Developmental and epileptic encephalopathies: Managing more than seizures - Dr. Scott Demarest

Besides seizures, people with developmental and epileptic encephalopathies experience a wide variety of symptoms, including sleep problems, vision problems, and behavioral issues. Dr. Scott Demarest discusses how neurologists may be able to address some of these, improving outcomes and quality of life.

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

Let us know how we're doing: podcast@ilae.org.

The International League Against Epilepsy is the world's preeminent association of health professionals and scientists, working toward a world where no person's life is limited by epilepsy. Visit us on Facebook, X (Twitter), Instagram, and LinkedIn.

Transcript

[00:00:08] Dr. Scott Demarest: My name is Scott Demarest. I'm a pediatric neurologist and epileptologist, and I focus both my clinical practice and my research on genetic causes of early life epilepsy and often developmental and epileptic encephalopathies.

In addition to my research role, I am also the clinical director for precision medicine at our hospital, which is in Colorado. I'm at Children's Hospital, Colorado and the University of Colorado as faculty. 

[00:00:37] ILAE: Thanks. Today we're here to talk about outcomes other than seizures in developmental and epileptic encephalopathies.

If you could start by explaining for listeners who might not be familiar with them, what DEEs are—I'm just going to shorten it because it's very long—what they are, and maybe give us a few examples of the more common ones. Although, as I understand, they're all quite rare. 

[00:01:09] Dr. Scott Demarest: So developmental and epileptic encephalopathies are a term that has been introduced within the last decade by ILE Terminology Task Force to help to understand the intersection between developmental challenges and epilepsy.

And there's two components to the terminology. One is the developmental encephalopathy, which is to say that you have an individual who has abnormal development or developmental challenges. It's not a particularly specific term necessarily, but just that there is some deviation from typical development.

And that could be due to a variety of causes, but then you overlay on top of that this concept of epileptic encephalopathy. And for that, the theory behind it is that the seizures themselves or the epileptic activity within the brain is contributing to worsen development or neurologic function in some way.

And so you have both a developmental component over time, due to whatever the underlying etiology is, but you also have a contribution to worsening brain function due to the epilepsy itself. And so therefore you have this developmental and epileptic encephalopathy. 

I think what's interesting though is that in clinical practice, it is really difficult to actually distinguish between those two components: How much is coming from the underlying etiology impacting development and how much is coming from the epilepsy or the epileptic activity that is worsening function. So, in many cases, from a practical standpoint, we have to classify something as a developmental and epileptic encephalopathy because we presume that there are contributions from both of those phenomena, though that may be difficult to actually prove.

And I guess the last thing I would say about it is that that can come from a variety of etiologies. My interest is heavily within genetic causes of epilepsy, and certainly there are many neurogenetic conditions that either have a strong component of epilepsy or have a higher risk than normal for epilepsy. And that is often overlaid with a developmental component and often with numerous other neurologic challenges that I think we'll discuss further. But there are also, you can have a developmental and epileptic encephalopathy due to an acquired injury, infection, trauma, et cetera, as well. So these are not isolated to genetic etiologies. 

Common forms of DEEs would include things like Lennox-Gastaut Syndrome, we could see infantile spasms. And we know for both of those as syndromes that they can have a wide variety of etiologies that may be underpinning them, including both acquired and genetic etiologies.

In other cases, there may be things that we would think about that would be purely genetic and etiology or defined by their genetics. Things like SCN1A-related epilepsy, with a heavy overlap with Dravet syndrome. You could think about KCNQ2 and numerous other genes. And you're right that those individually are generally quite rare, with the most frequent single gene disorders causing epilepsy probably having an incidence in about 1 in 15,000 or 1 in 20, 000 per live birth sort of range and going down to, you know, a handful of patients in the world sort of incidence. 

And so you see this wide range of rare conditions, but collectively they're actually quite common and contribute significantly to the underpinning etiologies for epilepsy throughout the lifespan.

[00:05:06] ILAE: Got it. Thank you. Thinking from the perspective of an epileptologist, clearly, their main focus is going to be in someone with a DEE, how to control the seizures. I don't know if you want to speak to seizure control frequency, how often that's possible or not. But what I was hoping we could get at in this talk is what are some of the other drivers of quality of life in both people with DEEs and their families, and how can neurologists, epileptologists address those.

[00:05:42] Dr. Scott Demarest: Sure. I think to your first point I would never want to encourage us to not try to treat and pay attention to epilepsy certainly.

Within the DEEs, uncontrolled epilepsy is a driver of morbidity and potentially of mortality, and it is something we need to take seriously. I think to your point it's not always possible to achieve seizure freedom for many of these etiologies. We know from longitudinal data from esteemed investigators like Dr. Ann Berg that there are many patients who never achieve seizure freedom and have lifelong epilepsy, and that's probably in around the 10 percent range of all epilepsies. And then we also know that there is a group of patients that have sort of a relapsing, remitting course of epilepsy, that we can achieve seizure freedom for a period of time or we can get a relatively good control, but then we'll have additional bouts where it is uncontrolled. 

And I think the majority of DEEs tend to fall into those two categories, where it's either very difficult to control completely or that we have periods of control, but it never fully comes under control, and we often have a hard time to get off of medications.

That is not universally true. There are certain examples—epileptic infantile spasms as an example that we alluded to earlier—where we may be able to treat and be able to address the infantile spasms and then not continue to need medications throughout life. But those tend to be a little bit more of the exception within the DEE group.

So we should always try to reduce the amount of seizures. And I think it's important to think about this with a strong goal-setting priority with families. And so if we're not thinking about this from the perspective in a particular patient that we think seizure freedom is likely, then how do we reduce the morbidity of epilepsy as our primary goal?

And that may mean we want to focus on trying to reduce the impact of long seizures. Or we want to avoid status as something that is most disruptive. But maybe we tolerate smaller seizures that have less impact on day-to-day activities or quality of life. And I think that comes from a discussion with families around prioritization.

 The other aspect to that is really making sure that we have clear and open communication with families when we're thinking through how do we choose what we're focusing on from a seizure perspective, and take into account the side effects of medications and treatments. If we are trying so hard to stop seizures that we are also reducing the ability to function, to be alert and attentive to the environment because they're on so many medications, then that may not be an appropriate tradeoff for our patients. And that's an aspect we need to consider along with families. 

I think there's also then thinking about non-epilepsy treatment, as you alluded to. And so this could be thought about in domains of neurologic challenges. So we could think about sleep challenges, challenges in terms of mobility, activities of daily living. We can think about this in terms of other aspects of quality of life, behavioral challenges, or even things like cortical visual impairment or vision challenges that may impact quality of life and overall functioning in individuals with DEEs.

And really all of these different aspects are things that we should think about and consider with within the DEEs. 

The unifying factor in my mind for DEEs is that there is significant brain dysfunction, whether that is from an acquired ideology or genetic ideology. The whole brain has some sort of struggle, and that's why you often see both developmental challenges and significant epilepsy. But it is also why you see all of these other comorbid aspects of disease, because if you can think of some aspect of brain function, it is also possible for that to be dysfunctional in the case of a DEE and should be looked for and attempted to mitigate, adapt for, or in some way address as part of clinical care.

And if it's appropriate, I'm happy to go through sort of how do we approach those different aspects, but I think we have to think about them all holistically. 

[00:10:32] ILAE: Yeah, I would love to hear maybe a couple of, I don't know, anecdotes or case studies having to do with maybe sleep and CVI, cortical visual impairment, behavior.

And also whether any of those, particularly I'm thinking about the sleep aspect, whether any of those would impact seizure frequency as well. 

[00:10:53] Dr. Scott Demarest: Yeah, so I think those are great examples. And I'll speak anecdotally to my own personal treatment experience.

I've had numerous patients with DEEs who have very, very difficult-to-treat epilepsy. And if I'm being completely honest with this community, I'm not entirely sure that my treatment choices were making much of a difference on their seizures. 

However, they also had dysregulated sleep. Their brain just didn't regulate sleep function very well. They would often have all-night parties and stay awake and they weren't necessarily upset, but they were very disruptive to family life and family function. And they would, in some cases, then have daytime sleepiness where they were not participating in their daily activities, because they were sleepy. 

There are several both behavioral, but also medication approaches that one can take to try to help to regulate sleep in those types of individuals. And when implementing those, I felt like that had a bigger impact on overall quality of life than any of my seizure treatments actually did.

Various treatments that have been utilized for this are not different than what they might be for other pediatric sleep conditions. So I'm speaking about this from a pediatric perspective, where we don't tend to use as many of the traditional sleep medications that have been approved. But we tend to think about things like clonidine, we tend to think about trazodone, gabapentin. As things that are relatively gentle, generally not habit forming, pretty safe, even in a pediatric population, that can help with sleep. We often will try things like melatonin for initiation of sleep, but that may not help maintain sleep through the night. 

I don't tend to say that this is something that I have the perfect algorithm on, and I've had to do a little bit of trial and error myself to kind of figure out what works for particular patients. But I have found that it can be highly impactful for families in terms of helping them to get on a better, more secure sleep routine with more sleep at night for both the families and the patients, and less daytime sleepiness. 

It is not uncommon for that to result in some improvement in seizure control. That's not necessarily the reason for doing it, because the sleep itself is dysfunctional and disruptive enough to deserve treatment. But it definitely doesn't make epilepsy worse to have well-regulated sleep, which is not surprising to anybody in this audience. 

Thinking about some of those other aspects. Behavior, certainly not one of my areas of expertise in terms of medical management of behavior, but what I would say is that it can be absolutely as impactful as seizures or more so, and for some individuals we are able to actually achieve seizure control with medications and other treatments, and they're doing pretty well from a seizure standpoint, but behavior is highly disruptive to those individuals.

Behavioral challenges are a manifestation of encephalopathy. They are a manifestation of brain dysfunction. And so when we see disruptive behaviors, extreme inattentiveness or impulsiveness that can be dangerous to individuals themselves or to those around them, when we see screaming, hitting, this is extreme behavior that really becomes the focal point of the morbidity for that individual in that family, rather than their seizures in many cases. 

And so we need to have a team approach that can help address that. I collaborate at my institution with developmental pediatricians with psychiatrists and other behavioral health specialists who are able to provide the appropriate support to those individuals when it's beyond what I can handle myself.

And then finally cortical visual impairment, which is a passion of mine and I love to be able to talk about. I think this is a highly underdiagnosed aspect of DEEs as a whole, as well as sort of neurologic disorders more broadly. 

A significant portion of our brain volume goes into the interpretation of visual signals. And if we have a whole brain disorder that affects multiple types of neurologic function, it stands to reason that we would also have an impact on visual interpretation. So, to provide simple definitions, Cortical visual impairment also sometimes referred to as cerebral visual impairment, depending on which side of the pond you're on. Our European colleagues prefer cerebral visual impairment. And I see their point and it doesn't have to be a cortical-based dysfunction. But to avoid the controversy, I'll refer to it as CVI from now on. 

So CVI is essentially that there is some functional visual impairment that is demonstrable in that individual that is not adequately explained by ocular findings. So if an ophthalmologist looks in their eyes and they don't have cataracts or retinal disease or, or other explanations for their visual impairment, or their visual function is disproportionately impacted to what the findings are in their eyes, then that suggests that there is some other cause for their visual impairment, which is either that there is some inability to get signals to the brain or inability of the brain to interpret those signals. And we often see, particularly within genetic causes of epilepsy, but also with many structural ideologies that may impact the occipital regions that there can be impairment in our ability to interpret visual signals.

How do you diagnose that? So I think fundamentally based on the definition, you have to have somebody have a really good look in the eyes. And if you as a neurologist aren't comfortable with that, then an ophthalmologist is appropriate. And then you have to do a visual assessment. For us in clinic that involves looking at optokinetic nystagmus, which can be done in very young individuals, even down to babies. It is assessment of basic function, like tracking and fixing on objects. Does an individual look at what they are interacting with when they reach or grab for something or are manipulating it? Or are they sort of looking away and groping for objects? Is there concern around tripping or, or struggling with steps or transitions for those individuals who are mobile and able to walk around?

That can be a little bit confusing with inattentiveness and ADHD symptoms. So you have to be a little bit careful about that, but it can be a sign that there is some visual impairment or reduced interest in attentiveness to certain visual fields. 

And I think what's important with visual impairment is it's not all or nothing. It is not blindness. They do see, they just don't see as well as other individuals and they may see better with certain colors or high contrast situations, or they may see better in certain visual fields than in other visual fields. And so it does require some relatively thorough assessment of vision, but it's all things that can be done as part of a basic neurologic exam and easily performed in the clinic. And if there is not a better explanation from ocular findings, then it's appropriate to provide a diagnosis of CVI. 

The next question then is, what does that mean? And what do you do about that? And really, that's around adaptive strategies. So certainly when thinking about what is the psychoeducational circumstances for that individual, what types of therapies are they involved in? We want to think about this in terms of setting individuals up for success around how they're interacting with their visual environment. So if we know that they have some amount of visual impairment, we need to try to figure out: What do they see well, are there certain colors that they like better, do we need to provide larger objects for visual interaction? Do we need to provide high contrast: bright colors on a dark background rather than light colors on a light background? Allow that individual to learn and grow and maximize their potential. 

We're doing it in a way that sets them up for success from a visual standpoint, rather than providing them with new associations to learn with a communication device, for example, where they're actually not even seeing what they're supposed to build an association with.

That's a trial-and-error process, but I've found that even by providing that diagnosis and cluing in a therapy team that they need to watch for that they're able to be creative about making adaptations for that. And increasingly, there are also resources available on the Internet to sort of guide therapists around how to adapt for individuals with visual impairment. 

[00:20:04] ILAE: Would that be something that you screen for, or is it something that a family brings to your attention or how are you generally alerted to it? 

[00:20:15] Dr. Scott Demarest: Within my genetic epilepsy clinic, I screen all patients for it. It is part of my standard exam and across a variety of DEEs I've seen that the incidence may be as high as 80% or 90% of populations have cortical visual impairment in something like CDKL5 deficiency disorder. And I've seen it down probably in the single digits for other disorders like SLC6A1, with many disorders having something in the middle: 50, 60 percent of individuals may have some visual impairment that we can identify based on a clinical exam alone. Again, in the context of them also having had an ophthalmologic exam to ensure that there are not other explanations.

It's interesting because some families will say, “Oh, I've always been worried about their vision and that I feel like they don't see well,” and other families say, “Well, I've always been told they see fine because they had an eye exam and the eye exam was normal.”

But the eye exam didn't do a functional assessment of how they visually interact with their environment, which is what I provide as part of my screening test. And so some families, as you start to describe what CVI is, if you feel that their child has it, they kind of go, “Oh, yeah, no, that is definitely them. They do that. They grope for objects. They don't look at what they're trying to interact with. They struggle with stairs and they grope with their foot going down the stairs rather than looking down and making the step.” And so it tends to click for some families once you start to discuss it. 

[00:21:50] ILAE: So are there any unique outcomes other than seizures that could be addressed in older, like teenagers or young adults or older adults with that maybe aren't applicable to younger children? 

[00:22:05] Dr. Scott Demarest: I certainly think that the challenges that individuals with DEEs face changes throughout their life course. We're increasingly learning that actually the epilepsy natural history changes throughout the lifespan for many of these individuals, some of whom may have much more severe seizures in early ages that tend to get better as they get older. We could point to the example of STXBP1 in that category, but other ones tend to get worse and worse as they get older and are really tough to deal with in their teen years. And we could point to something like MECP2 duplication syndrome as an example in that category. And so that type of information is certainly helpful. 

But we also see that the comorbidities evolve throughout the lifespan. And we could point to something like mobility as an example of something that we have to address differently across the lifespan.

So many individuals with DEEs when they are young have hypotonia, and in some cases it can be pretty severe hypotonia. That hypotonia tends to improve as they get older, so the tone increases some. But in some cases, they actually flip over to being hypertonic and spastic as they get older. And now an individual who was hypotonic throughout their life needs medications for their high tone as they become teens and adults.

You can look at individuals with Dravet who have had—there’s a thorough description in the literature of their crouched gait that occurs as they get older. And some patients even seem to have sort of Parkinsonian-type features where they have increasing challenges with mobility, even if they're ambulatory, they have smaller steps, they may have pausing or struggling with fidelity of movement.

And so those challenges are ones that we have to be prepared to support as they get older and as those challenges change from one of being hypotonic to being hypertonic as well as other related challenges. You could think about scoliosis as being something that has a relatively high incidence in this population and needs to be monitored for. That isn't so much of a problem in babies, but certainly can be problematic as you get into your teen years and adulthood.

[00:24:33] ILAE: So my last question is just about what is not known about DEEs and what you would most like to have revealed to you, if you could. What areas of research do you think show the most promise or what areas would you like to know more about in order to advance the field?

[00:24:55] Dr. Scott Demarest: What's really critical for a richer understanding of the natural history and best treatment approaches in DEEs is that we have what I call quantitative phenotyping. And what I mean by that is much of the literature that currently exists is looking at these comorbidities and various neurologic features in binary terms. They have hypotonia or don't have hypotonia. They have developmental delay. Sometimes we describe it as mild, moderate or severe, but only in very rare cases do we actually have good neuropsychological testing where we can quantify by different domains what is their developmental trajectory like. 

We have a difficult time describing the severity of the sleep disruption, the severity of the visual impairment.

And I think if we really want to understand genotype phenotype correlation, if we really want to be ready for clinical trials that are headed our way rapidly, if we want to be able to guide care, we need to go beyond “They have it” or “They don't have it” as a symptom. We need to be able to quantify the impact of that symptom and the severity of that symptom.

And that requires us to start to adopt new tools and new assessments to measure non-epilepsy phenotypes in patients with DEEs. And that's really on us as providers to be able to bring that to our clinics, and that allows us to both say what is most impactful for this patient right now, and how can we address it.

But as we get increasingly novel therapeutics and precision approaches to epilepsy, it means that we can monitor the success of those treatments in categories other than seizures. So going beyond counting that seizures are reduced or that we've had less episodes of status or other metrics like that within the epilepsy realm, but that we can also say we feel confident that sleep has improved, that behavior challenges improve, that we are making better developmental strides than we otherwise would have expected to as a result of these therapies.

And that's critical, both within the clinical trial setting, but also, once drugs are approved by regulatory agencies and are part of clinical care, we need to know what's working and what's not working for our patients.

[00:27:33] ILAE: Thank you. Is there anything else you wanted to mention that we haven't discussed?

[00:27:38] Dr. Scott Demarest: We covered a wide range of topics that I think are really important for us to grapple with as a community. And I'm excited that there's attention being paid increasingly to what we often refer to as the comorbidities of epilepsy, which I think are really fundamental aspects of the disease that these individuals have and not so much some sort of sidelined phenotype or comorbidity. They are pivotal aspects of disease that directly impact quality of life, and we as neurologists and epileptologists have to take those into account.

[00:28:18] ILAE: Well, thank you so much for your time and for the discussion. 

[00:28:22] Dr. Scott Demarest: Thank you for the invitation and I appreciate being able to participate.