An Approach to Successful Development of Clinician-Scientists in Neurology: The NINDS R25 Experience.

OBJECTIVE: Training clinician-scientists is a primary objective of many academic neurology departments, as these individuals are uniquely positioned to perform insightful clinical or laboratory-based research informed both by clinical knowledge and their own experiences caring for patients. Despite its importance, training clinician-scientists has perhaps never been so challenging. The National Institute of Neurologic Disorders and Stroke (NINDS) R25 program was designed in an attempt to support these individuals, decrease the time needed to obtain National Institutes of Health K awards, and to help educate a cohort of trainees preparing for a career in academic neurology. We endeavored to describe the structure and features of the program while examining its outcomes. METHODS: R25 outcome data from 2009 to 2024 were reviewed. Statistical comparisons were made using 2-sided Mann-Whitney U testing. RESULTS: A total of 67% of adult neurologists who received an R25 had a successful application for a National Institutes of Health K award compared with 45% of adult neurologists who had not received R25 support (p < 0.0001). Among child neurologists, 73% who applied went on to receive K funding after R25 support, compared with 45% who had not been part of the R25 program (p < 0.001). The average time between completion of residency and obtaining a K award for R25 participants was decreased by 26 months among those with an MD/PhD degree, and 32 months for those with an MD degree compared with non-R25 individuals. INTERPRETATION: The R25 program has been successful in achieving its training goals, but stands as only one component of support for aspiring clinician-scientists. Investments and commitments made by academic neurology departments are key to supporting this success. ANN NEUROL 2024.

Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications.

BACKGROUND AND OBJECTIVES: Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. METHODS: A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. RESULTS: The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. DISCUSSION: These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM.

This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.

Association of Prenatal Exposure to Antiseizure Medications With Creative and Executive Function at Age 4.5 Years.

BACKGROUND AND OBJECTIVES: Neurodevelopmental effects of fetal antiseizure medication (ASM) exposure on creativity and executive functions are poorly understood. We previously found fetal valproate exposure to adversely affect measures of creativity and executive functions. In this study, we examine fetal exposure of newer ASMs on these functions in children of women with epilepsy (WWE) compared with children of healthy women (HW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational cohort study of WWE and HW enrolled in pregnancy and their offsprings. This report examines blindly assessed creativity and executive functions in 4.5-year-old children of WWE vs HW. In addition, exposure-dependent ASM effects during the third trimester were examined in children of WWE, using a ratio of maximum observed ASM concentrations and ratio of defined daily dose (ratio DDD). For polytherapy, ratios were summed across ASMs. Linear regression models adjusted for multiple potential confounding factors were conducted for all analyses. The primary outcome for 4.5-year-old children was the Torrance Test of Creative Thinking-Figural Creativity Index. Secondary outcomes included the Global Executive Composite Score from the Behavior Rating Inventory of Executive Function-Preschool Version and subscales and other indexes of both measures. RESULTS: The primary analysis included 251 children of WWE and 73 of HW. No differences in creativity or executive function were found between children of WWE vs HW. No ASM exposure-dependent effects were found for the creativity measures, but exposure-dependent effects for executive function were present for ratio ASM concentration and ratio DDD. DISCUSSION: Our findings at 4.5 years show no differences in creative thinking between children of WWE vs HW (-3.2 [-9.0 to 2.7], p = 0.286) or associations with fetal exposure to ASMs (-2.6 [-11.0 to 5.7], p = 0.530). Secondary analyses revealed fetal exposure-dependent effects for executive function in children of WWE (7.0 [2.9-11.2], p = 0.001), which are most marked for levetiracetam (12.9 [4.2-21.6], p = 0.004). Our findings suggest that even for relatively safe ASMs, dosing needs to be adjusted to concentrations that prevent seizures, but balance risks to the fetus that high concentrations may pose. TRIAL REGISTRATION INFORMATION: The study is registered at ClinicalTrials.gov as NCT01730170.

The impact of pregnancy-related hormonal and physiological changes on antiseizure medications: expert perspective.

INTRODUCTION: Epilepsy is a disorder of recurrent, unprovoked seizures affecting approximately 15 million individuals of childbearing potential worldwide. Patients with epilepsy rely on regular daily therapy with antiseizure medications (ASMs). Furthermore, ASMs are also prescribed for other neuropsychiatric indications (e.g. bipolar disorder, pain, migraines) with over 2% of the pregnancies in the United States involving prenatal exposure to ASMs. AREAS COVERED: ASM concentrations are affected by hormonal and physiological changes in pregnancy, including increases in renal and hepatic blood flow, decreased protein binding, and changes in enzyme activity. Clearance changes typically reverse within a few weeks after delivery. During pregnancy, many ASMs, such as lamotrigine, levetiracetam, and oxcarbazepine, should have serum concentrations monitored and doses increased to maintain the individualized target range for seizure control. ASMs metabolized via glucuronidation, primarily lamotrigine, undergo marked increases in clearance throughout pregnancy, requiring about 3-fold the pre-pregnancy daily dose by delivery. Postpartum, ASM doses are usually decreased over several weeks to prevent drug toxicity. EXPERT OPINION: In the future, the development of a physiologically-based pharmacokinetic model for various ASMs may enable empiric dose adjustments in pregnancy without the difficulties of frequent therapeutic drug monitoring.

Depot medroxyprogesterone acetate concentrations in patients with and without the use of antiseizure medications.

OBJECTIVES: To measure plasma concentrations of medroxyprogesterone acetate (MPA) in users with epilepsy treated with antiseizure medications and compare these to MPA concentrations in those without epilepsy. STUDY DESIGN: For this multisite cross-sectional study, we obtained a single blood sample from those with epilepsy treated with various antiseizure medications (n = 18) within the week before their next depot medroxyprogesterone injection. Among the participants without epilepsy (n = 20), 10 similarly were scheduled within the week prior to the next injection, and 10 were scheduled at earlier intervals to attempt to balance the time intervals between groups. MPA concentrations were determined by a validated assay. RESULTS: MPA concentrations were similar among those with epilepsy and controls and between groups with and without the use of enzyme-inducing medications. The lowest MPA concentrations, under 0.07 ng/mL, were observed among two of eight using enzyme-inducing antiseizure medications, one of 10 using noninducing medications, and one of 19 controls had concentrations below 0.2 ng/mL. CONCLUSIONS: In this exploratory study, lower MPA concentrations in some participants using enzyme-inducing antiseizure medications suggest a potential interaction that could reduce depot medroxyprogesterone efficacy.

Risk of Autism after Prenatal Topiramate, Valproate, or Lamotrigine Exposure.

BACKGROUND: Maternal use of valproate during pregnancy has been associated with an increased risk of neurodevelopmental disorders in children. Although most studies of other antiseizure medications have not shown increased risks of these disorders, there are limited and conflicting data regarding the risk of autism spectrum disorder associated with maternal topiramate use. METHODS: We identified a population-based cohort of pregnant women and their children within two health care utilization databases in the United States, with data from 2000 through 2020. Exposure to specific antiseizure medications was defined on the basis of prescription fills from gestational week 19 until delivery. Children who had been exposed to topiramate during the second half of pregnancy were compared with those unexposed to any antiseizure medication during pregnancy with respect to the risk of autism spectrum disorder. Valproate was used as a positive control, and lamotrigine was used as a negative control. RESULTS: The estimated cumulative incidence of autism spectrum disorder at 8 years of age was 1.9% for the full population of children who had not been exposed to antiseizure medication (4,199,796 children). With restriction to children born to mothers with epilepsy, the incidence was 4.2% with no exposure to antiseizure medication (8815 children), 6.2% with exposure to topiramate (1030 children), 10.5% with exposure to valproate (800 children), and 4.1% with exposure to lamotrigine (4205 children). Propensity score-adjusted hazard ratios in a comparison with no exposure to antiseizure medication were 0.96 (95% confidence interval [CI], 0.56 to 1.65) for exposure to topiramate, 2.67 (95% CI, 1.69 to 4.20) for exposure to valproate, and 1.00 (95% CI, 0.69 to 1.46) for exposure to lamotrigine. CONCLUSIONS: The incidence of autism spectrum disorder was higher among children prenatally exposed to the studied antiseizure medications than in the general population. However, after adjustment for indication and other confounders, the association was substantially attenuated for topiramate and lamotrigine, whereas an increased risk remained for valproate. (Funded by the National Institute of Mental Health.).

Prescription Stimulant Use During Pregnancy and Risk of Neurodevelopmental Disorders in Children.

Importance: Use of medications for attention-deficit/hyperactivity disorder (ADHD) during pregnancy is increasing in the US. Whether exposure to these medications in utero impacts the risk of neurodevelopmental disorders in children is uncertain. Objective: To evaluate the association of childhood neurodevelopmental disorders with in utero exposure to stimulant medications for ADHD. Design, Setting, and Participants: This cohort study included health care utilization data from publicly insured (Medicaid data from 2000 to 2018) and commercially insured (MarketScan Commercial Claims Database data from 2003 to 2020) pregnant individuals aged 12 to 55 years in the US with enrollment from 3 months prior to pregnancy through 1 month after delivery, linked to children. Children were monitored from birth until outcome diagnosis, disenrollment, death, or end of the study (December 2018 for Medicaid and December 2020 for MarketScan). Exposures: Dispensing of amphetamine/dextroamphetamine or methylphenidate in the second half of pregnancy. Main Outcomes and Measures: Autism spectrum disorder, ADHD, and a composite of any neurodevelopmental disorder were defined using validated algorithms. Hazard ratios were estimated comparing amphetamine/dextroamphetamine and methylphenidate to no exposure. Results: The publicly insured cohort included 2 496 771 stimulant-unexposed, 4693 amphetamine/dextroamphetamine-exposed, and 786 methylphenidate-exposed pregnancies with a mean (SD) age of 25.2 (6.0) years. The commercially insured cohort included 1 773 501 stimulant-unexposed, 2372 amphetamine/dextroamphetamine-exposed, and 337 methylphenidate-exposed pregnancies with a mean (SD) age of 31.6 (4.6) years. In unadjusted analyses, amphetamine/dextroamphetamine and methylphenidate exposure were associated with a 2- to 3-fold increased risk of the neurodevelopmental outcomes considered. After adjustment for measured confounders, amphetamine/dextroamphetamine exposure was not associated with any outcome (autism spectrum disorder: hazard ratio [HR], 0.80; 95% CI, 0.56-1.14]; ADHD: HR, 1.07; 95% CI, 0.89-1.28; any neurodevelopmental disorder: HR, 0.91; 95% CI, 0.81-1.28). Methylphenidate exposure was associated with an increased risk of ADHD (HR, 1.43; 95% CI, 1.12-1.82]) but not other outcomes after adjustment (autism spectrum disorder: HR, 1.06; 95% CI, 0.62-1.81; any neurodevelopmental disorder: HR, 1.15; 95% CI, 0.97-1.36). The association between methylphenidate and ADHD did not persist in sensitivity analyses with stricter control for confounding by maternal ADHD. Conclusions and Relevance: The findings in this study suggest that amphetamine/dextroamphetamine and methylphenidate exposure in utero are not likely to meaningfully increase the risk of childhood neurodevelopmental disorders.

Behavioral Outcomes and Neurodevelopmental Disorders Among Children of Women With Epilepsy.

Importance: The association of fetal exposure to antiseizure medications (ASMs) with outcomes in childhood are not well delineated. Objective: To examine the association of fetal ASM exposure with subsequent adaptive, behavioral or emotional, and neurodevelopmental disorder outcomes at 2, 3, and 4.5 years of age. Design, Setting, and Participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational cohort study conducted at 20 epilepsy centers in the US. A total of 456 pregnant women with epilepsy or without epilepsy were enrolled from December 19, 2012, to January 13, 2016. Children of enrolled women were followed up with formal assessments at 2, 3, 4.5, and 6 years of age. Statistical analysis took place from August 2022 to May 2023. Exposures: Exposures included mother's epilepsy status as well as mother's ASM blood concentration in the third trimester (for children of women with epilepsy). Women with epilepsy were enrolled regardless of ASM regimen. Main Outcomes and Measures: The primary outcome was the Adaptive Behavior Assessment System, Third Edition (ABAS-3) General Adaptive Composite (GAC) score among children at 4.5 years of age. Children of women with epilepsy and children of women without epilepsy were compared, and the associations of ASM exposures with outcomes among exposed children were assessed. Secondary outcomes involved similar analyses of other related measures. Results: Primary analysis included 302 children of women with epilepsy (143 boys [47.4%]) and 84 children of women without epilepsy (45 boys [53.6%]). Overall adaptive functioning (ABAS-3 GAC score at 4.5 years) did not significantly differ between children of women with epilepsy and children of women without epilepsy (parameter estimate [PE], 0.4 [95% CI, -2.5 to 3.4]; P = .77). However, in adjusted analyses, a significant decrease in functioning was seen with increasing third-trimester maximum ASM blood concentrations (PE, -7.8 [95% CI, -12.6 to -3.1]; P = .001). This decrease in functioning was evident for levetiracetam (PE, -18.9 [95% CI, -26.8 to -10.9]; P < .001) and lamotrigine (PE, -12.0 [95% CI, -23.7 to -0.3]; P = .04), the ASMs with sample sizes large enough for analysis. Results were similar with third-trimester maximum daily dose. Conclusions and Relevance: This study suggests that adaptive functioning of children of women with epilepsy taking commonly used ASMs did not significantly differ from that of children of women without epilepsy, but there was an exposure-dependent association of ASMs with functioning. Thus, psychiatric or psychological screening and referral of women with epilepsy and their offspring are recommended when appropriate. Additional research is needed to confirm these findings.

Lamotrigine and exogenous estrogen among females with epilepsy: A retrospective analysis of administrative claims data.

OBJECTIVE: Exogenous estrogen reduces lamotrigine serum concentrations. Little is known about whether providers adjust lamotrigine doses for addition of exogenous estrogen among people with epilepsy, despite expert recommendations. We determined the incidence of dose increases in lamotrigine following incident prescription of estrogen among females with epilepsy (FWE) in claims data. METHODS: We used Optum's de-identified Clinformatics® Data Mart Database to create a cohort of U.S. FWE prescribed lamotrigine at a stable dose, with a subsequent prescription for estrogen from 2011 to 2021. We calculated cumulative incidence functions of dose increases in lamotrigine following prescription of exogenous estrogen. We performed a Cox proportional hazards model for multiple candidate predictors of a lamotrigine dose increase. RESULTS: The cohort included 643 FWE, with median age of 31 (interquartile ratio [IQR] 20-42). The cumulative incidence of any lamotrigine increase was 28% (95% confidence interval [CI] 25%-32%). The median number of days after the first estrogen fill until the first lamotrigine adjustment was 118 (IQR 48-188). In unadjusted Cox models, older age, use of estrogen in hormone replacement therapy as opposed to contraception, and annual household income of $50,000-$99,999 (compared with <$50,000) were significant negative predictors of a dose adjustment in lamotrigine with hazard ratios (HRs) of 0.82 (95% CI 0.72-0.92), 0.63 (95% CI 0.42-0.95), and 0.62 (95% CI 0.40-0.95). In the adjusted Cox model, age and income remained significant predictors with HRs of 0.79 (95% CI 0.66-0.94) and 0.59 (95% CI 0.36-0.95). CONCLUSION: Dose increase of lamotrigine following addition of exogenous estrogen is rare among U.S. FWE, with potential disparities based on age and income level. More guidance may be needed for providers on this topic.

Initiation and Duration of Breastfeeding in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.

BACKGROUND AND OBJECTIVES: Breastfeeding has important health benefits for both mother and child. We characterize breastfeeding initiation and duration in mothers with epilepsy relative to control mothers in a large prospective cohort. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a prospective, multicenter observational, US cohort study. Pregnant individuals with and without epilepsy, aged 14-45 years, were enrolled between December 19, 2012, and February 11, 2016. Exclusion criteria included intelligence quotient (IQ) <70, and gestational age >20 weeks at enrollment. Breastfeeding was assessed through electronic diary and at study visits until 2 years postpartum. Odds of initiating breastfeeding was compared between cohorts using unadjusted and adjusted logistic regression models. Duration of breastfeeding was compared between cohorts using the log-rank test. RESULTS: Three hundred fifty-one pregnant individuals with epilepsy and 105 pregnant controls were enrolled. Breastfeeding data were available for 325 mothers with epilepsy and 98 controls. Study cohorts were similar demographically except race (p = 0.008); 84.9% of mothers with epilepsy and 71.4% of controls were White. The mean IQ was lower in mothers with epilepsy compared with that in controls (97.7 vs 104.2, p < 0.001). Breastfeeding was initiated by 74.8% mothers with epilepsy and 88.8% controls; this difference was significant in unadjusted logistic regression (odds ratio [OR] 0.4 [95% CI 0.2, 0.7], p = 0.004), but not in adjusted model (OR 0.5 [95% CI 0.2, 1.0], p = 0.051). Factors associated with breastfeeding were higher maternal education and IQ. There was no difference in duration of breastfeeding between mothers with and without epilepsy (median duration 8.5 months vs 9.9 months, p = 0.793). Among mothers with epilepsy, both convulsive seizures and all seizures that impair awareness during pregnancy were associated with lower breastfeeding initiation (OR 0.4 [95% CI 0.2, 0.8], p = 0.013) and (OR 0.4 [95% CI 0.2, 0.8], p = 0.003, respectively). Any peripartum seizures were associated with shorter breastfeeding duration (median 6 months vs 9.7 months, [p = 0.040]). DISCUSSION: Mothers with epilepsy were less likely to initiate breastfeeding compared with controls; however, this difference was not significant when controlling for maternal IQ and education level. Continuation of breastfeeding once initiated was not different between mothers with and without epilepsy. Seizure control was associated with breastfeeding initiation and duration in mothers with epilepsy. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier NCT01730170.

Increasing challenges to trial recruitment and conduct over time.

OBJECTIVE: This study was undertaken to evaluate how the challenges in the recruitment and retention of participants in clinical trials for focal onset epilepsy have changed over time. METHODS: In this systematic analysis of randomized clinical trials of adjunct antiseizure medications for medication-resistant focal onset epilepsy, we evaluated how the numbers of participants, sites, and countries have changed since the first such trial in 1990. We also evaluated the proportion of participants who completed each trial phase and their reasons for early trial exit. We analyzed these trends using mixed effects generalized linear models accounting for the influence of the number of trial sites and trial-specific variability. RESULTS: The number of participants per site has steadily decreased over decades, with recent trials recruiting fewer than five participants per site (reduction by .16 participants/site/year, p < .0001). Fewer participants also progressed from recruitment to randomization over time (odds ratio = .94/year, p = .014). Concurrently, there has been an increase in the placebo response over time (increase in median percent reduction of .4%/year, p = .02; odds ratio of increase in 50% responder rate of 1.03/year, p = .02), which was not directly associated with the number of sites per trial (p > .20). SIGNIFICANCE: This historical analysis highlights the increasing challenges with participant recruitment and retention, as well as increasing placebo response. It serves as a call to action to change clinical trial design to address these challenges.

Empiric dosing strategies to predict lamotrigine concentrations during pregnancy.

INTRODUCTION: Maintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy. OBJECTIVE: Our objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity. METHODS: Lamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one-compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single-patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population-level simulations (N = 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively. RESULTS: Individual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6-8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%-100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%-100% of women). SIGNIFICANCE: A substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary "one-size-fits-all" philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.

Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy.

We evaluated the occurrence and distribution of patterns of catamenial epilepsy in a heterogenous cohort of women with epilepsy on no hormonal therapies, enrolled in a prospective, observational study. The primary aim of the study was pregnancy rate in women with epilepsy with no prior reproductive problems. In this analysis, we included women who recorded one or more menstrual cycles with one or more seizures. We measured progesterone concentrations for one to three cycles. We defined catamenial patterns as twofold or greater average daily seizure frequency around menstruation (C1), ovulation (C2), and for anovulatory cycles, from midcycle through menstruation (C3). Twenty-three of the 89 enrolled women with epilepsy were eligible for this analysis; 12 of 23 met criteria for catamenial epilepsy; five of 23 demonstrated only a C1 pattern, two of 23 only a C2 pattern, five of 23 a combined C1/C2 pattern, and the one woman with anovulatory cycles did not demonstrate a C3 pattern. There were no differences in likelihood of demonstrating a catamenial pattern between those who reported a prior catamenial pattern and those who did not (p = .855). This analysis demonstrates the utility of app-based tracking to determine a catamenial pattern. Larger prospective studies could confirm these findings and inform potential therapeutic trial designs for catamenial epilepsy.

Cognitive outcomes at age 3 years in children with fetal exposure to antiseizure medications (MONEAD study) in the USA: a prospective, observational cohort study.

BACKGROUND: The neurodevelopmental effects of fetal exposure to most antiseizure medications are unclear. We aimed to investigate the effects of fetal exposure to commonly used antiseizure medications on neuropsychological outcomes at age 3 years. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicentre cohort study at 20 specialty epilepsy centres in the USA. We have investigated pregnancy outcomes in women (aged 14-45 years) with and without epilepsy who were enrolled during pregnancy (≤20 weeks' gestational age), and their children. The primary outcome for children at age 3 years was a blindly assessed Verbal Index score, which was calculated by averaging scores on the Naming Vocabulary and Verbal Comprehension subtests of Differential Ability Scales-II, Expressive Communication and Auditory Comprehension subscales of Preschool Language Scale-5, and Peabody Picture Vocabulary Test-4. Children of women with and without epilepsy were compared, and the associations of medication exposures to outcomes in exposed children were assessed. The MONEAD study is registered with ClinicalTrials.gov, NCT0730170, and is ongoing. FINDINGS: Between Dec 19, 2012, and Jan 13, 2016, 456 pregnant women (351 with epilepsy and 105 without epilepsy) were enrolled into the study. 345 children were born to women with epilepsy and 106 children were born to women without epilepsy. Verbal Index scores at age 3 years did not differ for children of women with epilepsy (n=284; adjusted least-square mean 102·7, 95% CI 101·4 to 103·9) versus those without epilepsy (n=87; 102·3, 99·8 to 104·7). Significant risk factors for reduced Verbal Index scores included maternal intelligence quotient, maternal education, post-birth anxiety, gestational age at enrolment, child's sex, and child's ethnicity. For Verbal Index scores, antiseizure medication exposure effects were not seen for maximum third trimester blood concentrations (n=258; adjusted parameter estimate -2·9, 95% CI -6·7 to 1·0). However, in secondary analyses, exposure-dependent effects were present on multiple cognitive measures, which varied by medication. INTERPRETATION: We found no difference in neurodevelopmental outcomes between children with fetal exposure to newer antiseizure medications compared with unexposed children. However, some exposure-dependent antiseizure medication effects were seen in secondary analyses. The adverse effects of maternal post-birth anxiety emphasise the importance of screening mothers during pregnancy and postpartum and implementing interventions. Additional studies are needed to clarify the exposure-dependent effects. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institute of Child Health and Development.

Severity of Epilepsy and Response to Antiseizure Medications in Individuals With Multiple Sclerosis: Analysis of a Real-World Dataset.

Background and Objectives: Epilepsy is an important comorbidity that affects outcomes for people with multiple sclerosis (MS). However, it is unclear whether seizure severity among individuals with coexistence of MS and epilepsy (MS + E) is higher than in those with other focal epilepsies. Our goal was to compare the overall severity of epilepsy in individuals with MS + E vs those with focal epilepsy without MS (E - MS), as defined by seizure-related health care utilization, frequency and duration of status epilepticus, and frequency of antiseizure medication (ASM) regimen changes. Methods: In this hypothesis-generating study, we analyzed a US commercial nationwide deidentified claims data set with >86 million individuals between January 1, 2008, and August 31, 2019. Using validated algorithms, we identified adults with E - MS and those with MS + E. We compared the number and length of seizure-related hospital admissions, the number of claims and unique days with claims for status epilepticus, and the rates of ASM regimen changes between the MS + E and E - MS groups. Results: During the study period, 66,708 individuals with E - MS and 537 with MS + E had ≥2 years of coverage after their initial diagnosis of epilepsy. There was no difference between the MS + E and E - MS groups in the percentage of individuals admitted for seizures and/or status epilepticus. However, MS + E with seizure-related admissions had more admissions and longer hospital stays than those with E - MS. MS + E who experienced status epilepticus had more unique days with status epilepticus claims compared with E - MS. MS + E were more likely to have ASM regimen changes in 2 years after the initial diagnosis of epilepsy and had more ASM changes during 2 years compared with E - MS. Among individuals with MS + E, there were no differences in our measures of seizure severity for those treated with sodium channel blockers/modulators vs other ASM classes. Discussion: This study supports the notion that individuals with MS + E can have more severe epilepsy than those with E - MS. Seizure severity among individuals with MS + E treated with sodium channel blockers/modulators vs other ASM classes shows no significant differences. Classification of Evidence: This study provides Class III evidence that individuals with MS + E can have more severe epilepsy than those with E - MS.

Breastfeeding while on treatment with antiseizure medications: a systematic review from the ILAE Women Task Force

We carried out a systematic review of published information on transfer of antiseizure medications (ASMs) into breastmilk, ASM serum concentrations in breastfed infants, and the wellbeing of infants breastfed by mothers on ASM treatment. Information was extracted from 85 relevant articles. No data on ASM levels in breastmilk or in breastfed infants was identified for cannabidiol, cenobamate, clobazam, eslicarbazepine-acetate, everolimus, felbamate, fenfluramine, retigabine, rufinamide, stiripentol, tiagabine, and vigabatrin. For ASMs, with available information on levels in breastfed infants, very low concentrations (in the order of 10% or less of maternal serum concentrations) were reported for carbamazepine, gabapentin, levetiracetam, oxcarbazepine, phenytoin, valproate, and clonazepam. Slightly higher levels (up to approximately 30% of maternal serum concentrations) have been observed with lamotrigine and topiramate, and in single case reports for brivaracetam, lacosamide, and perampanel. High infant levels (30% up to 100% of maternal serum concentrations) have been reported with ethosuximide, phenobarbital and zonisamide. Adverse infant effects during breastfeeding by mothers on ASMs appear to be rare regardless of the type of ASM, but systematic study is limited. Prospective long-term follow-up studies of developmental outcomes among children who have been breastfed by mothers taking ASMs are sparse and have mainly involved children whose mothers were taking carbamazepine, lamotrigine, levetiracetam, phenytoin or valproate as monotherapy while breastfeeding. Although these studies have not indicated poorer outcome among breastfed children compared with those who were not breastfed, further data on long-term outcomes are needed to draw firm conclusions. It is concluded that breastfeeding should in general be encouraged in women taking ASMs, given the well-established benefits of breastfeeding with regard to both short- and long-term infant health in the general population. Counselling needs to be individualized including information on the current knowledge regarding the woman's specific ASM treatment.

Association of Antidepressant Use During Pregnancy With Risk of Neurodevelopmental Disorders in Children.

Importance: Antidepressant use during pregnancy has been associated with neurodevelopmental disorders in children in some studies. However, results may be explained by uncontrolled confounding by parental mental health status, genetics, and environmental factors. Objective: To evaluate the association between antidepressant use in pregnancy and neurodevelopmental outcomes in children. Design, Setting, and Participants: This cohort study of health care utilization data was separated into cohorts of publicly and privately insured pregnant individuals and their children nested in the Medicaid Analytic eXtract (MAX; 2000-2014) and the IBM MarketScan Research Database (MarketScan; 2003-2015). A total of 1.93 million pregnancies in MAX and 1.25 million pregnancies in MarketScan were recorded. Children were followed from birth until outcome diagnosis, disenrollment, death, or end of study (maximum 14 years). Analyses were conducted between August 2020 and July 2021. Exposures: Dispensing of antidepressant medication from gestational week 19 until delivery, the period of synaptogenesis. Main Outcomes and Measures: Neurodevelopmental disorders in children defined using validated algorithms. Early pregnancy exposure was considered in sensitivity analyses, and approaches to confounding adjustment included propensity score fine stratification, discontinuers comparison, and sibling analyses. Results: Among the individuals included in the analysis, there were 145 702 antidepressant-exposed and 3 032 745 unexposed pregnancies; the mean (SD) age among the antidepressant exposed and unexposed was 26.2 (5.7) and 24.3 (5.8) years in MAX and 32.7 (4.6) and 31.9 (4.6) years in MarketScan, respectively; and in MAX, which collected information on race and ethnicity, 72.4% of the antidepressant-exposed and 37.1% of the unexposed individuals were White. Crude results suggested up to a doubling in risk of neurodevelopmental outcomes associated with antidepressant exposure; however, no association was observed in the most fully adjusted analyses. When comparing antidepressant-exposed and unexposed siblings, hazard ratios were 0.97 (95% CI, 0.88-1.06) for any neurodevelopmental disorder, 0.86 (95% CI, 0.60-1.23) for autism spectrum disorder, 0.94 (95% CI, 0.81-1.08) for attention-deficit/hyperactivity disorder, 0.77 (95% CI, 0.42-1.39) for specific learning disorders, 1.01 (95% CI, 0.88-1.16) for developmental speech/language disorder, 0.79 (95% CI, 0.54-1.17) for developmental coordination disorder, 1.00 (95% CI, 0.45-2.22) for intellectual disability, and 0.95 (95% CI, 0.80-1.12) for behavioral disorders. Results were generally consistent for antidepressant classes and drugs and across exposure windows. Conclusions and Relevance: The results of this cohort study suggest that antidepressant use in pregnancy itself does not increase the risk of neurodevelopmental disorders in children. However, given strong crude associations, antidepressant exposure in pregnancy may be an important marker for the need of early screening and intervention.

Prospective Cohort Study of Depression During Pregnancy and the Postpartum Period in Women With Epilepsy vs Control Groups.

BACKGROUND AND OBJECTIVES: Assess the incidence and factors associated with major depressive episodes (MDEs) and symptoms of depression and anxiety during pregnancy and postpartum periods in pregnant women with epilepsy (PWWE) compared with healthy pregnant women (HPW) and nonpregnant women with epilepsy (NPWWE) in comparable timeframes. Previous studies have reported higher rates of postpartum depression in women with epilepsy compared with women without epilepsy. However, the incidence of MDE using a structured interview during pregnancy and postpartum has not been directly compared with control groups, and the comparison of depression and anxiety symptoms and the role of associated factors remain ambiguous. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study is a multicenter NIH-funded prospective observational parallel group cohort study of PWWE and their children. This report examines mood disorders. Unlike previous epilepsy pregnancy studies, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV (SCID) provided lifetime diagnoses, and repeated SCID mood modules assessed for MDE, the a priori primary outcome. Symptoms of depression (Beck Depression Inventory [BDI] and Edinburg Postnatal Depression Scale [EPDS]) and anxiety (Beck Anxiety Inventory [BAI]) were also assessed along with multiple clinical factors. RESULTS: This study included PWWE (n = 331) and HPW (n = 102) during pregnancy and postpartum and NPWWE (n = 102) at comparable times. No difference in SCID-diagnosed MDE incidence was found across groups, but BDI depressive symptoms were worse during pregnancy in PWWE vs NPWWE and during postpartum vs HPW and NPWWE. BAI anxiety symptoms were worse during pregnancy in PWWE vs HPW and NPWWE and during postpartum vs HPW. Factors associated with MDE during pregnancy/postpartum for PWWE included >1 seizure/90 days, anticonvulsant polytherapy, unplanned pregnancy, and lifetime history of mood disorder. Suicidal ideation from BDI or EPDS was related to BAI anxiety symptoms. DISCUSSION: Although SCID-based MDE did not differ across groups, this prospective study confirms higher rates of psychiatric symptoms in patients with epilepsy during pregnancy and postpartum, provides new data on associated factors, and underscores the importance of anxiety in risk for depression and thoughts of death/dying or suicide. Given the risks, PWWE should be routinely assessed and symptomatic patients should be offered treatment. TRIAL REGISTRATION INFORMATION: This study is registered at ClinicalTrials.gov as NCT01730170.