Epigraph Vol. 24 Issue 4, Fall 2022

NORSE/FIRES: International recommendations for diagnosis and treatment

Reported by Dr. Maryam Nabavi Nouri Edited and produced by Nancy Volkers

Cite this article: Nabavi Nouri M. NORSE/FIRES: International recommendations for diagnosis and treatment. Epigraph. 2022;24(4):67-72.

First-line immunotherapy and the ketogenic diet are two main recommendations for treatment of NORSE/FIRES of unknown cause, according to results from an international consensus group. Dr. Maryam Nabavi Nouri interviews first author Dr. Ronny Wickstrom.

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Podcast Transcript

Dr. Nabavi NouriSo thank you for joining us on this episode of Sharp Waves – I’m joined by Dr. Ronny Wickstrom from Stockholm. He’s going to tell us about the international consensus recommendation for management of new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES), and I know there are two papers published: one is on summary and clinical tools and the other one statements and supporting evidence.

Dr. Wickstrom: Thanks for the opportunity to present these papers. I’m Ronny Wickstrom; I’m a pediatric neurologist and epileptologist in Stockholm in Sweden. I’m also professor of child neurology at Karolinska. 

So my field for a long time has been working with neuroinflammatory diseases, both demyelinating diseases and also encephalitis cases of different kinds, and then I work with epilepsy. And these have been my two fields, and these two fields meet in FIRES, so that’s how I came to start with this. 

Headshot of Dr. Ronny Wickstrom
Dr. Ronny Wickstrom (Sweden)

I had a case actually, six or seven years ago, a FIRES case, that did not end well, of course, like they often do not. He survived but he had severe sequelae. It sort of puzzled me, this whole FIRES thing and I wasn’t aware of FIRES until then. I’d heard of it, but this is an epilepsy phenotype where we believe that autoimmune or some sort of immunological at least components are involved. So that’s where I came into it, because those were my two worlds met anyway. 

But when it started out, it started as a FIRES discussion. And we in the pediatric field had some FIRES communities. And what’s happened over the last couple of years, and which I’ve had the privilege of being involved in, is that this has merged with the NORSE community, which was also existing. So NORSE was perceived as an adult disease and FIRES as a pediatric disease, and one of the things we want to emphasize here is that that’s probably not true.

One of the things we were doing in the FIRES field and also in the NORSE field is there’s a lot of research trying to be done, and there’s some data coming out, but it’s very hard, these are hard areas to study. One of course is that this is new onset, so there’s no population to study until they end up in refractory status epilepticus. And this, it’s very rare, and also it’s rare in a very hyperacute thing, so if you try to set up clinical trials, with standardized sampling and standardized testing and standardized treatment for these patients, it’s very difficult because you’re in a hyperacute situation where you have to do everything for your patient. So designing trials is extremely difficult. 

We went through all the data before we started this and there’s a lot of case series and case presentations, and even in the larger case series and the ones we tried to compile, for instance, all the children that have been treated with IL-1 inhibition – one of the lessons we learned from that is even though we tried to standardize the data when we looked at it, it really ended up being 26 children, 26 individuals. It’s really, really difficult. That means what you’re left with as a clinician is there’s not a lot of solid data to base anything on. 

So what we wanted to do with this Delphi approach, which, I’d been a part of another Delphi approach where we tried to summarize treatment in NMDA encephalitis. So I thought one way to do this or to try to summarize what we do know and give some sort of recommendations — we’ve been careful not to call these guidelines or anything like that because they’re not — we don’t have any evidence to say that they are guidelines. This is a recommendation, something to hold onto as a clinician and as a researcher. And we tried to compile this group of people that we thought for one or another reason were important to have as a part of it, and compile recommendations that covered everything from what is NORSE and FIRES, and also diagnostics and workup, treatment and long-term treatment, and then, and that’s the second part of why we undertook this and why I thought it was important, it also provided a possibility to try to bring everyone together because that’s the next step here. 

This is a very rare and hyperacute and complicated thing. We at least need to try to, I mean we obviously need to study it better and we need large consortia to do this, and we need a common understanding, and common data elements, and speak the same language, and tests standardized and things like that, even if it’s only real-world studies. So the second idea of bringing this together was to create a platform like a solid ground, and this is the first step, to start a research consortium and international consortium where we can do these studies.

Dr. Nabavi NouriThank you. I understand there was a core group, and then a bigger group, an expert panel of 48 people internationally. Of course the Delphi method is quite interesting too, in that in this particular project there was a pre-set of questions and then it led to a stage 1 and a stage 2.

Dr. Wickstrom: Yeah, so the Delphi methodology is an interesting way of doing things. It’s a standardized way of reaching a consensus, basically that’s what that is. You can be very orthodox or less orthodox and there are different ways of doing it. But the basic principle is the same. The idea is that rather than asking questions, you try to phrase statements like a recommendation or a guideline, if you have enough data for that. And for statements where you reach a consensus that’s all fine, and in statements where you do not reach a consensus for some reason, the idea is that you try to mold or adjust these statements until they are acceptable by the group as a consensus. 

So a couple of things here. One is of course how do you select the group, how do you choose what group? How do you form the questions or the statements? And then, what is a consensus? I mean 100% is obviously a consensus but is 70% a consensus? There’s no definition, I mean no clear definition on this. We chose the methods that had most often been used in how to do this.

So a couple of things were unusual in this case. One is that for a Delphi process, having 48 experts is a very large group. It’s almost impossible. Of course this gives you so much input, and so that’s not the problem. The problem of course is if there’s too much input, and trying to get a consensus, and also trying to get all of these people together is very difficult. The other side of that is that I think the people in this group were perfect. I think we could have probably found 48 others too that should have been on this group. Looking at representation, it’s very heavy in Europe and North America and there’s a lot of great research coming out of Asia, for instance, and we have suboptimal representation from Japan, Korea, China, and other places. 

And then what we did, which is also unusual, is that we had this initial question of, we’re dealing with two things, there are two ways of slicing this if you want to. We’re dealing with adults and children, and should we, are the questions usable for both groups or should we divide them? 

And also we’re dealing with NORSE and FIRES and those are more or less the same, because NORSE children are perceived to have FIRES and adults have NORSE. So we asked the group, and we were divided on this: Should we perform one Delphi, which is what we did, or should we divide it and do a pediatric and an adult one? 

The reason we actually decided to go with the Delphi, one Delphi, is that there’s not a whole lot of evidence supporting that this is pediatric disease on one hand and NORSE is different. A lot of evidence points to this being very overlapping diseases or conditions. And if nothing else the traditional or the use of anti-inflammatory treatment in children as, for instance, IL-1 inhibition using anakinra, whereas in adults it’s IL-6 inhibition and in this case it was tocilizumab. There’s no real reason for this, it’s just in adults that’s been used more and it’s different traditions. We felt in this case the differences, we can probably learn more from the differences from the adult and pediatrics sides that it won’t cause a problem. 

Joining or defining FIRES as a part of NORSE, we corroborated that here. But that’s in the definitions that was published in 2019 and 2018, even. So that was nothing new, but it’s important to emphasize that if you look at adults with NORSE in the Yale cohort for instance right now, their preliminary data show that more than half of the adult NORSE patients actually fulfill FIRES criteria as well. And conversely there are children who don’t fulfill FIRES criteria. But it’s quite rare. It’s obvious that the children, in children, in younger ages, the prevalence of an infection preceding the illness is much higher. It’s not 100% but it’s getting there.

The important things in this is to try to look at all kinds of NORSE, including FIRES, as a potentially immunological problem. Especially cryptogenic NORSE. So NORSE today is a condition that can include infectious diseases, it can include autoimmune diseases, and if you find that of course you treat that. If you don’t find that and then you’re stuck with, so you have inconclusive results, cases of no etiology, we want to emphasize the importance of trying to break a vicious circle which is probably, I’m not going to say it’s inflammatory but at least it’s immunological. And that’s been more used in the pediatric field because it’s so obvious, I mean from a preceding illness, that this could be some sort of activation, whereas that’s not the case in adults. There are some data looking at refractory status epilepticus in adults showing that immunological treatments are not really on the table, or definitely not as early as they should be. 

So to think that this is possibly immunological, there’s an immunological component in this and you have to target that, because if you don’t break that circle, none of your regular anti-seizure medications are going to work. So that’s one of the things, to start early with first-line immunotherapy, and escalate early and aggressively to second-line immunotherapy.

The other thing that’s also in this, which is not primarily immunological, is that we advocate the use of ketogenic diet as early as possible. And that’s also used in pediatrics but not so much in adults. The reason for advocating that is that’s one of the few treatments that has actually been shown in small but still case series to be effective. So we believe that adding ketogenic diet early, which is in this case was defined in the recommendations as seven days, is of importance. 

Dr. Nabavi NouriThank you. What would be the implications of the results?

Dr. Wickstrom: The important implication is to look at your local guidelines on how you treat status epilepticus and refractory status epilepticus in your hospitals. We can see, we haven’t shown that here but there’s data showing that a lot of hospitals don’t have clear guidelines on this and the ones that do have them rarely include immunotherapy. So looking at these guidelines, this would affect your local guidelines for refractory status epilepticus and super-refractory status epilepticus, if these are new onset, during the first week of treatment. 

When it comes to workup and diagnostics, there’s a lot of recommendations on how to do this. And this also differs a little bit. We know that in pediatrics, for instance, we sometimes don’t take all the antibodies that we should do. We know in adult situations, it’s perceived as not so important to look at genetics or metabolic disease, of course because it’s not as prevalent, but it should be part of your workup. So during the first couple of days, during the workup, the implications of these papers is that that it can give you recommendations on where to look and try to widen your screening. 

And then the big implications is of course the treatment implication from day three, and that includes primary immunotherapy or first line immunotherapy, and then escalating that by day seven.

Dr. Nabavi-NouriWell I think having those timeframes arguably could be altering outcomes, especially when we’re really dealing with, as you mentioned you had one case and it will never leave you for the rest of your career, always trying to understand what you can do better. What would be the next steps of this, next steps of this very impressive consensus group?

Dr. Wickstrom: So the next step everyone is dreaming about, which we were thinking about, I mean it’s been a couple of years that we’ve been thinking that this should have been started, is clinical trials of treatments. It’s just it’s very, very difficult it turns out. It’s difficult to agree on if we do a treatment, how do we do it, is it head-to-head treatment and if so, what do we use? It’s going to be really, really hard to design those trials at this point. I don’t think we have enough data for anyone because you as a treating clinician, you need to treat your patient the way you think is best, and it’s hard to randomize patients. You have to have compliance from the group. And that was part of doing this, was to increase compliance and let everyone have a say in how to design these clinical trials. 

I’m hoping we can fairly soon arrive at clinical trials, but I also think we need to think differently than that and think about how we can design real-life studies that are usable. For instance, can we look at some sort of clinical decision support that can serve both the purpose of filling up a biobank of data and possibly samples, at the same time that it offers you as a clinician help.

But I hope the work that we’ve done is to create awareness in this group and in other groups that there is a consortium or there will be a consortium and this is open – the more people who want to join the better the stronger we can get. And we can use this to do good research, to get funding to do research and also to try to help these children and adults. And hopefully expand into refractory status epilepticus (RSE), because I mean – one debate now is, what actually differs? Why is NORSE different from other RSE? That’s a valid question.  I think in many cases it will be, for instance if you have structural, some sort of etiologies, or if you have an ongoing epilepsy, that’s probably a different sort. But immunological components may be a part even in that case. 

But I think what NORSE as a concept offers is it offers a sort of umbrella that can help us in forwarding and advancing our knowledge. And maybe in 2 years or 5 or 10 years we’ll decide there’s no such thing as NORSE, it’s just RSE that happens to be new onset and we understand what it is. 

Dr. Nabavi NouriLastly, and second to last question would be about the CSF cytokines. I’m very intrigued that it made it to the consensus. It’s been a big point of debate for two reasons: one is for clinical availability in terms of using reliable labs that can give you a clinical turnaround time as quickly as you would like to use it as a biomarker to guide treatment, and the other one is always timing, I find, because the cytokine profile can change quite drastically. I see there were two questions in the consensus – one whether it would be used for a biomarker of disease progression and response to treatment, and the other one was a choice of medication. 

Dr. Wickstrom: So one of the hypotheses concerning FIRES and also NORSE is that it at least involves, maybe that’s not the whole mechanism, but it involves cytokine release. And that part of the immunological activation is actually the problem. There is some evidence to support that from animal data, and also there’s evidence in humans from blocking IL-1 and IL-6 mainly, with good results. So that’s the idea why cytokines appear to be important. 

Just as you mentioned, there are several problems with cytokines. One is that it’s hugely complex – it’s really a web of different cytokines and they affect one another. For instance, we know that IL-1, which is a regulator of the proinflammatory system, we hardly ever see it because it has a very short half-life. Just by looking at lab data we have for IL-1, for instance, you would never use an IL-1 blocker, that would be a logical result of that, and still we know that it works. Looking at IL-1 levels doesn’t really help. 

The second problem with cytokines is that they’re hard to analyze, if you don’t have access to a lab, but they’re also hard to sample. Whereas antibodies are very stable, cytokines are not stable, so you really, if you don’t sample it the right way for instance from the start, then you go to your bacterial or microbiology lab and say do you have any CSF left, and it’s been standing on a lab bench for two hours and cytokines have degenerated.

I would love to say you should look at cytokines and you should use that, but we don’t know that. But tentatively, if we believe that cytokines are involved in this, it should or could be possible to have it both as a marker of disease and also as disease progression. But just like you said, it’s not a question of whether this goes up and then it goes down and then it’s gone. Inflammation is a tricky thing because it’s an endogenous response you want to have. And one of the consequences of a proinflammatory response – when we say inflammation, we usually mean proinflammation – the other thing is we have anti-inflammation. The proinflammatory cytokines will increase the anti-inflammatory response and we know for instance in studies of encephalitis cases, you really need to look at the ratio between pro- and anti-inflammatory to understand it. 

Dr. Nabavi Nouri: What do young clinician researchers listening, how can they get more involved in this type of research? Are there any organizations or consensus groups with in the ILAE or within this consortium that they could approach and explore being more involved in this type of research?

Dr. Wickstrom: Right now this consortium that I’m referring to isn’t really a consortium, it’s something we want to evolve into. But people are there and it’s open, 100% open to everyone who wants to join, both from a learning perspective and because this is an area to which you want to contribute is fantastic. 

One way of accessing this or being involved is via the NORSE Institute. And that’s NORSEinstitute.org. It’s a North American institute that was started by the mother of a patient who died from this, and she’s done a fantastic job in trying to promote this research and bringing all of us together. You can find the names and email addresses of many of the people who have been part of this, and we regularly update it with published literature and how to find your way to the different ongoing studies, and that’s a way in.

Dr. Nabavi-Nouri: To conclude, I’d like to ask if there’s anything more that you’d like to add and most importantly any take home messages that we’d like to leave our listeners with.

Dr. Wickstrom: I really, really want to emphasize the immunological treatment because I can see that’s not working perfectly, of course not, but it could be improved a lot in kids, but even more so in adults, because they’re not using immunological treatment at all, and I’m convinced it will help so many adults with NORSE. And FIRES, probably both NORSE and FIRES. That’s an important take-home message.


Families affected by NORSE/FIRES can join the NORSE Family Registry and contribute information that may help shape and initiate research. NORSE Family Registry registration is available in multiple languages: English | françaisMandarin | español