Catamenial Epilepsy From Epilepsy_1

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Catamenial epilepsy from Epilepsy.com

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 andtreatment 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 inrelation to the menstrual cycle. Traditionally, the term has been used to refer to seizureexacerbation at the time of menstruation.

In its purest form, a woman with catamenial epilepsy may have seizures only at the time ofmenstruation, 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
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The three patterns of catamenial exacerbation o

epilepsy in relation to serum estradiol (E2) and

rogesterone (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 normalmenstrual 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 seizureexacerbation is prolonged rather than focused. These women have anovulatory cycles and

inadequate luteal phase syndrome.4Because they do not ovulate, no corpus luteum (derived
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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 ofcatamenial 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.5In women with epilepsy, intravenousadministration 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 - aminobutyric acid (GABA)-a receptor with a potency

almost a thousandfold greater than that of pentobarbital and greater than the most potentbenzodiazepine, nitroflurazepam.7,8In 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 levelsjust before and during menstruation.

In a woman with an anovulatory cycle, estrogen levels rise at the end of the follicular phase andstay elevated throughout the luteal phase until premenstrually, as in normally menstruating

women. Little or no progesterone is secreted, however, creating an estrogen:progesterone (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 excessrelative to progesterone contribute to the catamenial pattern of seizure exacerbation in both

normal women and in women with menstrual irregularities.1,2,10The 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 inanticonvulsant medication levels.11,12In women with catamenial epilepsy, phenytoin levels

decline premenstrually by up to one-third.11,12This decline may be due to an increased rate ofclearance at the beginning of menstruation, with an associated reduction in the half-life of

phenytoin from 19 to 13 hours.11Hepatic microsomal enzymes metabolize both gonadal steroids

and anticonvulsants such as phenytoin, with competition between the two. The premenstrualdecline in gonadal steroid secretion may therefore permit increased metabolism of AEDs,
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resulting in lower serum levels.11It is not certain whether all AEDs are affected. Phenobarbital

is not, and catamenial fluctuation in serum levels of other AEDs 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


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 isdivided into four phases:

1. menstrual, days -3 to +32. follicular, days +4 to +93. ovulatory, days +10 to +164. 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 thecycle.

If a catamenial pattern of seizure exacerbation is established from this record, additional steps inthe 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 troughAED levels on day 22 (when estradiol and progesterone levels are high and the AEDlevel should be "normal") and day 1 (when estradiol and progesterone levels are low).

Low AED 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:
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Academic Press; 1997. p. 207-232.

With permission from Elsevier(www.elsevier.com).


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Treatment


Endocrine treatment of seizures may rationally be aimed at those endocrinologic aspects ofseizures 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 increasedseizure 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.14,15Progesterone 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 studies16,17although 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 12weeks intramuscularly or 20 to 40 mg orally daily) resulted in a 40% average seizure

reduction.16Weekly 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 catamenialexacerbation of complex partial seizures of temporal lobe origin, 72% of the women

improved.18The 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 progesteronelozenges (200 mg tid) on days 15 through 25 of each menstrual cycle, with taper over days 26through 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,19,20whereas synthetic progestins are not metabolized in this way.
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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 AED 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 AED, 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).

http://www.elsevier.com/http://www.elsevier.com/http://www.elsevier.com/http://www.elsevier.com/

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