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Objective: Focal to bilateral tonic-clonic seizures (FBTCS) represent a challenging subtype of focal temporal lobe epilepsy (TLE) in terms of both severity and treatment response. Most studies have focused on regional brain analysis that is agnostic to the distribution of white matter (WM) pathways associated with a node. We implemented a more selective, edge-wise approach that allowed for identification of the individual connections unique to FBTCS., Methods: T1-weighted and diffusion-weighted images were obtained from 22 patients with solely focal seizures (FS), 43 FBTCS patients, and 65 age/sex-matched healthy participants (HPs), yielding streamline (STR) connectome matrices. We used diffusion tensor-derived STRs in an edge-wise approach to determine specific structural connectivity changes associated with seizure generalization in FBTCS compared to matched FS and HPs. Graph theory metrics were computed on both node- and edge-based connectivity matrices., Results: Edge-wise analyses demonstrated that all significantly abnormal cross-hemispheric connections belonged to the FBTCS group. Abnormal connections associated with FBTCS were mostly housed in the contralateral hemisphere, with graph metric values generally decreased compared to HPs. In FBTCS, the contralateral amygdala showed selective decreases in the structural connection pathways to the contralateral frontal lobe. Abnormal connections in TLE involved the amygdala, with the ipsilateral side showing increases and the contralateral decreases. All the FS findings indicated higher graph metrics for connections involving the ipsilateral amygdala. Data also showed that some FBTCS connectivity effects are moderated by aging, recent seizure frequency, and longer illness duration., Significance: Data showed that not all STR pathways are equally affected by the seizure propagation of FBTCS. We demonstrated two key biases, one indicating a large role for the amygdala in the propagation of seizures, the other pointing to the prominent role of cross-hemispheric and contralateral hemisphere connections in FBTCS. We demonstrated topographic reorganization in FBTCS, pointing to the specific WM tracts involved., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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., (© 2023 International League Against Epilepsy.)

Objective: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ)., Methods: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms., Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3)., Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation., (© 2023 International League Against Epilepsy.)

Objective: We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program., Methods: We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic-clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic-clonic (PGTC) seizures who received ≥1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days that a patient received cenobamate during completed studies or up to June 1, 2022, for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years., Results: A total of 2132 patients (n = 2018 focal epilepsy; n = 114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic-clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of .88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130 to 620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% confidence interval [CI] .84-2.0), which was not significantly different from the general population., Significance: These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Despite the approval of ~20 additional antiseizure medications (ASMs) since the 1980s, one-third of epilepsy patients experience seizures despite therapy. Drug-resistant epilepsy (DRE) is associated with cognitive and psychiatric comorbidities, socioeconomic impairment, injuries, and a 9.3-13.4 times higher mortality rate than in seizure-free patients. Improved seizure control can reduce morbidity and mortality. Two new ASMs were launched in the United States in 2020: cenobamate for focal epilepsy in adults and fenfluramine for Dravet syndrome (DS). They offer markedly improved efficacy. Cenobamate achieved 21% seizure freedom with the highest dose and decreased tonic-clonic seizures by 93% during maintenance treatment in a randomized clinical trial (RCT). In long-term, open-label studies, 10%-36% of patients were seizure-free for a median duration of ~30-45 months. Fenfluramine treatment in DS reduced convulsive seizure frequency by 56% over placebo at the highest dose, with 8% of patients free of convulsive seizures, and 25% with only one convulsive seizure over 14 weeks. These results were sustained for up to 3 years in open-label extension studies. Mortality was reduced 5-fold. These results are superior to all other approved ASMs, placing these two drugs among the most effective antiseizure therapies. The adverse event profiles resemble those of other ASMs. Despite greater efficacy and similar toxicity, these medications are infrequently used. Two years after US market entry, < 5% of either adults with focal DRE or patients with DS were treated with either cenobamate or fenfluramine. We believe this is a failure of our medical system, resulting from limited knowledge about these drugs stemming partly from the separation of academia from industry; restrictions to access created by health care payors, hospitals, and regulatory agencies; and insufficient post-launch information about the efficacy and safety of these ASMs., (© 2023 International League Against Epilepsy.)

How responsive neurostimulation (RNS) decreases seizure frequency is unclear. Stimulation may alter epileptic networks during inter-ictal epochs. Definitions of the epileptic network vary but fast ripples (FRs) may be an important substrate. We, therefore, examined whether stimulation of FR-generating networks differed in RNS super responders and intermediate responders. In 10 patients, with subsequent RNS placement, we detected FRs from stereo-electroencephalography (SEEG) contacts during pre-surgical evaluation. The normalized coordinates of the SEEG contacts were compared with those of the eight RNS contacts, and RNS-stimulated SEEG contacts were defined as those within 1.5 cm 3 of the RNS contacts. We compared the post-RNS placement seizure outcome to (1) the ratio of stimulated SEEG contacts in the seizure-onset zone (SOZ stimulation ratio [SR]); (2) the ratio of FR events on stimulated contacts (FR SR); and (3) the global efficiency of the FR temporal correlational network on stimulated contacts (FR SGe). We found that the SOZ SR (p = .18) and FR SR (p = .06) did not differ in the RNS super responders and intermediate responders, but the FR SGe did (p = .02). In super responders, highly active desynchronous sites of the FR network were stimulated. RNS that better targets FR networks, as compared to the SOZ, may reduce epileptogenicity more., (© 2023 International League Against Epilepsy.)

Objective: Intermittent rescue therapy may be used for seizure clusters, which are clinical emergencies that may persist ≥24 h and increase risk of status epilepticus, emergency room visits, and reduced quality of life for patients with epilepsy. Beyond effectiveness for aborting seizure clusters, no data exist on how intermittent rescue therapy may impact the long-term natural course of seizure clusters. This novel analysis explores SEIzure interVAL (SEIVAL; time between seizure clusters) in patients from a long-term safety study of diazepam nasal spray (Valtoco) to assess SEIVAL changes with intermittent rescue therapy across time., Methods: Patients were aged 6-65 years. Age- and weight-based doses of diazepam nasal spray were administered during a 12-month treatment period with an optional follow-up period. SEIVAL was evaluated in patients receiving two or more doses of diazepam nasal spray using 90-day periods., Results: Of 163 treated patients, 151 had one or more SEIVALs. One hundred twenty had SEIVALs in Period 1 and one or more other periods. An increase in SEIVAL was noted from Period 1 compared with all subsequent periods (p ≤ .001). A consistent cohort (n = 76) had one or more SEIVALs in each of Periods 1-4 (360 days); mean SEIVALs increased significantly (p < .01) from 12.2 days (Period 1) to 25.7 days (Period 4). Similar SEIVAL patterns occurred when repeat doses within a seizure cluster were eliminated and irrespective of age group, treatment duration, and change to concomitant medications. In adults, Quality of Life in Epilepsy scores were maintained with increased SEIVALs., Significance: Across 12 months, increases in SEIVAL were demonstrated in patients using diazepam nasal spray for seizure cluster treatment in a phase 3 safety study. Increased time between seizure clusters may reflect a previously unrecognized beneficial effect of intermittent rescue therapy. These results generate a range of biological and behavioral hypotheses and warrant exploration of the impact of intermittent rescue therapy., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines., (© 2022 International League Against Epilepsy.)

Neuromodulation is a key therapeutic tool for clinicians managing patients with drug-resistant epilepsy. Multiple devices are available with long-term follow-up and real-world experience. The aim of this review is to give a practical summary of available neuromodulation techniques to guide the selection of modalities, focusing on patient selection for devices, common approaches and techniques for initiation of programming, and outpatient management issues. Vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (DBS-ANT), and responsive neurostimulation (RNS) are all supported by randomized controlled trials that show safety and a significant impact on seizure reduction, as well as a suggestion of reduction in the risk of sudden unexplained death in epilepsy (SUDEP). Significant seizure reductions are observed after 3 months for DBS, RNS, and VNS in randomized controlled trials, and efficacy appears to improve with time out to 7 to 10 years of follow-up for all modalities, albeit in uncontrolled follow-up or retrospective studies. A significant number of patients experience seizure-free intervals of 6 months or more with all three modalities. Number and location of epileptogenic foci are important factors affecting efficacy, and together with comorbidities such as severe mood or sleep disorders, may influence the choice of modality. Programming has evolved-DBS is typically initiated at lower current/voltage than used in the pivotal trial, whereas target charge density is lower with RNS, however generalizable optimal parameters are yet to be defined. Noninvasive brain stimulation is an emerging stimulation modality, although it is currently not used widely. In summary, clinical practice has evolved from those established in pivotal trials. Guidance is now available for clinicians who wish to expand their approach, and choice of neuromodulation technique may be tailored to individual patients based on their epilepsy characteristics, risk tolerance, and preferences., (© 2022 International League Against Epilepsy.)

Objective: The medial temporal lobe (MTL) encodes and recalls memories and can be a predominant site for interictal spikes (IS) in patients with focal epilepsy. It is unclear whether memory deficits are due to IS in the MTL producing a transient decline. Here, we investigated whether IS in the MTL subregions and lateral temporal cortex impact episodic memory encoding and recall., Methods: Seventy-eight participants undergoing presurgical evaluation for medically refractory focal epilepsy with depth electrodes placed in the temporal lobe participated in a verbal free recall task. IS were manually annotated during the pre-encoding, encoding, and recall epochs. We examined the effect of IS on word recall using mixed-effects logistic regression., Results: IS in the left hippocampus (odds ratio [OR] = .73, 95% confidence interval [CI] = .63-.84, p < .001) and left middle temporal gyrus (OR = .46, 95% CI = .27-.78, p < .05) during word encoding decreased subsequent recall performance. Within the left hippocampus, this effect was specific for area CA1 (OR = .76, 95% CI = .66-.88, p < .01) and dentate gyrus (OR = .74, 95% CI = .62-.89, p < .05). IS in other MTL subregions or inferior and superior temporal gyrus and IS occurring during the prestimulus window did not affect word encoding (p > .05). IS during retrieval in right hippocampal (OR = .22, 95% CI = .08-.63, p = .01) and parahippocampal regions (OR = .24, 95% CI = .07-.8, p < .05) reduced the probability of recalling a word., Significance: IS in medial and lateral temporal cortex contribute to transient memory decline during verbal episodic memory., (© 2022 International League Against Epilepsy.)

Clinical studies of rescue medications for seizure clusters are limited and are designed to satisfy regulatory requirements, which may not fully consider the needs of the diverse patient population that experiences seizure clusters or utilize rescue medication. The purpose of this narrative review is to examine the factors that contribute to, or may influence the quality of, seizure cluster research with a goal of improving clinical practice. We address five areas of unmet needs and provide advice for how they could enhance future trials of seizure cluster treatments. The topics addressed in this article are: (1) unaddressed end points to pursue in future studies, (2) roles for devices to enhance rescue medication clinical development programs, (3) tools to study seizure cluster prediction and prevention, (4) the value of other designs for seizure cluster studies, and (5) unique challenges of future trial paradigms for seizure clusters. By focusing on novel end points and technologies with value to patients, caregivers, and clinicians, data obtained from future studies can benefit the diverse patient population that experiences seizure clusters, providing more effective, appropriate care as well as alleviating demands on health care resources., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Current diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0-4 h after the first dose., Methods: Two datasets were analyzed. The first, a long-term, repeat-dose safety study of diazepam nasal spray, compared rates of treatment-emergent adverse events (TEAEs), serious TEAEs, and treatment-related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min-4 h) following the first dose., Results: In the repeat-dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4-24 h only (80.5%, n = 41). The most common treatment-related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min-4 h)., Significance: These data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The primary purpose is to determine whether the time between epilepsy surgery and first seizure recurrence can estimate the timing of the next seizure event for temporal and extratemporal epilepsy. A secondary endpoint aimed to compare temporal and extratemporal epilepsy surgery and examine which subgroup has a higher hazard of subsequent seizure recurrence., Methods: Data used were from a retrospective database at Thomas Jefferson University Hospital. Records were stratified into temporal (n = 943) and extratemporal (n = 125) surgeries. Analyses were done using SAS and utilized Cox proportional hazards models while controlling for demographics and clinical factors. The primary predictor of time between surgery and first recurrence was treated as a nominal variable binned into six segments, whereas secondary endpoints used a categorical predictor of epilepsy location while controlling for seizure latency., Results: Generally, as seizure latency following surgery increased, the time between first seizure and second seizure increased. These results were statistically meaningful in the temporal set (Wald chi-squared = 40.4715, df = 5, p < .0001). Outcomes could also be interpreted based on predictor group; for instance, if Seizure 1 occurred 1-2 months following surgery in the temporal set, the median number of days until the next seizure was 35.5 days (95% confidence interval [CI] = 21-89 days). Secondary analysis showed that temporal lobe epilepsy had a lower hazard of a second seizure than extratemporal lobe epilepsy (89.2% reduction in hazard; 95% CI = .015-.795)., Significance: This analysis provides a framework to use initial seizure latency to predict the median number of days until the next seizure event, while stratifying based on epilepsy location and controlling for multiple variables. It also suggests that the hazard of seizure recurrence in temporal lobe epilepsy is lower than in extratemporal lobe epilepsy., (© 2022 International League Against Epilepsy.)

Objective: An exploratory analysis from a long-term, phase 3, open-label, repeat-dose safety study of diazepam nasal spray for acute treatment of seizure clusters assessed the use of a second dose up to 24 hours after the initial dose and effectiveness in potentially reducing the number of seizures., Methods: Seizures and doses were recorded in diaries., Results: Of 175 patients enrolled, 163 received ≥1 dose of diazepam nasal spray and were included in the safety population; those patients received a total of 4390 doses for a total of 3853 seizure clusters. Less than half of these patients used a second dose a least once during the study (79 patients [48.5%]), with a total of 485 second doses for seizure clusters (12.6% of all seizure clusters). Among these 79 patients, 33 (41.8%) used only one second dose during the study (range: 1-82). The proportion of seizure clusters treated with a second dose over time was consistently low across 24 h: 0-4 h, 152 (3.9%); 4-6 h, 72 (1.9%); 6-8 h, 39 (1.0%); 8-12 h, 55 (1.4%); 12-16 h, 42 (1.1%); 16-20 h, 42 (1.1%); 20-24 h, 83 (2.2%). Rates of treatment-emergent adverse events (TEAEs) and treatment-related TEAEs occurring within 1 day of a second dose were low (15.2% and 5.1%, respectively)., Significance: Patients with epilepsy may experience seizure clusters lasting up to 24 hours, and little is known about the effectiveness of rescue therapies for that duration. The current labeling of the US Food and Drug Administration (FDA)-approved outpatient treatments for seizure clusters (rectal diazepam, intranasal midazolam, and diazepam nasal spray) allows for a second dose, if needed, for control. These findings support the safety profile of second doses, and the low use supports the effectiveness of diazepam nasal spray across 24 hours., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The International League Against Epilepsy (ILAE) seizure classification scheme has been periodically updated to improve its reliability and applicability to clinicians and researchers alike. Here, members of the Epilepsy Study Consortium propose a pragmatic seizure classification, based on the ILAE scheme, designed for use in clinical trials with a focus on outcome measures that have high reliability, broad interpretability across stakeholders, and clinical relevance in the context of the development of novel antiseizure medications. Controversies around the current ILAE classification scheme are discussed in the context of clinical trials, and pragmatic simplifications to the existing scheme are proposed, for intended use by investigators, industry sponsors, and regulatory agencies., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To report post hoc results on how adjustments to baseline antiseizure medications (ASMs) in a subset of study sites (10 US sites) from a long-term, open-label phase 3 study of adjunctive cenobamate affected tolerability, efficacy, and retention., Methods: Patients with uncontrolled focal seizures taking stable doses of one to three ASMs were administered increasing doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50 mg/day biweekly increments were allowed during maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until last visit, at data cut-off, on or after September 1, 2019., Results: A total of 240 patients meeting eligibility criteria were assessed (median [max] exposure 30.2 [43.0] months), with 177 patients continuing cenobamate at data cut-off. Most common baseline concomitant ASMs were lacosamide, levetiracetam, lamotrigine, zonisamide, and clobazam. For most baseline concomitant ASMs, ~70% of patients taking that ASM were continuing cenobamate at data cut-off. Patients continuing cenobamate had greater mean ASM dose reductions and percent dose changes from baseline vs those who discontinued. Of patients continuing cenobamate, 24.6% discontinued one or more concomitant ASMs completely. Dose decreases for all concomitant ASMs generally occurred during titration or early maintenance phases and were mostly due to central nervous system (CNS)-related adverse events such as somnolence, dizziness, unsteady gait, and fatigue. Responder rates from ≥50% through 100% for patients continuing cenobamate were generally similar regardless of concomitant ASMs (of those most commonly taken), with ~81% being ≥50% responders and ~12% achieving 100% seizure reduction in the maintenance phase, which lasted up to 40.2 (median = 29.5) months., Significance: Concomitant ASM dose reductions were associated with more patients remaining on cenobamate. This is likely due to efficacy and improved tolerability, with overall reduced concomitant drug burden in patients with uncontrolled seizures despite taking one to three baseline concomitant ASMs., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To report long-term post hoc efficacy and safety data from 10 US study sites from an open-label Phase 3 study of adjunctive cenobamate (NCT02535091)., Methods: Patients with uncontrolled focal seizures taking stable doses of 1-3 antiseizure medications (ASMs) were administered increasing daily doses of cenobamate (12.5, 25, 50, 100, 150, 200 mg/day) over 12 weeks at 2-week intervals (target dose = 200 mg/day). Further increases to 400 mg/day by 50-mg/day increments biweekly were allowed during the maintenance phase. Dose adjustments of cenobamate and concomitant ASMs were allowed. Data were assessed until the last clinic visit on or after September 1, 2019., Results: Of 255 patients, 240 with focal aware motor, focal impaired awareness, or focal to bilateral tonic-clonic seizure data while on treatment were evaluated (median [maximum] exposure = 30.2 [43.0] months across the entire study). Median baseline seizure frequency/28 days was 2.8 (mean = 18.1). Of the 240 patients, 177 (73.8%) were continuing cenobamate treatment at data cutoff. The ≥50% responder rate for the total treatment duration was 71.7% (172/240). During titration, the ≥50% responder rates were 48.1% during Weeks 1-4 (12.5-25 mg/day cenobamate) and 61.7% during Weeks 5-8 (50-100 mg/day cenobamate). Among all patients who received a dose of cenobamate in the maintenance phase (n = 214), 13.1% (28/214) and 40.2% (86/214) achieved 100% and ≥90% seizure reduction during their entire maintenance treatment duration (median = 29.5 months). Among all patients, 87 (36.3%) had any consecutive ≥12-month duration of 100% seizure reduction. Common treatment-emergent adverse events among all 240 patients included fatigue (34.6%), dizziness (32.1%), and somnolence (29.6%)., Significance: This post hoc analysis of a subset of patients from the long-term open-label study showed high rates of sustained 100% and ≥90% seizure reduction, with many achieving response early during titration. These findings suggest durable seizure frequency reduction with cenobamate in adults with uncontrolled focal seizures., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Interictal epileptiform discharges (IEDs) were shown to be associated with cognitive impairment in persons with epilepsy. Previous studies indicated that IED rate, location, timing, and spatial relation to the seizure onset zone could predict an IED's impact on memory encoding and retrieval if they occurred in lateral temporal, mesial temporal, or parietal regions. In this study, we explore the influence that other IED properties (e.g., amplitude, duration, white matter classification) have on memory performance. We were specifically interested in investigating the influence that lateral temporal IEDs have on memory encoding., Methods: Two hundred sixty-one subjects with medication-refractory epilepsy undergoing intracranial electroencephalographic monitoring performed multiple sessions of a delayed free-recall task (n = 671). Generalized linear mixed models were utilized to examine the relationship between IED properties and memory performance., Results: We found that increased IED rate, IEDs propagating in white matter, and IEDs localized to the left middle temporal region were associated with poorer memory performance. For lateral temporal IEDs, we observed a significant interaction between IED white matter categorization and amplitude, where IEDs with an increased amplitude and white matter propagation were associated with reduced memory performance. Additionally, changes in alpha power after an IED showed a significant positive correlation with memory performance., Significance: Our results suggest that IED properties may be useful for predicting the impact an IED has on memory encoding. We provide an essential step toward understanding pathological versus potentially beneficial interictal epileptiform activity., (© 2021 International League Against Epilepsy.)

Objective: In epilepsy surgery, which aims to treat seizures and thereby to improve the lives of persons with drug-resistant epilepsy, the chances of attaining seizure relief must be carefully weighed against the risks of complications and expected adverse events. The interpretation of data regarding complications of epilepsy surgery and invasive diagnostic procedures is hampered by a lack of uniform definitions and method of data collection., Methods: Based on a review of previous definitions and classifications of complications, we developed a proposal for a new classification. This proposal was then subject to revisions after expert opinion within E-pilepsy, an EU-funded European pilot network of reference centers in refractory epilepsy and epilepsy surgery, later incorporated into the ERN (European Reference Network) EpiCARE. This version was discussed with recognized experts, and a final protocol was agreed to after further revision. The final protocol was evaluated in practical use over 1 year in three of the participating centers. One hundred seventy-four consecutive procedures were included with 35 reported complications., Results: This report presents a multidimensional classification of complications in epilepsy surgery and invasive diagnostic procedures, where complications are characterized in terms of their immediate effects, resulting permanent symptoms, and consequences on activities of daily living., Significance: We propose that the protocol will be helpful in the work to promote safety in epilepsy surgery and for future studies designed to identify risk factors for complications. Further work is needed to address the reporting of outcomes as regards neuropsychological function, activities of daily living, and quality of life., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: A Phase 3 open-label safety study (NCT02721069) evaluated long-term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters., Methods: Patients were 6-65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment-emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded., Results: Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment (n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis., Significance: In this large open-label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To develop and validate a pragmatic algorithm that classifies seizure types, to facilitate therapeutic decision-making., Methods: Using a modified Delphi method, five experts developed a pragmatic classification of nine types of epileptic seizures or combinations of seizures that influence choice of medication, and constructed a simple algorithm, freely available on the internet. The algorithm consists of seven questions applicable to patients with seizure onset at the age of 10 years or older. Questions to screen for nonepileptic attacks were added. Junior physicians, nurses, and physician assistants applied the algorithm to consecutive patients in a multicenter prospective validation study (ClinicalTrials.gov identifier: NCT03796520). The reference standard was the seizure classification by expert epileptologists, based on all available data, including electroencephalogram (EEG), video-EEG monitoring, and neuroimaging. In addition, physicians working in underserved areas assessed the feasibility of using the web-based algorithm in their clinical setting., Results: A total of 262 patients were assessed, of whom 157 had focal, 51 had generalized, and 10 had unknown onset epileptic seizures, and 44 had nonepileptic paroxysmal events. Agreement between the algorithm and the expert classification was 83.2% (95% confidence interval = 78.6%-87.8%), with an agreement coefficient (AC1) of .82 (95% confidence interval = .77-.87), indicating almost perfect agreement. Thirty-two health care professionals from 14 countries evaluated the feasibility of the web-based algorithm in their clinical setting, and found it applicable and useful for their practice (median = 6.5 on 7-point Likert scale)., Significance: The web-based algorithm provides an accurate classification of seizure types, which can be used for selecting antiseizure medications in adolescents and adults., (© 2021 International League Against Epilepsy.)

Objective: This study was undertaken to examine long-term (up to 7.8 years) retention rate, safety, and tolerability of the antiseizure medication (ASM) cenobamate as adjunctive treatment in the open-label extension (OLE) of study YKP3089C013 (C013; ClinicalTrials.gov: NCT01397968)., Methods: Patients who completed the 12-week, multicenter, multinational, double-blind, randomized, placebo-controlled C013 study, which examined adjunctive cenobamate treatment of adults with uncontrolled focal seizures, were eligible to enroll in the OLE. During the OLE, dose adjustments of cenobamate and concomitant ASMs were allowed. Safety assessments included frequency of treatment-emergent adverse events (TEAEs) and serious TEAEs, TEAE severity, and TEAEs leading to discontinuation. Probability of patient continuation in the OLE was examined using a Kaplan-Meier analysis., Results: One hundred forty-nine patients entered the OLE (median duration of cenobamate treatment = 6.25 years). As of the data cutoff, 57% of patients (85/149) remained in the OLE (median treatment duration = 6.8 years, range = 6.4-7.8 years). The median modal daily cenobamate dose was 200 mg (range = 50-400 mg). The probability of treatment continuation at 1-6 years of cenobamate treatment was 73%, 67%, 63%, 61%, 60%, and 59%, respectively. Among patients who continued at 1 year (n = 107), the probability of continuing at Years 2-5 was 92%, 87%, 83%, and 82%. The most common discontinuation reasons were patient withdrawal (19.5%, 29/149), adverse event (10.1%, 15/149), and lack of efficacy (5.4%, 8/149). TEAEs leading to discontinuation in 1% or more of patients were fatigue (1.3%, 2/149), ataxia (1.3%, 2/149), and memory impairment or amnesia (1.3%, 2/149). Dizziness (32.9%, 49/149), headache (26.8%, 40/149), and somnolence (21.5%, 32/149) were the most frequently reported TEAEs and were primarily mild or moderate in severity., Significance: Long-term retention in the C013 OLE study demonstrated sustained safety and tolerability of adjunctive cenobamate treatment up to 7.8 years in adults with treatment-resistant focal seizures taking one to three ASMs., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in epilepsy. The aim of this study is to evaluate the validity of the SUDEP-7 inventory and its components as tools for predicting SUDEP risk, and to develop and validate an improved inventory., Methods: The study included 28 patients who underwent video-electroencephalography (EEG) monitoring and later died of SUDEP, and 56 age- and sex-matched control patients with epilepsy. The SUDEP-7 score, its individual components, and an alternative inventory were examined as predictors of SUDEP., Results: SUDEP-7 scores were significantly higher among SUDEP patients compared with controls, both at time of admission (p = 0.024) and most recent follow-up (p = 0.016). SUDEP-7 scores declined only among controls, who demonstrated reduced seizure frequency. Seizure freedom after epilepsy surgery was also associated with survival. Several components of the SUDEP-7 inventory were independently associated with higher risk of SUDEP, including more than three generalized tonic-clonic (GTC) seizures (p = 0.002), one or more GTC seizures (p = 0.001), or one or more seizures of any type within the last year (p = 0.013), and intellectual disability (p = 0.031). In stepwise regression models, SUDEP-7 scores did not enhance the prediction of SUDEP over either GTC seizure frequency or seizure frequency alone. A novel SUDEP-3 inventory comprising GTC seizure frequency, seizure frequency, and intellectual disability (p < 0.001) outperformed the SUDEP-7 inventory (p = 0.010) in predicting SUDEP., Significance: Our findings demonstrate the limitations of the SUDEP-7 inventory. We propose a new three-item SUDEP-3 inventory, which predicts SUDEP better than the SUDEP-7., (© 2021 International League Against Epilepsy.)

Objective: Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness., Methods: A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen., Results: Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam., Significance: This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study., Methods: After the 3-month blinded and 9-month unblinded phases, subjects continued to be assessed during long-term follow-up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed., Results: One hundred ten implanted subjects accumulated a total of 938 device-years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow-up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic-clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite-plus-probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person-years. Overall mortality was 6.9 deaths per 1000 person-years., Significance: The long-term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug-resistant focal epilepsy., (© 2021 International League Against Epilepsy.)

Objective: To determine if long interspersed element-1 (L1) retrotransposons convey risk for idiopathic temporal lobe epilepsy (TLE)., Methods: Surgically resected temporal cortex from individuals with TLE (N = 33) and postmortem temporal cortex from individuals with no known neurological disease (N = 33) were analyzed for L1 content by Restriction Enzyme Based Enriched L1Hs sequencing (REBELseq). Expression of three KCNIP4 splice variants was assessed by droplet digital PCR (ddPCR). Protein ANalysis THrough Evolutionary Relationships (PANTHER) was used to determine ontologies and pathways for lists of genes harboring L1 insertions., Results: We identified novel L1 insertions specific to individuals with TLE, and others specific to controls. Although there were no statistically significant differences between cases and controls in the numbers of known and novel L1 insertions, PANTHER analyses of intragenic L1 insertions showed statistically significant enrichments for epilepsy-relevant gene ontologies in both cases and controls. Gene ontologies "neuron projection development" and "calcium ion transmembrane transport" were among those found only in individuals with TLE. We confirmed novel L1 insertions in several genes associated with seizures/epilepsy, including a de novo somatic L1 retrotransposition in KCNIP4 that occurred after neural crest formation in one patient. However, ddPCR results suggest this de novo L1 did not alter KCNIP4 mRNA expression., Significance: Given current data from this small cohort, we conclude that L1 elements, either rare heritable germline insertions or de novo somatic retrotranspositions, may contribute only minimally to overall genetic risk for idiopathic TLE. We suggest that further studies in additional patients and additional brain regions are warranted., (© 2021 International League Against Epilepsy.)

Objective: This study was undertaken to identify clinical factors associated with seizure freedom after magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) in temporal lobe epilepsy patients with unilateral mesial temporal sclerosis (MTS)., Methods: We identified 56 patients with magnetic resonance imaging-defined MTS who underwent MRgLiTT with at least 1 year of follow-up. Primary outcome was seizure freedom at 1 year. We examined the association of seizure freedom and the following clinical factors: age at surgery, gender, history of febrile seizures, history of focal to bilateral tonic-clonic seizures, duration of epilepsy at the time of surgery, frequency of interictal epileptiform discharges (IEDs), seizure frequency, and presence of bilateral IEDs., Results: Thirty-five (62.5%) patients were seizure-free at 1 year. The presence of bilateral IEDs and age at surgery were associated with 1-year seizure freedom after MRgLiTT. The presence of bilateral IEDS was associated with lower odds of seizure freedom (odds ratio [OR] = .05, 95% confidence interval [CI] = .01-.46, p = .008), whereas increasing age at surgery was associated with increased odds of seizure freedom (OR = 1.10, 95% CI = 1.03-1.19, p = .009)., Significance: This study demonstrates associations between presence of bilateral IEDs and age at surgery and seizure freedom at 1 year after MRgLiTT., (© 2021 International League Against Epilepsy.)

Objective: This study was undertaken to evaluate the influence that subject-specific factors have on intracranial interictal epileptiform discharge (IED) rates in persons with refractory epilepsy., Methods: One hundred fifty subjects with intracranial electrodes performed multiple sessions of a free recall memory task; this standardized task controlled for subject attention levels. We utilized a dominance analysis to rank the importance of subject-specific factors based on their relative influence on IED rates. Linear mixed-effects models were employed to comprehensively examine factors with highly ranked importance., Results: Antiseizure medication (ASM) status, time of testing, and seizure onset zone (SOZ) location were the highest-ranking factors in terms of their impact on IED rates. The average IED rate of electrodes in SOZs was 34% higher than the average IED rate of electrodes outside of SOZs (non-SOZ; p < .001). However, non-SOZ electrodes had similar IED rates regardless of the subject's SOZ location (p = .99). Subjects on older generation (p < .001) and combined generation (p < .001) ASM regimens had significantly lower IED rates relative to the group taking no ASMs; newer generation ASM regimens demonstrated a nonsignificant association with IED rates (p = .13). Of the ASMs included in this study, the following ASMs were associated with significant reductions in IED rates: levetiracetam (p < .001), carbamazepine (p < .001), lacosamide (p = .03), zonisamide (p = .01), lamotrigine (p = .03), phenytoin (p = .03), and topiramate (p = .01). We observed a nonsignificant association between time of testing and IED rates (morning-afternoon p = .15, morning-evening p = .85, afternoon-evening p = .26)., Significance: The current study ranks the relative influence that subject-specific factors have on IED rates and highlights the importance of considering certain factors, such as SOZ location and ASM status, when analyzing IEDs for clinical or research purposes., (© 2020 International League Against Epilepsy.)

Objective: Optimal choice of antiseizure medication (ASM) depends on seizure type, syndrome, age, gender, comorbidities and co-medications. There are no fixed rules on how to weigh these factors; choices are subjective and experience-driven. We investigated agreement among experts in selecting ASM as monotherapy and used their prevailing choices to validate a web-based decision-support application., Methods: Twenty-four international experts, blinded to the app, selected the optimal ASM for 25 individual patient-cases covering a wide variation of seizure types and other factors influencing ASM selection. The app ranked ASMs in order of likely appropriateness for each case. In a second step, experts rated anonymously the choices of the app., Results: Of the 25 patient-cases (age 13-74 years), 13 were female, 18 (72%) had comorbidities, six (24%) were on contraceptives, and 13 (52%) had other co-medications. The median number of experts who selected the same ASM for a given case was 15 (62.5%) and interquartile range (IQR) 13-18 (54%-75%). Gwet's agreement coefficient among experts was 0.38 (95% confidence interval [CI] 0.32-0.44), corresponding to a "fair" agreement. Agreement between the app and the prevailing expert choice for each case was 0.48 (95% CI 0.29-0.67), corresponding to a "moderate" beyond chance agreement. The percent agreement between the highest ranked selections of the app and the expert selections was 73% (95% CI 64%-82%). Ninety-five percent of the experts considered that no incorrect or potentially harmful ASMs were ranked highest by the app, and most experts strongly agreed with the app's selections., Significance: This app, now validated by experts, provides an objective, reproducible method for selecting ASM that accounts for relevant clinical features. It is freely available at: https://epipick.org., (© 2020 International League Against Epilepsy.)

In patients with epilepsy, the potential to prevent seizure-related injuries and to improve the unreliability of seizure self-report have fostered the development and marketing of numerous seizure detection devices for home use. Understanding the requirements of users (patients and caregivers) is essential to improve adherence and mitigate barriers to the long-term use of such devices. Here we reviewed the evidence on the needs and preferences of users and provided an overview of currently marketed devices for seizure detection (medically approved or with published evidence for their performance). We then compared devices with known needs. Seizure-detection devices are expected to improve safety and clinical and self-management, and to provide reassurance to users. Key factors affecting a device's usability relate to its design (attractive appearance, low visibility, low intrusiveness), comfort of use, confidentiality of recorded data, and timely support from both technical and clinical ends. High detection sensitivity and low false alarm rates are paramount. Currently marketed devices are focused primarily on the recording of non-electroencephalography (EEG) signals associated with tonic-clonic seizures, whereas the detection of focal seizures without major motor features remains a clear evidence gap. Moreover, there is paucity of evidence coming from real-life settings. A joint effort of clinical and nonclinical experts, patients, and caregivers is required to ensure an optimal level of acceptability and usability, which are key aspects for a successful continuous monitoring aimed at seizure detection at home., (© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Olfactory dysfunction has been well documented in individuals with temporal lobe epilepsy, but its use in presurgical planning has yet to be examined. We assessed the role of preoperative odor identification in mesial onset seizure localization utilizing stereoelectroencephalography (S-EEG) and magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) outcome., Methods: We identified 30 patients who had typical seizures captured during S-EEG monitoring or MRgLiTT of mesial temporal structures (n = 17 S-EEG, n = 13 MRgLiTT); seizure onset zone was classified as unilateral mesial seizure onset, or multifocal with unilateral mesial onset and nonmesial onset. Odor identification ability was assessed using the Sniffin' Sticks Odor Identification Test (SSOIT). Patients also completed measures of confrontation naming and auditory-verbal learning/memory using the Boston Naming Test and Hopkins Verbal Learning Test-Revised, respectively., Results: Overall, patients with intractable focal epilepsy exhibited poor olfactory performance (median [M] = 10.4, interquartile range [IQR] = 9.4-11.8). Of 19 patients who underwent MRgLiTT, 10 patients (52.6%) were seizure-free at last follow-up (M = 13 months, IQR =10-18). Patients who were seizure-free after MRgLiTT (n = 10) had poorer odor identification scores (M = 9, IQR = 7-13) compared to patients with seizure reoccurrence (M = 13, IQR = 12.5-15). Odor identification score was inversely associated with seizure freedom, with odds ratio = 0.60 (95% confidence interval [CI] = 0.38-0.95, P = .03). Receiver operating characteristic analysis revealed that an SSOIT score of 12 was the ideal cutoff for predicting favorable seizure outcome (area under the curve = 0.84, 95% CI = 0.64-1.0). Sensitivity was 88.9% and specificity was 78.9%, with a likelihood ratio of 2.9 of seizure failure in patients who had an odor identification score ≥ 12., Significance: Interictal olfactory dysfunction is commonly seen in patients with intractable focal epilepsy. Odor identification is a novel, noninvasive presurgical biomarker to distinguish who may or may not benefit from MRgLiTT of mesial temporal structures., (© 2020 International League Against Epilepsy.)

Objective: Antiseizure medications (ASMs) are the first-line treatment for epilepsy. Many ASMs are available; this offers the opportunity to improve therapy by tailoring it to individual characteristics, but also increases the possibility of healthcare professionals making inappropriate treatment choices. To assist healthcare professionals, we developed a pragmatic algorithm aimed at facilitating medication selection for individuals whose epilepsy begins at age 10 years and older., Methods: Utilizing available evidence and a Delphi panel-based consensus process, a group of epilepsy experts developed an algorithm for selection of ASMs, depending on the seizure type(s) and the presence of relevant clinical variables (age, gender, comorbidities, and comedications). The algorithm was implemented into a web-based application that was tested and improved in an iterative process., Results: The algorithm categorizes ASMs deemed to be appropriate for each seizure type or combination of seizure types into three groups, with group 1 ASMs considered preferred, group 2 considered second line, and group 3 considered third line. Depending on the presence of relevant clinical variables, the ranking of individual ASMs is adjusted in the prioritization scheme to tailor recommendations to the characteristics of the individual. The algorithm is available on a web-based application at: https://epipick.org/#/., Significance: The proposed algorithm is user-friendly, requires less than 2 minutes to complete, and provides the user with a range of appropriate treatment options from which to choose. This should facilitate its broad utilization and contribute to improve epilepsy management for healthcare providers who desire advice, particularly those who lack special expertise in the field., (© 2020 International League Against Epilepsy.)