Angiotensin Receptor Blockers for Hypertension and Risk of Epilepsy.

Importance: Animal and human studies have suggested that the use of angiotensin receptor blockers (ARBs) may be associated with a lower risk of incident epilepsy compared with other antihypertensive medications. However, observational data from the US are lacking. Objective: To evaluate the association between ARB use and epilepsy incidence in subgroups of US patients with hypertension. Design, Setting, and Participants: This retrospective cohort study used data from a national health administrative database from January 2010 to December 2017 with propensity score (PS) matching. The eligible cohort included privately insured individuals aged 18 years or older with diagnosis of primary hypertension and dispensed at least 1 ARB, angiotensin-converting enzyme inhibitor (ACEI), ß-blocker, or calcium channel blocker (CCB) from 2010 to 2017. Patients with a diagnosis of epilepsy at or before the index date or dispensed an antiseizure medication 12 months before or 90 days after initiating the study medications were excluded. The data analysis for this project was conducted from April 2022 to April 2024. Exposures: Propensity scores were generated based on baseline covariates and used to match patients who received ARBs with those who received either ACEIs, ß-blockers, CCBs, or a combination of these antihypertensive medications. Main Outcomes and Measures: Cox regression analyses were used to evaluate epilepsy incidence during follow-up comparing the ARB cohort with other antihypertensive classes. Subgroup and sensitivity analyses were conducted to examine the association between ARB use and epilepsy incidence in various subgroups. Results: Of 2 261 964 patients (mean [SD] age, 61.7 [13.9] years; 1 120 630 [49.5%] female) included, 309 978 received ARBs, 807 510 received ACEIs, 695 887 received ß-blockers, and 448 589 received CCBs. Demographic and clinical characteristics differed across the 4 comparison groups prior to PS matching. Compared with ARB users, patients receiving ACEIs were predominantly male and had diabetes, CCB users were generally older (eg, >65 years), and ß-blocker users had more comorbidities and concurrent medications. The 1:1 PS-matched subgroups included 619 858 patients for ARB vs ACEI, 619 828 patients for ARB vs ß-blocker, and 601 002 patients for ARB vs CCB. Baseline characteristics were equally distributed between comparison groups after matching with propensity scores. Use of ARBs was associated with a decreased incidence of epilepsy compared with ACEIs (adjusted hazard ratio [aHR], 0.75; 95% CI, 0.58-0.96), ß-blockers (aHR, 0.70; 95% CI, 0.54-0.90), and a combination of other antihypertensive classes (aHR, 0.72; 95% CI, 0.56-0.95). Subgroup analyses revealed a significant association between ARB use (primarily losartan) and epilepsy incidence in patients with no preexisting history of stroke or cardiovascular disease. Conclusions and Relevance: This cohort study found that ARBs, mainly losartan, were associated with a lower incidence of epilepsy compared with other antihypertensive agents in hypertensive patients with no preexisting stroke or cardiovascular disease. Further studies, such as randomized clinical trials, are warranted to confirm the comparative antiepileptogenic properties of antihypertensive medications.

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

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

Time-course of drug-related psychiatric and behavioral treatment-emergent adverse events during brivaracetam treatment in adults with focal-onset seizures.

OBJECTIVE: We previously analyzed data from three phase lll trials of adjunctive brivaracetam (BRV) in adults showing that the incidence and prevalence of drug-related central nervous system treatment-emergent adverse events (TEAEs) quickly peaked and decreased over several weeks following BRV treatment initiation. However, that analysis did not assess psychiatric and behavioral side effects which can occur with antiseizure medication (ASM) treatment. Here, we investigate the time-course of psychiatric and behavioral TEAEs by week of BRV treatment and how these TEAEs were managed. METHODS: Data were pooled from three trials (N01252 [NCT00490035]; N01253 [NCT00464269]; N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal-onset seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the incidence and prevalence of drug-related psychiatric or behavioral TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) or placebo (PBO) during the 12-week treatment period. A logistic regression model was used to determine if psychiatric or behavioral comorbid conditions were predictors for drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. RESULTS: A total of 803 patients received BRV 50-200 mg/day, and 459 patients received PBO. Drug-related psychiatric or behavioral TEAEs were reported by 11.0 % of patients during adjunctive BRV treatment (PBO: 4.8 %) with onset early after BRV initiation (median time to onset of first drug-related psychiatric or behavioral TEAE: 15 days). Incidence peaked at week 1 and decreased over the first 4 weeks following BRV initiation. Prevalence peaked at week 4 and then remained stable between weeks 5-12. In an analysis excluding patients on concomitant levetiracetam (BRV: n = 744; PBO: n = 422), the incidence of drug-related psychiatric or behavioral TEAEs was similar to the incidence in the overall population. The most common drug-related psychiatric or behavioral TEAEs were irritability, insomnia, depression, and anxiety. Only 2 % of patients discontinued BRV due to psychiatric or behavioral TEAEs (PBO: 1.3 %), while most patients on BRV who reported drug-related psychiatric or behavioral TEAEs did not require a change in dose (84.1 %; PBO: 63.6 %). A history of psychiatric or behavioral comorbid conditions (not ongoing at BRV initiation) was not associated with an increased likelihood of drug-related psychiatric or behavioral TEAEs, or BRV discontinuation due to psychiatric or behavioral TEAEs. Ongoing psychiatric or behavioral comorbid conditions at BRV initiation increased the likelihood of drug-related psychiatric or behavioral TEAEs, but not the likelihood of BRV discontinuation due to psychiatric or behavioral TEAEs. CONCLUSIONS: Drug-related psychiatric and behavioral TEAEs occurred early during BRV treatment, and most patients did not require a change in BRV dose. These data can help guide clinician monitoring and patient expectations after starting BRV.

Novelty preference assessed by eye tracking: A sensitive measure of impaired recognition memory in epilepsy.

OBJECTIVE: Epilepsy patients often report memory deficits despite normal objective testing, suggesting that available measures are insensitive or that non-mnemonic factors are involved. The Visual Paired Comparison Task (VPCT) assesses novelty preference, the tendency to fixate on novel images rather than previously viewed items, requiring recognition memory for the "old" images. As novelty preference is a sensitive measure of hippocampal-dependent memory function, we predicted impaired VPCT performance in epilepsy patients compared to healthy controls. METHODS: We assessed 26 healthy adult controls and 31 epilepsy patients (16 focal-onset, 13 generalized-onset, 2 unknown-onset) with the VPCT using delays of 2 or 30 s between encoding and recognition. Fifteen healthy controls and 17 epilepsy patients (10 focal-onset, 5 generalized-onset, 2 unknown-onset) completed the task at 2-, 5-, and 30-minute delays. Subjects also performed standard memory measures, including the Medical College of Georgia (MCG) Paragraph Test, California Verbal Learning Test-Second Edition (CVLT-II), and Brief Visual Memory Test-Revised (BVMT-R). RESULTS: The epilepsy group was high functioning, with greater estimated IQ (p = 0.041), greater years of education (p = 0.034), and higher BVMT-R scores (p = 0.024) compared to controls. Both the control group and epilepsy cohort, as well as focal- and generalized-onset subgroups, had intact novelty preference at the 2- and 30-second delays (p-values ≤ 0.001) and declined at 30 min (p-values > 0.05). Only the epilepsy patients had early declines at 2- and 5-minute delays (controls with intact novelty preference at p = 0.003 and p ≤ 0.001, respectively; epilepsy groups' p-values > 0.05). CONCLUSIONS: Memory for the "old" items decayed more rapidly in overall, focal-onset, and generalized-onset epilepsy groups. The VPCT detected deficits while standard memory measures were largely intact, suggesting that the VPCT may be a more sensitive measure of temporal lobe memory function than standard neuropsychological batteries.

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Prenatal Exposure to Opioids and Neurodevelopmental Disorders in Children: A Bayesian Mediation Analysis.

This study explores natural direct and joint natural indirect effects (JNIE) of prenatal opioid exposure on neurodevelopmental disorders (NDDs) in children mediated through pregnancy complications, major and minor congenital malformations, and adverse neonatal outcomes, using Medicaid claims linked to vital statistics in Rhode Island, United States, 2008-2018. A Bayesian mediation analysis with elastic net shrinkage prior was developed to estimate mean time to NDD diagnosis ratio using posterior mean and 95% credible intervals (CrIs) from Markov chain Monte Carlo algorithms. Simulation studies showed desirable model performance. Of 11,176 eligible pregnancies, 332 had ≥2 dispensations of prescription opioids anytime during pregnancy, including 200 (1.8%) having ≥1 dispensation in the first trimester (T1), 169 (1.5%) in the second (T2), and 153 (1.4%) in the third (T3). A significant JNIE of opioid exposure was observed in each trimester (T1, JNIE = 0.97, 95% CrI: 0.95, 0.99; T2, JNIE = 0.97, 95% CrI: 0.95, 0.99; T3, JNIE = 0.96, 95% CrI: 0.94, 0.99). The proportion of JNIE in each trimester was 17.9% (T1), 22.4% (T2), and 56.3% (T3). In conclusion, adverse pregnancy and birth outcomes jointly mediated the association between prenatal opioid exposure and accelerated time to NDD diagnosis. The proportion of JNIE increased as the timing of opioid exposure approached delivery.

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

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

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

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

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

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

Utilization of Antiseizure Medications in Women of Childbearing Age With Epilepsy and Nonepilepsy Indications: A Retrospective Cohort Study.

BACKGROUND AND OBJECTIVES: Antiseizure medications (ASMs) are among the most commonly prescribed teratogenic drugs in women of childbearing age. Limited data exist on utilization patterns across different indications for therapy and for the newer-generation ASMs in this population. Thus, we assessed the pattern of ASM use in women of childbearing age with epilepsy and nonepilepsy indications (pain and psychiatric disorders). METHODS: We conducted a retrospective analysis of deidentified administrative data submitted to the Optum Clinformatics database. Eligible participants included women aged 12-50 years who filled ASMs between year 2011 and 2017. Participants were followed from date of index prescription filled to study end or insurance disenrollment, whichever came first. For the overall cohort and potential therapy indications, we assessed the type and frequency of ASMs filled; proportion of participants on monotherapy, polytherapy, or treatment switching; and duration of continuous use. Trends were characterized using annual percent change from study start to study end. RESULTS: Our analysis included 465,131 participants who filled 603,916 distinct ASM prescriptions. At baseline, most of the participants had chronic pain (51.0%) and psychiatric disorders (32.7%), with epilepsy the least common (0.9%). The most frequently dispensed were diazepam (24.3%), lorazepam (20.1%), gabapentin (17.4%), clonazepam (12.7%), topiramate (11.3%), and lamotrigine (4.6%). Significant linear increase in trends were observed with gabapentin (annual percent change [95% CI]: 8.4 [7.3-9.4]; p < 0.001) and levetiracetam (3.4 [0.7-6.2]; p = 0.022) and decreasing trends for diazepam (-3.5 [-2.4 to 4.5]; p < 0.001) and clonazepam (-3.4 [-2.3 to 4.5]; p = 0.001). No significant change in trend was observed with valproate (-0.4 [-2.7 to 1.9]; p = 0.651), while nonlinear changes in trends were observed with lorazepam, topiramate, lamotrigine, and pregabalin. DISCUSSION: Decreasing trends were observed with older ASMs in the overall cohort and across the potential indications for therapy. Conversely, increasing trends were seen with the newer ASMs. Considering the risk of teratogenicity associated with the newer medications largely unknown, counseling and education in addition to a careful consideration of the benefits vs potential risks should remain pivotal when prescribing ASMs for women of childbearing age.

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project.

OBJECTIVE: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. METHODS: Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. RESULTS: Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. SIGNIFICANCE: This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

Multisite thalamic recordings to characterize seizure propagation in the human brain.

Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

Comparative Safety Analysis of Opioid Agonist Treatment in Pregnant Women with Opioid Use Disorder: A Population-Based Study.

INTRODUCTION AND OBJECTIVE: Receipt of opioid agonist treatment during early and late pregnancy for opioid use disorder may relate to varying perinatal risks. We aimed to assess the effect of time-varying prenatal exposure to opioid agonist treatment using buprenorphine or methadone on adverse neonatal and pregnancy outcomes. METHODS: We conducted a retrospective cohort study of pregnant women with opioid use disorder using Rhode Island Medicaid claims data and vital statistics during 2008-16. Time-varying exposure was evaluated in early (0-20 weeks) and late (≥ 21 weeks) pregnancy. Marginal structural models with inverse probability of treatment weighting were applied. RESULTS: Of 400 eligible pregnancies, 85 and 137 individuals received buprenorphine and methadone, respectively, during early pregnancy. Compared with 152 untreated pregnancies with opioid use disorders, methadone exposure in both periods was associated with an increased risk of preterm birth (adjusted odds ratio [aOR]: 2.52; 95% confidence interval [CI] 1.07-5.95), low birth weight (aOR: 2.99; 95% CI 1.34-6.66), neonatal intensive care unit admission (aOR, 5.04; 95% CI 2.49-10.21), neonatal abstinence syndrome (aOR: 11.36; 95% CI 5.65-22.82), respiratory symptoms (aOR, 2.71; 95% CI 1.17-6.24), and maternal hospital stay > 7 days (aOR, 14.51; 95% CI 7.23-29.12). Similar patterns emerged for buprenorphine regarding neonatal abstinence syndrome (aOR: 10.27; 95% CI 4.91-21.47) and extended maternal hospital stay (aOR: 3.84; 95% CI 1.83-8.07). However, differences were found favoring the use of buprenorphine for preterm birth versus untreated pregnancies (aOR: 0.17; 95% CI 0.04-0.77), and for several outcomes versus methadone. CONCLUSIONS: Methadone and buprenorphine prescribed for the treatment of opioid use disorder during pregnancy are associated with varying perinatal risks. However, buprenorphine may be preferred in the setting of pregnancy opioid agonist treatment. Further research is necessary to confirm our findings and minimize residual confounding.

Mood and Anxiety Disorders and Suicidality in Patients With Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity.

BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

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

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

Effects of Maternal Use of Antiseizure Medications on Child Development.

Most children born to women with epilepsy (WWE) are normal, but have increased risks for malformations and poor neuropsychological outcomes. Antiseizure medications (ASMs) are among the most commonly prescribed teratogenic medications in women of childbearing age. However, WWE typically cannot avoid using ASMs during pregnancy. Teratogenic risks vary across ASMs. Valproate poses a special risk for anatomic and behavioral teratogenic risks compared with other ASMs. The risks for many ASMs remain uncertain. Women of childbearing potential taking ASMs should be taking folic acid. Breastfeeding while taking ASMs seems safe. WWE should receive informed consent outlining risks before conception.