Role of Hormones in Susceptibility to Seizures in Women With Epilepsy
Role of Hormones in Susceptibility to Seizures in Women With Epilepsy
This study will measure and compare hormone levels in women with catamenial epilepsy
 (epilepsy in which seizures are more frequent during menstrual periods), women with seizures
 not related to their menstrual cycle, and normal control subjects. It will determine whether
 there are differences among the three groups in their hormone levels or in how fast the
 levels change. It will also examine what relationship, if any, exists between hormone changes
 and seizures in women with catamenial epilepsy. The hormones under study include the gonadal
 hormones estrone, estradiol and progesterone, and the neuroactive steroids allopregnanolone,
 pregnenolone, and dehydroepiandrosterone.

 Women who meet the following criteria may be eligible for this 3-month study:

 -  Between 18 and 45 years of age, with catamenial epilepsy

 -  Between 18 and 45 years of age, with seizures, but not catamenial epilepsy

 -  Between 18 and 45 years of age, without seizures

 All participants will have a physical examination at the beginning of the study, at each
 clinic visit, and at completion or withdrawal from the study. In addition, they will undergo
 the following procedures:

 Baseline Monitoring

 For the first 2 months, all participants will keep a diary of their temperature and onset of
 menses. Women with epilepsy will also record their seizures.

 Electroencephalography (EEG)

 Healthy volunteers will have a 45-minute EEG (recording of the electrical activity of the
 brain) at the beginning of each menstrual cycle and each day during the menses. Women with
 epilepsy will have continuous EEG monitoring for 8 days, beginning 5 days before their
 menstrual period is expected. The continuous monitoring can be done on an outpatient basis,
 using a portable EEG recording device, or as an inpatient, with admission to the hospital for
 the 8 days of recording.

 Blood Sampling

 All participants will have a small blood sample (2 teaspoons) drawn once a day on days 10,
 14, 17, 19 and 21 of their menstrual cycle and three times a day on day 6 and for a period of
 8 days, starting 5 days before the expected menses and continuing for 3 days of the next
 cycle. For the days with three blood draws, a small needle that can stay in place for up to
 72 hours will be placed in the arm to avoid the discomfort of multiple needle sticks.
Objectives. This is an initial pilot study to acquire information upon which a more specific,
 statistically rigorous follow-on investigation will be based. The objectives of the overall
 project are: (1) to compare the absolute levels and rates of change in levels of gonadal and
 neuroactive steroids in women with complex partial seizures and catamenial epilepsy with
 those of women with non-catamenial epilepsy and women volunteers without epilepsy, and (2) to
 determine if fluctuations in the levels of gonadal hormones (estrone, estradiol,
 progesterone) and neuroactive steroids (allopregnanolone, pregnenolone and
 dehydroepiandrosterone) correlate with seizure occurrence and the frequency of interictal
 spikes/wave discharges in women with catamenial seizure exacerbations.

 Study Populations. Group A: adult women with complex partial seizures and catamenial
 exacerbations. Group B: adult women with complex partial seizures without catamenial seizure
 exacerbations. Group C: adult female volunteers without epilepsy.

 Design. Subjects will undergo baseline monitoring of seizures and menses for two months prior
 to entry. Upon enrollment into the study, blood (10 ml) will be drawn for determinations of
 estradiol, estrone, progesterone, allopregnanolone, dehydroepiandrosterone (DHEA) and
 pregnenolone in all study populations once daily at 08:30 hr on menstrual cycle days, 10, 14,
 17, 19 and 21; and three times daily at 08:30, 13:30 and 18:00 starting 5 days before
 expected menses and continuing for a total of 8 days as well as on menstrual cycle day 6.
 During 8 days starting 5 days before expected menses interictal spike activity and seizures
 will also be monitored continuously with EEG. Comparisons of the rates of change of hormone
 levels and spike and seizure frequency will be made using the time derivatives of
 fluctuations in hormone levels or hormone level ratios. Comparisons of time series data will
 be made using nonlinear regression with an arbitrary (cubic spine) model.

 Outcome Parameters. The goal of this preliminary study is to obtain data regarding the
 fluctuation, during one menstrual cycle, of several hormones in epileptic and non-epileptic
 women of reproductive age. If the data show a relationship between (i) falling levels of
 plasma progesterone and allopregnanolone, (ii) increased levels of DHEA or pregnenolone or
 (iii) increased ratios of estrogen/progesterone, DHEA/progesterone, DHEA/allopregnanolone,
 pregnenolone/allopregnanolone and seizure manifestations and EEG documented interictal spike
 and seizure activity it would support the hypothesis that alterations in the levels of these
 steroid hormones are related to seizure exacerbations in women with catamenial epilepsy.
-  INCLUSION CRITERIA:

 Group A subjects will be 8 women between 18 and 45 years of age who have complex partial
 seizures with Type 1 catamenial seizure exacerbation as previously defined.

 Group B subjects will be 8 women between 18 and 45 years of age with complex partial
 seizures who do not meet the criteria for catamenial seizure exacerbations. The presence or
 absence of Type 1 catamenial seizure exacerbation will be documented by a standard seizure
 calendar self-reported for at least two consecutive menstrual cycles.

 Patients receiving antiepileptic drug therapy will continue on their medications.

 All subjects must agree to use double barrier contraceptives, have an intrauterine device
 in place or practice abstinence during the course of the study.

 Patients will be recruited from the epilepsy patient population at the National Institutes
 of Health.

 Subjects in groups A and B will be matched for seizure frequency. Volunteers will be
 matched with the subjects in group A by age. In this pilot study, no attempt will be made
 to match patients according to anticonvulsant medications.

 The patient will be properly informed of the nature and risks of the study and give
 informed consent in writing, prior to entering the study.

 EXCLUSION CRITERIA:

 Any of the following conditions are cause for exclusion from the study:

 Any illness requiring chronic drug therapy other than antiepileptic drugs.

 Any history of an illness likely to be adversely affected by the trial.

 Psychiatric hospitalization lasting more than 2 months at any time prior to the study.

 Use of tricyclic antidepressants within 4 weeks prior to randomization and/or
 anti-psychotic drugs within 2 weeks prior to randomization.

 Children will not be included in this pilot study, because the profile of hormonal
 secretion undergoes profound changes during puberty.

 Use of illicit drugs, alcoholism or binge drinking as per medical history inventory.

 Women who are unwilling to use an alternative to oral contraceptives for contraception,
 (double barrier contraceptives, intrauterine device or abstinence), and establish that they
 are currently not pregnant by submitting to a pregnancy test.

 Exposure to any other investigational drug within 12 weeks prior to randomization.

 Any history of endocrine dysfunction.

 Women will be excluded if they do not have regular menstrual cycle intervals between 27 and
 32 days or if they are pregnant, nursing or taking oral contraceptives or other
 reproductive hormones.

 If a need should arise to change the antiepileptic regime during the study this subject
 will be excluded and replaced with another patient.

 Women currently taking Phenobarbital or another barbiturate.

 Women who are unwilling to refrain from strenuous exercise during the study.

 Women who are unwilling to refrain from usage of herbal and soy products.