Faculty Bibliography

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.

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/CONCLUSIONS: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.

IMPORTANCE/UNASSIGNED:The association of fetal exposure to antiseizure medications (ASMs) with outcomes in childhood are not well delineated. OBJECTIVE/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

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.

Substantial efforts are underway towards 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 trials 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, while seizures represent one critical therapeutic target, targeting non-seizure 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 as well as other non-seizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics from drug discovery to translational application.

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/CONCLUSIONS: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.

OBJECTIVES:To identify the type, frequency, and consequences of seizures while driving (SzWD) in people with epilepsy before diagnosis. METHODS:We performed a retrospective cohort study using the Human Epilepsy Project (HEP) to identify prediagnostic SzWD. Clinical descriptions from seizure diaries and medical records were used to classify seizure types and frequencies, time to diagnosis, and SzWD outcomes. Data were modeled using multiple logistic regression to assess for factors independently associated with SzWD. RESULTS:= 0.02). DISCUSSION:This study identifies the consequences of seizure-related MVAs and hospitalizations people experience before epilepsy diagnosis. This highlights the need for further research aimed at improving seizure awareness and improving time to diagnosis.

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/CONCLUSIONS: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.

INTRODUCTION:Maintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy. OBJECTIVE:Our objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity. METHODS:Lamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one-compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single-patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population-level simulations (N = 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively. RESULTS:Individual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6-8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%-100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%-100% of women). SIGNIFICANCE:A substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary "one-size-fits-all" philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.