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ABSTRACT Background Epileptiform activity, including status epilepticus (SE), occurs in up to one‐third of comatose survivors of cardiac arrest and may predict poor outcome. The relationship between SE and hypoxic–ischemic brain injury (HIBI) is not established. Methods This is a single‐center retrospective study on consecutive patients with post‐anoxic super‐refractory SE. HIBI was graded as non‐widespread (group 1) or widespread (group 2) by qualitative analysis of DWI/ADC and T2w‐FLAIR. Between‐group differences in the rate of poor neurological outcome at 6 months (primary outcome), SE resolution and consciousness recovery before discharge, and mortality at 6 months (secondary outcomes) were investigated. Results From January 2011 to February 2023, 40 patients were included. HIBI was widespread in 45% of patients and non‐widespread in 55%. The rate of poor neurological outcome at 6 months was 27% in group 1 and 83% in group 2 (OR 12.8, CI 95% [2.5–64.3], p = 0.002). The rate of consciousness recovery before discharge was 73% in group 1 versus 22% in group 2 (OR 8.8, CI 95% [1.9–40.3], p = 0.005). SE resolved in 95% of patients in group 1 versus 67% in group 2 (OR 10.5, CI 95% [1.1–97.9], p = 0.039). Mortality rate at 6 months was 27% in group 1 versus 50% in group 2 (OR 0.4, CI 95% [0.1–1.9], p = 0.303). Conclusion Patients with widespread HIBI had higher odds of poor outcome at 6 months, lower probability of SE resolution and of consciousness recovery before discharge compared to those with non‐widespread HIBI. Mortality at 6 months did not differ significantly between the two groups.

Key Points Nonconvulsive status epilepticus (NCSE) is defined as a continuous state of seizures without convulsions, or multiple nonconvulsive seizures for more than 30 min without interictal full recovery The variable and subtle clinical features of NCSE make diagnosis and treatment challenging, as they can arise from other pathological conditions The introduction of continuous electroencephalography and the characterization of electrographic criteria have delineated several NCSE types that are associated with different prognoses in various clinical settings The classification of NCSE should mainly be based on aetiology, as the outcomes of NCSE are driven largely by the underlying pathology Treatment of NCSE encompasses general intensive care, rapid administration of antiepilepic drugs, and treatment of the underlying or concomitant diseases Nonconvulsive status epilepticus has subtle symptoms and can be difficult to treat, meaning it is associated with considerable morbidity and mortality. In this Review, Sutter and colleagues discuss the epidemiology, clinical features and diagnosis of nonconvulsive status epilepticus, and discuss current recommendations for treatment. Nonconvulsive status epilepticus (NCSE) is a state of continuous or repetitive seizures without convulsions. Owing to the nonspecific symptoms and considerable morbidity and mortality associated with NCSE, clinical research has focused on early diagnosis, risk stratification and seizure termination. The subtle symptoms and the necessity for electroencephalographic confirmation of seizures result in under-diagnosis with deleterious consequences. The introduction of continuous EEG to clinical practice, and the characterization of electrographic criteria have delineated a number of NCSE types that are associated with different prognoses in several clinical settings. Epidemiological studies have uncovered risk factors for NCSE; knowledge of these factors, together with particular clinical characteristics and EEG observations, enables tailored treatment. Despite these advances, NCSE can be refractory to antiepileptic drugs, necessitating further escalation of treatment. The presumptive escalation to anaesthetics, however, has recently been questioned owing to an association with increased mortality. This Review compiles epidemiological, clinical and diagnostic aspects of NCSE, and considers current treatment options and prognosis.

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.

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.

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.

Studies using experimental animal models have demonstrated IL-1[beta] expression in microglia and astrocytes after seizures and that IL-1[beta] itself can enhance neuronal excitability. 4 Based on these findings, a hypothesis has been proposed that the vicious cycle consisting of seizure activity and inflammation contribute to the further progression of inflammation-mediated status epilepticus. 1 However, this paradigm has not been definitively demonstrated in human status epilepticus. [...]the present study unveiled a previously unrecognised relationship between a group of proinflammatory cytokines/chemokines and refractory status epilepticus in a human disease.

Status epilepticus (SE) treatment strategies vary substantially from one institution to another due to the lack of data to support one treatment over another. To provide guidance for the acute treatment of SE in critically ill patients, the Neurocritical Care Society organized a writing committee to evaluate the literature and develop an evidence-based and expert consensus practice guideline. Literature searches were conducted using PubMed and studies meeting the criteria established by the writing committee were evaluated. Recommendations were developed based on the literature using standardized assessment methods from the American Heart Association and Grading of Recommendations Assessment, Development, and Evaluation systems, as well as expert opinion when sufficient data were lacking.

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.

Status epilepticus is a common neurological emergency with considerable associated health-care costs, morbidity, and mortality. The definition of status epilepticus as a prolonged seizure or a series of seizures with incomplete return to baseline is under reconsideration in an effort to establish a more practical definition to guide management. Clinical research has focused on early seizure termination in the prehospital setting. The approach of early escalation to anaesthetic agents for refractory generalised convulsive status epilepticus, rather than additional trials of second-line anti-epileptic drugs, to avoid neuronal injury and pharmaco-resistance associated with prolonged seizures is gaining momentum. Status epilepticus is also increasingly identified in the inpatient setting as the use of extended electroencephalography monitoring becomes more commonplace. Substantial further research to enable early identification of status epilepticus and efficacy of anti-epileptic drugs will be important to improve outcomes.

Status epilepticus (SE) is a common medical emergency associated with significant morbidity and mortality. Management that follows published guidelines is best suited to improve outcomes, with the most severe cases frequently being managed in the intensive care unit (ICU). Diagnosis of convulsive SE can be made without electroencephalography (EEG), but EEG is required to reliably diagnose nonconvulsive SE. Rapidly narrowing down underlying causes for SE is crucial, as this may guide additional management steps. Causes may range from underlying epilepsy to acute brain injuries such as trauma, cardiac arrest, stroke, and infections. Initial management consists of rapid administration of benzodiazepines and one of the following non-sedating intravenous antiseizure medications (ASM): (fos-)phenytoin, levetiracetam, or valproate; other ASM are increasingly used, such as lacosamide or brivaracetam. SE that continues despite these medications is called refractory, and most commonly treated with continuous infusions of midazolam or propofol. Alternatives include further non-sedating ASM and non-pharmacologic approaches. SE that reemerges after weaning or continues despite management with propofol or midazolam is labeled super-refractory SE. At this step, management may include non-sedating or sedating compounds including ketamine and barbiturates. Continuous video EEG is necessary for the management of refractory and super-refractory SE, as these are almost always nonconvulsive. If possible, management of the underlying cause of seizures is crucial particularly for patients with autoimmune encephalitis. Short-term mortality ranges from 10 to 15% after SE and is primarily related to increasing age, underlying etiology, and medical comorbidities. Refractoriness of treatment is clearly related to outcome with mortality rising from 10% in responsive cases, to 25% in refractory, and nearly 40% in super-refractory SE.