[00:00:00] Dr. Alina Ivaniuk: Hello, everyone. This is Alina from the YES-ILAE bringing you another episode of the Sharp Waves podcast. In today's talk, we'll discuss the recent international expert consensus on management of the epilepsy with eyelid myoclonia, also known as Jeavons syndrome. The syndrome is rare, but you probably have seen it in your clinic. If you have not seen it in your clinic, you probably will. So please stick with us and listen carefully to what we'll discuss with our today's guest, who is Kelsey Smith of Mayo Clinic. She was the main or first author on the consensus paper.
Dr. Smith, good morning. Thank you so much for being with us today. Could you please introduce yourself briefly to our audience?
[00:00:44] Dr. Kelsey Smith: Well, thank you. I'm Kelsey Smith. I'm a neurologist and epileptologist at Mayo Clinic. I'm an adult epileptologist and I kind of got involved with epilepsy with eyelid myoclonia early in my training and that led to these consensus papers that we put together over the last year. I'm excited to be here to talk about them today.
[00:01:03] Dr. Alina Ivaniuk: That's fantastic. Thank you so much again for being with us today. And let's begin our discussion with discussing the broad topic. What is epilepsy with eyelid myoclonia? And you mentioned that you're an adult neurologist and the pathologist. Could you also mention why exactly you became interested in studying this apparently pediatric disorder?
[00:01:27] Dr. Kelsey Smith: Epilepsy with eyelid myoclonia is considered to be a genetic generalized epilepsy syndrome of childhood onset. And it has a pretty well-defined triad that we look for to make the diagnosis, which involves eyelid myoclonia with or without absence seizures, and then eye-closure-induced either seizures or changes on the EEG, and photosensitivity is the third part of that triad.
And while this syndrome has eyelid myoclonia is the main seizure type, there's also frequently other seizure types, such as generalized tonic-clonic seizures in these patients. And we know it has a childhood onset. It was well defined as an epilepsy syndrome in the recent ILAE classification papers, but it does have the prior name of Jeavons syndrome and then also eyelid myoclonia with or without absence was previously used in the literature for the syndrome.
Although it starts in childhood, we know that it persists lifelong in many patients, and there's also usually a significant delay in diagnosis. So, a lot of times the diagnosis might not even be made until these patients are seeing an adult epileptologist. And like many of these syndromes, if they start in childhood but then persist lifelong, an adult epileptologist is going to be managing a significant proportion of these cases. So I think it's really important as a diagnosis for adult epileptologists to recognize.
The way I actually first got involved with research in the area and an interest in the syndrome was when I was an intern starting out my neurology residency here at Mayo Clinic. I got involved with Dr. Elaine Wirrell and Dr. Lily Wong-Kisiel trying to look for a research project and they suggested this project on Jeavons syndrome. And we put that together back around 2018 or so as a retrospective study. So that was my first look at the syndrome. And then from there, it kind of led to this project later on.
[00:03:20] Dr. Alina Ivaniuk: Thank you so much for this introduction to what Jeavons syndrome is, and for highlighting that it's really important for adult neurologists as well to be aware of the syndrome, of how it's diagnosed, what it is about, and also how to manage this. And the recommendations were all about management, and it's so important for rare disorders to have guidelines and recommendations for management.
Why was it important to write down how Jeavons syndrome is managed and why was the consensus group developed overall? How did this idea came across of making the recommendations for management?
[00:04:03] Dr. Kelsey Smith: The idea for the project started both with CURE Epilepsy, who was involved and funded this project, and they reached out to Dr. Elaine Wirrell, who's done similar projects for syndromes such as Dravet syndrome, which are, you know, these are rarer syndromes and really with epilepsy with eyelid myoclonia, we know it's rare. We know it's frequently misdiagnosed or there's a delay in diagnosis. And given how rare it is, it does make prospective studies more difficult to perform from a logistical standpoint. And so really one of the goals of the project was to try and see what experts around the world are doing to both diagnose and manage the syndrome. See if there are differences and see if there are questions that we still need to try and answer with future research projects.
And so that's kind of how the idea came about. And a lot of that was kind of prompted by CURE Epilepsy's involvement in the project.
[00:04:56] Dr. Alina Ivaniuk: Yeah, that's great to know that CURE Epilepsy was one of the drivers of the recommendation development as a very well-organized patient and stakeholder group who requested that for the patients themselves. That's really great. And who were the experts who got together to develop the recommendations?
[00:05:17] Dr. Kelsey Smith: We had a steering committee, which was a smaller group of this expert committee that helped kind of guide each step of the process really. And we met with our expert steering committee on about a monthly basis as we were working on the project.
This committee was created by identifying experts in the field that had published or that CURE was aware of. They had already identified some before we even kind of officially started the project. The expert steering committee was best represented by people from North America, but we did have some international representation on that committee.
Then, when we went out to do the surveys through the Delphi process for the consensus, we then all nominated people and then voted to have international representation from all over the world. And the other thing that was important was that we had representation by both patients and caregivers on both the steering committee and the expert panel, which helped us highlight what was important to the patient population.
[00:06:25] Dr. Alina Ivaniuk: That's great that patients themselves also became a part of the project and it's important as well. You mentioned briefly the Delphi process. Could you please explain to our listeners what is that about and how did it apply to the development of these recommendations?
[00:06:41] Dr. Kelsey Smith: Yeah, so the Delphi process has been used in other areas of medical research, including other epilepsy syndromes. And basically, it's using rounds of surveys, more or less, to try and identify areas where people who are experts in the field have a consensus about what they agree about or disagree about, or, you know, how to manage and diagnose these patients.
We ask questions in a way that were strongly agree, agree, neutral, disagree, and strongly disagree. And then if panelists, if 80 percent strongly agreed or agreed we called that a strong consensus. And then if panelists, if 67 percent strongly agreed or agreed, we called that a moderate consensus.
And then we also had open-ended questions and questions posed in different ways. We analyzed that first survey to determine if there were areas where there was consensus. And then we built off that survey with the second survey to kind of do a similar process trying to clarify further points. We had three total surveys over a few-month period to try and put this together with our results.
[00:07:51] Dr. Alina Ivaniuk: Now let's discuss the actual recommendations. Probably the most important one is the first one mentioned on the paper, which are the goals of care, which may be different for different patients. And people may argue how much of a disturbance eyelid myoclonia can cause to the patients, but apparently it's a large problem and large burden for them. What should be the goals of care? What are the recommendations?
[00:08:19] Dr. Kelsey Smith: Yeah. So for epilepsy with eyelid myoclonia as the diagnosis, the name of the diagnosis suggests, the eyelid myoclonia is a big part of the syndrome. And we know that a lot of these patients will have this frequent eyelid myoclonia where there's kind of a jerking back of the eyelids, the eyelids will roll back, the head may jerk back. And these episodes can happen many times a day and be associated with or without loss of awareness. And with these episodes, they're also usually induced by bright lights, like going out in the sun.
These episodes can be very difficult to treat. And so one of the questions we asked for our management paper was what are the goals of care? The goals of treatment? And does that include accepting eyelid myoclonia, as long as the patients are not losing awareness and their other seizures, their generalized tonic-clonic seizures, are controlled?
And when we asked that question, we actually had a strong consensus from the physician panelists with agreement among the patients and caregivers that they would accept eyelid myoclonia as long as the other seizures are well controlled. And I think that's obviously something that is very individual and that you would have to talk to these patients about how much the eyelid myoclonia is impacting their lives. Because in further questions we ask in the surveys, there was also agreement that there's psychosocial impact from the uncontrolled eyelid myoclonia. And then I think, as we'll talk about later, we’re not sure that it's safe to drive if you have uncontrolled eyelid myoclonia, even if you're not losing awareness.
And so there are still significant ways that it could impact your life. But there's obviously always the tradeoff of side effects of anti-seizure medications. And so I think, although this is what our consensus was, I think it's an individual decision kind of weighing the risk and benefits with patients individually.
[00:10:05] Dr. Alina Ivaniuk: And which medications were deemed to be helpful for epilepsy with eyelid myoclonia?
[00:10:12] Dr. Kelsey Smith: We gave a long list of kind of all the anti-seizure medications to see what people thought would be the best treatments, what people have had success with throughout the world for these patients, and there was a strong consensus that there were three medications, kind of first-line medications, the first one being valproic acid, that being the medication of choice but obviously there are side effects and teratogenic risk associated with valproic acid.
And so then levetiracetam and lamotrigine were the other two medications that we had a strong consensus for kind of first-line treatment. And that those would be usually the preferred medications in women of childbearing age. The only other medications that we had any consensus for use were ethosuximide and clobazam.
[00:10:56] Dr. Alina Ivaniuk: Are there any non-pharmacological measures that could help people with epilepsy with eyelid myoclonia?
[00:11:03] Dr. Kelsey Smith: In the literature, things have been published on dietary therapy, with the ketogenic diet, modified Atkins diet and low-glycemic-index diet and then also these photosensitive blue lenses that patients can use, given that the light can really cause the eyelid myoclonia.
And then lastly, another area that's kind of been more recent and more publicly a few case reports on, is the use of neuromodulation. There’s been some cases in these case series with vagus nerve stimulation, and then case reports with RNS (responsive neurostimulation) or DBS (deep-brain stimulation) targeting central medial nucleus.
And so we tried to ask about these among the consensus panel. But I think, not surprising, there just was less experience with these treatments. A lot of the physicians or even caregivers, new people had tried either dietary therapy or the photosensitive lenses, but just less experience of the outcome from those.
The lenses also aren't kind of readily available in North America. And then physicians and patients and caregivers mentioned that they're somewhat intolerable. They make the world quite dark, or can make the world quite dark. And so compliance with them, you know, if the treatment is, if people can't stand it, then they won't use them.
So we didn't have many areas of consensus in those treatments, the non-pharmacologic treatments, just because of less experience, but they’re definitely areas that require further research in the future.
[00:12:32] Dr. Alina Ivaniuk: Oh, absolutely. And returning back to the pharmacological treatments, what did experts think about discontinuation of the treatment if the seizures are controlled? Is this something worth pursuing?
[00:12:45] Dr. Kelsey Smith: We asked a lot of questions about this as well to try and see when physicians would discontinue medications and what their thoughts were. And there was, first of all, strong consensus that only rarely patients are able to discontinue meds and remain seizure free, and that this is usually a syndrome that we think of that persists lifelong, requiring essentially lifelong anti-seizure medications.
But as we kind of do in a lot of different epilepsies, if a patient's been seizure free for 2 years, then a lot of times we would at least discuss or consider withdrawal of anti-seizure medications. And so we asked about that among our panel and there was a consensus, a moderate consensus, to consider withdrawing medications after 2 years, if an EEG is normal.
Some of the panelists pointed out that it really depends on the age of the patient, whether you would consider withdrawing medication. Withdrawing medication was more likely if they were adolescents or adults than, you know, younger children.
We also asked patients and caregivers, “If you'd been seizure free for two years, would you want your physician to consider withdrawing medications?” and three of four agreed with that as well.
[00:13:58] Dr. Alina Ivaniuk: From everything that you pointed out it, it's evident that the management is challenging and the discontinuation of medications is probably more unlikely than likely, as you mentioned, it does limit patients in lots of ways and one of them is driving, which for many people is essential and not being able to drive limits them in many ways.
What are the consensus statements or decisions regarding the possibility of those people to drive? What determines the possibility for the patients to drive and what is the role of EEG in all of that?
[00:14:37] Dr. Kelsey Smith: Yeah. So I think driving is an interesting area for this syndrome specifically, because we know a lot of these patients have normal cognition. And so a lot of these patients are, are trying to drive and lead as normal lives as possible. The first question we asked that we were trying to get consensus on is if you have a patient with uncontrolled eyelid myoclonia, should you advise them not to drive?
And there was no consensus. So it's clear from that, people may be doing things in different ways, or, you know, we don't really know. And one thing we do know with these patients is that these eyelid myoclonia can be very brief, less than a second. They can not be losing awareness with them. A lot of these patients develop kind of eye flutter events, but there's no change on EEG.
And so when do you know if driving is safe or not? The answer is we don't really know. We did have a strong consensus though that physicians rely on the results of an EEG, whether that's a routine EEG or a prolonged EEG, to make the recommendations about driving.
So if you have this EEG, would you recommend driving? Would you not? And the first thing is, obviously, they can't have any seizures, you know, with loss of awareness during the time period and wherever they live—since this was an international consensus panel and even in the United States, there's different requirements for how long you have to be seizure free before driving.
So that's the first part. And then if they have a normal interictal EEG, would you let them drive, whether that's routine or prolonged? And there was a moderate consensus for that. But no consensus if there's very brief generalized spike and wave on a routine EEG. And then we ask about prolonged EEGs and when to use that, and we kind of had varying results. Some panelists pointed out that they even rely more on, is there still a photo-paroxysmal response on the EEGs, and so it just wasn't clear that everyone's doing things the same way in this area.
And I'm not sure that there's a best recommendation. And this is not just kind of unique to epilepsy with eyelid myoclonia in some ways, because we know with generalized epilepsy, patients can report seizure freedom and still have an abnormal EEG. There's been some studies previously looking at this, trying to see, you know, can you still have good response times and things?
And so I don't know that we have a clear way of knowing what's best. And this is an area that requires further research. For the most part, what I've done after looking at these results for these patients is if they have no seizures, their routine EEG is normal, and they tell me they've had no seizures over this period of time, then I don't think there's necessarily a way to say you shouldn't drive. And so a lot of times, after discussing risks and benefits, they may be able to drive in that scenario.
Now, if they have anything abnormal on their routine EEG, then I will do a prolonged EEG, usually in the hospital setting where they could have response testing during that period of time. And if there's any prolonged discharges, you know, more than a few seconds, then I would still recommend at least trying to escalate therapy before allowing driving. That's kind of my own personal, how I've approached this since.
But I think this is an area that still requires further research because driving is really important to a lot of people's quality of life. It’s an area where we need to have the best answers possible, and we obviously want the roadway to be safe, both for our patients and for everyone else driving.
[00:18:02] Dr. Alina Ivaniuk: Is there anything else that you wish would be answered by this consensus and it wasn't, what else remained unaddressed?
[00:18:12] Dr. Kelsey Smith: It's a good question. I mean, I think there's still a lot of open-ended questions and a lot more research that needs to be done in this area that I'm not so sure that the consensus itself could answer. And that's kind of completely understanding the natural history of this syndrome, how patients do, all the psychosocial impacts, the cognitive issues, understanding the underlying pathophysiology and genetics. So I think there's a lot of unanswered questions, but I'm not so sure that the consensus panel itself could have answered them, but it has kind of more or less identified areas that require research in other ways.
[00:18:51] Dr. Alina Ivaniuk: Oh, absolutely. And hopefully these research efforts will be carried out and we'll know more about the syndrome. Do you see or did the group discuss any barriers in diagnosing and treating the syndrome across the globe? Does it differ across the countries? We know from the responses already that yes, it does, but are there any barriers for delivering care to those individuals? And do you think these recommendations can be applied worldwide?
[00:19:21] Dr. Kelsey Smith: Yeah, so I think there definitely can be barriers depending on the availability of different testing and things like that. Such as genetic testing. You know, I would do genetic testing if I had more availability for genetic testing, or this isn't available where I'm at and there's different, you know, ranging how available things like prolonged EEG, how easy that is to get completed. So, I do think it depends on kind of the resources in the area and also even the education of people, recognizing the diagnosis, because even if you're an expert in the field, but you're not having patients referred to you, then you're seeing less of these patients in general.
And so I think there can be barriers, but one thing as well is this diagnosis can be made without an MRI. And that was in the papers for the syndrome classifications. So MRI imaging is not necessary to make this diagnosis and largely diagnosis is made based on history and EEG. And so places who have that available are usually able to make the diagnosis.
But as I'm sure, you know, throughout the globe, people are doing things slightly differently.
[00:20:33] Dr. Alina Ivaniuk: Of course, Dr. Smith, thank you so much for this overview of the recommendations and for pulling this group together and for making the recommendations available for the audience. Is there anything else that you think is important to mention that we didn't discuss or anything else that our listeners should know about the syndrome?
[00:20:51] Dr. Kelsey Smith: I just want to mention that the diagnosis is important to recognize. It's nice to give patients a name to the syndrome that they have. And so it is important to try and make the appropriate syndrome diagnosis. I also want to mention that, you know, CURE Epilepsy had a huge part in this project and they were very supportive both financially, because they funded the project, but also at each step of the project, and they were really a pleasure to work with.
And even from here, they kind of expanded their efforts on the patient front—they put together some focus groups to talk to patients because one thing that there isn't currently, is a strong patient group to kind of push forward research and patient advocacy in the area. They worked on things like having a day for this epilepsy syndrome. I'm hopeful that those efforts will continue to progress the research in the area and help unite some patients, because I know when patients have a rare disease, it's nice to know that there are other people in your corner.
[00:21:57] Dr. Alina Ivaniuk: Wonderful. Dr. Smith again. Thank you so much for all your expertise and for being with us today.
[00:22:03] Dr. Kelsey Smith: Thank you so much for having me.