Reported, edited and produced by Nancy Volkers, ILAE communications officer
What does it take to define and classify 39 epilepsy syndromes? Dr. Elaine Wirrell chaired the ILAE task force that undertook this charge in 2017. Through in-person meetings, Zoom calls, emails, and gallons of coffee, the group of international experts shaped four classification papers, along with a fifth explaining the methodology and listing the syndromes. We also spoke with Dr. Kate Riney, who was part of the task force and instrumental in building epilepsydiagnosis.org, an online guide and a key resource for the team.
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Transcript
The 2017 classification of the epilepsies defined three diagnostic levels, including seizure type, epilepsy type and epilepsy syndrome. Epilepsy syndromes have been recognized as distinct entities long before the first classification of epilepsy syndromes was proposed in 1985, but a formally accepted ILAE classification of epilepsy syndromes was lacking. So in 2017, the Nosology and Definitions Task Force was charged with this endeavor.
Sharp Waves talked with Dr. Elaine Wirrell, task force chair, about the process, which spanned more than five years, hundreds of Zoom meetings, and lots and lots of coffee. She spoke about the significance of the classifications, which were published in five separate papers in May of 2022, as well as implications for the future.
The group started with a meeting in Barcelona, when they tackled the important question: What is an epilepsy syndrome?
Dr. Wirrell: Kate Riney and her colleagues had put together epilepsydiagnosis.org, and that had a fair bit of information on the syndromes though they were not ILAE specific syndromes at that point in time. And then we had this great resource in the Guide Bleu, that had gone through several revisions as well, and those were really our starting points. And before we did that, we had to define within our group what a syndrome was, right? That was – most of the first meeting in Barcelona was just coming up with a succinct, appropriate definition of what an epilepsy syndrome was, and that’s listed in our methodology paper.
And then we had to look through what were the established, recognized syndromes, and then were there other syndromes that were not in the Guide Bleu or at epilepsydiagnosis.org that probably met criteria for syndromes. We looked through different papers, different ages, and came together with a list and had people vote on whether the felt this was or was not a syndrome, and we went with a majority vote. The ones that were close, we discussed.
Then we had individuals within each group – we divided our task force into different groups and those were neonatal-infantile, child, adolescent/variable age, and then the IGE group. We had people within those groups propose a write-up for those different syndromes that was circulated to the rest of the subgroup.
We had lots of Zoom meetings that were usually very early in the morning for me and very late in the evening for the Australians, where we discussed different criteria and came to consensus. And then once we had consensus on the different, what were the syndromes and what were the criteria for the syndromes, we took it to the Delphi methodology and we included all of our task force members and additionally enriched our group with epilepsy experts, both pediatric and adult, from the other ILAE regions. So we had good representation internationally from the various regions.
Then we did the Delphi process and that was a couple of rounds of Delphi process, where we would propose the criteria – to make a diagnosis of childhood absence epilepsy you must have absence seizures, that was a mandatory criterion. Or if you had this seizure type that was exclusionary, you could not make a diagnosis with those exclusionary criteria.
And so with that, we got very good consensus even with our first round. Where people did not agree, we had text boxes and we asked people to list reasons why they disagreed. We also asked if they had other criteria they felt should be listed either as mandatory or exclusionary, and we discussed that amongst the group.
There were occasional ones that we included in the second round. The ones we didn’t get agreement on, we discussed it within the group, made revisions and then put that around to a second round.
So we did both rounds of the Delphi. Following that, we wrote up our papers, put them online, sent them in to Epilepsia, invited public comments online as well as comments from the Epilepsia reviewers. And then we created a second task force which had, for the most part, all of the lead authors on the first paper, and then some new people that had not been on the first task force. That group addressed all of the comments that had come in.
It sounds like a long, but fruitful and very collaborative process.
All of us commented, great to see the papers published, but we’re actually going to miss meeting at 6 am!
You need a discussion – you can’t send these things around just by email, and I mean this was hundreds of hours, and I know that we certainly met, some of us met at the [American Epilepsy Society annual meeting]. We often met at the international meetings, but that still just gives you 8 hours at a time, and so those were really – we kept those discussions for areas where maybe there was more disagreement between the group and we needed to examine and discuss things. Things where we had a higher likelihood of agreement, those were mostly on Zoom. Although there were some interesting Zoom conversations too.
So for anyone listening who may not be aware, what is the significance of being able to classify all of these epilepsy syndromes?
The one thing about syndromes: Syndromes are really pretty distinct epilepsies. As you know, the epilepsies are really a large group of disorders that all come together and cause unprovoked seizures. If you can identify a syndrome, that gives you a much more specific clinical entity, so you often have specific seizure types, you often have specific comorbidities that you know are going to come with this that you can monitor for, or conversely a lack of comorbidities so you can actually be reassuring to the family, “Your child has this, and this is not associated with intellectual disability or other things.” It often helps hone your investigation.
Not all syndromes have specific etiologies, but with some of the syndromes, if you know it, you can choose appropriately the highest-yield investigations. That’s saving money, pokes for a child if you’re having bloodwork or different tests done, and then finally, often times syndromes help you choose the best therapy from the get-go. So you’re not going through lots of different therapies, you’re not choosing therapies that can actually make the seizures worse – you can choose the right medication and treatment and have the patient have improved seizure control or even seizure freedom much earlier, and then hopefully less in the comorbidities and lessen the side effects from trying different medications before you find a therapy.
With those criteria, and we really chose those criteria to be applicable worldwide, and we ensured they were helpful to resource-limited regions as well, who maybe don’t have access to the latest genetic testing or high-quality MRI. So with those, clinicians will be able to identify these unique entities.
Syndromes are common – they’re certainly more common in kids. If you look at kids less than 2 or 3 years of age, about half of kids presenting with epilepsy can be defined as having a certain syndrome, so that’s a big number. If you look at children overall it’s about a third, a little less common in adults but I think it’s probably underrecognized in adults so hopefully we’ll get more data in adults as well.
What about implications for research? Now that these syndromes are classified, there can be a little more common ground?
I think for research, certainly. We’ve seen a lot of clinical trials recently, being focused on Dravet Syndrome, we’ve seen clinical trials focused on Lennox-Gastaut Syndrome, and I think we’re going to see more clinical trials focused on syndromes, so these definitions will allow us to choose a very uniform population and ensure that the patients we’re studying to see if drug A or drug B is effective in Lennox Gastaut actually do have Lennox Gastaut and not something else. So I think that’s really important.
I think going toward the future, and we addressed a few of these in the papers, is etiology-specific syndromes. And so these are where we identify a specific etiology that is associated with a very unique clinical presentation in addition. Those are important, because many of those types of conditions are amenable to disease-modifying therapies.
Some of them are gene related, many of them are gene related, and even if we don’t have a specific gene-modulating therapy now, we’ve seen so many advances in different gene therapies or antisense oligonucleotides and what we know with a lot of those conditions is that they are devastating not only from an epilepsy standpoint but from a developmental standpoint as well.
The sooner you can pick those up and recognize them, if you have a disease-modifying therapy, the hope is that you can prevent a lot of comorbidity, a lot of intellectual disability. Whereas if you make a diagnosis when a kid is 12 years old versus 12 months old, you’re going to have a lot more comorbidities and things that you can’t do anything about. The hope is that combining syndrome etiology is going to be even more helpful toward getting the best therapy as quick as we can for patients.
Now that the classifications are finished, and there are 39 syndromes classified, which groups do you want to reach? Who needs to see these and how are you going to disseminate them?
Where we really need to get it is into particularly the adult epilepsy world, where syndromes aren’t on their radar. Syndromes are on the radar of pediatric epileptologists. And then the general neurologist. So you’re not just thinking is there a lesion on your MRI or not, but you’re thinking what is the syndrome this patient has? So targeting and getting it out to the general neurology group is going to be important.
We have this epilepsydiagnosis.org resource and that is being revamped, so Nicola Specchio has been tasked with that and Kate Riney who did the original work is also going to be involved in that. That’s a great resource. It’s free, it’s online, I tell all of my residents about it, I teach a course at the Child Neurology Society and I tell all of my residents that I do the course with. You can look at EEGs, watch videos of patients having seizures of different types, so that’s a really good resource.
We also are putting together a summary PowerPoint, similar to what has been done with the classification that Ingrid Scheffer has done, now looking at classification of epilepsy syndromes, so that people could download that for review, for teaching, things like that.
And then, we are planning at various epilepsy meetings to be presenting: This is how to think about epilepsy syndromes in neonates, this is how to think about epilepsy syndromes in childhood.
Were there any topics that were particularly controversial, or took a little time to work through?
So there were a couple of issues – when we look at the classification of the epilepsies paper, they talk about the [developmental epileptic encephalopathies, or DEEs] and I think that’s a great term, but if you have somebody who’s normal until they’re 40 and then they have an illness where they have epilepsy and lose cognitive skills and motor skills, that’s not really a DEE, because they were developmentally normal and it’s not an epileptic encephalopathy because it’s not the epilepsy that’s causing that, it’s an organic process. We had a fair bit of discussion as to how to classify those and that’s when we came up with “progressive neurological deterioration.”
And then we also had quite a bit of discussion around the concept of the genetic generalized epilepsies [GGEs] versus the idiopathic generalized epilepsies [IGEs]. That was a little bit less clear, and there was a lot of unhappiness from several people when the classification came out in 2017, kind of lumping those a little bit together. So we had quite a bit of discussion with people on why do we need to keep the IGEs separate, and what specifically is an IGE? What syndromes are included in that? And that took a fair bit of discussion. We had that discussion at one of the big meetings at one of the international congresses so we could have most of the task force present.
It was a great learning process for me. It was a lot of work but I really enjoyed it and feel grateful to have worked on such a great team to make this happen. We had some amazing, very much “get it done” people on the task force who really worked very hard. It’s a testament to the efforts of our group that we got this done.
Dr. Kate Riney spearheaded the development of epilepsydiagnosis.org more than a decade ago, and the site’s information was a valuable resource for the task force during its efforts.
So the next step is going to be an update of the website to reflect the current terms and syndromes. That’s going to be a bit of work, because the syndromes are kind of interconnected across the whole website, and some of the syndromes are now etiology-specific syndromes but we have an etiology section and a syndrome section, so we have to work out the mechanics of the website according to that paper. The other thing we are committed to doing which went on hold, it was to be the next development of the website, which is multilanguage translation.
So the website was translated entirely into Spanish and we were under way with French, Arabic, and Mandarin, but all of that had to be put on hold with the syndrome work because it became clear there was going to have to be a re-update of the English website, which is going to create a bit of a challenge given that there’s a parallel existing translation in Spanish. We’ll just have to work through it step by step.
As a member of the task force, Dr. Riney was involved in the entire classification process, as well as first author on one of the five publications, published in Epilepsia in May 2022.
Dr. Riney: Elaine was a really fantastic chair. It involves collaborating and resolving differences of opinion across a lot of very big experts in the field. And Elaine’s stewardship through that was really instrumental in continuing forward progress, navigating solutions to variations in opinion and seeing that huge piece of work through, so Elaine would have put in an enormous amount of time. There’s a total of 39 syndromes have been published with their agreed definitions and detailed text on the wider entity of the syndrome, which I think will take us forward quite a long way.
The interesting point to note is that this had not been done for decades – the last real international collaboration where international experts got together and published a bible or a book on the epilepsy syndromes happened under Henri Gastaut, I think it was in the late 1970s early 1980s, he had a collaborative of I think it was only 13 international experts in epilepsy came together in Marseilles in France. Out of that the Guide Bleu was published.
It must have been quite different to how we did things now – there was no internet, no emails, no Zoom, no Teams, so people really did have to get together, and it was probably hard-copy paper typing. But yeah, the editing process would have even been very different in those days I’m sure as well, so historically it feels like a big moment to have produced that level of collaboration.
On a personal note, obviously it was a fantastic journey. I got to spend my evenings in many late-night meetings with lots of people that I didn’t know beforehand but we got to know each other’s personality, styles, the way that we collaborated, our thought processes, I got to hear other people’s views on things, perspectives that were refreshing. We were you know, for some of us it was late night and there was coffee involved and trying to stay awake, and for others it was early morning and they were fresh out of a shower with the first coffee of the day, so we became this extra family – which was very nice to be part of.
I guess going forward it will be interesting to see how the international community consider the papers now that they’ve been published and I’m sure there will be areas for improvement as time goes on, future work, really intending to, intending to expand on the etiology syndromes because we know more about underlying cause now for many conditions that we didn’t even know the underlying cause before. Now we can understand that better and we’re probably going to be describing very specific presentations related to specific underlying causes, so more of those what we call etiology-specific epilepsy syndromes going forward.
Relevant disclosures: Elaine Wirrell has served as a paid consultant for Encoded Therapeutics and Biomarin. She is the editor-in-chief of Epilepsy.com. Kate Riney reports no disclosures.
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