Joseph E. Sullivan, MD: 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.

Kelly Knupp, MD: 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.

Joseph E. Sullivan, MD: 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?

Kelly Knupp, MD: 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.

Joseph E. Sullivan, MD: 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.

Kelly Knupp, MD: 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.

Joseph E. Sullivan, MD: 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.

Tracy Dixon-Salazar, PhD: 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.

Joseph E. Sullivan, MD: 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.

Transcript Edited for Clarity