Reproductive Endocrine Considerations and Hormonal Therapy for Women with Epilepsy

Summary: Animal experimental and human clinical investigations show that estrogens lower and progestins raise many seizure thresholds. In women, seizure frequency varies with the serum estradiol to progesterone ratio. The fluctuation of this ratio during the menstrual cycle is a major factor in catamenial epilepsy. A decline in serum antiseizure medication levels premenstrually may be another factor. Estradiol to progesterone ratios are elevated in anovulatory or inadequate luteal phase cycles. This may explain a propensity for seizure onset at the time of menarche and the exacerbation of seizures during the months or years leading up to menopause. It may also be an important factor in the association between reproductive endocrine disorders and epilepsy. Specifically, polycystic ovarian syndrome and hypogonadotro-pic hypogonadism are significantly overrepresented among women with epilepsy. Epilepsy may promote the development of these disorders. These disorders, in turn, are characterized by inadequate luteal phase cycles that may promote the development or occurrence of seizures. In the setting of catamenial epilepsy or reproductive endocrine disorders, progestins, such as natural progesterone and parenteral medroxyprogesterone, or antiestrogenic agents, such as clomi-phene, constitute rational and effective adjuncts to therapy.     

Reproductive Endocrine Considerations and Hormonal Therapy for Men with Epilepsy

Summary: Androgen deficiency is unusually common among men with epilepsy. It may contribute to reproductive and sexual dysfunction and possibly exacerbate seizure frequency. The most important androgen is testosterone. It exists in the serum in a free form or bound to albumin or sex hormone-binding globulin (SHBG). Free testosterone levels have correlated significantly with measures of potency and sexual interest. The possibility that measures of non-SHBG-bound testosterone may provide a more sensitive assessment of biologically and perhaps clinically significant androgen levels is raised for consideration. Androgen deficiency may result from increased catabolism and binding induced by antiepileptic drugs (AEDs). It is a feature of the reproductive endocrine disorders that are often associated with epilepsy: hypogonad-otropic hypogonadism, hypergonadotropic hypogonadism, and functional hyperprolactinemia. It may be a consequence of medication-induced elevations in serum estradiol. Estradiol exerts a potent inhibitory influence on luteinizing hormone secretion and may contribute to premature aging of the reproductive system, both at the level of the testes and the hypothalamus. Testosterone therapy may moderately benefit reproductive and sexual function. Despite its antiseizure effects in animal experiments, however, it has not been reported to improve seizures clinically. One possible explanation is that AEDs that induce enzyme synthesis may enhance the conversion of testosterone to estradiol by aromatase. This possibility is supported by the improved seizure control achieved with the adjunctive use of the aromatase inhibitor testolactone or the antiestrogen clomiphene.     

Clinical Study of Oral Administration of DN-1417, a TRH Analog, in Patients with Intractable Epilepsy

An open dose-finding trial of orally administered DN-1417 was undertaken to investigate dose, efficacy, and adverse reactions. One hundred ninety patients, with epilepsy resistant to conventional drug treatment, were randomly allocated to two treatment groups of low dose (20 mg/day for adult) and high dose (80 mg/day for adult). Medication was given while fasting, once a day, for 8 weeks. If at the end of the first 4-week treatment period the patient had a satisfactory response, the dose was doubled. Patient response was assessed by global improvement rating (GIR) based on changes in seizure frequency, EEG findings, and nonparoxysmal clinical manifestations. The responses assessed by GIR was "slightly to markedly improved" in 48% of the patients with low-dose treatment and 55% with high-dose treatment. There was no clear dose-related difference between the two treatments. In patients with Lennox-Gastaut syndrome having no history of West syndrome, the rate of response assessed by GIR was found to be slightly dose-related (low dose, 61%; high dose, 73%).     

Pregnancy and Epilepsy

Summary: : Women with epilepsy account for approximately 0.5% of all pregnancies. Their pregnancies are high risk because of an increased frequency of maternal seizures, complications of pregnancy, and adverse pregnancy outcomes. The increase in seizure frequency is associated with a progressive decline in antiepileptic drug (AED) levels during pregnancy even with constant dosing. Fetal deaths after a generalized seizure, although rare, have been reported, and a marked decline in fetal heart rate has been demonstrated after such seizures during delivery. AEDs have been implicated in causing a twofold increase in the rate of congenital malformations, a variety of minor physical anomalies, mostly involving the midface, and a neonatal hemorrhagic disorder. The clinician caring for a pregnant woman with epilepsy is therefore faced with a dilemma and must carefully chart a middle ground providing effective seizure control while minimizing fetal exposure to AEDs     

Adjunctive Therapy for Intractable Epilepsy with Ethotoin

In a retrospective study, records of 46 patients (24 women and 22 men aged 17-51 years; mean 29.2 years), who had been treated with ethotoin (EHN) as adjunctive therapy for control of intractable seizures were reviewed. Overall, approximately 51% of this highly selected patient population had a reduction greater than 50% in overall seizure frequency 1 month after initiation of treatment. This was reduced to approximately 25% for the last 3 months of follow-up (mean follow-up period 10.6 months). Tonic seizure frequency was reduced most dramatically, by greater than 50%, in 60% of patients at 1 month and in 35% of patients for the last 3 months of follow-up. This study suggests that prospective controlled trials of EHN, especially for tonic seizures, are needed.     

Treatment of Intractable Childhood Epilepsy with High-Dose Valproate

Forty-six children with refractory epilepsy (12 with symptomatic generalized epilepsy, 14 with symptomatic partial epilepsy, and 20 with undetermined epilepsy) were treated by high-dose (serum level above 100 micrograms/ml) valproate (VPA) therapy. Monotherapy was used with 34 patients and two drugs with 12. Serum VPA concentrations ranged from 105.1 to 198.4 micrograms/ml. Assessment of initial response to treatment, after the serum level had reached the appropriate level, showed seizures to be completely controlled in 15 (32.6%) of 46 patients and improved in 12 (26.1%) (50% or more). Follow-up of more than 6 months after the time of initial response showed control of seizures in 14 (30.4%) and improvement in 11 (23.9%). The initial effect on EEG was the disappearance of epileptic discharges in 3 (6.5%) of 46 patients and marked improvement in 15 (32.6%). Follow-up revealed the disappearance of epileptic discharges in 7 (15.2%) and marked improvement in 9 patients (19.6%). High-dose VPA therapy was especially effective for West syndrome and for epilepsy with continuous spike-waves during slow-wave sleep. Control of atypical absences and myoclonic seizures was relatively good. Hypofibrinogenemia and thrombocytopenia were sometimes encountered but these side effects were reversible with reduction of dosage.     

Discontinuation of Antiepileptic Drugs in Children Who Have Outgrown Epilepsy: Effects on Cognitive Function

Summary: Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls.     

Hormones and Epilepsy Through the Lifetime

Summary: Hormones influence brain function from gestation throughout life and may affect the seizure threshold by altering neuronal excitability. Estrogen enhances and progesterone diminishes neuronal excitability experimentally, whereas testosterone and corticosteroids have less consistent effects. Hormonal effects in the CNS also depend on the region of brain in which the hormone acts. Sites of action for most steroid hormones include the hypothalamus and limbic cortex, providing a mechanism for modulating behavior and endocrine function. Seizure patterns may change at certain life stages, perhaps as a result of alterations in hormones. At puberty, epilepsy and benign rolandic epilepsy often remit, while juvenile myoclonic and photosensitive epilepsy may arise. Other types of epilepsy do not respond predictably to events in the reproductive life or to advancing age. In some women, fluctuations in hormones over the menstrual cycle appear to increase seizure vulnerability, probably reflecting changes in relative amounts of estrogen and progesterone. Seizure patterns can be altered, for better or worse, during pregnancy. Whether this reflects the effects of hormones or changes in levels of antiepileptic drugs is not resolved. More information is needed about changes in established epilepsy at menopause and in the elderly. Better understanding of endocrine effects on seizures over a lifetime should lead to more effective epilepsy therapies.     

Three Patterns of Catamenial Epilepsy

Summary: Purpose: On the basis of the neuroactive properties of estradiol and progesterone and the menstrually related cyclic variations of their serum concentrations, we propose the existence of three hormonally based patterns of seizure exacerbation. Because previous reports both support and refute the concept of catamenial epilepsy, we test the hypothesis by charting seizures and menses and measuring midluteal serum progesterone levels to estimate the frequency of epileptic women with catamenial seizure exacerbation. Methods: One hundred eighty-four women with intractable complex partial seizures (CPS) charted their seizure occurrence and onset of menstruation on a calendar for one cycle during which they had a midluteal blood sample taken for serum progesterone determination on day 22. Levels >5 ng/ml were considered ovulatory. The cycle was divided into four phases with onset of menstruation being day 1: menstrual (M) = -3 to +3, follicular (F) = 4 to 9, ovulatory (O) = 10 to -13, and luteal (L) =?12 to ?4. Average daily seizure frequency for each phase was calculated and compared among phases by repeated-measures analysis of variance (ANOVA) and the Student-Newman-Keul's test, separately for ovulatory and anovulatory cycles. Results: The 1,324 seizures recorded during 98 ovulatory cycles occurred with significantly greater (p < 0.001) average daily frequency during the M (0.59) and O (0.50) phases than during the F (0.41) and L (0.40) phases, offering support for perimenstrual (catamenial 1) and preovulatory (catamenial 2) patterns of seizure exacerbation. The 1,523 seizures recorded during 86 anovulatory cycles occurred with significantly lower (p < 0.001) average daily frequency during the F phase (0.49) than during all other phases (M = 0.78, O = 0.74, L = 0.74), offering support for seizure exacerbation throughout the second half of inadequate luteal phase cycles (catamenial pattern 3). Although 71.4% of the women with ovulatory cycles and 77.9% with inadequate luteal phase cycles had seizure exacerbation in relation to one of the three patterns of catamenial epilepsy, approximately one third of the women showed at least a twofold increase in average daily seizure frequency. We propose a twofold or greater increase as a reasonable definition of catamenial epilepsy. Conclusions: Charting of seizures and menses and determination of day 22 progesterone levels during each cycle may be sufficient to establish the existence of three distinct patterns of catamenial epilepsy. Approximately one third of women with intractable CPS may have catamenial epilepsy.     

Cognitive Function and Time-of-Day Variation in Serum Carbamazepine Concentration in Epileptic Patients Treated with Monotherapy

Different parameters of antiepileptic drug (AED) treatment have been shown to affect cognitive function. The drug, dose, and duration of treatment have been studied. The present study assessed cognitive function in relation to time-of-day variation in serum carbamazepine (CBZ) concentration in epileptic patients treated with monotherapy. We studied 10 males and 12 females with a mean age of 36 years and a mean duration of CBZ-therapy of 4.4 years. Patients had been seizure-free for at least 1 month and took two daily CBZ doses. The test battery included tests of motor speed, reaction time, attention, and memory. In the experimental design, the subjects were tested twice at times close to expected daily maximum and minimum serum CBZ concentration. They were studied in two balanced blocks (block 1 tested at 8 a.m. and noon, block 2 tested at noon and 8 p.m.). Blood samples were collected every 2 hr from 8 a.m. to 8 p.m. The subjects showed significant differences in serum CBZ concentration between testing times, with suggested maximum concentration between 10 a.m. and noon. The test battery showed no consistent differences between performance at times of high versus low serum concentration. A supplementary analysis of correlations between mean performance level on cognitive tests and variables related to CBZ treatment did not show consistent trends.     

Double-Blind Study of Gabapentin in the Treatment of Partial Seizures

Forty-three patients completed a double-blind, placebo-controlled study of Gabapentin (GBP) as add-on therapy in partial and secondarily generalized seizures. All patients were followed for an initial 3-month baseline period, after which they were randomly allocated to receive either a placebo or 900 or 1,200 mg/day GBP for 3 months. A statistically significant difference in seizure frequency from the baseline to the treatment phase was noted between patients receiving placebo and GBP 1,200 mg, in whom seizure frequency decreased 57%. The GBP dosage of 900 mg appeared to be ineffective. A close relationship was observed between the serum GBP concentrations and the GBP dosage based on the seizure frequency. Serum GBP concentrations greater than 2 micrograms/ml resulted in a lower frequency of seizures. The adverse effects were minor and consisted mainly of transient drowsiness. GBP appears to be effective in the treatment of partial epileptic seizures in a dosage-related manner.     

Calcium antagonist nimodipine in intractable epilepsy.

The influx of Ca2+ into the neuron seems to play an important role in the genesis of epileptic seizures, and current research suggests that calcium entry blockers may have anticonvulsant activity. We used nimodipine, a calcium antagonist with high central nervous system affinity at a fixed dosage of 30 mg, t.i.d., in 21 patients with intractable epilepsy caused by organic brain lesions in addition to basal antiepileptic drug (AED) therapy. After a 12-week treatment period 14 patients (67%) showed a decrease in seizure frequency, four patients had no change, and three had an increase. In eight patients (38%) seizure frequency decreased by greater than 40%. The p value with one-tailed t-test was 0.0491. No significant modifications in AED or electrolyte serum levels were found. One patient had a lowering of blood pressure at this dosage.     

Carbamazepine Does Not Affect Short-Latency Somatosensory Evoked Potentials: A Longitudinal Study in Newly Diagnosed Epilepsy

Somatosensory evoked potentials from median nerve stimulation were recorded in 12 patients with newly diagnosed epilepsy, before and after 1 year of treatment with carbamazepine. The plasma concentrations of the drug were consistently within therapeutic range. We assessed the latencies of the early components at the level of the cervical spine (N9 and N13) and on the parietal scalp (P14, N20, P25) and the interpeak latencies (N9-N13, N13-N20, P14-N20). None of the patients presented anomalies in any of the parameters, and there was no significant difference between the patient and control means or between the patient means before and after 1 year of treatment.     

Effects of Vigabatrin on Cognitive Function and Mood When Used as Add-on Therapy in Patients with Intractable Epilepsy

Cognitive function and mood of patients with epilepsy who received 2 g/day vigabatrin (GVG) in addition to their usual antiepileptic drugs (AEDs) was assessed on two occasions: before start of treatment (baseline) and 4 weeks after start of treatment. A battery of selected psychological tasks measuring attention, mental speed, motor speed, central cognitive processing, and perceptuomotor performance was used, along with standardized, objective mood assessments. A comparison group (n = 15) of patients receiving stable medication was also tested to evaluate practice effects of the psychometric tests. Administration of 2 g/day GVG significantly decreased response time on a test of central cognitive processing ability (arithmetic). No adverse effect was noted on any other test of cognitive function or mood.     

The Effects of Epilepsy and Its Treatment on Sexual and Reproductive Function

Summary: Male and female sexuality and reproductive functions are complex systems with cortical, limbic system, hypothalamic, pituitary, and end organ interactions. Sexual steroids are produced in the sexual glands, the adrenals, and the brain. They undergo interconversion in the brain, bind to different brain areas, and have multiple effects behaviorally and neuro-physiologically. Progesterone, estrogen and testosterone have neuroendocrine effects that alter epileptogenicity. Seizure frequency may change throughout the life cycle as a result of hormonal status. Changes in central control, peripheral hormone levels, and/or medication effects may all contribute to decreased libido, potency, and fertility. Antiepileptic drugs (AEDs) interact with hormone-binding metabolism, resulting in altered human reproductive function. AEDs alter contraceptive hormone treatments. Information on the effects of new AEDs is being gathered by the National Pregnancy Registry. Catamenial epilepsy and some sexual dysfunction in men may be treatable.     

Phenytoin Levels in Catamenial Epilepsy

We studied the fluctuations in phenytoin (PHT) levels during ovulatory and menstrual phases of the cycle, in eight patients with catamenial epilepsy and in eight age-matched controls. Pharmacokinetic studies of PHT were done in five patients with catamenial epilepsy. The difference in PHT levels during menstrual and ovulatory phase in catamenial group was 3.44 +/- 3.25 micrograms/ml as compared with 0.91 +/- 2.03 micrograms/ml in controls. The mean fall during menstrual phase was significant (p less than 0.05) in the catamenial group. There was also rapid though statistically nonsignificant clearance of PHT during menses as compared with the ovulatory period. It is presumed that the fall in plasma PHT levels during menses, though still within therapeutic range, may be responsible for catamenial exacerbation of epilepsy.     

Neuropsychological Aspects of Learning Disabilities in Epilepsy

Summary: Cognitive impairment is regarded as the link between epileptic conditions and the inability to learn in school. The neuropsychological approach to learning disabilities in epilepsy, therefore, first concentrates on analyzing the differential effects of epileptic factors on cognitive function. The impact of seizure activity, localization of epileptogenic foci, and antiepileptic treatment on cognitive functioning can be evaluated based upon the results of continuous assessment with a computerized neuropsychological test system. Second, learning disabilities may be evaluated on observations made during classroom performance. Three issues seem to predominate in learning studies among disabled children with epilepsy: test-retest variability, deterioration, and the supposed specificity of the learning disabilities.     

Clobazam in Therapy-Resistant Patients with Partial Epilepsy: A Double-Blind Placebo-Controlled Crossover Study

Clobazam was compared with placebo as antiepileptic adjunct medication in 129 therapy-resistant epileptic patients who were mainly suffering from complex partial seizures. The study was performed in five European countries according to a double-blind crossover design lasting 7 months. Two treatment periods of 3 months (1 month adjustment and 2 months maintenance medication) were separated by one medication switch-over month. The difference in seizure reduction between clobazam and placebo was significant (p less than 0.05). Nineteen percent of patients receiving clobazam became seizure-free during the maintenance dose period. In contrast, freedom from seizures was not observed in any placebo patient. Electroencephalogram (EEG) signs, mood ratings, and global impressions also indicated therapeutic effects of clobazam in epilepsy. The most frequent adverse reactions to clobazam were drowsiness and dizziness. However, the sedative effects of clobazam seemed to be less pronounced in comparison with other benzodiazepines. The study gives evidence of the therapeutic value of clobazam as adjunct medication in therapy-resistant partial seizures. The use of clobazam as monotherapy and long-term treatment, as well as the particular seizure response pattern to clobazam, has to be further investigated.