[show abstract][hide abstract] ABSTRACT: To assess progesterone treatment of intractable seizures in women with partial epilepsy.
This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles.
There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3.
There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures. Classification of evidence: This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.
[show abstract][hide abstract] ABSTRACT: The purpose of this prospective observational investigation was to determine whether the frequency of premenstrual dysphoric disorder (PMDD) and the severity of PMDD symptoms differ between women with epilepsy and controls without epilepsy and whether there exists a relationship between the severity of PMDD symptoms and some epileptic, antiepileptic drug, and reproductive endocrine features. The results suggest that epilepsy, antiepileptic drug levels, ovulatory status, and hormone levels and ratios may all influence PMDD in women with epilepsy. PMDD severity scores may be greater in people with right-sided than in those with left-sided epilepsy, and in people with temporal than in those with nontemporal epileptic foci. PMDD severity scores may be greater with anovulatory cycles, and scores may correlate negatively with midluteal serum progesterone levels and positively with midluteal estradiol/progesterone ratios. Mood score may vary with particular antiepileptic drugs, favoring carbamazepine and lamotrigine over levetiracetam. PMDD severity scores may correlate directly with carbamazepine levels, whereas they correlate inversely with lamotrigine levels.
[show abstract][hide abstract] ABSTRACT: To determine if seizure frequency differs between anovulatory and ovulatory cycles.
The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic-clonic seizures - 2°GTCS, complex partial seizures - CPS, simple partial seizures - SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis.
ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only.
Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.
[show abstract][hide abstract] ABSTRACT: Neuroendocrine research in epilepsy focuses on the interface among neurology, endocrinology, gynecology/andrology and psychiatry as it pertains to epilepsy. There are clinically important reciprocal interactions between hormones and the brain such that neuroactive hormones can modulate neuronal excitability and seizure occurrence while epileptiform discharges can disrupt hormonal secretion and promote the development of reproductive disorders. An understanding of these interactions and their mechanisms is important to the comprehensive management of individuals with epilepsy. The interactions are relevant not only to the management of seizure disorder but also epilepsy comorbidities such as reproductive dysfunction, hyposexuality and emotional disorders. This review focuses on some of the established biological underpinnings of the relationship and their clinical relevance. It identifies gaps in our knowledge and areas of promising research. The research has led to ongoing clinical trials to develop hormonal therapies for the treatment of epilepsy. The review also focuses on complications of epilepsy treatment with antiepileptic drugs. Although antiepileptic drugs have been the mainstay of epilepsy treatment, they can also have some adverse effects on sexual and reproductive function as well as bone density. As longevity increases, the prevention, diagnosis and treatment of osteoporosis becomes an increasingly more important topic, especially for individuals with epilepsy. The differential effects of antiepileptic drugs on bone density and their various mechanisms of action are reviewed and some guidelines and future directions for prevention of osteoporosis and treatment are presented.
[show abstract][hide abstract] ABSTRACT: Hyposexuality is commonly associated with low bioavailable testosterone (BAT) and relative estradiol elevation in men with epilepsy. This prospective, randomized, double-blind trial compared the effects of depotestosterone+the aromatase inhibitor anastrozole (T-A) versus depotestosterone+placebo (T-P) on sexual function, hormone levels, mood, and seizure frequency in men with epilepsy. Forty men with focal epilepsy, hyposexuality, and hypogonadism were randomized 1:1 to two groups (T-A or T-P) for a 3-month treatment trial of depotestosterone+either anastrozole or matching placebo. Outcomes included both efficacy and safety measures. Normalization of sexual function (S-score) occurred with greater frequency in the T-A (72.2%) than in the T-P (47.4%) group, but the difference was not statistically significant. T-A resulted in significantly lower estradiol levels and S-scores correlated inversely with estradiol levels at baseline and during treatment. Beck Depression Inventory II (BDI-II) scores improved significantly in both groups and changes in S-score correlated inversely with changes in BDI-II score. Changes in seizure frequency correlated with changes in BDI-II score. Seizure frequency decreased with both treatments and showed significant correlations with estradiol levels. Triglyceride levels increased with T-P and decreased with T-A. The difference in triglyceride changes between the two treatments was significant and correlated with changes in estradiol levels. Significant correlations between estradiol levels and S-scores, as well as seizure outcomes and triglyceride levels, suggest further study regarding a potential role for anastrozole in the treatment of men with epilepsy who have hyposexuality and hypogonadism.
[show abstract][hide abstract] ABSTRACT: The temporal distribution of seizures in women with localization-related epilepsy occurs periodically according to a model "clock" with the peak phase of occurrence corresponding to menstrual onset. The location and laterality of the epileptic lesion as well as patient age may affect periodicity.
Baseline data from seizure and menstrual diaries of approximately 3 months duration were obtained from 100 women enrolled in a trial of hormonal therapy for localization-related epilepsy. Durations of individual cycles were normalized to a common menstrual phase and period. Normalized data were then combined to create distributions evaluated by localization (lobar: temporal [TL], extratemporal [XL], multifocal [MF], unknown), lateralization (left, right, bilateral, unknown), and age. Distributions were evaluated with analysis of variance (ANOVA) and curve-fitted by nonlinear least squares cosinor analysis.
A total of 71 patients had TL (left = 25, right = 29, bilateral = 17), 10 XL, 14 MF, and 5 unknown seizure foci. XL and MF seizures occurred randomly across the 28-day cycle. TL seizures (left = 875, right = 706) occurred nonrandomly (ANOVA p = 0.0003) and cyclically with peak occurrence near onset of menses ([value +/- SD] peak = 1.6 +/- 2.3 days, period = 27.0 days). Left-side TL seizures peaked cyclically at onset of menses (ANOVA p = 0.04, peak = 0.0 +/- 3.0 days, period = 30 days); right-side TL seizures occurred randomly. Age did not have a cyclical effect. Women below the median age had a significantly higher seizure rate than those above the median age.
Circalunar rhythms of seizures in women, and therefore, possibly strategies of hormonal treatments of catamenial epilepsy, vary with the neuroanatomic substrate of the seizure focus.
[show abstract][hide abstract] ABSTRACT: Seizures do not occur randomly in the majority of people with epilepsy. They tend to cluster. Seizure clusters, in turn, commonly occur with a temporal rhythmicity that shows a readily identifiable and predictable periodicity. When the periodicity of seizure exacerbation in women conforms to that of the menstrual cycle, it is commonly known as catamenial epilepsy. This may be attributable to 1) the neuroactive properties of steroid hormones and 2) the cyclic variation in their serum levels. If hormones play a role in seizure occurrence, hormones may also have a role in treatment. Progesterone has potent GABAergic metabolites that may provide safe and effective seizure control in women who have catamenial epilepsy.
[show abstract][hide abstract] ABSTRACT: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well.
This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC).
Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS).
The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle.
[show abstract][hide abstract] ABSTRACT: Malformations of cortical development are disorders of altered brain anatomy and architecture that arise from abnormalities in the usual processes of cerebral cortical development. Although they often lead to epilepsy, cognitive delay, and motor impairment, little is known about their effect on sleep. Since malformations may anatomically or functionally disrupt the cerebral circuits that mediate sleep spindles, we hypothesized that these disorders would be associated with abnormal spindle characteristics. We analyzed the density, maximum frequency, laterality and distribution of sleep spindles seen in routine and long-term electroencephalographic recordings performed in ten brain malformation subjects and ten matched controls. There were no significant differences in spindle density or maximum frequency between the two groups, but malformation subjects had a significantly lower proportion of bilateral spindles and a significantly higher proportion of anterior and diffuse spindles compared to controls. In addition, unilateral malformations appeared to be associated with a skewing of unilateral spindles toward the contralateral side. Our findings suggest that brain malformations disrupt the thalamocortical circuits responsible for sleep spindle generation, and support the need for further studies on the relationships between cortical maldevelopment and sleep.
Brain & development 08/2008; 31(2):163-8. · 1.74 Impact Factor
[show abstract][hide abstract] ABSTRACT: Reproductive disorders are unusually common among women and men with epilepsy. They are generally associated with and may be the consequence of reproductive endocrine disorders. Both epilepsy itself and antiepileptic drug use have been implicated in their pathophysiology. This review focuses on how temporolimbic dysfunction in epilepsy may disrupt normal neuroendocrine regulation and promote the development of reproductive endocrine disorders. The particular nature of the dysregulation may relate to the laterality and focality of the epilepsy and some hormonal changes may develop in close temporal relation to the occurrence of epileptiform discharges. In women, reproductive endocrine disorders include polycystic ovary syndrome, hypothalamic amenorrhea, functional hyperprolactinemia, and premature menopause. In men, hypogonadism may be hypogonadotropic, hypergonadotropic or related to hyperprolactinemia. The significance of these reproductive endocrine disorders is that they may contribute not only to sexual dysfunction and infertility but may also have an adverse impact on seizure control.
[show abstract][hide abstract] ABSTRACT: Seizures do not occur randomly. They tend to cluster in the majority of men and women with epilepsy. Seizure clusters, in turn, often show a periodicity. When the periodicity of seizure exacerbation aligns itself with that of the menstrual cycle, it is designated as catamenial epilepsy. The neuroactive properties of reproductive steroids and the cyclic variation in their serum concentrations are important pathophysiologic factors. Recent investigations have demonstrated and confirmed the existence of at least three patterns of catamenial seizure exacerbation: perimenstrual and periovulatory in ovulatory cycles and entire luteal phase in anovulatory cycles. A rational mathematical basis for the categorization of seizure exacerbation as catamenial epilepsy has been developed. It identifies approximately one third of women as having catamenial epilepsy. If seizures show hormonal sensitivity in their occurrence, they may also respond to hormonal treatment. Successful open label trials using cyclic natural progesterone supplement, depomedroxyprogesterone and gonadotropin-releasing hormone analogues in women and using testosterone with or without aromatase inhibitor in men have been reported. Prospective, randomized, placebo-controlled, double-blind investigations are warranted and under way.
[show abstract][hide abstract] ABSTRACT: Purpose: Little consensus exists for the definition of catamenial epilepsy. Few studies have evaluated the periodicity of seizures to test the hypothesis that seizures in women have periodic patterns of occurrence independent of a priori hormonal considerations. In the present study, we determined seizure periodicity according to a “menstrual clock” provided by a common phase marker of the onset of menses.Methods: Seizure and menstrual diaries of ∼3 months duration were obtained from women enrolled in a trial of hormonal therapy for localization-related epilepsy. Midluteal progesterone levels identified ovulatory (≥5 ng/ml, OC) from anovulatory cycles (AC). Individual cycles were normalized to a common phase and period (day 0 = menses onset, intervening days = 28 bins). Periodicity of combined data was estimated with cosinor-nonlinear least squares analysis. Best-fit rhythms were estimated with 95% confidence limits.Results: 100 patients provided 3344 seizures within 293 cycles (77% OC, 20% AC, indeterminate 3%). OC seizures displayed a circalunar rhythm with peak phase of occurrence at onset of menses. AC seizures also featured a circalunar rhythm that peaked at menses onset but also had ultralunar rhythms of ∼14 and ∼9 days.Discussion: Seizures in women with epilepsy occur in circalunar rhythms. OC and AC seizures differ in seizure timing with the latter occurring in ultralunar rhythms in addition to the predominant circalunar rhythm. This finding supports the existence of catamenial epilepsy and differences in patterns of seizure occurrence between OC and AC.
[show abstract][hide abstract] ABSTRACT: Migraine is 3 times more common in postpubertal women than in men. Migraine is frequently exacerbated perimenstrually and commonly occurs exclusively at that time. It is often benefited by pregnancy and menopause. Estrogen withdrawal has been implicated as a mechanism for triggering migraines. The mechanism, however, is not well understood. Reproductive steroids have neuroactive properties that can modulate neuronal morphology and physiology. Increasing evidence suggests that circulating reproductive steroid levels regulate the balance of neuroexcitatory and neuroinhibitory activities in some brain regions by influencing synaptic plasticity. Estrogen has neuroexcitatory, whereas progesterone has neuroinhibitory, effects in most preclinical and clinical models. Several neurotransmitter systems that are implicated in migraine vary with reproductive steroid levels during the reproductive cycle. Estrogen stabilization may provide effective treatment in susceptible women, especially for catamenially exacerbated migraine.
Headache The Journal of Head and Face Pain 10/2007; 47 Suppl 2:S68-78. · 2.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Seizure severity is an important aspect of epilepsy. The relationship between seizure severity and quality of life in epilepsy, however, has been incompletely explored. With a data set of 118 women from the baseline phase of a clinical treatment trial, the relationship between seizure severity and aspects of quality of life was evaluated. Two domains of the Quality of Life in Epilepsy-31 (QOLIE-31) correlated highly significantly with seizure severity: Seizure Worry (r=-0.265, P=.004) and Social Functioning (r=-0.280, P=0.002). Two additional domains were significantly correlated: Overall Quality of Life (r=-0.210, P=0.023) and Cognitive (r=-0.209, P=0.024). When the potentially confounding effect of depression, measured by the Beck Depression Inventory, was controlled for, the regression of seizure severity with QOLIE-31 Seizure Worry remained significant (P=0.006, R(2)=0.153), as did the regression with QOLIE-31 Social Functioning (P=0.002, R(2)=0.184) and the regression with QOLIE-31 Cognitive (P=0.037, R(2)=0.30). These findings indicate that severe and potentially injurious seizure behaviors contribute to anxiety and socially avoidant behavior for persons with intractable epilepsy.
[show abstract][hide abstract] ABSTRACT: To compare serum levels of neuroactive steroids among men with epilepsy who take various antiepileptic drugs, untreated men with epilepsy and normal controls (NC).
Subjects were 85 men with localization-related epilepsy [unmedicated >6 months (No Rx)-10, carbamazepine (CBZ)-25, phenytoin (PHT)-25, lamotrigine (LTG)-25] and 25 NC. Sexual function scores (S-Score), hormone levels [dehydroepiandrosterone sulfate (DHEAS), bioactive (BA) testosterone (T), estradiol (BAE), and androstanediol (BAL)] and the ratios of inhibitory to excitatory neuroactive metabolites of T, i.e., BAL/BAE, were compared among groups.
S-scores, DHEAS, and bioactive testosterone (BAT) were significantly (p < 0.05) lower and BAL and BAL/BAE were significantly higher among CBZ and PHT groups than among NC and LTG groups. LTG did not differ from NC in any of these measures. BAT correlated significantly with BAL/BAE for PHT (r = 0.44, p = 0.02) and CBZ (r = 0.42, p = 0.03) but not for NC (r = 0.03, p = NS) and LTG (r = 0.06, p = NS) groups.
In comparison to LTG, enzyme inducing AEDs (CBZ, PHT) are associated with a more favorable neuroactive steroid balance (lower DHEAS and higher BAL/BAE) for seizure management, but at the expense of reduced serum bioavailable testosterone levels and sexual function.
[show abstract][hide abstract] ABSTRACT: Previous reports have suggested that hormone replacement therapy (HRT) could increase seizure activity in women with epilepsy. We sought to determine whether adding HRT to the medication regimen of postmenopausal women with epilepsy was associated with an increase in seizure frequency.
This was a randomized, double-blind, placebo-controlled trial of the effect of HRT on seizure frequency in postmenopausal women with epilepsy, taking stable doses of antiepileptic drugs (AEDs), and within 10 years of their last menses. After a 3-month prospective baseline, subjects were randomized to placebo, Prempro (0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate or CEE/MPA) daily, or double-dose CEE/MPA daily for a 3-month treatment period.
Twenty-one subjects were randomized after completing baseline. The subjects' ages ranged from 45 to 62 years (mean, 53 years; SD, +/-5), and the number of AEDs used ranged from none to three (median, one). Five (71%) of seven subjects taking double-dose CEE/MPA had a worsening seizure frequency of at least one seizure type, compared with four (50%) of eight taking single-dose CEE/MPA and one (17%) of six taking placebo (p = 0.05). An increase in seizure frequency of the subject's most severe seizure type was associated with increasing CEE/MPA dose (p = 0.008). An increase in complex partial seizure frequency also was associated with increasing CEE/MPA dose (p = 0.05). Two subjects taking lamotrigine had a decrease in lamotrigine levels of 25-30% while taking CEE/MPA.
CEE/MPA is associated with a dose-related increase in seizure frequency in postmenopausal women with epilepsy. CEE/MPA may decrease lamotrigine levels.
[show abstract][hide abstract] ABSTRACT: Women with epilepsy are more likely to have menstrual disorders than women in the general population. Estimates vary because of different definitions of menstrual disorder. Our best estimate is that perhaps one of every three women with epilepsy may be affected compared with one of seven in the general population. Menstrual disorders are significant because they are associated with anovulatory cycles that may increase the risks for infertility, migraine, emotional disorders, and female cancers. They are neurologically important because they are associated with greater seizure frequency. Increasing evidence implicates both epilepsy itself and antiepileptic drug (AED) use as causal or contributory factors. These factors can alter reproductive hormone levels and promote the development of reproductive endocrine disorders, especially polycystic ovarian syndrome (PCOS). Among AEDs, valproate has been associated with the development of characteristic PCOS features. The risk appears to be particularly high when valproate use is started in childhood or adolescence. Menopause tends to occur earlier in women with epilepsy, especially in the setting of a high lifetime number of seizures and lifetime use of multiple enzyme-inducing AEDs. The intricate relationship between reproductive disorders and epilepsy suggests that reproductive function should be monitored closely as part of the comprehensive care of women with epilepsy.
[show abstract][hide abstract] ABSTRACT: To compare sexual function and reproductive hormone levels among men with epilepsy who took various antiepileptic drugs (AEDs), untreated men with epilepsy, and normal controls.
Subjects were 85 men with localization-related epilepsy (25 on carbamazepine [CBZ], 25 on phenytoin [PHT], 25 on lamotrigine [LTG], and 10 untreated for at least 6 months [no AED]) and 25 controls. Sexual function scores (S-scores), hormone levels (bioactive testosterone, estradiol), hormone ratios (bioactive testosterone/bioactive estradiol), and gonadal efficiency (bioactive testosterone/luteinizing hormone) were compared among the five groups.
S-scores, bioactive testosterone levels, bioactive testosterone/bioactive estradiol, and bioactive testosterone/luteinizing hormone were significantly greater in the control and LTG groups than in the CBZ and PHT groups. Sex hormone binding globulin was significantly higher in the CBZ and PHT groups than in all other groups. S-scores were below the control range in 20% of the men with epilepsy, including 32.0% on CBZ, 24% on PHT, 20% on no AEDs, and 4% on LTG (chi2: p = 0.08 for all four groups; chi2: p = 0.02 for the three AED groups). Bioactive testosterone was below the control range in 28.2%, including 48% on CBZ, 28% on PHT, 20% on no AEDs, and 12% on LTG (chi2: p = 0.02). Among men with epilepsy who had low S-scores, 70.6% had bioactive testosterone levels below the control range as compared to 17.6% among men with normal S-scores (chi2: p < 0.0001). Among men with epilepsy who had abnormally low bioactive testosterone, 50.0% had low S-scores; among men with normal bioactive testosterone, 8.2% had low S-scores (chi2: p < 0.0001). Bioactive testosterone decline with age was significantly greater among men with epilepsy than among controls and notably greater in the CBZ and PHT groups than in the LTG and untreated groups.
Sexual function, bioavailable testosterone levels, and gonadal efficiency in men with epilepsy who took lamotrigine were comparable to control and untreated values and significantly greater than with carbamazepine or phenytoin treatment.