Sharp Waves: ILAE's epilepsy podcast
Sharp Waves: ILAE's epilepsy podcast
Dravet Syndrome: Dr. Ingrid Scheffer
Use Left/Right to seek, Home/End to jump to start or end. Hold shift to jump forward or backward.
The latest on Dravet syndrome: Diagnosis, genetic testing, comorbidities, treatment, and more. Dr. Parthvi Ravat interviews Dr. Ingrid Scheffer.
Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.
Let us know how we're doing: info@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, Instagram, and LinkedIn.
Dr. Parthvi Ravat: [00:00:00] Welcome to the podcast of the International League Against Epilepsy. I'm Parthvi, and today we are delving into one of the most influential papers in recent years, the International Consensus on Diagnosis and Management of Dravet Syndrome, published in Epilepsia in 2022. Joining me is Professor Ingrid Scheffer, an internationally renowned clinician scientist from the University of Melbourne and one of the key authors of this consensus. Professor, it's such a pleasure to have you with us today. Let's start with diagnosis. Can you tell us, how do we diagnose Dravet syndrome?
Dr. Ingrid Scheffer: A diagnosis of Dravet syndrome requires a high index of suspicion. So as soon as a baby comes along with their first seizure, often triggered by fever, anywhere between the age of six weeks and nine or 10 months. We know of quite a few patients now with onset after 12 months of age and they have a seizure that's more prolonged or even status [00:01:00] epilepticus, and that's defined as 30 minutes.
Then one should think, could this be Dravet syndrome? Their first seizure in about half the patients is a bilateral or generalized tonic-clonic seizure, and in about a third of patients it's hemiclonic. So if you see jerking down one side of the body, either one arm or an arm and a leg, you should automatically think of Dravet syndrome.
If they come along with a second seizure and it was on the right side on one occasion and on the left side on the other, you should absolutely have Dravet Syndrome up the top of your list. We found that 3% of babies never had seizures with fever. So the fever is not universal, but it's most of the patients.
And you can look for triggers. Has the baby been unwell? Have they had a fever, have they had a vaccination? And we know that vaccination will trigger the first seizure in a third of individuals. So it's [00:02:00] really around the seizure type. It typically occurs in babies of fairly normal development, and then they present with their first seizure.
And then you go from there. We are doing some studies now on the natural history that shows that their development may not be quite as normal as we thought, but essentially, they look like a normally developing infant.
Dr. Parthvi Ravat: So then the consensus made a clear point about vaccination for children diagnosed with Dravet. Can you elaborate a bit more about that?
Dr. Ingrid Scheffer: When we were starting to do the work on this, in the early 2000s, there was a condition called vaccine encephalopathy, and this is where a baby had had a vaccine and then presented with a prolonged seizure, their first seizure, typically, and the families had actually gone to the vaccine companies and sued them for what the vaccine had allegedly done to their baby's brain and the [00:03:00] babies, their development slowed or regressed, and they developed drug-resistant epilepsy. And in 2006 in Lancet Neurology, we showed that the vast majority of these babies actually had Dravet Syndrome.
They had an SCN1A pathogenic variant. And then we went on and did another study in Lancet Neurology in 2010 showing that a third of babies with Dravet syndrome actually are triggered, had their first seizure triggered by vaccines. So if a baby presents with a seizure after vaccination, you need to think, could this be Dravet syndrome? And you need to expedite molecular genetic testing, because if they do have a pathogenic variant in SCN1A, the gene encoding the alpha one subunit of the sodium channel, then you know this baby's very likely to have Dravet syndrome.
So this work on vaccination has led to a lot of caution around vaccinating these babies. And it [00:04:00] needs to be done with thought, but it definitely needs to be done. And the reason that we must vaccinate these babies, especially for influenza, is that influenza is associated with both morbidities and mortality in babies with Dravet syndrome. And we published a paper a couple of years ago now with Katherine Howell showing that there were quite a few babies that died. Following influenza A or B infection or children, not just babies, older children as well, they actually had very severe complications and actually got sicker with regression following influenza A or B. So vaccination is critical for individuals with Dravet syndrome, particularly influenza vaccination is even more important than COVID vaccination, but I would strongly recommend both.
So nowadays, we always recommend antipyretics to try and prevent fever prior to the vaccination and through [00:05:00] the first few days. Certainly in Melbourne, we have a very established protocol for children with Dravet syndrome to be admitted to the Royal Children's Hospital to have prophylaxis and monitoring with vaccination usually for 48 hours, but we know that their risk period can be longer than that, and we know it can depend on the vaccine.
If you're talking triple antigen, it's usually within the first 48 to 72 hours that you're at high risk of a seizure. If we're talking measles, a live attenuated viral vaccine, then we are talking day five to day 12. So you need to understand that. Now, we can't admit someone to hospital for 12 days, but the families need to know that their child is in a period of high risk. We have to be very careful though to impress upon families just how important vaccination is for children with Dravet syndrome. Much more important than for [00:06:00] your unaffected child.
Dr. Parthvi Ravat: Right. And do you recommend anti-seizure medications around that period?
Dr. Ingrid Scheffer: So, yes. The protocol that is done at the Royal Children's Hospital, and you can download that from the web actually, recommends extra cover with clobazam or clonazepam over that period and has been shown to make a difference.
Dr. Parthvi Ravat: Great. And then the consensus also reached a strong agreement about how comorbidities evolve, cognitive behavioral, gait, sleep, everything. So from your perspective, what are the most pressing, unmet needs when it comes to managing these comorbidities, especially how to engage with caregivers during those times?
Dr. Ingrid Scheffer: So, it's absolutely essential that both child and adult neurologists are aware of the myriad of morbidities that can occur and usually do occur in a child or adult with [00:07:00] Dravet syndrome.
Now, these morbidities differ according to the age of the child, so an infant and a toddler in addition to seizures will often show slowing of development, and that may not be identified unless you ask the parents and think about it carefully. If you have a diagnosis of Dravet syndrome, the child needs to be carefully monitored with ongoing speech, physio, OT, to make sure that these therapies are used in an early intervention sense as the child's development goes off.
So we have developmental slowing most commonly, but often regression with prolonged seizures or status epilepticus. And then we have intellectual disability. And don't forget, at the end of the day, around 40% of individuals have severe intellectual disability, about 20% moderate, about 20% mild, and just 5% or so are of normal intellect. So it's very [00:08:00] important to make sure you have supports in place to help their learning. So that's the first morbidity.
The second morbidity, very common in younger children, is sleep problems. We did a study some years ago showing that 75% of individuals with Dravet syndrome have sleep disturbances. And these sleep disturbances differ at different ages, so you have different types of sleep disruption. And you really need to identify the type of sleep disruption and then manage that appropriately. You know, could it be the need for melatonin? Could it be other types of sleep problems like obstructive sleep apnea?
Other morbidities very commonly can involve behavioral psychiatric morbidities. And these can include autism spectrum disorder, with around 40% of individuals with Dravet syndrome having a formal diagnosis of autism spectrum disorder. Other psychiatric morbidities include behavioral problems that often become more of an issue when the child is [00:09:00] 5 to 20 years of age, not so much in the younger child. But those behavioral problems can be very severe, and if they have severe intellectual disability, it can be very hard to manage them. So we need to ensure families have support and guidance and that involves the psychologist and in the more severe patients, they may need a psychiatrist with behavioral medications. The very autistic, severely behaviorally impaired children might need drugs such as you know, risperidone or aripiprazole. That's only a small subgroup, but for those families it can be incredibly difficult.
Other psychiatric issues: one has to think about mood disorders, hard to pick up, but that can happen. Then the next group of problems would be musculoskeletal, and I've got a number of my adolescents and adults who are developing scoliosis and some of them have required surgery, so they need very close following, ideally by orthopedic [00:10:00] surgeons.
And another issue that we first described, and now many groups have done a lot of work on, is the gait problem that evolves in many individuals with Dravet syndrome, probably 70 to 80%, so not all, develop a crouch gait. A crouch gait is where you have hip flexion, knee flexion, and ankle dorsiflexion with bilateral planovalgus (flat foot). And in our original paper in 2012 by Jill Rodda and colleagues, we sort of said it began at about 9 years of age with the adolescent growth spurt, but I have now seen it in younger children of 3 or 4, but in general it definitely becomes much more apparent with puberty and you have lengthening of bones. I've had one patient go to surgery and that helped, but only transiently and he's now very severe. Not everyone has it and the physiotherapists need to think about how to manage it, but there's a [00:11:00] lot of interest in understanding the gait disturbance.
You know, there are many other issues that can happen. You can have gut problems and the most common one would be anorexia, and this may partly relate to medications because we use a range of medications in children with Dravet syndrome and adults that can cause anorexia. These include fenfluramine and stiripentol and topiramate, sometimes cannabidiol. So one has to be able to manage these very carefully. Sometimes even high doses of valproate can cause anorexia or nausea, whereas it's more usually associated with weight gain, but sometimes if it's high it can put the child off their food.
So we've learned to do valproate levels quite readily if there are concerns because you can miss that, particularly in young children.
Dr. Parthvi Ravat: Right. And how do we engage with caregivers [00:12:00] during those times?
Dr. Ingrid Scheffer: Thank you. It's incredibly important to engage closely with parents and caregivers. Obviously in childhood it's usually parents, sometimes grandparents. And then as you get into adult life, you, if you're lucky, you still have parental involvement because they're the most important advocates for their children, even adult children, but also having long-term caregivers who know the individual really well is important. I think good medicine involves always engaging with the family. That's your day job when you see patients with intellectual disability and epilepsy, and it's really important when you see these patients, and I can't emphasize how important it's to see them in the flesh, in person, not just on Zoom. I do Zoom with my Dravet families all around the world, the patient [00:13:00] wanders in, says hello, and then wanders away. But if they're in the room with you, you can look at their gaze, you can look at their interaction, you can look to see if they look well or don't look well. And that is so much better.
But I think what's really important as a clinician is to ask the families what's worrying you, what's number one, it's not just about seizures. And I think as neurologists we're a bit guilty about just going into the seizures, the drugs, okay, bye. And that's not good enough with any individual. Whether they have a developmental and epileptic encephalopathy such as Dravet syndrome or they are completely normal intellectually and in other facets of life, you should always start with, “How can I help you? What's number one on your list?”
And the other issue I think that's critical with good medicine is when you finish the consultation, you have to say to them, “What else is on your list? What else are you worried about?” Because often that's when [00:14:00] the important bit will come out. You know, the parents might tell you they've split up, the marriage has failed, or the parents might tell you, the mother might just burst into tears and say, “I just can't cope anymore.” And then it's your job to be an advocate for your patient and the family to try and get them more resources. So I think our job as a pediatric and adult epileptologist or neurologist is to deliver holistic care.
Dr. Parthvi Ravat: Wonderful. That resonates and I’m sure will resonate with a lot of listeners.
Dr. Ingrid Scheffer: So let's talk about treatment. When you're treating a child or an adult with Dravet syndrome, I think the drug that we start with is usually valproate, and that's an inexpensive drug and it's available around the world, so that's really important. What's just as important is to make sure that you don't use specific sodium channel blockers, and by that I mean carbamazepine and oxcarbazepine. They should [00:15:00] never be used in Dravet syndrome and we know that they cause seizure exacerbation or worsening. In an ideal world, after valproate, I would probably go straight to fenfluramine if I could, but this has not been approved yet under two years of age.
And there are formal studies to show that it is safe at 1 to 2 years of age. So at the moment, what you would do is go valproate, stiripentol, and clobazam, but you wouldn't necessarily have them on all three, although often you may need that. I would put cannabidiol, pharmaceutical grade only, not the dodgy CBDs. There are many now, and they're making a lot of money. The reason you don't want those is you don't know that every time you are giving that child or the adult the drug dose, you don’t know what's actually in it. And when they test those doses, often there's almost no CBD in it, or there might be [00:16:00] THC, which of course is the part that can cause early-onset psychosis. So be very careful, always pharmaceutical grade CBT. And then I think topiramate can be a very useful drug for Dravet syndrome. And there's always fear about word finding difficulties, but I've used topiramate in probably hundreds of patients now, and their language can improve when they go on it because their epilepsy is so much better. Equally though, when you stop it down the track, sometimes their language improves. So it's, it's not straightforward.
There's a lot of debate about other sodium channel blockers such as lamotrigine and phenytoin and people say, oh, just don't use sodium channel blockers. I think that is completely wrong. There are many sodium channel blockers. They have different modes of action. We currently are doing a study of phenytoin versus levetiracetam for acute use, just acute use, for status. And phenytoin looks to be as good as [00:17:00] levetiracetam. So it's very dangerous to say you shouldn't use it when it could save someone's life.
Lamotrigine, there's a bit of debate both ways about it. I've had patients on it longer term with good success, and I've stopped it and it's been a disaster. So I think we have to be careful with those two.
So, back to summarize how you treat Dravet syndrome. Valproate first, and then you consider fenfluramine, stiripentol, and clobazam. I think fenfluramine is top, then stiripentol, and then the next rung down is CBD and topiramate. But you should also remember the ketogenic diet, and particularly in younger children, I've often suggested that to older individuals and their families just do not want to do it. So you have to tailor your treatment regimen to your patient, as we always do.
Dr. Parthvi Ravat: Okay. Looking forward to disease modifying therapies in Dravet syndrome. Can you tell us about that?
Dr. Ingrid Scheffer: [00:18:00] The landscape is super exciting. And there are a number of different initiatives evolving around disease modifying therapies.
The first thing to say is that the best drugs already modify the disease. So without talking gene therapies, if you use a drug like fenfluramine and hopefully the drugs like it that are in trials at the moment, you can see that by stopping seizures, the child's development improves so that they might start to walk and talk, whereas previously they haven't walked or talked. So these very good drugs are already modifying the outcomes of the disease, but when we talk about disease modifying therapies, we're really often thinking about genetic therapies.
The most advanced of those is by Stoke, and it's an antisense oligonucleotide, and that involves intrathecal injection every three to four months, four months I think, and that means a [00:19:00] lumbar puncture every four months. And many of these patients require general anesthetic, but not all of them for that, depending on the age of a child. That is already showing very promising results in Phase Ib/II trials. And I understand that their major paper is currently under review in the New England Journal of Medicine. They're already seeing significant improvements in developmental progress with executive function, for example.
So I think these disease-modifying therapies are exciting. I'm not sure they're going to fix the disease. And in fact I think they won't, which is a pity because I was hopeful they would, but they're certainly looking to be very promising.
So that's the main one. The second one that is already under trials is from a company called Encoded. And we are very fortunate to be doing trials in Australia with Encoded, and that involves an AAV-9 [00:20:00] therapy, which is a one-off therapy. It’s intracerebroventricular, by the neurosurgeon. And this is a viral therapy that brings a promoter to SCN1A, and the idea is to upregulate both alleles of SCN1A. The mutated allele doesn't make protein and that is taken away by nonsense-mediated decay. On the other hand, the good allele is upregulated. So the idea is to get double the amount of that. Now that is in early-phase open-label studies. And the next step for the AAV-9 therapy will be to go to a Phase III study, which I suspect will involve sham as well because the FDA is saying we need sham.
There are a number of other companies now looking at ASOs (antisense oligonucleotides) or other types of gene therapies [00:21:00] in Dravet syndrome. The space is becoming very exciting and I think we are heading towards disease modifying therapies, but they're not quite out there yet.
Dr. Parthvi Ravat: Right. And these therapies might benefit older patients who are not a part of these trials. So how might this change how we look at about inclusion and access?
Dr. Ingrid Scheffer: This is an incredibly important question at the moment. In all of the developmental and epileptic encephalopathies where gene therapies are being looked at and remembering we have more than 950 genes now that cause developmental and epileptic encephalopathies, in all of these studies and the trials, people are focusing on the babies and young children, because of course that’s where the most hope lies. If you can modify the disease, you can really improve outcomes. But I think it's really important to also consider the adolescents and adults because many of these therapies may improve them as well, and we know they're still [00:22:00] modifiable.
We know that if you have a 60-year-old and at that stage if they stop carbamazepine, they can get brighter and regain some skills. So we know there is a modifiable component and we need to hope that the drug companies, the pharmaceutical and gene therapy companies, will ensure they look at older populations as well.
Dr. Parthvi Ravat: Another powerful topic whenever we talk about pediatric epilepsies is the transition model. So what does an ideal transition model for Dravet look like?
Dr. Ingrid Scheffer: Transition is very important in epilepsy and is generally done very poorly. You need to ensure the transition is to a neurologist who is able to consider holistic care and for the patients with developmental and epileptic encephalopathies, including Dravet syndrome, they need to understand this multi-morbidity disease and how they need to consider all aspects of care.
It [00:23:00] gets very difficult in adult land because you lose your general pediatrician. We don't have good generalists. And in neurology we tend to think seizures, cardiologists think heart, and you really need someone who can bring it all together. And we need to appreciate that these patients are actually too complicated for the GPs in general to manage unless there are GPs who specialize in individuals with intellectual disability.
So with transition, I think it is good to meet with the adult neurologist with their pediatric neurologist, maybe more than once. I think the model of doing it once is probably nowhere near enough. The other important issue is for the adult neurologist not to change everything when they meet the patient. And I have this myself, even though I look after children and adults and about a third of my practice is adult, I sometimes get an adult with severe disability that comes to me and the first thing you should do is do nothing. [00:24:00] You should take a history. You should get to know the family, because they love their pediatrician or their pediatric neurologist, and they are terrified when they come to adult land. Parents are scared and they have to learn to gain confidence in you.
The other issue is they have to learn that you can't be everything to them. I can't be their general pediatrician, but what I can do is guide them and I can say, well, there's this problem. Let's send you over to this person or whatever, and that way that you can help to be there, sort of their rock that they can use and they can ring up and say, “I'm worried.”
This has happened to me in both my normal adults and my disabled adults, that they've suddenly developed psychosis. And the first person that the parent rings is me. And I'll go, “Hmm, I'm worried about psychosis.” And mostly I'm right. So I think it's really, you can be such an important center of helping them [00:25:00] coordinate their medical care, but not with being the coordinator. It has to be the GP, but you can be that wise person that sort of recognizes what's going on because you understand these multi-morbidity diseases.
Dr. Parthvi Ravat: And finally, if we fast forward a decade, how do you envision the landscape of Dravet Syndrome, especially the management in the era of precision medicine?
Dr. Ingrid Scheffer: Great question. I think in 10 years’ time we'll be using disease-modifying therapies routinely. We need to help pediatricians and pediatric neurologists to diagnose Dravet Syndrome at the first or second seizure, and then we need to instigate those disease-modifying therapies from the beginning. What we will also need to do though, is to watch the patients in the longer term and to make sure that we detect any of these other morbidities and manage them in a very proactive manner. [00:26:00] These are complex patients. We need to ensure they're under our care. I think the trials will follow in the longer term, but one of the intriguing and slightly worrying issues around genetic therapies is that there may be side effects we don't even know about yet, and those side effects need long-term management and following. So 15, 20, 50 years down the track, we need to be thinking, would this be a side effect of this disease modifying therapy?
So the future is bright, but we also need to be vigilant and careful to ensure the best for our patients.
Resources:
Protocol for immunization of children with Dravet Syndrome – Royal Children’s Hospital Melbourne (PDF)