NeuroVoices: Scott Perry, MD, on the Intricacies and Value of Diagnosing Lennox-Gastaut Syndrome

Scott Perry, MD

Lennox-Gastaut syndrome (LGS) is a severe form of epilepsy with seizures that being in early childhood, usually between the ages of 2 and 5, and continue into adulthood. About 10% to 30% of children with LGS have a prior history of earlier onset epilepsy syndromes, such as West syndrome or Ohtahara Syndrome. Children with LGS experience several different types of drug-resistant seizures, including tonic seizures, atonic seizures, atypical absence seizures, myoclonic seizures, and generalized tonic-clonic seizures.

The appearance of multiple types of seizures in early childhood, particularly a combination of tonic, atonic, and atypical absence seizures, is a key diagnostic indicator of LGS. Additionally, the presence of developmental delays, cognitive impairments, or behavioral problems may aid in the diagnosis. Research has also shown some genetic connection, as pathogenic variants in CDKL5, DNM1, STXBP1, or SCN2A may cause LGS. In a small percentage of children with LGS, larger pieces of DNA are missing or extra that affect multiple genes.

Despite some of the challenges, receiving an accurate LGS diagnosis is imperative for patients, as it opens the door for available therapies specific to the condition, like cannabidiol (CBD; Epidiolex) and fenfluramine (Fintepla; UCB Pharma). In addition, it gives patients the opportunity to enroll in clinical trials for drugs that may have a direct impact on patient quality of life, says Scott Perry, MD. Perry, head of neurosciences at the Jane and John Justin Neurosciences Center of Cook Children’s Medical Center, sat down with NeurologyLive^® as part of an iteration of NeuroVoices to discuss the importance of accurate LGS diagnosis and the downstream impacts inaccurate diagnosis can cause for patients.

Perry, who also serves as the medical director of the Genetic Epilepsy Clinic, gave thoughts on the reasons why LGS goes undiagnosed at times and the complexities with seeing multiple seizure types at once. Furthermore, he spoke on the ways clinicians can recognize potential LGS cases early, as well as some of the emerging science from a drug development standpoint.

NeurologyLive: What does an accurate description of an LGS diagnosis entail?

Scott Perry, MD: LGS has clinical criteria for it that were recently revised. [To have LGS] you have to have multiple seizure types. And essentially, every seizure type can almost can occur in Lennox-Gastaut syndrome, tonic seizures being one of the more prominent types you usually see. But also atypical absence, generalized tonic clonic seizures, etc. You need certain EEG characteristics. Generalized slow spike wave, as well as generalized paroxysmal fast frequency are the two types of waveforms that will be seen on an EEG. And then you need some amount of intellectual cognitive developmental impairment. Those are the criteria but the problem is that those things aren't always there at the same time, and there's where in lies the problem. Those may come over time. If the clinician doesn't ask the questions, or the person doesn't review back to the records, and maybe an EEG wasn't done during the time that maybe one of those patterns is present, it sometimes makes it difficult for people to feel like they've got the information to make the diagnosis, which can be a problem.

Has there been challenges with the diagnosis of LGS? Are clinicians hesitant to make the diagnosis?

I guess I think one part of it is people sometimes don't want to use the word or just don't want to give the diagnosis of Lennox-Gastaut syndrome. Why? Well, because the person who just got the diagnosis will go Google it, the family will Google it, whatever, and you’ll see a lot of information. For some, I think that's a fear of giving that diagnosis.

I think that for some, again, it’s because they don't have all the components, or at least they're not aware that they had all the components now some of that information is there. If you have an older person, it's sometimes harder, to go back and get the history of seizures, but you can get a feel that they had multiple seizure types, so that part is not too hard. The EEG becomes a little harder, because if they don't have all the EEG components, you might be a little hesitant. The generalized paroxysmal fast frequency tends to persist into adulthood. That's something you can definitely look for to make people feel more comfortable. I think those are probably the two main reasons.

I think a third reason maybe you don't see it [diagnosing LGS] as much is because the etiology of Lennox-Gastaut is varied. There could be lots of reasons to have Lennox-Gastaut. For some people they come in and say they have drug resistant epilepsy, they get a workup, maybe they have genetic testing, and we've identified some gene that causes their epilepsy. Then they get the diagnosis of that gene epilepsy. Let's use Dravet (syndrome) or SCN1a as an example, because they potentially could present with Lennox-Gastaut syndrome. So they'll get the diagnosis of Dravet Syndrome, even though they may also meet criteria for Lennox Gaston syndrome, but then you don't use that word. That may be a reason for some as well.

Do you feel as though a lack of continued follow up can contribute to misdiagnosing LGS?

I don't know if it's that they don't do enough follow up. One thing I’ve always tried to do and especially when I don't have like an understanding of the diagnosis, almost every visit, you're revisiting from the beginning to the end. Because sometimes the story of epilepsy is told over many years, maybe decades, to see the whole story of an electroclinical syndrome. It's not going to be done in one meeting. It's always important to go back to details unless you have solidified the diagnosis. It’s always important to go back to details to try to look for that answer.

What are some of the downstream impacts of incorrect or unrecognized diagnosis of LGS?

The first thing that comes to mind is there are treatments that are specifically indicated for Lennox-Gastaut syndrome, meaning the studies were done in people with Lennox-Gastaut syndrome, not that the treatments may necessarily be specific to the mechanism. But if you don't have the diagnosis, maybe you're limiting the options of that patient, potentially, because they can't get approval for those drugs. I think probably one of the most important limitations of not getting the diagnosis is that those people are unable to connect with others that have the condition, they're unable to connect to advocacy organizations like the Lennox-Gastaut Syndrome Foundation, or other resources where they can get more information about their condition, they can get information about the breadth of treatments that are available. Because maybe they're not hearing about everything that's out there, they can hear about the clinical trials that are available for this condition.

So there's a big knowledge gap for them if they don't understand what they have. There's also a support gap if they are not connected with other people who share the same experiences as they do. I think the third thing that's important is that if you don't have the diagnosis, and we're not getting people with the diagnosis, then we're already limiting the population we can work with to try to get it the answer of why does it happen? Because that's a really big problem. Lennox-Gastaut is a defined entity, we know what it is from an electroclinical standpoint. But why do you get Lennox-Gastaut syndrome? Yes, there's lots of etiologies, but why do all those etiologies end at slow spike wave and an epileptic encephalopathy? There's something they have in common that brought them all to that point, and what is it? The more people we have correctly diagnosed with it, the more we have to choose from a data perspective try to answer those questions.

How can we continue to make LGS diagnosis easier for the clinical community going forward?

There are some like scales out there people can use to see if they meet certain clinical criteria and they give a predictive value to suggest this is a person [with LGS]. Frankly, I don't know that you need to use a scale if you got a person coming in who has drug-resistant epilepsy, of which tonic type seizures is one of those seizure types, and they have developmental delays. You should just logically be thinking this may be Lennox-Gastaut syndrome, begin to start to look at past EEG reports, as well as looking at a present EEG to see if that's there. If you don't necessarily have all that history, but you've got drug-resistant epilepsy and intellectual disability, ask the questions. Sometimes if you don't ask about certain seizure types, you don't show a person what that seizure looks like. Or if you describe it to them, then they're not going to know to tell you they don't necessarily know what it's called. You have to probe for that information. You have to be thinking about it. You don't just sign things off as well that's just drug resistant epilepsy. It's drug resistant epilepsy, which drug resistant epilepsy and why is it a drug resistant? What is the reason? You just have to ask some more questions.

On a general note, what are some of the emerging concepts in LGS care that may come into play in the coming years?

As an epileptic encephalopathy, it's one of the more common epileptic encephalopathies, but it's been shocking the relative paucity of people who have like dedicated their life to studying Lennox-Gastaut syndrome for such a common thing. We're seeing more people get interested in it, more people getting interested in that common pathway, that final common pathway that leads to slow spike wave. Some of the things we're going to see is a little better understanding of the connectivity of the brain, and maybe hotspots in the brain that lead us to this and may explain why certain etiologies end up this way.

We're seeing some exciting work in the world of neuromodulation, where we target the thalamus as kind of a central connection point to treat this low spike wave pattern and this epilepsy. I think we're seeing an increased interest from the community as a whole, both from providers and the patients, at tracking not just the seizure and natural history, but also all the comorbid conditions and symptoms that come with it. We’re also understanding more about the condition, understanding the sleep problems, understanding the behavior problems of these conditions, to get a true kind of natural history and better understanding of how to deal with it. I think there is a heightened awareness around it, I'm seeing a lot more people getting excited and thinking of it more from a from a research standpoint, and not just as a diagnosis.

Transcript edited for clarity. Click here for more iterations of NeuroVoices.