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.

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.

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.

Dobbs Versus Jackson: Epilepsy, Reproductive Health, and Abortion.

On June 24, 2022, Dobbs vs Jackson Women's Health Organization was decided by the Supreme Court effectively overturning the former precedent of Roe v. Wade. This ruling has direct consequences for the care of persons with epilepsy of childbearing potential. Now more than ever we need to provide informed and comprehensive care to our patients with epilepsy who are particularly vulnerable to the impact of this legislation on their reproductive decision-making. Important areas to understand include (1) the current state of affairs on abortion in the United States; (2) contraception options, their effectiveness, and interactions with anti-seizure medications (ASM); (3) teratogenic effects and adverse neurocognitive outcomes of ASMs; (4) folic acid supplementation; (5) the effect on perinatal and pediatric care; and (6) unique issues related to people of color.

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.

Use of antiepileptic drugs by trimester.

OBJECTIVE: To determine which antiepileptic drugs pregnant women receive by trimester. METHODS: This retrospective cohort study using the IBM Watson Health MarketScan Research Databases evaluated which antiepileptic drugs pregnant women with epilepsy received by trimester. Women with aged 15-54 years with a history of seizure disorder who underwent a delivery hospitalization between 2008 and 2017 were included in the analysis. Descriptive statistics were performed. RESULTS: Of 34,144 women with a seizure disorder diagnosis and a delivery hospitalization, 10,289 (30.1%) received an anti-epileptic medication during pregnancy of which more than half received lamotrigine or levetiracetam. Other antiepileptic medications used by >5% of the population during any one trimester in the study period included carbamazepine, clonazepam, and topiramate. In evaluating medication use in the 1st trimester versus the 2nd trimester, clonazepam use decreased 32.0% (95% CI 60.0%, 77.0%) from 5.6% to 3.8% of patients receiving antiepileptics from the 1st to the 2nd trimester, gabapentin deceased 22.1% (95% CI 0.68%, 0.90%) from 4.1% to 3.2%, and topiramate decreased 30.0% (95% CI 62.8%, 77.9%) from 7.2% to 5.1%. In comparison, levetiracetam increased from 22.5% to 33.3% between the 1st and 3rd trimester and lamotrigine 22.2% to 27.5% between the 1st and 3rd trimester, 48.3% and 24.0% increases respectively. CONCLUSION: Antiepileptic drugs with less favorable fetal risk profiles such as topiramate decreased by trimester while medications with more favorable fetal risk profiles such as lamotrigine and levetiracetam increased. These findings broadly support that there are opportunities to improve pre-conceptional counseling of women with epilepsy.

The Effect of Epilepsy on Sleep Quality During Pregnancy and Postpartum.

OBJECTIVE: This study seeks to understand how sleep is affected in pregnant women with epilepsy (WWE) relative to healthy pregnant women during pregnancy and postpartum and to non-pregnant WWE during comparative time periods. BACKGROUND: Sleep impacts maternal health and mood during pregnancy. Maternal sleep disturbances are related to poor fetal growth and increased fetal deaths. Epilepsy is the most common neurologic condition in pregnancy. Sleep disruption can worsen epileptic seizures. The interplay between epilepsy, pregnancy, and sleep is poorly understood. DESIGN: /Methods: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter study, enrolling women from December 2012 through January 2016. Sleep quality was assessed utilizing the average Pittsburgh Sleep Quality Index collected during pregnancy; postpartum; or analogous time periods. Sleep scores range from 0 to 21 with higher scores indicating worse sleep quality; scores > 5 are associated with poor sleep quality. RESULTS: Of 351 pregnant WWE, 105 healthy pregnant women, and 109 non-pregnant WWE enrolled in MONEAD, data from 241 pregnant WWE, 74 healthy pregnant women, and 84 non-pregnant WWE were analyzed. Pregnant WWE had worse sleep (higher mean sleep score) during pregnancy compared to healthy pregnant women in unadjusted analysis (p=0.006), but no longer significant in adjusted analysis (p=0.062), pregnant WWE (least square mean sleep score (95% CI) = 5.8 (5.5, 6.1)) vs. healthy pregnant women (5.1 (4.6, 5.7)). During postpartum, pregnant WWE (5.6 (5.4, 5.9)) had similarly impaired sleep compared to healthy pregnant women (5.7 (5.2, 6.2); adjusted p=0.838). Sleep was significantly worse in pregnant WWE vs non-pregnant WWE (for comparable time period) in pregnancy and postpartum in unadjusted and adjusted analyses. Adjusted scores for pregnant WWE in pregnancy (5.7 (5.4, 6.0)) and postpartum (5.7 (5.4, 6.0)) compared to non-pregnant WWE (4.7 (4.2, 5.3); p=0.002) and (4.1 (3.6, 4.7); p<0.001), respectively. Sleep quality between pregnancy and postpartum varied only in healthy pregnant women (change in mean score = 0.8 (0.2, 1.3); p=0.01), whose sleep was worse in postpartum. CONCLUSIONS: Pregnant WWE had worse sleep during pregnancy and postpartum than non-pregnant WWE during comparable periods in the adjusted analysis.The study is registered at clinicaltrials.gov as NCT01730170.

Maternal morbidity and mortality associated with epilepsy.

OBJECTIVE: Prior research demonstrated large increased risk for maternal mortality among women with epilepsy. The objective of this study was to estimate risk for adverse maternal outcomes during delivery hospitalizations among women with epilepsy. METHODS: Truven Health MarketScan databases were used to compare risk for adverse maternal outcomes during delivery hospitalizations based upon whether there was diagnosis of epilepsy and receipt of anti-epileptic drugs prior to delivery. Outcomes included: (i) death during delivery hospitalization, (ii) severe maternal morbidity, (iii) cesarean delivery, (iv) postpartum hemorrhage, (v) placental abruption, (vi) preeclampsia, (vii) preterm delivery, (viii) premature rupture of membranes, and (ix) stillbirth. Adjusted models including hospital and demographic factors were performed with adjusted risk ratios (aRR) with 95% CIs as measures of effect. RESULTS: Women with epilepsy prior to delivery who received antiepileptic drugs (n = 6019) during pregnancy were not at increased risk for mortality with no deaths occurring in this group (p = .27). Risk for severe maternal morbidity in this group was approximately double (aRR 2.16, 95% CI 1.86-2.51) with risks for other outcomes including placental abruption (aRR 1.29, 95% CI 1.04-1.60), cesarean delivery (aRR 1.14, 95% CI 1.10-1.18), and preterm delivery (aRR 1.25, 95% CI 1.15-1.35) slightly increased compared to women without seizures. CONCLUSION: No significant difference in mortality risk was found for women with epilepsy. Increased risk for other adverse maternal outcomes for women with epilepsy on antiepileptics was modest.

Tracking Multisite Seizure Propagation Using Ictal High-Gamma Activity.

PURPOSE: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment. METHODS: Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared. RESULTS: Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03). CONCLUSIONS: Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal.

Antiseizure Medication Withdrawal in Seizure-Free Patients: Practice Advisory Update Summary: Report of the AAN Guideline Subcommittee.

OBJECTIVE: To update a 1996 American Academy of Neurology practice parameter. METHODS: The authors systematically reviewed literature published from January 1991 to March 2020. RESULTS: The long-term (24-60 months) risk of seizure recurrence is possibly higher among adults who have been seizure-free for 2 years and taper antiseizure medications (ASMs) vs those who do not taper ASMs (15% vs 7% per the 1 Class I article addressing this issue). In pediatric patients, there is probably no significant difference in seizure recurrence between those who begin tapering ASMs after 2 years vs 4 years of seizure freedom, and there is insufficient evidence of significant difference in risk of seizure recurrence between those who taper ASMs after 18 months of seizure freedom and those tapering after 24 months. There is insufficient evidence that the rate of seizure recurrence with ASM withdrawal following epilepsy surgery after 1 year of seizure freedom vs after 4 years is not significantly different than maintaining patients on ASMs. An epileptiform EEG in pediatric patients increases the risk of seizure recurrence. ASM withdrawal possibly does not increase the risk of status epilepticus in adults. In seizure-free adults, ASM weaning possibly does not change quality of life. Withdrawal of ASMs at 25% every 10 days to 2 weeks is probably not significantly different from withdrawal at 25% every 2 months in children who are seizure-free in more than 4 years of follow-up. RECOMMENDATIONS: Fourteen recommendations were developed.

Two-Year-Old Cognitive Outcomes in Children of Pregnant Women With Epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study.

Importance: The neurodevelopmental risks of fetal exposure are uncertain for many antiseizure medications (ASMs). Objective: To compare children at 2 years of age who were born to women with epilepsy (WWE) vs healthy women and assess the association of maximum ASM exposure in the third trimester and subsequent cognitive abilities among children of WWE. Design, Setting, and Participants: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a prospective, observational, multicenter investigation of pregnancy outcomes that enrolled women from December 19, 2012, to January 13, 2016, at 20 US epilepsy centers. Children are followed up from birth to 6 years of age, with assessment at 2 years of age for this study. Of 1123 pregnant women assessed, 456 were enrolled; 426 did not meet criteria, and 241 chose not to participate. Data were analyzed from February 20 to December 4, 2020. Main Outcomes and Measures: Language domain score according to the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), which incorporates 5 domain scores (language, motor, cognitive, social-emotional, and general adaptive), and association between BSID-III language domain and ASM blood levels in the third trimester in children of WWE. Analyses were adjusted for multiple potential confounding factors, and measures of ASM exposure were assessed. Results: The BSID-III assessments were analyzed in 292 children of WWE (median age, 2.1 [range, 1.9-2.5] years; 155 female [53.1%] and 137 male [46.9%]) and 90 children of healthy women (median age, 2.1 [range, 2.0-2.4] years; 43 female [47.8%] and 47 male [52.2%]). No differences were found between groups on the primary outcome of language domain (-0.5; 95% CI, -4.1 to 3.2). None of the other 4 BSID-III domains differed between children of WWE vs healthy women. Most WWE were taking lamotrigine and/or levetiracetam. Exposure to ASMs in children of WWE showed no association with the language domain. However, secondary analyses revealed that higher maximum observed ASM levels in the third trimester were associated with lower BSID-III scores for the motor domain (-5.6; 95% CI, -10.7 to -0.5), and higher maximum ASM doses in the third trimester were associated with lower scores in the general adaptive domain (-1.4; 95% CI, -2.8 to -0.05). Conclusions and Relevance: Outcomes of children at 2 years of age did not differ between children of WWE taking ASMs and children of healthy women. Trial Registration: ClinicalTrials.gov Identifier: NCT01730170.

Changes in Seizure Frequency and Antiepileptic Therapy during Pregnancy.

BACKGROUND: Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups. METHODS: In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth) (epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy) (epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the two groups during the first 9 months of epoch 1. RESULTS: We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the two epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 pregnant women (23%) and in 23 controls (25%) (odds ratio, 0.93; 95% confidence interval [CI], 0.54 to 1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82 to 10.59). CONCLUSIONS: Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.).

Epilepsy.

The management of epilepsy during pregnancy involves optimizing seizure control for the mother, while ensuring the best outcome for the developing fetus. Preconception counseling regarding contraception, folic acid, and antiseizure medications (ASMs) will maximize positive outcomes. Folic acid supplementation is recommended to decrease risk of neural tube defects, similar to the general population, and has been associated with improved cognitive outcomes and decreased risk of autistic traits in offspring. Efforts should be made to optimize the ASM regimen before pregnancy to the fewest number of ASMs, lowest effective doses, with avoidance of more teratogenic agents such as valproic acid. Valproic acid is associated with the highest increased risk of major congenital malformations, as well as reduced cognitive outcomes and neurodevelopmental disorders. Decreasing or changing ASMs during pregnancy should be done with caution, as convulsive seizures have been associated with adverse fetal outcomes including cognitive impairment. Physiologic changes during pregnancy affect ASM levels and in turn, risk for seizures, necessitating frequent monitoring of ASM serum concentrations. Mothers should also be counseled postpartum about how the benefits of breastfeeding outweigh the transmission of medication into breast milk. Communication between providers (obstetrics and neurology) and pregnant women with epilepsy is essential.

All-cause mortality and SUDEP in a surgical epilepsy population.

Epilepsy surgery is considered to reduce the risk of epilepsy-related mortality, including sudden unexpected death in epilepsy (SUDEP), though data from existing surgical series are conflicting. We retrospectively examined all-cause mortality and SUDEP in a population of 590 epilepsy surgery patients and a comparison group of 122 patients with pharmacoresistant focal epilepsy who did not undergo surgery, treated at Columbia University Medical Center between 1977 and 2014. There were 34 deaths in the surgery group, including 14 cases of SUDEP. Standardized mortality ratio (SMR) for the surgery group was 1.6, and SUDEP rate was 1.9 per 1000 patient-years. There were 13 deaths in the comparison group, including 5 cases of SUDEP. Standardized mortality ratio for the comparison group was 3.6, and SUDEP rate was 4.6 per 1000 patient-years. Both were significantly greater than in the surgery group (p < 0.05). All but one of the surgical SUDEP cases, and all of the comparison group SUDEP cases, had a history of bilateral tonic-clonic seizures (BTCS). Of postoperative SUDEP cases, one was seizure-free, and two were free of BTCS at last clinical follow-up. Time to SUDEP in the surgery group was longer than in the comparison group (10.1 vs 5.9 years, p = 0.013), with 10 of the 14 cases occurring >10 years after surgery. All-cause mortality was reduced after epilepsy surgery relative to the comparison group. There was an early benefit of surgery on the occurrence of SUDEP, which was reduced after 10 years. A larger, multicenter study is needed to further investigate the time course of postsurgical SUDEP.

Fetal loss and malformations in the MONEAD study of pregnant women with epilepsy.

OBJECTIVE: To examine occurrence of severe adverse fetal outcomes (SAO), including fetal loss and major congenital malformations (MCMs), in pregnant women with epilepsy (PWWE) vs healthy pregnant women (HPW). METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes for both mother and child, which enrolled women December 2012 through January 2016. RESULTS: The 351 PWWE had 365 conceptions, and 105 HPW had 109 conceptions. SAOs occurred more often in PWWE (7.9%) vs HPW (1.9%) (p = 0.025) with odds ratio (OR) 4.45 (95% confidence intervals [CI] 1.04-19.01). There were no significant differences for fetal loss (2.8% vs 0%, p = 0.126) or MCMs (5.2% vs 1.9%, p = 0.185; OR 2.86, 95% CI 0.65-12.53) individually. No fetal losses in PWWE appeared to be related to acute seizures. Outcomes were not affected by periconceptional folate, unplanned/unwanted pregnancies, prior maternal pregnancy history, or antiepileptic drug (AED) blood levels, except for an AED level effect for fetal loss that appeared to be due to polytherapy. Combined maternal or paternal family history of MCM was marginally associated with increased SAOs (p = 0.046). CONCLUSIONS: The findings provide additional information on risks of SAOs in PWWE, assessing effects of both AED levels and periconceptional folate. Group differences in average enrollment gestational age could have affected fetal loss results. Analyses are limited by small sample sizes as the MONEAD study was not powered for these secondary outcomes. The large majority of pregnancies in women with epilepsy do not have SOAs.

Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy.

Importance: There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy. Objective: To provide direct, objective information on antiepileptic drug exposure through breast milk. Design, Setting, and Participants: This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019. Exposures: Antiepileptic drug exposure in infants who were breastfed. Main Outcomes and Measures: The percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle. Results: A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants. Conclusions and Relevance: Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

Epilepsy Overview and Revised Classification of Seizures and Epilepsies.

PURPOSE OF REVIEW: The classification of seizures, epilepsies, and epilepsy syndromes creates a framework for clinicians, researchers, and patients and their families. This classification has evolved over the years, and in 2017 the International League Against Epilepsy (ILAE) published an operational classification of seizures and epilepsies. Understanding this classification is important in the diagnosis, treatment, and understanding of seizures and epilepsies, including epilepsy incidence. RECENT FINDINGS: The 2017 ILAE classification system builds on newly formulated definitions of seizures and epilepsy. Seizure classification begins by determining whether the initial manifestations of the seizure are focal or generalized. If the onset of the seizure is missed or unclear, the seizure is of unknown onset. Focal seizures are classified according to the individual's level of awareness, the most prominent motor or nonmotor features of the seizure, and whether the focal seizure evolves to a bilateral tonic-clonic seizure. Similarly, generalized seizures are classified according to motor or nonmotor manifestations. Motor seizures are either tonic-clonic or other motor seizures. Nonmotor generalized seizures primarily refer to absence seizures. Similar to seizure classification, the epilepsies can be classified as focal or generalized. In addition, the new classification system recognizes two new categories: combined generalized and focal epilepsy and unknown epilepsy. The concept of an epilepsy syndrome has been introduced under the new classification system and refers to a cluster of features incorporating seizure types, EEG, imaging, and other features including genetics. The new classification system emphasizes the etiology of seizures and epilepsies. SUMMARY: The recent ILAE seizure and epilepsy classification system aims to create a framework to better classify seizures and the epilepsies. Universal adoption and implementation of this system will enable patients, their families, clinicians, and researchers to better define and treat the epilepsies. Incidence studies have not generally classified seizures and the epilepsies, and use of this classification system, which emphasizes etiology, will lead to a better understanding of epilepsy incidence.

Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects.

Medically refractory epilepsy remains an area of intense clinical and scientific interest since a significant porportion of patients continue to suffer from debilitating seizures despite available therapies. In this setting, recent studies have focused on assessing the benefits of cannabidiol (CBD)-enriched cannabis, a plant based product without psychoactive properties which has been shown to decrease seizure frequency in animal models. More recently, several randomized controlled and open label trials have studied the effects of Epidiolex, a 99% pure oral CBD extract, on patients with refractory epilepsy. This in turn has led to the FDA approval of and more recently, to the Drug Enforcement Administration's placement of Epidiolex into schedule V of the Controlled Substances Act (CSA). In this review, we summarize the major findings of several recent large-scale studies using this product with a focus on its adverse effects.

A pilot study of levonorgestrel concentrations and bleeding patterns in women with epilepsy using a levonorgestrel IUD and treated with antiepileptic drugs.

OBJECTIVES: We explored levonorgestrel (LNG) concentrations, bleeding patterns and endometrial thickness in women with epilepsy (WWE) initiating an LNG-intrauterine device (IUD) co-administered with antiepileptic drugs (AEDs). STUDY DESIGN: This pilot study included 20 WWE ages 18 to 45 years with well-controlled seizures and stable AED regimens initiating a 52-mg LNG-IUD (20 mcg/d initial release). We collected blood and measured endometrial thickness before IUD placement and 21 days, 3 months and 6 months thereafter. Participants recorded bleeding/spotting daily. We measured total LNG (radioimmunoassay), serum hormone binding globulin (SHBG, immunoassay) and calculated the free LNG index. We compared total LNG, free LNG index, SHBG and endometrial thickness over time using a linear mixed-effects model. RESULTS: Total LNG, free LNG index and SBHG levels remained stable from day 21 throughout. Endometrial thickness decreased from a median of 5.9 mm [interquartile range (IQR) 4.6-7.5] at day 21 to 3.3mm (2.8-4.9) by month 6 (p=0.02). Bleeding and spotting days decreased from a median of 16 (IQR 13-23) in month 1 to 6.5 (IQR 4-8.5) in month 6 regardless of AED regimen. CONCLUSION: Like women without epilepsy, WWE initiating the LNG-IUD experience stable total LNG concentrations and decreasing endometrial thickness and bleeding over the first 6 months of use. IMPLICATIONS: Like women without epilepsy, WWE using antiepileptic drugs can expect a stable LNG concentration and decreasing bleeding during the first 6 months of LNG-IUD use. Our data can be useful for guidance of WWE considering use the LNG-IUD.