Lennox-Gastaut syndrome (LGS) is an epilepsy syndrome that can develop over time from childhood seizures that remain uncontrolled by treatments. It’s common for children with genetic epilepsy to develop LGS which can then further exacerbate their symptoms. To better understand LGS, we speak to Dr Tracy Dixon-Salazar, Director of Research and Strategy for the Lennox-Gastaut Foundation.
You can listen to and subscribe to the SCN2A Insights podcast via Apple Podcasts, Spotify, and Google Podcasts or in your podcast app.
Dr Tracy Dixon-Salazar is the Director of Research and Strategy for the Lennox-Gastaut Foundation. Tracy has a background as a neuroscientist and geneticist and is the mother of an adult with Lennox-Gastaut Syndrome (LGS).
You can read more about Tracy’s background in this profile piece in Brain & Life.
Ms Kris Pierce RN MHSc MWellness, is a rare disease advocate and mother to Will who has SCN2A. Kris has held a range of board, project management, advocate and consumer representative roles and has been instrumental in working with local, state and federal governments to secure funding for multi-million dollar projects. Kris is highly skilled in building teams to work together collaboratively and is a co-founder of Genetic Epilepsy Team Australia (GETA) and SCN2A Australia, and a RARE Global Advocacy Leadership Council member.
Welcome to SCN2A Insights bringing you the latest research and clinical updates on SCN2A and genetic epilepsy from around the world.
Dr. David Cunnington: Welcome to this episode of SCN2A Insights. And welcome, Kris.
Ms. Kris Pierce: Thanks for having me.
Dr. David Cunnington: In this episode, we’re talking about Lennox-Gastaut Syndrome. And we had the pleasure of interviewing Tracy Dixon-Salazar, who’s Director of Research and Strategy for the Lennox-Gastaut Foundation. And great job setting up that interview, Kris.
Ms. Kris Pierce: Thank you. Yeah, Tracy is a real powerhouse in the rare epilepsy world and it was a real pleasure to have her on our podcast.
Dr. David Cunnington: And as you’ll hear in the interview, I think it gives a really good understanding of what Lennox-Gastaut Syndrome is, much more than I ever understood when I was in medical school or in my work as a doctor. So it’s a great interview. Well done, Kris.
Ms. Kris Pierce: We welcome Tracy Dixon-Salazar, who is the director of Research and Strategy at the Lennox-Gastaut Syndrome Foundation based in the US. And we’re going to talk today about what LGS is, and a bit about Tracy, her background and how LGS fits into other genetic disorders. So welcome, Tracy.
Tracy Dixon-Salazar: Thank you. And it’s great to be here.
Ms. Kris Pierce: So can you just tell us a little bit about your background and how you came to be working in this space.
Tracy Dixon-Salazar: Twenty-four years ago now, my daughter had a seizure out of the blue. She’s 26 years old now and back then she was two. And I was a very young stay-at-home mom and I had no idea what was about to happen to us and to our lives. She had a couple of seizures. They were tonic-clonic seizures in the beginning. And then she went six months without having any seizures at all and we thought we had dodged a bullet really, and that huh, we missed that.
And then when she was three, the seizures came back full force with a vengeance. She started having seizures every day. She started having multiple types of seizures. Ultimately ended up having six different types of seizures, probably more than that now. From the time she was three to the time she was 18 years old, she basically seize every day. A good day was five to 10 seizures, a bad day was hundreds, too many to count. And you really never knew what day you were going to get if it was going to be hundreds of seizures day or a five seizure days.
And so our lives were absolute hell across that whole time. She got the diagnosis of Lennox-Gastaut Syndrome when she was five. And before that, it was intractable epilepsy. And, you know, we now know, years later that Lennox-Gastaut Syndrome is not something that anyone is born with. It’s something that develops over time in some children to have uncontrolled seizures. And it’s a sign that the seizures are really taking over brain development and causing the brain to form in very unusual ways, but ways that are very similar across LGS kids. So we were pretty devastated when she was five at that diagnosis. And I have been in the space ever since trying to leave it better than we found it.
Ms. Kris Pierce: You’re the Director of Research and Strategy, how did you get into that role? Like how did you progress from being a mom of a child who’s had this devastating diagnosis into that role?
Tracy Dixon-Salazar: So I started volunteering immediately for our local Epilepsy Foundation. We live in California, and I didn’t really find a lot of resources to help us because our daughter’s epilepsy was just so severe, and back then the focus was really on how you can live a full life with epilepsy, and we weren’t living any sort of life whatsoever. We were just at the mercy of the seizures whenever they struck.
And so I actually started reading everything I could get my hands on. What caused it? No one could ever tell us why she started having seizures at two. She had been typical before that. So I – I started reading as much as I could. I would check out internet time at the library back then. And before the World Wide Web was in everyone’s house, stumbled across some scientific papers on what caused epilepsy. Actually, the first papers I read were by the Australian group in Melbourne, Ingrid Scheffer and Sam Berkovic, it was one of the first papers that I ever read. And I didn’t understand every fifth word of it.
And so I enrolled in college as a 25-year-old mother, thinking that I needed to take some English classes so I could understand Dr. Scheffer and Dr. Berkovic because clearly their paper was in English and I didn’t understand it. And so I took a few English classes, I did really well. And then I said, you know, maybe I need to take some science classes. And it turns out that their papers are very much in science and medicine, which are not all that much like English, or at least the English I spoke.
And I fell in love with it. I fell in love with the subject. And after 12 very long years, I ultimately got, I stay in school for a very long time. And school gave me an identity apart from being a mother of a sick kid. It gave me something else to do. I couldn’t stop my child’s seizures, but I could study and I was very good at it. So, after 12 years, I got a PhD in neuroscience. I just wanted to be a part of that group of people around the world that we’re looking for causes of epilepsy.
Back 20 years ago, the dogma was, you know, thankfully, we don’t need to know what causes epilepsy in order to treat it. And you can’t die from seizures and seizures don’t damage the brain. And this was not playing out at all in our lives. Of course, the seizures were damaging her brain, none of the drugs or therapies targeted against her seizures, the symptom worked. And she had multiple near-death experiences. And so I just thought, you know, at least I’ll be a part of the group of people trying to make it better.
So I spent 12 years, I studied basic neuroscience and I did a postdoc in neurogenetics in California, right about the time that genomic and genetic revolution happened, where we were finding genes left and right, that caused early-onset epilepsy. So it’s a very exciting time. And I spent multiple years doing my postdoc and then moved to nonprofit work because the scientists had really moved on. The scientists had found all these genes, and they were going to keep finding genes. And they were going to study them, but no patients were getting genetic testing. I’m in the lab, and I’m screaming, “This is going to change the way we practice medicine!” And the scientists were like, “Yeah, that’s great. But that’s not what we do.”
So I left the lab, and I worked for Cure Epilepsy for about four years as a funder. And now, I work at the LGS Foundation as a Research Director, really trying to encourage physicians, and it’s been a long haul, trying to get them to understand the science and move faster. But really, to get them to order the test, and to understand how knowing the gene that causes your seizures really can lead to a change in management and a change to prognosis, movement into clinical trials and things that are happening now around personalized genomic medicine.
So a long answer to how I ended up here, but where I am now, and I love it, and I suppose next I have to go work for an insurance company because they’re certainly not covering the test the way they should be. So, as I follow this problem through my life.
Dr. David Cunnington: So, I can certainly relate to that experience, you know, our son is 18 and, you know, we certainly can recall being told, you know, we’ll just manage the seizures and that strategy wasn’t working too well. And it wasn’t until many years later it was then “Well, why is he having seizures? And is there an explanation for it?” So Lennox-Gastaut Syndrome had a sort of definition. I remember when I was in medical school, 30 years ago, it had a particular definition, but how define it in 2020?
Tracy Dixon-Salazar: The last 10 years in Lennox-Gastaut Syndrome Research has been probably the most exciting. When I first came into the space, it really is a collection of symptoms. So if you have more than one seizure type, if you have intractable seizures, if you have the age of onset of your seizures under the age of about eight years old, and you have a very specific EEG pattern called slow spike-and-wave, then you have LGS. And that was the definition.
And you know, 20 years ago, and actually 50 years ago, where LGS has been around since the ’60s. That’s how we did practice medicine. We described it, we didn’t have all these fancy technological tools to dive deep into the genetics and the genomic and then see EEG. And we know a lot more of it now. And I think that because it’s been around for so long, people just thought that it was this thing that sprung up, you know, usually see the slow spike-and-wave on EEG between the age of two and five years old. And so they thought it was, for a long time its own distinct clinical entity.
But in the last five to 10 years, we know that it evolved. About 30% of infantile spasm kids will develop LGS. Tuberous sclerosis, about 40% of those patients, you know they’re born with a gene defect, they’ll – 80% will develop infantile spasms, and from those that have infantile spasms due to the TS gene will be evolved into LGS.
And what LGS means and again, out of some amazing work coming out of John Archer’s lab in Melbourne, that we know is that it’s a sign that the wiring you know, the brain during development and the child is putting itself together, it’s connecting the wires and the neurons are talking to each other. And LGS and slow spike-and-wave are a sign that the brain is putting itself together in a very abnormal way. But that abnormal way is consistent across patients with LGS. So compared to normal people, this brain wiring is very abnormal, but compared to other LGS people it’s pretty similar. And so you get this little spike-and-wave and you can now see on with advanced neuroimaging that it’s a wiring defect.
And so our whole premise has really been over the last three years that I’ve been at the LGS Foundation is to talk about this evolution. We have six drugs in the United States that are FDA approved for the treatment of Lennox-Gastaut Syndrome, but all of them are towards the symptoms, the seizures. And by the time you have the slow spike-and-wave, the chances of you reversing that slow spike-and-wave, the chances of you stopping the seizures are very low. More than 85% of LGS kids continue to have seizures into adulthood. More than 95% are moderate to severe intellectual disability.
And so we have been huge proponents at the LGS Foundation of intervening earlier. If there’s a gene like in tuberous sclerosis-like I just described, that can be targeted, please, for the love of God target it before the devastation. If you can target the evolution somehow if you know that the infantile spasms are a trigger or are likely to evolve, how can you target that evolution?
So we spend a lot of time trying to really drive research around the evolution, and we’re here to support anyone that does have LGS and we are there for them. But you’ll be hard-pressed to meet an LGS parent that doesn’t wish that it could have been stopped early.
Dr. David Cunnington: Yeah, that’s a really helpful explanation of LGS and how it interdigitates with a specific genetic diagnosis. So someone might have a specific genetic diagnosis and left untreated evolves into an LGS, which is then a common manifestation across different genes of how the brain responds to that insult or the metabolic effects of the defect from the gene.
Tracy Dixon-Salazar: Absolutely. And we know that about 50% of all LGS cases are genetic. There’s no one gene that says you will develop LGS. It’s a predisposition gene. But there are many genes, actually over 100, I’m tracking to about 130 now, where there have been cases where the person, you know, the child has a gene defect in one of these genes, and they also developed LGS. We spend a lot of time thinking about genes like SCN2A, which you guys are very interested in, thinking about how that can be targeted early to prevent the evolution of LGS and how we can support your foundation to make that happen.
I personally can’t give devoted attention to 150 genes. So anytime a new gene organization pops up, I’m so, so thrilled. But we also need to work together and collaborate whenever we can. And honestly, my money is on the SCN2A families to really drive it your home faster than treating the symptoms as we have been.
Ms. Kris Pierce: In the SCN2A space, we’ve got some exciting research happening, and hopefully, as you say, treating the cause rather than the symptoms. So hopefully, as that evolves, it’ll have an impact on those families that progress to the Lennox-Gastaut Syndrome.
And we’re going to move on, you talked a little bit about collaborating and, you know, working with all the different gene groups, but I guess across epilepsy as a whole. And I just want to touch on last year in November, you organized or convened a patient-focused drug development meeting for DEEs with the FDA, is that correct?
Tracy Dixon-Salazar: Yes, that’s great. It was a great opportunity for us to go and speak to them.
Ms. Kris Pierce: So what was the focus of that meeting,
Tracy Dixon-Salazar: The purpose of the patient-focused drug development meetings is really for patients to get a chance to speak to the FDA. The FDA, and all other regulatory agencies outside the US, by and large, have been approving drugs, especially the FDA, based on the burden of the disease, the currently available treatments, and also the safety and tolerability. But they’ve done this really without having heard directly from us, as patients. We have six FDA-approved drugs for LGS and they’ve largely been listening to, they’ve been reading the literature, they’ve been listening to themselves, they’ve been listening to physicians. And so this is a chance for patients to tell the FDA what it’s like to live with this disease.
And it’s online, you can actually go watch it. It’s a three-and-a-half hour meeting. It is utterly heartbreaking. We applied to host this meeting, the FDA will host a number of them each year. And we applied and we’re told that we were granted and it was the LGS Foundation that hosted it, but we – for all the reasons I’ve already explained, we didn’t really feel like we could do it on only LGS. We wanted to do it on the DEEs as a whole. And I know that we had representatives there from SCN2A as well.
And it was really to talk about this evolution of LGS from the genes, from the other things that cause it, and targeting along the way. I know that right now, there are many drug companies that are making drugs against the symptoms of LGS. And I really hope that they don’t stop because then that would be saying to families that live with LGS today that don’t know the cause, right? Or their cause isn’t genetic. It would be saying, “Well, we’re really sorry, we can’t help you.”
But I also hope five to 10 years from now that we’re doing a better job at targeting the evolution and not doing it the exact same way that we’ve been doing drug development for the last 50 years in epilepsy. And so, it was our chance. We had patients there who had genetic epilepsies, we had patients there who had injuries and that’s how their child started developing epilepsy. Infantile spasms were represented there a little bit.
And they all talked about this evolution, you know, once, once these families and mine too, develop LGS it’s awful. It’s you know, it’s daily seizures, thousands and thousands of seizures every couple of months, you know, and they’re seizing every day, injuries, aspiration pneumonia, near-death experiences. They’re on anywhere between seven and 10 meds on average, they’ve tried twice that many. They all get the corpus callosotomy, the VNS, the diet, they’ve all tried.
In some ways, designing a drug for LGS is very profitable, because we are desperate, we will try anything. But that doesn’t mean it works. And so it was our chance to tell the FDA, you know, the stories, eight families, eight parents testified, and including myself, and seven of the stories were very sad. And the children were irreparably harmed, including one mom who testified about how her son had died of SUDEP. And then, you know, it was just, it was heartbreaking.
And then our testimony was one that was a positive story. We found the genetic cause of my daughter’s epilepsy when she was 18. And something we found when I was in the lab doing sequencing on everybody and found a medicine that actually miraculously really helped her. So she’s 26 now, she’s developing again. She will never catch up to her typical peers. But we found something after, you know, all those decades of horrible seizures that really made a difference.
And I think it spoke to not giving up, that targeting, you know, the gene in patients, even if they’re older can make a huge impact, that there is data now that we can target genes early, and we should be and we should be exploring that for research. And, you know, I think we made a few FDA members cry, which is always heartbreaking. But I do think they want to help, and they did hear us.
Ms. Kris Pierce: Yeah, that’s fantastic. It’s really important that the people doing the work in this space, whether it’s the lab scientists, the people making decisions about what drugs, you know, that they’re all aware of the impact on families. And this has evolved, I think, probably you would have seen it more so than us where the patient voice is getting louder and include us in the conversation and listen to us, hear what we have to say. So that’s a fantastic impetus for that meeting. What – did you actually get any outcomes from the meeting?
Tracy Dixon-Salazar: Well, we got some really great feedback. There was some very high head of neurology products there that commented that the meeting was very helpful, it was very informative, they learned things. What will happen now is that we’re working on a Voice of the Patient Report, which is usually what comes out of these meetings. And it will stick you know, it will organize everything that was said in the meeting and also link to the transcripts. But then this will go to the FDA where we, as the patient group, can actually request another meeting where we asked them, “OK, you’ve heard, you’ve listened. Now, how is this going to change research and development within the FDA?” So it’s called the Critical Path Institute meeting. So we’re looking at doing that.
And there have been some groups that have hosted these meetings who have used their Voice of the Patient report to begin to talk to payers, insurance providers, about what is a meaningful treatment, right? So in LGS, the biggest issues we’re dealing with are obviously seizures, but it’s injuries, its hospitalizations, its frequent rescue medicine use, going to the ER. And if there was a medicine that maybe, maybe it didn’t drop seizures by 50%, but it kept families out of the hospital or kept kids from busting their faces open, our families would see that as value-added, because who wants to go to the hospital? Nobody. Nobody.
Ms. Kris Pierce: Right.
Tracy Dixon-Salazar: And the same thing with rescue meds, if we can reduce, you know, our families are using rescue meds weekly and monthly, and my daughter was getting it two to three times a week at her worst point, and that has gone on for years. They work acutely, but not in the long term. So, if we can reduce rescue med use, you know, because she would be out for hours after that, that’s value-added, but maybe it didn’t decrease seizures by 50%, which seems to be the standard that everybody, you know, running around with.
For us in LGS, if your child is having 300 seizures a day and you drop those down to 150, it’s great, but I’m not really sure that quality of life changed. And so, how can we have conversations with payers about what really does change quality of life?
Ms. Kris Pierce: Yes. And also working, you know, as we’re moving into clinical trials in SCN2A, it’s having that voice within the industry and the biotech companies that are developing these treatments, like what are the endpoints that families and people affected by these genetic conditions or syndromes, like what are the endpoints that they want? Sure we want a cause but what are the steps in between that would make a difference to families? It’s really important to have that voice and we continue to press on to make sure that’s heard. Is there anything else that you want to share with the community about LGS, where you’re heading, the next steps, in terms of what you’re doing?
Tracy Dixon-Salazar: So you know, LGS Foundation is going to just keep pressing on, really trying to unite the community where we can work together. And then, you know, fiercely dividing where we need to, the science of SCNA is very different than the science of you know, in the other genes and the science even of slow spike-and-wave in two to five-year-olds. And so, I think we still need to be pursuing those fronts individually, but we can collaborate.
I just would say to families that are out there that I didn’t have a lot of hope as a young mom, you know about the future, really for my first about 12 or 13 years in the epilepsy space, we did the same thing the same way and expected different results, and I didn’t understand it. And slowly things started to change, the genomic revolution obviously has brought a lot of hope, the interest of companies coming in and creating specific therapies, you know, I think is really, really helpful.
I mean, Batten’s disease now has a treatment that can really help these kids to live longer. Batten’s disease for CLN2, to used to be a death sentence. And now these kids, you know, especially if you intervene early to make a huge difference. So it’s a time of hope. And I don’t think we have that. It’s also a time when there’s a lot of work to be done still. So anything you can do to spread the word, it’s going to take all of us pushing, talking about the severe epilepsy is talking about gene-specific therapies, talking about the help that we need. And so, everyone who has a story, if you’re comfortable talking about it – I tell everyone that will listen to me, poor people that sit next to me on airplanes have to hear the whole story, but we just need to educate. So that’s it, I would just say, keep fighting, don’t give up.
Ms. Kris Pierce: So Dave, what were your take homes from the interview with Tracy?
Dr. David Cunnington: I think one of the key things for me was really understanding that Lennox-Gastaut Syndrome is a clinical syndrome where you can get these disastrous things happen as a consequence of having severe epilepsy, but it’s not actually a genetic diagnosis. And those two things can occur in parallel, which has been a thing of confusion within the community where someone might say, for example, a child has SCN2A is a genetic disorder but also previously had a diagnosis before their gene diagnosis of Lennox-Gastaut Syndrome, you know, is one wrong or is the other wrong? No, in actual fact you can have both. You have SCN2A as the abnormal gene that makes you prone to getting epilepsy. And that epilepsy over time causes Lennox-Gastaut or results in Lennox-Gastaut Syndrome, which then becomes a problem in its own right. So I thought that was really well explained by Tracy and helped me really understand that.
Ms. Kris Pierce: Keep up with the latest updates by subscribing to this podcast. You can also get regular updates on SCN2A through SCN2A Australia’s Facebook or Twitter @SCN2AAustralia.
Dr. David Cunnington: Thanks a lot.
This podcast is not intended as a substitute for your own independent health professionals advice, diagnosis or treatment. Always seek the advice of your physician or other qualified health provider within your country or place of residency with any questions you may have regarding a medical condition.