•The NORSE definition provides standardized criteria for future multicenter research.•Extensive patient-specific investigations are required to find rare causes of NORSE.•The etiology is identified ...in approximatively 50% of adult cases.•Recent immunotherapies and ketogenic diet are sometimes efficacious.
To summarize the clinical features, suggested work-up, treatment and prognosis of new-onset refractory status epilepticus (NORSE), a condition recently defined as the occurrence of refractory status epilepticus (RSE) in a patient without active epilepsy, and without a clear acute or active structural, toxic or metabolic cause; and of the related syndrome of febrile infection-related epilepsy syndrome (FIRES), also recently defined as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of RSE.
Narrative review of the medical literature about NORSE and FIRES.
NORSE and FIRES mainly affect school-age children and young adults. A prodromal phase with flu-like symptoms precedes the SE onset in two third of NORSE cases, and by definition in all FIRES. Status epilepticus usually starts with repeated focal seizures with secondary bilateralization. Most cases evolve to super RSE (SRSE) and have unfavorable outcome, with short-term mortality of 12–27%, long-term disability and epilepsy. No specific imaging or laboratory abnormalities have been identified so far that allows an early diagnosis and half of adult cases remain of unknown etiology. A standardized diagnostic algorithm is provided and. Autoimmune encephalitis is the most frequent identified cause. In the absence of specific diagnosis, immunotherapy could be tried in addition to antiepileptic treatment.
This review presents the rare but devastating syndrome of NORSE, including the subcategory of FIRES. Early recognition with complete work-up is primordial to identify the underlying cause and promptly start appropriate treatment.
Current prognostic scores for status epilepticus (SE) may not be adequate for patients in ICU who usually have more severe systemic conditions or more refractory episodes of SE. We aimed to compare ...the prognostic performance of two SE scores, Status Epilepticus Severity Score (STESS) and Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) score, with four systemic severity scores, Acute Physiology and Chronic Health Evaluation 2 (APACHE-2), Simplified Acute Physiology Score 2 (SAPS-2), Sequential Organ Failure Assessment (SOFA) score, and Inflammation, Nutrition, Consciousness, Neurologic function and Systemic condition (INCNS) score in critically ill patients with SE.
This retrospective observational study of a prospectively identified SE cohort was conducted in the ICU at a tertiary-care center. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and associations with outcomes of STESS, EMSE, INCNS, APACHE-2, SAPS-2, and SOFA score for the prediction of in-hospital mortality and no return to baseline condition were assessed.
Between January 2015 and December 2020, 166 patients with SE in ICU were included in the study. In predicting in-hospital death, APACHE-2 (0.72), SAPS-2 (0.73), and SOFA score (0.71) had higher AUCs than STESS (0.58) and EMSE (0.69). In predicting no return to baseline condition, the AUC of APACHE-2 (0.75) was the highest, and the AUC of INCNS (0.55) was the lowest. When the specificity approached 90%, the sensitivity values of these scores were not quite acceptable (< 40%). Neither SE scores nor systemic severity scores had desirable prognostic power. In the multivariate logistic regression analyses, the best combinations of scores always included at least one or more systemic severity scores.
STESS and EMSE were insufficient in outcome prediction for SE patients in ICU, and EMSE was marginally better than STESS. Systemic illness matters in ICU patients with SE, and SE scores should be modified to achieve better accuracy in this severely ill population. This study mostly refers to severely ill patients in the ICU.
Summary
We report the proceedings of the First International new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) Symposium. To promote awareness of ...this condition and foster research efforts, we conveyed the First International new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood‐ and adult‐onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine‐mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES.
Summary
We convened an international group of experts to standardize definitions of New‐Onset Refractory Status Epilepticus (NORSE), Febrile Infection‐Related Epilepsy Syndrome (FIRES), and related ...conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in‐person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion‐Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super‐refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.
While embryonic stem (ES) cells have been used for several years to generate specific populations of neural cells in a translational perspective, they have also emerged as a promising approach in ...developmental neurobiology, by providing reductionist models of neural development. Here we review recent work that indicates that ES-based models are not only able to mimic normal brain development, but also provide novel tools to dissect the relative contribution of intrinsic and extrinsic mechanisms of neural specification. These have thus not only revealed insights on early steps such as neural induction and regional patterning, but also temporal specification of distinct neuronal subtypes, as well as the later acquisition of more complex features such as cytoarchitecture and hodological properties.
Purpose
To determine the temporal evolution, clinical correlates, and prognostic significance of electroencephalographic (EEG) patterns in post-cardiac arrest comatose patients treated with ...hypothermia.
Methods
Prospective cohort study of consecutive post-anoxic patients receiving hypothermia and continuous EEG monitoring between May 2011 and June 2014 (
n
= 100). In addition to clinical variables, 5-min EEG clips at 6, 12, 24, 48, and 72 h after return of spontaneous circulation (ROSC) were reviewed. EEG background was classified according to the American Clinical Neurophysiological Society critical care EEG terminology. Clinical outcome at discharge was dichotomized as good Glasgow outcome scale (GOS) 4–5, low to moderate disability vs. poor (GOS 1–3, severe disability to death).
Results
Non-ventricular fibrillation/tachycardia arrest, longer time to ROSC, absence of brainstem reflexes, extensor or no motor response, lower pH, higher lactate, hypotension requiring >2 vasopressors, and absence of reactivity on EEG were all associated with poor outcome (all
p
values ≤0.01). Suppression-burst at any time indicated a poor prognosis, with a 0 % false positive rate (FPR) 95 % confidence interval (CI) 0–10 %. All patients (54/54) with suppression-burst or a low voltage (<20 µV) EEG at 24 h had a poor outcome, with an FPR of 0 % 95 % CI 0–8 %. Normal background voltage ≥20 µV without epileptiform discharges at any time interval carried a positive predictive value >70 % for good outcome.
Conclusions
Suppression-burst or a low voltage at 24 h after ROSC was not compatible with good outcome in this series. Normal background voltage without epileptiform discharges predicted a good outcome.
Objective
The objective of this study was to investigate inflammation using cerebrospinal fluid (CSF) and serum cytokines/chemokines in patients with new‐onset refractory status epilepticus (NORSE) ...to better understand the pathophysiology of NORSE and its consequences.
Methods
Patients with NORSE (n = 61, including n = 51 cryptogenic), including its subtype with prior fever known as febrile infection‐related epilepsy syndrome (FIRES), were compared with patients with other refractory status epilepticus (RSE; n = 37), and control patients without SE (n = 52). We measured 12 cytokines/chemokines in serum or CSF samples using multiplexed fluorescent bead‐based immunoassay detection. Cytokine levels were compared between patients with and without SE, and between the 51 patients with cryptogenic NORSE (cNORSE) and the 47 patients with a known‐etiology RSE (NORSE n = 10, other RSE n = 37), and correlated with outcomes.
Results
A significant increase of IL‐6, TNF‐α, CXCL8/IL‐8, CCL2, MIP‐1α, and IL‐12p70 pro‐inflammatory cytokines/chemokines was observed in patients with SE compared with patients without SE, in serum and CSF. Serum innate immunity pro‐inflammatory cytokines/chemokines (CXCL8, CCL2, and MIP‐1α) were significantly higher in patients with cNORSE compared to non‐cryptogenic RSE. Patients with NORSE with elevated innate immunity serum and CSF cytokine/chemokine levels had worse outcomes at discharge and at several months after the SE ended.
Interpretation
We identified significant differences in innate immunity serum and CSF cytokine/chemokine profiles between patients with cNORSE and non‐cryptogenic RSE. The elevation of innate immunity pro‐inflammatory cytokines in patients with NORSE correlated with worse short‐ and long‐term outcomes. These findings highlight the involvement of innate immunity‐related inflammation, including peripherally, and possibly of neutrophil‐related immunity in cNORSE pathogenesis and suggest the importance of utilizing specific anti‐inflammatory interventions. ANN NEUROL 2023;94:75–90
Summary
Objective
The interpretation of critical care electroencephalography (EEG) studies is challenging because of the presence of many periodic and rhythmic patterns of uncertain clinical ...significance. Defining the clinical significance of these patterns requires standardized terminology with high interrater agreement (IRA). We sought to evaluate IRA for the final, published American Clinical Neurophysiology Society (ACNS)–approved version of the critical care EEG terminology (2012 version). Our evaluation included terms not assessed previously and incorporated raters with a broad range of EEG reading experience.
Methods
After reviewing a set of training slides, 49 readers independently completed a Web‐based test consisting of 11 identical questions for each of 37 EEG samples (407 questions). Questions assessed whether a pattern was an electrographic seizure; pattern location (main term 1), pattern type (main term 2); and presence and classification of eight other key features (“plus” modifiers, sharpness, absolute and relative amplitude, frequency, number of phases, fluctuation/evolution, and the presence of “triphasic” morphology).
Results
IRA statistics (κ values) were almost perfect (90–100%) for seizures, main terms 1 and 2, the +S modifier (superimposed spikes/sharp waves or sharply contoured rhythmic delta activity), sharpness, absolute amplitude, frequency, and number of phases. Agreement was substantial for the +F (superimposed fast activity) and +R (superimposed rhythmic delta activity) modifiers (66% and 67%, respectively), moderate for triphasic morphology (58%), and fair for evolution (21%).
Significance
IRA for most terms in the ACNS critical care EEG terminology is high. These terms are suitable for multicenter research on the clinical significance of critical care EEG patterns.
A PowerPoint slide summarizing this article is available for download in the Supporting Information section http://dx.doi.org/10.1111/epi.12653/supinfo.
Objective
This study was undertaken to develop consensus‐based recommendations for the management of adult and pediatric patients with new onset refractory status epilepticus (NORSE)/febrile ...infection‐related epilepsy syndrome (FIRES) based on best evidence and experience.
Methods
The Delphi methodology was followed. A facilitator group of nine experts was established, who defined the scope, users, and suggestions for recommendations. Following a review of the current literature, recommendation statements concerning diagnosis, treatment, and research directions were generated, which were then rated on a scale of 1 (strongly disagree) to 9 (strongly agree) by a panel of 48 experts in the field. Consensus that a statement was appropriate was reached if the median score was ≥7 and inappropriate if the median score was ≤3. The analysis of evidence was mapped to the results of each statement included in the Delphi survey.
Results
Overall, 85 recommendation statements achieved consensus. The recommendations are divided into five sections: (1) disease characteristics; (2) diagnostic testing and sampling; (3) acute treatment; (4) treatment in the postacute phase; and (5) research, registries, and future directions in NORSE/FIRES. The detailed results and discussion of all 85 statements are outlined herein. A corresponding summary of findings and practical flowsheets are presented in a companion article.
Significance
This detailed analysis offers insight into the supporting evidence and the current gaps in the literature that are associated with expert consensus statements related to NORSE/FIRES. The recommendations generated by this consensus can be used as a guide for the diagnosis, evaluation, and management of patients with NORSE/FIRES, and for planning of future research.
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