Kimford J. Meador

Although genetic testing is recommended as a standard component of the diagnostic evaluation for epilepsies with unknown etiology, its optimal application in adult populations remains poorly defined. The aim of this study was to assess the diagnostic yield of genetic testing in adult patients with epilepsy, identify associated risk factors, and develop a clinical score to guide patient selection for testing. A single-center cross-sectional study was conducted at Stanford University. The Stanford electronic health record cohort discovery tool and manual chart review were used to identify eligible patients aged ≥18 years who were evaluated between 2018 and 2024. Multivariable logistic regression analysis was used to investigate the association between the clinical phenotypes and the probability of detecting pathogenic genetic variants, which served as the basis for the Genetic Risk Index for Seizure Etiology (Gen-RISE). A total of 508 patients were included. A significant delay in genetic testing after seizure onset (11.2 ± 11.1 years) was observed, with no significant difference between those with and without a genetic etiology (p = 0.89). Pathogenic variants were identified in 32.9% of patients, with 2.6% having unrelated pathogenic variants as secondary findings. Low-frequency (50% likelihood of identifying a pathogenic variant, with a sensitivity of 98.6% in an independent literature-based validation cohort. Genetic testing for epilepsy is underused, evidenced by marked testing delays. It should be considered for adult epilepsy patients with unknown or suspected genetic etiology because approximately one-third may have identifiable genetic variants. We developed Gen-RISE, a novel and practical, publicly available tool to identify optimal candidates for genetic testing, enhancing diagnostic efficiency and patient care.

Objective: Unanticipated changes in antiseizure medication (ASM) exposure can lead to subtherapeutic or toxic medication concentrations in the mother and unnecessary drug exposure for the fetus. The objectives of this study were to characterize ASM concentrations in mother's and cord blood at delivery in women with epilepsy (PWWE). Methods: The analysis included PWWE (aged 14–45 years) from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs study who were on ASM monotherapy or polytherapy at delivery. Women with an intelligence quotient < 70, major medical illness, substance use, and poor treatment adherence were excluded. Blood samples were collected from the mother and umbilical cord on the day of delivery. The ratio of umbilical cord to maternal plasma concentration at birth was used as a measure of fetal in utero exposure. Pearson correlation coefficients were calculated to determine the degree of correlation between ASM maternal and cord plasma concentrations. A p ‐value of <.05 was deemed to be significant. Results: Data from 207 infants included eight pairs of twins (104 females and 103 males) born to 199 women (140 on monotherapy and 59 on polytherapy), yielding 305 paired maternal and umbilical cord ASM concentrations. Significant correlation was observed between umbilical cord and maternal plasma concentrations for total and unbound carbamazepine, total and unbound carbamazepine‐10,11‐epoxide, gabapentin, lamotrigine, levetiracetam, total and unbound oxcarbazepine, and zonisamide. The mean ratios (SD) of umbilical cord plasma concentration to maternal plasma concentration were as follows: carbamazepine = .84 (.18), unbound carbamazepine = 1.15 (.47), carbamazepine‐10,11‐epoxide = .87 (.18), unbound carbamazepine epoxide = 1.17 (.36), gabapentin = 1.56 (.28), lacosamide = .96 (.29), levetiracetam = 1.1 (.53), lamotrigine = .92 (.26), oxcarbazepine = 1.01 (.22), unbound oxcarbazepine = 1.1 (.46), topiramate = .98 (.38), valproic acid = 1.03 (.85), unbound valproic acid = .73 (.74), and zonisamide = .93 (.12). Significance: Umbilical cord to maternal ASM concentration ratios were close to 1.0, indicating placental passage of ASMs. Gabapentin had the highest ratio, suggesting possible accumulation of drug. Additional studies are needed for infrequently prescribed ASMs.

Objective: This study was undertaken to evaluate whether seizure freedom in pregnancy predicts seizure freedom in the postpartum period in women with epilepsy (WWE). Prior studies have shown that seizure freedom prior to conception strongly predicts seizure freedom during pregnancy. The postpartum period is considered especially vulnerable to recurrent seizures given rapid hormonal changes, shifting antiseizure medication pharmacokinetics, and disrupted sleep. There is a lack of sufficient data on whether seizure freedom during pregnancy predicts postpartum outcomes. Methods: Pregnant WWE (aged 14–45 years) were enrolled at p < .0001), with a predictive value of 78% (95% CI = 72%–84%). Retrospectively reported preconception seizure freedom was also independently associated with postpartum seizure freedom (OR = 5.84, 95% CI = 3.57–9.58, p < .0001). Long‐term seizure freedom during pregnancy and preconception was associated with 85% postpartum seizure freedom, whereas long‐term presence of seizures was associated with only 36% postpartum seizure freedom. There were no significant differences by seizure type. Among participants with seizures during pregnancy, median postpartum seizure frequency declined by 77% (interquartile range = seizure‐free to 31% reduced). Significance: Our data demonstrated that seizure freedom during pregnancy was a robust predictor of seizure freedom during the postpartum period. These data can be used to counsel patients about seizure risk in the postpartum period.

Antiseizure medications (ASMs) undergo marked pharmacokinetic alterations during pregnancy and postpartum. Suboptimal ASM management can lead to adverse maternal and child outcomes. However, there is scant literature to guide how to adjust ASM dosing. This study analyzed how ASMs were dosed in a large observational cohort study of pregnant women with epilepsy (PWWE) who had favorable seizure outcomes. Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) was a prospective, observational cohort study that enrolled PWWE 2012-2016 across 20 US epilepsy centers. Inclusion criteria were PWWE, ages 14-45 years, and <20 weeks' gestational age. Seizures and ASM type(s) and doses were documented in a daily diary. Our analysis included ASM doses in pregnancy through early postpartum (6 weeks post-delivery). For each ASM, we analyzed percent participants who underwent ≥1 dose change in pregnancy and postpartum, time of first dose change after enrollment, time to subsequent changes, amount of each dose adjustment, and percent of conception dose at delivery and 6-week postpartum. A total of 299 participants (median 31 [range 17-46] years) were eligible for analysis. Median enrollment was 14-weeks gestation. Dose increases were made in 246/363 (67.8%) of ASMs during pregnancy beginning median 32 days post-enrollment; dose decreases were made within 6 weeks post-delivery for 171/357 (47.9%) of ASMs beginning median 3 days postpartum. For lamotrigine, 128/146 (87.7%) participants had doses increased, by 100 mg/d (median), reaching 191% of conception dose (mean) by delivery. Postpartum, 103/146 (70.5%) had dose tapers, by 100 mg/d (median), to 116% of conception dose (mean) by 6 weeks. For levetiracetam, 70/125 (56.0%) participants had doses increased, by 500 mg/d (median), reaching 177% of conception dose (mean) by delivery. Postpartum, 43/125 (34.4%) had dose tapers, by 500 mg/d (median), to 136% of conception dose (mean) by 6 weeks. For other ASMs, 10/14 had doses increased in pregnancy and 8/14 were tapered early postpartum. Previous MONEAD analyses showed no difference in seizure control between pregnant and nonpregnant women with epilepsy. We detail how ASMs were managed in pregnancy and early postpartum to achieve this favorable outcome. These findings can be useful for the management of PWWE. Limitations of this study include limited data in the first trimester, enrollment from epilepsy centers, and limited number of participants on a wider variety of ASMs. ClinicalTrials.gov Identifier: NCT01730170. Study Details | Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) | ClinicalTrials.gov. First submitted: November 9, 2012. First patient enrolled: December 19, 2012.

Objective: We previously reported in a prior cohort that fetal exposure to antiseizure medications (ASMs), especially valproate, was associated with reduced right‐handedness and poorer verbal versus nonverbal performance in children at age 6 years. Given changes in prescribing practices in epilepsy over the past 2 decades, we enrolled a new cohort of the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study to determine whether fetal exposure to newer generation ASMs is associated with altered cerebral lateralization in children at age 6 years and to assess exposure‐dependent effects on handedness, manual dexterity, and verbal/nonverbal abilities. Methods: The MONEAD multicenter prospective cohort study followed children of women with epilepsy (WWE) on ASMs and healthy women (HW) until age 6 years. We assessed handedness using the Edinburgh Handedness Inventory, manual dexterity through the Grooved Pegboard Test, and verbal/nonverbal abilities with the Differential Ability Scales‐II. Outcomes were analyzed in relation to ASM exposure, controlling for confounders. Results: Of 1123 screened pregnant women, 351 children born to WWE and 105 to HW were enrolled. The overall distribution of handedness and verbal/nonverbal scores did not differ between groups. However, subgroup analyses revealed that higher third‐trimester levetiracetam concentrations were significantly associated with nondextrality ( p = .03, 95% confidence interval [CI] = .03–.67). Across the WWE cohort, higher ASM concentrations correlated with poorer manual dexterity (coefficient = 6.76, 95% CI = .40–13.11, p = .037). Additionally, periconceptional folate supplementation was associated with better nonverbal outcomes (coefficient = 2.54, 95% CI = .93–4.15, p = .002) and parental stress was linked to poorer verbal scores (coefficient = −19.74, 95% CI = −28.48 to −11, p < .001). Significance: This cohort reassuringly showed no overall difference in verbal/nonverbal abilities between WWE and HW. Fetal ASM exposure had exposure‐dependent effects on manual dexterity. Modifiable factors, including folate supplementation and parental stress, significantly influenced developmental outcomes, underscoring the importance of proactive screening and providing intervention when appropriate.

To assess the recent prescribing practices for antiseizure medications (ASMs) to pregnant people with and without epilepsy and prescribers' preferences beyond the first-line ASMs for patients with refractory generalized epilepsy. A retrospective survey extracted electronic medical data from 20 US tertiary centers (January 1, 2021-December 31, 2022) on ASM prescriptions in pregnant people with and without epilepsy. A second survey asked epileptologists for next-line ASM choices after lamotrigine and levetiracetam failure in women with generalized epilepsy. The final analyses included 17 centers, 378,808 pregnant people who were prescribed ASMs-12,908 with and 365,900 without epilepsy. Key findings include the following: (1) benzodiazepines represented the most prescribed ASM group (12.13%); (2) gabapentin was the second most prescribed ASM (4.16%); (3) among pregnant people with epilepsy, levetiracetam (28.28%), lamotrigine (15.61%), and gabapentin (11.12%) were most frequent exposures; (4) other common ASMs in this group included topiramate (5.86%), oxcarbazepine (3.32%), lacosamide (2.93%), and zonisamide (2.90%); and (5) valproate use was high, with 492 (3.81%) epilepsy exposures and 1,419 overall. Thirty-two US epileptologists survey responders selected zonisamide and lacosamide as second-line ASM choices for female patients with generalized epilepsy. Valproate use in pregnancy remains high despite its known teratogenicity. Many commonly used ASMs in pregnancy have inadequate safety information.