The etiology and mortality of new-onset refractory status epilepticus (NORSE) in adults: A systematic review and meta-analysis

Abstract

New-onset refractory status epilepticus (NORSE) is a devastating neurological presentation. There is a paucity of large studies on NORSE as it is a relatively new clinical syndrome. The aim of this review was to summarize the etiologies and establish a mortality rate for NORSE. Two independent authors systematically searched the following electronic databases from January 1, 2005 April 20, 2021: PubMed, Embase, OVID, Scopus, Web of Science, "Clinicaltrials.gov," and the International Standard Randomised Controlled Trial Number (ISRCTN) registry. We included all primary research studies of NORSE in adults and excluded commentaries, reviews, pre-clinical studies, and pediatric populations. Etiology was extracted from all studies meeting eligibility criteria, whereas data relating to treatments, hospital stay, functional outcomes, and mortality were extracted from studies with sample size ≥5. We conducted a random-effects meta-analysis of mortality rate with meta-regression testing for significant covariates. Of 1482 studies, 109 case reports and case series met our criteria, comprising 395 cases of NORSE. The most common etiology was cryptogenic in 197 cases (49.9%), followed by autoimmune in 143 cases (36.2%). The pooled mortality rate was 22% (95% confidence interval 17%-27%; $N_{\text{studies}}$ = 15), with low heterogeneity ( $I^2$ = 0%). Meta-regression revealed that year of study, treatment with ketogenic diet or immunotherapy, percentage of cryptogenic cases, and length of intensive care unit stay were not significant covariates for mortality. Common treatments included antiseizure medications (median 5), general anesthesia, and immunotherapy such as corticosteroids, intravenous immunoglobulin, and plasma exchange. Mean length of intensive care admission was 33.4 days, with 52% of cases diagnosed with epilepsy on discharge. Neurocognitive impairment was a common sequela of NORSE. NORSE is associated with a high mortality. Half of cases remain cryptogenic, which presents a diagnostic challenge. Future focus should be on elucidating the underlying neurobiology and determining the most effective therapeutic interventions.