hormones catamenial epilepsy

[angel]

http://professionals.epilepsy.com/wi...nes_catamenial

hi I just found this thought some of you would like to read it...


Catamenial epilepsy
Patterns and causes
Evaluation
Treatment

Catamenial (from the Greek kata, by; men, month) epilepsy refers to seizure exacerbation in relation to the menstrual cycle. Traditionally, the term has been used to refer to seizure exacerbation at the time of menstruation. This section discusses the evaluation, diagnosis and treatment of women with catamenial epilepsy.




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Patterns and causes
Author: P Klein and AG Herzog

Catamenial (from the Greek kata, by; men, month) epilepsy refers to seizure exacerbation in relation to the menstrual cycle. Traditionally, the term has been used to refer to seizure exacerbation at the time of menstruation.

In its purest form, a woman with catamenial epilepsy may have seizures only at the time of menstruation, but this form is not very common. More typically, the woman may tend to have more seizures at particular times during her menstrual cycle, usually just before or during the onset of menstruation or at the time of ovulation.1-3

Patterns of catamenial epilepsy
Three patterns of catamenial seizure exacerbation may be observed:2


The three patterns of catamenial exacerbation of epilepsy in relation to serum estradiol (E2) and progesterone (P) levels. C1 = perimenstrual; C2 = preovulatory; C3 = luteal phase.


perimenstrual
at the time of ovulation
throughout the second half of the menstrual cycle
Seizure exacerbation around the time of menstruation or ovulation occurs in women with normal menstrual cycles.

Women with abnormal menstrual cycles may have exacerbation in the second half (luteal phase) of the cycle. This pattern is the most difficult one to distinguish because the time of seizure exacerbation is prolonged rather than focused. These women have anovulatory cycles and inadequate luteal phase syndrome.4 Because they do not ovulate, no corpus luteum (derived from the egg leaving the ovary) is formed during the second (luteal) half of the menstrual cycle and no progesterone is secreted.

Causes of catamenial epilepsy
Menstrually related hormonal fluctuations in estrogen and progesterone underlie the patterns of catamenial seizure exacerbation. Estrogens facilitate seizures, whereas progesterone protects against seizures. During the menstrual cycle, serum levels of estradiol and progesterone fluctuate.

Estrogens (in particular estradiol, the most important of the different estrogen forms) have potent proconvulsant properties. They exert an excitatory effect on neurons by stimulating the N-methyl-D-aspartate (NMDA)- type glutamate receptor.5 In women with epilepsy, intravenous administration of conjugated estrogens activates epileptiform discharges and may result in seizures.6

Progesterone hyperpolarizes neurons, acting via one of its natural endogenous metabolites, allopregnanolone, as an agonist at the γ- aminobutyric acid (GABA)-a receptor with a potency almost a thousandfold greater than that of pentobarbital and greater than the most potent benzodiazepine, nitroflurazepam.7,8 In women with partial seizures, intravenous infusion of progesterone, resulting in luteal phase plasma levels, suppresses interictal epileptiform discharges.9

In a normally menstruating woman, the surge of serum estrogen levels at the time of ovulation may be associated with increased seizure tendency; as may the fall in serum progesterone levels just before and during menstruation.

In a woman with an anovulatory cycle, estrogen levels rise at the end of the follicular phase and stay elevated throughout the luteal phase until premenstrually, as in normally menstruating women. Little or no progesterone is secreted, however, creating an estrogenrogesterone (E/P) imbalance with a relative excess of estrogen (or deficiency of progesterone) throughout the whole second (luteal) half of the menstrual cycle. Seizure exacerbation results.10

A number of studies have suggested that both progesterone deficiency and estrogen excess relative to progesterone contribute to the catamenial pattern of seizure exacerbation in both normal women and in women with menstrual irregularities.1,2,10 The E/P ratio appears to determine the overall reproductive hormonal effect upon seizure frequency.10

In addition, premenstrual exacerbation of seizures may also be related to a decline in anticonvulsant medication levels.11,12 In women with catamenial epilepsy, phenytoin levels decline premenstrually by up to one-third.11,12 This decline may be due to an increased rate of clearance at the beginning of menstruation, with an associated reduction in the half-life of phenytoin from 19 to 13 hours.11 Hepatic microsomal enzymes metabolize both gonadal steroids and anticonvulsants such as phenytoin, with competition between the two. The premenstrual decline in gonadal steroid secretion may therefore permit increased metabolism of anti-epileptic drugs, resulting in lower serum levels.11 It is not certain whether all anti-epileptic drugs are affected. Phenobarbital is not, and catamenial fluctuation in serum levels of other anti-epileptic drugs has not been studied.


Adapted from: Klein P and Herzog AG. Endocrine aspects of partial seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 207-232.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised February 2004 by Cynthia Harden, MD, Weill Cornell Medical College.



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Evaluation
Author: P Klein and AG Herzog

The best way of establishing whether the patient's seizures tend to worsen at certain points of the menstrual cycle is to have her keep a careful seizure diary in relation to her menstrual cycle. Using the first day of menstrual bleeding as the first day of the cycle, the menstrual cycle is divided into four phases:

menstrual, days -3 to +3
follicular, days +4 to +9
ovulatory, days +10 to +16
luteal, days +17 to -4
The number of seizures in each phase is counted. The average daily number of seizures for each menstrual phase is then compared with the average daily number of seizures for the rest of the cycle to look for a pattern of exacerbation or remission at certain phases of the menstrual cycle. A useful definition of seizure exacerbation is a twofold or greater increase in average daily seizure frequency during the affected part of the cycle in comparison to the remainder of the cycle.

If a catamenial pattern of seizure exacerbation is established from this record, additional steps in the evaluation will help to guide treatment:13

Establish the menstrual pattern: normal or abnormal menstrual cycles.
Check midluteal serum progesterone levels (for example, on day 22 of a 28-day menstrual cycle) to see whether the luteal phase is inadequate.
If the woman has perimenstrual (type I) catamenial seizure exacerbation, check trough anti-epileptic drug levels on day 22 (when estradiol and progesterone levels are high and the anti-epileptic drug level should be "normal") and day 1 (when estradiol and progesterone levels are low). Low anti-epileptic drug levels at this time (perhaps related to increased drug metabolism) could be the cause of perimenstrual seizure exacerbation.

Adapted from: Klein P and Herzog AG. Endocrine aspects of partial seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 207-232.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised February 2004 by Cynthia Harden, MD, Weill Cornell Medical College.



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Treatment
Author: P Klein and AG Herzog

Endocrine treatment of seizures may rationally be aimed at those endocrinologic aspects of seizures that act either to exacerbate or to ameliorate them. Because progesterone has anticonvulsant effects and estrogen has proconvulsant effects, treatment with progesterone or estrogen antagonists may prove to be useful adjunctive treatments in appropriate patients.

Progesterone
Low progesterone levels or rapid withdrawal of progesterone may be a factor in the increased seizure frequency seen during the premenstrual and early follicular phase of women with catamenial epilepsy and normal ovulatory cycles, and during the entire luteal phase of women with anovulatory cycles.14,15 Progesterone may be expected to be beneficial in these women.

Synthetic progestin therapy may be considered. Little or no benefit has been noted with oral forms in a number of studies16,17 although occasional benefits have been described in single case reports.

In one study of women with refractory partial seizures and normal ovulatory cycles, a medroxyprogesterone dose large enough to induce amenorrhea (120 to 150 mg every 6 to 12 weeks intramuscularly or 20 to 40 mg orally daily) resulted in a 40% average seizure reduction.16 Weekly doses of 400 mg of intramuscular depo medroxyprogesterone may be more effective.

Potential side effects include depression, sedation, and breakthrough vaginal bleeding. The use of depo medroxyprogesterone also may delay the return of regular menstrual cycles.

Natural progesterone may be a more effective treatment. In a study of 25 women with catamenial exacerbation of complex partial seizures of temporal lobe origin, 72% of the women improved.18 The average decline in seizure frequency was 55%. Of the 25 women in the study, 14 had anovulatory cycles or an inadequate luteal phase. These women took progesterone lozenges (200 mg tid) on days 15 through 25 of each menstrual cycle, with taper over days 26 through 28. The 11 women with normal cycles and perimenstrual seizure exacerbation took the same type and dose of progesterone on days 23 through 25 of each menstrual cycle.18

The natural and synthetic progestins are not equivalent because natural progesterone is metabolized to allopregnanolone, which has very potent GABA-a mimetic and anticonvulsant action,19,20 whereas synthetic progestins are not metabolized in this way.

Potential side effects of progesterone treatment may include:

sedation
depression
weight gain
breast tenderness
breakthrough vaginal bleeding
All of these effects are readily reversed if the hormone is stopped or the dose is lowered.

Medication adjustments
If low anti-epileptic drug levels are found during certain phases of the woman's menstrual cycle, it may be helpful to increase the dose slightly around that time, or in some cases to add a low dose of another anti-epileptic drug, such as a benzodiazepine.


Adapted from: Klein P and Herzog AG. Endocrine aspects of partial seizures. In: Schachter SC, Schomer DL, eds. The comprehensive evaluation and treatment of epilepsy. San Diego, CA: Academic Press; 1997. p. 207-232.
With permission from Elsevier (www.elsevier.com).

Reviewed and revised February 2004 by Cynthia Harden, MD, Weill Cornell Medical College.



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[angel]

http://www.ncbi.nlm.nih.gov/pubmed/3...?dopt=Abstract

Neurology. 1986 Dec;36(12):1607-10.Related Articles, Links
Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders.

Herzog AG.

We studied eight women who had complex partial seizures and anovulatory cycles or inadequate luteal phases. Progesterone suppositories were given during the premenstrual phase or entire second half of the cycle in doses of 50 to 400 mg q12h. Antiseizure medication levels were kept in the therapeutic range. Average monthly seizure frequency declined by 68% (p less than 0.05, Wilcoxon matched-pairs test) in a 3-month treatment period compared with the 3 months prior to therapy, and six of the eight women had fewer seizures. None experienced more seizures or disruption of menses. Transient tiredness and depression were noted in some when progesterone dosage was raised above minimally effective levels. These symptoms cleared within 48 hours of lowering the dosage. The value of intermittent natural progesterone therapy as a safe, well-tolerated, and effective adjunct to antiseizure therapy should be assessed further.

Publication Types:
Research Support, Non-U.S. Gov't

PMID: 3785677 [PubMed - indexed for MEDLINE]

[angel]

http://www.pubmedcentral.nih.gov/art...?artid=1874326


The possible effect of reproductive hormones on seizures was recognized over 2,000 years ago. Clinical observations of a relationship between the menstrual cycle and seizure occurrence in women of reproductive age were cited in medical journals as early as the turn of the 19th century. In 1942, experimental work in rats demonstrated the anticonvulsant properties of progesterone (1). Since then, many animal studies have confirmed the effects of progestins and estrogens on seizure threshold and epileptogenesis. Many cellular and molecular mechanisms contribute to the changes in brain excitability mediated by these hormones. Although an oversimplification, studies generally support the finding that the estrogens have proconvulsant properties and progestins have anticonvulsant properties. The three principal circulating estrogens are estrone, estradiol, and estriol. The progestins include progesterone and progesterone derivatives. Dihydroprogesterone is the immediate 5-α-reduced metabolite of progesterone and is further metabolized to allopregnanolone (3α-hydroxy-5α-pregnan-20-one), a GABAA-receptor–modulating neurosteroid (1,2). Much of the antiseizure effect of progesterone may be due to the conversion to this metabolite, and synthetic progestins are not converted to this or other known neurosteroids.

The findings of experimental studies parallel nicely the clinical observation that seizure frequency is increased in many women with epilepsy in association with certain phases of the menstrual cycle (catamenial epilepsy). In women with localization-related epilepsy, 39% demonstrate a catamenial pattern (3). The patterns described correlate with phases of relatively high estrogen/progesterone ratios: perimenstrual and periovulation in normal menstrual cycles and throughout the inadequate luteal phase in anovulatory cycles. Additionally, an open-label treatment trial with supplemental progesterone in women (n=25) demonstrated a 54% decline in the average frequency of daily complex partial seizures (p < 0.01) and a 58% decline in secondarily generalized tonic–clonic seizures (p < 0.02) (4). Nonetheless, no Class I evidence is available for the benefits of progesterone use in women with epilepsy during the reproductive years, although a multicenter, double-blind, randomized, placebo-controlled trial is currently underway (3).

Understanding the effects of endogenous and exogenous reproductive hormones on seizure control during the perimenopausal transition and postmenopause has been more elusive. Perimenopause is marked by erratic and frequently high estrogen levels, while postmenopause is characterized by stable, low estrogen levels (5). Studies in women during these later life stages are very limited. Previously, Harden et al. performed a retrospective questionnaire study of perimenopausal and postmenopausal women with epilepsy (n=81) (6). Their findings suggest that seizure frequency can increase with perimenopause and can improve once the menopausal transition is complete, especially for women who had a catamenial pattern to her seizures. In the postmenopausal group, hormone replacement therapy (HRT) was significantly associated with an increase in seizures.

The present study by Harden et al. explores the effects of the combination of conjugated equine estrogens and medroxyprogesterone acetate (CEE/MPA) at two different doses, using a design that meets criteria for Class I evidence (i.e., double-blind, placebo-controlled, randomized trial). Several factors distinctive to the study design may have enhanced the likelihood of a positive finding regarding the effect of the combination hormonal treatment on seizure frequency. The authors astutely remark that postmenopausal women may be more susceptible to the effects of exogenous hormones on seizures, given that their hormonal milieu is one of low and stable estrogen and progesterone levels. Estrone is the primary estrogen after menopause, with its main source from subcutaneous fat. Each of the estrogens has distinct biological actions, although individual effects on seizure frequency are unknown. Similarly, the various equine estrogens are likely to have distinct actions from physiologic forms of estrogen in women, and the complex mixture of CEE extracted from horses includes androgens and progestins (1). CEE/MPA was commonly used as hormone replacement therapy at the time this trial was initiated. Moreover, the investigators utilized an elegant approach of randomizing a third of the patients to double-dose CEE/MPA, which was a common prescription dose for menopausal women who did not have symptom relief with single-dose CEE/MPA.

The Harden et al. trial was ended early because of results from the Women's Health Initiative study (n=16,60. It was a shock to the medical community that not only was HRT not a useful preventive medicine tool, but it could actually increase the risk for invasive breast cancer, coronary heart disease, stroke, and pulmonary embolism (7). The Harden et al. study initially predicted that 120 women, 40 in each treatment arm, would be needed for a power of 80% and a two-tailed significance level of 0.05. Because recruitment had to be terminated, only six subjects were randomized to the placebo group, eight to the single-dose CEE/MPA group, and seven to the double-dose CEE/MPA group. The groups were similar by other characteristics, except that the frequency of simple partial seizures was higher in the double-dose CEE/MPA group, which may have influenced the outcome data. What is truly remarkable is that despite discontinuing the study prematurely and limited enrollment, the results were still positive and even were able to demonstrate statistical significance for a dose-related response for CEE/MPA and increased seizure frequency.

After the report of the Women's Health Initiative study, the prescriptions for oral HRT in the United States decreased by approximately one-third by June 2003, from their peak in 2000. However, 59.6 million prescriptions for these products were still dispensed in 2003, another 7.5 million dispensed for transdermal products, and an additional 8.9 million for oral progestins (. Although long-term HRT is no longer recommended for health maintenance, short-term HRT is still prescribed for the management of menopausal symptoms, such as hot flashes, insomnia, and vaginal atrophy (9). Thus, the findings of the Harden et al. study remain clinically relevant. Updated results of dispensing practices are not yet available; however, the search for products for menopausal symptom relief continues and has moved firmly into the alternative therapy arena (10,11). The possible effects of various alternative agents on seizure threshold are not known.

Although the Harden et al. trial cautions against use of CEE/MPA in postmenopausal women with epilepsy, it cannot differentiate between the possible effects of the many different equine estrogens, equine androgens, or even the equine progestins and synthetic progestin MPA. In addition, a possible confounder is that in the two lamotrigine-treated patients, lamotrigine levels decreased by 25% to 33% with single-dose CEE/MPA. No changes were observed in other antiepileptic drug levels, but the number of subjects on each anti-epileptic drug was small. A possible alternative to the CEE/MPA combination medicine may be one that uses a more pure human-like estrogen derivative, such as estradiol or possibly estrone, and natural progesterone, which can be metabolized to the beneficial neurosteroid allopregnanolone.

The early termination of this trial resulted in limited enrollment and may have reduced it to a Class II study, as there were a high percentage of subjects who discontinued, many subjects who were evaluated after just 30 to 60 days, a higher number of simple partial seizures in the double-dose group, and comparisons by seizure-frequency strata could not be performed, as originally planned. The investigators state that the seizure frequency increases were mild, but details were not provided; any increase in daily seizure rate from baseline was counted as a positive response. It would have been helpful if the authors had reported on the magnitude of seizure increases, as it could help put their findings into the context of everyday treatment decisions and patient counseling.

Nonetheless, having Class I or Class II evidence from a treatment trial assessing the influence of reproductive hormones on seizures in humans is unique at this point in time. These findings further the understanding of the impact of hormones on seizure control in women with epilepsy, and the principles learned can be extended to other life epochs, including puberty, menstrual cycles, pregnancy, and perimenopause. Future studies on whether other estrogens with natural progesterone could circumvent the risk for increased seizures would be beneficial for postmenopausal women with epilepsy.

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COMMENTARY
References

[RobinN]

Also look here Angel:

Seizures during the menstrual cycle
Migraine related seizures
Migraine related seizures
Seizure frequency linked to the menstrual cycle

[mamaruns]

Those are all excellent links, thanks for posting them. This is an issue I suffer from, especially midcycle and right before/beginning of menses. I think I'm going to look into natural hormone therapy treatment, along with dietary changes, to see if it helps.

I'm a little confused about the article that says women like me suffer from anovulatory cycles though. I had no issues getting pregnant after I developed this problem. However, I wouldn't doubt if I had the inadequate luteal phase syndrome.

[RobinN]

I know it is confusing isn't it. I sure do wish they would do more studies in this area. When I was researching it after a neurologist told me that hormones were not a cause of seizures, I found medical articles that said in the conclusion that it would be a good idea to research it more. I wonder when that will happen.

Rebecca was asked by a gyn to do the basil temp chart, every morning, and she also had her hormone levels checked. This is not a traditional medical approach. This was done by a orthomolecular doctor that believes in alternative approaches. So most likely it won't be picked up by a doctor that is covered by insurance. Or if it is, you need to be the squeaky wheel.

I would think that like anything else, the cycle can be anovulatory one month and perhaps not the next.

I am glad that the links were helpful.

P.S. I also wanted to add that your anti-epileptic drugs can change around the TOM some are less potent and some are made stronger. It is something to discuss with your doctor.

[brain]

Even worse - HRT can actually induce
seizures! Insulting isn't it?
And yet - Neuroscience is taking another
look at HRT again??



And to make the matters worse, for
someone who's extremely irregular
(like I am), Diamox (which is often
used for women who suffers from these
Catamenial Epilepsy) and Birth Control
DO help for those who are more stabled,
but are of little use for those who aren't
"regular" or "predictable".

However, they are finding Women who
are very irregular, upon having seizures
and having the lab workup - it's very
revealing.

Not only is it frustrating & confusing,
but how does the Doctor deal with a
Woman who's so irregular, having
all the woman's issues that goes along
with it? (Ovarian cysts, painful inter-
courses, Miscarriages, Problematic
pregnancies & births, and so on.)

It's a whole big ball park to deal with.

Women's Issues in Epilepsy from Dr.
Martha Morrell - which is offered by
the Epilepsy Foundation; is a very
popular book - and can be purchased
anywhere - even speaks of this issues
as well.

CWE has this book in the recommendation
Resource Information area.


Then there's puberty, womanhood,
peri-menopause, menopause, and
thereon ... and seizures involving it
really impacts woman in different
degrees and variations.

You will get all kinds of reports, findings
and conclusions. But in turn all you
get is ... 100% frustrated seizing
women - the ones that they're not
able to control their Catamenial
Epilepsy.

Originally believed that hysterectomy
was the answer; but the problem was
not "down there", but rather the tiny
little Pituitary Gland in the brain!

It's now being found far more common
with Women who have FLE and temporal lobe epilepsy
and those who are intractable or as
they've changed the terminology now
today as refractory - both words are
the same thing. It is still being studied
up on, and surgeries have been done;
but I haven't gotten that far yet to
look into Clinical Studies and results of
that phase altogether.

But I can state this one thing...

IT IS A MAJOR PITA! (Pain in the A$$)!

[Readergal]

Thank you for posting those wonderful articles on a subject you NEVER see addressed. I've had seizures around this time for years and have been basically had my head patted and told that my monthly cycle had nothing to do with it. I'll have to check these out and find some natural progesterone. Thanks again.

[RobinN]

Yes I was told the same thing Readergal. It did not make sense to me when it was happening over and over at that time for my daughter. Plus I had been told for years that my migraines were not connected to my time of the month, when I started charting them they fell on the same time every single month. So I voted to believe my experience.

Thank goodness for the internet, you put in hormone and seizure into a search and up pops a ton of info. Take that to your doctor.

Recently I have been told that intestinal issues are not connected and darn it I have pages of info to leave with that GI doctor.

The bio-identical progesterone has worked well for my daughter. Make sure it isn't the over the counter variety. You will most likely need a prescription and then take it to a compounding pharmacy.

Good Luck with it.... oh and WELCOME

[Readergal]

Thanks for the welcome, Robin! That was my first post.

I found a place online called Women to Women and they sell the natural progesterone creme. I'm going to contact them and see about getting some. I'm sorry about your migraines. My boss used to suffer from them and it was awful what she went through. I also hope your G.I. doc pays attention.

I wanted to tell you how much I enjoyed your stories (diary) of your experiences with the Neurofeedback. VERY interesting. I was reading some of the info from your and others links. Isn't it amazing that it's been around this long and doctors still don't know that much about it?

Thanks for all of the info. And yes, I do like the little critters.