The etiology and mortality of new‐onset refractory status epilepticus (<scp>NORSE</scp>) in adults: A systematic review and meta‐analysis

Tharmaraja, Thahesh; Ho, Jean K.; Rajakulendran, Sanjeev; Neligan, Aidan

doi:10.1111/epi.17523

Cited by 8 publications

(9 citation statements)

References 64 publications

(195 reference statements)

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“…Likely, there are yet autoantibodies to discover or they have been discovered at the time point of diagnosis, which might account for some but not all of the cryptogenic cases. 5 In a mixed cohort comprising adults and children, Gopaul et al 7 linked the seasonal differences with AEs that have a higher reported prevalence in summer-autumn and in warmer months. 18,19 However, data from a Danish AE register did not suggest a strong seasonality of antibody detection in Denmark making a direct and substantial link between the seasonality of NORSE and AE less likely.…”

Section: Discussionmentioning

confidence: 99%

“…Around one third of NORSE patients have autoimmune encephalitis (AE), the remainder is caused by infections (e.g., herpes encephalitis) and various rare etiologies. 5,6 Seasonal variations may provide important hints towards the precipitating triggers of NORSE and may therefore help with understanding the pathophysiological mechanisms causing cryptogenic NORSE. Gopaul et al recently examined the seasonality of adult and pediatric NORSE patients from four different cohorts from North America, Germany, and Belgium.…”

Section: Plain Language Summarymentioning

confidence: 99%

“…Around one third of NORSE patients have autoimmune encephalitis (AE), the remainder is caused by infections (e.g., herpes encephalitis) and various rare etiologies. 5 , 6 …”

Section: Introductionmentioning

confidence: 99%

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NORSE seasonality may vary geographically in adults

Bolle,

Gaist,

Kuljis

et al. 2024

Epilepsia Open

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The mechanisms causing new onset refractory status epilepticus (NORSE) are often unknown. Recently, a seasonal variation with NORSE peaking during the summer was described in a mixed cohort of adults and children why we here studied the seasonal variation in a Danish status epilepticus (SE) cohort. This retrospective cohort study comprised SE patients aged ≥18 diagnosed and treated 2008–2017 at the Odense University Hospital. Clinical characteristics and seasonality of patients fulfilling the diagnostic criteria for NORSE were compared with patients with refractory SE (RSE) due to other reasons and with the seasonal variation of autoantibodies associated with autoimmune encephalitis in the Danish autoimmune encephalitis register. In this cohort, 26 patients met NORSE criteria. As compared to RSE patients not fulfilling NORSE criteria (n = 152), NORSE patients were more likely to have symptoms of systemic inflammation (C‐reactive protein concentrations ≥10 mg/L or fever ≥38°C) at admission; nine fulfilled the criteria for febrile infection related epilepsy syndrome (FIRES). In contrast to the even seasonal distribution of patients with RSE not fulfilling the NORSE criteria, admissions due to NORSE peaked during the winter (46.1%, p = 0.04 as compared to non‐NORSE RSE); six out of nine FIRES episodes occurred in the winter season. The seasonal variation was not explained by a seasonal variation of the detection rates of autoantibodies associated with autoimmune encephalitis (incl. NMDAR, LGI1, CASPR2, GABAR, GFAP) in a Danish nationwide register (n = 259). In conclusion, we confirm the seasonality of NORSE in a Danish cohort, however, with a peak during winter suggesting a geographical variation not solely explained by autoimmune encephalitis associated with known autoantibodies.Plain Language SummaryThe study investigated the seasonal patterns of new‐onset refractory status epilepticus (NORSE), i.e. severe seizures that occur without an obvious cause and require very intensive treatment. In contrast to the previously observed peak frequency in summer, this Danish study found that NORSE cases peak in winter. Furthermore, the seasonal variation in NORSE cases was not found to be associated with autoimmune encephalitis caused by known autoantibodies. Together with the high rate of patients showing symptoms of systemic inflammation compared to other status epilepticus patients, the data suggest a link between misdirected immune system responses and NORSE. The study can therefore help in the further search for the currently unknown causes of NORSE.

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Section: Discussionmentioning

confidence: 99%

Section: Plain Language Summarymentioning

confidence: 99%

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NORSE seasonality may vary geographically in adults

Bolle,

Gaist,

Kuljis

et al. 2024

Epilepsia Open

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“…NORSE/FIRES represent a devastating condition with high mortality rates and poor neurocognitive outcomes ( 58 ). The necessity of rapid effective treatment is reflected in the timeline of the current therapeutic consensus ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

Neuromodulation in new-onset refractory status epilepticus

2023

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BackgroundNew-onset refractory status epilepticus (NORSE) and its subset of febrile infection-related epilepsy syndrome (FIRES) are devastating clinical presentations with high rates of mortality and morbidity. The recently published consensus on the treatment of these conditions includes anesthetics, antiseizure drugs, antivirals, antibiotics, and immune therapies. Despite the internationally accepted treatment, the outcome remains poor for a significant percentage of patients.MethodsWe conducted a systematic review of the use of neuromodulation techniques in the treatment of the acute phase of NORSE/FIRES using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.ResultsOur search strategy brought up 74 articles of which 15 met our inclusion criteria. A total of 20 patients were treated with neuromodulation. Thirteen cases represented FIRES and in 17 cases the NORSE remained cryptogenic. Ten had electroconvulsive therapy (ECT), seven had vagal nerve stimulation (VNS), and four had deep brain stimulation (DBS); one patient had initially VNS and later DBS. Eight patients were female and nine were children. In 17 out of 20 patients, the status epilepticus was resolved after neuromodulation, while three patients died.ConclusionNORSE can have a catastrophic course and the first treatment goal should be the fastest possible termination of status epilepticus. The data presented are limited by the small number of published cases and the variability of neuromodulation protocols used. However, they show some potential clinical benefits of early neuromodulation therapy, suggesting that these techniques could be considered within the course of FIRES/NORSE.

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“…It will therefore be necessary to look for other signs of encephalitis, such as recent psychiatric or cognitive symptoms, abnormal movements (clonus, myoclonus, dyskinesia, dystonia), MRI-hyperintensities (especially in temporal regions), lymphocytic meningitis on lumbar puncture and EEG abnormalities [15–17]. A systematic review of the etiologies of NORSE highlighted that an autoimmune etiology was identified in 36.2%, whilst no cause was identified in almost half of cases (49.9%) [18 ▪ ]. Regarding causes of SRSE, a recent study highlighted that the only independent predictor of this severe form of SE was central nervous system infection [4], suggesting that the neuro-inflammatory process in infectious encephalitis could induce major neuronal excitotoxicity [16].…”

Section: Aetiologiesmentioning

confidence: 99%

Status epilepticus: what's new for the intensivist

Benghanem,

Pruvost-Robieux,

Neligan

et al. 2024

Current Opinion in Critical Care

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Purpose of review Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. Recent findings Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. Summary Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

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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.

Cited by 8 publications

References 64 publications

NORSE seasonality may vary geographically in adults

NORSE seasonality may vary geographically in adults

Neuromodulation in new-onset refractory status epilepticus

Status epilepticus: what's new for the intensivist

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