Catamenial Epilepsy

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Exacerbation of seizure frequency in relationship to the menstrual cycle is termed catamenial epilepsy. This term does not refer to a specific seizure type or epilepsy syndromic classification and therefore is probably somewhat misappropriated. A current working definition of catamenial epilepsy is a two-fold increase in average daily seizure frequency that occurs at three different times of the menstrual cycle: (i) most commonly, immediately premenstrually and at the onset of menses when estradiol and progestin levels decline; (ii) around ovulation when estradiol and progestin levels increase; and (iii) during an inadequate luteal phase, which is characterized by low progesterone levels [69]. The correlation of times of seizure exacerbation during the menstrual cycle fits well with the known effects of these reproductive hormones on neural excitability. Specifically, oestrogen promotes neuronal excitability in women with epilepsy [70] and progesterone is an anti-convulsant, via its metabolism to allopregnanolone, which is a potent positive allostearic modulator of receptor for y-amino-butyric acid (GABA), a powerful brain inhibitory neurotransmitter [71-73].

The two-fold increase in seizure frequency as a cut-off point for catamenial vs. non-catamenial seizure exacerbation was derived from evaluating a large number of monthly seizure patterns in women with partial epilepsy. A daily seizure increase of 1.6-1.8 times

Table 9.3 Menopausal age correlated with seizure frequency. Adapted from [68]

Seizure frequency

Number of patients

Mean age

Mean age at last menses*

< 20 seizures in lifetime

15

55

49.9

> 20 seizures in lifetime;

25

54

47.7

< 1 seizure per month

> 1 seizure per month

28

52

46.7

^Significantly different between groups (P=0.04).

during perimenstrual days, at ovulation or during the luteal phase compared with other days in the menstrual cycle reliably distinguished between women with seizure exacerbations at those times and those without [70]. Therefore, the findings suggest that an approximately twofold increase in seizure frequency during these times of the menstrual cycle is an appropriate amount of seizure increase to constitute a catamenial seizure exacerbation. It is estimated that up to 40% of women with partial epilepsy have catamenial seizure exacerbations [74].

The hormonal fluctuations during normal menstrual cycling and during anovulatory menstrual cycling explain catamenial seizure exacerbations to some extent, but probably not completely. As low progesterone levels during the luteal phase or progesterone withdrawal prior to the onset of menses are associated with catamenial seizure occurrence, the treatment approach for catamenial seizures has involved progesterone augmentation. One of the first attempts to use a progestin was with medroxyprogesterone acetate, given either orally or by intramuscular injection in a small group of women with poorly controlled seizures [75]. Half of the 14 women treated had a marked seizure reduction of 35-71%; these were women whose menses ceased while taking medroxyprogesterone. Since this synthetic progestin is not active at the GABA receptor, it may be that the main therapeutic mechanism was via cessation of normal hormonal cycling.

The first report of natural progesterone was in eight women with epilepsy who had anovulatory cycles or low progesterone during the luteal phase [76]. Seizure frequency declined by 70% during treatment, and side-effects were infrequent; several women experienced fatigue and depression at increased doses. In a second trial of 25 women with temporal lobe epilepsy and catamenial seizure exacerbations, using progesterone lozenges at 200 mg three times a day during the luteal phase reduced seizure frequency by approximately 50% overall [77]. Focal and generalized seizures were both improved. The long-term results of this study were later reported; 23 women remained on the treatment for 3 years with sustained seizure reduction and three of the women were seizure free [78]. These small, open studies suggest that natural progesterone can be a useful treatment for women with epilepsy and currently, a randomized, double-blind, placebo-controlled trial for women with epilepsy of reproductive age is under way.

Other treatments for catamenial seizure exacerbations include acetozolamide, oral contraceptives (OCs), intermittent benzodiazepines and intermittent increases in AEDs. Acetazolamide has long been used for the treatment of catamenial seizures, although the evidence for its effectiveness is largely anecdotal. Acetozolamide is a sulfonamide carbonic anhydrase inhibitor, and the anti-seizure mechanism is thought to be related to increased brain bicarbonate accumulation, which has an inhibitory effect on neuronal activity [79]. A retrospective review of 20 women with catamenial epilepsy treated with acetozolamide found that seizure frequency was significantly reduced in 40% of women and seizure severity was reduced in 30% of women [80].

Although intermittent benzodiazepines have also been used to treat women with catamenial seizures for years, only clobazam (which is not available in the United States) has been studied in this population. In a study of women with pre-menstrual seizure exacerbations, intermittent clobazam produced a > 50% seizure reduction in 14 of 18 evaluable cases [81]. In this study, one of the main concerns about benzodiazepine use, tolerance, was not present in nine women treated for more than 1 year [82].

Cyclic increases in patients' usual AED therapy during menstrual cycle-seizure exacerbation have not been systematically investigated. Patients seem to often initiate this approach, however, because it seems easy and does not involve adding another medication. However, this method does present the potential for confusion about the AED regimen and for AED toxicity. For phenytoin, which has a non-linear metabolism, even an intermittent dose increase could result in toxicity and, therefore, this approach is not recommended. The treatment approaches discussed above with the doses used in trials are listed in Table 9.4.

Since OCs suppress ovulation and most formulations provide a stable reproductive hormonal milieu during the 3-week treatment phase (followed by 1 week of placebo), it

Table 9.4 Treatments of catamenial epilepsy: reports of effectiveness in small open trials (*) or case reports (f)

Treatment

Dose

Medroxyprogesterone acetate*

Natural progesterone*

Acetozolamide*

Intermittent benzodiazepines*

Intermittent increase in AEDs already in regiment

Using the intramuscular depot formulation,150 mg every 10-12 weeks

100-200 mg three times a day on days 15-28 of the menstrual cycle with 2-day taper-off at onset of menses 4 mg/kg, with a range of 8-30 mg/kg/day in one to four divided doses, not to exceed 1 g per day Add low dose starting 4 days before menses, continuing for 10 days

Increase dose slightly for duration as above

seems logical, based on the likely association between reproductive hormones and seizure occurrence, that OCs could be of benefit for catamenial seizure exacerbations. Outside of a few case reports showing either improved seizures or worsening seizures, no studies have been performed to evaluate this treatment [79].

Other treatment approaches to catamenial epilepsy include anti-oestrogens such as clomiphene citrate, and androgenic derivatives such as danazol and gonadotropin analogues, all of which have been used in small clinical trials. Owing to the profound reproductive alterations and the risks of adverse events inherent in these treatments, they are not practical interventions for most neurologists. A synthetic neuroactive steroid, ganaxolone, remains under investigation for the treatment of epilepsy, and may be particularly helpful for women with epilepsy of reproductive age [79].

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