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In patients with convulsive status epilepticus, the addition of cooling to 32 to 34°C for 24 hours did not have a significant effect on the percentage of patients with good outcomes at 90 days as compared with standard seizure treatment alone. Convulsive status epilepticus is among the most challenging life-threatening neurologic emergencies. 1 Antiepileptic drug treatment is initiated rapidly and adjusted in response to clinical and electroencephalographic (EEG) findings. 2 The in-hospital mortality associated with this condition is approximately 20% and, if status epilepticus remains refractory to treatment, can be as high as 40%. 3 – 7 Functional impairments after status epilepticus may be due to the effect of seizures on cortical neurons or to cerebral damage due to the underlying process that caused the seizures. In a prospective, multicenter study, 50% of survivors of convulsive status epilepticus who were admitted to an intensive care . . .

Background Electroencephalographic (EEG) status epilepticus is described in 10 to 35% of patients with postanoxic encephalopathy after successful cardiopulmonary resuscitation and is associated with case fatality rates of 90 to 100%. It is unclear whether these EEG patterns represent a condition to be treated with anticonvulsants to improve outcome, or an expression of severe ischemic damage, in which treatment is futile. Methods/Design TELSTAR is a multicenter clinical trial with two parallel groups, randomized treatment allocation, open label treatment, and blinded endpoint evaluation (PROBE design). We aim to enroll 172 adult patients with postanoxic encephalopathy and electroencephalographic status epilepticus after successful cardiopulmonary resuscitation, admitted to the ICU, in whom continuous EEG monitoring is started within 24 hours after admission. Patients are randomly assigned to either medical treatment to suppress all electrographic seizure activity, or no treatment of electroencephalographic status epilepticus. Antiepileptic treatment is based on guidelines for treatment of overt status epilepticus and is started within 3 hours after the diagnosis. If status epilepticus returns during tapering of sedative medication after suppression of all epileptiform activity for 2 × 24 hours, it will be considered refractory. The primary outcome measure is neurological outcome defined as the Cerebral Performance Category (CPC) score at 3 months, dichotomized into ‘good’ (CPC 1 to 2 = no or moderate neurological disability) and ‘poor’ (CPC 3 to 5 = severe disability, coma, or death). Secondary outcome measures include mortality and, for patients surviving up to 12 months, cognitive functioning, health related quality of life, and depression. Trial registration Clinicaltrials.gov; NCT02056236 . Date of registration: 4 February 2014.

The prediction of outcomes in convulsive status epilepticus (CSE) remains a constant challenge. The Encephalitis-Nonconvulsive Status Epilepticus-Diazepam Resistance-Image Abnormalities-Tracheal Intubation (END-IT) score was a useful tool for predicting the functional outcomes of CSE patients, excluding cerebral hypoxia patients. With further understanding of CSE, and in view of the deficiencies of END-IT itself, we consider it necessary to modify the prediction tool. The prediction model was designed from a cohort of CSE patients from Xijing Hospital (China), between 2008 and 2020. The enrolled subjects were randomly divided into training cohort and validation cohort as a ratio of 2:1. The logistic regression analysis was performed to identify the predictors and construct the nomogram. The performance of the nomogram was assessed by calculating the concordance index, and creating calibration plots to check the consistency between the predicted probabilities of poor prognosis and the actual outcomes of CSE. The training cohort included 131 patients and validation cohort included 66 patients. Variables included in the nomogram were age, etiology of CSE, non-convulsive SE, mechanical ventilation, abnormal albumin level at CSE onset. The concordance index of the nomogram in the training and validation cohorts was 0.853 (95% CI, 0.787-0.920) and 0.806 (95% CI, 0.683-0.923), respectively. The calibration plots showed an adequate consistency between the reported and predicted unfavorable outcomes of patients with CSE at 3 months after discharge. A nomogram for predicting the individualized risks of poor functional outcomes in CSE was constructed and validated, which has been an important modification of END-IT score.

Patients with prolonged seizures that do not respond to intravenous benzodiazepines and a second-line anticonvulsant suffer from refractory status epilepticus and those with seizures that do not respond to continuous intravenous anesthetic anticonvulsants suffer from super-refractory status epilepticus. Both conditions are associated with significant morbidity and mortality. A strict pharmacological treatment regimen is urgently required, but the level of evidence for the available drugs is very low. Refractory complex focal status epilepticus generally does not require anesthetics, but all intravenous non-anesthetizing anticonvulsants may be used. Most descriptive data are available for levetiracetam, phenytoin and valproate. Refractory generalized convulsive status epilepticus is a life-threatening emergency, and long-term clinical consequences are eminent. Administration of intravenous anesthetics is mandatory, and drugs acting at the inhibitory gamma-aminobutyric acid (GABA) A receptor such as midazolam, propofol and thiopental/pentobarbital are recommended without preference for one of those. One in five patients with anesthetic treatment does not respond and has super-refractory status epilepticus. With sustained seizure activity, excitatory N -methyl-d-aspartate (NMDA) receptors are increasingly expressed post-synaptically. Ketamine is an antagonist at this receptor and may prove efficient in some patients at later stages. Neurosteroids such as allopregnanolone increase sensitivity at GABA A receptors; a Phase 1/2 trial demonstrated safety and tolerability, but randomized controlled data failed to demonstrate efficacy. Adjunct ketogenic diet may contribute to termination of difficult-to-treat status epilepticus. Randomized controlled trials are needed to increase evidence for treatment of refractory and super-refractory status epilepticus, but there are multiple obstacles for realization. Hitherto, prospective multicenter registries for pharmacological treatment may help to improve our knowledge.

Status epilepticus (SE) is a severe type of epileptic seizure and induces molecular and cellular changes in the brain tissues which contribute to neuron injury. Here we used RNA sequencing to determine changes in hippocampal gene expression in pilocarpine-induced SE mice at 3-hour (SE-3h) and 24-hour (SE-24h) time points, a crucial stage of SE-induced brain acute damage. A total of 366 differentially expressed genes (DEGs) were identified from the SE-3h hippocampus and 570 DEGs from the SE-24h hippocampus, and most of them were up-regulated upon SE induction. Bioinformatical analyses showed that, compared to SE-3h up-regulated genes with poor scores in functional and pathway enrichment, the SE-24h up-regulated genes were predominantly enriched in inflammatory and immune response, positive regulation of response to external stimuli and inflammatory response (GO function), and Microglia pathogen phagocytosis pathway and Tyrobp causal network in microglia (WikiPathway). Specifically, a subset of DEGs such as Tyrobp , C1qc , Itgb2 , Ncf2 , and Nckap1l involved in the two pathways are present in the inflammatory and immune cascades. Therefore, this study delineates early altered transcriptional profiles in the hippocampus after SE, and highlights up-regulation of a subset of genes might be involved in the activation of microglia-mediated inflammatory and immune responses linked to the early pathogenesis of SE-induced brain injury.

Stage 1 Plus is defined here as a naïve, previously untreated, status epilepticus (SE) that is probably refractory to Benzodiazepines (BDZ). These cases include not only prolonged SE as previously proposed by the author (SE lasting > 10 min) but also other cases notoriously associated with BDZ refractoriness such as the absence of prominent motor phenomena and acute etiology (especially primary central nervous system etiology). Interestingly, the absence of prominent motor phenomena as is the case of non convulsive SE might implicitly fall in the category of prolonged SE due to the delay in recognition and treatment. Future studies should help identify other factors associated with BDZ refractoriness, therefore widening the definition of Stage 1 Plus. The appropriate timing for defining prolonged SE may also differ depending on different etiology. Consequently, in future tailored models of SE, the definition of prolonged SE could be enhanced by defining it for a longer duration than Tx, a time point that changes based on different etiologies (x), Tx being much shorter than 10 min in acute etiologies. These cases of naïve probably BDZ refractory SE (Stage 1 Plus) might require a different approach: combined polytherapy from the start. The objective of this review is to provide pathophysiological and pre-clinical evidence, mostly from animal studies, for the different approach of combined polytherapy from the start for those cases of SE falling in the definition of Stage 1 Plus.

Background Status epilepticus (SE) imposes a significant burden in terms of in-hospital mortality and costs, but the relationship between SE causes, patient comorbidities, mortality, and cost remains insufficiently understood. We determined the in-hospital mortality and cost-driving factors of SE using a large and comprehensive database. Methods We conducted a retrospective cohort study involving patients experiencing their first hospitalization with an ICD-10 code diagnosis of SE, spanning from January 1, 2015, to December 31, 2019, using the French health insurance database which covers 99% of population. Patient characteristics, SE causes, Intensive Care Unit (ICU) admissions, mechanical ventilation, discharge status, and health insurance costs were extracted for each hospitalization. Results We identified 52,487 patients hospitalized for a first SE. In-hospital mortality occurred in 11,464 patients (21.8%), with associated factors including age (Odds Ratio [OR], 10.3, 95% Confidence Interval [CI] 7.87–13.8 for ages over 80 compared to 10–19), acute causes (OR, 15.3, 95% CI 13.9–16.8 for hypoxic cause), tumors (OR, 1.75, 95% CI 1.63–1.8), comorbidities (OR, 3.00, 95% CI 2.79–3.24 for 3 or more comorbidities compared to 0), and prolonged mechanical ventilation (OR, 2.61, 95% CI 2.42–2.82). The median reimbursed cost for each SE hospitalization was 6517€ (3364–13,354), with cost factors mirroring those of in-hospital mortality. Conclusion Causes and co-morbidities are major determinants of mortality and hospital costs in status epilepticus, and factors associated with higher mortality are also often associated with higher costs. Further studies are needed to identify their long-term effects.

Refractory and super-refractory status epilepticus (SE) are serious illnesses with a high risk of morbidity and even fatality. In the setting of refractory generalized convulsive SE (GCSE), there is ample justification to use continuous infusions of highly sedating medications—usually midazolam, pentobarbital, or propofol. Each of these medications has advantages and disadvantages, and the particulars of their use remain controversial. Continuous EEG monitoring is crucial in guiding the management of these critically ill patients: in diagnosis, in detecting relapse, and in adjusting medications. Forms of SE other than GCSE (and its continuation in a “subtle” or nonconvulsive form) should usually be treated far less aggressively, often with nonsedating anti-seizure drugs (ASDs). Management of “non-classic” NCSE in ICUs is very complicated and controversial, and some cases may require aggressive treatment. One of the largest problems in refractory SE (RSE) treatment is withdrawing coma-inducing drugs, as the prolonged ICU courses they prompt often lead to additional complications. In drug withdrawal after control of convulsive SE, nonsedating ASDs can assist; medical management is crucial; and some brief seizures may have to be tolerated. For the most refractory of cases, immunotherapy, ketamine, ketogenic diet, and focal surgery are among several newer or less standard treatments that can be considered. The morbidity and mortality of RSE is substantial, but many patients survive and even return to normal function, so RSE should be treated promptly and as aggressively as the individual patient and type of SE indicate.

Status epilepticus occurs when a seizure lasts more than five minutes or when multiple seizures occur with incomplete return to baseline. SE induces a myriad of pathological changes involving synaptic and extra-synaptic factors. The transition from a self-limiting seizure to a self-sustaining one is established by maladaptive receptor trafficking, whereby GABAA receptors are progressively endocytosed while glutamatergic receptors (NMDA and AMPA) are transported to the synaptic membrane, causing excitotoxicity and alteration in glutamate-dependent downstream signaling. The subsequent influx of Ca2+ exposes neurons to increased levels of [Ca2+]i, which overwhelms mitochondrial buffering, resulting in irreversible mitochondrial membrane depolarization and mitochondrial injury. Oxidative stress resulting from mitochondrial leakage and increased production of reactive oxygen species activates the inflammasome and induces a damage-associated molecular pattern. Neuroinflammation perpetuates oxidative stress and exacerbates mitochondrial injury, thereby jeopardizing mitochondrial energy supply in a state of accelerated ATP consumption. Additionally, Ca2+ overload can directly damage neurons by activating enzymes involved in the breakdown of proteins, phospholipids, and nucleic acids. The cumulative effect of these effector pathways is neuronal injury and neuronal death. Surviving neurons undergo long-term alterations that serve as a substrate for epileptogenesis. This review highlights the multifaceted mechanisms underlying SE self-sustainability, pharmacoresistance, and subsequent epileptogenesis.

Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2·5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference −10·3%, 95% CI −24·0 to 3·4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. UCB Pharma.