Dr. Danielle Andrade is a professor of neurology from the University of Toronto. She is going to discuss genetic testing and the transition to adult care. She's the director of the Adult Genetic Epilepsy Program and the co-chair of the ILE task force on transition. Thank you. Thanks for the invitation to be here today. And I know you already raised your hand several times, but I'm going to ask you one more time. If you are a child neurologist, please raise your non-dominant hand. You know why I asked you to raise your non-dominant hand? Just to show you how we adult neurologists think a little different from child neurologists. And one of the things I thought differently was that when we were planning the session, we would be asking you questions. So I prepared just five slides. And I hope you help me with the questions that I will ask, so I won't look like a fool here. Let me start with my disclosures and the learning objectives. So I think what I understood, you wanted me to talk about, was to understand the importance of genetic diagnosis in adults with epilepsy, to learn how to go about making this diagnosis and supporting the adult patient with a genetic epilepsy, as well as their family, and understand some of the challenges treating adults with genetic epilepsy. So please, if you can, and just shout out. You don't have to come to one of the microphones. Or if you are closed and you want, please tell me what you think one of the advantages of testing adults with possibly genetic epilepsy. Family planning. Family planning. That's a good one. But the family may say, you know what? He's already 18. And we have another child who is 16. I don't think we're going to have more kids. Caregivers have always wondered why. Caregivers always wonder why. And I had parents who, when they had the genetic diagnosis, a mother especially said, so this is not about the wine I had. I had a glass of wine. I didn't know I was pregnant yet. And this mother, and I know many others, carried for many, many years this guilt that maybe it was that glass of wine or it was that big fight that she had. And she left the room and slammed the door. And that might have done something bad to her child. So learning why and getting rid of the guilt is an important reason. I'm looking for one more. Sorry? Treatment adjustments. Excellent. So there are conditions that now we know this medication might not be the best for this specific condition. Of course, the classic example is a patient with Dravet syndrome. And for child neurologists, you don't even think about this anymore. But I'll tell you, the adult neurologists are not familiar with these genetic conditions. And some of them will learn that, yes, especially if they have a transition program and they communicate frequently with a child neurologist. Otherwise, they will not know that you should not use a sodium channel inhibitor. Or if it is another epilepsy that apparently responds to memantine or seizures may respond to fluoxetine, depending on the genetic mutation. An adult neurologist will never know that. One more reason. Yes. That's very important. So we want to discover new genes. When you find a new gene in an adult patient, it's a bit more challenging. And one of the reasons why it's challenging is because most of what you're going to read about this gene was described by child neurologists. So when you read the literature, you're going to see a lot of things that happened to this patient or a group of these patients when they were children. And now, as an adult neurologist, you might not have access to the entire chart, or you may not have time to read the entire chart. And this is something very important when planning the transition of this patient. So we might not actually know if the phenotype we are seeing in this adult really corresponds to the phenotype seen in a few other children. There's one more hand. Excellent, excellent. Perfect, perfect. That's exactly the points that I was wanting to get as well. So many times the siblings of a patient with a genetic epilepsy is afraid of starting their own family, especially if they don't have a diagnosis. So what happened to my sister could happen to my children. So having the diagnosis in this adult sibling will give some measure of comfort to this healthy child to decide whether or not they want to have children. Just to give you an example, I had a 28-year-old patient that came to me for DBS, actually, and we decided to do some genetic testing. This was a child that had some intellectual development growing up, but he was mobile. He used to play soccer and horseback ride, and had seizures, and with time seizures were getting worse and worse. He became nonverbal, and when I saw him, he had quadruple paresis, nonverbal, having seizures all the time, and no one knew what the problem was. We started doing genetic investigation. Turns out he had a MECP2 duplication, which meant, and we checked the mother. The mother had the MECP2 duplication, asymptomatic, but his sister was pregnant at the time. So we end up offering genetic counseling to the sister, because if she was also carrying the duplication, there was a risk to her child, especially if she were caring for a boy. So there you see how it's important, even in an adult, where you say, well, he's not going to be part of any genetic drug trial, but you can think of family planning to the siblings. Changes in treatment we talked about, so let me see if we missed something. And then the fact of understanding, as you pointed out, the natural history of the disease. So when you look at an adult with a certain condition, and you start seeing many of them with that condition, you start getting a sense of what's going to happen to children with this particular mutation when they grow older. So one of the largest cohorts that we have is of patients with Dravet syndrome, and we see our patients with Dravet syndrome getting Parkinsonian symptoms in their early 20s. We see them getting gait problems. We see them getting certain types of, or even regression, which you shouldn't see in a developmental epilepsy. And it gives you a sense of what to expect when you have children with that disease, how they may grow up, and what they may become. Now, this is one more reason why it's important to have some kind of transition program. The adult neurologist is not trained to treat patients with genetic epilepsy. So what happens is that in the past, and I'm talking about 10 or more years ago, or even more, the child neurologist would see the patient with a clear genetic epilepsy, would do all possible investigation, the $1 million workup, including metabolic tests, fish, karyotype, biopsies, that's what was available 20 years ago, and there was no diagnosis. So this patient would come to us with a diagnosis of a symptomatic generalized epilepsy. The adult neurologist would only repeat the prescriptions of what the child neurologist did and never investigate again. The thought is, if the child neurologist couldn't find a cause, I'm not going to find anything. Most of the time, we get patients with newer genetic tests. So they have a panel, they have an exome, sometimes even a genome sequencing, and they still are microarray, and they still come to us without a diagnosis. And still, many of the adult neurologists will say they did everything that was possible in the pediatric side, so I'm not going to find anything, I'm going to stop investigating a genetic cause, and I'll just focus on treatment. So this is where a planned transition to the adult side is very important. So when you are referring this patient to the adult neurologist, it might be worth writing down, we did this and this in this investigation, we didn't have a cause, we have a boost here and there, we recommend that this investigation be repeated again in two or three years and so forth until a cause is found, because this is very likely a genetic diagnosis. So now what happens is, and then you have the other side, which is, you do have patients coming to you with a genetic diagnosis of conditions like CDK05, STXBP1, PCDH19, and you say, okay, I never heard about this condition, what do I do? I'm going to repeat what the child neurologist did and hope for the best. And that's usually what happens. So again, as part of the transition process, the best thing that a child neurologist can do is summarize the whole course of the pediatric care and provide some literature. One of the things that we did, and Dr. Perry was part of that, for instance, with Dravet syndrome, we did a quick two-page transition cheat sheet so that if the family with a child with Dravet syndrome comes to the emergency room, they can show that little cheat sheet to the emergency room physician, so that person will know what Dravet syndrome is, what are possible treatments, what are common comorbidities, and things like that. So that's just one of the ways that transition can be improved. Now again, with your non-dominant hand, please raise your hand if you know who you're going to send your child or pediatric patients when they move to the adult system. Do you have a neurologist in mind already? Good. So better than I expected, honestly. So what are the possible challenges that you see when transitioning a patient with a genetic epilepsy? You said you're having a hard time to find a neurologist to see your patient. Anything else? I'm sorry. Can you talk on the microphone? I'm having a hard time. Does it work? Oh, yeah. It does. The patients probably in their family have a relationship with their child neurologist. They will have probably hard time transitioning to a new person who they don't know yet and establishing the new relationship would be hard. The child neurologist has been following them for a long time. They know everything about them, which kinds of complications there might be, which kinds of medication reactions probably, what has been tried, what has been not tried. And it's a huge bulk of information that is hard to transfer to another person. And there should be a very good transition program in place to make the knowledge transfer available and to make the family feel safe and secured while transitioning to another person. That's an excellent point. That's an excellent point. The families come to us always with uncertainty and they have a foot behind and they go like, will this person know about my son's condition? My child neurologist knew so much about this and now I have to see this new person in this new building with new nurses, new everything. How it's going to be? And they really have a hard time trusting the adult system, which is very different. It's very different. So most of the times things are scattered through different hospitals. If you need just a simple blood work to get drug levels, you need to send them to that particular technician in the lab that you know can deal with patients that behave like children, adult patients that behave like children. Or that particular EEG technologist that has a good way of dealing with adults with intellectual disability. Otherwise, you're going to have a hard time really taking care of the basic things that are needed for this patient. Another challenge. Excellent, excellent. So the issue with comfort level of the adult neurologist, and we did some research about 10 years ago, and it's amazing how uncomfortable adult neurologists are with treating patients with genetic epilepsy, and not only the seizure, but all the comorbidities that come with that. So usually the child neurologist will look after seizures, sleep, behavior, or if they are not able to, they have a group of physicians that can send their patients to most of the times in the same hospital, so the family is seeing the right specialist in a closed environment and they know they talk to each other. The adult system is completely different, so if you need a sleep study, it's going to be a challenge to get that done. If you need an adult psychiatrist to treat a non-verbal patient, it's going to be a huge challenge, so that's a big issue as well. Anything else? Oh. I actually have a very difficult time with my patients' families who have limited medical literacy, understanding the value in genetic testing, and trying to reopen that door after it wasn't successful earlier on in their life. That's an excellent point, that's an excellent point. One of the things that we have to sometimes talk more than once, and eventually the patients will get there, or the families will get there, is the fact that you had a genetic test in the past that was negative doesn't mean this is not a genetic disease. And again, yes, we might not have a treatment for this now, but we may learn about comorbidities, we may learn about family planning for the adult siblings, we may learn about modified or repurposed drugs for this genetic condition. So it might be a challenge, but we have to think and talk to them. This was just another slide about factors that impact transfer of care for patients with genetic epilepsy. And availability of an adult neurologist knowledgeable of the condition was certainly the highest one. The other issue is patients on ketogenic diet. So we just heard Christas talking about the patient with GLUT1 deficiency. So that's a big issue. If your patient is on a ketogenic diet and is doing well, where are you going to send this patient in the adult system? Is there one that has a keto diet program? A few other things, and again, patient might be too complex for the system, and they feel that they will not have the same support that they had in the pediatric system. So just to finish up, I think it's very important to talk about old misconceptions, and one of the big ones I see are patients with encephalitis. So patients that have post-encephalitis intractable epilepsy. And if you dig down the story, they had, yes, febrile seizures or febrile status epilepticus. But if you can't find that CSF results, you'll see that there was never a pathogen identified in that so-called encephalitis. The encephalitis was not ruled out at the time. And that's one opportunity to talk to the family and say, this might be a genetic epilepsy, so we should reinvestigate with the new technology we have now. And again, discussing the pros and cons of genetic testing, as we heard just now, is very important to set up the right expectations. One more time, communication between pediatric and adult providers. It's extremely important. So if the adult provider sees a patient, again, another example, patient sent to me for DBS, patient with Lennox-Gastaut sent to me for DBS. Our fellow saw the patient and came and said, this patient has a diagnosis of Lennox-Gastaut, but I think it is a dravet case because she has that gait and she has this and that motor signs that I think it could be a dravet. And when you talk to the mother, the mother at the time was in her early 70s. She couldn't remember if the patient had febrile seizures. She couldn't remember if the patient had myoclonic seizures. At the age the patient was at the time in her 40s, she didn't have myoclonic seizures anymore. They couldn't tell me about absence seizures anymore. I didn't know about febrile seizures. You get a genetic test, you get an SCN1A. This time, luckily, was a pathogenic variant, but it could have been a WUS. And then what do you do with a WUS if you don't have the proper history of when the patient was growing up? So it's very important that the child neurologist sends to the adult neurologist a proper transition document letter or transfer letter with all the types of seizures that happened in the past, the response to medications, to treatments, to ketogenic diet, this and that. So when we do genetic testing in the adult, we can better interpret that based on the information that we have, but things that we don't see anymore in this patient. And I think, just to summarize, if clinically suspicious, always look for a genetic diagnosis. Even if recent genetic investigation was done, like I said, you have to redo this every two to three years. Think of the benefit for the patient and the family, even if you don't have a genetic treatment for most genetic disorders. You don't have it today, but once we have diagnosis, we can start looking for what is new for that condition. Think of comorbidities, and remember, this is a great opportunity to learn about the natural history of these conditions. So I'll stop here. Thank you.

genetic testing

epilepsy

transition care

neurology

inheritance risks

treatment adjustment