Summary Background Many women of childbearing potential take antiepileptic drugs, but the cognitive effects of fetal exposure are uncertain. We aimed to assess effects of commonly used antiepileptic ...drugs on cognitive outcomes in children up to 6 years of age. Methods In this prospective, observational, assessor-masked, multicentre study, we enrolled pregnant women with epilepsy on antiepileptic drug monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) between October, 1999, and February, 2004, at 25 epilepsy centres in the UK and the USA. Our primary outcome was intelligence quotient (IQ) at 6 years of age (age-6 IQ) in all children, assessed with linear regression adjusted for maternal IQ, antiepileptic drug type, standardised dose, gestational birth age, and use of periconceptional folate. We also assessed multiple cognitive domains and compared findings with outcomes at younger ages. This study is registered with ClinicalTrials.gov , number NCT00021866. Findings We included 305 mothers and 311 children (six twin pairs) in the primary analysis. 224 children completed 6 years of follow-up (6-year-completer sample). Multivariate analysis of all children showed that age-6 IQ was lower after exposure to valproate (mean 97, 95% CI 94–101) than to carbamazepine (105, 102–108; p=0·0015), lamotrigine (108, 105–110; p=0·0003), or phenytoin (108, 104–112; p=0·0006). Children exposed to valproate did poorly on measures of verbal and memory abilities compared with those exposed to the other antiepileptic drugs and on non-verbal and executive functions compared with lamotrigine (but not carbamazepine or phenytoin). High doses of valproate were negatively associated with IQ ( r =–0·56, p<0·0001), verbal ability ( r =–0·40, p=0·0045), non-verbal ability ( r =–0·42, p=0·0028), memory ( r =–0·30, p=0·0434), and executive function ( r =–0·42, p=0·0004), but other antiepileptic drugs were not. Age-6 IQ correlated with IQs at younger ages, and IQ improved with age for infants exposed to any antiepileptic drug. Compared with a normative sample (173 93% of 187 children), right-handedness was less frequent in children in our study overall (185 86% of 215; p=0·0404) and in the lamotrigine (59 83% of 71; p=0·0287) and valproate (38 79% of 40; p=0·0089) groups. Verbal abilities were worse than non-verbal abilities in children in our study overall and in the lamotrigine and valproate groups. Mean IQs were higher in children exposed to periconceptional folate (108, 95% CI 106–111) than they were in unexposed children (101, 98–104; p=0·0009). Interpretation Fetal valproate exposure has dose-dependent associations with reduced cognitive abilities across a range of domains at 6 years of age. Reduced right-handedness and verbal ( vs non-verbal) abilities might be attributable to changes in cerebral lateralisation induced by exposure to antiepileptic drugs. The positive association of periconceptional folate with IQ is consistent with other recent studies. Funding US National Institutes of Health, UK Epilepsy Research Foundation.
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.
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.
Advances have also been made in the availability of diagnostic tools to identify the cause of new onset seizures, particularly for patients with autoimmune encephalitis, which is often accompanied by ...the presence of leucine-rich glioma-inactivated 1 (LGI1), NMDA receptor, or GABAB receptor antibodies in the serum or CSF.3 In an observational cohort study of 153 patients who met the criteria for autoimmune encephalitis, 110 (72%) had recurrent seizures.3 Although 98 (89%) of these 110 patients eventually became seizure free, 52 (53%) did so shortly after immunotherapy, and only 14 (14%) became seizure free while taking anti-seizure medications alone. ...time to seizure freedom was shorter after the start of immunotherapy than after the start of anti-seizure medications (median 28 vs 59 days, p<0·0001). A single-centre study of 30 patients who had selective laser amygdalohippocampectomy using magnetic resonance-guided laser interstitial thermal therapy helped to further define which patients are good candidates for this procedure.5 This study compared patients who were treated on the basis of neuroimaging evidence of mesial temporal sclerosis (n=18) with patients who required invasive stereo-EEG to confirm mesial temporal lobe onsets (n=12). In summary, the results of these studies increase the understanding of underlying causes of seizures, and highlight the benefits of using new diagnostic and localising tools and tissue ablative approaches in the right patients, and the major gains that can be made by adjusting treatment patterns on the basis of evidence for improved outcomes.
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.
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•Metabolic changes were associated with lamotrigine and levetiracetam monotherapy.•Metabolic variations included maternal health and fetal development pathways.•Associations with one‑carbon, neurotransmitter and steroid metabolism were observed.•Folate metabolites were decreased in lamotrigine treatment.•The metabolome provides an integrated measure of anti-epileptic drug pharmacology.
To compare the proportions of unintended pregnancies, prenatal vitamin or folic acid (PNVF) use, adequate prenatal care visits, and breastfeeding among women with epilepsy (WWE) to women without ...epilepsy (WWoE).
The Pregnancy Risk Assessment Monitoring System (PRAMS) is an annual survey of randomly sampled postpartum women administered by the Centers for Disease Control and Prevention. We used PRAMS data from 13 states from 2009 to 2014 to compare the primary outcomes in WWE and WWoE, as well as our secondary outcomes of contraception practices, newborn outcomes, and time to recognition of pregnancy. We adjusted for maternal age, race, ethnicity, and socioeconomic status (SES), and we calculated odds ratios for these outcomes using logistic regression.
This analysis included 73,619 women, of whom 541 (0.7%) reported epilepsy, representing 3,442,128 WWoE and 26,635 WWE through weighted sampling. In WWE, 55% of pregnancies were unintended compared to 48% in WWoE. After adjustment for covariates, epilepsy was not associated with unintended pregnancy or with inadequate prenatal care. WWE were less likely to report breastfeeding but more likely to report daily PNVF use. Newborns of WWE had higher rates of prematurity.
Although planning for pregnancy is of utmost importance for WWE, more than half the pregnancies in WWE were unintended. Maternal age and SES differences likely contribute to the higher rates in WWE compared to WWoE. The proportion of women reporting breastfeeding is lower in WWE despite studies indicating the safety of breastfeeding in WWE.
Biological sex and sociocultural gender represent major sources of diversity among patients, and recent research has shown the association of sex and gender with health. A growing body of literature ...describes widespread associations of sex and gender with cells, organs, and the manner in which individual patients interact with health care systems. Sex- and gender-informed medicine is a young paradigm of clinical practice and medical research founded on this literature that considers the association of sex and gender with each element of the disease process from risk, to presentation, to response to therapy.
Characteristics that underlie sex and gender involve both endogenous and exogenous factors that change throughout the life course. This review details clinical examples with broad applicability that highlight sex and gender differences in the key domains of genetics, epigenomic modifiers, hormonal milieu, immune function, neurocognitive aging process, vascular health, response to therapeutics, and interaction with health care systems. These domains interact with one another in multidimensional associations, contributing to the diversity of the sex and gender spectra. Novel research has identified differences of clinical relevance with the potential to improve care for all patients.
Clinicians should consider incorporating sex and gender in their decision-making to practice precision medicine that integrates fundamental components of patient individuality. Recognizing the biological and environmental factors that affect the disease course is imperative to optimizing care for each patient. Research highlights the myriad ways sex and gender play a role in health and disease. However, these clinically relevant insights have yet to be systematically incorporated into care. The framework described in this review serves as a guide to help clinicians consider sex and gender as they practice precision medicine.
Objective
To evaluate the effects of epilepsy and antiepileptic drugs (AEDs) used during pregnancy on fetal growth and preterm delivery.
Methods
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).
Results
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.
Interpretation
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
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