Seizure Control In Women Research Articles

Seizure control in women with epilepsy undergoing assisted reproductive technology.

The objective of this study was to determine seizure control in women with epilepsy (WWE) undergoing assisted reproductive technology (ART). Through retrospective chart review, WWE undergoing ART were identified. Demographics and details regarding epilepsy type, seizure control, and ART procedures were extracted. Seizure frequency prior to and during ART were compared. We identified 12 WWE, who underwent 29 embryo transfers, resulting in 16 pregnancies and 10 live births. Nine women were seizure-free at least 2 years before fertility treatment, including three with resolved epilepsy. Seven were on antiseizure medications throughout fertility treatment and pregnancy, with only one on polytherapy. Eleven (all with controlled epilepsy or epilepsy in remission) remained seizure-free throughout fertility treatment. One woman with drug-resistant epilepsy continued to have seizures throughout fertility treatment and pregnancy without an exacerbation of seizure frequency. There was no increased seizure frequency associated with fertility treatment and subsequent pregnancy in this small series of WWE. Although this study was statistically underpowered, our results provide some preliminary evidence that ART might not pose a threat to seizure control, but larger, confirmatory studies are necessary.

Changes in seizure frequency and anti-seizure medication therapy during pregnancy and one year postpregnancy

Seizure control in women with epilepsy (WWE) during pregnancy is a vital concern. The aim of this study was to compare changes in seizure frequency and anti-seizure medication (ASM ) therapy in WWE in a real-world setting over three epochs (prepregnancy, pregnancy, and postpregnancy). We screened WWE who were pregnant between 1 January 2010 and 31 December 2020 from the epilepsy follow-up registry database of a tertiary hospital in China. We reviewed and collected follow-up data for the following time periods: 12 months before pregnancy (epoch 1), throughout pregnancy and the first 6 weeks postpartum (epoch 2), and from 6 weeks to 12 months postpartum (epoch 3). Seizures were classified into two categories: tonic‒clonic/focal to bilateral tonic‒clonic seizures and non-tonic‒clonic seizures. The main indicator was the seizure-free rate over the three epochs. Using epoch 1 as a reference, we also compared the percentage of women with an increased seizure frequency, as well as changes in ASM treatment, in epochs 2 and 3. Ultimately, 271 eligible pregnancies in 249 women were included. The seizure-free rates in epoch 1, epoch 2, and epoch 3 were 38.4%, 34.7%, and 43.9%, respectively (P = 0.09). The top three ASMs used in the three epochs were lamotrigine, levetiracetam, and oxcarbazepine. Using epoch 1 as a reference, the percentages of women with increased frequencies of tonic‒clonic/focal to bilateral tonic‒clonic seizures in epoch 2 and epoch 3 were 17.0% and 14.8%, respectively, while the percentages of women with an increased frequency of non-tonic‒clonic seizures in epoch 2 and epoch 3 were 31.0% and 21.8% (P = 0.02). The percentage of women whose ASM dosages were increased in epoch 2 was higher than that in epoch 3 (35.8% vs. 27.3%, P = 0.03). The seizure frequency during pregnancy may not differ significantly from that during prepregnancy and postpregnancy if WWE are treated according to the guidelines.

Seizure Control in Women with Epilepsy Undergoing Assisted Reproductive Technology (P14-1.011)

<h3>Objective:</h3> The objective of this study was to determine the effect of assisted reproductive technology on seizure control in women with epilepsy. <h3>Background:</h3> Information available about seizure control in women with epilepsy undergoing assisted reproductive technology is sparse, limited to only a few case reports. Extrapolations are often made from situations that similarly heighten the oestrogen-progesterone ratio. <h3>Design/Methods:</h3> From a database of 3858 women who underwent in vitro fertilization (IVF) or frozen embryo transfer (FET) from January 1992–May 2021, 12 women with epilepsy were identified. Data was obtained through retrospective chart review. <h3>Results:</h3> From the 12 women identified, the median age of epilepsy onset was 20 years of age (range 25 – 42) with 6 (50%) having epilepsy onset in childhood. There were 26 embryo transfers, resulting in 14 pregnancies and 8 live births. Nine women (75%) were seizure free for &gt;2 years prior to infertility treatment. Seven women (58%) were on anti-seizure medications (ASMs) throughout fertility treatment and pregnancy with only one on polytherapy. Levels of ASMs were followed and adjusted in 3 of the 7 (43%). Eleven women (all with controlled epilepsy or epilepsy in remission) remained seizure free throughout fertility treatment. One woman, who had drug-resistant epilepsy, continued to have seizures throughout infertility treatment and pregnancy without an exacerbation of seizure frequency and with close monitoring and adjustment of ASMs. <h3>Conclusions:</h3> There was no seizure worsening in this cohort of 12 women with epilepsy undergoing assisted reproductive technology. <b>Disclosure:</b> Dr. Abdulrazaq has nothing to disclose. Dr. Ainsworth has nothing to disclose. Dr. Britton has received personal compensation in the range of $0-$499 for serving as a Online course with American Clinical Neurophysiology Society. Dr. Shenoy has nothing to disclose. Dr. Babayev has nothing to disclose. Dr. Cascino has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for International League Against Epilepsy . The institution of Dr. Cascino has received research support from Neurelis, Inc.. The institution of Dr. Cascino has received research support from Epilepsy Study Consortium. The institution of Dr. Cascino has received research support from NINDS. Dr. Cascino has received intellectual property interests from a discovery or technology relating to health care. Dr. Cascino has received publishing royalties from a publication relating to health care. Dr. Cascino has received publishing royalties from a publication relating to health care. The institution of Dr. Smith has received research support from CURE Epilepsy.

Doing without valproate in women of childbearing potential with idiopathic generalized epilepsy: Implications on seizure outcome.

Valproate (VPA) use in women with idiopathic generalized epilepsy (IGE) who are of reproductive age has been a matter of concern and debate, which eventually led to the recent restrictions by regulatory agencies. The aim of our study was to investigate the relationship between VPA avoidance/switch and seizure outcome in women of childbearing potential. We retrospectively reviewed data from female patients with IGE, 13-50years of age, followed since 1980. We evaluated the prescription habits, and the rate of VPA switch for other antiepileptic drugs (AEDs) and its prognostic implications. Seizure remission (SR) was defined as the absence of any seizure type more than 18months before the last medical observation. The main aim of the study was to assess (a) possible changes in seizure outcome related to VPA switch for other AEDs, especially in patients planning a pregnancy; and (b) possible differences in SR based on the presence/absence of VPA at last observation. One hundred ninety-eight patients were included in the study. Overall SR at last medical observation was 62.7%. SR significantly differed between subjects taking and those not taking VPA (P<.001) at last visit. Multiple regression models showed that taking VPA at last medical observation was strongly associated with SR in both the general population (P<.001) and the juvenile myoclonic epilepsy (JME) group (P<.001). Thirty-six (70.6%) of 51 patients who switched from VPA during follow-up experienced a clinical worsening. Switching back to VPA was more frequently associated with SR at last observation (P<.001). In those patients who substituted VPA in view of a pregnancy, SR and drug burden (monotherapy vs polytherapy) differed significantly before and after the switch. Our study suggests that VPA avoidance/switch might be associated with unsatisfactory seizure control in women with IGE who are of childbearing potential. Our findings further highlight the complexity of the therapeutic management of female patients of reproductive age.

INCREASED LEVETIRACETAM CLEARANCE IN PREGNANCY: IS SEIZURE FREQUENCY AFFECTED?

BackgroundEmerging data on the teratogenic potential of valproate and topiramate have resulted in a prescribing shift towards lamotrigine and levetiracetam in women of childbearing age with epilepsy. However use of...

Genetic association analysis of transporters identifies ABCC2 loci for seizure control in women with epilepsy on first-line antiepileptic drugs

The ATP-binding cassette (ABC) superfamily of transporters is known to efflux antiepileptic drugs (AEDs) primarily in the brain, gastrointestinal tract, liver, and kidneys. In addition, they are also known to be involved in estrogen disposition and may modulate seizure susceptibility and drug response. The objective of the present study was to investigate the role of genetic variants from ABC transporters in seizure control in epilepsy patients treated with monotherapy of first-line AEDs for 12 months. On the basis of gene coverage and functional significance, a total of 98 single nucleotide polymorphisms from ABCB1, ABCC1, and ABCC2 were genotyped in 400 patients from North India. Of these, 216 patients were eligible for therapeutic assessment. Genetic variants were compared between the 'no-seizures' and the 'recurrent-seizures' groups. Bonferroni corrections for multiple comparisons and adjustment for covariates were performed before assessment of associations. Functionally relevant promoter polymorphisms from ABCC2: c.-1549G>A and c.-1019A>G either considered alone or in haplotype and diplotype combinations were observed for a significant association with seizure control in women (odds ratio>3.5, P<10, power>95%). Further, low protein-expressing CGT and TGT (c.-24C>T, c.1249G>A, c.3972C>T) haplotypes were always observed to be present in combination with the AG (c.-1549G>A, c.-1019A>G) haplotype that was over-represented in women with 'no seizures'. The distribution of the associated variants supports the involvement of ABCC2 in controlling seizures in women possibly by lowering of its expression. The biological basis of this finding could be an altered interaction of ABCC2 with AEDs and estrogens. These results necessitate replication in a larger pool of patients.

Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives

Contraceptive management in women with epilepsy is critical owing to the potential maternal and fetal risks if contraception or seizure management fails. This article briefly describes the pharmacokinetic interactions between antiepileptic drugs (AEDs) and hormonal contraceptives and the rational strategies that may overcome these risks. Hormonal contraception, including the use of oral contraceptives (OCs), is widely used in many women with epilepsy – there is no strong evidence of seizures worsening with their use. AEDs are the mainstay for seizure control in women with epilepsy. However, there are many factors to consider in the choice of AED therapy and hormonal contraception, since some AEDs can reduce the efficacy of OCs owing to pharmacokinetic interactions. Estrogens and progestogens are metabolized by cytochrome P450 3A4. AEDs, such as phenytoin, phenobarbital, carbamazepine, felbamate, topiramate, oxcarbazepine and primidone, induce cytochrome P450 3A4, leading to enhanced metabolism of either or both the estrogenic and progestogenic component of OCs, thereby reducing their efficacy in preventing pregnancy. OCs can also decrease the concentrations of AEDs such as lamotrigine and, thereby, increase the risk of seizures. Increased awareness of AED interactions may help optimize seizure therapy in women with epilepsy.

Hormonal Therapies: Progesterone

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.

Now We Know the Drug of First Choice—Or Do We?

The SANAD Study of Effectiveness of Carbamazepine, Gabapentin, Lamotrigine, Oxcarbazepine, or Topiramate for Treatment of Partial Epilepsy: An Unblinded Randomised Controlled Trial. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR; SANAD Study group. Lancet 2007;369(9566):1000–1015. BACKGROUND: Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1,721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0·78 [95% CI 0·63–0·97]), gabapentin (0·65 [0·52–0·80]), and topiramate (0·64 [0·52–0·79]), and had a non-significant advantage compared with oxcarbazepine (1·15 [0·86–1·54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0·75 [0·63–0·90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0·91 [0·77–1·09]), topiramate (0·86 [0·72–1·03]), and oxcarbazepine (0·92 [0·73–1·18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (–8 to 7) and 5 (–3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine. INTERPRETATION: Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures. The SANAD Study of Effectiveness of Valproate, Lamotrigine, or Topiramate for Generalised and Unclassifiable Epilepsy: An Unblinded Randomised Controlled Trial. Marson AG, Al-Kharusi AM, Alwaidh M, Appleton R, Baker GA, Chadwick DW, Cramp C, Cockerell OC, Cooper PN, Doughty J, Eaton B, Gamble C, Goulding PJ, Howell SJ, Hughes A, Jackson M, Jacoby A, Kellett M, Lawson GR, Leach JP, Nicolaides P, Roberts R, Shackley P, Shen J, Smith DF, Smith PE, Smith CT, Vanoli A, Williamson PR; SANAD Study group. Lancet 2007;369(9566):1016–1026. BACKGROUND: Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. METHODS: SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. FINDINGS: For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. INTERPRETATION: Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

Hormone Replacement Therapy in Women with Epilepsy

To the Editors: Changes in reproductive hormone levels may influence seizure activity (Scharfman and MacLusky, 2006). A previous survey suggested that hormone replacement therapy (HRT) may adversely affect seizure control in women with epilepsy (Harden et al., 1999). Although this trial was terminated prematurely, resulting in greatly reduced statistical power, the results provide evidence that intake of estrogen/medroxyprogesterone acetate HRT in postmenopausal women with epilepsy is associated with some worsening in seizure control. A more recent study by Harden and colleagues (Harden et al., 2006) confirms the results of their previous survey (Harden et al., 1999), and raises a number of interesting points for discussion: Although HRT was widely used at the time the trial was initiated, intriguing ethical issues exist in conducting a placebo-controlled study to test the hypothesis that active treatment could cause seizure aggravation. One may argue, however, that based on evidence available at the time, HRT might have been a safe option in the enrolled population. Because an adverse influence on seizure control was confirmed, the question arises, what HRT component was responsible for the effect? The bulk of the evidence points to estrogens, which can have a facilitating effect on seizure activity (Logothetis et al., 1959; Logothetis and Harner, 1960; Hom and Buterbaugh, 1986; McEwen, 2002), although evidence on this is not univocal (Scharfman and MacLusky, 2006). Whether medroxyprogesterone acetate contributed to seizure deterioration is unknown. The authors elected to test the HRT preparation most widely prescribed in the United States. However, it might have been preferable in this population to combine estrogens with natural progesterone. Natural progesterone is converted to neuroactive metabolites, such as allopregnanolone, which have anticonvulsant activity in animal models by acting as positive allosteric modulators at the GABAA receptor (Kokate et al., 1994; Herzog, 1995; Reddy, 2001; Lonsdale and Burnham, 2003; Scharfman and MacLusky, 2006). Preliminary evidence suggests a positive effect of progesterone in catamenial epilepsy (Herzog, 1995, 1999). Whether use of natural progesterone instead of MPA would be a safer option for HRT is unknown. From a practical point of view, the relevance of this study has been reduced by the drastic decline in the use of HRT in postmenopausal women, after publication of the WHI results (Rossouw et al., 2002). Today, HRT is no longer recommended as preventive treatment in asymptomatic women, because the increased risks of breast cancer, coronary heart disease, stroke, and pulmonary embolism clearly outweigh any benefits. The authors are correct in pointing out that their results should not be interpreted as contraindicating the use of HRT for short-term control of postmenopausal symptoms in women with epilepsy. Their results do suggest, however, that the HRT regimen tested may not be the optimal one to use in these women. An interesting ancillary observation was that serum lamotrigine (LTG) levels decreased after initiation of HRT in both women who were treated with this drug. Although exclusion of these women from the analysis did not alter the results, these findings confirm previous reports that serum LTG levels can be reduced to a clinically significant extent by estrogen-containing preparations, including oral contraceptives (Sabers, 2003; Reimers et al., 2005; Sidhu et al., 2006). Careful clinical observation and, if possible, monitoring of serum LTG levels are recommended whenever estrogen-containing preparations are started or discontinued in women taking LTG.

The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial

Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1.57 [95% CI 1.19-2.08]), but there was no significant difference between valproate and lamotrigine (1.25 [0.94-1.68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1.55 [1.07-2.24] and topiramate (1.89 [1.32-2.70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0.76 [0.62-0.94]), and for the subgroup with an idiopathic generalised epilepsy 0.68 (0.53-0.89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.