Seizure Frequency In Women Research Articles

Sex steroid hormones and epilepsy: Effects of hormonal replacement therapy on seizure frequency of postmenopausal women with epilepsy-A systematic review.

Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

Prospective, case-control study on the effect of pregnancy on seizure frequency in women with epilepsy.

To evaluate if pregnancy induces a change in seizure frequency and in percentage of subjects remaining seizure-free. This is a prospective case-control study conducted in our tertiary epilepsy centre. Controls were matched 2:1 with the cases for relevant clinical parameters. Cases had to be referred to our centre forat least 9months before-pregnancy, during pregnancy and the-9-months-after-birth. Controls were followed for the correspondent periods of time: namedrespectively control period 1-2-3. Seizure frequency was defined as "improved" if there was a 50% of reduction, "worsened" if there was a 50% ofincrease, and "unchanged" in the rest of cases. We recruited 36 cases and 72 controls [in both group mean age was 28years, partial epilepsy (80.6%), generalized epilepsy (19.4%)]; 30 cases and 60 controls were seizure-free before pregnancy and in period 1, respectively. During pregnancy 72% of cases remained "unchanged" while 8 and 19% respectively "improved" and "worsened"; moreover, there was no statistical difference in the number of seizure-free patients and in the monthly seizure frequencies. No differences were found in controls. In this prospective case-control study, pregnancy does not affect seizure frequency in women with epilepsy.

Dancing the Delta Shuffle: Neurosteroids Regulate GABAA Receptor Expression

Ovarian Cycle-linked Changes in GABA(A) Receptors Mediating Tonic Inhibition Alter Seizure Susceptibility and Anxiety Maguire JL, Stell BM, Rafizadeh M, Mody I Nat Neurosci 2005;8(6):797–804 Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by δ subunit–containing GABAA receptors ( δGABAA Rs). Here we demonstrate periodic alterations in specific GABAA R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of δGABAA Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of δGABAA Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of δGABAA Rs in individuals with catamenial epilepsy or PMDD. Short-term Steroid Treatment Increases δ GABAA Receptor Subunit Expression in Rat CA1 Hippocampus: Pharmacological and Behavioral Effects Shen H, Gong QH, Yuan M, Smith SS Neuropharmacology 2005;49(5):573–586 In this study, 48-h administration of 3 α-OH-5 β-pregnan-20-one (3 α,5 β-THP) or 17 β-estradiol (E2)+progesterone (P) to female rats increased expression of the δ subunit of the GABAA receptor in CA1 hippocampus. Coexpression of α4 and δ subunits was suggested by an increased response of isolated pyramidal cells to the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4- c]pyridin-3-ol (THIP), following 48-h steroid treatment, and nearly complete blockade by 300 μM lanthanum (La3+). Because α4 βδ GABAA receptors are extrasynaptic, we also recorded pharmacologically isolated GABAergic holding current from CA1 hippocampal pyramidal cells in the slice. The La3+-sensitive THIP current, representative of current gated by α4 βδ GABAA receptor, was measurable only following 48-h steroid treatment. In contrast, the bicuculline-sensitive current was not altered by steroid treatment, assessed with or without 200 nM gabazine to block synaptic current. However, 48-h steroid treatment resulted in a tonic current insensitive to the benzodiazepine agonists lorazepam (10 μM) and zolpidem (100 nM). These results suggest that 48-h steroid treatment increases expression of α4 βδ GABAA receptors, which replace the ambient receptor population. Increased anxiolytic effects of THIP were also observed following 48-h steroid treatment. The findings from the present study may be relevant for alterations in mood and benzodiazepine sensitivity reported across the menstrual cycle.

Gonadal steroids regulate GABA A receptor subunit mRNA expression in NT2-N neurons

Changes in gonadal steroid hormone levels during the menstrual cycle affect seizure frequency in women with catamenial epilepsy. Since GABA A receptors (GABARs) contribute to the prevention and termination of seizures by reducing neuronal excitability, we hypothesized that fluctuating gonadal steroid levels might affect GABAR subunit expression, which could alter inhibitory tone leading to increased seizure activity. To address this question in a simplified environment in vitro, we examined the effects of gonadal steroids on NT2-N neuronal cells. We have previously shown that NT2-N cells express functional GABARs, and that the expression pattern of GABAR subunits is regulated by chronic benzodiazepine exposure and hypoxia. NT2-N neurons were exposed to progesterone (0.1 μM), β-estradiol (3 nM), or vehicle (DMSO) for 2 days or 7 days prior to RNA harvesting. GABAR subunit mRNA levels were assessed by semiquantitative RT-PCR normalized to actin levels. Progesterone exposure for 7 days increased α2 and γ3 and decreased α5 subunit mRNAs, while β-estradiol caused significant increases in α3, β3 and ε expression. Further analysis revealed differential regulation of α4, α5, ε and π subunit expression. Plots of relative PCR density in progesterone-treated cells for α2 vs. α5, α5 vs. γ3 and α2 vs. γ3 showed correlation between samples, suggesting coordinate regulation. Both progesterone and estrogen nuclear receptor mRNAs were detected by RT-PCR, and 2 days but not 7 days estrogen exposure upregulated progesterone receptor mRNA. Gonadal steroid fluctuations regulate GABA A receptor subunit expression in NT2-N cells. Such changes, if observed in vivo, could affect seizure frequency.

Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety

Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by delta subunit-containing GABA(A) receptors (deltaGABA(A)Rs). Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of deltaGABA(A)Rs in individuals with catamenial epilepsy or PMDD.

Hormonal considerations in women with seizures.

The relationships between seizures in epileptic women and the hormones estrogen and progesterone are under increasing study. Serum concentrations of estrogen and progesterone parallel cerebrospinal concentrations, and circulating sex hormones are concentrated in specific areas of the brain that regulate sexual behavior. These centers include two potentially epileptogenic regions--the amygdala and hippocampus. Many of these structures are physiologically affected in vitro by estrogen and progesterone. Exogenous sex hormones change the seizure threshold in animal models of epilepsy. Cyclical hormonal variations may influence electroencephalographic activity and affect seizure frequency in women with epilepsy. Hormonal therapy may be appropriate adjunctive anticonvulsant treatment, particularly for women with seizures that are catamenial or associated with a menstrual or reproductive endocrine disorder.