Article In Brief
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.
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.
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.
“Learning about the pathogenesis of this condition will help us improve treatments and ensure that the majority of patients survive with a good quality of life.”—DR. ELEONORA ARONICA
“In patients with NORSE overall, the elevation of serum innate immunity-associated pro-inflammatory cytokines (IL-6, CXCL8, CCL2, and MIP-1alpha) correlated with worse outcomes at ICU discharge and several months after SE [status epilepticus] ended,” the authors wrote.
Differences in cytokine/chemokine levels were more prominent in the serum than in the CSF of patients with NORSE compared with patients with other forms of RSE, the authors found, which held true when patients with cNORSE were compared to known etiology RSE. “Moreover, serum cytokine/chemokine levels were more closely associated with outcomes than CSF ones,” they noted. “These results suggest that peripheral inflammation may play a pathogenic role in NORSE.”
Neurologists and other subspecialists who investigate NORSE have theorized for some time that the condition is an auto-inflammatory phenomenon caused by an overactive immune system. “In smaller prior studies, involving single cases and in series, we have seen elevations of the same cytokines we found here,” said lead author Aurelie Hanin, PharmD, PhD, a postdoctoral research fellow at Yale. “Our study is the first to compare patients with NORSE to other groups of patients with RSE as well as control patients, and we were able to confirm those earlier findings in a much larger cohort, with controls, in much more detail, and with outcome correlation.”
Eleonora Aronica, MD, PhD, professor of neuropathology at the University of Amsterdam's faculty of medicine and a member of the medical and scientific advisory board for the NORSE Institute, noted that the investigators were able to recruit a relatively large number of patients for the rare disorder. “While it would be nice if this data could be validated in a separate cohort, this cohort already gives us some information about potential biomarkers and supports our existing theory of pathogenesis related to an uncontrolled immune response,” she said.
“This is a very significant study for our understanding of an extremely difficult clinical entity,” said Peter Crino, MD, PhD, the Dr. Richard and Kathryn Taylor Endowed Professor of Neurology at the University of Maryland and an expert in developmental brain disorders. “The fact that there is an immuno-profile to this is very compelling. To see there's a biological signature to this tells me there may be a limited-time or single event that's causative.”
He noted that it is particularly important that authors assessed both serum and CSF. “The CSF allows you to assess where these proteins are coming from—is it a blood response or a central nervous system response? The levels of change in serum and CSF don't fully overlap, which is a question to be further explored.”
“CSF is difficult to get but significant for exploratory studies because it reflects better than serum changes in the brain,” Dr. Aronica noted. “They also explored a relatively large number of cytokines in the context of the potentially inflammatory pathogenesis of this disease, which makes the results more compelling.”
Implications for Treatment
“The advantage for the targets identified by this study is that drugs are already available and in use for diseases not related to these,” Dr. Aronica said.
Although a number of reviews have been published on the topic, no randomized controlled trials have been done, she pointed out, so most treatment approaches have relied on expert consensus based on case reports, case series, and limited observational studies.
In August 2022, the International NORSE Consensus Group published its treatment recommendations in a paper in Epilepsia. Noting that postinfectious immune activation is likely an important cause for NORSE/FIRES, and that inflammatory activation in the CNS is likely to precede the development of seizures and contribute to their persistence, they recommended using CSF cytokines to guide treatment choice in these conditions. The current study suggests that serum cytokines may be just as useful.
If patients do not respond to first-line immunotherapies such as corticosteroids and intravenous immune globulin (IVIG), which should be given within the first 72 hours of seizure onset, the group recommended escalation to second-line immunological treatment within seven days of seizure onset, based on suspected etiology.
“If a pathogenic antibody is identified or highly suspected, rituximab treatment should be initiated,” the researchers wrote. “In cryptogenic NORSE/FIRES without clinical features of autoimmune encephalitis, IL-1RAs or IL-6 antagonists should be initiated.”
The results of the new study provide stronger support for this approach, Dr. Crino said. “It leads you to the conclusion that our current therapies with immunomodulation make some biological sense.”
“If the patient remains refractory after giving steroids and IVIG, the debate is often focused on whether to give an IL-1 receptor antagonist like anakinra or an IL-6 antagonist like tocilizumab, or a broader treatment such as rituximab,” said Lawrence J. Hirsch, MD, FAAN, professor of neurology and co-director of the Yale Comprehensive Epilepsy Center as well as a member of the medical and scientific advisory board for the NORSE Institute. “Now we may be able to use the results of this study to help guide those decisions.”
The elevation of CXCL8/IL-8 found in the study raises another interesting possibility, he added. “No one has tried an IL-8 blocker yet in NORSE or FIRES, but it has been studied in animals and does seem effective, with findings that this molecule was able to reduce both status duration and recurrence of spontaneous seizures after status,” Dr. Hirsch said.
Dr. Aronica would like to see future studies designed to further pinpoint combinations of targets that would be most useful for therapy in specific patients. “This paper certainly supports the use of anti-inflammatory therapies; it would be nice to develop trials to look at not only short-term but long-term effects of these therapies on patients.”
The NORSE Institute has an ongoing, multicenter, prospective, observational study of NORSE/FIRES patients as well as a family registry and a recently started open biorepository. “We are trying to enroll 100 patients in the multicenter study, which involves about 25 centers, mostly in North America,” Dr. Hirsch said. “The pandemic slowed accrual, but it is now moving much faster, and we have about two-thirds of the number we need enrolled.”
Interestingly, the incidence of NORSE/FIRES also decreased during the pandemic. “This further lends credence to the theory that this is a post-infectious inflammatory syndrome, because people were isolating and wearing masks and there were fewer infections,” he said. “There is post-COVID NORSE, but we've seen only a few cases, and I don't think that there's anything too special about COVID in that regard, or we would have seen many more cases. It seems that many routine viral infections are able to trigger this.”
The NORSE Institute has a new open NORSE/FIRES biorepository that can take serum, CSF, brain tissue, and other samples from anywhere in the world. “New samples from acute patients are ideal, but even older samples can be used if they were obtained and stored properly,” Dr. Hirsch said. “We can also use autopsy or brain biopsy specimens.”
Samples and results from the biorepository are made available to external researchers via an application and steering committee review.
For patients currently enrolled in both biorepositories, the NORSE Institute researchers have developed a system for measuring the cytokine profile identified in the new study. “We will obtain results within a few days and send back the results to the treating center,” Dr. Hanin said. “When we have more patients, we will also be able to investigate the evolution of the cytokines over time based on the treatments received by the patients, their comorbidities, and other factors.”
In the near future, Dr. Hirsch said, the goal is to develop clinical trials that will more clearly elucidate the direct clinical implications of these findings. “The best way to test the theory of cause and effect is to block some of these pathways and see if we improve outcomes,” he said.
“NORSE requires intensive care over a long period of time, with one initial intervention and then multiple ongoing interventions,” Dr. Aronica said. “Once you get out of that first critical phase when you are fighting for the patient's life, then the problem is to avoid the severity of seizure development later on, and to improve the comorbidities. Learning about the pathogenesis of this condition will help us improve treatments and ensure that the majority of patients survive with a good quality of life.”
Drs. Hanin and Hirsch had no disclosures.
How to Donate Samples for Testing
To donate samples to the NORSE Institute, email [email protected]. The Institute also offers guidelines for diagnostic evaluation and treatment recommendations, research references, and resources for patients and families at https://wwwnorseinstitute.org.