Unraveling the enigma of new‐onset refractory status epilepticus: a systematic review of aetiologies

Abstract

Background and purpose New‐onset refractory status epilepticus (NORSE) is a clinical presentation, neither a specific diagnosis nor a clinical entity. It refers to a patient without active epilepsy or other pre‐existing relevant neurological disorder, with a NORSE without a clear acute or active structural, toxic or metabolic cause. This study reviews the currently available evidence about the aetiology of patients presenting with NORSE and NORSE‐related conditions. Methods A systematic search was carried out for clinical trials, observational studies, case series and case reports including patients who presented with NORSE, febrile‐infection‐related epilepsy syndrome or the infantile hemiconvulsion‐hemiplegia and epilepsy syndrome. Results Four hundred and fifty records were initially identified, of which 197 were included in the review. The selected studies were retrospective case–control (n = 11), case series (n = 83) and case reports (n = 103) and overall described 1334 patients both of paediatric and adult age. Aetiology remains unexplained in about half of the cases, representing the so‐called ‘cryptogenic NORSE’. Amongst adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either non‐paraneoplastic or paraneoplastic. Infections are the prevalent aetiology of paediatric non‐cryptogenic NORSE. Genetic and congenital disorders can have a causative role in NORSE, and toxic, vascular and degenerative conditions have also been described. Conclusions Far from being a unitary condition, NORSE is a heterogeneous and clinically challenging presentation. The development and dissemination of protocols and guidelines to standardize diagnostic work‐up and guide therapeutic approaches should be implemented. Global cooperation and multicentre research represent priorities to improve the understanding of NORSE.

An ultra-long new onset refractory status epilepticus: Winning the battle but losing the war?

“…Recently, Sculier and Gaspard [15] proposed a helpful diagnostic and treatment algorithm and reviewed latest relevant findings. Particularly, autoimmune or paraneoplastic encephalitis have been suggested to be a possible cause of this entity, [11] , [16] even in the case where a specific anti-neural antibodies has not been detected. Consequently, immunotherapic strategies have been increasingly proposed in the treatment of NORSE of unknown etiology, with variable results.…”

“… [21] , [22] , [23] Seizures, themselves, can lead to a cascade of cytokine-mediated events, further contributing to the progression of an inflammation-mediated status epilepticus. [16] Encouraging results have been reported regarding the administration of IL-6 and IL-1 receptor antagonist antibodies in case series of patients with NORSE [22] and FIRES [23] , [24] . Regarding our case, interleukin inhibitors were not administered due to the limited supporting evidence at that time of occurrence in 2016 though despite this lack of treatment, SE eventually resolved.…”

Molecular Mechanisms in the Genesis of Seizures and Epilepsy Associated With Viral Infection

“…Febrile infection-related epilepsy syndrome (FIRES), a subtype of new-onset refractory status epilepticus (NORSE), is a catastrophic epileptic syndrome that strikes previously healthy children between the age of 2 and early adulthood and has unknown pathogenesis and few treatments ( Fox et al, 2017 ; Sculier et al, 2021 ; Lattanzi et al, 2022 ; Nausch et al, 2022 ). Affected children experience a non-specific illness with fever starting between 2 weeks and 24 h before the onset of prolonged refractory status epilepticus.…”

Estado epiléptico refractario de inicio reciente (NORSE): caso clínico

“…También se han encontrado cambios inflamatorios leves, en ausencia de una infección documentada o una condición autoinmune específica, es por eso que se podría conferir un papel inmunológico en la patogénesis de esta afección [12,13]. En una revisión sistemática llevada a cabo por Latanzzi y colaboradores en 2022, donde se incluyeron 197 estudios a nivel mundial, no se pudo establecer la etiología en la mayoría de los casos [5]. La causa más común identificada en los adultos es la encefalitis autoinmune, esporádica o paraneoplásica [4] (figura 3).…”

“…Recientemente se han reportado casos de NORSE en pacientes infectados con el coronavirus SARS-CoV-2, tanto en sintomáticos como en asintomáticos, y se sugiere que pueda ser causado por la respuesta inmune con compromiso del SNC [5]. En el caso presentado se realizaron pruebas séricas de autoinmunidad y anticuerpos descarboxilasa del ácido glutámico (GAD), pero no fue posible realizar los otros anticuerpos mencionados por falta de disponibilidad en nuestro laboratorio.…”