Genetic Testing and Epilepsy-Genetic Testing in Epilepsy: Impacts on Clinical Care

Video Transcription

So, these are my disclosures. I work with a lot of people to help kids with epilepsy. So, these are some of my learning objectives.  I hope that you'll be able to understand how genetic testing in clinical practice has changed over time.  I'll illustrate how early genetic testing can potentially affect outcomes and demonstrate barriers to genetic testing in the clinic and some possible solutions.  So, there's a lot of kids who have epilepsy diagnosed every year, and there's not very many child neurologists.  And the number of genes that have been associated with epilepsy has been steadily increasing since the 90s and really skyrocketed in the last 5 or 10 years.  So, child neurologists can't do it alone. We have to also rely on pediatricians, genetics, genetic counselors, that's all part of the  team, and really the whole healthcare team to help families, help patients to learn about epilepsy.  Thankfully, I think the number of genetic counselors has been increasing a lot recently to deal with this and really help the pressure on the system to increase expertise and make  this care better and better. So, in my short talk, I wanted to use a couple of cases to really drive home the point of  how things have changed in clinical practice, the impact on clinical practice. And so, I've chosen a couple of cases of children that were born 2010, 2017, to show how people  or how the doctors dealt with the same presentation in different points in time and how there's been a shift in the approach.  So, this baby was born in 2010, and they started having seizures on the first day of life. And they were witnessed in the hospital, they were recognized as seizures.  The child had stiffening, head deviation, crying, and perioral cyanosis, which lasted 10 to 20 seconds. It happened multiple times per day. An EEG was performed.  In the top panel, you can see the birth suppression pattern between seizures. And on the bottom panel, the signature of an asymmetric focal tonic seizure with attenuation  and asymmetric low-voltage fast activity. Of course, a baby having seizures had an extensive evaluation, first ruling out infection  in the NICU, MRI, ruling out stroke, et cetera, and then the ensuing metabolic tests. More lumbar punctures, more blood tests, more urine tests.  Every medication that was used didn't work. Dozens were tried in just a short period of time.  After a couple of months, the seizures evolved into infantile spasms with hypsarrhythmia, and the child had emerging signs of developmental delays, not meeting milestones.  Now, back then, we would do single gene testing, as was discussed, and we would really focus on the specific presentation and only do gene testing for that specific diagnosis.  So this was a baby having seizures, and we would think of genes like ARX, STX, BP1 back then.  And we would wait six months, would come back, then do insurance pre-approval for the next test. And so this was really going on and on, a diagnostic odyssey, and repeating MRIs and  talking about muscle biopsies, et cetera.  Well, we heard that KCNQ2, which was already known from the 90s as being associated with benign familial neonatal epilepsy, had been associated with some more severe cases.  And so that was the next test that was sent. And this testing company didn't know what to make of it.  They said it was of uncertain significance, but more likely pathogenic than benign. And many of you are seeing the difference in the terminology.  It was just 10 years ago, 2012, and now we have the ACGME criteria, which makes it much more clear what the test means, with variant of uncertain significance and so on.  Just at that time, there was a publication which had other cases with the same presentation and actually the same variant in one of the children.  So now we knew that this child had KCNQ2 encephalopathy with focal onset tonic seizures  in the first week of life and a discontinuous background with multifocal epileptiform discharges. So what did this do for the family? It changed their life.  The diagnostic odyssey was over. They immediately went to the internet, like many people would, and they zeroed in on Ed Cooper, who had been studying this in his lab for a decade.  And he had been getting reports from other doctors around the country already about these cases of KCNQ2 encephalopathy.  The family got me in touch with him as well and started their own family foundation, a not-for-profit raising money with a mission of advocacy and research and supporting other  parents. They wrote about their experience in epilepsy. They've attended the American Epilepsy Society meeting and had a booth for their foundation.  And they've organized, along with other family groups, the annual meetings where we bring parents and professionals together to talk about research and clinical care.  I'm the guy with the tie. So fast forward just five years, so 2012 to 2017, it feels like a lifetime that all this has happened.  Another child born not too far away, but at a different hospital, started having, after a normal pregnancy and delivery, was in the newborn nursery to new parents and was having  whole body stiffening, head deviation, crying, perioral cyanosis, lasting 10 seconds. You all know what that is now, right? Just from that one description.  The nurses and the doctors in the hospital didn't see these seizures. And they said, well, maybe it's something to do with feeding. Go home. It'll be OK.  They went to their pediatrician for the well child check where it was witnessed, and they  were immediately sent into the local hospital where they had an EG, which captured the focal tonic seizures.  They were given multiple medications in the hospital after a thorough evaluation, MRI, EG. Genetic testing was considered, but could only be ordered as an outpatient and was in  insurance preapproval. So they were suffering with 25 seizures a day, not knowing where to turn.  They were referred, finally, to an epilepsy center where, just with that description and the EG pattern, the genetic syndrome of KCNQ2 encephalopathy was highly suspected.  There's already been a publication just three years after that KCNQ2 encephalopathy paper about the effect of sodium channel blockers on reducing the seizures in these patients.  They were started on giving a load of phosphonatone. The seizure stopped immediately and started on carbamazepine.  Since then, they remain completely seizure free, but over the first, second, third year of life, it was evident that they did not have the normal developmental course and they've  had developmental concerns like the other child. So even though we stopped the seizures, which is important, we haven't really affected the disease itself.  Who knows whether identifying the patient at birth and doing genetic testing, even if  you didn't know what it was, what it was specifically with a panel, you would catch the KCNQ2, confirming  that may have stopped the seizures earlier and prevented those 25 seizures a day for three months. So I think those two cases have really shown me how things have changed.  You know, it's been another five years, and so how is that at all of your practices now and your hospitals?  Does everybody here know about KCNQ2 and suspect, or if you see a baby having seizures, suspect a genetic cause and send genetic testing?  These are some of the things that I talk to families about in the clinic, that epileptic encephalopathy is usually not inherited, so there doesn't need to be a family history.  They're usually new in the patient. And that phenotypic heterogeneity is an important concept. You know, many genes like SCN2A can have different presentations.  You can have neonatal seizures, epilepsy of infancy with migrating focal seizures. You can have infantile spasms.  And then there's some conditions like infantile spasms that have multiple genes associated with it.  The genetic testing is very important for counseling parents about what to expect and limiting the number of invasive tests.  I can't remember the last time we did a muscle biopsy, but 2007, 2008, when I was in training, we felt like we were doing them every month, looking for mitochondrial disease in kids  we couldn't explain their epilepsy. Now with genetic testing, we don't need to do that anymore as much. And choosing anticonvulsants, I've already covered.  And precision medicine is that thing in the sky we're really excited to achieve. But learning about genetic testing and finding that genetic diagnosis can help us understand  the pathogenesis and possibly develop new treatments. Here's a few examples of genes with treatment implications, SCN1A and POLG1. These are drugs.  You might avoid drugs for them, ALDH7A1 and SLC2A1. These treatments, pyridoxine and the ketogenic diet, might not only control the seizures  but also change the development or help slow developmental decline. And we talked about KCNQ2 and SCN2A responding to sodium channel blockers. So why are a lot of doctors here?  Because they feel like they have barriers to utilizing genetic testing in their clinics. Do you have concerns about doing the pre- and post-test counseling effectively in the  short time that we have to spend with patients and the time to follow up the variants of uncertain significance and do additional testing?  And is that because they haven't had the education, they're not aware of the sodium channel blockers or avoiding valproic acid and POLG and how important that is?  Are they concerned about having the primary responsibility for the results? As I mentioned as I started out, we don't write the formal report for MRIs. But we understand MRIs.  We read the MRIs. We look at them. We explain them to patients. So really, hopefully, it will be part of our training to understand what genetic testing  is and to explain it to our patients. And cost always comes up. But I think that's less and less of a problem now. Really not any more expensive than an EEG or an MRI.  There's even free testing available for genetic testing, which isn't available for EEG and MRI.  And if you're not doing MRIs every year looking for a focal cortical dysplasia, you're saving money to the system and to that family.  So one possible solution, I think a lot of regional epilepsy centers have created epilepsy genetics clinics.  These are not just epileptologists, as I've mentioned before, but genetic counselors, nurses, social workers, and geneticists.  And the neurologists may refer either before they've tested at all, if they can get the kids in quickly enough.  And the team there can develop a personalized testing algorithm to decide whether a panel is the best thing, or a microarray, or doing a whole exome sequencing first, perhaps, and  doing the appropriate counseling about the process. And post-test counseling, if the testing has already been done, say a panel was done and  the child neurologist has a VUS, which they don't know how to explain to the family. These clinics will refer families to genetic studies and gene-specific therapeutic clinical  trials. And some of these already exist for a lot of specific diseases, but I think that framework  for Angelman clinics and the staff for Rett syndrome clinics can be applied across epilepsy genetics as a good basis.  So in conclusion, I think we all have been emphasizing how early genetic testing in the course of your practice is important, and thinking about a personalized testing algorithm,  which test to order first, which will be covered later in the talks. And all these things are important for family counseling, potentially changing treatments  and stopping the diagnostic odyssey, which is not only important to doctors, but to the patients. And I'll just ask you to remember one thing from my talk.  If you see a newborn baby with focal tonic seizures, it's probably KCNQ2. Thanks very much.

Video Summary

The presentation focused on the evolving role of genetic testing in diagnosing epilepsy, especially in children. It highlighted how genetic tests can influence treatment outcomes by identifying specific genetic disorders, like KCNQ2 encephalopathy, which presents with neonatal seizures. Through case studies, the speaker illustrated the shift from laborious, single-gene tests to more efficient diagnostic methods using genetic panels and sequencing. This shift aids in stopping the "diagnostic odyssey" for families, providing clearer treatment directions and support. Although barriers such as cost, counseling, and test interpretation exist, the rise of specialized epilepsy genetics clinics aims to address these challenges by integrating diverse healthcare professionals. These advancements have not only enhanced the ability to diagnose accurately but also align with precision medicine goals, ultimately improving patient care and quality of life for those with genetic forms of epilepsy.

Asset Subtitle

Presenter:

John J Millichap, MD, FAAN, FAAP, FACNS, FAES, is Adjunct Associate Professor of Neurology at Northwestern University Feinberg School of Medicine and Pediatric Epileptologist at Precision Epilepsy PLLC. Current clinical practice utilizes an innovative telehealth approach to the precision diagnosis and treatment of pediatric epilepsy. Dr. Millichap has over 60 peer-reviewed medical publications and serves as the Editor of Pediatric Neurology Briefs. As a member of the academic faculty of Northwestern University, he is involved in the education of trainees and grant-funded clinical research concerning epileptic encephalopathies and epilepsy genetics. He is involved in clinical trials and translational research regarding epilepsy genetics.

Keywords

genetic testing

epilepsy diagnosis

KCNQ2 encephalopathy

precision medicine

epilepsy genetics clinics