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.

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 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. 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.

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.

Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Seizure frequency is associated with age at menopause in women with epilepsy.

OBJECTIVE: To determine whether the age at menopause in women with epilepsy is associated with seizure frequency. METHODS: Women with epilepsy ages 45 and older from urban epilepsy centers were surveyed by interview and chart review for reproductive and general health characteristics, as well as seizure history, including frequency and treatment. Women who were not menopausal (> or = 1 year since last menses) were excluded. Subjects were divided into low, high, and intermediate seizure frequency groups. Statistical analyses included a one-way analysis of variance along with post hoc analysis (Bonferroni approach) to calculate pairwise comparisons. RESULTS: Sixty-eight subjects had a mean age at last menses (menopause) of 47.8 years (SD +/- 4.1, range 37 to 59 years). The age at menopause was 49.9 years in the low seizure frequency group (n = 15), 47.7 years in the intermediate seizure frequency group (n = 25), and 46.7 in the high seizure frequency group (n = 28). The difference in age at menopause in the three groups spanned approximately 3 years (p = 0.042). There was a negative correlation between the age at menopause and seizure group based on estimated lifetime seizures (p = 0.014, r = -0.310). No confounding influences such as history of cigarette smoking, number of pregnancies, or use of enzyme-inducing antiepileptic drugs were present. CONCLUSIONS: Seizure frequency or lifetime number of seizures is associated with the timing of cessation of reproductive cycling. Seizures may disrupt hypothalamic and pituitary function or alter neurally mediated trophic effects on the ovary.

GnRH-immunoreactive fiber changes with unilateral amygdala-kindled seizures.

PURPOSE: To assess whether unilateral amygdala seizures are associated with a change in the number and lateral distribution of gonadotropin releasing hormone (GnRH)-staining fibers in the ventromedial hypothalamus of female rats. METHODS: The study compared three groups of female rats: (1) amygdala seizures induced by focal injection of kainic acid (KA); (2) saline injected controls; and (3) nai;ve controls. The animals were sacrificed at 4 weeks in the diestrus phase. GnRH fibers were counted in the ventromedial hypothalamus and compared among groups. RESULTS: GnRH fiber counts were significantly lower in KA than saline and nai;ve animals ipsilaterally but not contralaterally. CONCLUSIONS: This finding may support a potential mechanism by which (1) temporolimbic epilepsy may promote the development of reproductive endocrine disorders and (2) the laterality of the epilepsy may influence the particular nature of the reproductive endocrine disorder.

Reproductive dysfunction in women with epilepsy: recommendations for evaluation and management.

BACKGROUND: Epilepsy is commonly associated with reproductive endocrine disorders. These include polycystic ovary syndrome (PCOS), isolated components of this syndrome such as polycystic ovaries, hyperandrogenaemia, hypothalamic amenorrhoea, and functional hyperprolactinaemia. OBJECTIVE: To summarise the currently known relations between epilepsy and reproductive endocrine disorders. METHODS: A review of clinical experience and published reports. RESULTS: The most likely explanations for endocrine disorders related to epilepsy or antiepileptic drugs are: (1) a direct influence of the epileptogenic lesion, epilepsy, or antiepileptic drugs on the endocrine control centres in the brain; (2) the effects of antiepileptic drugs on peripheral endocrine glands; (3) the effects of antiepileptic drugs on the metabolism of hormones and binding proteins; and (4) secondary endocrine complications of antiepileptic drug related weight changes or changes of insulin sensitivity. Regular monitoring of reproductive function at visits is recommended, including questioning about menstrual disorders, fertility, weight, hirsutism, and galactorrhoea. Particular attention should be paid to patients on valproate and obese patients or those experiencing significant weight gain. Single abnormal laboratory or imaging findings without symptoms may not constitute a clinically relevant endocrine disorder. However, patients with these kinds of abnormalities should be monitored to detect the possible development of a symptomatic disorder associated with, for example, menstrual disorders or fertility problems. CONCLUSIONS: If a reproductive endocrine disorder is found, antiepileptic drug treatment should be reviewed to ensure that it is correct for the particular seizure type and that it is not contributing to the endocrine problem. The possible benefits of a change in treatment must be balanced against seizure control and the cumulative side effect of alternative agents.

Menstrual cycle interval and ovulation in women with localization-related epilepsy.

Article abstract-- In an investigation of 100 women with localization-related epilepsy, anovulatory cycles were significantly greater in proportion in women with 21-25 or 33-35 day cycles (Group B) and in women with less than 21 or more than 35 day cycles (Group C) than in women with normal 26-32 day intervals (Group A). Groups B and C also had significantly higher estradiol/progesterone ratios than Group A. Nevertheless, almost one-half (46.2%) of the anovulatory cycles occurred in women with normal 26-32 day cycles.

Spasmodic torticollis and reproductive function in women.

This investigation assessed a possible relationship between idiopathic spasmodic torticollis (ST) and reproductive function in women. Fifth decade ST onset, the peak decade for menopause, was over represented. Menstrual exacerbation of symptoms was significantly more common than in controls. Oral contraceptive use and pregnancy did not have adverse effects. Reproductive disorders and hysterectomy were significantly more common than in neurological and normal controls. The possibility that ST onset and severity may relate to reproductive state and hormonal factors warrants further investigation.

Transcranial magnetic stimulation evidence of a potential role for progesterone in the modulation of premenstrual corticocortical inhibition in a woman with catamenial seizure exacerbation.

A transcranial magnetic stimulation paired-pulse paradigm was used to determine that cortical excitability was less during the late luteal phase than in the early follicular phase in a woman with epilepsy who had premenstrual seizure exacerbation. The data are consistent with the possibility that a reduction in GABA-mediated cortical inhibitory activity may be responsible. The administration of progesterone, a reproductive steroid with potent GABAergic metabolites, during the luteal phase restored cortical excitability to normal range.

Lateral asymmetry in activation of hypothalamic neurons with unilateral amygdaloid seizures.

PURPOSE: Reproductive disorders are unusually frequent among women with temporal lobe seizures. The particular type of disorder may be related to the laterality and focality of epileptiform discharges. Here we examined whether unilateral amygdaloid seizures activate hypothalamic neurons involved in reproductive function and reproductive endocrine secretion in female rats and whether such activation shows lateral asymmetry. METHODS: Numbers of Fos-immunoreactive (Fos-ir) neurons in various hypothalamic regions were compared for three groups of animals: (a) unilateral amygdala-kindled, (b) implanted but unstimulated, and (c) unimplanted. RESULTS: Fos-ir neurons showed strong ipsilateral occurrence in the medial preoptic, ventrolateral part of the ventromedial, and ventral premammillary nuclei, sexually dimorphic regions involved in reproductive endocrine regulation. No significant lateral asymmetry was observed for other investigated hypothalamic regions. CONCLUSIONS: Unilateral amygdaloid seizures activate hypothalamic neurons that regulate reproductive endocrine secretion in a laterally asymmetric fashion. This may explain the clinical association of different reproductive endocrine disorders with left and right temporal epileptiform discharges.

Late-onset congenital adrenal hyperplasia: presentation as nonepileptic seizures.

This is a report of a woman with refractory nonepileptic seizures, anxiety disorder, and rapidly cycling mood changes in whom high levels of excitatory neuroactive steroids due to late-onset congenital adrenal hyperplasia origin may have played a role in pathogenesis and in whom endocrine treatment was the only efficacious therapeutic modality.

Late-onset congenital adrenal hyperplasia: a treatable cause of anxiety.

BACKGROUND: Some intermediaries of cortisol synthesis, especially the sulfated ester of dehydroepiandrosterone (DHEAS), are picrotoxin-like antagonists of the gamma-aminobutyric acid A (GABA-A) receptor and exert potent anxiogenic effects. We report 5 men and 7 women with refractory anxiety disorders, who had late-onset congenital adrenal hyperplasia (CAH), and in whom interactions between neuroactive steroids and anomalous brain substrates may have participated in the pathophysiology and treatment of anxiety. METHODS: Twelve patients with refractory anxiety disorders as defined by DSM-IV had elevated DHEAS and specific enzyme deficiencies diagnostic of CAH. All were treated with adrenal suppressive therapy using ketoconazole or low (physiologic) dose glucocorticoids. Anxiety was rated by the Tension Scale of the Profile of Mood States (POMS Tension) questionnaire before and during hormonal treatment. RESULTS: Reduction of DHEAS was associated with lower anxiety scores in all twelve cases. POMS Tension scores decreased by 55%. Hormonal treatment, which failed to lower DHEAS, was ineffective. CONCLUSIONS: These findings suggest that late onset CAH can contribute to anxiety disorders and that adrenal suppressive therapy or inhibition of steroidogenesis with ketoconazole may be efficacious as adjuvant therapy.

Psychoneuroendocrine aspects of temporolimbic epilepsy. Part I. Brain, reproductive steroids, and emotions.

The temporolimbic structures of the brain that subserve emotional representation are highly epileptogenic and play an important role in the modulation of hormonal secretion and mediation of hormonal feedback. Estrogen is highly epileptogenic and exerts energizing and antidepressant effects. Excessive estrogen influence produces anxiety, agitation, irritability, and lability. It can promote the development of anxiety manifestations (e.g., panic, phobias, and obsessive-compulsive disorder). Progesterone and its metabolites inhibit kindling and seizure activity. They have potent anxiolytic effects, possibly by virtue of their GABAergic activity. Excessive progesterone influence produces sedation and depression. Testosterone has two major metabolites: estradiol, which can exacerbate seizures, and dihydrotestosterone, which blocks NMDA-type glutamate transmission and may be responsible for antiseizure effects. Testosterone has energizing effects and increases sexual desire in both men and women. In excess, however, it may promote aggressive, impulsive, and hypersexual behavior. Hormonal effects tend to be exaggerated or idiosyncratic in the setting of an abnormal or anomalous temporolimbic substrate, especially temporolimbic epilepsy. This may reflect altered neuronal responsivity to hormonal exposure perhaps by virtue of changes in the number of dendritic spines and receptors.