Seizures and Study: One Mother’s Journey to Cure Lennox-Gastaut Syndrome

SAP Partner | <b>Lennox-Gastaut Syndrome Foundation</b>

How Tracy Dixon-Salazar, PhD, the executive director of the LGS Foundation, went from a new mother to a neuroscientist, and her decades-long quest to improve the lives of patients like her daughter, Savannah.

Many who make the decision to enter the medical science field are often driven by a desire to help others. Physicians take the Hippocratic Oath and swear to treat the ill and do no harm, and researchers are, many times, motivated by this desire to make key discoveries, both large and small. But for some, the compelling force for their career choice is influenced by a far more personal connection: family.

There are hundreds of stories of clinicians who treat patients and study diseases that have directly affected those they love. Losing a parent or sibling to a disease or being part of a loved one’s journey with it can provide a lifetime’s worth of motivation to change an outcome or improve quality of life for others dealing with the same condition. The emotions associated with that experience can be challenging to describe in words, and for some, like Tracy Dixon-Salazar, PhD, there are perhaps no words to accurately match those feelings. “I honestly was just kind of lost. It was devastating. There was nothing I could do,” she told NeurologyLive®.

Now, Dixon-Salazar is an accomplished neuroscientist and geneticist and patient advocate, who works as the executive director of the Lennox-Gastaut Syndrome (LGS) Foundation. Founded in 2008 by Christina SanInocencio, PhD, CPH, CNP, in just a few short years, the foundation has grown into a giant of the space, working in a variety of ways to improve the lives of patients with LGS, a rare epileptic encephalopathy that affects 0.1 to 0.28 per 100,000 individuals.1 Under the leadership of Dixon-Salazar and others, in 2021 alone, the foundation raised more than $60,000 at its annual Walk ‘n’ Wheel event.2

Although the vision for her life is clear now, in 1995, that may not have been the case. But, unbeknownst to her at the time, Dixon-Salazar was on the brink of a massive change that would alter her and her family’s path forever.

The First Seizure

At that time, she was 23 years old. A mother by the age of 19 with the birth of her son, Dixon-Salazar welcomed her daughter Savannah to the world at 21, and for a while, all was well. Her children were healthy, and the family was making things work. But one night, Dixon-Salazar and her husband awoke to the sounds of choking coming from 2-year-old Savannah’s room. When they entered, they realized she was experiencing a seizure. What had caused it was a mystery.

“She wasn't sick. We didn't have a family history, she didn't have any brain injury or head injury or anything like that—all of these things that might precipitate a seizure,” Dixon-Salazar explained to NeurologyLive®. “Then she had a couple of more seizures over the next few months, and then she went 6 months without having any seizures at all. And then, all of a sudden, when she was 3, the seizures came back, and she started having seizures every day, and she started having 6 different types of seizures. That's really when she began to fall behind in her development.”

“I had to sit by helplessly and watch her get subsequently more and more brain damage. I couldn't help her. Mommy is supposed to kiss it and make it better, right? Mommy is supposed to fix it. And I couldn’t.”
– Tracy Dixon-Salazar, PhD

LGS can result in varying degrees of cognitive dysfunction and delays in developmental milestones. Some children, like Savannah, can develop normally before the onset of seizures, but can experience psychomotor regression post onset.1 Additionally, as LGS-associated seizures are often treatment-resistant, intellectual impairment and learning problems experienced by those affected can worsen with time.3,4 Many children with LGS can develop behavioral problems that vary from hyperactivity and irritability to autistic symptoms and psychosis, and often, these patients require multiple medications.3-5

Savannah would not be diagnosed with LGS until the age of 5 years, spending 2 years of her life seeing doctors and trying a variety of medications and diets to control the seizures to no avail. In those years, the experience took its toll on the family. Dixon-Salazar was distraught, and after years of little improvement, exhausted.

“I had to sit by helplessly and watch her get subsequently more and more brain damage,” she said. “I couldn't help her. Mommy is supposed to kiss it and make it better, right? Mommy is supposed to fix it. And I couldn’t.”

Although her path forward was still unclear at that point, she would not sit idly as her child continued to worsen. By her own admission, Dixon-Salazar had struggled in high school, and with her and her husband needing to support a budding family, had foregone higher education. But she dug in her heels and forced herself to learn what she could. It began by reading science and research journal articles to better understand what was happening. This led her to enrolling in college courses—first with an English class to improve her reading comprehension, and then a science course to better understand the jargon and terminology. But what began as a quest to help her daughter slowly evolved into a love of neuroscience.

“I couldn't stop my kid’s seizures, but I could study. The more I learned about the brain, and the more I learned about developmental neuroscience, and the more I learned about genetics—all that pushed me to be a better mom to Savannah,” she explained. “And then, when I couldn't help her, that pushed me to be a better student. It became this sort of vicious cycle.”

The Long Road Ahead

The next decade was no easier, nor did life immediately improve once she enrolled in classes. In the late 1990s, access to information required far more time, resulting in trips to the library to check out books or log internet time in the computer lab. But school was not the only challenge that she would face on that long road that would follow. LGS is a rare condition, and although the Epilepsy Foundation existed then, its resources and community at the time were not geared toward those with rarer seizure conditions, focusing more on helping those with controlled seizures navigate their new world. Dixon-Salazar began volunteering with the organization, and while they appreciated the difficulty in balancing the ends of the epilepsy spectrum, she and her family did not see themselves reflected in the messaging.

For those like Savannah, who at this time was becoming progressively intellectually disabled and having hundreds of seizures a day, there was no community to rally around. “It had completely taken over our lives,” Dixon-Salazar explained.

“How do you tell people who are new to epilepsy, or people who are living with it, that it can be deadly, and it can cause brain damage—but don't be afraid to live your life? And then how do you tell people at the other end don't be afraid to live your life? That you could be Prince, or you could be Dostoevsky. You can live your full life, and you don't want to let epilepsy limit you. You can manage it,” she said. “How do you say that to people like me, who were sitting there on drug number 26?”

READ MORE: Improving Awareness and Diagnosis in Lennox-Gastaut Syndrome

Dixon-Salazar was driven by a desire to do something about their situation, but the challenges were piling up, and she found herself fighting the urge to drop out of school to help more at home. With all that was required of her and her husband, it took her 7 years to complete her bachelor’s degree. The pair would operate completely around Savannah’s schedule, barely seeing one another at times, with Dixon-Salazar attending school during the day and spending late nights studying, helping with her tasks around the house, and doing her part caring for their children. Life was chaotic for the family, and things did not improve much for Savannah over these years, either. At this point, she was experiencing up to 300 seizures per month, sleeping 18 hours daily, and functioning at about a 2- to-3-year-old level.

“Up until my second year of postdoctoral work, she was having seizures every day. They were completely unpredictable. I counted every seizure and graphed it, and there was no pattern that you could see,” Dixon-Salazar explained. “All the medicines that we tried from the time she was 3 years old to the time she was 18 years old failed. We tried drugs, diets, devices, and even some alternative therapies. Nothing worked.”

“She was on 7 medications, plus a vagus nerve stimulator [VNS], plus a diet, and every week, 2 to 4 times per week, she would get Diastat, so rectal rescue medicine, to stop seizures that wouldn’t stop on their own. She was going into basically nonconvulsive status epilepticus 2 to 4 times per week, and that had been going on for a decade. She had no quality of life, really,” she said.

Finding Direction in Genetics

Things began to shift once Dixon-Salazar was accepted to graduate programs. Once on the brink of giving up on a future in science, she was accepted to every program she applied to in the San Diego area, and although Savannah’s seizures were becoming more severe as she entered puberty and years of the family struggling to stay afloat, Dixon-Salazar began to see a path forward in graduate school, studying developmental neurophysiology.

“At that point, I really did think that I had something to contribute to the field. That I could help. I was learning all about developmental neuroscience and then I came into genetics. For me, the motivating factor was getting into the program and thinking that I had something to contribute,” she explained.

It was then, in her 3 years of postdoctoral work in the genetics lab, that she had her breakthrough moment. Exome sequencing technology had become commercially available, but was still in its infancy, with the earliest works having been published just a few years prior. In the lab, Dixon-Salazar was running captured exome data into throughput sequencers. In her second year doing so, the lab’s principal investigator offered to sequence Savannah, who was now 18 years old. Originally apprehensive to the idea out of fear of overstepping her role and putting her grief into the spotlight, she agreed.

“We sequenced her, and I analyzed her data, and didn’t find a single thing. But I kept analyzing the data in different ways until I ultimately discovered that she's got 7 mutations in L-type calcium channel genes,” Dixon-Salazar explained. “We didn't know about de novo mutations back then. When we were sequencing, we were sequencing families who had a family history. So sequencing Savannah in our lab was really unusual because she was de novo. She was a sporadic case with no family history. But she had this really high mutation load, and she had a bunch of mutations in calcium channels. That led me to do a little more research, which led me to a drug that we actually had already on the market that's used for high blood pressure and that specifically targets L-type calcium channels.”

This breakthrough led to a trip to the physician’s office, where Dixon-Salazar suggested they try Savannah on the drug, verapamil, as they were essentially out of options. Although somewhat apprehensive at first because of a limited understanding of the genetics involved, Savannah’s physician was familiar with the calcium channel blocker, and the pair decided to try it.

“I never got into this thinking I would help someone. I didn't have that much self-confidence. But accidentally, I did end up helping her, and dramatically. Within two weeks of going on this drug, she had a 95% reduction in her seizures, and she stopped going into status. After 16 years of hell,” Dixon-Salazar said. But even this came with its challenges. Behavioral problems are common among patients with LGS, and once the seizures were controlled, the dynamic between mother and daughter shifted drastically.

“I had a 2-year-old in an 18-year-old’s body, and I needed to now start offering discipline. That's one kind of behavior issue. But then there's the behavior issue where they go into these rages,” she explained. In adults, these fits can be extremely difficult for both patient and caregiver, and Dixon-Salazar noted that some adults have hurt their caregivers unintentionally. She explained it as if it were a subway line, describing diagnosis and treatment as the first 5 stops, and everything that comes after seizure control as the remaining stops on the map—and really, the bulk of the journey. “The rest of it is navigating the world with this really sick kid,” she said.

“Now it's been 10 years, and she's doing great. She's learning again, she's only on 4 medicines and the VNS is off. She's can walk, she can talk, she sleeps about 13 hours a day, and she's come off a bunch of medicines. She's not seizure-free, but she doesn't have seizures and sadness all the time like she used to,” Dixon-Salazar said.

Ultimately, the breakthrough that led to Savannah’s seizure control was a watershed moment for Dixon-Salazar. It opened the door to a future that likely never seemed possible after more than a decade of failed attempts to provide her daughter with some semblance of quality of life. This is when the seeds of the forthcoming work she would do were laid, and the budding interest in advocacy began to grow.

“To me, it was like, ‘Oh, my God, this broke open the hole.’ All the de novo mutations that came out of the early epileptic encephalopathies. In the lab, we're finding all of these genes, and I'm like, ‘Oh, my God, this is going to change everything. This is going to change the way we practice medicine. We’ve got to fund it; we’ve got to move it to medicine.’ So, I left the lab and started working in advocacy,” she explained.

Seeing the Future in Advocacy

Despite the large numbers of medical professionals deriving motivation for their work from a loved one, the long-held mantra in the field was that scientists should not study the disease they have a connection to. Dixon-Salazar heard similarly in her time as a postdoctoral researcher, being told that it would make it difficult for her to be objective in her work.

“I did all this research and I found that there are a lot of scientists who have studied their diseases or the disease of someone that they love,” she said. “The reality is that we're even more on the line to be objective because if we get it wrong, the consequences fall on our loved one, or ourselves. I had to go through several years of sort of that mentality before I was like, ‘Forget that, I’m going to do this.’”

In 2008, SanInocencio reached out to Dixon-Salazar and asked her to join the newly formed LGS Foundation. Originally joining as a member of the professional advisory board, she forewent working more directly with the organization, first spending 5 years with Cure Epilepsy which, in its role as the largest private funder of epilepsy research, gave her an opportunity to pursue the precision genetic medicine research that served as the first real step of progress in Savannah’s journey. As the technology was still new, funding for such research was a risk to investors, and thus otherwise difficult to secure.

“By the time I left Cure Epilepsy, the NIH is funding it, Obama's talked about it, and precision medicine is a thing and we're finding genes. Now, today there are 750 genes that are affiliated with epileptic encephalopathies. When I left there were like, 75. But none of this was getting to my community,” Dixon-Salazar said. All too familiar with the difficulties inherent in merely developing an LGS community, she saw this as an opportunity to enact change. She then joined the LGS Foundation full time as the director of research and strategy, helping to identify and push forward essential research. In 2020, she would be promoted to her current role as executive director.6

“I did all this research and I found that there are a lot of scientists who have studied their diseases or the disease of someone that they love. The reality is that we're even more on the line to be objective because if we get it wrong, the consequences fall on our loved one, or ourselves. I had to go through several years of sort of that mentality before I was like, ‘Forget that, I’m going to do this.’”

– Tracy Dixon-Salazar, PhD

After all of the years of struggling to find a path forward for her daughter and her family, Dixon-Salazar now had a purpose. The literature was showing the importance of identifying de novo mutation and the potential in developing precision-targeted therapy, but families in the LGS community were still not undergoing genetic testing. And thus, Dixon-Salazar had a new quest.

“My impetus that coming in was to educate our families about genetic sequencing and about the concept of precision medicine, making sure they get the testing. Initially, it was that nobody was getting it done. Then it was that if you're being seen at one of these 5 academic centers that actually do genetics, you're getting it done. Now, if you're being seen at really any of the major epilepsy centers, you get it,” she explained.

In recent years, this push has moved into the pediatric space, and according to Dixon-Salazar, the importance of genetic testing for early-onset, unexplained epilepsies has become apparent. For adults, though, it has remained difficult. “I still can't get my adults tested. I've completely failed on that front. It's been 10 years since Savannah had genetic testing, and I still have adults who kind of missed the genomic revolution, and insurance doesn't want to cover it, the families are tired and just don't want to do it. They're already fighting for just daily medications, so it's hard to fight for genetic testing.

“Adult neurologists are also a very different animal than pediatric neurologists. They were like, ‘It's not going to change the way I treat them anyway, so I don't need to know anything,’” she explained, noting that the work is ongoing to improve the partnership and communication of needs between the physician, research, and patient communities. In the past, physicians, she explained, often led these conversations and spoke for the patients. But, as Dixon-Salazar pointed out, they were often wrong about patients’ desires.

“We have been treating LGS the same exact way for the last 35 years, at least. We throw an antiseizure medicine at it, and we hope for the best. We don't learn from every patient. Honestly, if it weren't for patients today pushing for change, I just don't think doctors would change it because they look at the LGS diagnosis as being this utterly devastating, horrible thing—and it is. But it doesn't have to continue to be that way for another 35 years,” she said.

Answering the Big Questions

Although challenges still remain to be addressed in LGS, Dixon-Salazar is no stranger to facing a challenge. Savannah’s road has been long and arduous, but her life has improved.

Similarly, the field of LGS treatment has seen rapid advances in the last several years. In 2018, the FDA approved cannabidiol oral solution (Epidiolex; GW Pharmaceuticals) for the treatment of seizures associated with LGS based on successful phase 3 data,7 and an oral formulation of clobazam (Sympazan; Aquestive Therapeutics) as an adjunctive treatment.8 In more recent years, novel approaches have made their way through the prospective pipeline, with agents such as ganaxolone (Ztalmy; Marinus Pharmaceuticals), fenfluramine (Fintepla; Zogenix), and perampanel (Fycompa; Eisai) all showing promise in studies of LGS,9-11 with fenfluramine recently winning approval by the FDA this month for LGS.12

But for Dixon-Salazar, the therapeutic progress is only one part of the equation. Answering the big questions about causation has always been front of mind for her. Translating that information into education for the LGS community helped to achieve that goal for a time, but it always came back to the big question: Why?

“LGS is a really hard disease to understand. It's almost like metastasis of epilepsy when epilepsy spreads or takes over developments. It’s a network disease. Only about 50% of cases of LGS are genetic. The other 50% of acquired, so it's a lack of oxygen at birth, stroke at birth, or some sort of early life brain injury that then leads to seizures," she said. "Pretty much anything that can lead to seizures can lead to LGS. But there's no home run etiology. There's no home run gene.”

Education has always played an enormous role in her work as an advocate. And while she provides this to families in the community, the buck does not stop there. Educating doctors and researchers and advocating the FDA have been major focuses. Educating the industry players has also been essential to improving the therapeutic landscape. Educating these other stakeholders to improve the overall state of advocacy and to advocate on behalf of patients is crucial for Dixon-Salazar, as well. The families can only take things so far, let alone be expected to carry the torch by themselves.

“The only reason I could advocate was because I'd been paroled from LGS prison. Before, I wasn't going to advocate because I was exhausted,” she explained. “Most of our families are just devastated. Brain injuries, hospitalizations, comas, seizures. For 16 years, we sheltered in place before sheltering in place was a thing like it’s been with COVID. That's what our families do. Our worlds just get smaller, and smaller, and smaller, and smaller because the disease is just so severe that it impacts every aspect of daily life.”

WATCH NOW: Collaboration and Communication While Treating Patients With Dravet and Lennox-Gastaut Syndromes

In the last few years, the evolution of LGS has become better understood, at least from Dixon-Salazar’s perspective. Despite the variance in the incidence of LGS, intervention points have been identified, particularly because of the ability to identify tubers in utero. In vitro fertilization serves as the first intervention point, early genetic therapy as the second, postbirth EEG pattern identification as the third, and infantile spasms as the fourth.

“Even though we have all that, 40% of the tuberous sclerosis babies are going to evolve into LGS. There's another window. You’ll hear physicians say, ‘They look like they're going LGS.’ How do we quantify that and do a prevention trial there? Then, when you get to LGS, that's yet another intervention point,” Dixon-Salazar said. “There's actually some great research coming out of Australia that shows that the slow spike in wave and the GPFA from LGS come from very specific nuclei in the brain. It's a network, so it starts in the cortex, and then that signals down to specific nuclei in the brainstem and the pons, which signals back up then to the thalamus and specific nuclei. You get this self-sustaining network.”

“I spend a lot of time trying to convince neuroscientists, doctors, and neurologists that this is a network disease, and we need to attack it as such at each of these possible intervention and prevention points, systematically,” she added.

For the future, Dixon-Salazar is still concentrated on solving the puzzle and answering that big question. The focus now, she explained to NeurologyLive®, is on enacting change at those intervention points across the trajectory and development of LGS. Prevention is key, but identification of those at-risk can help to improve that prevention before cases evolve into LGS.

As the disease impacts a network within the brain, it is unlikely that just one drug will solve the whole problem. But she postulated that perhaps a cocktail that targets the different parts of the network will help to achieve that goal. It is understood that the condition is reversible. Seizure freedom is an attainable goal for those in LGS and taking the steps to address the problem when those intervention points occur is essential to the process, she said.

“We know LGS is reversible, and we believe LGS is preventable. If you cure the tuberous sclerosis baby, there would be less LGS,” she said. “And you have a short time window to reverse it and to change it. Figuring out how can we do that really early is important. Then, for kids like mine who are 18 years old, that hope is not all lost. You may still find something. Knowing your etiology, and never giving up, is really important. That's really become my life's work now.”

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6. Lennox-Gastaut Syndrome (LGS) Foundation Announces New Executive Director. LGS Foundation. December 3, 2020. Accessed March 25, 2022. https://www.prnewswire.com/news-releases/lennox-gastaut-syndrome-lgs-foundation-announces-new-executive-director-301185551.html
7. Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox—Gastaut Syndrome. N Engl J Med. 2018;378:1888-1897. doi:10.1056/NEJMoa1714631
8. Aquestive Therapeutics Announces U.S. Food and Drug Administration (FDA) Approval for SYMPAZAN™ (clobazam) Oral Film. News release. Aquestive Therapeutics. November 2, 2018. Accessed March 22, 2022. prnewswire.com/news-releases/aquestive-therapeutics-announces-us-food-and-drug-administration-fda-approval-for-sympazan-clobazam-oral-film-300742913.html
9. Miller I, Nocera R, Aimetti A, Rybak E. Ganaxolone treatment in patients with CDKL5 deficiency disorder with comorbid Lennox-Gastaut syndrome: A post hoc analysis from the Marigold study. Presented at AES 2021; December 3-7, 2021; Chicago, IL and Virtual. Abstract 2.098.
10. Knupp K, Sullivan J, Nickels K, et al. Efficacy and safety of fintepla (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized, double-blind, placebo-controlled clinical trial. Presented at AES 2020 Annual Meeting; December 4–8, 2020. Abstract 852.
11. Bonnani P, Di Bonaventura C, D’Souza W, et al. Perampanel for treatment of patients with Lennox-Gastaut syndrome in clinical practice. Presented at AES 2021; December 3-7, 2021; Chicago, IL and Virtual. Abstract 2.107.
12. 1. FINTEPLA® (fenfluramine) Oral Solution Now FDA Approved for Treatment of Seizures Associated with Lennox-Gastaut Syndrome (LGS). News release. UCB. March 28, 2022. Accessed March 28, 2022. https://finance.yahoo.com/news/fintepla-fenfluramine-oral-solution-now-050000058.html