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2-deoxy-D-glucose (2DG) has been proposed as a potential antiseizure treatment based on seizure suppressive actions in multiple acute and chronic seizure models, including models of status epilepticus (SE). Here we summarize recently completed preclinical toxicological studies of single doses of an intravenous formulation of 2DG supporting potential safety of 2DG for acute treatment of SE and acute repetitive seizures (ARS)., Competing Interests: Declaration of competing interest T.S. and N.F. hold equity interests in Hexokine Therapeutics, Inc. which is developing 2DG for potential human use., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: An epilepsy monitoring unit (EMU) is a specialized unit designed for capturing and characterizing seizures and other paroxysmal events with continuous video electroencephalography (vEEG). Nearly 260 epilepsy centers in the United States are accredited by the National Association of Epilepsy Centers (NAEC) based on adherence to specific clinical standards to improve epilepsy care, safety, and quality. This study examines EMU staffing, safety practices, and reported outcomes., Method: We analyzed NAEC annual report data and results from a supplemental survey specific to EMU practices reported in 2019 from 341 pediatric or adult center directors. Data on staffing, resources, safety practices and complications were collated with epilepsy center characteristics. We summarized using frequency (percentage) for categorical variables and median (inter-quartile range) for continuous variables. We used chi-square or Fisher's exact tests to compare staff responsibilities., Results: The supplemental survey response rate was 100%. Spell classification (39%) and phase 1 testing (28%) were the most common goals of the 91,069 reported admissions. The goal ratio of EEG technologist to beds of 1:4 was the most common during the day (68%) and off-hours (43%). Compared to residents and fellows, advanced practice providers served more roles in the EMU at level 3 or pediatric-only centers. Status epilepticus (SE) was the most common reported complication (1.6% of admissions), while cardiac arrest occurred in 0.1% of admissions., Significance: EMU staffing and safety practices vary across US epilepsy centers. Reported complications in EMUs are rare but could be further reduced, such as with more effective treatment or prevention of SE. These findings have potential implications for improving EMU safety and quality care., 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 © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

2-deoxy-D-glucose (2DG) is a glucose analog differing from glucose only by removal of an oxygen atom at the 2 position, which prevents the isomerization of glucose-6-phosphate to fructose-6-phosphate, and thereby reversibly inhibits glycolysis. PET studies of regional brain glucose utilization positron-emitting 18F-2DG demonstrate that brain regions generating seizures have diminished glucose utilization during interictal conditions, but rapidly transition to markedly increased glucose delivery and utilization during seizures, particularly in status epilepticus (SE). 2-deoxy-D-glucose has acute antiseizure actions in multiple in vivo and in vitro seizure models, including models of SE induced by the chemo convulsants pilocarpine and kainic acid, suggesting that focal enhanced delivery of 2DG to ictal brain circuits is a potential novel anticonvulsant intervention for the treatment of SE., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Sutula and N. Fountain are equity holders in Hexokine Therapeutics, Inc. which has a commercial interest in the therapeutic use of 2DG., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Status epilepticus (SE) is a neurological emergency that can occur in patients with or without epilepsy. Rapid treatment is paramount to mitigate risks of neuronal injury, morbidity/mortality, and healthcare-cost burdens associated with SE. Fosphenytoin is the prodrug of phenytoin designed to enable faster administration and improved tolerability as compared to intravenous (IV) phenytoin in the treatment of SE., Areas Covered: This review evaluates the chemistry, pharmacokinetics, pharmacodynamics, safety, and tolerability of fosphenytoin. Efficacy data for fosphenytoin in the treatment of SE in adults and children are analyzed from initial phase I trials in 1988 through current phase III trials, including the Established Status Epilepticus Treatment Trial (ESETT)., Expert Opinion: IV phenytoin is an established treatment of SE, but its alkaline aqueous vehicle is associated with dermatologic irritation and systemic complications when rapidly infused. The water-soluble nature of its prodrug, fosphenytoin, allows for rapid infusion, and it is rapidly converted to phenytoin when administered intravenously or intramuscularly. In the ESETT, IV fosphenytoin demonstrated similar efficacy in treatment of established SE when compared to IV levetiracetam and IV valproate in adults and children, making it a reasonable choice in the treatment of SE that is unresponsive to benzodiazepines.

Fosphenytoin (FOS) and its active form, phenytoin (PHT), levetiracetam (LEV), and valproic acid (VPA) are commonly used second-line treatments of status epilepticus. However, limited information is available regarding LEV and VPA concentrations following high intravenous doses, particularly in young children. The Established Status Epilepticus Treatment Trial, a blinded, comparative effectiveness study of FOS, LEV, and VPA for benzodiazepine-refractory status epilepticus provided an opportunity to investigate early drug concentrations. Patients aged ≥2 years who continued to seizure despite receiving adequate doses of benzodiazepines were randomly assigned to FOS, LEV, or VPA infused over 10 minutes. A sparse blood-sampling approach was used, with up to 2 samples collected per patient within 2 hours following drug administration. The objective of this work was to report early drug exposure of PHT, LEV, and VPA and plasma protein binding of PHT and VPA. Twenty-seven children with median (interquartile range) age of 4 (2.5-6.5) years were enrolled. The total plasma concentrations ranged from 69 to 151.3 μg/mL for LEV, 11.3 to 26.7 μg/mL for PHT and 126 to 223 μg/mL for VPA. Free fraction ranged from 4% to 19% for PHT and 17% to 51% for VPA. This is the first report in young children of LEV concentrations with convulsive status epilepticus as well as VPA concentrations after a 40 mg/kg dose. Several challenges limited patient enrollment and blood sampling. Additional studies with a larger sample size are required to evaluate the exposure-response relationships in this emergent condition., (© 2020, The American College of Clinical Pharmacology.)

Objective: This study was undertaken to describe patterns of benzodiazepine use as first-line treatment of status epilepticus (SE) and test the association of benzodiazepine doses with response to second-line agents in patients enrolled in the Established Status Epilepticus Treatment Trial (ESETT)., Methods: Patients refractory to an adequate dose of benzodiazepines for the treatment of SE were enrolled in ESETT. Choice of benzodiazepine, doses given prior to administration of second-line agent, route of administration, setting, and patient weight were characterized. These were compared with guideline-recommended dosing. Logistic regression was used to determine the association of the first dose of benzodiazepine and the cumulative benzodiazepine dose with the response to second-line agent., Results: Four hundred sixty patients were administered 1170 doses of benzodiazepines (669 lorazepam, 398 midazolam, 103 diazepam). Lorazepam was most frequently administered intravenously in the emergency department, midazolam intramuscularly or intravenously by the emergency medical services personnel, and diazepam rectally prior to ambulance arrival. The first dose of the first benzodiazepine (N = 460) was lower than guideline recommendations in 76% of midazolam administrations and 81% of lorazepam administrations. Among all administrations, >85% of midazolam and >76% of lorazepam administrations were lower than recommended. Higher first or cumulative benzodiazepine doses were not associated with better outcomes or clinical seizure cessation in response to second-line medications in these benzodiazepine-refractory seizures., Significance: Benzodiazepines as first-line treatment of SE, particularly midazolam and lorazepam, are frequently underdosed throughout the United States. This broad and generalizable cohort confirms prior single site reports that underdosing is both pervasive and difficult to remediate. (ESETT ClinicalTrials.gov identifier: NCT01960075.)., (© 2021 International League Against Epilepsy.)

The Established Status Epilepticus Treatment Trial was a blinded, comparative-effectiveness study of fosphenytoin, levetiracetam, and valproic acid in benzodiazepine-refractory status epilepticus. The primary outcome was clinical seizure cessation and increased responsiveness without additional anticonvulsant medications. Weight-based dosing was capped at 75 kg. Hence, patients weighing >75 kg received a lower mg/kg dose. Logistic regression models were developed in 235 adults to determine the association of weight (≤ or >75 kg, ≤ or >90 kg), sex, treatment, and weight-normalized dose with the primary outcome and solely seizure cessation. The primary outcome was achieved in 45.1% and 42.5% of those ≤75 kg and >75 kg, respectively. Using univariate analyses, the likelihood of success for those >75 kg (odds ratio [OR] = 0.9, 95% confidence interval [CI] = 0.54-1.51) or >90 kg (OR = 0.85, 95% CI = 0.42-1.66) was not statistically different compared with those ≤75 kg or ≤90 kg, respectively. Similarly, other predictors were not significantly associated with primary outcome or clinical seizure cessation. Our findings suggest that doses, capped at 75 kg, likely resulted in concentrations greater than those needed for outcome. Studies that include drug concentrations and heavier individuals are needed to confirm these findings., (© 2020 International League Against Epilepsy.)

Background: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups., Methods: In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075., Findings: Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group., Interpretation: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus., Funding: National Institute of Neurological Disorders and Stroke, National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed at determining the current state of practice of treatment for acute generalized convulsive status epilepticus (GCSE) and responsiveness to therapy., Methods: This observational study was performed by retrospectively identifying patients with GCSE presenting to an emergency room setting. The primary outcome was seizure cessation following medication administration. Secondary outcomes were rates of intubation and mortality., Results: One hundred seventy-seven episodes of GCSE were identified. All patients, except 1, received a benzodiazepine for first-line treatment. Only 11% of these patients, all children, were treated with at least 0.1mg/kg of lorazepam or an equivalent dose of an alternative benzodiazepine. A first-line treatment was effective in 56% of the patients, a second-line treatment in an additional 28%, and a third-line treatment in 12%. Phenytoin was the most prescribed second-line treatment (41%) but statistically significantly least effective (22% versus 86% seizure cessation, p<0.0001) compared with all other second-line agents together. Propofol was the most prescribed third-line treatment., Conclusions: Results emphasize that, in clinical practice, approximately half of GCSE patients respond to first-line therapy and, among nonresponders, approximately two-thirds respond to second-line and approximately three-quarters respond to third-line therapies. The variations in treatment selection reflect that there are no randomized controlled trials to guide treatment beyond use of benzodiazepines for first-line treatment. The observation that phenytoin is statistically substantially worse than other second-line treatments raises the possibility that the most commonly selected second-line treatment is the least effective and provides equipoise for a large randomized controlled trial of second-line therapies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The pathophysiology of seizures is multifactorial and incompletely understood. Experimental work demonstrates that prolonged, abnormal, and excessive neuronal electrical activity in itself is injurious through several mechanisms independent of systemic acidosis and hypoxia. Population survival studies and laboratory investigations support the idea that brain injury and epileptogenesis result from status epilepticus. The basic distinction in seizure types is that of generalized and partial seizures. Correct classification of seizure types will aid in clinical communications and guide correct therapies. Revised definitions of generalized convulsive status epilepticus suggest making this diagnosis with as few as 5 minutes of continuous seizure activity., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: S: The natural history of nonconvulsive status epilepticus (NCSE) is not well defined, especially mortality and morbidity. The authors hypothesized that the mortality of NCSE is higher when NCSE is due to acute medical causes (systemic or neurologic) or associated with severe impairment of mental status or with acute complications, and lower when associated with generalized spike-wave (SW) discharges on EEG., Methods: The authors retrospectively identified 100 consecutive patients with NCSE from an EEG database. Data were collected from systematic review of medical records and actual EEG tracings. Specific etiologies were divided into three groups: acute medical, epilepsy, and cryptogenic., Results: Of the 100 patients, 18 died. Fourteen of 52 patients in the acute medical group died, 1 of 31 in the epilepsy group died, and 3 of 17 in the cryptogenic group died. Mental status impairment was severe in 33, complications occurred in 39, and generalized SW discharges occurred in 36. Mortality rates were higher in patients 1) in the acute medical group (27%) vs the epilepsy (3%) and the cryptogenic (18%) groups (p < 0.02), 2) with severe mental status impairment (39%) compared to those with mild impairment (7%, p < 0.001), and 3) with acute complications (36%) when compared with those without complications (7%, p < 0.0002). The presence of generalized SW discharges on EEG did not correlate with mortality. Mental status impairment and etiology were independently associated with mortality (p < 0.001)., Conclusion: NCSE is associated with substantial mortality. Mortality is associated with an acute medical cause as the underlying etiology, severe mental status impairment, and development of acute complications, but not the type of EEG discharge.

Status epilepticus is common and associated with significant mortality and complications. It affects approximately 50 patients per 100,000 population annually and recurs in >13%. History of epilepsy is the strongest single risk factor for generalized convulsive status epilepticus. More than 15% of patients with epilepsy have at least one episode of status epilepticus and low antiepileptic drug levels are a potentially modifiable risk factor. Other risks include young age, genetic predisposition, and acquired brain insults. Fever is a very common risk in children, as is stroke in adults. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Neuronal injury leading to temporal lobe epilepsy is probably mediated by excess excitation via activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and consequent elevated intracellular calcium that causes acute necrosis and delayed apoptotic cell death. Some forms of nonconvulsive status epilepticus may also lead to neuronal injury by this mechanism, but others may not. Based on clinical and experimental observations, complex partial status epilepticus is more likely to result in neuronal injury similar to generalized convulsive status epilepticus. Absence status epilepticus is much less likely to result in neuronal injury, and complications because it may be mediated primarily through excess inhibition. Future research strategies to prevent complications of status epilepticus include the study of new drugs (including NMDA antagonists, new drug delivery systems, and drug combinations) to stop seizure activity and prevent acute and delayed neuronal injury that leads to the development of epilepsy.

Generalized convulsive status epilepticus (GCSE) is a medical emergency requiring prompt resolution. Acute treatment is often delayed by difficulty in obtaining intravenous (i.v.) access. Refractory GCSE is often difficult to treat, and traditional therapy with barbiturates induces hypotension and respiratory depression and prolongs recovery. Midazolam is particularly useful for treating acute GCSE because it has an imidazole ring that is open at low pH, allowing it to be dissolved in aqueous solution for intramuscular injection, but closed at physiologic pH, increasing lipophilicity and rendering good intramuscular absorption, brain penetration, and fast onset of action. When given intramuscularly as a 0.2 mg/kg bolus, it has efficacy at least equal to that of i.v. diazepam, is well tolerated, induces little respiratory compromise, and has a shorter latency to onset of action. Therefore, it should be considered for the treatment of acute GCSE when i.v. access is problematic. For refractory GCSE, continuous i.v. midazolam infusion at 0.1-0.6 mg/kg/hr after a 0.2 mg/kg i.v. bolus is effective and has advantages over traditional therapies because it induces less hypotension and cardiorespiratory depression and can be easily titrated. Further prospective studies are needed to define the role of continuous i.v. midazolam compared to other contemporary therapies.

We investigated whether entorhinal cortex (EC) layer IV neurons are hyperexcitable in the post-selfsustaining limbic status epilepticus (post-SSLSE) animal model of temporal lobe epilepsy. We studied naive rats (n = 44), epileptic rats that had experienced SSLSE resulting in spontaneous seizures (n = 45), and electrode controls (n = 7). There were no differences between electrode control and naive groups, which were pooled into a single control group. Intracellular and extracellular recordings were made from deep layers of EC, targeting layer IV, which was activated by stimulation of the superficial layers of EC or the angular bundle. There were no differences between epileptic and control neurons in basic cellular characteristics, and all neurons were quiescent under resting conditions. In control tissue, 77% of evoked intracellular responses consisted of a short-duration [8.6 +/- 1.3 (SE) ms] excitatory postsynaptic potential and a single action potential followed by gamma-aminobutyric acid-A (GABAA) and GABAB inhibitory post synaptic potentials (IPSPs). Ten percent of controls did not contain IPSPs. In chronically epileptic tissue, evoked intracellular responses demonstrated prolonged depolarizing potentials (256 +/- 39 ms), multiple action potentials (13 +/- 4), and no IPSPs. Ten percent of epileptic responses were followed by rhythmic "clonic" depolarizations. Epileptic responses exhibited an all-or-none response to progressive increases in stimulus intensity and required less stimulation to elicit action potentials. In both epileptic and control animals, intracellular responses correlated precisely in morphology and duration with extracellular field potentials. Severing the hippocampus from the EC did not alter the responses. Duration of intracellular epileptic responses was reduced 22% by the N-methyl--aspartate (NMDA) antagonist (-)-2-amino-5-phosphonovaleric acid (APV), but they did not return to normal and IPSPs were not restored. Epileptic and control responses were abolished by the non-NMDA antagonist 6, 7-dinitroquinoxaline-2-3-dione (DNQX). A monosynaptic IPSP protocol was used to test connectivity of inhibitory interneurons to primary cells by direct activation of interneurons with a stimulating electrode placed near the recording electrode in the presence of APV and DNQX. Using this protocol, IPSPs similar to control (P > 0.05) were seen in epileptic cells. The findings demonstrate that deep layer EC cells are hyperexcitable or "epileptiform" in this model. Hyperexcitability is not due to interactions with the hippocampus. It is due partially to augmented NMDA-mediated excitation. The lack of IPSPs in epileptic neurons may suggest inhibition is impaired, but we found evidence that inhibitory interneurons are connected to their target cells and are capable of inducing IPSPs.

The cellular and molecular pathophysiology of status epilepticus (SE) provides a conceptual framework for understanding clinical scenarios and prospectively designing logical therapies. SE is a dynamic process that evolves over time in a predictable manner with an established sequence of EEG, motor, physiologic, and cellular changes. Neuronal injury and death are the result of processes intrinsic to the brain, mediated by a complex neurotoxic cascade consisting of multiple serial and parallel processes. The risk of cell injury depends also on the overall pathophysiologic profile, including the presence of alterations resulting from SE and occurring independent of SE. On neurophysiologic grounds, we divide SE into "spike-wave" and "nonspike-wave" forms. Spike-wave "absence" status epilepticus carries a low risk of epileptic brain damage, and therapy should be adjusted accordingly. All nonspike-wave SE has a theoretical basis for epileptic brain damage, but the actual risk is variable. There is a significant known risk of cell injury during generalized convulsive SE, a variety of nonspike-wave SE, so aggressive treatment is warranted to prevent sequelae. There is also a theoretical basis for epileptic brain damage in nonspike-wave nonconvulsive SE, but prospective studies are needed to determine which of these patients warrant aggressive therapy. Based on pathophysiologic principles, future treatment of nonspike-wave SE may use a combination of anti-ictal agents, including gamma-aminobutyric acid agonists and N-methyl-D-aspartate antagonists, as well as various neuroprotectants.