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In Small Case Series, Tocilizumab Shows Promise for New-Onset Refractory Status Epilepticus

Shaw, Gina

doi: 10.1097/01.NT.0000552941.54468.3b
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In a small case series, tocilizumab aborted seizures in patients with new-onset refractory status epilepticus. Epileptologists who were not involved with the study said that the results were promising for the rare and debilitating disorder. One expert noted, however, that neurologists should be aware of the drug's potential for adverse side effects.

Seizures were aborted in six of seven patients with new-onset refractory status epilepticus (NORSE) within three days after treatment with the interleukin-6 receptor inhibitor tocilizumab (Actemra), according to a new case series report published online November 8 in Annals of Neurology. All seven NORSE patients had been unresponsive to conventional immunotherapy therapies and rituximab.

NORSE is a rare condition characterized by new onset of refractory status epilepticus in a patient without epilepsy or another relevant preexisting neurologic disorder, without a clear acute or active structural, toxic, or metabolic cause.

“These are patients without any preexisting history of epilepsy who [suddenly] go into status epilepticus,” said Jeffrey W. Britton, MD, FAAN, professor of neurology at the Mayo Clinic in Rochester, MN, who was not involved with the study. “The mortality and morbidity of refractory status epilepticus is very high, and for survivors the functional consequences can be significant.”

Between 20- and 30-percent of patients with NORSE do not survive, and most survivors have lifelong epilepsy as well as significant neurological sequelae, according to a study published earlier this year in Epilepsia.

The treatment response to standard immune therapies such as steroids, intravenous immune globulin, and plasma exchange has been disappointing for NORSE, Dr. Britton noted. “This case report, although a small series, is eye-opening, given the usual course of the disease. Anyone who has cared for these patients knows how tragic this condition can be, usually involving young people in the prime of life, as was the case with five of these seven patients, who were between 18 and 50.”

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Study Details

In the current study, three of the patients (43 percent) had good or fair functional outcomes, defined as a having score greater than 3 on the modified Rankin Scale at discharge and the use of antiepileptic drugs at the last follow-up.

The study, led by Jin-Sun Jun, MD, professor of neurology at the Kyungpook National University School of Medicine and colleagues at Seoul National University Hospital in South Korea, found that some of those on tocilizumab had severe adverse events, however. Two patients experienced adverse events of grade 3 or higher: A 22-year-old man had pneumonia and a 19-year-old woman died after experiencing a worsening of preexisting sepsis. Other adverse events included leukopenia (grade 2, n=3) and diarrhea (grade 2, n=1).

The authors acknowledged some significant limitations to the study, including heterogeneity in both the patients' pretreatment histories and the tocilizumab regimens they were given, which could limit the ability to generalize based on their results.

The authors also noted that while three of the seven patients had good or fair outcomes after discharge, those outcomes were not better than those reported in a previous large case series reported in Neurology in 2015.

The severity of their patient group, however, could possibly explain this, according to the research team. Their study included NORSE cases refractory to conventional immunotherapies and rituximab; these patients had a much longer duration of status epilepticus, with a median of 30 days, compared with the five days reported in the previous case series.

About half of all cases of NORSE are classified as cryptogenic, and in many of these cases the subject had a fever between 24 hours and two weeks before seizure onset, according to the Genetic and Rare Diseases Information Center of the National Institutes of Health. Cases similar to NORSE preceded by fever but occurring in children are referred to as Febrile Infection-Related Epilepsy Syndrome (FIRES). Although an immune etiology has been posited for NORSE and FIRES, the use of immunotherapy remains controversial.

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Expert Commentary

Commenting on the study findings, Dr. Britton of the Mayo Clinic pointed out that four of the seven patients in the case series had significant elevations of interleukin-6, the target of tocilizumab, which provides some potential mechanistic evidence as to why this particular drug may have worked. He cited his own center's recent experience with a pediatric FIRES patient refractory to standard treatment, whose analysis of cerebrospinal fluid interleukin levels suggested a potential response to the IL-1 antagonist anakinra (Kineret), a rheumatoid arthritis medication. “She responded well and made an excellent recovery,” Dr. Britton said.

“This is the first report I've seen of this particular anti-inflammatory medication for NORSE,” said Lawrence J. Hirsch, MD, professor of neurology and chief of the division of epilepsy and EEG at Yale University and co-director of the Yale Comprehensive Epilepsy Center. “And although it seems small, in the world of NORSE, a case group of seven patients is actually a fairly good-sized series.

“I love the idea that we might be moving toward real personalized treatments based on a patient's specific cytokine profile, in which you can pick the specific anti-inflammatory drug based on the cytokines that are elevated,” said Dr. Hirsch, who co-chairs the medical advisory board for the NORSE Institute. “That's a great idea, but it would be difficult to test it given the rarity of the condition. I think it's extremely hard if not impossible to do a powered prospective randomized trial in such a rare condition, particularly when we're getting new immune treatment medications all the time now. Perhaps what we could do is randomize people to treating them based on their specific cytokine profile, versus just treating them without knowing their profile, which is the standard of care now.”

The role of IL-6 continues to be explored in epilepsy in general, said Sarah E. Schmitt, MD, associate professor of neurology and vice chair of education at the Medical University of South Carolina. “There is some evidence that in people with refractory drug-resistant temporal lobe epilepsy, there may be an inflammatory component to their disease. A 2015 study in the journal Seizure found cytokine levels were elevated in patients with temporal lobe epilepsy but failed to find the same in those with extratemporal epilepsy. This is an area of research that is still in its infancy, and this work should spawn additional studies. As time goes by, with more and more autoimmune etiologies of epilepsy being suggested, there is increasing excitement about using immunotherapy to treat these patients with severe syndromes.”

But the experts cautioned that this study should not necessarily be used as justification for wide-scale use of tocilizumab in NORSE cases. “You're in such dire straits with these patients [that] I think the temptation, based on this article, is going to be to use this earlier, and in a more indiscriminate manner,” said Dr. Britton. “These inflammatory markers are not widely available, and not every lab is going to be able to do them for the clinician at the bedside.”

If a NORSE patient has failed usual and customary treatment, they should be referred to a tertiary center with specific expertise early in their course, Dr. Hirsch said. “These cases are rare and very complicated, and should be treated in centers that have continuous EEG monitoring and are familiar with refractory status cases. This should happen promptly: There was a hint in this study that those who got tocilizumab earlier in the course of their illness responded better than those who got it later. You don't want to wait several weeks before initiating immunotherapy, as it looks like doing so earlier is much more effective, based on this series and others.”

Dr. Schmitt advised caution, however, pointing to the severity of the adverse events in the case series. “As a rule, people with NORSE don't die from epilepsy per se; they die from complications related to their long stays in the intensive care unit, such as venous thromboembolism and respiratory complications. If these medications potentially worsen the risk of these infections, we might be treating their status epilepticus effectively but at the same time making them more susceptible to blood-borne pathogens and other types of illness. So I would be extremely cautious, given those results, about treating a patient with those medications if they were known to have any type of ongoing infection.”

Five of the seven patients had been treated with IVIg, steroids, and rituximab, while the other two had been treated with IVIg plus steroids. “Additive immune suppression really increases a patient's chance of developing dangerous opportunistic infections,” Dr. Schmitt said. “When do you try it? That's the challenge. Although patients who got this this medication earlier appeared to do better, I would be a little nervous about the significant risks of adverse events. I would say this medication might be a third-line alternative to cyclophosphamide, which some people have been using as a third-line option and which is also associated with a significant risk of immunosuppression complications. There is relative equipoise between those two drugs, but I would not use this agent before methylprednisolone or IVIg.”

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Link Up for More Information

•. Jun JS, Lee ST, Kim R, et al Tocilizumab treatment for new-onset refractory status epilepticus Ann Neurol 2018;Epub 2018 Nov 8.
    •. Gaspard N, Hirsch LJ, Sculier C, et al New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives Epilepsia 2018;59(4):745–752.
    © 2019 American Academy of Neurology