Patients with new-onset refractory status epilepticus had significantly higher serum levels of several key pro-inflammatory cytokines than study participants with other forms of refractory status epilepticus, suggesting that immune therapies targeting specific aspects of the innate immune system may be helpful for treating patients with cryptogenic NORSE.
Innate immunity-related inflammation plays a key role in the pathogenesis and outcomes of new-onset refractory status epilepticus (NORSE), according to a new international multicenter study led by investigators from Yale University School of Medicine published in Annals of Neurology in March.
NORSE is a rare, confounding clinical entity with a high mortality rate of 16 to 27 percent in adults and around 12 percent in children, the study authors pointed out. It strikes suddenly and without warning, often in young, previously healthy individuals. In the initial presentation, patients experience a sudden onset of continuous seizures or a flurry of very frequent seizures, without any apparent cause, that do not respond to standard anticonvulsant medications. Typically, they require prolonged anesthesia with coma-inducing drugs to get the seizures under control.
The majority of patients who survive usually live with major long-term neurocognitive and functional disabilities, often including drug-resistant epilepsy. About half of all patients with NORSE have an unknown etiology for their condition even after extensive workups, referred to as cryptogenic NORSE.
Study Details
In the new study, patients with NORSE had significantly higher serum levels of several key pro-inflammatory cytokines compared with study participants with other forms of refractory status epilepticus (RSE). The findings suggest that immune therapies targeting specific aspects of the innate immune system, such as IL-6 blockers or anti-CXCL8, may be helpful for treating patients with cryptogenic NORSE.
The study enrolled 61 patients—15 of whom were cryptogenic—at 13 hospitals in the United States, one in Canada, and one in France, all between February 2013 and July 2022. The patients with NORSE were at least 2 years old. The NORSE patient cohort included 24 patients with a prior febrile illness between one and 14 days prior to the onset of RSE, a subtype of NORSE known as febrile infection-related epilepsy syndrome (FIRES). Investigators also enrolled 37 patients with other forms of RSE from known etiology, 12 patients with autoimmune encephalitis without status epilepticus, 22 patients with drug-resistant epilepsy who had a seizure (but not SE) within 24 hours before sample collection, and 18 control patients without epilepsy.
The researchers collected serum samples for all patients and cerebrospinal fluid samples from 29 patients with NORSE, 14 with RSE, 10 with autoimmune encephalitis, and 17 controls.
Pro-Inflammatory Cytokines
The serum analysis showed overproduction of pro-inflammatory cytokines/chemokines in the serum and in the CSF of patients with status epilepticus compared with patients without status epilepticus. They found differences among the five subgroups of patients for nine serum cytokines/chemokines and five CSF cytokines/chemokines.
Patients with NORSE had significantly higher serum levels of CXCL8, MIP-1alpha, and CCL2 and significantly higher CSF levels of IL-1beta than those with other forms of RSE. Those with cNORSE also had significantly higher serum levels of CXCL8, MIP-1alpha, and CCL2 compared to all non-cryptogenic RSE.
https://journals.lww.com/neurotodayonline/Fulltext/2023/05180/The_Role_of_Inflammation_in_New_onset_Refractory.2.aspx
Hanin A, Cespedes J, Dorgham K, Pulluru Y, Gopaul M, Gorochov G, Hafler DA, Navarro V, Gaspard N, Hirsch LJ. Cytokines in New-Onset Refractory Status Epilepticus Predict Outcomes. Ann Neurol. 2023 Mar 5. doi: 10.1002/ana.26627. Epub ahead of print. PMID: 36871188.
Abstract
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
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