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Objective To investigate neurophysiologic and neuroimaging characteristics of patients with late onset unexplained epilepsy (LOUE). Methods We performed a retrospective chart review of elderly patients with ICD9 diagnosis codes consistent with epilepsy/seizures. Inclusion criteria included unprovoked seizures, and absence of cortical lesions on magnetic resonance imaging (MRI). Electroencephalograms (EEGs) findings were also analyzed. MRI images were scored for degree of white matter hyperintensities (Fazekas Scale) and mesial temporal atrophy (MTA). Vascular risk factors, and Framingham Heart Study general cardiovascular disease (FHS-CVD) risk scores were compared to controls from the Harvard Aging Brain study (HABS). Results We identified 224 LOUE patients and 8% were drug resistant. Epileptiform abnormalities were captured on EEG in 35%. The location was temporal with left sided predominance in 49%. Fazekas scale consisted of 25% beginning of confluent lesions, and 10% large confluent lesions. MTA scores consisted of 21% moderate-severe hippocampal atrophy. LOUE patients had on average a 2.3% (adjusted), 7.4% (unadjusted) increased FHS-CVD score. Conclusions Our findings highlight LOUE as pharmacosensitive and left temporal predominant. Given the higher prevalence of vascular risk factors, investigations are needed to study their role in pathophysiology. Significance Physicians caring for patients with LOUE should evaluate for vascular risk factors and investigate the presence of hippocampal atrophy.

ObjectivesTo provide information on the effect of the coronavirus disease of 2019 (COVID-19) pandemic on people with epilepsy and provide consensus recommendations on how to provide the best possible care for people with epilepsy while avoiding visits to urgent care facilities and hospitalizations during the novel coronavirus pandemic.MethodsThe authors developed consensus statements in 2 sections. The first was “How should we/clinicians modify our clinical care pathway for people with epilepsy during the COVID-19 pandemic?” The second was “What general advice should we give to people with epilepsy during this crisis? The authors individually scored statements on a scale of −10 (strongly disagree) to +10 (strongly agree). Five of 11 recommendations for physicians and 3/5 recommendations for individuals/families were rated by all the authors as 7 or above (strongly agree) on the first round of rating. Subsequently, a teleconference was held where statements for which there was a lack of strong consensus were revised.ResultsAfter revision, all consensus recommendations received a score of 7 or above. The recommendations focus on administration of as much care as possible at home to keep people with epilepsy out of health care facilities, where they are likely to encounter COVID-19 (including strategies for rescue therapy), as well as minimization of risk of seizure exacerbation through adherence, and through ensuring a regular supply of medication. We also provide helpful links to additional helpful information for people with epilepsy and health providers.ConclusionThese recommendations may help health care professionals provide optimal care to people with epilepsy during the coronavirus pandemic.

IMPORTANCE: Neurodevelopmental disorders are associated with poor health and social outcomes. Population-based data on incidence, age at diagnosis, and demographic variations are essential to identify modifiable risk factors and inform the planning of services and interventions. OBJECTIVES: To assess the incidence and timing of diagnosis of neurodevelopmental disorders during childhood in the US and to evaluate differences by population characteristics. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used nationwide data on birth cohorts nested in the 2000-2014 Medicaid Analytic eXtract and the 2003-2015 IBM MarketScan Research Database on 2 070 541 publicly and 1 309 900 privately insured children enrolled at birth. Data were analyzed between May 1, 2020, and June 30, 2021. MAIN OUTCOMES AND MEASURES: Neurodevelopmental disorders, autism spectrum disorders, attention-deficit/hyperactivity disorder, learning disabilities, speech or language disorders, developmental coordination disorders, intellectual disabilities, and behavioral disorders were identified based on validated algorithms. Kaplan-Meier analyses were used to estimate the incidence and timing of diagnosis, stratified by child’s sex, birth year, maternal age at delivery, and race and ethnicity. RESULTS: The cohorts comprised 2 070 541 publicly insured children (1 045 426 boys [50.5%]) and 1 309 900 privately insured children (667 607 boys [51.0%]) enrolled at birth. By 8 years of age, 23.9% of publicly insured children and 11.0% of privately insured children received a diagnosis of 1 or more neurodevelopmental disorders (autism spectrum disorder, 1.6% and 1.3%; attention-deficit/hyperactivity disorder, 14.5% and 5.8%; learning disability, 1.2% and 0.6%; speech or language disorder, 8.4% and 4.5%; developmental coordination disorder, 0.9% and 0.7%; intellectual disability, 0.7% and 0.1%; and behavioral disorder, 8.4% and 1.5%). Risks were substantially higher among boys (incidence of ≥1 neurodevelopmental disorder by age 8 years for boys vs girls: 30.7% vs 16.7% among publicly insured children and 15.0% vs 6.7% among privately insured children) and White children (30.2% vs 9.1% among Asian children, 23.0% among Black children, 15.4% among Hispanic children, and 22.7% among children of unknown race or ethnicity; information on race and ethnicity was available only for publicly insured children). The association of maternal age and birth year with incidence of neurodevelopmental disorders varied by outcome. Except for attention-deficit/hyperactivity disorder, the diagnosis tended to be established somewhat earlier for privately insured children. The association of race and ethnicity with age at diagnosis varied by outcome. Co-occurring neurodevelopmental disorders were common, especially among children with autism spectrum disorder and intellectual disability (>70% had ≥1 other disorder). CONCLUSIONS AND RELEVANCE: In this population-based cohort study, a relatively high incidence of and co-occurrence of neurodevelopmental disorders as well as the disparity in incidence and timing of diagnosis by insurance type and race and ethnicity were found. These findings represent important public health concerns and underscore the need for timely and accessible developmental assessments and educational services to help reduce the burden of these disorders.

Background and ObjectivesAssess 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.MethodsThe 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.ResultsThis 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.DiscussionAlthough 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 InformationThis study is registered at ClinicalTrials.gov as NCT01730170.

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study was a prospective observational multicenter study in the USA and UK, which enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study aimed to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, and valproate). In this report, we examine fetal AED exposure effects on learning and memory functions in 221 six-year-old children (including four sets of twins) whose mothers took one of these AEDs during pregnancy. Their performance was compared with that of a national sample of normally developing six year olds from the standardization sample of the Children's Memory Scale (CMS). The major results of this study indicate that the mean performance levels of children exposed to valproate were significantly below that of the children in the normal comparison group across all seven of the CMS Indexes. With one exception, this finding held up at the subtest level as well. These findings taken together with nonsignificant verbal and nonverbal forgetting scores appear to indicate that, as a group, children exposed to valproate experienced significant difficulty in their ability to process, encode, and learn both auditory/verbal as well as visual/nonverbal material. In addition, they exhibited significant difficulty holding and manipulating information in immediate auditory working memory. However, once the information was learned and stored, the valproate-exposed children appeared to be able to retrieve the information they did learn at normal levels. Finally, the processing, working memory, and learning deficits demonstrated by the valproate-exposed children are dose-related. In contrast to valproate, the findings pertaining to the children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy are less clear. Therefore, further research will be required to delineate the potential risks to learning and memory functions in children exposed to carbamazepine, lamotrigine, and phenytoin in monotherapy during pregnancy. Additional research employing larger prospective studies will be required to confirm the long-term cognitive and behavioral risks to children of mothers who are prescribed these four AEDs during pregnancy as well as to delineate any potential risks of newer AEDs and to understand the underlying mechanisms of adverse AED effects on the immature brain.

Changes in Seizure Frequency and Antiepileptic Therapy During Pregnancy Pennell PB, French JA, May RC, et al. N Engl J Med. 2020;383:2547-56. https://pubmed.ncbi.nlm.nih.gov/33369356/. doi:10.1056/NEJMoa2008663.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 2 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 2 epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 (23%) pregnant women and in 23 (25%) controls (odds ratio, 0.93; 95% CI, 0.54-1.60). 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, 3.82-10.59).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.)

The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer’s disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD., Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .

The ILAE Task Force on Women and Pregnancy conducted a survey among ILAE Chapters of their use of guidelines or recommendations for the management of women with epilepsy during pregnancy. A web-based questionnaire including 10 questions was sent to the 118 ILAE Chapters in December 2017 with repeated reminders until the end of February 2018. In total, 77 chapters (65%) responded, although not to all questions. Out of those responding, 68% reported having guidelines or recommendations, 34% of which were from 2014 or earlier. At least 20% of the guidelines did not include information on possible risk to cognitive development, information regarding specific risks with specific antiepileptic drugs, nor recommendations regarding selection of antiepileptic drugs. Among those responding to the question, 91% reported that recommendations were made regarding folate supplementation, but the recommended dose ranged from 0.4 mg/d to 4 mg/d or more; 34% did not include recommendations regarding drug level monitoring during pregnancy, and 19% did not include guidelines on breastfeeding. Our survey demonstrates that there is a need for the development of up-to-date, globally applicable recommendations for the management of epilepsy during pregnancy. Fil: Tomson, Torbjörn. Karolinska Huddinge Hospital. Karolinska Institutet; Suecia. Karolinska University Hospital. Department of Neurology; Suecia Fil: Battino, Dina. Fondazione IRCCS Istituto Neurologico Carlo Besta. Department of Neurophysiology and Experimental Epileptology. Epilepsy Center; Italia Fil: Bromley, Rebecca. Central Manchester University Hospitals NHS Foundation Trust; Reino Unido. University of Manchester; Reino Unido Fil: Kochen, Sara Silvia. Universidad Nacional Arturo Jauretche. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Provincia de Buenos Aires. Ministerio de Salud. Hospital Alta Complejidad en Red El Cruce Dr. Néstor Carlos Kirchner Samic. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Unidad Ejecutora de Estudios en Neurociencias y Sistemas Complejos; Argentina Fil: Meador, Kimford J.. University of Stanford; Estados Unidos Fil: Pennell, Page B.. Brigham and Women's Hospital. Harvard Medical School. Department of Neurology. Divisions of Epilepsy and Women's Health; Estados Unidos Fil: Thomas, Sanjeev V.. Sree Chitra Tirunal Institute of Medical Sciences and Technology. Department of Neurology; India

There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy.To provide direct, objective information on antiepileptic drug exposure through breast milk.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.Antiepileptic drug exposure in infants who were breastfed.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.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.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.

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one‑carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.

ObjectiveTo 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).MethodsThe 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.ResultsThe 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).ConclusionsThe 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.

OBJECTIVE: We analyzed current prescribing patterns for antiepileptic drugs (AEDs) in pregnant women with epilepsy (PWWE) at 20 USA tertiary epilepsy centers. METHODS: The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is an NIH-funded, prospective, observational, multi-center investigation of pregnancy outcomes for both mother and child, which enrolled women from December 2012 to January 2016. Inclusion criteria for PWWE included ages 14–45 years and up to 20 weeks gestational age. Exclusion criteria included history of psychogenic non-epilepstic spells, expected IQ

Neuroactive steroids have rapid, nongenomic effects on neuronal excitability. The effects in humans are less clear. We compared seizure control and concentrations of neuroactive steroids, known to influence neuroexcitability in animal studies, in pregnant women. Participants were prospectively followed throughout pregnancy with seizure-medication diaries and blood samples, assayed for steroid concentrations with gas chromatography-mass spectrometry. Baseline seizure frequency was calculated for the preconception year, and it was determined if seizure frequency was increased in each trimester. The Wilcoxon rank-sum test was used to compare neuroactive steroid concentrations in between the group with increased frequency to the group without, as calculated for the respective trimester, with the Holm-Bonferroni method to correct for multiple comparisons. Among eighty-three pregnancies included, twenty-eight had increased seizure frequency during at least one trimester (15, 18 and 10, respectively) compared to preconception seizure frequency. Allopregnanolone concentrations were lower in the 3(rd) trimester (p< 0.001), with a similar trend in the 1(st) (p=0.08), for pregnancies with increased compared to those with stable seizure frequency. Other neuroactive steroid concentrations were similar. Our findings suggest that lower allopregnanolone concentrations are associated with increased seizure frequency during pregnancy. Validation of these finding in a larger cohort has potential important clinical applications.

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.

ObjectiveTo assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications.MethodsThis population-based study nested in the US 2000–2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted.ResultsThe risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56–5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65–26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54–3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53–5.07) and for doses >100 mg it was 5.16 (95% CI 1.94–13.73). Results were similar when lamotrigine was used as a reference group.ConclusionThe increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.

ObjectiveEmerging evidence suggests potential positive neuropsychological effects of periconceptional folate in both healthy children and children exposed in utero to antiseizure medications (ASMs). In this report, we test the hypothesis that periconceptional folate improves neurodevelopment in children of women with epilepsy by re-examining data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study.MethodsThe NEAD study was an NIH-funded, prospective, observational, multicenter investigation of pregnancy outcomes in 311 children of 305 women with epilepsy treated with ASM monotherapy. Missing data points were imputed with Markov chain Monte Carlo methods. Multivariate analyses adjusted for multiple factors (e.g., maternal IQ, ASM type, standardized ASM dose, and gestational birth age) were performed to assess the effects of periconceptional folate on cognitive outcomes (i.e., Full Scale Intelligence Quotient [FSIQ], Verbal and Nonverbal indexes, and Expressive and Receptive Language indexes at 3 and 6 years of age, and executive function and memory function at 6 years of age).ResultsPericonceptional folate was associated with higher FSIQ at both 3 and 6 years of age. Significant effects for other measures included Nonverbal Index, Expressive Language Index, and Developmental Neuropsychological Assessment Executive Function at 6 years of age, and Verbal Index and Receptive Language Index at 3 years of age. Nonsignificant effects included Verbal Index, Receptive Index, Behavior Rating Inventory of Executive Function–Parent Questionnaire Executive Function, and General Memory Index at 6 years of age, and Nonverbal Index and Expressive Index at 3 years of age.ConclusionsUse of periconceptional folate in pregnant women with epilepsy taking ASMs is associated with better cognitive development.ClinicalTrials.gov identifier:NCT00021866.

ABSTRACT Child-bearing years are often the most precarious management period in the life of a woman with epilepsy. This article reviews the results of many different studies with findings that enable the healthcare team to make confident decisions and recommendations during these critical periods. Preconceptional planning, effective contraception and folic acid supplementation are important fundamentals in preparation for pregnancy. There is growing evidence to avoid valproic acid use during the child-bearing years. Emerging data on congenital malformations and neurocognitive outcomes are available for some of the second-generation antiepileptic drugs and appear reassuring for lamotrigine and levetiracetam. Also reviewed are the benefits of postpartum drug tapers and favorable breastfeeding facts. Counseling the mother and her family on medication choices enables the healthcare team to implement informed decisions that are beneficial for the mother and child.

OBJECTIVE. Folic acid supplementation during the periconceptual period has been shown to improve cognitive outcomes in children of women with epilepsy taking antiseizure medications (ASMs). The dose of folic acid necessary to provide positive cognitive outcomes is unclear. In many countries including the United States, food is fortified with folic acid, but no data exists on how food fortification may affect cognition in children with fetal-ASM exposure. This study evaluates the effect of dietary folate from natural folates plus folic acid fortification, separate from folic acid vitamin supplements, on age-6 year IQ in children with fetal-ASM exposure. METHODS. Data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study was retrospectively analyzed for this investigation. Assessment of nutrient intake was conducted using the Block Food Frequency Questionnaire-98. The primary outcome of the present study was to assess association of maternal pre-pregnancy nutrient levels to child age-6 IQ. RESULTS. Folate from food alone without supplement was not associated with improvement of age-6 IQ in children with fetal ASM exposure (95% CI: −11.7 – 2.3, p = 0.187). Periconceptual folate supplement use was associated with a 10.1 point higher age-6 IQ (95% CI: 5.2 – 15.0, p

Although prenatal exposure to antiepileptic drugs (AEDs) is known to impart relatively higher risks of major congenital malformations, prospective studies have provided refined data that allow us to differentiate the risks of different types and doses of AEDs. As the number of AED prescriptions has dramatically increased in reproductive-aged women with a variety of neuropsychiatric indications, the evolving concepts learned from studies in women with epilepsy can be applied to a much larger group of pregnant women to improve child outcomes while maintaining maternal disease control. In addition to careful selection of the type of medication, the amount of fetal exposure at conception and in the first trimester probably matters across all AEDs. Some AED polytherapy regimens are not associated with a higher risk of malformations, although other outcomes have not yet been formally studied. The individual woman’s drug target concentration should be established preconception and maintained during pregnancy, to prevent seizure worsening. Substantial pharmacokinetic changes occur with many of the medications during pregnancy and postpartum, and interindividual variability supports the use of therapeutic drug monitoring for most AEDs. During pregnancy, vigilance and close monitoring should also include intrauterine fetal growth, obstetric complications, and neonatal complications. Breastfeeding can provide additional neurodevelopmental benefit and should be an option for women on AEDs. Knowledge of these key principles enhances our ability to make treatment recommendations with resultant improved maternal and child outcomes. Additional prospective studies are needed to further define the risk–benefit ratio across a variety of medications, dosing strategies, and neuropsychiatric disorders.

Epilepsy and antiepileptic drugs affect the menstrual cycle, aspects of contraception, reproductive health, pregnancy, and menopause through alteration of sex steroid hormone pathways. Sex steroid hormones often have an effect on seizure frequency and may alter the level of some antiepileptic drugs. Approximately one-third of women experience an increase in perimenstrual and/or periovulatory seizure frequency. Some women experience an increase in seizure frequency during pregnancy. Balancing maternal seizure control and the risk of congenital malformations associated with fetal antiepileptic drug exposure may be challenging. Some antiepileptic drugs are associated with cognitive and behavioral teratogenesis and should be avoided if possible during pregnancy.

This study used the most recent national data on epilepsy from the 2017 National Health Interview Survey (NHIS) to examine the distribution of types of provider visits in the last 12 months among 2.9 million adult respondents aged ≥ 18 years with active epilepsy (self-reported doctor-diagnosed epilepsy taking antiseizure medications and/or having ≥ 1 seizure in the past year) and compared these estimates with 2010 NHIS data. We calculated age-standardized percentages of visits to a general doctor and an epilepsy specialist during the past 12 months, accounting for the complex survey design. Among US adults with active epilepsy in 2017, 27.1% saw a general doctor only, 9.0% saw a neurologist/epilepsy specialist only, 53.0% visited both a general doctor and a neurologist/epilepsy specialist, and 11.4% did not see either a general doctor or a neurologist/specialist. Overall, 62.0% [95% confidence interval (CI) = 55.2%–67.5%] of adults with active epilepsy visited a neurologist or epilepsy specialist in the past year. A visit in the past 12 months with both provider types was not significantly different in 2017 compared with 2010 (53.0% vs 46.2%) while seeing a general doctor only had declined (41.8% vs 27.1%, p, Highlights • We used NHIS data to examine past 12-month provider visits for adults with epilepsy. • In 2017, 62% of adults visited a neurologist or epilepsy specialist in the past year. • In 2017, 27% of US adults with epilepsy saw a general doctor only. • In 2017, 11% of adults did not see either a general doctor or a neurologist/specialist. • Past 12-month visits with both provider types were the same in 2017 as in 2010.

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

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

Objective The objectives of this study were to investigate the effect of age on pharmacokinetic parameters of lamotrigine (LTG) and estimate parameter variability. Methods Patients (>18 years old) who were already on a steady-state dose of LTG therapy with no interacting comedications were enrolled. Patients with significant cardiac disease, severe kidney dysfunction, or moderate-to-severe liver dysfunction were excluded. Fifty milligrams of a stable-labeled intravenous LTG formulation (SL-LTG) replaced 50 mg of a patient's normal daily oral LTG dose. Thirteen blood samples were collected in each person over 96 hours. SL-LTG and unlabeled LTG concentrations were measured simultaneously by gas chromatography-mass spectrometry. Concentration-time data were analyzed by nonlinear mixed-effects modeling (NONMEM version 7.3). Results Twenty-eight patients representing 16 young (18-48 years old) and 12 elderly (63-87 years old) patients were included, yielding 382 unlabeled and 351 SL-LTG concentrations. A two-compartment model with first-order absorption and elimination adequately described the plasma concentration-time data. Bioavailability of oral LTG was approximately 74% and did not differ by age. LTG clearance was 27.2% lower in elderly than in young patients (1.80 L/h for a 70-kg patient). Significance Although LTG bioavailability was not affected by age, LTG clearance was 27.2% lower in elderly versus young patients of comparable body weight, possibly indicating lower dosages being needed in this population.

The clinical management of women with epilepsy on antiepileptic drugs (AEDs) during pregnancy presents unique challenges. The goal of treatment is optimal seizure control with minimal in utero fetal exposure to AEDs in an effort to reduce the risk of structural and neurodevelopmental teratogenic effects. This paper reviews the following key issues pertaining to women with epilepsy during pregnancy: AED pharmacokinetics; clinical management of AEDs; seizure frequency; major congenital malformation; neurodevelopmental outcomes; perinatal complications; and breast feeding.

Over a million women with epilepsy are of childbearing age in the USA and require careful consideration of not only type of antiepileptic drug (AED) but also dosage, in the event of a planned or unplanned pregnancy. Careful selection of AEDs can lower the potential adverse effects of AEDs while maintaining seizure control for the health of not only on the patient, the mother, but also the unborn fetus. The number of treatment options has increased significantly in the last 20 years and remarkable progress has been made in characterizing the risks AEDs pose to pregnant women and fetuses. There are now robust data on teratogenesis, a growing body of data on neonatal/obstetrical outcomes and on neurodevelopmental problems associated with each AED, and some data about seizure control during pregnancy. Based on clinical evidence so far, levetiracetam and lamotrigine have emerged as the safest during pregnancy, although others may also be suitable. Despite being a common belief, not all polytherapy combinations may be detrimental, especially when avoiding valproate and topiramate. Here, we review the available clinical research, highlighting recent findings and provide thoughts for future directions in the field.

Objective:To assess whether first-trimester exposure to pregabalin is associated with an increased risk of major congenital malformations, as recently suggested in a pregnancy registry study.Methods:We performed a cohort study nested in the US Medicaid Analytic eXtract (MAX). The study population included 1,323,432 pregnancies resulting in a live-born infant between 2000 and 2010. We examined the risk of major congenital malformations among infants born to women exposed to pregabalin during the first trimester compared with women unexposed to anticonvulsants. We used propensity score fine stratification to control for >50 potential confounders, and we estimated relative risks (RRs) and 95% confidence intervals (CIs) in generalized linear models. The analyses were replicated in the Truven Health MarketScan Commercial Database (MarketScan). Pooled estimates based on the adjusted RR produced in MAX, MarketScan, and the previous registry study were calculated.Results:Of 477 infants exposed to pregabalin during the first trimester in MAX, 28 (5.9%) had malformations compared to 3.3% in nonexposed infants. The crude RR of major congenital malformations for pregabalin was 1.80 (95% CI 1.26–2.58). After propensity score adjustment, the RR moved to 1.16 (95% CI 0.81–1.67). Restriction to pregabalin monotherapy and sensitivity analyses produced similar results. The adjusted RR for major congenital malformations for the 174 infants exposed in MarketScan was 1.03 (95% CI 0.56–1.90). The pooled RR was 1.33 (95% CI 0.83–2.15) for pregabalin any use and 1.02 (95% CI 0.69–1.51) for pregabalin monotherapy.Conclusions:Findings did not confirm the suggested teratogenic effects of pregabalin, although they cannot rule out the possibility of a small effect.

To evaluate the effects of epilepsy and antiepileptic drugs (AEDs) used during pregnancy on fetal growth and preterm delivery.This study included singleton liveborn infants born to women enrolled in the North American Antiepileptic Drug Pregnancy Registry between 1997 and 2016. Data were collected prospectively through telephone interviews. The prevalence of preterm birth (37 weeks) and small for gestational age status (SGA) among infants exposed prenatally to AEDs when used by women with epilepsy (WWE) or women without epilepsy (WWOE) was compared with that among infants unexposed to AEDs and born to WWOE. Multivariate log-binomial regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs).The study population included infants born to 6,777 AED-WWE, 696 AED-WWOE, and 486 no-AED-WWOE. The risk of prematurity was 6.2% for no-AED-WWOE, 9.3% for AED-WWE (RR = 1.5, 95% CI = 1.0-2.1), and 10.5% for AED-WWOE (RR = 1.5, 95% CI = 1.0-2.4). Prenatal exposure to AEDs in WWE and WWOE was associated with a mean lower birth weight of 110 and 136g, respectively, as compared to no-AED-WWOE. The prevalence of SGA was 5.0% for no-AED-WWOE, 10.9% for AED-WWE (RR = 2.0, 95% CI = 1.3-3.0), and 11.0% for AED-WWOE (RR = 1.9, 95% CI = 1.2-2.9). Within users of AEDs in monotherapy, the prevalence of SGA ranged from 7.3% for lamotrigine to 18.5% for topiramate.Women on AEDs during pregnancy, whether for epilepsy or for other neuropsychiatric indications, are at a higher risk of delivering prematurely and giving birth to SGA newborns. The risk may vary by drug. Ann Neurol 2017;82:457-465.

Children of women treated with antiepileptic drugs (AEDs) are at increased risk for adverse outcomes detectable in the neonatal period, which may be associated with the amount of AED in the fetal circulation. Placental passage of AEDs can be measured by calculating the ratio of umbilical cord to maternal AED concentrations collected at delivery. The aims of this study were to determine the umbilical cord concentrations and umbilical to maternal ratios for AEDs, and to determine whether higher cord concentrations are associated with increased risk of neonatal complications. AED cord and maternal blood concentrations from 70 mother-newborn dyads and neonatal complications were recorded. Logistic regressions were performed to determine the association between AED concentrations and complications. Mean umbilical to maternal ratios for total concentrations ranged from 0.79 for carbamazepine to 1.20 for valproic acid, and mean umbilical to maternal ratios for free concentrations ranged from 0.86 for valproic acid to 1.42 for carbamazepine, indicating complete placental passage. Neither umbilical cord concentrations nor umbilical to maternal ratios were associated with adverse neonatal outcomes. Additional investigations are warranted to delineate the relationship between quantified fetal AED exposure and neonatal complications.

The aims of this study were to characterize the alterations in total and free carbamazepine (CBZ) and in total and free carbamazepine-epoxide (CBZ-EPO) clearances during pregnancy, to calculate the change in free fractions of CBZ and CBZ-EPO during pregnancy, and to determine whether seizure worsening is associated with a low ratio to nonpregnant baseline concentration of total or free CBZ or CBZ-EPO. Women on CBZ were enrolled before conception or during pregnancy in this prospective, observational study. Concomitant medications and seizure frequency were recorded. Serum total and free CBZ and CBZ-EPO were collected at each visit. Changes in the clearance of all four compounds and free fractions of CBZ and CBZ-EPO were compared with nonpregnant baseline. During pregnancy, the ratios to baseline concentrations of total and free CBZ and CBZ-EPO were compared for months with and without increased seizure frequency. Total and free CBZ and CBZ-EPO clearances were calculated in 15 pregnancies in 12 women. Clearances did not change for any of these compounds during pregnancy. The free fraction of CBZ increased from 0.23 at baseline to a maximum of 0.32 in the third trimester (p=0.008). In the six women on CBZ monotherapy with adequate seizure diaries and blood sampling, seizure worsening did not correspond to a ratio to baseline concentration of less than 0.65 for total or free CBZ or CBZ-EPO. In conclusion, total and free CBZ and CBZ-EPO clearances did not change substantially during pregnancy, and seizure frequency worsening was not associated with decreased concentrations of total or free CBZ; therefore, therapeutic drug monitoring may not be necessary for all women on CBZ during pregnancy. Further studies with larger sample sizes are needed before definitive recommendations can be made. Carbamazepine monotherapy may be a relatively safe and cost effective treatment option for women with focal epilepsy syndromes during pregnancy.

Objective The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines. Methods Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model. Results A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase in LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a 10-fold higher rate in 77% of the women (0.118 L/h per week) compared to 23% (0.0115 L/h per week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks. Interpretation The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery.

Purpose Patients with intracerebral hemorrhage (ICH) are often initiated on antiepileptic drugs without a clear indication. We compared the percentage of patients with spontaneous ICH who had seizures at onset or during hospitalization, and examined empiric use of antiepileptic drugs (AEDs) in these patients in 2 cohorts 10 years apart. Methods Using a clinical data registry at a tertiary care adult hospital, we retrospectively selected admissions for spontaneous ICH between 1/1/99–12/31/00 (Cohort A, n =30) and 1/1/09–12/31/10 (Cohort B, n =108). Clinical, neurophysiological and radiological data were collected in both cohorts. Results In Cohorts A and B respectively, AEDs were started in 53.3% and 50.0%, and continued on discharge in 50.0% and 20.4% of patients; 86.6% and 59.1% of patients discharged on AEDs did not have a clinical/electrographic seizure or epileptiform EEG findings. Seizures occurred in 6.6% and 13.0% in Cohorts A and B respectively. The presence of a seizure at presentation ( p =0.01) and during hospitalization ( p =0.02) were predictors for continuing AED on discharge. Conclusion In both cohorts, a significant number of patients were discharged on AEDs without a clear indication, though there is a change in practice between the two cohorts.

The objective of the study was to investigate the pharmacokinetics (PK) of unbound and total plasma carbamazepine (CBZ) concentrations following simultaneous administration of intravenous and oral formulations. We tested the hypothesis that age-related alterations in physiology and patient characteristics influence CBZ disposition and protein binding. Patients (n = 113) on maintenance therapy received a 100 mg dose of a novel, intravenous, stable-labeled (SL) CBZ formulation as partial replacement of their morning CBZ dose. A two-compartment model described unbound and total SL-CBZ data. The stable-labeled intravenous dosing methodology enabled the estimation of the CBZ clearance (CL) and volumes of distribution. The CL of CBZ was dependent on race through the model equation unbound CL (L/hour) = 11.2 × (1.30)(Race); where Race = 1 for Caucasian, 0 for African American. Total body weight explained 57% and 70% of the interindividual variability in the central and peripheral volumes of distribution, respectively. Age, sex, smoking, plasma albumin, and alpha 1-acid glycoprotein concentrations had no effect on CL, binding or volumes of distribution. The model was evaluated via bootstrap and predictive check. Results may support race specific dosing for CBZ where an average African-American individual would receive 70% of the standard dose prescribed for the Caucasian person.

SummaryObjective This study examines medication adherence among women with epilepsy via use of an electronic diary, as part of a prospective multicenter observational study designed to evaluate fertility in women with epilepsy (WWE) versus age-matched controls. Methods WWE and healthy age-matched controls, seeking pregnancy, were given an iPod Touch using a customized mobile application (the WEPOD App) for daily data tracking. Eighty-six WWE tracked seizures and antiepileptic drugs (AEDs). Tracking of nonepilepsy medications was optional. Diary data were counted from enrollment date until date of delivery, or up to 12 months if pregnancy was not achieved. Each day that subjects reported missing one or more AED was counted as nonadherence. Because adherence can only be determined in women who track consistently, we elected to include adherence data only for women who tracked >80% of days in the study. Results Approximately 75% of WWE tracked >80% of days and were included in medication adherence data analysis. In this group, medication adherence rate was 97.71%; 44% of women admitted to missing an AED on at least 1 day. Among the subgroup of WWE who recorded nonepilepsy medications, AED adherence rate was 98.56%, versus 93.91% for non-AEDs. Significance The 75% compliance rate with an electronic diary suggests that it may be useful to track medication adherence in future studies and in the clinical setting. In those who tracked, the observed medication adherence rate was considerably higher than the 75% adherence rate seen in previous epilepsy studies. This might be explained in part by selection bias, but may also result from properties of the diary itself (daily reminders, real time feedback given to the provider). Women reported a higher rate of adherence to AEDs than to other prescribed medications and supplements, suggesting that perceived importance of medications likely influences medication adherence, and warrants future study.

Objective To determine if anti-mullerian hormone (AMH), a neuroactive peptide hormone and a measure of ovarian reserve, is different between women with epilepsy (WWE) and healthy controls (HC) seeking pregnancy and to evaluate epilepsy-related factors associated with AMH concentrations. Methods Subjects were participants in Women with Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD), a multi-center prospective, observational cohort study evaluating fecundity in WWE compared to HC, ages 18–40 years. WWE were divided into a Sz+ group or a Sz− group, dependent on whether they had seizures within the 9 months prior to enrollment. Serum was collected, and AMH concentrations were measured as an exploratory analysis. Linear and logistic regression models were used to assess associations and control for covariates. Results Serum AMH concentrations were measured in 72 out of 90 enrolled WWE and 97 out of 109 HC; the remaining subjects became pregnant before serum was obtained. Thirty WWE were in the Sz+ group and 40 in the Sz− group (retrospective seizure information was missing for two). All AMH concentrations were within the range, however, the normal inverse correlation between age and AMH was present in the HC and in the Sz− groups, but was lacking in the Sz+ group. Mean AMH concentration was higher in the Sz− group (3982 pg/ml (SD +/−2452)) compared to the Sz+ group of WWE (2776 pg/ml (SD +/−2308)) and HCs (3241 (SD ± 2647)). All values were within the expected range for age. In WWE, by linear regression, after controlling for age and BMI, seizure occurrence remained associated with AMH (p = 0.025). In the prospective phase of the study, AMH concentrations were also associated with seizure occurrence during the menstrual cycle in which the serum sample was obtained (p = 0.012). Antiepileptic drugs and other epilepsy factors were not associated with AMH concentrations. When analyzing the Sz− WWE group and the HC group by linear regression with AMH as the dependent variable, after controlling for age and BMI, the association with AMH was also present (p = 0.017). AMH concentrations of the Sz+ group and HCs did not differ. Significance In this exploratory analysis, seizure freedom was associated with higher AMH concentrations compared to women with ongoing seizures and to HCs. Future studies should further investigate the mechanism of the association of AMH with seizure occurrence, whether AMH could have a direct seizure-protective neuroactive hormone effect, as well as implications of AMH concentrations as a biomarker for ovarian reserve in women with epilepsy.

Offspring of women with epilepsy (WWE) on AEDs are at increased risks for major congenital malformations and reduced cognition. They may be at risk for other adverse neonatal outcomes. Women with epilepsy on carbamazepine (CBZ), lamotrigine (LTG), phenytoin (PHT), or valproate (VPA) monotherapy were enrolled in a prospective, observational, multicenter study of the neurodevelopmental effects of AEDs. The odds ratio for small for gestational age (SGA) was higher for VPA vs. PHT, VPA vs. LTG, and CBZ vs. PHT. Microcephaly rates were elevated to 12% for all newborns and at 12 months old, but normalized by age 24 months. Reduced Apgar scores occurred more frequently in the VPA and PHT groups at 1 min, but scores were near normal in all groups at 5 min. This study demonstrates increased risks for being born SGA in the VPA and CBZ groups, and transiently reduced Apgar scores in the VPA and PHT groups. Differential risks among the AEDs can help inform decisions about AED selection for women during childbearing years.

Reproductive factors are associated with seizures in women with epilepsy. We prospectively examined the association between reproductive factors and the risk of adult-onset isolated seizure, epilepsy, or any unprovoked seizure (defined as single unprovoked seizure or epilepsy) among 114,847 Nurses' Health Study II participants followed from 1989 to 2005. Validated seizure questionnaires and medical records were used to confirm incident cases of isolated seizure (n = 95) or epilepsy (n = 151). Overall, there were no significant associations between any reproductive factor and risk of any unprovoked seizure (n = 196). However, menstrual irregularity at ages 18-22 years was specifically associated with an increased risk of epilepsy [relative risk (RR) 1.67, 95% confidence interval (CI) 1.12-2.51]. Menstrual irregularity during follow-up (RR 2.21, 95% CI 1.16-4.20) and early age at menarche (

The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom that enrolled pregnant women with epilepsy on antiepileptic drug (AED) monotherapy from 1999 to 2004. The study seeks to determine if differential long-term neurodevelopmental effects exist across four commonly used AEDs (carbamazepine, lamotrigine, phenytoin, valproate). In this article, we examine fetal AED exposure effects on motor, adaptive, and emotional/behavioral functioning in 229 children who completed at least one of these tests at 3 years of age. Adjusted mean scores for the four AED groups were in the low average to average range for motor functioning, parental ratings of adaptive functioning, and parental ratings of emotional/behavioral functioning. A significant dose-related performance decline in motor functioning was seen for both valproate and carbamazepine. A significant dose-related performance decline in parental ratings of adaptive functioning was also seen for valproate, with a marginal performance decline evident for carbamazepine. Further, parents endorsed a significant decline in social skills for valproate that was dose related. Finally, on the basis of parent ratings of attention span and hyperactivity, children of mothers who took valproate during their pregnancy appear to be at a significantly greater risk for a future diagnosis of attention-deficit/hyperactivity disorder. Additional research is needed to confirm these findings, examine risks of other AEDs, define the risks in the neonate associated with AEDs for treatment of seizures, and determine the underlying mechanisms of adverse AED effects on the immature brain.

Summary Purpose: To determine if seizure frequency differs between anovulatory and ovulatory cycles. Methods: The data came from the 3-month baseline phase of an investigation of progesterone therapy for intractable focal onset seizures. Of 462 women who enrolled, 281 completed the 3-month baseline phase and 92 had both anovulatory and ovulatory cycles during the baseline phase. Midluteal progesterone levels ≥5 ng/ml were used to designate cycles as ovulatory. Among the 92 women, average daily seizure frequency (ADSF) for all seizures combined and each type of seizure considered separately (secondary generalized tonic–clonic seizures – 2°GTCS, complex partial seizures – CPS, simple partial seizures – SPS) were compared between anovulatory and ovulatory cycles using paired t-tests. A relationship between the proportional differences in ADSF and estradiol/progesterone (EP) serum level ratios between anovulatory and ovulatory cycles was determined using bivariate correlational analysis. Key Findings: ADSF was 29.5% greater for 2°GTCS during anovulatory than during ovulatory cycles. ADSF did not differ significantly for CPS or SPS or for all seizures combined. Proportional differences in anovulatory/ovulatory 2°GTCS ADSF ratios correlated significantly with differences in anovulatory/ovulatory EP ratios. Among the 281 women, the three seizure types did not differ in ovulatory rates, but EP ratios were greater for cycles with 2°GTCS than partial seizures only. Significance: Seizure frequency is significantly greater for 2°GTCS, but not CPS or SPS, during anovulatory cycles than ovulatory cycles. Because the proportional increases in 2°GTCS frequency during anovulatory cycles correlate with the proportional increases in EP level ratios, these findings support a possible role for reproductive steroids in 2°GTCS occurrence.

Clinical trial designs need to control for genetic and environmental influences when examining cognitive outcomes in children for whom clinical considerations preclude randomization. However, the contributions of maternal and paternal IQ and education to pediatric cognitive outcomes are uncertain in disease populations. The Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study is an ongoing prospective observational multicenter study in the United States and United Kingdom, which enrolled pregnant women with epilepsy to determine if differential long-term neurodevelopmental effects exist across four commonly used antiepileptic drugs. Here, we examined the relationship of IQ and education in both parents to child IQ at age 3 years. IQ and education for both parents were statistically correlated to child IQ. However, paternal IQ and education were not significant after accounting for maternal IQ effects. Because maternal IQ and education are independently related to child cognitive outcome, both should be assessed in studies investigating the effects of fetal drug exposures or other environmental factors that could affect the child's cognitive outcome.

Importance Prior studies report lower birth rates for women with epilepsy (WWE) but have been unable to differentiate between biological and social contributions. To our knowledge, we do not have data to inform WWE seeking pregnancy if their likelihood of achieving pregnancy is biologically reduced compared with their peers. Objective To determine if WWE without a prior diagnosis of infertility or related disorders are as likely to achieve pregnancy within 12 months as their peers without epilepsy. Design, Setting, and Participants The Women With Epilepsy: Pregnancy Outcomes and Deliveries study is an observational cohort study comparing fertility in WWE with fertility in control women (CW) without epilepsy. Participants were enrolled at 4 academic medical centers and observed up to 21 months from November 2010 to May 2015. Women seeking pregnancy aged 18 to 40 years were enrolled within 6 months of discontinuing contraception. Exclusion criteria included tobacco use and a prior diagnosis of infertility or disorders that lower fertility. Eighteen WWE and 47 CW declined the study, and 40 WWE and 170 CW did not meet study criteria. The Women With Epilepsy: Pregnancy Outcomes and Deliveries electronic diary app was used to capture data on medications, seizures, sexual activity, and menses. Data were analyzed from November 2015 to June 2017. Main Outcomes and Measures The primary outcome was proportion of women who achieved pregnancy within 12 months after enrollment. Secondary outcomes were time to pregnancy using a proportional hazard model, pregnancy outcomes, sexual activity, ovulatory rates, and analysis of epilepsy factors in WWE. All outcomes were planned prior to data collection except for time to pregnancy. Results Of the 197 women included in the study, 142 (72.1%) were white, and the mean (SD) age was 31.9 (3.5) years among the 89 WWE and 31.1 (4.2) among the 108 CW. Among 89 WWE, 54 (60.7%) achieved pregnancy vs 65 (60.2%) among 108 CW. Median time to pregnancy was no different between the groups after controlling for key covariates (WWE: median, 6.0 months; 95% CI, 3.8-10.1; CW: median, 9.0 months; 95% CI, 6.5-11.2; P = .30). Sexual activity and ovulatory rates were similar in WWE and CW. Forty-four of 54 pregnancies (81.5%) in WWE and 53 of 65 pregnancies (81.5%) in CW resulted in live births. No epilepsy factors were significant. Conclusions and Relevance Women with epilepsy seeking pregnancy without prior known infertility or related disorders have similar likelihood of achieving pregnancy, time to pregnancy, and live birth rates compared with their peers without epilepsy.

IMPORTANCE: Valproate sodium is used for the treatment of epilepsy and other neuropsychiatric disorders in women of childbearing potential. However, there are concerns about impaired cognitive development in children who have been exposed to valproate during pregnancy. OBJECTIVE: To estimate the association between long-term school performance and prenatal exposure to valproate and a number of other antiepileptic drugs (AEDs). DESIGN, SETTING, AND PARTICIPANTS: In a prospective, population-based cohort study conducted from August 1, 2015, to May 31, 2017, data used in the study were provided by Statistics Denmark on April 15, 2016. All children born alive in Denmark between 1997 and 2006 (n = 656 496) were identified. From this cohort, children who did not participate in the national tests, with presumed coding errors in gestational age and children missing information on their mother's educational level or household income were excluded (n = 177 469) leaving 479 027 children for the analyses. Children were identified and linked across national registers that had information on exposure, covariates, and outcome. The primary outcome was performance in national tests, an academic test taken by students in Danish primary and lower secondary state schools. We assessed performance in Danish and mathematics at different grades among valproate-exposed children and compared their performance with that of unexposed children and children exposed to another AED (lamotrigine). Test scores were standardized to z scores and adjusted for risk factors. MAIN OUTCOME AND MEASURES: Difference in standardized z scores in Danish and mathematics tests among valproate-exposed children compared with unexposed and lamotrigine-exposed children. RESULTS: Of the 656 496 children identified, 479 027 children who participated in the national tests were evaluated, including children exposed to the following AEDs in monotherapy: valproate, 253; phenobarbital, 86; oxcarbazepine, 236; lamotrigine, 396; clonazepam, 188; and carbamazepine, 294. The mean (SD) age of the 244 095 children completing the sixth-grade Danish test was 12.9 (0.39) years; 122 774 (50.3%; 95% CI, 50.1% to 50.5%) were boys and 121 321 (49.7%; 95% CI, 49.5% to 49.9%) were girls. Valproate-exposed children scored worse on the sixth-grade Danish tests (adjusted difference, −0.27 SD; 95% CI, −0.42 to −0.12) and sixth-grade mathematics tests (adjusted difference, −0.33 SD; (95% CI, −0.47 to −0.19) compared with unexposed children and children exposed to lamotrigine (adjusted difference, −0.33 SD; 95% CI, −0.60 to −0.06). Also, children exposed to clonazepam scored worse in the sixth-grade Danish tests (adjusted difference, −0.07 SD; 95% CI, −0.12 to −0.02). Carbamazepine, lamotrigine, phenobarbital, and oxcarbazepine were not linked to poor school performance compared with unexposed children. CONCLUSIONS AND RELEVANCE: Maternal use of valproate was associated with a significant decrease in school performance in offspring compared with children unexposed to AEDs and children exposed to lamotrigine. Findings of this study further caution against the use of valproate among women of childbearing potential.

Patients with epilepsy are at high risk for major depressive disorder (MDD) and, according to one report, postpartum depression (PPD) as well. The study described here sought to determine the prevalence and risk factors for PPD among women with epilepsy. Fifty-six women with epilepsy participating in a prospective study of perinatal antiepileptic drug (AED) pharmacokinetics were included. Participants completed the Beck Depression Inventory (BDI) during pregnancy and the postpartum period. Fourteen participants (25.0%) had a postnatal BDI score > or =12 indicative of PPD. Logistic regression indicated that significant risk factors for PPD among women with epilepsy included multiparity (odds ratio=12.5) and AED polytherapy (odds ratio=9.3). The rate of PPD was unaffected by the use of specific AEDs. In conclusion, PPD rates are higher among women with epilepsy than the general population, particularly those who are multiparous or receiving AED polytherapy, and there is no evidence that AED selection modifies this risk.

The relationships among hormones, epilepsy, and the medications used to treat epilepsy are complex, with tridirectional interactions that affect both men and women in various ways. Abnormalities of baseline endocrine status occur more commonly in people with epilepsy. Abnormalities are most often described for the sex steroid hormone axis, commonly presenting as sexual dysfunction in men and women with epilepsy and lower fertility. Other signs and symptoms in women with epilepsy include menstrual irregularities, premature menopause, and polycystic ovarian syndrome. The evaluation and care of adult patients with epilepsy should include considerations of the common hormonal aberrations that occur in this patient population. Questions about reproductive health disorders, sexual function, symptoms of thyroid disorders, and bone health should be part of the evaluation of all adult patients with epilepsy. Further laboratory or radiologic testing and referral to other specialists to participate in collaborative care may be warranted if underlying disorders are suspected, especially given that many of these hormone abnormalities can result in long-term health risks as well as negatively affect quality of life. AEDs and hormones have a bidirectional interaction that can impair the efficacy of contraceptive hormone treatments and of the AEDs. Endogenous hormones can influence seizure severity and frequency, resulting in catamenial patterns of epilepsy. However, this susceptibility to hormonal influences can be used to develop hormonal strategies to improve seizure control in women with epilepsy with use of cyclic PROG supplementation or alteration of the endogenous hormone release. Additionally, development of the neurosteroid analog ganaxolone provides a novel approach that can potentially be used across both genders and all age groups.

A committee assembled by the American Academy of Neurology (AAN) reassessed the evidence related to the care of women with epilepsy (WWE) during pregnancy, including antiepileptic drug (AED) teratogenicity and adverse perinatal outcomes. It is highly probable that intrauterine first-trimester valproate (VPA) exposure has higher risk of major congenital malformations (MCMs) compared to carbamazepine (CBZ), and possibly compared to phenytoin (PHT) or lamotrigine (LTG). It is probable that VPA as part of polytherapy and possible that VPA as monotherapy contribute to the development of MCMs. AED polytherapy probably contributes to the development of MCMs and reduced cognitive outcomes compared to monotherapy. Intrauterine exposure to VPA monotherapy probably reduces cognitive outcomes and monotherapy exposure to PHT or phenobarbital (PB) possibly reduces cognitive outcomes. Neonates of WWE taking AEDs probably have an increased risk of being small for gestational age and possibly have an increased risk of a 1-minute Apgar score of