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Purpose: Spatial patterns of long-range seizure propagation in epileptic networks have not been well characterized. Here, we use ictal high-gamma activity (HGA) as a proxy of intense neuronal population firing to map the spatial evolution of seizure recruitment., Methods: Ictal HGA (80-150 Hz) was analyzed in 13 patients with 72 seizures recorded by stereotactic depth electrodes, using previously validated methods. Distinct spatial clusters of channels with the ictal high-gamma signature were identified, and seizure hubs were defined as stereotypically recruited nonoverlapping clusters. Clusters correlated with asynchronous seizure terminations to provide supportive evidence for independent seizure activity at these sites. The spatial overlap between seizure hubs and interictal ripples was compared., Results: Ictal HGA was detected in 71% of seizures and 10% of implanted contacts, enabling tracking of contiguous and noncontiguous seizure recruitment. Multiple seizure hubs were identified in 54% of cases, including 43% of patients thought preoperatively to have unifocal epilepsy. Noncontiguous recruitment was associated with asynchronous seizure termination (odds ratio = 19.7; p = 0.029). Interictal ripples demonstrated greater spatial overlap with ictal HGA in cases with single seizure hubs compared with those with multiple hubs (100% vs. 66% per patient; p = 0.03)., Conclusions: Ictal HGA may serve as a useful adjunctive biomarker to distinguish contiguous seizure spread from propagation to remote seizure sites. High-gamma sites were found to cluster in stereotyped seizure hubs rather than being broadly distributed. Multiple hubs were common even in cases that were considered unifocal., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 by the American Clinical Neurophysiology Society.)

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 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.)