Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

mTORC1 functional assay reveals SZT2 loss-of-function variants and a founder in-frame deletion.

Biallelic pathogenic variants in SZT2 result in a neurodevelopmental disorder with shared features, including early-onset epilepsy, developmental delay, macrocephaly, and corpus callosum abnormalities. SZT2 is as a critical scaffolding protein in the amino acid sensing arm of the mTORC1 signalling pathway. Due to its large size (3432 amino acids), lack of crystal structure, and absence of functional domains, it is difficult to determine the pathogenicity of SZT2 missense and in-frame deletions, but these variants are increasingly detected and reported by clinical genetic testing in individuals with epilepsy. To exemplify this latter point, here we describe a cohort of 12 individuals with biallelic SZT2 variants and phenotypic overlap with SZT2-related neurodevelopmental disorders. However, the majority of individuals carried one or more SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterization to determine, which, if any, of these VUS were pathogenic. Thus, we developed a novel individualized platform to identify SZT2 loss-of-function variants in the context of mTORC1 signalling and reclassify VUS. Using this platform, we identified a recurrent in-frame deletion (SZT2 p.Val1984del) which was determined to be a loss-of-function variant and therefore likely pathogenic. Haplotype analysis revealed that this single in-frame deletion is a founder variant in those of Ashkenazi Jewish ancestry. Moreover, this approach allowed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five individuals with biallelic pathogenic or likely pathogenic variants. Clinical features of these five individuals consisted of early-onset seizures (median 24 months), focal seizures, developmental delay and macrocephaly similar to previous reports. However, we also show a widening of the phenotypic spectrum, as none of the five individuals had corpus callosum abnormalities, in contrast to previous reports. Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals of Ashkenazi Jewish ancestry, and demonstrate that corpus callosum abnormalities is not a hallmark feature of this condition. Our approach is widely applicable to other mTORopathies including the most common causes of the focal genetic epilepsies, DEPDC5, TSC1/2, MTOR and NPRL2/3.

Contraception, fecundity, and pregnancy in women with epilepsy: an update on recent literature.

PURPOSE OF REVIEW: Caring for women with epilepsy requires specialized knowledge about potential teratogenicity of antiseizure medications, interactions with hormonal contraception, and pregnancy outcomes. RECENT FINDINGS: There has been an improvement in understanding the cognitive outcomes of infants exposed in utero in recent years. Folic acid supplementation helps mitigate the cognitive teratogenicity of antiseizure medications. Recent updates provide reassurance that seizure frequency tends to remain stable throughout pregnancy. There is conflicting evidence about the fecundity impact of epilepsy and antiseizure medications in women with epilepsy. SUMMARY: Recent research highlights the importance of early counseling about the risks and interactions of contraception, pregnancy, and antiseizure medications. More research is needed to understand fertility in women with epilepsy.

Contraceptive vaginal ring reduces lamotrigine levels.

OBJECTIVE: The objective of the study was to describe the effect of the vaginal ring and transdermal patch on lamotrigine serum levels in women with epilepsy. BACKGROUND: Previous studies demonstrate that oral hormonal contraceptives containing synthetic estrogen increase lamotrigine clearance through induction of glucuronidation. This leads to variable lamotrigine serum concentrations throughout monthly cycles in women who are on combined oral contraceptives (COCs). The effects of estrogen-containing nonoral hormonal contraceptive methods, including the vaginal ring and transdermal patch, on lamotrigine pharmacokinetics are not well described. METHODS: Retrospective chart review was performed to identify serum lamotrigine levels drawn from women with epilepsy while on the active phase of vaginal ring or transdermal patch and while off contraception. Wilcoxon signed-rank tests for paired data were used to compare the difference in dose-corrected lamotrigine concentration in plasma between values while on hormonal contraception to those while off contraception in patients using a vaginal ring. RESULTS: Six patients were using the vaginal ring, and one patient was using the transdermal patch. Lamotrigine dose-corrected concentrations were decreased during the active phase of the vaginal ring compared with concentrations during the period off contraception (p = .04). There was one patient without a decrease in concentration, but the other five patients on the vaginal ring had a decrease in dose-corrected lamotrigine concentration ranging from 36 to 70% while on the vaginal ring. Similarly, one patient using the transdermal patch had a decrease of 37% in dose-corrected lamotrigine concentration while on the patch. CONCLUSIONS: The findings support that the vaginal ring contraceptive method decreases lamotrigine concentrations during the active phase of treatment. This has important implications for contraceptive counseling and maintaining therapeutic levels in women of childbearing age with epilepsy.

Use of a simulation-based mastery learning curriculum for neurology residents to improve the identification and management of status epilepticus.

BACKGROUND: Appropriate and timely treatment of status epilepticus (SE) decreases morbidity and mortality. Therefore, skill-based training in the identification and management of SE is crucial for clinicians. OBJECTIVE: The objective of the study was to develop and evaluate the impact of a simulation-based mastery learning (SBML) curriculum to train neurology residents on the identification and management of SE. METHODS: We used pretest-posttest design with a retention test on SE skills for this study. Neurology residents in the second postgraduate year (PGY-2) were eligible to participate in the SE SBML curriculum. Learners completed a baseline-simulated SE skills assessment (pretest) using a 26-item dichotomous skills checklist. Next, they participated in a didactic session about the identification and management of SE, followed by deliberate skills practice. Subsequently, participants completed another skills assessment (posttest) using the same 26-item checklist. All participants were required to meet or exceed a minimum passing standard (MPS) determined by a panel of 14 SE experts using the Mastery Angoff standard setting method. After meeting the MPS at posttest, participants were reassessed during an unannounced in situ simulation session on the medical wards. We compared pretest with posttest simulated SE skills performance and posttest with reassessment in situ performance. RESULTS: The MPS was set at 88% (23/26) checklist items correct. Sixteen neurology residents participated in the intervention. Participant performance improved from a median of 44.23% (Interquartile range (IQR): 34.62-55.77) at pretest to 94.23% (IQR: 92.13-100) at the posttest after SBML (p < .001). There was no significant difference in scores between the posttest and in situ test up to 8 months later (94.23%; IQR: 92.31-100 vs. 92.31%; IQR: 88.46-96.15; p = .13). CONCLUSIONS: Our SBML curriculum significantly improved residents' SE identification and management skills that were largely retained during an unannounced simulated encounter in the hospital setting.

Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures.

OBJECTIVE: The optimal treatment of nonconvulsive seizures in critically ill patients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. METHODS: The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. RESULTS: Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). INTERPRETATION: LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.

Stroke-like migraine attacks after radiation therapy: A misnomer?

OBJECTIVE: To understand the frequency of electrographic and clinical seizures in patients with stroke-like migraine attacks after radiation therapy (SMART), and determine whether SMART warrants comprehensive electroencephalographic (EEG) monitoring and aggressive seizure management. METHODS: We searched our magnetic resonance brain imaging report database for all patients between January 2013 and December 2015 for suspected SMART syndrome. Clinical inclusion criteria were further applied as follows: inpatient adults (>18 years of age) with history of cranial radiation presenting with acute neurologic deficits as primary admission reason who lacked evidence of recurrent or new brain malignancy, stroke, or infectious agents in cerebrospinal fluid. Six patients were identified. All 6 patients underwent prolonged video EEG monitoring as part of our standard protocol. RESULTS: All patients but 1 were found to have multiple or prolonged electrographic seizures consistent with status epilepticus during video EEG monitoring. Their neurological deficit and/or mental status change improved in parallel with resolution of the seizure activity. SIGNIFICANCE: SMART is likely a misnomer that underestimates the significance of seizures and status epilepticus in the pathophysiology and clinical presentation of the syndrome. Systematic continuous EEG monitoring and appropriate seizure management is warranted to reduce symptom duration and optimize clinical outcome.

Counseling by epileptologists affects contraceptive choices of women with epilepsy.

INTRODUCTION: There are several important interactions between antiepileptic drugs (AEDs) and hormonal contraception that need to be carefully considered by women with epilepsy (WWE) and their practitioners. Many AEDs induce hepatic enzymes and decrease the efficacy of hormonal contraception. In addition, estrogen-containing hormonal contraception can increase the metabolism of lamotrigine, the most commonly prescribed AED in women of childbearing age. The intrauterine device (IUD) is a highly effective form of reversible contraception without AED drug interactions that is considered by many to be the contraceptive of choice for WWE. Women with epilepsy not planning pregnancy require effective contraceptive counseling that should include discussion of an IUD. There are no guidelines, however, on who should deliver these recommendations. The objective of this study was to explore the hypothesis that contraceptive counseling by a neurologist can influence the contraceptive choices of WWE. In particular, we explored the relationship between contraceptive counseling in the epilepsy clinic and the likelihood that patients would obtain an IUD. METHODS: We conducted a retrospective chart review of female patients age 18-45 seen at our institution for an initial visit between 2010 and 2014 to ascertain the type of contraceptive counseling each patient received as well as AED use and contraceptive methods. Patients who were pregnant or planning pregnancy at the first visit were excluded from further analyses as were patients with surgical sterilization. We also examined a subgroup of 95 patients with at least 4 follow-up visits to evaluate the efficacy of epileptologists' counseling. Specifically, we looked at the likelihood a patient obtained an IUD based on the type of counseling she had received. Fisher exact tests assessed associations between counseling type and whether patients had obtained an IUD. RESULTS: Three hundred and ninety-seven women met criteria for inclusion. Only 35% of female patients were counseled about contraception at the first visit. If women were not counseled at the first visit, they were unlikely to be counseled at subsequent visits; only 37% had ever received counseling by their fourth visit. Of the 95 patients who completed 4 visits, 28.4% were counseled about an IUD as an optimal contraceptive choice, 38.9% were generally counseled about contraceptive interactions, and 32.6% were not counseled about contraception. Women with epilepsy who received IUD-specific counseling were significantly more likely to switch to an IUD (44.4%) compared with women who received no contraceptive counseling (6.5%; p=0.0009). Women with epilepsy who received IUD-specific counseling also tended to switch to an IUD more often than those women receiving general counseling about AEDs and contraceptive interactions (18.9%; p=0.027). There was no significant difference in the likelihood of acquiring an IUD between the general counseling and no counseling groups. CONCLUSIONS: Contraceptive counseling by epileptologists and specific mention of an IUD is significantly associated with patient selection of an IUD as a contraceptive method. This suggests that neurologists can play an important role in patients' contraceptive choices.

"Ictal" lateralized periodic discharges.

OBJECTIVE: Whether lateralized periodic discharges (LPDs) represent ictal or interictal phenomena, and even the circumstances in which they may represent one or the other, remains highly controversial. Lateralized periodic discharges are, however, widely accepted as being ictal when they are time-locked to clinically apparent symptoms. We sought to investigate the characteristics of "ictal" lateralized periodic discharges (ILPDs) defined by time-locked clinical symptoms in order to explore the utility of using this definition to dichotomize LPDs into "ictal" and "nonictal" categories. METHODS: Our archive of all continuous EEG (cEEG) reports of adult inpatients undergoing prolonged EEG monitoring for nonelective indications between 2007 and 2011 was searched to identify all reports describing LPDs. Lateralized periodic discharges were considered ILPDs when they were reported as being consistently time-locked to clinical symptoms; LPDs lacking a clear time-locked correlate were considered to be "nonictal" lateralized periodic discharges (NILPDs). Patient charts and available neuroimaging studies were also reviewed. Neurophysiologic localization of LPDs, imaging findings, presence of seizures, discharge outcomes, and other demographic factors were compared between patients with ILPDs and those with NILPDs. p-Values were adjusted for false discovery rate (FDR). RESULTS: One thousand four hundred fifty-two patients underwent cEEG monitoring at our institution between 2007 and 2011. Lateralized periodic discharges were reported in 90 patients, 10 of whom met criteria for ILPDs. Nine of the patients with ILPDs demonstrated motor symptoms, and the remaining patient experienced stereotyped sensory symptoms. Ictal lateralized periodic discharges had significantly increased odds for involving central head regions (odds ratio [OR]=11; 95% confidence interval [CI]=2.16-62.6; p=0.018, FDR adjusted), with a trend towards higher proportion of lesions involving the primary sensorimotor cortex (p=0.09, FDR adjusted). CONCLUSIONS: When defined by the presence of a time-locked clinical correlate, ILPDs appear to be strongly associated with a central EEG localization. This is likely due to cortical irritability in central head regions having greater propensity to manifest with positive, clinically apparent, and time-locked symptoms. Thus, dichotomization of ILPDs and NILPDs on this basis principally reflects differences in underlying anatomical locations of the periodic discharges rather than providing a clinically salient categorization.

Subarachnoid extension of hemorrhage is associated with early seizures in primary intracerebral hemorrhage.

BACKGROUND: Seizures are common in patients with subarachnoid hemorrhage, potentially by inciting cortical irritability. Seizures are also commonly seen after intracerebral hemorrhage (ICH), although the mechanisms and risk factors within that population are not well understood. The objective of this study is to evaluate whether subarachnoid hemorrhage extension (SAHE) is associated with early seizures in patients with primary ICH. METHODS: Patients with primary ICH were enrolled into a prospective registry between December 2006 and July 2012. Patients were managed per a structured protocol. SAHE was identified on imaging by expert reviewers blinded to outcomes. Electroencephalograms were routinely obtained in patients with unexplained, poor level of arousal. Seizure was determined by clinically observed convulsions or traditional electroencephalographic criteria. Early seizures were defined as occurring within 3 days of hemorrhage. A binary logistic regression model was developed to test whether the occurrence of SAHE was independently associated with seizures. RESULTS: A total of 234 patients were studied. Of these, 93 (40%) had SAHE and 9 (4%) had early seizures. SAHE was associated with early seizures (P = .03). No additional variables were identified by regression modeling to mediate the association between SAHE and early seizures (odds ratio 5.62 [95% confidence interval 1.14-27.7], P = .034). CONCLUSIONS: SAHE is associated with early seizures in patients with primary ICH. Further study is needed to confirm these findings and determine whether modifications to routine care based on the presence of SAHE would be of benefit.

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.

Teratogenesis, Perinatal, and Neurodevelopmental Outcomes After In Utero Exposure to Antiseizure Medication: Practice Guideline From the AAN, AES, and SMFM.

This practice guideline provides updated evidence-based conclusions and recommendations regarding the effects of antiseizure medications (ASMs) and folic acid supplementation on the prevalence of major congenital malformations (MCMs), adverse perinatal outcomes, and neurodevelopmental outcomes in children born to people with epilepsy of childbearing potential (PWECP). A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies through August 2022. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. The following are some of the major recommendations. When treating PWECP, clinicians should recommend ASMs and doses that optimize both seizure control and fetal outcomes should pregnancy occur, at the earliest possible opportunity preconceptionally. Clinicians must minimize the occurrence of convulsive seizures in PWECP during pregnancy to minimize potential risks to the birth parent and to the fetus. Once a PWECP is already pregnant, clinicians should exercise caution in attempting to remove or replace an ASM that is effective in controlling generalized tonic-clonic or focal-to-bilateral tonic-clonic seizures. Clinicians must consider using lamotrigine, levetiracetam, or oxcarbazepine in PWECP when appropriate based on the patient's epilepsy syndrome, likelihood of achieving seizure control, and comorbidities, to minimize the risk of MCMs. Clinicians must avoid the use of valproic acid in PWECP to minimize the risk of MCMs or neural tube defects (NTDs), if clinically feasible. Clinicians should avoid the use of valproic acid or topiramate in PWECP to minimize the risk of offspring being born small for gestational age, if clinically feasible. To reduce the risk of poor neurodevelopmental outcomes, including autism spectrum disorder and lower IQ, in children born to PWECP, clinicians must avoid the use of valproic acid in PWECP, if clinically feasible. Clinicians should prescribe at least 0.4 mg of folic acid supplementation daily preconceptionally and during pregnancy to any PWECP treated with an ASM to decrease the risk of NTDs and possibly improve neurodevelopmental outcomes in the offspring.

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.

Assessment of a quasi-piezoelectric mattress monitor as a detection system for generalized convulsions.

The risk of sudden unexpected death in epilepsy (SUDEP) is highest with nocturnal, unattended generalized convulsions, and basic resuscitation may be able to prevent SUDEP. This study investigates an under-mattress device (ElectroMechanical Film - Emfit®) which is triggered by rhythmic motor activity of a specifiable duration, frequency, and intensity using a quasi-piezoelectric material sensitive to changes in mattress pressure. The device was tested during inpatient video-EEG monitoring. Eighteen GTCSs were recorded, 10 out of wakefulness and 8 out of sleep. Sixteen of the 18 seizures (89%) resulted in Emfit® activation with both false negative alarms occurring during wakefulness. On average, the device was activated within 9 s of onset of bilateral clonic motor movements (range: -37 to +39 s) and occurred, on average, 45 s before seizure end (range: 19 to 76 s). Only 21 false alarms were encountered, all occurring during wakefulness (PPV: 43%). The data suggest that the Emfit® detection device has a high predictive value for generalized convulsions, offers caregivers a reliable and early warning to assist the patient during convulsions, and may be a novel way to prevent SUDEP.

Antiseizure Medications in Pregnancy.

Epilepsy affects up to 15 million of people assigned female at birth of childbearing age globally. Up to 65% of these people with epilepsy and gestational capacity have an unplanned pregnancy. Seizure control during pregnancy is important for both the childbearer's and fetus' safety. There are multiple antiseizure medications (ASMs) that can be used to control epilepsy; however, each medication has its own teratogenic risk profile, which must be considered. The majority of these ASMs will require frequent plasma concentration monitoring during pregnancy with corresponding dosage adjustments. Dosages can be reduced back to prepregnancy levels within 3 weeks postpartum. Breastfeeding on ASMs is recommended.

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.

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.

Neurodevelopmental and Epilepsy Phenotypes in Individuals With Missense Variants in the Voltage-Sensing and Pore Domains of KCNH5.

BACKGROUND AND OBJECTIVES: KCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants. METHODS: We screened 893 individuals with developmental and epileptic encephalopathies for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details. RESULTS: We report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death. DISCUSSION: We describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders and epilepsy.