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Objective: To describe the prescription patterns of home, non-intravenous rescue benzodiazepines (non-IV-rBZDs) for febrile seizures and the factors associated with their prescription., Methods: Retrospective descriptive study using the MarketScan Commercial Database, a large database of employer-sponsored privately insured patients in the United States. We used data from January 1st 2006 to December 31st 2022. We studied patients with febrile seizures as the main code for the healthcare encounter (identified with International Classification of Diseases codes) with age from 6 months to 5 years of age and with at least 1 month of follow-up., Results: There were a total of 82,835 patients [median (p 25 -p 75 ) age 1.0 (1.0-2.0) years, 56.7 % males] with at least one febrile seizure, of whom 9,737 (11.8 %) filled at least one non-IV-rBZD prescription. Among the 9,737 patients who filled at least one prescription, the median (p 25 -p 75 ) time from first febrile seizure to non-IV-rBZD prescription was 27 (2-186) days. Among the factors known at the time of the first febrile seizure, complex febrile seizure (OR: 3.51, 95 % CI: 3.24-3.79), and an initial inpatient hospitalization for febrile seizure (OR: 3.53, 95 % CI: 3.29-3.79) were the factors most strongly associated with filling a non-IV-rBZD prescription. In contrast, sex, rural patient's residence, and salary employment (versus other employment class) were not independently associated with filling a non-IV-rBZD prescription. Among the factors known at the end of follow-up, complex febrile seizures, type of initial encounter, and an eventual diagnosis of epilepsy were major independent factors associated with filling a non-IV-rBZD prescription., Conclusion: Only approximately 12 % of children with a febrile seizure filled a prescription for a home non-IV-rBZD. The major factors independently associated with prescription were complex febrile seizure, hospital admission, recurrent febrile seizures, and an eventual diagnosis of epilepsy., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest related to this manuscript., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To describe the changes in Food and Drug Administration (FDA)-approved non-intravenous rescue benzodiazepine (non-IV-rBZD) use and cost after the introduction of intranasal midazolam and intranasal diazepam., Methods: Retrospective descriptive study using the MarketScan Database between the years 2016 and 2022. We considered patients who had at least one non-IV-rBZD prescription before the introduction of intranasal rescue medications and at least one non-IV-rBZD prescription after the introduction of intranasal rescue medications., Results: There were 4,444 patients (45.8 % female, median (p 25 -p 75 ) age of 10.0 (5.0-15.0) years). 2,255 of 4,444 (50.7 %) patients switched from rectal diazepam to either intranasal midazolam (1,110 (25.0 %)) or intranasal diazepam (1,145 (25.8 %)) as their last non-IV-rBZD. The change from rectal to intranasal non-IV-rBZDs has been increasing over the years from 2019 to 2022. On multivariable analysis, having a non-IV-rBZD for epilepsy (rather than for other reasons including febrile seizures), the year of the last rescue medication, urban (non-rural) patient's residence, and certain regions of the United States were the factors most strongly associated with a change from rectal diazepam to intranasal non-IV-rBZDs. After adjusting for inflation, the median (p 25 -p 75 ) average wholesale price (AWP) of the last non-IV-rBZD was higher than that of the first non-IV-rBZD [702 (406-748) versus 417 (406-426), Wilcoxon signed rank test p < 0.0001)]. This difference was mainly driven by the patients who changed from rectal diazepam to intranasal non-IV-rBZD [748 (714-755) versus 417 (406-426), Wilcoxon signed rank test p < 0.0001)]. After adjusting for inflation, the median (p 25 -p 75 ) patient cost of the last non-IV-rBZD was higher than that of the first non-IV-rBZD [16 (3-55) versus 12 (6-31), Wilcoxon signed rank test p < 0.0001)]. This difference was mainly driven by the patients who changed from rectal diazepam to intranasal non-IV-rBZD [41 (6-83) versus 12 (6-30), Wilcoxon signed rank test p < 0.0001)]., Conclusion: Approximately half of patients changed from rectal diazepam to intranasal midazolam or intranasal diazepam and that transition has been progressively increasing from the year 2019 to the year 2022. The inflation-adjusted AWP and patient cost increased, especially among those patients who changed from rectal to intranasal rescue medication., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The USA spends more in healthcare per capita than any other country in the world, but ranks last among high-income industrialized nations in major markers of healthcare effectiveness such as life expectancy, maternal mortality, neonatal mortality, and infant mortality. Unlike other high-income industrialized nations, the USA does not have a national agency that systematically evaluates the cost-effectiveness of health care interventions and negotiates their price accordingly. This manuscript aims to introduce the rationale, terminology, advantages, and limitations of cost-effectiveness analysis. Cost-effectiveness analysis compares health interventions and evaluates their incremental value and their incremental cost compared with already existing healthcare interventions. Cost-effectiveness analysis integrates the best available evidence with patients' preferences to inform clinical decision making. Patients with neurological conditions are facing increasing challenges to access healthcare and prescription drugs. Cost-effectiveness analysis may help improve access to the most effective healthcare interventions and prescription drugs while containing healthcare costs., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To describe the evolution in use and cost of antiseizure medications (ASM) in the United States of America (USA)., Methods: Retrospective descriptive study using the IBM MarketScan Commercial Database (data of privately-insured patients) for the years 2006 to 2021. We identified patients with epilepsy who were on ASM. We adjusted cost for inflation with the Gross Domestic Product Implicit Price Deflator., Results: We evaluated 347,158 patients (46.9 % males; median (p 25 -p 75 ) age: 33 (17-49) years; 28 % with pediatric-onset epilepsy and 72 % with adult-onset epilepsy) with a total of 1,385,382 person-years and 588,285,065 ASM prescription days. The most commonly prescribed (as percentage of prescription days) ASMs in 2006 were valproate (18 %) and lamotrigine (17 %) in pediatric-onset epilepsy and phenytoin (21 %) and carbamazepine (17 %) in adult-onset epilepsy, but starting in the 2010s, levetiracetam and lamotrigine became the most commonly prescribed ASMs in both pediatric-onset (in 2021, levetiracetam 25 %, lamotrigine 16 %) and adult-onset (in 2021, levetiracetam 27 %, lamotrigine 20 %) epilepsy. The proportion of generic ASM use increased 3.6-fold: from 23 % of prescription days in 2006 to 83 % of prescription days in 2021. The median (p 25 -p 75 ) average wholesale price (AWP) per person-year increased by 102 % from $2,684 ($990-$5,509) in 2006 to $5,417 ($2,858-$12,310) in 2021. The increases were greater in absolute terms for brand-name ASMs by 419 %: $3,109 ($1,564-$5,068 in 2006 and $16,149 ($12,950-$23,377) in 2021 than for generic ASMs by 462 %: $699 ($457-$1,678) in 2006 and $3,931 ($2,618-$6,081) in 2021. The costs directly borne by the patient (copay, coinsurance, deductibles, and pharmacy processing fees) increased by 69 % for brand-name ASMs from $393 ($246-$570) in 2006 to $665 ($335-$1,308) in 2021, but decreased by 37 % for generic ASMs from $147 ($98-$213) in 2006 to $92 ($51-$141) in 2021., Conclusions: The median cost of ASMs per person-year approximately doubled from 2006 to 2021. The increase in use of generic ASMs probably helped buffer the growing costs of ASMs. However, generic ASMs already represent 83 % of prescription days in 2021, with limited room to further contain costs by just increasing the proportion of generics., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest related to this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Purpose: Delayed treatment in status epilepticus (SE) is independently associated with increased treatment resistance, morbidity, and mortality. We describe the prehospital management pathway and Emergency Medical Services (EMS) timeliness in children who developed refractory convulsive status epilepticus (RCSE)., Methods: Retrospective multicenter study in the United States using prospectively collected observational data from June 2011 to March 2020. We selected pediatric patients (one month-21 years) with RCSE initiated outside the hospital and transported to the hospital by EMS., Results: We included 91 patients with a median (percentile 25 -percentile 75 ) age of 3.0 (1.5-7.3) years. The median time from seizure onset to hospital arrival was 45 (30-67) minutes, with a median time cared for by EMS of 24 (15-36) minutes. Considering treatment by caregivers and EMS before hospital arrival, 20 (22%) patients did not receive any anti-seizure medications (ASM) and 71 (78%) received one to five doses of benzodiazepines (BZD), without non-BZD ASM. We provided the prehospital treatment flow path of these patients through caregivers and EMS including relevant time points. Patients with a history of SE were more likely to receive the first BZD in the prehospital setting compared to patients without a history of SE (adjusted HR 3.25, 95% CI 1.72-6.12, p<0.001)., Conclusion: In this multicenter study of pediatric RCSE, prehospital treatment may be streamlined further. Patients with a history of SE were more likely to receive prehospital rescue medication., Competing Interests: Declaration of Competing Interest M.A.G. was supported by Fundación Alfonso Martín Escudero and the Epilepsy Research Fund. I.S.F. was supported by Fundación Alfonso Martín Escudero, the HHV6 Foundation, and the Epilepsy Research Fund. R.A. receives research support from NIH NINDS R01 NS115929 and Procter Foundation (Procter Scholar Award 2018–2021). C.B.A. was supported by Fundación Alfonso Martín Escudero. J.N.B. has served as a consultant for Novartis. T.A.G. is funded by NIH grants 2U01-NS045911, U10-NS077311, R01-NS053998, R01-NS062756, R01- NS043209, R01-LM011124, and R01-NS065840. He has received consulting fees from Supernus, Sunovion, Eisai, and UCB. He also serves as an expert consultant for the US Department of Justice and has received compensation for work as an expert on medico-legal cases. He receives royalties from a patent license. E.J.N. is a professional advisory board of the Epilepsy Foundation of America and served on Advisory Board for Zogenix. J.J.R. is a member of a data safety monitoring board for GW Pharmaceuticals. His-spouse is an editor for Uptodate. D.T. receives research funding from Children's Miracle Network Hospitals and has previously received consultation fees from Gerson Lehrman Group, Guidepoint, IQVIA, and bioStrategies Group. M.S.W. serves as a scientific consultant and on the clinical advisory board for Sage Pharmaceuticals. A.W. receives research funding from Novartis, Eisai, Pfizer, UCB, Acorda, Lundbeck, GW Pharma, Upsher-Smith, and Zogenix and receives publication royalties from Up to date. T.L. is part of pending patent applications to detect and predict seizures and diagnose epilepsy. He receives research support from the NIH, the Epilepsy Research Fund, the Epilepsy Foundation of America Epilepsy Venture Fund (Shark Tank Award), MIKU, and Epitel. He received device donations from Epitel, MIKU, Empatica, and neuroelectrics. In the past, he received research grants from Sage, Lundbeck, Eisai, Upsher-Smith, Proximagen, UCB, Mallinckrodt, Pfizer, and Empatica. In the past, he served as a consultant for Engage and Upsher Smith. The remaining authors have no disclosures relevant to this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Cognitive and Behavioral Comorbidities: AN UNWANTED EFFECT OF ANTIEPILEPTIC DRUGS IN CHILDREN: Adriana Ulate-Campos, Iván Sánchez Fernández Seminars in Pediatric Neurology Volume 24, Issue 4, November 2017, Pages 320-330 Epilepsy is one of the most common neurological disorders and, despite optimally chosen and dosed antiepileptic drugs (AEDs), approximately 20%-30% of patients will continue to have seizures. Behavior and cognition are negatively impacted by seizures, but AEDs are also a major contributor to behavioral and cognitive deficits. However, the cognitive and behavioral effect of AEDs in children is insufficiently emphasized in the literature. This review summarizes the cognitive and behavioral effects of AEDs in the pediatric population with the objective of helping pediatricians and pediatric neurologists to select the AEDs with the best profile for their individual patient's needs., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To describe the temporal trends in the cost and use of adrenocorticotropic hormone (ACTH), oral prednisolone, and vigabatrin, the first-line treatments for infantile epileptic spasms syndrome (IESS)., Methods: Retrospective observational study using the MarketScan Commercial database from 2006 to 2020. We identified patients with IESS diagnosed between birth and 18 months of age who received at least one of the first-line treatments within 60 days of diagnosis. Costs were adjusted for inflation using the Gross Domestic Product Implicit Price Deflator., Results: A total of 1131 patients received at least one first-line treatment (median [p 25 -p 75 ] age: 6.3 [4.5-8.3] months, 55% male), of whom 592 patients received ACTH, 363 patients received oral prednisolone, and 355 patients received vigabatrin. After adjusting for inflation, the median average wholesale price of a 14-day course of treatment increased for ACTH from $3718 in 2006 to $100 457 in 2020, ~2700% (by a factor of 27), whereas it decreased for oral prednisolone from $169 in 2006 to $89 in 2020, ~50% (by a factor of 0.5), and increased for vigabatrin from $1206 in 2009 (first year with data on vigabatrin used for IESS) to $4102 in 2020, ~340% (by a factor of 3.4). During the first 60 days after diagnosis, inpatient admission days and costs where higher for ACTH than for oral prednisolone and vigabatrin-5.0 (3.0-8.3) days vs 2.0 (0.0-5.0) days vs 2.0 (0.0-6.0) days, p < .0001; and $32 828 ($14 711-$67 216) vs $16 227 ($0-$35 829) vs $17 844 ($0-$47 642), p < .0001. ACTH use decreased from representing 78% of first-line treatments in 2006 to 18% in 2020 (p < .0001). Sensitivity analyses confirmed the robustness of the results., Significance: The gap between the cost of ACTH and the cost of oral prednisolone or vigabatrin has widened markedly from 2006 to 2020, whereas the relative proportion of ACTH use has decreased., (© 2023 International League Against Epilepsy.)

Objective: To describe the demographics of epilepsy surgery utilization and its impact on health care resource use., Methods: Retrospective descriptive study using the MarketScan commercial claims database. We studied children and adults who underwent epilepsy surgery in the USA in the period 2006-2019. Our main outcome was health care resource utilization., Results: Among the 87,368 patients with refractory epilepsy, 2,011 (2.3%) patients underwent resective epilepsy surgery, 188 (0.2%) patients underwent partial or total hemispherectomy, and 183 (0.2%) patients underwent corpus callosotomy. The proportion of patients undergoing epilepsy surgery has barely increased in the period 2006 to 2019. The year of resective epilepsy surgery was associated with high healthcare costs per person-year [median (p 25 -p 75 ): $140,322 ($88,749-$225,862)], but healthcare costs per person-year substantially decreased in the 5 years after compared to the 5 years before the year of resective epilepsy surgery [$7,691 ($2,738-$22,092) versus $18,750 ($7,361-$47,082), p-value < 0.0001]. This result held in all resective epilepsy surgery subgroups: children, adults, temporal, extratemporal, subdural EEG monitoring, stereoEEG monitoring, and no intracranial monitoring. Similarly, the year of hemispherectomy was associated with high healthcare costs per person-year [$260,983 ($154,791-$453,986)], but healthcare costs per person-year substantially decreased in the 5 years after compared to the 5 years before the year of hemispherectomy [$26,834 ($12,842-$52,627) versus $54,596 ($19,547-$136,412), p-value < 0.0001]. In contrast, the year of corpus callosotomy was associated with high healthcare costs per person-year [$162,399 ($108,150-$253,156)], but healthcare costs per person-year did not substantially decrease in the 5 years after than in the 5 years before the year of corpus callosotomy [$25,464 ($10,764-$69,338) versus $36,221 ($12,841-$85,747), p-value = 0.2142]., Conclusion: In privately insured patients in the USA, resective epilepsy surgery and hemispherectomy substantially decrease healthcare utilization in subsequent years. Epilepsy surgery may help contain costs in the field of epilepsy., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objectives: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients., Design: Retrospective cohort study with prospectively collected data between June 2011 and January 2019., Setting: Seventeen academic hospitals in the United States., Patients: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups., Interventions: None., Measurements and Main Results: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments., Conclusions: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus., Competing Interests: Dr. Vasquez’s, Dr. Arya’s, Ms. Clark’s, Dr. Peariso’s, Dr. Sands’s, and Dr. Loddenkemper’s institutions received funding from Epilepsy Research Fund, American Epilepsy Society/Epilepsy Foundation of America, and Pediatric Epilepsy Research Foundation, and they disclosed off-label product use of nonapproved status epilepticus treatments; these are part of general treatment algorithms. Dr. Amengual-Gual was funded by “Fundación Alfonso Martín Escudero” and she disclosed work for hire. Dr. Sánchez Fernández is funded by the Epilepsy Research Fund and was funded by Fundación Alfonso Martín Escudero and the Human Herpes Virus 6 (HHV-6) Foundation. Dr. Brenton has served as a consultant for Novartis. Dr. Chapman disclosed that he received grant funding to support enrollment of patients via different funding mechanisms over the years. Drs. Gaillard’s and Morgans’s institution received funding from Pediatric Epilepsy Research Foundation. Drs. Glauser’s and Piantino’s institutions received funding from Boston Children’s Hospital. Dr. Glauser received funding from Supernus, Neurelis, Eisai, UCB Pharma, Myriad Genetics, and WedMD; he received support for article research from the National Institutes of Health (NIH); and he disclosed off-label product use of an anticonvulsant in status epilepticus. Dr. Goodkin received funding from UptoDate, Elsevier, and NIH grant support. Dr. Novotny is on the professional advisory board of the Epilepsy Foundation of America. Dr. Riviello is a consultant with Biomarin, and Early Neuronal ceroid lipofuscinosis 2 (CLN2) Signs North American Advisory Board, and he disclosed off-label product use of seizure medications. His spouse is an editor for Uptodate. Dr. Tchapyjnikov receives research funding from Children’s Miracle Network Hospitals and has previously received consultation fees from Gerson Lehrman Group, Guidepoint, IQVIA, and bioStrategies Group. Dr. Wainwright is a member of Clinical Advisory Board Sage Therapeutics. Dr. Wilfong’s institution received funding from Zogenix, Marinus, and OVID, and he received funding from UptoDate, Medtronic (data and safety monitoring board member of Stereotactic Laser Ablation for Temporal Lobe Epilepsy national trial), LivaNova, UCB, and Greenwich. Dr. Loddenkemper serves on the Council of the American Clinical Neurophysiology Society, as founder and consortium principal investigator (PI) of the pediatric status epilepticus research group, as an Associate Editor for Wyllie’s Treatment of Epilepsy 6th edition and 7th editions (Elsevier), and as a member of the New Onset Refractory Status Epilepsy Institute and Critical Care EEG Monitoring Research Consortium, and is coinventor of the TriVox Health technology. He served as an Associate Editor of Seizure (Elsevier) and served on the Laboratory Accreditation Board for Long Term (Epilepsy and Intensive Care Unit) Monitoring, and American Board of Clinical Neurophysiology in the past. He is part of patent applications to detect and predict clinical outcomes, and to detect, manage, diagnose, and treat neurological conditions, epilepsy, and seizures. Dr. Loddenkemper and Boston Children’s Hospital might receive financial benefits from this technology in the form of compensation in the future. He received research support from the Epilepsy Research Fund, NIH, Center for Integration of Medicine & Innovative Technolody/Department of Defense, Patient-Centered Outcomes Research Institute, the Epilepsy Foundation of America, the American Epilepsy Society, the Epilepsy Therapy Project, the Pediatric Epilepsy Research Foundation, the Danny Did Foundation, Cure, and the HHV6 Foundation, and received research grants from Lundbeck, Eisai, Upsher-Smith, Mallinckrodt, Sunovion, Sage, Empatica, Acorda, and Pfizer, including past device donations from various companies, including Empatica, SmartWatch, and Neuro-electrics. In the past, he served as a consultant for Eisai, Lundbeck, UCB, Amzell, Sunovion, Upsher Smith, and Zogenix. He performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies at Boston Children’s Hospital and affiliated hospitals and bills for these procedures and he evaluates pediatric neurology patients and bills for clinical care. He has received speaker honorariums/Grand Round travel support from national/international societies and national/international academic centers. Some of Dr. Loddenkemper’s trainees received salary support from international foundations/societies and academic centers while working in his laboratory. His wife, Dr. Stannard, is a pediatric neurologist and she performs video electroencephalogram long-term and ICU monitoring, electroencephalograms, and other electrophysiological studies and bills for these procedures, and she evaluates pediatric neurology patients and bills for clinical care. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Objective: To develop and test a deep learning model to automatically detect malformations of cortical development (MCD)., Methods: We trained a deep learning model to distinguish between diffuse cortical malformation (CM), periventricular nodular heterotopia (PVNH), and normal magnetic resonance imaging (MRI). We trained 4 different convolutional neural network (CNN) architectures. We used batch normalization, global average pooling, dropout layers, transfer learning, and data augmentation to minimize overfitting., Results: There were 45 subjects (866 images) with a normal MRI, 52 subjects (790 images) with CM, and 32 subjects (750 images) with PVNH. There was no subject overlap between the training, validation, and test sets. The InceptionResNetV2 architecture performed best in the validation set in all models and was evaluated in the test set with the following results: 1) the model distinguishing between CM and normal MRI yielded an area under the curve (AUC) of 0.89 and accuracy of 0.81; 2) the model distinguishing between PVNH and normal MRI yielded an AUC of 0.90 and accuracy of 0.84; 3) the model distinguishing between the three classes (CM, PVNH, and normal MRI) yielded an AUC of 0.88 and accuracy of 0.74. Visualization with gradient-weighted class activation maps and saliency maps showed that the deep learning models classified images based on relevant areas within each image., Significance: This study showed that CNNs can detect MCD at a clinically useful performance level with a fully automated workflow without image feature selection., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: This study was undertaken to describe long-term clinical and developmental outcomes in pediatric refractory status epilepticus (RSE) and identify factors associated with new neurological deficits after RSE., Methods: We performed retrospective analyses of prospectively collected observational data from June 2011 to March 2020 on pediatric patients with RSE. We analyzed clinical outcomes from at least 30 days after RSE and, in a subanalysis, we assessed developmental outcomes and evaluated risk factors in previously normally developed patients., Results: Follow-up data on outcomes were available in 276 patients (56.5% males). The median (interquartile range [IQR]) follow-up duration was 1.6 (.9-2.7) years. The in-hospital mortality rate was 4% (16/403 patients), and 15 (5.4%) patients had died after hospital discharge. One hundred sixty-six (62.9%) patients had subsequent unprovoked seizures, and 44 (16.9%) patients had a repeated RSE episode. Among 116 patients with normal development before RSE, 42 of 107 (39.3%) patients with available data had new neurological deficits (cognitive, behavioral, or motor). Patients with new deficits had longer median (IQR) electroclinical RSE duration than patients without new deficits (10.3 [2.1-134.5] h vs. 4 [1.6-16] h, p = .011, adjusted odds ratio = 1.003, 95% confidence interval = 1.0008-1.0069, p = .027). The proportion of patients with an unfavorable functional outcome (Glasgow Outcome Scale-Extended score ≥ 4) was 22 of 90 (24.4%), and they were more likely to have received a continuous infusion., Significance: About one third of patients without prior epilepsy developed recurrent unprovoked seizures after the RSE episode. In previously normally developing patients, 39% presented with new deficits during follow-up, with longer electroclinical RSE duration as a predictor., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Time to treatment in pediatric refractory status epilepticus is delayed. We aimed to evaluate the influence of weekends and holidays on time to treatment of this pediatric emergency., Methods: We performed a retrospective analysis of prospectively collected observational data of pediatric patients with refractory status epilepticus., Results: We included 329 patients (56% males) with a median (p25 to p75) age of 3.8 (1.3 to 9) years. The median (p25 to p75) time to first BZD on weekdays and weekends/holidays was 20 (6.8 to 48.3) minutes versus 11 (5 to 35) minutes, P = 0.01; adjusted hazard ratio (HR) = 1.20 (95% confidence interval [CI]: 0.95 to 1.55), P = 0.12. The time to first non-BZD ASM was longer on weekdays than on weekends/holidays (68 [42.8 to 153.5] minutes versus 59 [27 to 120] minutes, P = 0.006; adjusted HR = 1.38 [95% CI: 1.08 to 1.76], P = 0.009). However, this difference was mainly driven by status epilepticus with in-hospital onset: among 108 patients, the time to first non-BZD ASM was longer during weekdays than during weekends/holidays (55.5 [28.8 to 103.5] minutes versus 28 [15.8 to 66.3] minutes, P = 0.003; adjusted HR = 1.65 [95% CI: 1.08 to 2.51], P = 0.01)., Conclusions: The time to first non-BZD ASM in pediatric refractory status epilepticus is shorter on weekends/holidays than on weekdays, mainly driven by in-hospital onset status epilepticus. Data on what might be causing this difference may help tailor policies to improve medication application timing., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE)., Methods: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever., Results: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function., Significance: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: To describe the epidemiology and health resource utilization for convulsive status epilepticus (SE) in the emergency department (ED)., Methods: Retrospective descriptive study in the Nationwide Emergency Department Sample (NEDS). Primary SE and secondary SE (SE in a case who visited the ED for other primary reason) were compared with non-SE seizures. Secondary SE is expected to have worse outcomes and higher costs because of another primary cause for ED visit., Results: In the period 2010-2014, there were 149,750 ED visits with primary SE; 83,459 ED with secondary SE; and 5,359,103 ED visits with non-SE seizures. On multivariable analysis adjusting for potential confounders, the odds of hospital admission were 7 times higher for primary SE than for non-SE seizures, and 5 times higher for secondary SE than for non-SE seizures; the odds of transfer to another hospital were 9 times higher for primary SE than for non-SE seizures, and 3 times higher for secondary SE than for non-SE seizures; the odds of death were 2.5 times higher for primary SE than for non-SE seizures, and 12 times higher for secondary SE than for non-SE seizures; and the charges (in January 2020 USA dollars) were $9000 higher in primary SE than in non-SE seizures, and $35,000 higher in secondary SE than in non-SE seizures., Conclusion: Among all reasons for ED visits, SE, and in particular, secondary SE, are among the most resource-consuming conditions, being much more expensive than non-SE seizures in the ED., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the effectiveness and cost-effectiveness of adrenocorticotropic hormone (ACTH) and oral steroids as first-line treatment for infantile spasm resolution, we performed a systematic review, meta-analysis, and cost-effectiveness study., Methods: A decision analysis model was populated with effectiveness data from a systematic review and meta-analysis of existing literature and cost data from publicly available prices. Effectiveness was defined as the probability of clinical spasm resolution 14 days after treatment initiation., Results: We included 21 studies with a total of 968 patients. The effectiveness of ACTH was not statistically significantly different from that of oral steroids (.70, 95% confidence interval [CI] = .60-.79 vs. .63, 95% CI = .56-.70; p = .28). Considering only the three available randomized trials with a total of 185 patients, the odds ratio of spasm resolution at 14 days with ACTH compared to high-dose prednisolone (4-8 mg/kg/day) was .92 (95% CI = .34-2.52, p = .87). Adjusting for potential publication bias, estimates became even more favorable to high-dose prednisolone. Using US prices, the more cost-effective treatment was high-dose prednisolone, with an incremental cost-effectiveness ratio (ICER) of $333 per case of spasms resolved, followed by ACTH, with an ICER of $1 432 200 per case of spasms resolved. These results were robust to multiple sensitivity analyses and different assumptions. Prednisolone at 4-8 mg/kg/day was more cost-effective than ACTH under a wide range of assumptions., Significance: For infantile spasm resolution 2 weeks after treatment initiation, current evidence does not support the preeminence of ACTH in terms of effectiveness and, especially, cost-effectiveness., (© 2020 International League Against Epilepsy.)

Status epilepticus (SE) is one of the most common neurological emergencies in children and has a mortality of 2 to 4%. Admissions for SE are very resource-consuming, especially in refractory and super-refractory SE. An increasing understanding of the pathophysiology of SE leaves room for improving SE treatment protocols, including medication choice and timing. Selecting the most efficacious medications and giving them in a timely manner may improve outcomes. Benzodiazepines are commonly used as first line and they can be used in the prehospital setting, where most SE episodes begin. The diagnostic work-up should start simultaneously to initial treatment, or as soon as possible, to detect potentially treatable causes of SE. Although most etiologies are recognized after the first evaluation, the detection of more unusual causes may become challenging in selected cases. SE is a life-threatening medical emergency in which prompt and efficacious treatment may improve outcomes. We provide a summary of existing evidence to guide clinical decisions regarding the work-up and treatment of SE in pediatric patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: Treatments for convulsive status epilepticus (SE) have a wide range of effectiveness. The estimated effectiveness of non-intravenous benzodiazepines (non-IV BZDs) ranges from approximately 70% to 90% and the estimated effectiveness of non-benzodiazepine antiseizure medications (non-BZD ASMs) ranges from approximately 50% to 80%. This study aimed to quantify the clinical and economic burden of decisional uncertainty in the treatment of SE., Methods: We performed a decision analysis that evaluates how decisional uncertainty on treatment choices for SE impacts hospital admissions, intensive care unit (ICU) admissions, and costs in the United States. We evaluated treatment effectiveness based on the available literature., Results: Use of a non-IV BZD with high estimated effectiveness, like intranasal midazolam, rather than one with low estimated effectiveness, like rectal diazepam, would result in a median (p 25 -p 75 ) reduction in hospital admissions from 6 (3.9-8.8) to 1.1 (0.7-1.8) per 100 cases and associated cost reductions of $638 ($289-$1064) per pediatric patient and $1107 ($972-$1281) per adult patient. For BZD-resistant SE, use of a non-BZD ASM with high estimated effectiveness, like phenobarbital, rather than one with low estimated effectiveness, like phenytoin/fosphenytoin, would result in a reduction in ICU admissions from 9.1 (7.3-11.2) to 3.9 (2.6-5.5) per 100 cases and associated cost reduction of $1261 ($445-$2223) per pediatric patient and $319 ($-93-$806) per adult patient. Sensitivity analyses showed that relatively minor improvements in effectiveness may lead to substantial reductions in downstream hospital admissions, ICU admissions, and costs., Significance: Decreasing decisional uncertainty and using the most effective treatments for SE may substantially decrease hospital admissions, ICU admissions, and costs., (© 2020 International League Against Epilepsy.)

Objective: To determine whether publication of evidence on delays in time to treatment shortens time to treatment in pediatric refractory convulsive status epilepticus (rSE), we compared time to treatment before (2011-2014) and after (2015-2019) publication of evidence of delays in treatment of rSE in the Pediatric Status Epilepticus Research Group (pSERG) as assessed by patient interviews and record review., Methods: We performed a retrospective analysis of a prospectively collected dataset from June 2011 to September 2019 on pediatric patients (1 month-21 years of age) with rSE., Results: We studied 328 patients (56% male) with median (25th-75th percentile [p 25 -p 75 ]) age of 3.8 (1.3-9.4) years. There were no differences in the median (p 25 -p 75 ) time to first benzodiazepine (BZD) (20 [5-52.5] vs 15 [5-38] minutes, p = 0.3919), time to first non-BZD antiseizure medication (68 [34.5-163.5] vs 65 [33-142] minutes, p = 0.7328), and time to first continuous infusion (186 [124.2-571] vs 160 [89.5-495] minutes, p = 0.2236). Among 157 patients with out-of-hospital onset whose time to hospital arrival was available, the proportion who received at least 1 BZD before hospital arrival increased after publication of evidence of delays (41 of 81 [50.6%] vs 57 of 76 [75%], p = 0.0018), and the odds ratio (OR) was also increased in multivariable logistic regression (OR 4.35 [95% confidence interval 1.96-10.3], p = 0.0005)., Conclusion: Publication of evidence on delays in time to treatment was not associated with improvements in time to treatment of rSE, although it was associated with an increase in the proportion of patients who received at least 1 BZD before hospital arrival., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Describe hospital readmission for status epilepticus (SE) in the United States, and study potential risk factors for readmission., Methods: This is a retrospective observational study using the Healthcare Cost and Utilization Project's 2016 Nationwide Readmissions Database. We studied patients of all ages admitted to the hospital due to SE., Results: We included 32 327  patients admitted for SE in 2016. 8.4% of these patients were readmitted for SE at least one more time within 2016 (cross-sectional analysis). The incidence rate was 18 readmissions for SE per 1000 patient-months. Among the survivors of the index admission for SE who had at least 6 months of follow-up within this database (16 043  patients), the cumulative probability of having a readmission for SE at 1, 3, and 6 months from the index admission was approximately 3.5%, 7.5%, and 11%, respectively (time-to-event analysis). Patients with refractory epilepsy were more likely to have a readmission for SE compared to patients without refractory epilepsy (hazard ratio [HR] 1.49, 95% confidence interval [CI] 1.23-1.82, adjusted P =.0006), and pediatric patients were more likely to have a readmission for SE compared to adult patients (HR 1.53, 95% CI 1.26-1.87, adjusted P = .0003) during 6-month follow-up., Significance: Hospital readmissions for SE in the United States are frequent. Independent factors associated with readmission in this database were refractory epilepsy and pediatric age., (© 2020 International League Against Epilepsy.)

Objective: To develop and test a deep learning algorithm to automatically detect cortical tubers in magnetic resonance imaging (MRI), to explore the utility of deep learning in rare disorders with limited data, and to generate an open-access deep learning standalone application., Methods: T2 and FLAIR axial images with and without tubers were extracted from MRIs of patients with tuberous sclerosis complex (TSC) and controls, respectively. We trained three different convolutional neural network (CNN) architectures on a training dataset and selected the one with the lowest binary cross-entropy loss in the validation dataset, which was evaluated on the testing dataset. We visualized image regions most relevant for classification with gradient-weighted class activation maps (Grad-CAM) and saliency maps., Results: 114 patients with TSC and 114 controls were divided into a training set, a validation set, and a testing set. The InceptionV3 CNN architecture performed best in the validation set and was evaluated in the testing set with the following results: sensitivity: 0.95, specificity: 0.95, positive predictive value: 0.94, negative predictive value: 0.95, F1-score: 0.95, accuracy: 0.95, and area under the curve: 0.99. Grad-CAM and saliency maps showed that tubers resided in regions most relevant for image classification within each image. A stand-alone trained deep learning App was able to classify images using local computers with various operating systems., Conclusion: This study shows that deep learning algorithms are able to detect tubers in selected MRI images, and deep learning can be prudently applied clinically to manually selected data in a rare neurological disorder., Competing Interests: ISF has received an Amazon Web Services Cloud Credits for Research support in the form of computational credits for his project on “Identification and localization of tubers in Tuberous Sclerosis Complex with deep learning convolutional neural networks”. JYW, DK, HN, MEB, MS, and JP received funding to collect the data as a part of the TACERN collaborative. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Estimate the cost of status epilepticus (SE) admissions in the USA using claim databases based on ICD-10 codes., Method: Descriptive retrospective study using national estimates for the year 2016 from the KID's Inpatient Database (KID) for pediatric patients and from the National Inpatient Sample (NIS) for adults. These databases are comprehensive collections of all-payer, encounter-level hospital care data in the United States of America., Results: From a population of 6,106,405 pediatric admissions there were 580 admissions related to SE. From a population of 29,274,158 adult admissions there were 1,405 admissions related to SE. The median (p25-p75) cost of pediatric admissions related to SE was $8,749 ($4,875-$19,067) in 2016 USA dollars [$9,295 ($5,180-$20,258) in inflation-adjusted 2019 USA dollars], and for adult admissions related to SE it was $14,678 ($7,203-$28,388) in 2016 USA dollars [$15,595 ($7,653-$30,161) in inflation-adjusted 2019 USA dollars]. Transforming to 2019 USA dollars, the values from the current study are consistent with prior estimates in the literature from the KID and NIS databases with a progressive increase, except for the cost of super-refractory SE in children that has increased disproportionately., Conclusions: This study estimates that the cost of admissions related to SE in the USA is approximately $9,000 in children and $15,000 in adults and shows that the cost estimates have not markedly changed with the advent of ICD-10., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: We aimed to determine whether clinical EEG reports obtained from children in the intensive care unit with refractory status epilepticus could provide data for comparative effectiveness research studies., Methods: We conducted a retrospective descriptive study to assess the documentation of key variables within clinical continuous EEG monitoring reports based on the American Clinical Neurophysiology Society's standardized EEG terminology for children with refractory status epilepticus from 10 academic centers. Two pediatric electroencephalographers reviewed the EEG reports. We compared reports generated using free text or templates., Results: We reviewed 191 EEG reports. Agreement between the electroencephalographers regarding whether a variable was described in the report ranged from fair to very good. The presence of electrographic seizures (ES) was documented in 46% (87/191) of reports, and these reports documented the time of first ES in 64% (56/87), ES duration in 72% (63/85), and ES frequency in 68% (59/87). Reactivity was documented in 16% (31/191) of reports, and it was more often documented in template than in free-text reports (40% vs. 14%, P = 0.006). Other variables were not differentially reported in template versus free-text reports., Conclusions: Many key EEG features are not documented consistently in clinical continuous EEG monitoring reports, including ES characteristics and reactivity assessment. Standardization may be needed for clinical EEG reports to provide informative data for large multicenter observational studies.

Purpose: To evaluate whether the onset of pediatric refractory status epilepticus (rSE) is related to time of day., Method: We analyzed the time of day for the onset of rSE in this prospective observational study performed from June 2011 to May 2019 in pediatric patients (1 month to 21 years of age). We evaluated the temporal distribution of pediatric rSE utilizing a cosinor analysis. We calculated the midline estimating statistic of rhythm (MESOR) and amplitude. MESOR is the estimated mean number of rSE episodes per hour if they were evenly distributed. Amplitude is the difference between MESOR and maximum rSE episodes/hour, or between MESOR and minimum rSE episodes/hour. We also evaluated the temporal distribution of time to treatment., Results: We analyzed 368 patients (58% males) with a median (p 25 - p 75 ) age of 4.2 (1.3-9.7) years. The MESOR was 15.3 (95% CI: 13.9-16.8) and the amplitude was 3.2 (95% CI: 1.1-5.3), p = 0.0024, demonstrating that the distribution is not uniform, but better described as varying throughout the day with a peak in the morning (11am-12 pm) and trough at night (11 pm-12 am). The duration from rSE onset to application of the first non-benzodiazepine antiseizure medication peaked during the early morning (2am-3 am) with a minimum during the afternoon (2 pm-3 pm) (p = 0.0179)., Conclusions: The distribution of rSE onset is not uniform during the day. rSE onset shows a 24-h distribution with a peak in the mid-morning (11am-12 pm) and a trough at night (11 pm-12am)., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: Compare the cost and effectiveness of nonbenzodiazepine antiepileptic drugs (non-BZD AEDs) for treatment of BZD-resistant convulsive status epilepticus (SE)., Methods: Decision analysis model populated with effectiveness data from a systematic review and meta-analysis of the literature, and cost data from publicly available prices. The primary outcome was cost per seizure stopped ($/SS). Sensitivity analyses evaluated the robustness of the results across a wide variation of the input parameters., Results: We included 24 studies with 1,185 SE episodes. The most effective non-BZD AED was phenobarbital (PB) with a probability of SS of 0.8 (95% confidence interval [CI]: 0.69-0.88), followed by valproate (VPA) (0.71 [95% CI: 0.61-0.79]), lacosamide (0.66 [95% CI: 0.51-0.79]), levetiracetam (LEV) (0.62 [95% CI: 0.5-0.73]), and phenytoin/fosphenytoin (PHT) (0.53 [95% CI: 0.39-0.67]). In pairwise comparisons, PB was more effective than PHT ( p = 0.002), VPA was more effective than PHT ( p = 0.043), and PB was more effective than LEV ( p = 0.018). The most cost-effective non-BZD AED was LEV (incremental cost-effectiveness ratio [ICER]: $18.55/SS), followed by VPA (ICER: $94.44/SS), and lastly PB (ICER: $847.22/SS). PHT and lacosamide were not cost-effective compared to the other options. Sensitivity analyses showed marked overlap in cost-effectiveness, but PHT was consistently less cost-effective than LEV, VPA, and PB., Conclusion: VPA and PB were more effective than PHT for SE. There is substantial overlap in the cost-effectiveness of non-BZD AEDs for SE, but available evidence does not support the preeminence of PHT, neither in terms of effectiveness nor in terms of cost-effectiveness., (© 2019 American Academy of Neurology.)

Purpose: Rescue medications for status epilepticus (SE) have a relatively high rate of failure. The purpose of this review is to summarize the evidence for the efficacy of novel drugs and early polypharmacotherapy for SE., Method: Literature review., Results: New drugs and treatment strategies aim to target the pathophysiology of SE in order to improve seizure control and outcomes. Changes at the synapse level during SE include a progressive decrease in synaptic GABA A receptors and increase in synaptic NMDA receptors. These changes tend to promote self-sustaining seizures. Current SE guidelines recommend a rapid stepwise treatment using benzodiazepines in monotherapy as the first-line treatment, targeting GABA A synaptic receptors. Novel treatment approaches target GABA A synaptic and extrasynaptic receptors with allopregnanolone, and NMDA receptors with ketamine. Novel rescue treatments used for SE include topiramate, brivaracetam, and perampanel, which are already marketed in epilepsy. Some available drugs not marketed for use in epilepsy have been used in the treatment of SE, and other agents are being studied for this purpose. Early polytherapy, most frequently combining a benzodiazepine with a second-line drug or an NMDA receptor antagonist, might potentially increase seizure control with relatively minor increase in side effects. Although many preclinical studies support novel drugs and early polytherapy in SE, human studies are scarce and inconclusive. Currently, evidence is lacking to recommend specific combinations of these new agents., Conclusions: Novel drugs and strategies target the underlying pathophysiology of SE with the intent to improve seizure control and outcomes., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: To summarize the pathophysiology of convulsive status epilepticus (SE) with a focus on practical implications for treatment., Method: Narrative review of the medical literature on the pathophysiology of convulsive SE. We considered both animal models of SE and clinical studies., Results: Convulsive SE is an emergency in which prolonged convulsive seizures are associated with cardiorespiratory instability, hypoxia, hypoglycemia, and hyperthermia. Supportive treatment helps correct these physiological imbalances. When treatment is delayed, the ability of first line seizure suppressing medications to terminate the seizure can be reduced. Animal studies have suggested that GABA A receptor trafficking may contribute to the failure of the first line therapies and that NMDA receptor antagonists such as ketamine may become more effective as seizures last longer. Potential strategies to take advantage of these changes in pathophysiology include a rapid escalation from benzodiazepines to non-benzodiazepine antiepileptic drugs (AEDs), early polytherapy and use of NMDA antagonists such as ketamine for refractory convulsive SE. Despite the importance of a timely treatment of convulsive SE, major treatment delays are frequent in clinical practice. Policies to improve time to treatment, especially in convulsive SE that starts outside the hospital, may improve response to treatment and convulsive SE outcomes., Conclusions: Convulsive SE is a time-sensitive emergency in which the underlying pathophysiology may provide targets for improving treatment strategies. A timely transition from benzodiazepines to other AEDs may help reduce treatment resistance in convulsive SE., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology., Methods: This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using "no genetic testing" as a point of comparison., Results: Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33-0.57) (0.32 [95% CI: 0.22-0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18-0.29), and CMA: 0.08 (95% CI: 0.06-0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of $15,000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: $15,848/diagnosis) followed by WES (ICER: $34,500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: $15,336/diagnosis), although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: $18,385/diagnosis). While the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP., Conclusion: WES and EP are the most cost-effective genetic tests for epilepsy. Our analyses support, for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective., (© 2019 American Academy of Neurology.)

Background: The occurrence of epileptic seizures in seemingly random patterns takes a great toll on persons with epilepsy and their families. Seizure prediction may markedly improve epilepsy management and, therefore, the quality of life of persons with epilepsy., Methods: Literature review., Results: Seizures tend to occur following complex non-random patterns. Circadian oscillators may contribute to the rhythmic patterns of seizure occurrence. Complex mathematical models based on chaos theory try to explain and even predict seizure occurrence. There are several patterns of epileptic seizure occurrence based on seizure location, seizure semiology, and hormonal factors, among others. These patterns are most frequently described for large populations. Inter-individual variability and complex interactions between the rhythmic generators continue to make it more difficult to predict seizures in any individual person. The increasing use of large databases and machine learning techniques may help better define patterns of seizure occurrence in individual patients. Improvements in seizure detection -such as wearable seizure detectors- and in seizure prediction -such as machine learning techniques and artificial as well as neuronal networks- promise to provide further progress in the field of epilepsy and are being applied to closed-loop systems for the treatment of epilepsy., Conclusions: Seizures tend to occur following complex and patient-specific patterns despite their apparently random occurrence. A better understanding of these patterns and current technological advances may allow the implementation of closed-loop detection, prediction, and treatment systems in routine clinical practice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Tuberculosis is a major cause of morbidity and mortality in the developing world. Drug resistance, which is predicted to rise in many countries worldwide, threatens tuberculosis treatment and control., Objective: To identify features associated with treatment failure and to predict which patients are at highest risk of treatment failure., Methods: On a multi-country dataset managed by the National Institute of Allergy and Infectious Diseases we applied various machine learning techniques to identify factors statistically associated with treatment failure and to predict treatment failure based on baseline demographic and clinical characteristics alone., Results: The complete-case analysis database consisted of 587 patients (68% males) with a median (p25-p75) age of 40 (30-51) years. Treatment failure occurred in approximately one fourth of the patients. The features most associated with treatment failure were patterns of drug sensitivity, imaging findings, findings in the microscopy Ziehl-Nielsen stain, education status, and employment status. The most predictive model was forward stepwise selection (AUC: 0.74), although most models performed at or above AUC 0.7. A sensitivity analysis using the 643 original patients filling the missing values with multiple imputation showed similar predictive features and generally increased predictive performance., Conclusion: Machine learning can help to identify patients at higher risk of treatment failure. Closer monitoring of these patients may decrease treatment failure rates and prevent emergence of antibiotic resistance. The use of inexpensive basic demographic and clinical features makes this approach attractive in low and middle-income countries., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To estimate the cost of admissions related to status epilepticus (SE) in the USA and to evaluate SE mortality., Method: Descriptive retrospective study using national estimates from the KID's Inpatient Database (KID) for children and from the National Inpatient Sample (NIS) for adults for the years 2007-2012, the largest collection of all-payer, encounter-level hospital care data in the United States. The individual observation in this study is hospital admission., Results: From a population of 186,013,640 admissions, a total of 184,500 admissions were related to SE. The median (p 25 -p 75 ) cost of admissions related to SE was $7690 ($3893-$17,247) in the KID 2010-2012, $6529 ($3,370-$14,854) in the KID 2007-2009, $13,874 ($6699-$29,176) in the NIS 2012, $13,313 ($6,483-$28,598) in the NIS 2011, $12,999 ($6,366-$27,505) in the NIS 2010, $11,833 ($5721-$24,657) in the NIS 2009, $11,479 ($5,611-$24,326) in the NIS 2008, and $10,759 ($5493-$22,928) in the NIS 2007. Costs were more than two times higher for super-refractory SE admissions than for refractory SE admissions. Costs stratified by age followed an "U"-shaped distribution with higher costs in admissions of young children and older adults. Mortality ranged from 2.5% to 3% in children and from 12.7% to 14.9% in adults., Conclusions: This study estimates the cost of admissions related to SE in the USA to be approximately $7000 in children and $13,000 in adults, and quantifies how costs markedly increase once SE becomes super-refractory., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

We reviewed 37 studies reporting long-term outcomes after a status epilepticus (SE) episode in pediatric and adult populations. Study design, length of follow-up, outcome measures, domains investigated (mortality, SE recurrence, subsequent epilepsy, cognitive outcome, functional outcome, or quality of life), and predictors of long-term outcomes are summarized. Despite heterogeneity in the design of prior studies, overall risk of poor long-term outcome after SE is high in both children and adults. Etiology is the main determinant of outcome, and the effect of age or SE duration is often difficult to distinguish from the underlying cause. The effect of the treatment on long-term outcome after SE is still unknown., (© 2018 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Objective: We aimed to evaluate and compare the status epilepticus treatment pathways used by pediatric status epilepticus research group (pSERG) hospitals in the United States and the American Epilepsy Society (AES) status epilepticus guideline., Methods: We undertook a descriptive analysis of recommended timing, dosing, and medication choices in 10 pSERG hospitals' status epilepticus treatment pathways., Results: One pathway matched the timeline in the AES guideline; nine pathways described more rapid timings. All pathways matched the guideline's stabilization phase in timing and five suggested that first-line benzodiazepine (BZD) be administered within this period. For second-line therapy timing (initiation of a non-BZD antiepileptic drug within 20 to 40 minutes), one pathway matched the guideline; nine initiated the antiepileptic drug earlier (median 10 [range five to 15] minutes). Third-line therapy timings matched the AES guideline (40 minutes) in two pathways; eight suggested earlier timing (median 20 [range 15 to 30] minutes). The first-line BZD recommended in all hospitals was intravenous lorazepam; alternatives included intramuscular midazolam or rectal diazepam. In second-line therapy, nine pathways recommended fosphenytoin. For third-line therapy, eight pathways recommended additional boluses of second-line medications; most commonly phenobarbital. Two pathways suggested escalation to third-line medication; most commonly midazolam. We found variance in dosing for the following medications: midazolam as first-line therapy, fosphenytoin, and levetiracetam as second-line therapy, and phenobarbital as third-line therapy medications., Conclusions: The pSERG hospitals status epilepticus pathways are consistent with the AES status epilepticus guideline in regard to the choice of medications, but generally recommend more rapid escalation in therapy than the guideline., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to evaluate the performance of models predicting in-hospital mortality in critically ill children undergoing continuous electroencephalography (cEEG) in the intensive care unit (ICU). We evaluated the performance of machine learning algorithms for predicting mortality in a database of 414 critically ill children undergoing cEEG in the ICU. The area under the receiver operating characteristic curve (AUC) in the test subset was highest for stepwise selection/elimination models (AUC = 0.82) followed by least absolute shrinkage and selection operator (LASSO) and support vector machine with linear kernel (AUC = 0.79), and random forest (AUC = 0.71). The explanatory models had the poorest discriminative performance (AUC = 0.63 for the model without considering etiology and AUC = 0.45 for the model considering etiology). Using few variables and a relatively small number of patients, machine learning techniques added information to explanatory models for prediction of in-hospital mortality.

Objective: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE)., Methods: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model., Results: We studied 219 patients (53% males) with a median (25th-75th percentiles [p 25 -p 75 ]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p 25 -p 75 ) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion., Conclusion: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment., (© 2018 American Academy of Neurology.)

Importance: Treatment delay for seizures can lead to longer seizure duration. Whether treatment delay is associated with major adverse outcomes, such as death, remains unknown., Objective: To evaluate whether untimely first-line benzodiazepine treatment is associated with unfavorable short-term outcomes., Design, Setting, and Participants: This multicenter, observational, prospective cohort study included 218 pediatric patients admitted between June 1, 2011, and July 7, 2016, into the 11 tertiary hospitals in the United States within the Pediatric Status Epilepticus Research Group. Patients, ranging in age from 1 month to 21 years, with refractory convulsive status epilepticus (RCSE) that did not stop after the administration of at least 2 antiseizure medications were included. Patients were divided into 2 cohorts: those who received the first-line benzodiazepine treatment in less than 10 minutes and those who received it 10 or more minutes after seizure onset (untimely). Data were collected and analyzed from June 1, 2011, to July 7, 2016., Main Outcomes and Measures: The primary outcome was death during the related hospital admission. The secondary outcome was the need for continuous infusion for seizure termination. Multivariate analysis of mortality controlled for structural cause, febrile RCSE, age, and previous neurological history (including previous RCSE events). Use of continuous infusions was additionally adjusted for generalized RCSE, continuous RCSE, and 5 or more administrations of antiseizure medication., Results: A total of 218 patients were included, among whom 116 (53.2%) were male and the median (interquartile range) age was 4.0 (1.2-9.6) years. The RCSE started in the prehospital setting for 139 patients (63.8%). Seventy-four patients (33.9%) received their first-line benzodiazepine treatment in less than 10 minutes, and 144 (66.1%) received untimely first-line benzodiazepine treatment. Multivariate analysis showed that patients who received untimely first-line benzodiazepine treatment had higher odds of death (adjusted odds ratio [AOR], 11.0; 95% CI, 1.43 to ∞; P = .02), had greater odds of receiving continuous infusion (AOR, 1.8; 95% CI, 1.01-3.36; P = .047), had longer convulsive seizure duration (AOR, 2.6; 95% CI, 1.38-4.88; P = .003), and had more frequent hypotension (AOR 2.3; 95% CI, 1.16-4.63; P = .02). In addition, the timing of the first-line benzodiazepine treatment was correlated with the timing of the second-line (95% CI, 0.64-0.95; P < .001) and third-line antiseizure medications (95% CI, 0.25-0.78; P < .001)., Conclusions and Relevance: Among pediatric patients with RCSE, an untimely first-line benzodiazepine treatment is independently associated with a higher frequency of death, use of continuous infusions, longer convulsion duration, and more frequent hypotension. Results of this study raise the question as to whether poor outcomes could, in part, be prevented by earlier administration of treatment.

Aim: To evaluate the efficacy of clobazam treatment in reducing epileptiform discharges and modifying neuropsychological function in continuous spike-wave during slow wave sleep., Method: We performed a prospective clinical trial in patients with continuous spike-wave during sleep aged 4 to 10 years. Patients underwent neuropsychological assessment and overnight electroencephalographic monitoring before treatment, and subsequent repeat assessment and overnight electroencephalographic monitoring 3 months after treatment. Treatment consisted of 1mg/kg clobazam up to a maximum dose of 30mg during the first night, followed by 0.5mg/kg nightly for 3 months., Results: Nine patients completed the study and had pre- and post-neuropsychological evaluation. There was a qualitative reduction in median (p 25 -p 75 ) spike percentage after 3 months (72.2 [68.0-75.8] vs 32.7 [4.7-81.7]). There were no marked changes in median (p 25 -p 75 ) IQ comparing pre- and post-clobazam treatment (80.0 [74.0-88.0] vs 80.0 [67.0-89.0]). There was a qualitative increase in Verbal IQ (83.0 [69.0-92.0] vs 95.0 [83.0-99.0]) and a qualitative decrease in Non-verbal IQ (84.0 [74.0-87.0] vs 71.0 [60.0-84.0])., Interpretation: Qualitative improvements in epileptiform activity and cognition occurred in patients treated with clobazam for 3 months and the relationship between epileptiform activity and cognitive outcome should be studied in larger studies., What This Paper Adds: Verbal IQ in patients with continuous spike-wave during sleep improved following short-term treatment with clobazam. Other neuropsychological improvements were observed, but varied by patient. Cognitive improvement was observed despite some worsening of epileptiform discharges., (© 2017 Mac Keith Press.)

Purpose: Describe timing from intensive care unit (ICU) admission to initiation of continuous electroencephalogram (cEEG) in repeated ICU admissions., Method: We performed a retrospective observational study in pediatric patients who underwent repeated ICU admissions with cEEG from 2011 to 2013. The main outcome measure was time from ICU admission to cEEG., Results: There were 41 patients (54% males) with at least 2 ICU admissions with cEEG (median (p25-p75) age at first admission: 3.3 (0.3-8.4) years, at second admission: 3.9 (1.1-9.4) years), 7 patients (57% males, 9.9 (2.9-11.5) years) with at least 3 ICU admissions, and 5 patients (60% males, 10.1 (4-10.5) years) with at least 4 ICU admissions. One patient had 21 ICU admissions. The median (p25-p75) time from ICU admission to cEEG was not different during the first and second ICU admissions [10.7 (1.9-22.9) hours versus 13 (0.2-36.7) hours; p=0.908]. Among patients with electrographic seizures on first admission, time to cEEG was not different during the first and second admissions [7.9 (0.5-23.4) hours versus 14.5 (-2 to 44.5) hours; p=0.636]. Among patients with status epilepticus during the first admission, time to cEEG was not different between the first and second admissions [15.3 (9-79) hours versus 40.7 (19.3-42.6) hours; p=0.75]., Conclusions: The time from ICU admission to the initiation of cEEG did not decrease in second or subsequent ICU admissions, even in patients with seizures or status epilepticus on the first admission., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)