Kristen M. Fowler

Frequency of catamenial seizure exacerbation in women with localization‐related epilepsy

This investigation assessed the frequency of catamenial epilepsy in 87 women who charted seizures and menses during three cycles. Catamenial epilepsy designation was made if two of three cycles showed at least one of three previously defined catamenial patterns. Among ovulatory cycles, average daily seizure frequency was significantly greater during the perimenstrual and preovulatory phases. Among anovulatory cycles, average daily seizure frequency was substantially less during the midfollicular phase than during the remainder of the cycle. Overall, 39.1% of the women had catamenial epilepsy. Ann Neurol 2004;56:431–434

Hormone Replacement Therapy in Women with Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Study

Summary:  Purpose: 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.

The effect of seizure severity on quality of life in epilepsy

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.

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use

Objective: 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. Methods: 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). Results: 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). Conclusions: 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. AED = antiepileptic drug; BMI = basal metabolic index; COC = combined oral contraceptive; EIAED = enzyme-inducing antiepileptic drug; IGE = idiopathic generalized epilepsy; LRE = localization-related epilepsy; LTG = lamotrigine; VPA = valproate.

Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial

Objective: To assess progesterone treatment of intractable seizures in women with partial epilepsy. Methods: 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. Results: 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. Conclusion: 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.

Sexual hormones and epilepsy: threat and opportunities.

Purpose of reviewThis article reviews recent developments in our knowledge of the reciprocal interactions between epilepsy and sex hormones and how these interactions may play a role in the pathophysiology and treatment of both. Recent findingsCommunity studies confirm that menstrual disorders are overrepresented among women with epilepsy, especially among women with high seizure frequency and in those on valproate or polytherapy. Reproductive function is not affected in women with epilepsy who discontinued antiepileptic drug therapy during pubertal maturation. While valproate has been implicated as having particularly notable disruptive effects on reproductive function in women with epilepsy (polycystic ovaries and hyperandrogenemia), this was not evident in non-epileptic primates. The role of epilepsy itself is evident from a study that showed that the laterality of unilateral temporolimbic discharges is associated with predictable directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis. Epilepsy in men is associated with reduced levels of sexual function, bioactive testosterone and sperm. Various antiepileptic drugs may differ in this regard. SummaryEpilepsy and antiepileptic drugs can alter sex hormone levels to promote the development of reproductive endocrine disorders in both women and men. Reproductive endocrine disorders may adversely affect both reproductive function and seizure control. Treatment of epilepsy and selection of antiepileptic drugs may be important to reproductive health in women and men with epilepsy. Sex steroids and their metabolites may also provide treatment for seizures.

Laterality and location influence catamenial seizure expression in women with partial epilepsy

Objective: 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. Methods: Baseline data from seizure and menstrual diaries of ∼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. Results: 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. Conclusion: 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.

Variation of seizure frequency with ovulatory status of menstrual cycles.

Purpose:  To determine if seizure frequency differs between anovulatory and ovulatory cycles.

A comparison of anastrozole and testosterone versus placebo and testosterone for treatment of sexual dysfunction in men with epilepsy and hypogonadism

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.

SENSITIVITY AND SPECIFICITY OF THE ASSOCIATION BETWEEN CATAMENIAL SEIZURE PATTERNS AND OVULATION

Some ovarian steroids such as estradiol (E)1,2 and progesterone (P)3,4 have neuroactive properties that can affect neuronal excitability. Cyclic changes in the serum concentrations of these steroids in relation to the menstrual cycle may induce variation in seizure frequency that has been termed catamenial epilepsy.5,6 There is statistical evidence to support the existence of at least three patterns: 1) perimenstrual (C1: day −3 to 3), 2) periovulatory (C2: day 10 to −13) in ovulatory cycles, and 3) luteal (C3: day 10 to 3) in anovulatory cycles. Day 1 refers to the day of onset of menstrual flow and Day −14 is presumed to represent the day of ovulation in ovulatory cycles.5,6 There are also mathematically based levels of seizure exacerbation for designation of catamenial epilepsy for each of these patterns. Although different patterns of catamenial exacerbation have been observed with ovulatory and anovulatory cycles, their sensitivity and specificity remain to be established.5,6 ### Methods. The subjects were 100 women with localization-related epilepsy, 13 to 45 years of age, who had intractable seizures, i.e., persistence of two or more monthly seizures despite documented trials of at least two antiepileptic drugs with therapeutic range levels. The subjects were participating in the baseline phase of a clinical trial of progesterone therapy. The women recorded …