Joseph Sullivan, MD

Kelly and I, are both open-minded and we embrace the involvement of this it takes a village but sometimes you get the questions about trying something that seems so out there. It's like oh boy, where am I going to go with this one? I can imagine there are some providers out there that, oh that's just going to create more work for me because they're going to ask me all these questions that I don't know the answer to. What should providers know about the value and again we've touched on it but maybe just a summary statement, the value of connecting with sort of a disease specific group? Mary Anne, you want to go first?

: The biggest thing that we say is it's so important for our families to be able to find their people and in the long run it makes it easier for the professionals because if families have a place where they can ask questions of others who understand what they're going through it's going to cut down on the questions that come back to the physicians and the providers. It just offers peace of mind, overall because they feel like they start to get a better understanding of what this disease is like and what the trajectory might look like, things that they should be watching for it's important to give them that sense of empowerment.

: I agree. A few years ago, we flew in Dr Ingrid Schaefer, Pediatric Neurologist, Clinician-Scientist, President of the Australian Academy of Health and Medical Sciences] an epilepsy expert, world renowned and our families were like we met Karen from Ohio, this was the best conference ever and that's it. The number one thing we do is we connect people to somebody else who is walking in their shoes, and I would just say you can't underestimate it. This is a hard, horrible journey, and having other patients and families that are on it to help you navigate is crucial. I know a lot of physicians would also think these are the moms who are cooking up weed in their kitchen pressure cookers, and yes we are, But both the LGS and journey foundations, we are scientifically led organizations. We are willing to have these tough conversations about pressure cookers and weed and cooking that, but also we're willing to come forward and talk about the science. We try to make fact-based and provide the information as much as possible to our families, but then also allow them to save space to keep talking about how mercury in retrograde is causing all their kids' seizures too. It makes things easier in the long run for the clinician because we want to help you. We want to have these conversations with the families. You can't do it all, and we respect what you guys are asked to do as clinicians that's just above and beyond like the paperwork nightmare oh my gosh see the patient in 10 minutes and get them out of there. I would just strongly say connect in with us and we will help in the long run, that's what we're here to do.

: I just want to point out from the physician perspective, both of your organizations and other organizations all have scientific advisory boards and that can be helpful as well for a provider looking for a resource to figure out who's on the scientific advisory board and if you're struggling with something with a patient, most people on the scientific advisory board are very happy to talk about that particular disease and share what's known and what isn't known. So buried within there are some other resources for providers as well.

As you mentioned Tracy you have conferences, Ingrid, people who are watching and I'm sure would love to come and have a conversation with her, Mary Anne, the Dravet Syndrome Biennial Conference, right where it brings experts from all over the world both on the basic science and on the clinical side plus the families. It gets a whole mix of people together in one place in order to continue to move things forward.

: I would just say I think if we're speaking to providers, I would just say 2 things. One is, the LGS diagnosis may not be all that useful in the day to day of a provider who is seeing a patient who's had LGS for 10 years and we're just now trying treatment after treatment, but it means something to us as the families. It can be life-changing to find your community. The other thing I would just say is please don't give up on us. I know that there's been some surveys done where physicians feel like they failed in some way because they can't stop the seizures in this patient and then they see the progressive brain damage over time or the person has been seizing so many times and they have multiple chronic disabilities at this point and what's really going to walk, I'm just going to write a script. We never fault physicians for that, but we can't give up and so when you guys give up on us it breaks our heart because we can't give up on our families. I mean yes if you need to bring in a specialist, great another member of the team or if it's time for you to transition care because they're getting older, whatever but I would just say give the diagnosis and don't give up on us please. There is a lot of in the future for this one stop to be there's nothing we can do epilepsy, if there isn't nothing we can do. There are things we can do.

Well, I think that is a perfect note to close on. I couldn't have said it better myself, Tracy. Thank you for watching this NeurologyLive® peer connections. If you enjoyed the program, please subscribe for our E-newsletters to receive upcoming programs and other content right in your inbox.

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Mary Anne Meskis; Tracy Dixon-Salazar, PhD; Kelly Knupp, MD; and Joseph E. Sullivan, MD, provide advice for physicians treating patients with Dravet syndrome or LGS.

Advice for Managing Dravet Syndrome and LGS

To bring this full circle we're lucky to have Mary Anne and Tracy who are 2 moms of now young adults with developmental epileptic encephalopathy and yet you somehow found the time and energy to form a patient advocacy group and it’s been a testament to you and to other patient advocacy groups that have allowed Kelly and I and our colleagues to work as a team and have opportunities to participate in these clinical trials and to come to different conferences where we get to meet the families and meet other colleagues so thank you for that. Kelly, I'm curious with this wealth of resources that we have just with these 2 advocacy groups in our presence today, how else do you tell your patients about what other resources there are beyond your own institution?

: It sometimes depends on what the diagnosis is. For a patient with Dravet syndrome I'm going to share as many Dravet resources as I can and for somebody with Lennox-Gastaut I'm going to share those resources. For somebody who has a new diagnosis particularly if it's rare and we haven't been able to find a family support group for them that's one of the first things that our genetic counselors do is, is there a family support group for this diagnosis and provide that information. If that's not available, I encourage families to reach out through their epilepsy communities and try to identify who else may have this diagnosis because if it's so rare that I'm only seeing one patient I'm not going to know what's common across this. Academically speaking when there are 30 patients with a diagnosis, only the first 2 get published in the literature and unless somebody is coordinating that whole group to get information from all 30 of them we don't even know if there are 30 people out there with that diagnosis. I don't do social media as you guys probably now but my searching and the academic literature is a little bit disadvantaged outside of those first case reports, and I find that families with their motivation are able to quickly find families across the world who have that diagnosis and I encourage them to do that because as those families talk to each other and nobody knows your children better than you do. I may be asking standard questions about your seizures and your gait and your constipation but as families get together they talk about the nuances that we may not think about in clinic and they identify the nuances that are common amongst their children and I find that an incredible resource both for the families and for me when they come back and say I talked to 10 families and 8 of them are lamotrigine, maybe we should give it a try. I'm like I'm in, let's talk about adverse effects and we'll figure it out. As you had said earlier it takes a village and we have to learn from each other, and we have to be open to that too.

: There are resources out there that are pretty standard resources. NIH [National Institutes of Health] has rare disease pages. NORD [National Organization for Rare Disorders, Inc.] has rare disease information. The Epilepsy Foundation often has good resources but for some of the super rare disorders they may not be as organized yet and may not have as many clear resources available.

I'm curious if we do have a patient with LGS or with Dravet, Tracy and Mary Anne, and we give just the link to the website. What does that typical process look like for a new patient? I mean we have different levels of tech savviness. Some people may get overwhelmed by the website. I'm not on social media either, Kelly, I understand it's easy. I don't know. How does it look on the foundation side when you have a flurry of incoming new families?

: I would say probably our LGS foundation are similar in that we've worked hard to make sure we have a lot of resources available for families, educational videos or other opportunities in person but the biggest thing that both groups rely on are support groups. Just like Kelly said there's nothing like having another family that's walked that journey that can give advice or can answer a question that you have. We've also found trying to break up those opportunities in a variety of ways is important. We have families that are just not comfortable traveling because of the current medical condition of their child or they're afraid to go too far from their hospital so we try to give them a variety of ways that they can get the information that they need to provide the best medical care for their child without them feeling overwhelmed.

: It's the same for us and we have similar programs in some ways to the Dravet Syndrome Foundation. For us it's connecting a family with a regional ambassador or a patient navigator. Our ambassadors are in specific regions. We have 50 ambassadors in 7 different countries across the world and it's more answering questions like who do you see in our community, how do you navigate social security, what do you do with IEPs in that region. Then we have navigators that are like I'm considering this treatment. I am dealing with this specific issue so it's a very topical connection that we make in addition to our support groups. We always just say because we're living the same journey and LGS straddles all the DEEs because pretty much any ideology that you can think of that causes a DEE, a subset of them seem to evolve into LGS. There's no one DEE I think is probably the most well-known but there's no one DEE where all the patients get LGS. We seem to be an endpoint, a final common pathway or maybe not even final but a common pathway for a lot of them. We always just say, listen we divide on the science. The science is going to be different. I cannot pay attention to all 150 plus DEE genes and dedicate my time to those because that's just a subset of our bigger LGS and we're over here focusing on end stage LGS at the sort of the one that becomes a pathway, but you are welcome into our programs because we're on the same journey. We're navigating school issues, community issues, we're navigating the same medical systems, we see the same doctors, we're on the same treatments, we're in clinical trials together, we're at the same conferences so we try to be as inclusive as we can. We also try to make sure that when people come into our group now, you're dealing with frequent intractable seizures. This is not the place to send a newly diagnosed DEE patient; our community is not the place. You do not talk about LGS with IS patients until you have to because it's a very devastated population, but we do try to be inclusive, and you can learn from these other groups. Even if you're LGS-like you can come in and be a part of our community and learn and be supported.

Dravet Syndrome Foundation as well Mary Anne, right? I mean we try to be inclusive of the SCN1A epilepsies because there is some overlap there.

Kelly Knupp, MD; Mary Anne Meskis; and Tracy Dixon-Salazar, PhD, share education around patient advocacy and support groups as well as other resources for patients with Dravet syndrome or LGS.

Resources for Dravet Syndrome and LGS

Tracy, in terms of having this list available, is it a blessing or a curse? You have all these medications that are – they all have this 20% to 30%. You have some outliers, but what is your take on that?

: First of all if you’re treating and you don’t know the underlying etiology is genetic then you can really do some harm. This is how Dravet patients end up on sodium channel blockers when they shouldn’t be on them, and there is contraindications that other genetic DEEs and so really understanding that ideology is sort of the first thing. We often call it the dart board approach to treating LGS after that because we've already been on levetiracetam. That's what a lot of patients get tried on, carbamazepine, tegretol is still tried. We often get tried on those before we even get the LGS diagnosis or whatever the combination is. There's 6 different generations of doctors practicing medicine and I would bet that the way that LGS is treated or the way first line therapy for epilepsy is treated kind of depends on the generation where you were trained if there are no guidelines and there really aren't. There is a strong feeling in the space that these newer medicines so cannabidiol and fenfluramine are really designed with rigor and approach new mechanisms. If you look back at the older drugs, the older generation of people with LGS have tried all the old drugs but these 2 new ones sort of represent the unexplored, maybe this is going to have a bigger impact in the population so there is a real feeling of new mechanisms, new treatments coming out. I'll tell you what, we've tried and failed 26 different treatments before we found something, and you get into that loop. Doctors are happy because they're like oh we can at least do something and you're not happy as a patient. You want to be happy with them because there are a lot of neurological diseases that have no treatment and we do have a lot of anti-seizure treatments we can try but that hopes raised and hopes annihilated of try, it didn't work, try and then the change. The seizures are changing over time because the brain is developing but they're also changing in response to the medicines. When you give a medicine you never really know what's going to happen and it's brutal on the family. I'm happy to see though that more comparative effective work is coming out. There's the Cory funded study looking at surgery, any epilepsy surgery versus the next seizure medicine in LGS patients. That will be an interesting study. Dravet syndrome just had a great paper that came out that did look at consensus guidelines using a Delphi process across the globe. We have some consensus guidelines in the US [United States] that are a decade old and then we have one from across the pond in Europe which is a few years old for LGS but they don't really match. I do think that there is an interest now in exploring which are the most powerful. Certainly, the data that's coming out from health claims data and from our surveys in our community is suggesting that some of the drugs like clobazam, clobazam seems to be a drug that these patients go on and they stay on for a long time but we're still seeing a fair amount of phenobarbital use and phenytoin use. Those are difficult drugs when you start them in young children. This is where we strongly encourage our families. You don't have to have a pediatric epileptologist, or an adult epileptologist be your full time doctor that you see 4 times a year. They can be part of your home care team, but you need to be consulting them yearly because the data is just so complicated and so specialized that you need that sort of information. You need somebody weighing in on your treatment and we should probably at some point talk about adult providers who don't feel we struggle with them realizing they have LGS patients and not caring that there's a syndromic name for it and understanding why you would even need to know that. It gets into sort of a whole different ball game when you're talking about LGS in the adult sphere.

: Joe, one of the other areas where we can get some guidance is kind of hidden in some of our newer trials. If you go back and look at the trials, at the concomitant medicines that people are on before they went on their study drug, they tend to be pretty consistent across the trials. As you mentioned Tracy, clobazam, valproic acid, Lamictal tend to be sort of the mainstays that people are on before they went into the trials which is ironically somewhat like what we see in Dravet syndrome. We see valproic acid and clobazam and of course not lamotrigine, but we see some common medications despite the fact that many of the patients may have been on 20 something drugs before they went into the trial. There may be some data in there that's worth looking at that's kind of hidden in that background data.

This is not necessarily to be self-promoting of this generation but the trials that have been happening in the last 5 to 7 years are listening to our advocacy groups to look at some more patient centered outcomes. We're looking at quality of life measures, sleep, measures of executive function, all those things that you mentioned Tracy that are more than just seizures. We know seizures are important. We know we need to reduce seizures but what if as you said Kelly, what if some of the quote unquote side effects could improve upon some of these other comorbidities that are so pervasive in each of these patient groups. I think in the fenfluramine study Kelly, that you led, even though the seizure reduction was not as great as it was in the Dravet trial there still are a lot of patients that had improvements in their executive function. That can go a really long way in terms of the day to day sort of grind that these patients and their caregivers are living.

: I love that too. We had a medicine – most patients with DEEs have constipation issues with constipation. We were on a medicine that caused diarrhea. Diarrhea was one of the adverse effects and it was like yes because it counterbalanced the constipation problem that we were dealing with. Sometimes you can get that for sleep as well if you have a rambunctious that will just never sleep, sometimes the increased drowsiness and increased sleeping can be helpful in some cases.

Just to circle back on one thing too that you said Tracy; we need to also try to put up a call there for our adult epilepsy colleagues. Maybe the LGS maybe has an edge here because there's at least more awareness of LGS in adult populations than there is in Dravet but still there's not a whole lot of knowledge and this is not meant to be a criticism. It's just kind of an observation that the new medicines, oh they require this prior-authorization and for fenfluramine I must get the echo. Maybe adopt some of the newer approved medications whereas we can basically even if there's not a comparative effect in this trial, if we can just look at the efficacy of these different agents and the fact that the majority of patients had already been there, done that and failed 26 or the big 5 then that should be hopefully illuminating that is going to be worth trying in patients.

: I think phenytoin and phenobarbital were powerful drugs in their day and age and a lot of times we see older adults that are still on those. I know there's a temptation to go back to these powerhouse drugs. They're easier to get. They're cheaper. You've got your experience with them for the older generation, but when you think about it, again even on really strong agents like that are kids eating, drinking, sleeping, pooping, peeing, taking their medications? Even if they're an adult who is severely intellectually disabled are they doing any of that? With these newer medications you can improve a lot of those things in these patients by trying that next treatment and that's what we're seeing in our community is that they want to try that next thing. They don't want to go on something that is potentially oh it's been around for a long time, and it might help and we'll just leave you on it because what really happens in our community, no one really knows, we add another medicine. We have no idea if it's working or not because the day-to-day seizure variance is just changing all the time in LGS and then in the long term you can really see a change. The community wants to try these new treatments. The community is willing to go get the echo. The community is willing to be in the clinical trials and literally use the brains of our children to do more for science than science is really doing for us right now and it's our responsibility to be educating families about what's out there and giving them every opportunity to access that treatment. I do really respect what you guys as physicians must go through just to get access to these treatments for our families. Without a savvy physician that's willing to write a letter and work with us and work with our insurance company, which is I'm sure what you guys all went to medical school to do, without us getting that we are never going to get access to the treatment, so it falls to you guys in so many ways.

Tracy Dixon-Salazar, PhD, leads a discussion on challenges of treating LGS and real-world implications from clinical trial data on newer medications.

Challenges in Treatment Selection in LGS

We do have this long list of medications that are approved for LGS and they go back right topiramate, lamotrigine, felbamate, there are 7, I will see if I can list them all, clobazam. Those are all these and then we have the new ones of cannabidiol and fenfluramine. Which one did I miss? I think I got 6 there. Kelly, these patients come to you as a third opinion. They have already been on 3 of the older – these are not old meds I am just saying older, how do you go about approaching with the family the options in terms of new versus old etc.?

: It’s challenging because we don’t have as good guidelines of what’s next and there haven’t been comparison studies. Is felbamate better than valproic acid, I have no idea because it has never been compared. My approach is often to say what are the options that you haven’t tried yet, what are the adverse effect profiles of these, do we have data and Dravet syndrome that allows me to rank these and if you were to have a common adverse effects of this, is this a benefit for you or a problem, and adverse effects sometimes truly are a benefit. If we have a child who is overweight being on something like fenfluramine or felbamate that may decrease appetite may be to their benefit whereas a medicine that may increase appetite such as lamotrigine or oxcarbazepine or valproic acid for another patient maybe a benefit if they are a poor eater. A lot of it is trying to match up adverse effect profiles with the options that haven’t been tried yet. Also exploring things like ketogenic diet just as something that is realistic for a particular family, has a surgical evaluation then done. We can start a treatment while we are doing a surgical evaluation and then also reassessing has anybody looked at etiology. Do we have an underlying etiology and does that guide as in anyway and choosing a medication from one of these medications? I also emphasize to families that this maybe the choice of medication that we are using now but all these things that we are discussing maybe something that you need to think about at some point in time in your child’s life. This is choosing what the appropriate next medication maybe now and not taking any of these options off the table because at some point we may need to circle back to these. And you may decide to take a break, you may decide enough changes for a while. We are going to sit tight. We have found a balance of quality of life and seizures that is manageable for us, and we want to just be able to have a summer without unexpected responses to medication changes so that we can do some family things and come back and revisit this in 6 months knowing that that’s an OK option as well. Most often we end up choosing broad spectrum medications unless we have a child with Lennox Gastaut who is having a lot of focal seizures and then we may look at one of her sodium channel blockers. But we have a whole host of options to choose from and not a lot of guideline about which one might be better than the other, it really is looking at a lot of these factors and particularly looking at quality of life as we are choosing those medications.

Kelly Knupp, MD, provides insight on optimizing treatment for patients with Lennox-Gastaut Syndrome.

Approaching Treatment for LGS

In these last few years despite having already a handful of FDA approved medications for treatment of LGS. There have been 2 newly approved medications. First was cannabidiol and then followed by fenfluramine, Kelly I'm wondering if you could just share your take on the data for those 2 studies and maybe comment on how you see them sort of fitting into your treatment algorithm or treatment approach.

It's nice that we had placebo-controlled studies for both of these products specifically in the Lennox-Gastaut population, and I will say before I even present numbers that the numbers looked better in the Dravet population than the Lennox-Gastaut population but it's important to keep in mind that the Dravet population is a very homogeneous population with a similar gene involved in the vast majority of those patients, whereas the Lennox-Gastaut population is a much more heterogeneous population. There may be sub-populations within there that respond better or worse and it's a little challenging to sort that out when you've only enrolled 60 or 70 patients in a study. That's important to keep in mind and there probably is more work that could be done in these sub-populations who have Lennox-Gastaut. Both fenfluramine and cannabidiol showed positive results and that is very exciting. While these are results in groups of people it's hard to know until you try it what the individual response is going to be. When we look at cannabidiol we saw a dose response with that at the lower dose which was a 10 mg per kilo per day, we saw a reduction of about 37% in seizures associated with a drop. It's important to also keep in mind what the outcome measures were. It's often reported as a drop seizure which many of us think of as an atonic seizure but that wasn't what the outcome measure was. The outcome measure was seizures associate with a drop so that's any seizure that led to a fall or could have led to a fall if the patient were sitting up or standing up. That's not just an atonic seizure. That could have been a tonic seizure and it could have been a generalized tonic clonic seizure so it's important to keep that in mind. At the lower dose of 10 mg per kilo per day there was a 37% reduction in drop seizures. At the 20 mg per kilo per day there was a 42% reduction in seizures and compare that to placebo which only had a 17% reduction in seizures. Clearly there was benefit at both the low dose and the high dose that was statistically significant for that population. Again, for an individual patient it's hard to know how they're going to respond but until you try it you're not really going to know. Fenfluramine likewise had a lower response rate in the LGS population compared to the Dravet population but again we have to keep in mind that these are heterogeneous populations when we're looking at Lennox-Gastaut. Overall, there was a 26% reduction in seizures compared to a 7.6 reduction in seizures in the placebo group so that was statistically significant. I think also in fenfluramine as we look at longer term data in the open label extension for the patients who stayed on fenfluramine overall they had a 66% reduction in all seizure types not just seizures associated with a drop and that is pretty notable. That tells me that there are probably sub-populations that responded better to fenfluramine within the LGS population and again we won't know who those patients are at an individual level until we try the medication. That is pretty significant to have that much of a reduction in seizures. We spoke earlier in our conversation about this hypothetical drop of 30% seizures, taking somebody from 1000 seizures a day to 700 seizures a day but boy to go from 1000 seizures a day to 400 seizures a day that's got to get close to improving some quality of life even though it's not perfect. It's a step in the right direction. It’s also notable in the fenfluramine study is that there was a small percentage of patients that were seizure free or nearly seizure free and as we've talked about Lennox-Gastaut that is not something that we really expect from any of our treatments. It's something we always hope for but not something that we set as a reasonable expectation and so to have a small percentage of patients that are seizure free or nearly seizure free in both of these populations, both the fenfluramine and the CBD population, is really notable and again we won't know for an individual patient until we try it if they're going to fall in that small percentage.

We had spoken before that it's not that they're 2 studies that are comparing one to the other. They were very similar study designs. A lot of the patient background, they have been on a lot of the same medications so that theme of you won't know until you try it and then if you end up being one of those so-called super responders then that means a lot for that individual patient. I wish there was a way we could predict but it's just them being willing to try and hoping that you are one of those patients because then if you are you hopefully will be thankful that you did try it.

Dr Kelly Knupp examines data on fenfluramine and cannabidiol for the management of Lennox-Gastaut Syndrome.

Newer Treatments for LGS

Thankfully despite the sobering statistics that Kelly you said about seizure freedom we do have a lot of treatment options for Lennox Gastaut. Go back into the late 90s, medications topiramate, lamotrigine, and then more recently somewhat renewed interest in Lennox Gastaut patients with cannabidiol and fenfluramine also and then Kelly you had mentioned surgical options for these patients whether that be vagus nerve stimulator or something that maybe barbaric but corpus callosotomy but can be very, very helpful for some of these patients. Acknowledging Tracy like these are thousands of seizures a week sometimes and we have these sobering statistics of 20 to 30% reduction in seizures. Kelly, during our prior conversation trying to minimize polypharmacy. You can see there are lot of moving parts here, so you’re starting out at a baseline of thousand seizures a month let’s just say and we are going to get 30% reduction with the first medication. Tracy, if you’re meeting me for the first time we are going to get Savannah down to 700. Is that just like don’t go there or is that the best you can, or I’ll take it?

: It has to be a conversation in a larger picture, going from a thousand seizures a month to 700 does not have a huge improvement on quality of life. But we know that not doing anything – if we know not trying that next treatment, we have zero percent chance of responding and we know that patients who are in placebo arm of epilepsy clinical trials are more at risk of SUDEP. For many reasons, we don’t want to let these seizures go out of control plus they are causing these brain changes and these damages. In the context of this bigger picture, we want to be fighting back against the seizures even if we may not achieve seizure freedom is the way that I would approach it with families and I do think if you look longitudinally and this is a little hand waving when you look at the data but if you look at older studies on LGS it was like 95% of patients continued to have seizures into adulthood. If you look now, it’s somewhere between 85% and 90%. They are still having seizures, but I think it’s slowly going down and while we don’t have the data I do think LGS is living longer. We are moving in the right direction and we are finding treatments that are specific for LGS. You can say yes maybe the numbers are dismal, but you can also flip it and say in the cannabidiol trial 8% were seizure free. And this percentage – I don’t know the percentage of the top of my head has 75% reduction because I will tell you that there have been some studies on this and there is something like 65% reduction in seizures is the tipping point for quality of status. I don’t know I mean it has not been replicated but there is a number there and certainly at 75% reduction and higher in seizures. But framing it that way is more attractive than we are going to get you down from 1000 to 700 seizures. It’s like we need to fight back against these because they are not OK. We are not going to normalize seizures. They are not good for your brain. They are a sign that something is wrong, and we are going to fight back or if they don’t like the fight language you can say we are going to push back, we are going to do everything we can to get them to the lowest number possible.

So glad you said that. It was almost like a softball. I was hoping because when we read these clinical trials for the purposes of reporting the paper and for getting regulatory approval, they look at 250 patients and look at the median reduction in seizures and they come up with the number. Statistically significant and placebo but then you look at some of the subsets and even though it may not reach statistical significance we are all scientists here and yes we know that there is chance and what not. But if 8% of patients have seizure freedom or 75% reduction in seizures, does it matter if it’s a chance. That’s like I’ll be a little bit flippant.

: We won’t know if that could be you unless you’ve tried.

: Exactly. That’s where I use these studies in my counseling to say this is what we can hopefully expect. We can set our bar at this, but this is the bell curve, we are hoping that you are going to do a little better, I appreciate you doing this. I am curious Kelly you were going to say something then.

: I just wanted to make sure we circle back a little bit to talk about epilepsy surgery because for providers who maybe listening in and for families to think about this. When you look at the overall data in patients with Lennox Gastaut the intervention that is most likely to make somebody seizure free is resective surgery and certainly not all patients are candidates for that. But as an epileptologist it is sometimes challenging to think about doing a receptive surgery in somebody with Lennox Gastaut because it’s a network disorder and what we see on our EEG are just charges everywhere. That causes us to pause to say boys is it worth this surgery in this patient who has focal lesion on their MRI, has a combination of different seizure types, some of which are focal coming from that lesion because we see abnormalities in other places and is it worth it to take this patient to surgery, are we going to see improvement. But the data suggest that we do see improvement in those patients. I think it’s an important thing for people to keep in mind that in a patient with Lennox Gastaut who has a lesion on their imaging and has some of their seizures coming from that lesion that they are – that intervention is more likely to lead to seizure-freedom than additional medications. I think it’s worthwhile at least mentioning that and think about it a little bit.

Absolutely. And as a plug for pediatric epilepsy specialist who just because we are aware of this and we may not feel that it’s going to be half of our patients but if we know about the lesion, if we know that this is a network disorder even if the EEG is not necessarily congruent we know that these patients actually and it takes a little bit of leap of faith but I see discharges everywhere but there is just one right frontal lesion, we are going to go after that. But I agree those are the cases that can be life changing. Tracy, you wanted to say something about surgery.

: I absolutely agree. We have to stop thinking about it as a last resort. I mean by the time you get an LGS patient, I love the way you said this Kelly is that you don’t see new-onset epilepsy. By the time you have LGS diagnosis, these families have been through it. You’re coming in at a much higher level in the conversation and whole tone of the conversation changes and now it’s time to bring surgery to the forefront. Surgery is more and more data is coming out on deep brain stimulation, on responsive neuro stimulation, on corpus callosotomy, and on resective surgery which has great numbers. There are some great papers out there showing that if you remove the focus that you can normalize the generalized EEG by removing the focus in LGS patient.

: Yes, it’s huge. You’re disrupting the network. Of course, none of us are lining about the door for brains surgery for our young children but I would rather have been presented with brain surgery early on and then like we need to move forward on this knowing what I know now about LGS. Knowing how devastating LGS is, it’s like you need to be aggressive a little bit earlier but you need to be aggressive smartly. We were aggressive with polytherapy. My kids were she was on 8 treatments and most LGSers are on 4 to 5 treatments on average if you take a poll. You maybe not as smart about that but being smart and aggressive in the beginning we know if we can make an impact earlier in the onset of this disease that it can have lasting consequences and often when you do get an improvement like that patient who was an adult who had resective surgery missed it, he has a lot of cognitive damage from the years of seizures but if we had intervened on that earlier he would have been much better. I think being smart about it and offering that to families and having an honest conversation and cancer never cuddles, they are like you have 3% chance of living. If you add radiation then that gives you an extra 3- 6 months. By the time you get LGS we should just be honest and presenting the data to our families, presenting the options and having the conversation with them so that they can make the best possible decision for their loved one. It’s a brutal thing to consider brain surgery and to do it and to have done one that wasn’t successful but it’s also brutal never have been given that option.

Yes, you have to be willing to ask the question as a provider just as much as we are expecting parents to consider trying one of these medications to give you a better chance like you said if you don’t try it, it’s 0%. At least if you try you will get something and you can make that decision whether or not that’s worth it for your child and your family but I think with surgery if we are not offering people aren’t usually coming in saying what about brain surgery, although sometimes they do.

Joseph E. Sullivan, MD, leads a discussion on treatment options for the management of patients with LGS and considers the impact of treatment on quality of life.

Treatment Options for LGS

This is a journey and journeys have a beginning, Kelly these patients are coming to you with few seizures the diagnosis wasn’t suspected but then it declared itself like you have LGS [Lennox Gastaut Syndrome]. I am wondering Kelly, the availability of the internet, Lennox Gastaut Syndrome Foundation, easy access for our families where they can go. We know they hear all this, but that’s a lot to unpack in the first few clinic visits where we still do want to focus on the seizures and medications, but not ignore all these incredibly important things that we know are going to come up and we know we’re going to be talking about. There is only so much time during those first few visits. I am wondering – now the provider journey of the new patient with LGS. How do you start with that?

: As an epileptologist, I don’t see new-onset seizures often. My experience is often somebody who had recent onset seizures, things aren’t going as expected, and one of my colleagues has referred them over to us. That first visit is often trying to provide some education, understand what’s going on and set reasonable expectations which is part of our job to be able to move forward. That first visit is usually assessing how many medications have been tried and having that conversation that if you have failed 2 or more medications the likelihood of more medicine making you seizure free is low. We must start thinking about what are all the treatment options that can happen. Tracy, you talked about the time that your daughter was diagnosed, and the truth is up until 2000 when we had that first publication that clarified that once you failed your first 2 to 3 medications the likelihood of being seizure free was low. That wasn’t our expectation. We thought we will just keep trying medications and we will eventually find something that works for you and that has changed our conversation. It’s hard for families to hear that but I it sets the framework for us to do reasonable goal setting so that we can say you’ve reached the point where it’s unlikely a medicine will make you seizure free. It doesn’t mean that we are not going to try, and we have lots of options to look at to get there but let’s talk about reasonable goals for the next couple of months. Maybe that’s finding a good balance between medications and adverse effects rather than pushing medicines that and make somebody so sedated that their quality of life is poor. We are also discussing what is your current development and in the setting of seizures setting some expectations that we know with ongoing seizures that we are going to see a decline in memory and learning. And what can we put in place to counteract that because I have just told you that I don’t think I can make you seizure free with medications. Do you have all the therapies that you need, maybe you’re not quite at the point where you qualify for therapies but we anticipate this need in the future, so let’s start to get those things in place so that we are giving you as much support as possible? How can we support your family, what’s stressful, are you sleeping at night, what are all these other supports that we can talk about and has anybody tried to figure out what the etiology is, that initial MRI was normal, your child’s development was initially normally, has anybody done genetic testing yet, there are lots of avenues that we need to start moving on so that we can prepare for what we expect in the future. We now have more knowledge to know what to expect when somebody has failed those first couple of medications. If we are starting to see cognitive changes in the setting of ongoing seizures, to me that’s a red flag that we need to get EEG not just to look for Lennox Gastaut, I need to make sure you are not having subclinical seizures during sleep that are impacting your learning. I need to make sure you don’t have electrographic status during sleep because I am going to treat your differently, as soon as we start to see that change in cognition with ongoing seizures that should be a red flag to everybody that they need to recheck that EEG because there are things that we can potentially manage differently that we may not obtain from history, so we need to continue to relook at that. Are you a surgical patient, do we know what these seizures look like, do we have the best understanding of electrographically what they look like, so there are lots of reasons to do more investigation. I do try to talk about SUDEP at that first visit as well because I am never sure if anybody has talked about it already. I know that families are going to come across it on the internet. We also talk about are you safe when you’re walking, how can we get your child into school, what is the family doing for respite? This is exhausting to have these unpredictable seizures. That’s one of the most horrible things about seizures, they are unpredictable. If you knew you are going to have a seizure every night at 8 o’clock you would plan your life around it and it wouldn’t be so intrusive but the fact that you don’t know if this going to happen when you’re at your brother’s wedding or at the grocery store or in my office where there is a really hard floor is can be challenging. Trying to assess all those other things in addition to talking about treatment options and where we can go next and starting to think outside the box a little bit about if medicines aren’t going to work. Are there other treatment options we need to look at that may work better for your child whether that’s a dietary therapy, vagus nerve stimulator, epilepsy surgery, or maybe an atypical seizure medication, something like calcium channel blocker once you’ve tried enough other medications would be reasonable to think about in that setting. Those are many of the things that we try to discuss. Obviously, we can’t discuss all of those things in that first visit unless we have a really long time to do it but that’s the list in my head for what can I get to you in this visit and what do I need to make sure I revisit the next time I see you.

: Yes, I heard a lot there. Getting back to Tracy when you have the bobcat sitting behind you, you don’t say it’s a kitty cat, so own it, own the diagnosis, don’t tiptoe around it. If all the features are there, have an open transparent conversation that your child has LGS and this is how we are going to approach it based on these first seizures types that presenting and here is what we need to also be thinking about. And again, we can’t cover it all but these other needs, I can’t list off all the seven ones that you mentioned there Tracy but the peering, pooping, eating, certainly sleep are key. And just I think maybe just putting under the umbrella of safety and happiness, quality of life, so how can we reduce seizures in a way that is well tolerated that is safe but that allows these children that become adults their best potential to thrive.

Kelly Knupp, MD, shares her perspective of a provider journey of a new patient with LGS and goal setting to manage the disease.

Goals of Therapy for LGS

You’re testing a lot. I want to get into what you see as a typical patient journey, let’s start the journey, thinking back to when your daughter was diagnosed with LGS and you are neuroscientist and I have heard your story so many times and it always brings me to tears. There was a delay in suspecting that at least LGS diagnosis, not to mention the calcium overactivation disorder but just the LGS diagnosis. Can you share a little bit about that?

: I wasn’t a neuroscientist back then. I was a 23-year-old mother of 2 kids. I hadn’t done well in high school. She only had her first seizure out of the blue in the middle of the night. It was tonic clonic, we had no idea it was tonic clonic, we thought she was chocking. And then 2 weeks later, she had another seizure, a tonic clonic, a month later she had another seizure, tonic clonic during the day, not at night and then 2 weeks after that she had another seizure tonic clonic, and then she went 6 months and didn’t have any seizures at all. We had gotten in immediately to see a pediatric neurologist. We got great care for that time. And then when she was 3, the seizures came on and they came on with a vengeance. Six different seizures on EEG, 100s of seizures a day and then that was our norm for the next 16 years. She wasn’t diagnosed with LGS until she was 5 when she went in for surgical workup and overnight 3 day EEG they came in after a day and said she has had too many seizures to count, you don’t have to stay for 3 days, she is not a candidate for surgery, and she has Lennox Gastaut syndrome. She is 29 years old now. This was back in 1998. We didn’t have EME monitoring like we do now, but all we knew back then was what was in the textbooks. LGS is catastrophic epilepsy syndrome. The prognosis is continued seizures, progressive intellectual disability, and premature death. That was it. That’s all I knew. Prior to that when she was 2 and seizing, doctors had said things to us like you can’t die from epilepsy. Seizures don’t damage the brain, and thankfully we don’t need to know what causes seizures in order to treat them. And they did because that was the dogma, not because there was anything negative about – that was the approach back then. But none of those things were true. We are seeing her become progressively brain damage up to the age of 5. We are resuscitating her, and the medications are not working. We did start treating when she was 3. We never talk about the medicines that make things catastrophically worse. We don’t like to talk about that in our patients, but she has had a few of those and maybe that exacerbated. Maybe there is a second hit in LGS that cause them to develop because not every kid evolves into LGS if you have the risk factors. But that was our journey, and she had been cognitively normal. Nobody expected that we were not going to be able to control her epilepsy and we were devastated. We lost a lot of trust in the medical system until we realized that they were working on the operating knowledge they had, but we thought we had been lied to and obviously that was not the case.

You said that she was developmentally normal even after those first few seizures when 6 months was out. And then when that horrible day where she had many, how long did it take for you to start seeing some changes in her?

: About 6 months. It’s hard. She was 3 years old. She was on all these medicines, we started monotherapy. We tried tegretol first, she got a rash, we cried. Depakote next, that one made her self-injurious and homicidal. She was just nuts. And then we tried dilantin as a third, phenytoin as a third, and within 6 months but it’s hard to know. It’s like what was medications what was seizures, and you have all the haters that were emerging and things like that but it was 6 months, we knew she was behind and then by the time we got the LGS diagnosis – I had read about LGS and I suspected it but it never hit me as oh she has that because there was just – I mean I had to check out internet time at a library. Back then there was a lot of information out there at the time. It’s much more now which is wonderful.

Like you said it wasn’t that your treating physicians at that time were incompetent. It was just status of things and now Kelly and I, we have the luxury of having genetic testing that we can get. We can get video EEG within a day if we need to and we now have the luxury of knowing that it does make a difference if we make this diagnosis. Maybe the patient journey now is different than it was 10 years ago and hopefully that is leading to a better outcomes, at least what we hope for.

: We are seeing a lot of families in our group that are coming in much younger, 1, 1.5 years old, 2 years old, that are getting in a lot earlier. Our understanding that there is this evolving and our understanding like it’s not the doctors that are failing you, it’s the treatment, it’s science and medicine have not gotten to the point where they can help in a lot of ways, but you don’t want to stop trying. And then families are supported. They are supported by other caregivers who have been there, done that. It’s faster and better. If you look at health claims data, if you look at medical claims data, most patients aren’t seen by the Kelly Knupp and Joe Sullivan’s of the world. Most LGS patients are seen out in general neurology or general practice even, it’s important for us to try to get them to see to you guys and know that there is hope on the horizon for these families.

This is a momentum in our field that people – pediatric epilepsy is already a subspecialize enough but now it’s getting that you’re a DEE specialist and then you are LGS, which is great. There is a lot of stuff going on and the pace of advances is crazy. It’s hard to keep to keep up and if we’re going to be doing our patients and their families justice that they deserve and give them the state of art then you almost do need to have this niche. That’s not to say that there is no role for a good card-carrying pediatric epileptologist that sees at all. I certainly have no ego, if I have something that I have only seen a few cases of and I know that my colleague has 5 or 10 of them, send them over there for second opinion because they are going to be in better hands. I am curious you commented a lot in terms of so many seizures and just being in constant crisis mode. This is something we hear a lot of our general DEE patients but certainly Lennox Gastaut. Having to be on them 24x7 because they are going to fall and end up with skull injury. I am wondering maybe share your personal journey and journey of some of your families in terms of how do those things impact your day-to-day ability to function as a family?

: For that 16-year period, from the time she was 3 till the time she was 18 when we found out her genetic diagnosis and tried the medicine for that, that reduced her seizures by 95% and stopped her status. She was going into status 2 to 4 times a week and getting at home rescue medications and when that didn’t work we go to the ER [emergency room]. We put her into coma if that didn’t work. For that 16-year period, that’s where most of the families that we work with live and having surveyed our families extensively and having held out patient for development meeting in recent years, we have come out with this hierarchy of needs for LGS. Just if you guys remember, Maslow's hierarchy if needs from a psyche class. If you want to live your full life at the top of the pyramid your basic needs must meet like food, clothing, water, shelter, social belongingness, love, feeling proud of yourself. And there is hierarchy of needs for our caregivers that impact our caregivers and our LGS level more. Although, in some ways they are happier than we are in some ways because they don’t realize how sick they are until they are in it and then they are so mentally young. My daughter is mental age of 2- to 7-year-old depending how this goes. She doesn’t comprehend that she is different, but the hierarchy is basically at the bottom of the pyramids. I don’t mean this to sound glib but is death. We have a lot of death in our community and then above that is crisis, all the things I have talked about, being in the hospital, being in the throes of a seizure status and seizures are more than just the actual event, it’s like all the pre stuff and the post stuff and cleaning up the pee and the poop. Now we have to sleep or not making it to work. You’ve got the injuries, drowning possibility, aspiration pneumonia. These are the crisis pieces of epilepsy, and we are just constantly trying to keep our kids out of crisis, they are going to go into crisis but and above that on the pyramid are they just doing the basic life skills. Are they eating, sleeping, drinking, pooping, peeing, and taking their medications and generally staying safe. These 7 things take all of our time. These 7 things will help them to not go into crisis, they are still going to go into crisis but these seven things are what we spend all our time on. And then above that on the pyramid is do they do any of those 7 things themselves, and the answer is never yes. We don’t know what’s at the top of the pyramid and we don’t know what self-actualization looks like in LGS space because our needs are so low on that pyramid as caregivers and our kids are they are so much suffering and so much devastation, so much brain damage that’s happening across the course of their LGS that they are suffering down there with us. That’s really been the journey. Most families are still living in that going into crisis all the time and then doing everything, all the care giving for the rest of their lives. I have been a caregiver for 29 years now for my daughter and will be for as long as I am able and she lives. It’s this never ending, and I that’s where most families on the LGS journey are living in that constant crisis and care giving and waiting for the next crisis to happen because it’s going to.

Tracy Dixon-Salazar, PhD, reflects on her daughter’s journey to diagnosis of Lennox-Gastaut Syndrome and the impact of the disease on caregivers.

Patient Journey to LGS Diagnosis

: I do want to mention one thing that we all brought up in terms of classic EEG features of Lennox-Gastaut. I certainly have sent a few patients who have nothing else to suggest on Lennox-Gastaut but they get an EEG, some slow spike and wave slow spike and wave during sleep. And they are sent to me second opinion for Lennox-Gastaut, I alluded to you, you need the clinic EEG and EEG pattern is the pattern that is most often associated with that clinical picture of Lennox-Gastaut but if someone else did everything it would be unusual but if a patient fit a seizure type and maybe didn’t have a slow spike, I still would approach them in that same way as Lennox-Gastaut. The same thing, if someone did not have any of those seizure types only had generalized tonic clonic seizures and then had slow spike and wave on their EEG, I would not give that patient Lennox-Gastaut. Do you both agree with the fact? Feel free to disagree.

If you had a patient with just generalized tonic clonic seizures but they had slow spike and wave and PFA on their EEG, I would be looking really closely to see if they have tonic seizures associated with PFA.

It may just be so subtle that you miss it, but it’s also important to keep in mind that just as this evolves probably at typical ages and of course every child hasn’t read the book and so not everybody does it exactly when they should. It also is something that does sometimes go away as children get older, and if somebody has missed the window in those 3 to 10-year-old age, it’s quite possible that we could have a teenager or young adult who otherwise fits Lennox-Gastaut, but no longer has those spike and wave PFA. This is something that people pay attention to more in clinical trials because many clinical trials trying to ensure that they have inappropriate diagnosis of Lennox-Gastaut will require slow spike and wave in PFA, but if you are going to require that for adults with Lennox-Gastaut, it’s going to be hard to find it. You must go back to the earlier records to look for it.

: The reality is as you know as scientists, we need these rigorous definitions as testing theories. If we want to learn to treat the Lennox-Gastaut network we need patients that have the classical EEG features. When you look in the communities that we serve, all the developmental and epileptic encephalopathies that have seizures as a main driver are dealing with – that we are living the same journey, we see the same doctors, we are on the same treatments, we all tend to be super refractory. Seizures are just the tip of the iceberg in all of us, but what distinguishes us is that there is developmental piece of it. We are much more drawn to a treatment that has been tested in our super refractory LGS population or Dravet population than someone with say adult-onset temporal lobe epilepsy, that there is not that developmental component that has further complicated the epilepsy. But the reality is we are all on the same journey, when you are in the community we unite. We divide on the science, but we unite on everything else as it relates to the developmental and epileptic encephalopathy including Dravet, tuberous sclerosis, I don’t even know how many there are now.

: I guess one other thing I would just say is that whenever you see LGS you should be thinking what is their LGS secondary to?

: We know the critical malformations. We know that de novo genetic mutations. We know that hypoxic ischemia and other birth injuries, stroke at birth, post chemotherapy seizures that involve LGS, down syndrome kids who develop seizures and evolve into LGS. TSC is a great example. Many of these babies, something like 40% to 50% of the kids that develop IS from their TSC mutation will evolve into LGS. What is the etiology, now you’re dealing with whatever the etiology is and this LGS network that has formed and the way that it has impacted development. I don’t know the relation, but I have heard some people say you can Dravet and LGS and I heard other people say absolutely not they can never exist in the same patient. We have patients with both in our community and I am not going to fight with them, they are welcome to be supported by us.

But that emphasizes the point that it is important to look for that etiology because it may impact treatment. There are children with Dravet syndrome with SCN9A mutations who check all the boxes for LGS. It’s important to make that diagnosis because we commonly use sodium channel blockers in children with LGS but if somebody has SCN9A mutation, we would not use the sodium channel blocker in that patient. In some ways, we may have 2 paths that we need to look at for as we are looking at treatment once we have the LGS diagnosis as well as the etiology.

: I would just add, would it hesitate to give the LGS diagnosis, the LGS Foundation held the meeting of minds last year, a seminar and Dennis Dlugos said we tend to hesitate to give you just diagnosis because parents don’t want to hear it, it’s bad, there is not a lot we can do and the science is changing first of all, so there is a lot we can do. And second, we have an amazing community of support. We don’t have cures and we are very unlikely that we are going to get seizure freedom. We are not going to give up looking for it, but if these two have a community that can help you manage to attempt to manage the disease, I would suggest we not hold back.

Agreed and something that I am curious to hear your thoughts on. Finding the more precise diagnosis. In my opinion, just because you think you may have one doesn’t mean that’s the right one. There have been some papers that have come up, just because maybe you had a little stroke in the neonatal period, maybe you should still do some genetic testing to see if there is something else going on because that could have a lot of potential treatment implications down the road.

Particularly yes, we are having more gene modifying therapies in trials. You very well can have LGS secondary to gene that has a gene modulatory therapy that is in trials, and we want to make sure that you have access to that.

: My own daughter has LGS secondary to calcium channel over-activation disorder. She has calcium channel mutations and the only drug that she has ever responded to has been something targeted towards her genetics and her genomics. We are a big proponent of that. Now about half of the LGS population is genetic and the other half is acquired and I don’t think we have looked at the acquired epilepsies that have evolved into LGS as closely genetically. You are right Dr Sullivan. I think there is element of we need to look there and see but we are big proponents of any sort of precision type of therapy or genomic medicine approach to our families because it really can make a difference.

: We have previously talked about Dravet, how it’s more homogeneous but yet it’s still a spectrum disorder. I guess LGS we would agree is much more heterogeneous with so many different background causes, but it still is a spectrum disorder and there still is going to be value to the community. I say this with any syndrome diagnosis I make like yes you can go online, and you can look it up but no one is your child, every child is going to act a little bit different. Yes, you may read some common themes and you may be able to reach out to other families to get support on some of those common themes but that really in my opinion isn’t something – even with the same genetic diagnosis with LGS phenotype those are still going to be different to different patients. I am just curious. In your foundation when you have families, how do they deal with that in terms of spectrum and finding someone that is more aligned with what they are living day to day.

: One of the things that came out of Rare Epilepsy Networks Study that was funded by PCORI was that when you looked across a bunch of different DEEs and you asked the question, how many seizures has your loved one had in the last 6 months. I remember Dravet of the top of my head, the answer was 100s, tuber sclerosis 100s, LGS was 1000s. The unifying theme in the LGS community, not that we are going to win any prizes for this, the seizures all suck. They're horrible. But we’re talking – our families are shifted. You often will hear people say epilepsy is more than seizures, we’re not really singing that tune over in the LGS space because if you don’t get the seizures which are often happening daily and my daughter was having 5 to 10 on her best day, 100s, too many to count on her worst day and that was our life for 16 years and most of our family has never achieved any stability from that. If you don’t do something about the seizures how are any of the other things like gait or GI [gastrointestinal] issues or sleep or behavior going to get better. Often people ask what’s the difference and for us it’s just we’re constantly dealing with the seizures and the things that are associated with those. Somebody recently asked me, why don’t we talk as much about SUDEP in the LGS community as they do in Dravet, and I think it’s because we’re just constantly trying to keep our kid alive from seizures and out of the emergency room. Their status, my kid had three skull fractures, had injuries, their aspiration pneumonia which is the number one killer in patients with LGS and there are cluster seizures. There is all of these sorts of things wasting away because we can’t stop the seizures and now they are in a coma, so we just spend our time thinking about all the death options and we are only worried about SUDEP in sleep. It’s a confined time period for the SUDEP that we get to worry about it, but we are just more thinking about just a constant barrage of seizures and the medical intervention and constant medical oversight that’s needed, do they need oxygen, make sure they don’t aspirate, do you need to do this and that. Those are the biggest differences but you’re right, our families are unified around this common theme of seizures but they are coming from all these etiologies that each is so uniquely rare but they are often in multiple communities. They will be in the hypoxic ischemia community; they will be in Dravet community and they will be in our community.

Tracy Dixon-Salazar, PhD, and Kelly Knupp, MD, emphasize key identifiers for the diagnosis of Lennox-Gastaut Syndrome and challenges in managing seizures in these patients.

Differential Diagnosis for LGS and Challenges in Managing Seizures

: I would like to get into some details about the epilepsy syndrome that has named after 2 doctors Lennox and Gastaut, Lennox-Gastaut syndrome. Kelly, I am wondering if you could maybe share with the audience what your definition is of Lennox-Gastaut syndrome. I know this is controversial. We can maybe have our epilepsy board definition and then maybe our day-to-day clinical practice when these patients come into us and how that is certified.

There is still a lot of work that needs to be done around this diagnosis because there is controversy. There are some standard criteria that most people would agree with. But first off it’s important to recognize that Lennox-Gastaut syndrome has a lot of different etiologies and it’s often a syndrome that children evolve into, they don’t start off having Lennox-Gastaut, and that’s one of the tricky things about trying to figure out this diagnosis and making sure that we don’t miss this diagnosis because it’s not something that presents from day one as Lennox-Gastaut, it’s something that evolves over time from those patients. To have a diagnosis of Lennox-Gastaut most people would agree that you should have multiple seizure types, maybe just 2, but at least one of those should be tonic seizures. There are character EEG patterns that should be seen with slow spike and wave and then also paroxysmal fast activity which is most often seen during sleep. It’s an important thing for providers to keep in mind that if they are getting EEGs and they don’t get a sleep phase that they could potentially be missing this diagnosis, it’s important to get both sleep and wake EEG to help make this diagnosis. These children almost universally had intellectual impairment. That is often considered one of the requirements for this and then many people will put in age requirement on this, and some people will say it has to present under the age of 11. There certainly are reports of people who presented during adolescence or in early adulthood with these signs and symptoms. Those are criteria that most of us would agree with. For the clinician because this is a syndrome that most children evolve into, what’s important is that when our families are starting to develop multiple seizure types that we do take another look and repeat their EEG and look for the electrographic findings of this and there are certain patient populations that we should probably always be very sensitive to and probably be looking for evolution into the syndrome. There is a whole list of genetic disorders that we know are frequently associated with Lennox-Gastaut syndrome. Children who have infantile spasms have high risk of evolving into Lennox-Gastaut particularly if they haven’t responded to treatments. There are definitely some high risk patients that we should be looking for this diagnosis in but we also have to keep in mind that’s not all of them and this can happen to any one of our children who presents with childhood epilepsy. We always have to be aware of that and making sure that we are clarifying what seizure types are you seeing, what’s happening at night and thinking about getting in EEG particularly in a child who is having multiple seizure types and has developed mental delay or intellectual impairment.

Yes. And maybe we can for the purpose of different background, you said infantile spasms, obviously a very common infantile epilepsy syndrome that has a high risk of evolving or developing Lennox-Gastaut. I wonder if you can share with us your experience and ballpark percentage of what percentages of those patients do or how do you counsel your infantile spasms on patients and does that risk change at all with how the infantile spasms are treated?

If you look at all comers with infantile spasms, the risk is about a third of them will evolve into Lennox-Gastaut. That’s based on old data. We reevaluated it at our infantile spasms cases to see if there was a change and there wasn’t, it was about a third evolved into Lennox-Gastaut. That’s something that we should be comparing our families for when they have a diagnosis of infantile spasms that we need to watch them. Many of those children did have developmental delay and most children who evolved into Lennox-Gastaut didn’t respond to standard therapies for treatment of infantile spasms. That gives us a cohort of children to watch for. Many of those children also had an underlying etiology that was identified for their infantile spasms, that’s something we can watch for in that particular population. For seeing a child with infantile spasms who has preexisting developmental delay we find an etiology and they are not responding to treatment. That’s somebody we must be particularly concerned about in their evolution to Lennox-Gastaut. There have been a handful of reports of evolving the EEG findings in that patient population. I find that tricky to follow. What is more important is that those patients who medicine is failing them, those are the patients that we need to keep a close eye on and watch for other seizure types.

You have an important second group. You’re going to have a group of children that maybe have an epilepsy risk factor – maybe they didn’t have infantile spasms but have epilepsy risk factor, whether neonatal stroke, maybe they actually have a developmental brain abnormality that was picked up on the brain MRI because that was done because they had developmental delay, but hadn’t had their first seizure yet but hopefully we would agree that that’s another group of patients with increased risk of maybe presenting – you don’t necessarily present with Lennox-Gastaut, you present with a few seizures and then it takes some time for the syndrome to evolve and declare itself and it’s our job as epilepsy providers to be aware of that evolution not only EEG wise, we don’t look at any of these things in isolation but how the whole picture fits together. And then there is a third group where no epilepsy risk factors, maybe even normal development has their first few seizures and then very quickly evolve into the Lennox-Gastaut picture. You can always get even more narrow and say specific genetic diagnosis.

It’s important for particularly as providers for us to keep in minds that while they may evolve quickly into Lennox-Gastaut they don’t usually have those findings on their first EEG. When a patient presents with their first seizure, we often do – we see them, we get a history, we get an EEG, we probably get imaging and that initial EEG usually doesn’t have features of Lennox-Gastaut, it’s something that evolves over time. That first child who has no risk factors and is presenting with this random seizure that we can’t explain, if things are not going well, we need to take another look at them to see if they are evolving into Lennox-Gastaut.

: The other fascinating thing to me and maybe Tracy as a scientist can comment on this is how does a patient that has history of infantile spasms then you have a different patient who has a developmental brain abnormality and then you have different patient who has normal brain MRI, how do they all converge on the same clinical phenotype that is the mix seizures and EEG patterns and I know there has been some animal models and things but I don’t know Tracy, I will have you put on your scientist hat here first and do you have any comments you want to make on how all these different etiologies converge on this epilepsy syndrome diagnosis.

: Yes, absolutely. The science in the last 10 years on Lennox-Gastaut syndrome has been phenomenal. And a lot of it has come from extensive brain mapping in children and adults who have Lennox-Gastaut syndrome. What we found is it doesn’t matter what your etiology is, it doesn’t matter what your age is but all of these patients converge on to the same unifying underlying epileptic network. And as a neuroscientist, my training as a neuroscientist we learn that cells that fire together wire together during brain development. And as you can imagine the brain is developing – most Lennox-Gastaut presents itself between ages of 2 and 5 years old and not exclusively but most of them do. This is a critical time for synaptic proliferation and then synaptic pruning happening. If you have all this excessive electrical activity cells are firing, they are wiring and so the predominant theory is that it’s wiring defect and there has been some great mapping. The biomarkers of LGS are the 2 key EEG features, slow spike and wave which is generalized paroxysmal fast activity, which is often associated with tonic seizure. And these have been mapped to a very stereotype network in the brain that starts in association cortices, not other cortical areas, association cortices. It runs down into the brain stem and the ponds and then up to the thalamus and this is across patients who have LGS, no matter etiology or age. We are starting to think about LGS much more as a network disorder. I mean I don’t know maybe there is cocktail that can target each of these networks, but we do know that if you can disrupt but once you have that network getting seizure control is very hard. Once you have that network learning and memory is severely impacted. My daughter was typically developing until she had her first seizures and then she developed the LGS network and then she stopped learning and that’s not uncommon, but we do know if you disrupt that network through brain surgery, through deep brain stimulation, through getting seizure control with the meds, that you can normalize the EEG and these patients can do better. It’s a network that can be disrupted and corrected and it’s better at younger ages but certainly impact has been seen in older adults where we have disrupted that repetitive recurrent network in these patients, and they have done better clinically.

: That this is one of the fascinating things about our field in terms of I always say as a pediatric neurologist we are following a moving target. There seems to be these critical windows of brain development that when things go an aberrant way like you say they fire and they get wired, there is some data about spasms and why infantile spasms and epileptic spasms unique seizure type and arrhythmia in those younger patients to slow spike and waves, it really is that moving target that keeps us all on our toes.

Kelly Knupp, MD, provides an overview of Lennox-Gastaut Syndrome (LGS).