Friday, January 25, 2019

Tocilizumab treatment for new onset refractory status epilepticus (NORSE)

Jun JS, Lee ST, Kim R, Chu K, Lee SK. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol. 2018 Dec;84(6):940-945.

We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE.

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…

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…

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….

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.”…

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.”,_Tocilizumab_Shows_Promise.2.aspx

No comments:

Post a Comment