Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of primary generalized tonic-clonic seizures.

OBJECTIVE: Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T-PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T-PSC design also could replicate the trial's safety and tolerability conclusions. METHODS: We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T-PSC relative to those observed during the full-length trial. RESULTS: Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full-length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T-PSC, respectively. When limited to treatment-related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment-related TEAEs that occurred before T-PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T-PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p = .035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T-PSC, one in placebo and two in perampanel). SIGNIFICANCE: Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T-PSC or delayed time to TEAE for placebo.

Prevalence of Suicidality in Adolescents With Newly Diagnosed Focal Epilepsy at Diagnosis and Over the Following 36 Months.

BACKGROUND AND OBJECTIVES: Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months. METHODS: This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records. RESULTS: A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10). DISCUSSION: The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.

Validation of the Seizure-Related Impact Assessment Scale (SERIAS): a study protocol.

INTRODUCTION: This study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the 'trade-off' between seizures and treatment-related adverse effects, and measures epilepsy disability qualitatively and quantitively. It fills an important gap in PROMs for epilepsy clinical trials and practice. METHODS AND ANALYSIS: Adults with epileptologist-confirmed epilepsy from two Australian Epilepsy Centres are being recruited. People with functional seizures, or who are unable to self-complete English-language validated instruments are excluded. Participants providing informed consent are invited to complete questionnaires at baseline, 3 and 6 months later. SERIAS includes five questions that ask about the number of days per month that seizures or treatment-related adverse effects partially or fully impact work/home/school and family/social/non-work activities, as well as a visual analogue scale regarding epilepsy-related disability. SERIAS is completed alongside seven internationally validated instruments measuring treatment-related adverse effects, mood disorders and quality of life. Target recruitment is n=100, ensuring>50 people complete all questionnaires at all timepoints. Comprehensive psychometric analysis will be performed. Convergent validity will be investigated using bivariate correlations with relevant measures. Reliability will be investigated using Cronbach's alpha, McDonald's omega and test-retest correlation coefficients. SERIAS will be a novel PROM for epilepsy clinical trials and practice. ETHICS AND DISSEMINATION: Multisite ethics approval was granted by the Alfred Health Ethics Committee (HREC 17/23). Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER: ACTRN12623000599673.

Unrecognized Focal Nonmotor Seizures in Adolescents Presenting to Emergency Departments.

BACKGROUND AND OBJECTIVES: Many adolescents with undiagnosed focal epilepsy seek evaluation in emergency departments (EDs). Accurate history-taking is essential to prompt diagnosis and treatment. In this study, we investigated ED recognition of motor vs nonmotor seizures and its effect on management and treatment of focal epilepsy in adolescents. METHODS: This was a retrospective analysis of enrollment data from the Human Epilepsy Project (HEP), an international multi-institutional study that collected data from 34 sites between 2012 and 2017. Participants were 12 years or older, neurotypical, and within 4 months of treatment initiation for focal epilepsy. We used HEP enrollment medical records to review participants' initial diagnosis and management. RESULTS: A total of 83 adolescents were enrolled between 12 and 18 years. Fifty-eight (70%) presented to an ED before diagnosis of epilepsy. Although most ED presentations were for motor seizures (n = 52; 90%), many patients had a history of nonmotor seizures (20/52 or 38%). Adolescents with initial nonmotor seizures were less likely to present to EDs (26/44 or 59% vs 32/39 or 82%, p = 0.02), and nonmotor seizures were less likely to be correctly identified (2/6 or 33% vs 42/52 or 81%, p = 0.008). A history of initial nonmotor seizures was not recognized in any adolescent who presented for a first-lifetime motor seizure. As a result, initiation of treatment and admission from the ED was not more likely for these adolescents who met the definition of epilepsy compared with those with no seizure history. This lack of nonmotor seizure history recognition in the ED was greater than that observed in the adult group (0% vs 23%, p = 0.03) and occurred in both pediatric and nonpediatric ED settings. DISCUSSION: Our study supports growing evidence that nonmotor seizures are often undiagnosed, with many individuals coming to attention only after conversion to motor seizures. We found this treatment gap is exacerbated in the adolescent population. Our study highlights a critical need for physicians to inquire about the symptoms of nonmotor seizures, even when the presenting seizure is motor. Future interventions should focus on improving nonmotor seizure recognition for this population in EDs.

The Posterior Shoulder Instability Questionnaire (PSI-Q): Internal consistency, content and criterion validity, responsiveness, and reliability of a new tool for the assessment of posterior shoulder instability.

INTRODUCTION: Posterior shoulder instability (PSI) is an increasingly recognized cause of shoulder dysfunction particularly in young active patients and certain athlete populations. When evaluating the efficacy of treatment for PSI, specific outcome measures for this population are essential. The aim of the current research was to describe the development and evaluation of a patient reported outcome measure (PROM) specific for PSI. METHODS: A retrospective cohort study design of patients with PSI was used to develop and evaluate the "Posterior Shoulder Instability Questionnaire (PSI-Q)". Items for PSI-Q were generated through an expert focus group and existing questionnaires. Preliminary data analysis identified redundancy of items and resulted in the PSI-Q being refined. The final PSI-Q was evaluated on 128 patients with PSI with a structural lesion requiring surgical intervention. Participants were excluded in the absence of a posterior glenohumeral joint lesion. Internal consistency (Cronbach α and corrected item-total correlation), content validity, criterion validity, responsiveness, and test-retest reliability (intraclass correlation coefficient; ICC) were examined. Content validity, criterion validity and responsiveness were compared with the Melbourne Instability Shoulder Score (MISS) and the Western Ontario Shoulder Index (WOSI). The minimum detectable change score (MDC) was calculated. RESULTS: The Cronbach α for the total scale pre and post-intervention was high (α = 0.97). All five domains (Pain, Instability/Weakness/Stiffness, Function, Occupation and Sport, and Quality of Life and Satisfaction) demonstrated acceptable internal consistency for each subsection and the overall score of the scale (α > 0.70). The corrected-item total correlation for each domain were within an acceptable range. The responsiveness of the PSI-Q questionnaire was excellent (effect size, 2.06; standard response mean, 1.34) and was higher than the MISS and WOSI. There were no relevant floor effects and one ceiling effect. Reliability was excellent (ICC (1,1) = 0.93) and the calculated MDC was 10.9 points. DISCUSSION: This study designed and validated a questionnaire specific for measuring symptoms and function in people with structural PSI requiring surgery. The PSI-Q demonstrates good measurement properties and provides an MDC that is useful for researchers and clinicians. In structural PSI, the PSI-Q has a higher responsiveness and more accurately reflects a patient's overall perceived shoulder status compared to current patient reported outcomes for shoulder instability. The psychometric properties of the PSI-Q are still to be determined in a non-surgical population.

Long-term seizure diary tracking habits in clinical studies: Evidence from the Human Epilepsy Project.

OBJECTIVE: To characterize seizure tracking patterns of people with focal epilepsy using electronic seizure diary entries, and to assess for risk factors associated with poor tracking. METHODS: We analyzed electronic seizure diary data from 410 participants with newly diagnosed focal epilepsy in the Human Epilepsy Project 1 (HEP1). Each participant was expected to record data each day during the study, regardless of seizure occurrence. The primary outcome of this post-hoc analysis was whether each participant properly tracked a seizure diary entry each day during their study participation. Using finite mixture modeling, we grouped patient tracking trajectories into data-driven clusters. Once defined, we used multinomial modeling to test for independent risk factors of tracking group membership. RESULTS: Using over up to three years of daily seizure diary data per subject, we found four distinct seizure tracking groups: consistent, frequent at study onset, occasional, and rare. Participants in the consistent tracking group tracked a median of 92% (interquartile range, IQR: 82%, 99%) of expected days, compared to 47% (IQR:34%, 60%) in the frequent at study onset group, 37% (IQR: 26%, 49%) in the occasional group, and 9% (IQR: 3%, 15%) in the rare group. In multivariable analysis, consistent trackers had lower rates of seizure days per tracked year during their study participation, compared to other groups. SIGNIFICANCE: Future efforts need to focus on improving seizure diary tracking adherence to improve quality of outcome data, particularly in those with higher seizure burden. In addition, accounting for missing data when using seizure diary data as a primary outcome is important in research trials. If not properly accounted for, total seizure burden may be underestimated and biased, skewing results of clinical trials.

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.

Learning difficulties often not documented in newly diagnosed focal epilepsy.

OBJECTIVE: A previous investigation of people with newly diagnosed focal epilepsy participating in the Human Epilepsy Project 1 (HEP1) revealed an association between learning difficulties and structural brain differences, suggesting an underlying relationship prior to seizure onset. To investigate physicians' practices of documentation learning difficulties during clinical encounters, we conducted a review of initial epileptologist encounter notes from HEP1 participants who self-reported early life learning difficulties separately as part of study enrollment. METHODS: HEP1 enrolled 67 North American participants between June 2012 and November 2017 who self-reported one or more difficulties with learning (i.e., having repeated grade, receiving learning support/remediation, and/or formal diagnosis of a learning disability) prior to epilepsy diagnosis as part of the study enrollment. The epileptologist's initial encounter note was then reviewed in detail for each of these participants. Documentation of learning issues and specific diagnoses of learning disabilities was compared to participant characteristics. Regression analysis was used to test for any independent associations between participant characteristics and physician documentation of learning difficulties. RESULTS: There were significant independent relationships between age, sex, and physician documentation of learning difficulties. On average, participants ages 22 and younger were 12.12 times more likely to have their learning difficulties documented compared to those 23 years and older (95 % CI: 2.226 to 66.02, p = 0.004). Additionally, male participants had 7.2 times greater odds of having their learning difficulty documented compared to female participants (95 % CI: 1.538 to 33.717, p = 0.012). There were no significant independent associations between race, language, employment, or geographical region. SIGNIFICANCE: These findings highlight disparities in physician documentation for people with newly diagnosed focal epilepsy and a history of learning difficulties. In the HEP1 cohort, physicians were more likely to document learning difficulties in males and in younger individuals. Systematic practice standards are important for reducing healthcare disparities across populations, improving clinical care to individuals, as well as enabling more accurate retrospective study of clinical phenomenon.

Improving epilepsy diagnosis across the lifespan: approaches and innovations.

Epilepsy diagnosis is often delayed or inaccurate, exposing people to ongoing seizures and their substantial consequences until effective treatment is initiated. Important factors contributing to this problem include delayed recognition of seizure symptoms by patients and eyewitnesses; cultural, geographical, and financial barriers to seeking health care; and missed or delayed diagnosis by health-care providers. Epilepsy diagnosis involves several steps. The first step is recognition of epileptic seizures; next is classification of epilepsy type and whether an epilepsy syndrome is present; finally, the underlying epilepsy-associated comorbidities and potential causes must be identified, which differ across the lifespan. Clinical history, elicited from patients and eyewitnesses, is a fundamental component of the diagnostic pathway. Recent technological advances, including smartphone videography and genetic testing, are increasingly used in routine practice. Innovations in technology, such as artificial intelligence, could provide new possibilities for directly and indirectly detecting epilepsy and might make valuable contributions to diagnostic algorithms in the future.

Racial disparities in the utilization of invasive neuromodulation devices for the treatment of drug-resistant focal epilepsy.

Racial disparities affect multiple dimensions of epilepsy care including epilepsy surgery. This study aims to further explore these disparities by determining the utilization of invasive neuromodulation devices according to race and ethnicity in a multicenter study of patients living with focal drug-resistant epilepsy (DRE). We performed a post hoc analysis of the Human Epilepsy Project 2 (HEP2) data. HEP2 is a prospective study of patients living with focal DRE involving 10 sites distributed across the United States. There were no statistical differences in the racial distribution of the study population compared to the US population using census data except for patients reporting more than one race. Of 154 patients enrolled in HEP2, 55 (36%) underwent invasive neuromodulation for DRE management at some point in the course of their epilepsy. Of those, 36 (71%) were patients who identified as White. Patients were significantly less likely to have a device if they identified solely as Black/African American than if they did not (odds ratio = .21, 95% confidence interval = .05-.96, p = .03). Invasive neuromodulation for management of DRE is underutilized in the Black/African American population, indicating a new facet of racial disparities in epilepsy care.

Current state of the epilepsy drug and device pipeline.

The field of epilepsy has undergone substantial advances as we develop novel drugs and devices. Yet considerable challenges remain in developing broadly effective, well-tolerated treatments, but also precision treatments for rare epilepsies and seizure-monitoring devices. We summarize major recent and ongoing innovations in diagnostic and therapeutic products presented at the seventeenth Epilepsy Therapies & Diagnostics Development (ETDD) conference, which occurred May 31 to June 2, 2023, in Aventura, Florida. Therapeutics under development are targeting genetics, ion channels and other neurotransmitters, and many other potentially first-in-class interventions such as stem cells, glycogen metabolism, cholesterol, the gut microbiome, and novel modalities for delivering electrical neuromodulation.

Testing the diagnostic accuracy of common questions for seizure diagnosis: Challenges and future directions.

OBJECTIVE: The aim of this study was to evaluate the diagnostic accuracy of common interview questions used to distinguish a diagnosis of epilepsy from seizure mimics including non-epileptic seizures (NES), migraine, and syncope. METHODS: 200 outpatients were recruited with an established diagnosis of focal epilepsy (n = 50), NES (n = 50), migraine (n = 50), and syncope (n = 50). Patients completed an eight-item, yes-or-no online questionnaire about symptoms related to their events. Sensitivity and specificity were calculated. Using a weighted scoring for the questions alone with baseline characteristics, the overall questionnaire was tested for diagnostic accuracy. RESULTS: Of individual questions, the most sensitive one asked if events are sudden in onset (98 % sensitive for epilepsy (95 % CI: 89 %, 100 %)). The least sensitive question asked if events are stereotyped (46 % sensitive for epilepsy (95 % CI: 32 %, 60 %)). Overall, three of the eight questions showed an association with epilepsy as opposed to mimics. These included questions about "sudden onset" (OR 10.76, 95 % CI: (1.66, 449.21) p = 0.0047), "duration < 5 min" (OR 3.34, 95 % CI: (1.62, 6.89), p = 0.0008), and "duration not > 30 min" (OR 4.44, 95 % CI: (1.94, 11.05), p = <0.0001). When individual seizure mimics were compared to epilepsy, differences in responses were most notable between the epilepsy and migraine patients. Syncope and NES were most similar in responses to epilepsy. The overall weighted questionnaire incorporating patient age and sex produced an area under the ROC curve of 0.80 (95 % CI: 0.74, 0.87)). CONCLUSION: In this study, we examined the ability of common interview questions used by physicians to distinguish between epilepsy and prevalent epilepsy mimics, specifically NES, migraines, and syncope. Using a weighted scoring system for questions, and including age and sex, produced a sensitive and specific predictive model for the diagnosis of epilepsy. In contrast to many prior studies which evaluated either a large number of questions or used methods with difficult practical application, our study is unique in that we tested a small number of easy-to-understand "yes" or "no" questions that can be implemented in most clinical settings by non-specialists.

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.

Prediction tools and risk stratification in epilepsy surgery.

OBJECTIVE: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2). METHODS: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures. RESULTS: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05). SIGNIFICANCE: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries.

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.

Challenges and directions in epilepsy diagnostics and therapeutics: Proceedings of the 17th Epilepsy Therapies and Diagnostics Development conference.

Substantial efforts are underway toward optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trial execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, although seizures represent one critical therapeutic target, targeting nonseizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves and other nonseizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics, from drug discovery to translational application.

Call for the use of the ILAE terminology for seizures and epilepsies by health care professionals and regulatory agencies to benefit patients and caregivers.

The International League Against Epilepsy (ILAE) introduced a classification for seizure types in 2017 and updated the classification for epilepsy syndromes in 2022. These classifications aim to improve communication among healthcare professionals and help patients better describe their condition. So far, regulatory agencies have used different terminology. This paper stresses the crucial need for consistently adopting ILAE terminology in both regulatory processes and clinical practice. It highlights how language plays a significant role in healthcare communication and how standardized terminology can enhance patient comprehension. The ongoing review of guidelines by regulatory bodies offers a timely opportunity. Aligning regulatory terminologies holds the potential to facilitate discussions on future drug development and harmonize practices across diverse regions, ultimately fostering improved care and research outcomes in epilepsy treatment.

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.

Patterns of antiseizure medication utilization in the Human Epilepsy Project.

OBJECTIVE: This study was undertaken to ascertain the natural history and patterns of antiseizure medication (ASM) use in newly diagnosed focal epilepsy patients who were initially started on monotherapy. METHODS: The data were derived from the Human Epilepsy Project. Differences between the durations of the most commonly first prescribed ASM monotherapies were assessed using a Cox proportional hazards model. Subjects were classified into three groups: monotherapy, sequential monotherapy, and polytherapy. RESULTS: A total of 443 patients were included in the analysis, with a median age of 32 years (interquartile range [IQR] = 20-44) and median follow-up time of 3.2 years (IQR = 2.4-4.2); 161 (36.3%) patients remained on monotherapy with their initially prescribed ASM at the time of their last follow-up. The mean (SEM) and median (IQR) duration that patients stayed on monotherapy with their initial ASM was 2.1 (2.0-2.2) and 1.9 (.3-3.5) years, respectively. The most commonly prescribed initial ASM was levetiracetam (254, 57.3%), followed by lamotrigine (77, 17.4%), oxcarbazepine (38, 8.6%), and carbamazepine (24, 5.4%). Among those who did not remain on the initial monotherapy, 167 (59.2%) transitioned to another ASM as monotherapy (sequential monotherapy) and 115 (40.8%) ended up on polytherapy. Patients remained significantly longer on lamotrigine (mean = 2.8 years, median = 3.1 years) compared to levetiracetam (mean = 2.0 years, median = 1.5 years) as a first prescribed medication (hazard ratio = 1.5, 95% confidence interval = 1.0-2.2). As the study progressed, the proportion of patients on lamotrigine, carbamazepine, and oxcarbazepine as well as other sodium channel agents increased from a little more than one third (154, 34.8%) of patients to more than two thirds (303, 68.4%) of patients. SIGNIFICANCE: Slightly more than one third of focal epilepsy patients remain on monotherapy with their first prescribed ASM. Approximately three in five patients transition to monotherapy with another ASM, whereas approximately two in five end up on polytherapy. Patients remain on lamotrigine for a longer duration compared to levetiracetam when it is prescribed as the initial monotherapy.

Efficacy and Safety of XEN1101, a Novel Potassium Channel Opener, in Adults With Focal Epilepsy: A Phase 2b Randomized Clinical Trial.

Importance: Many patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics. Objective: To evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs). Design, Setting, and Participants: This phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe. Interventions: Patients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose). Main Outcomes and Measures: The primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted. Results: A total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P < .001 vs placebo; IQR, -80.4% to -16.9%) for 25 mg, 46.4% (P < .001 vs placebo; IQR, -76.7% to -14.0%) for 20 mg, and 33.2% (P = .04 vs placebo; IQR, -61.8% to 0.0%) for 10 mg, compared with 18.2% (IQR, -37.3% to 7.0%) for placebo. XEN1101 was generally well tolerated and TEAEs were similar to those of commonly prescribed ASMs, and no TEAEs leading to death were reported. Conclusions and Relevance: The efficacy and safety findings of this clinical trial support the further clinical development of XEN1101 for the treatment of FOSs. Trial Registration: ClinicalTrials.gov Identifier: NCT03796962.