogen and progesterone may lead to a decrease in GABAergic inhibition, facilitating seizures.
Interestingly, the standard hormone replacement therapy which includes estrogen and a progestin can be postulated to have an effect on seizures in postmenopausal women with epilepsy that is more evident than that of oral contraceptives in cycling women with epilepsy, because reproductive hormone levels during menopause are low and unchanging.
The brain hormonal milieu in which exogenous hormones are introduced is markedly different in menopause from that in menstruating women. Finally, postmenopausal women with epilepsy deserve a special attention about the choice of the antiepileptic drugs: The diagnosis of catamenial epilepsy is established by careful assessment of menstrual and seizure diaries and characterization of cycle type and duration.
Some women with epilepsy appear to be at increased risk of ovulatory dysfunction. However, in another investigation of women with focal epilepsy, 39 had anovulatory cycles. Actually, there is no specific drug treatment for catamenial epilepsy, which is often refractory to many therapies. A variety of therapies for catamenial epilepsy catamenail been proposed, including nonhormonal acetazolamide, cyclical use of benzodiazepines, or conventional antiepileptic drugsand hormonal therapies.
However, evidence for the effectiveness of these treatments is not well established. Large multicenter trials are needed to identify the most effective treatment for women with catamenial epilepsy. Because progesterone has mainly been shown to have anticonvulsant effects, and because women with catamenial epilepsy under study often had inadequate luteal-phase or anovulatory cycles, it can be hypothesized that progesterone, progesterone metabolites, or estrogen antagonists may be used in conjunction with current antiepileptic medications, to treat these patients.
Natural progesterone, is a treatment option for patients with catamenial epilepsy and impaired luteal phase cycles. It is usually given in cyclic form during the luteal phase, taken orally at a dose of — mg, twice a day or three times a day. In fact, progesterone is poorly absorbed orally and has a short half-life, so that it must be administered multiple times per day. Systemic oral contraceptive pills have not been found to decrease seizure frequency.
Even though estrogen is a proconvulsant, combined oral contraceptives have not been associated with an increase in seizures. They may be used in women eiplepsy epilepsy also to prevent unwanted pregnancies. Gonadotropin releasing vatamenial analog, was studied in women with refractory perimenstrual seizures. The action mechanism of gonadotropin releasing hormone analog is the decreased luteinizing hormone and estrogen production with consequent amenorrhea.
In one study, this was given intramuscularly in a controlled-release depot preparation every 28 days. Clomiphene is an ovulatory stimulant that is used to treat infertility in women with oligoanovulation or anovulation.
Ganaxolone, a synthetic analog of allopregnanolone, is able to modulate most GABA-A receptors and is under investigation for the treatment of epilepsy.
Laxer et al 70 completed a multicenter, double-blind, randomized, catameial, monotherapy clinical trial that evaluated the safety, xatamenial, and antiepileptic activity of ganaxolone.
The study population consisted of 52 inpatients with medically- refractory, complex, partial seizures. Each patient was studied for up to 8 days, with patients receiving placebo or ganaxolone. The primary measure of antiepileptic activity was the duration of treatment prior to withdrawal from the study. Patients were withdrawn from the study at the occurrence of one of the following: Tolerability of ganaxolone was similar to that of placebo.
Ganaxolone may provide an effective approach for catamenial epilepsy therapy that is reliable, and that does not expose patients to the risk of hormonal side effects. New oral formulations of ganaxolone are going to be developed with enhanced bioavailability and more consistent absorption.
Acetazolamide, a carbonic anhydrase inhibitor, may be effectively used to treat catamenial seizures. It is clear, however, that tolerance develops, which results in diminishing efficacy over time. Therefore, this drug can only be administered on an intermittent basis, which is appropriate for catamenial epilepsy but not for ordinary seizure prophylaxis.
Benzodiazepines are of limited utility in seizure prophylaxis however, they could theoretically be used on an intermittent basis for the treatment catamenisl catamenial seizures. In fact, 1,5-benzodiazepine clobazam, administered intermittently, has been used to treat catamenial seizure exacerbations over long periods of time with good results.
National Center for Biotechnology InformationU. Int J Womens Health. Published online Sep Author information Copyright and License information Disclaimer.
This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC. Abstract Catameial epilepsy is defined as a pattern of seizures that changes in severity during particular phases of the menstrual catamenila, wherein estrogens are proconvulsant, increasing the neuronal excitability; and progesterone is anticonvulsant, enhancing GABA-mediated inhibition.
Diagnosis and management of catamenial seizures: a review
Introduction Women with epilepsy may have seizure patterns associated with changes in estrogen and progesterone levels. Relationship between epilepsy and the menstrual cycle Catamenial epilepsy is believed to occur secondarily to the neuroactive properties of endogenous steroid hormones and the natural cyclic variation in their serum levels throughout the menstrual cycle.
Pathophysiology of catamenial epilepsy It is known that estrogen and progesterone have important effects on neuronal development and plasticity in widespread cerebral and brainstem regions, 20 through their capacity to regulate synthesis, release, and transport of neurotransmitters.
Effects of progesterone Animal and humans studies 3839 clearly indicate that catamenial seizures are associated with a rapid decline in progesterone immediately before, during, and after menstruation. Menopause and changes in seizures pattern The marked hormonal changes that occur in the menopausal transition seem to have an effect on seizure susceptibility. Diagnosis The diagnosis of catamenial epilepsy is established by careful assessment of menstrual and seizure diaries and characterization of cycle type and duration.
Treatment Actually, there is no specific drug treatment for catamenial epilepsy, which is often refractory to many therapies. Hormonal therapy Because progesterone has mainly been shown to have anticonvulsant effects, and because women with catamenial epilepsy under study often had inadequate luteal-phase or anovulatory cycles, it can be hypothesized that progesterone, progesterone metabolites, or estrogen antagonists may be used in conjunction with current antiepileptic medications, to treat these patients.
Catamenial epilepsy – Wikipedia
Non hormonal therapy Acetazolamide, a carbonic anhydrase inhibitor, may be effectively used to treat catamenial seizures. Footnotes Disclosure The authors report no conflicts of interest in this work. Anticonvulsant activity of progesterone and neurosteroids in progesterone receptor knockout mice. J Pharmacol Exp Ther. Females, their estrogens, and seizures.
Role eepilepsy neurosteroids in catamenial epilepsy. The role of neurosteroids in the pathophysiology and treatment of catamenial epilepsy. How common is catamenial epilepsy?