Catamenial epilepsy
Encyclopedia
Catamenial epilepsy is a subtype of epilepsy
, which is a chronic neurological condition characterized by recurrent seizures. Catamenial epilepsy is a subset of this population, which includes women of whom their seizure exacerbation is aligned with their menstrual cycle. Women with catamenial epilepsy are unusually sensitive to endogenous hormonal changes. This seizure exacerbation has a statistically significant positive correlation to serum estradiol
/estrogen
levels and ratios.
Since at least the Greek times, there has been documented study of women with epilepsy and its correlation to the menstrual cycle. These patterns can easily be seen by charting out menses against seizure occurrence and type.
Our understanding of the major gonadal hormones, estrogen
, progesterone
, and testosterone
, has significantly increased in the last century. These hormones are synthesized in various locations in the body, including the ovaries, adrenal gland, liver, subcutaneous fat, and brain. There is considerable research showing that these steroidal hormones take part in an important role in the pathophysiology of epilepsy. Broadly defined, estrogen and its many forms are thought to be “proconvulsant,” whereas progesterone is thought to be “anticonvulsant.”
can be found in the female body in various forms, all of which affect women with catamenial epilepsy. Estrone (E1), estradiol (E2), and estriol (E3) are the three principal circulating estrogens in the body. These three forms influence neuronal excitability, but very little is known about their inter-hormone interactions, the relative concentrations and ratios of E1/E2/E3 and how that may influence the seizure frequency behavior in women with epilepsy. In normally menstruating women, serum estradiol levels are typically present by day 10 of the menstrual cycle, and persist until ovulation.
receptors bind several molecules other than only progesterone. Progestagens are group of natural non-synthetic hormones, including progesterone, which binds to progesterone receptors. Other than progesterone, progestagens have several neuroactive metabolites, most notably allopregnanolone
. Progesterone has been shown to lower the number of estrogen receptors, and thus act as an antagonist
to estrogen actions. In trials, both progesterone and allopregnanolone administration have shown a neuroprotective effect on hippocampal neurons in seizure models induced by kainic acid
.
cycles, days 10 to 3) is associated with a twofold or greater increase in average daily seizure occurrence during the O, L and M phases. Anovulatory
females do not typically have a midcycle surge of progesterone, but still experience a surge in estrogen. These women have abnormally low progesterone levels during the O, L and M, regardless of whether ovulation occurs. In study by El-Khayat et al., it was found that patients with C3 pattern of catamenial epilepsy had overall lower progesterone levels than healthy controls during the L phase of the menstrual cycle.
, there are drastic changes in the production of gonadal hormones. Most of the reproductive hormones, including the estrogens, progesterone and testosterone, diminish initially (perimenopause), becoming irregular, often showing wide and unpredictable fluctuations. As menopause progresses, there is cessation of estrogen production by the ovaries. Rosciszewska was one of the first researchers to report an increased risk of seizures during perimenopause, but found a marked decreased risk of seizures during menopause if there was a catamenial relationship. This difference may be associated with the radical fluctuations of estradiol and progesterone during the perimenopausal period than what is experienced during the menopausal period and menstrual cycles of reproductive years. Recall that estrone is the predominant estrogen present during menopause (from subcutaneous fat), and little is known about the effect of estrone specifically on epilepsy. Women with epilepsy who do not follow a catamenial pattern may have an unpredictable increase or decrease in seizure activity in perimenopause and menopause, but women with catamenial epilepsy typically follow a more predictable pattern.
(HRT), such as Premarin
, has shown severe negative effects on the seizure patterns of women with catamenial epilepsy. During perimenopause, women with catamenial epilepsy generally experience an increase in seizure frequency, and HRT use does not change this likelihood. However HRT use after perimenopause has been significantly associated with an increase in seizure frequency and severity. Women progressing through peri- and post-menopause using HRT may be in greater need of anticonvulsant
medication monitoring to maintain or reduce seizure occurrence. These same results have not been seen in laboratory counterparts. Adult female rats that have been ovariectomized, a parallel state to menopause, show increased seizure frequency overall. There are, however, several factors that could explain this difference, including ovariectomized rats do not have the analogous brain hormones milieu as menopausal women. Several studies following HRT use in women with catamenial epilepsy have demonstrated more influencable data than animal models, in this case.
, osteoporosis
, and cardiovascular disease
.
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, which is a chronic neurological condition characterized by recurrent seizures. Catamenial epilepsy is a subset of this population, which includes women of whom their seizure exacerbation is aligned with their menstrual cycle. Women with catamenial epilepsy are unusually sensitive to endogenous hormonal changes. This seizure exacerbation has a statistically significant positive correlation to serum estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
/estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
levels and ratios.
Since at least the Greek times, there has been documented study of women with epilepsy and its correlation to the menstrual cycle. These patterns can easily be seen by charting out menses against seizure occurrence and type.
Pathophysiology
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
, and testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, has significantly increased in the last century. These hormones are synthesized in various locations in the body, including the ovaries, adrenal gland, liver, subcutaneous fat, and brain. There is considerable research showing that these steroidal hormones take part in an important role in the pathophysiology of epilepsy. Broadly defined, estrogen and its many forms are thought to be “proconvulsant,” whereas progesterone is thought to be “anticonvulsant.”
Estrogen (Estradiol, Estrone, Estriol)
EstrogenEstrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
can be found in the female body in various forms, all of which affect women with catamenial epilepsy. Estrone (E1), estradiol (E2), and estriol (E3) are the three principal circulating estrogens in the body. These three forms influence neuronal excitability, but very little is known about their inter-hormone interactions, the relative concentrations and ratios of E1/E2/E3 and how that may influence the seizure frequency behavior in women with epilepsy. In normally menstruating women, serum estradiol levels are typically present by day 10 of the menstrual cycle, and persist until ovulation.
- EstroneEstroneEstrone is an estrogenic hormone secreted by the ovary as well as adipose tissue.Estrone is one of several natural estrogens, which also include estriol and estradiol...
’s main source is adipose tissueAdipose tissueIn histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
(subcutaneous fat), where it is formed by aromatization of androstenedioneAndrostenedioneAndrostenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
. Estrone is the major estrogen after menopause, and this hormoneHormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
may be very influential in seizure control of the catamenial woman if she is severely overweight or obese.
- EstradiolEstradiolEstradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
represents the most prolific estrogen ligand receptor in the female body, particularly in non-pregnant females, and is a more effective activator of estrogen receptor function than estrone or estriol. Estradiol directly increases NMDA mediated receptors of glutamate activity at the neuronal membrane. Through this mechanism hippocampal pyramidal neurons CA1 are excited, and a repetitive firing response is induced. Dendritic spine density on CA1 hippocampal pyramidal cells is dependent upon estradiol levels, showing a direct correlation during normal fluctuations during the menstrual cycle. Estradiol has been shown to apply its affects on dendritic spine density of hippocampal cells by using a mechanism that requires activation of NMDA receptors. Furthermore, Herzog postulates that, “estradiol may thus further increase excitatory input to the CA1 neurons.” Through many animal models, as well as human-use of estrogen-based hormone replacement therapyHormone replacement therapy (menopause)Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
, estrogens have been seen to increase the excitability of neurons, leading to a decreased seizure threshold. In female adult rat experimental trials, the limbic seizure threshold fluctuates inversely to estradiol levels during the estrous cycleEstrous cycleThe estrous cycle comprises the recurring physiologic changes that are induced by reproductive hormones in most mammalian placental females. Estrous cycles start after puberty in sexually mature females and are interrupted by anestrous phases or pregnancies...
.
- EstriolEstriolEstriol is one of the three main estrogens produced by the human body.-Synthesis:Estriol is only produced in significant amounts during pregnancy as it is made by the placenta from 16-Hydroxydehydroepiandrosterone sulfate , an androgen steroid made in the fetal liver and adrenal glands.The human...
is known to inhibit GABAGamma-aminobutyric acidγ-Aminobutyric acid is the chief inhibitory neurotransmitter in the mammalian central nervous system. It plays a role in regulating neuronal excitability throughout the nervous system...
and to promote kindlingKindling modelKindling is a commonly used model for the development of seizures and epilepsy in which the duration and behavioral involvement of induced seizures increases after seizures are induced repeatedly. The kindling model was first proposed in the late 1960s by Goddard and colleagues...
and epileptiform discharges. Estriol is only produced in significant quantities during pregnancy via placental aromatization of fetal androgen, however it can also be synthesized in smaller quantities (non-pregnancy) in the liver by hydroxylation of estrone.
Progesterone
Similar to estrogen, progesteroneProgesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
receptors bind several molecules other than only progesterone. Progestagens are group of natural non-synthetic hormones, including progesterone, which binds to progesterone receptors. Other than progesterone, progestagens have several neuroactive metabolites, most notably allopregnanolone
Allopregnanolone
Allopregnanolone is a prototypic neurosteroid present in the blood and also the brain. It is a metabolite of progesterone and potent modulator of GABAA receptors...
. Progesterone has been shown to lower the number of estrogen receptors, and thus act as an antagonist
Antagonist
An antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
to estrogen actions. In trials, both progesterone and allopregnanolone administration have shown a neuroprotective effect on hippocampal neurons in seizure models induced by kainic acid
Kainic acid
Kainic acid is a natural marine acid present in some seaweed. It is a specific agonist for the kainate receptor used as an ionotropic glutamate receptor which mimics the effect of glutamate...
.
Classification
The proper classification for catamenial epilepsy has been debatable for several decades. Researchers have defined catamenial epilepsy from the broadest definition of a “greater than” approach indicating an increase in seizure frequency or severity during any specific phase of the menstrual cycle, to a “sixfold increase” in average daily seizure frequency during specific times in the cycle. In recent years, Herzog’s 1997 proposal of an admittedly arbitrary “twofold” increase has generally been accepted: Perimenstrual (C1), Periovulatory (C2), and Luteal (C3). These three classifications are based upon serum estradiol:progesterone ratio, and a 24-34 day menstrual cycle in which menses begins on day 1, and ovulation occurs 14 days prior to menstruation. By this measure, approximately one third of women with epilepsy would be classified under the designation of catamenial epilepsy.Perimenstrual “C1”
Perimenstrual classification (in normal cycles, days -3 to 3 of menstruation) is associated with a twofold or greater increase in average daily seizure occurrence during the menstrual phase (M) compared to the follicular (F) and luteal (L) phases. The menstrual phase is characterized by drastic decreases in progesterone and estrogen levels. The estradiol:progesterone ratio is highest during the days before menstruation (C1) and ovulation (C2). Perimenstrual seizure exacerbation has been recognized as the withdrawal of the protective effects of progesterone. In a 2009 study, it was found that patients with C1 pattern of catamenial epilepsy had overall lower progesterone levels than healthy controls during the M phase.Periovulatory “C2”
Periovulatory classification (in normal cycles, days 10 to -13) is associated with a twofold or greater increase in average daily seizure occurrence during the O phase compared to the F and L phases. The ovulatory phase is characterized by a surge of estrogen before ovulation, while an associated progesterone surge does not occur until ovulation actually occurs. This estrogen effect, without a corresponding progesterone surge of protection, intensifies seizure events.Luteal “C3”
Luteal classification (abnormal or inadequate luteal phaseLuteal phase
The luteal phase is the latter phase of the menstrual cycle or the estrous cycle . It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis...
cycles, days 10 to 3) is associated with a twofold or greater increase in average daily seizure occurrence during the O, L and M phases. Anovulatory
Anovulation
An anovulatory cycle is a menstrual cycle during which the ovaries do not release an oocyte. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause...
females do not typically have a midcycle surge of progesterone, but still experience a surge in estrogen. These women have abnormally low progesterone levels during the O, L and M, regardless of whether ovulation occurs. In study by El-Khayat et al., it was found that patients with C3 pattern of catamenial epilepsy had overall lower progesterone levels than healthy controls during the L phase of the menstrual cycle.
Menopause
During menopauseMenopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
, there are drastic changes in the production of gonadal hormones. Most of the reproductive hormones, including the estrogens, progesterone and testosterone, diminish initially (perimenopause), becoming irregular, often showing wide and unpredictable fluctuations. As menopause progresses, there is cessation of estrogen production by the ovaries. Rosciszewska was one of the first researchers to report an increased risk of seizures during perimenopause, but found a marked decreased risk of seizures during menopause if there was a catamenial relationship. This difference may be associated with the radical fluctuations of estradiol and progesterone during the perimenopausal period than what is experienced during the menopausal period and menstrual cycles of reproductive years. Recall that estrone is the predominant estrogen present during menopause (from subcutaneous fat), and little is known about the effect of estrone specifically on epilepsy. Women with epilepsy who do not follow a catamenial pattern may have an unpredictable increase or decrease in seizure activity in perimenopause and menopause, but women with catamenial epilepsy typically follow a more predictable pattern.
Hormone replacement therapy
The use of hormone replacement therapyHormone replacement therapy (menopause)
Hormone replacement therapy is a system of medical treatment for surgically menopausal, perimenopausal and to a lesser extent postmenopausal women...
(HRT), such as Premarin
Premarin
Premarin is the commercial name for a compound cream of vaginally administered estrogens, consisting primarily of conjugated estrogens. Isolated from mares' urine , it is manufactured by Wyeth Pharmaceuticals and has been marketed since 1942...
, has shown severe negative effects on the seizure patterns of women with catamenial epilepsy. During perimenopause, women with catamenial epilepsy generally experience an increase in seizure frequency, and HRT use does not change this likelihood. However HRT use after perimenopause has been significantly associated with an increase in seizure frequency and severity. Women progressing through peri- and post-menopause using HRT may be in greater need of anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
medication monitoring to maintain or reduce seizure occurrence. These same results have not been seen in laboratory counterparts. Adult female rats that have been ovariectomized, a parallel state to menopause, show increased seizure frequency overall. There are, however, several factors that could explain this difference, including ovariectomized rats do not have the analogous brain hormones milieu as menopausal women. Several studies following HRT use in women with catamenial epilepsy have demonstrated more influencable data than animal models, in this case.
Treatment Methods
Several treatment methods have been determined exclusively for women with catamenial epilepsy. A great majority of these therapies include progestagens (naturally occurring) or progestins (synthetic progestagen). Drug interactions are an important factor when using progesterone therapy, as many antiseizure medications augment hepatic metabolism of gonadal steroids, and increase serum protein binding to hormones. There are many unfortunate side effects frequently seen in progesterone therapy usage, including vaginal dryness, dyspareuniaDyspareunia
Dyspareunia is painful sexual intercourse, due to medical or psychological causes. The symptom is reported almost exclusively by women, although the problem can also occur in men. The causes are often reversible, even when long-standing, but self-perpetuating pain is a factor after the original...
, osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
.
- Cyclic progesterone therapy supplements the patient with natural progesterone during the luteal phase when progesterone is normally low, and gradually reduces the supplementation premenstrually.
- Suppressive progestin therapy intends to suppress the menstrual cycle entirely by using injectable progestins or gonadotropin-releasing hormoneGonadotropin-releasing hormoneGonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
s (GnRH). GnRH basically mimics an ovary-free environment in the female, which is characteristic of the lack of menstrual cycle during menopause.