May 27, 2021
Here are the introductory comments:
Dr. Ángel Aledo-Serrano is a neurologist and epileptologist at two Comprehensive Epilepsy Centers in Spain, Hospital Ruber Internacional (Madrid) and Clinica Corachan (Barcelona). He has focused his clinical practice and research in complex epilepsies, both in pediatric and adult patients. He is currently working on epilepsy surgery, genetic epilepsies and developmental encephalopathies. He is involved in multiple clinical trials of precision medicine.
He is highly active as a scientific advisor for rare disease and collaborates with patient advocacy groups like ours.
Dr. Angel Aledo-Serrano is a neurologist and epileptologist at Hospital Ruber Internacional in Madrid. In this webinar, Dr. Aledo-Serrano focuses on seizures in SYNGAP1 patients as SYNGAP1 is one of the most frequent genetic causes of epilepsy. He begins by talking about the traditional classification of epileptic encephalopathies and the 3 stages of phenotyping in epilepsy. He then explains how seizures are characterized as generalized seizures, focal seizures, or others including epileptic spasms and atonic/tonic seizures. Dr. Aledo-Serrano shows video examples and the EEGs of patients experiencing seizures to aid in his explanation, while pointing out specific seizures in SYNGAP1 patients like myoclonic eyelid closures, pattern sensitivity seizures, and eating/drinking seizures. He also talks about when is the best time for an EEG and for how long. He concludes the webinar by explaining the “prescription cascade” which occurs when a prescribed drug can cause a new condition which then requires another prescribed drug and so on. This is why epilepsy precision medicine is crucial when treating patients.
Other Relevant Publications by Dr. Aledo-Serrano
Dr. Aledo-Serrano: Thank you for having me. Thank you all the Syngap Research Fund team for inviting me. I think you are you are doing really a great job because we need a lot of dissemination in this in this area of genetic epilepsies, of developmental and epileptic encephalopathies. We need more awareness and more research and and we need you. This is really important.
So I’m going to to talk about types of seizures, how are seizures in SYGNAP1 and also how important is electro electrocephalography in this in this population. I’m sorry for my strong Spanish accent. I hope you understand me fair enough.
So this is the classification of seizures and also the classifications of epilepsy types. You know, classically, traditionally, we were using a classification of epilepsies using only the information of whether the seizures were focal, if only a part of the of the brain was involved, or if the seizures were generalized when bilateral quickly bilateral or the whole brain was spiking at the same time.
So now in the last classification in 2017 we have the etiology part which is more and more important and the genetic part we know is important for more than 70 percent of people with epilepsy and SYNGAP1 is one of the examples. So we have like also a traditional classification of epileptic encephalopathies: West Syndrome, Lennox-Gastaut Syndrome, Dravet Syndrome. All of those were based only in EEG electrocephalography and semiology of seizures. So all the genetic information we have now it’s sometimes is difficult to get into these traditional classifications. So sometimes we I would say we “force” the syndrome to get into our patient. So we call it like “Dravet-like” syndrome or “Lennox-Gastaut-like” syndrome or “Rett-like” syndrome because these traditional syndromes are not useful for every patient. So the genetic information is more and more important and this is something we know is not something really rare. So in the last few years, in the last two or three years, we are deciphering the so-called epidemiological aspects of genetic epilepsies and we know that a lot of patients with epilepsy who are starting with seizures in their first years of life have a genetic background which is the cause of the of the disease. So we have like, two models. I would say one model which is the model of Dravet syndrome which is a success model because Dravet syndrome was a traditional a classical or a classical epileptic syndrome and most of patients with Dravet syndrome have a positive mutation in SCN1A.
However, all of these, SCN2A, CDKL5, STXBP1 or SYNGAP1, they don’t show a specific traditional syndrome. So it’s better to go reverse and to define new syndromes, new features, of epileptic seizures and semiologies regarding the specific mutations. So we could say that there were like three stages of phenotyping and semiologies in epilepsy. The first classic one was only taking in account the electroclinical syndromes, the EEG. Then during the 90s and the the last decade using neural imaging and stereo EEG, invasive EEG, we could also know some new features of semiology of seizures and epilepsy. And the last wave or the last stage is genetics. It’s the area or the field in epilepsy which is growing faster and faster in the last years.
So SYNGAP1 is one of the most frequent genetic causes of epilepsy. The first description curiously was in 2009 and the first patients described had no epilepsy. That seems interesting because actually more than 90 percent of people with SYGNAP1 have epilepsy and this is one example of something we were talking about previously, that SYNGAP1 encephalopathy we cannot introduce it included in one traditional syndromes, one traditional epileptic syndrome. This is a nice publication from 2019 in one of the most important journals in the world of neurology which is the Neurology journal. They described patients from a lot of countries and they described that most of them had epilepsy and the most frequent age of onset was two years of age. This is important but some patients started at six months, some patients at six seven years. And they could be include included in two classical syndromes: Doose Syndrome, which is an epilepsy with myoclonic atonic seizures (we will see some videos of these typical seizures) and also Jeavons Syndrome which is characterized by what we call absences with eyelid myoclonia. We will see later on some example of this. So you see some of these patients could not be included in none of the classic epileptic syndromes.
If we go reversely, so not from the genetics to the syndrome but from the syndrome to the genetics, we can see that in this nice publication, it was published last year in 2020 with people with myoclonic atonic seizures, you can see that some of these patients have the genetic testing positive for a SYNGAP1. So you can find SYNGAP1 reversely from syndrome to genetics, from genetics to syndrome. So just to have an overview how we classify, how we talk about seizures: we have generalized seizures, they are absence seizures, myoclonic seizures, generalized tonic-clonic seizures. We have also focal seizures when there is an area in brain which is causing mostly the seizures and they could be without an impairment of the awareness, or with impairment of the awareness. And we have other seizures like epileptic spasms or atonic/tonic seizures.
For example here we have a spasm. Spams are like that. Sometimes they are in clusters, like some of them in a short period of time. I would like to thank all the families who share their videos for educational and also research purpose.
For example, this is an example of focal seizures. Sometimes seizures are very, very mild and you need an EEG to see them. For example this smile was a focal seizure frontal missile. This is also a typical seizure we can see in in SYNGAP1 which is atonic seizure. You see there’s a drop, head drop during chewing which is very typical of SYNGAP1. There is also a tonic extension of upper limbs. The patient is this, the father is this.
So you see there are also myoclonic seizures. So this episode for example we could think is a normal myoclonic episode of sleeping which could be physiological, could be normal but if you perform an EEG, an electrocephalography, during night sometimes you can catch some of these episodes which could be also epileptic.
This is something quite typical in SYNGAP1 with photosensitivity and myoclonic seizures. Let’s see it again. With the light you see myoclonic jerking. This is typical for
a generalized. And here we have an example of tonic-clonic seizure, generalized tonic-clonic seizure during photosensitivity.
So this is important because the main seizure which is causing fractures and traumatic injuries are convulsive generalized tonic-clonic seizures, also atonic seizures, drop attacks could cause fractures also spinal cord and tongue problems. This is a SYNGAP1 patient you see here. This is the signature of eyelid myoclonia. You see there there is like jerking of the eyelid. This is important. I want you to see it properly. You see the eyelid the myoclonia is like a subtle jerking with the upward of the eyes. Now again. Now again.
Sometimes in SYNGAP1 we see these that if they are without attention without doing anything they just self provoke seizures. Also we see sometimes seizures which are triggered by visual patterns like these, like the shirt, the drawing of the shirt.
So this is the signature of eyelid myoclonia and eye closure sensitivity we call it, and this is typical of Jeavons Syndrome. Do you remember? Jeavons Syndrome is related to SYGNAP1. Some patients with Jeavons Syndrome has a genetic testing positive for SYNGAP1 and what we see in the in the electrocephalogram is this is the blinking, so the eye closure. This is the artifact. And then just after that we see the generalized discharge. So this is the typical electric signature of these patients. And we see this in Jeavons Syndrome. This has been studied for a long time that there are some interruption or some dysfunction in the occipital lobes which are the laws in charge of processing the visual information. So because of that in SYNGAP1, those who have a Jeavons-like syndrome, they have a photosensitivity, light sensitivity or visual pattern sensitivity or eye closure sensitivity. So this is also something described by my colleague Andres Jimenez Gomez and his team. They have described some changes in occipital areas in the EEG both in the background and in the electrons in the epileptic discharges. So this is another example of the eye cluster signature. You see here what we were talking about. The artifact of the eye closure like we are going to see it again. Here. You see the artifact of the eye close. You see the eye close and then just after that the discharge with a little bit fluttering of the of the eyelid.
And this is also something we see in SYNGAP1. Sometimes there are pattern sensitivity. This is not very frequent but we see sometimes pattern sensitivity and this is something we have to explore during the video EEG monitoring. We show some visual, specific visual patterns with lines, with circles, and so on.
And this is also something we have a specific diagnostic tool which are the Frenzel glasses. With these glasses we don’t allow the patient to fix the sight. So then we can see a fixation-off pattern which are the epileptic discharges during fixation-off. So when the patient cannot fixate the sight. And this was the case for this girl.
So this is also an example here with the tablet, with the screen. Just at the moment we have an atonic seizure, like losing the tongue and falling behind. We have this patient again. And this is something interesting because sometimes changes when the seizure starts are very subtle and the families are really professional in capturing and and detecting when the seizure began and you families sometimes say “we can see there is a subtle change in the face” mimic the face movement and this is something we can see in this patient. Right now You see? Like the face changes and this is an absence seizure. This is something we cannot control or we cannot monitor if we don’t perform a prolonged EEG. And you see this is the end of the seizure and again she has a normal expression in the face.
So the EEG is important. We know it. We could think about what is the best timing for an EEG and this is something which has been studied for a long time and we know the best moment for an EEG is just after a seizure. So if you have a, if the patient has a seizure if you perform an EEG in the 12 hours after, we will see more changes and it would be more useful. And for how long? It could be another question. For how long is better to perform an EEG? So we know it’s better as long as we can. So 12 hours is better than 4 hours and 24 hours maybe is the best to get some information regarding subtle seizures, discharges during sleep, and so on.
So this is another SYNGAP1 patient. You can see that during drinking or during chewing you can have a seizures like this. This is a tonic seizure and it was triggered by drinking and this is something which has been described typically in SYNGAP1 the eating epilepsy sometimes is also drinking epilepsy which is seizures provoked by this. But this is important. We were really really into the concept of epileptic encephalopathy that seizures and discharges could produce a developmental delay and cognitive problems but now we know that sometimes the cause is not epilepsy and it’s just that we have a cause, a genetic mutation like SYNGAP1, and the mutation has different symptoms. One of them could be the epilepsy and the others could be developmental delay, motor dysfunction, cognitive problems but the epilepsy is not the main character producing the developmental delay. It’s more the etiology, the cause, the genetic cause which is in the background. So because of that I always like talking about this: the quaternary prevention.
You know, I like the cognitive aspects or cognitive bias we doctors have when we treat patients and families and you know as doctors we like prescribing. We want to give pills, we want to treat everything but sometimes we have to, you know, to take care of our emotions and about our anxiety treating our patients and try to decrease the medication in some situations because we have, we can have what we call the “prescription cascade” because sometimes you start with a drug you produce a new medical condition which could be a new adverse event then you start another drug for the medical condition which which was caused by the first drug. So you are producing more and more problems regarding this.
So then sometimes we have to be more precise, perform EEG in our patients, slow down, taking care of the details, and sometimes deprescribe. So take out some medications if we don’t see any benefit in our patients and that’s epilepsy precision medicine. We have to look for specific etiologies, we have to look for specific patterns in EEG and to choose better and wiser our prescriptions. But for that, in order to get precision medicine, we have to perform more prolonged EEG, better MRI in some patients, and of course genetic testing but we know there is a huge diagnostic gap and this is something we have studied in our team the diagnostic gap in people with epilepsy and intellectual disability with probably genetic epilepsies and we know adult patients they are not studied well. They were not studied when they were children because we didn’t know the genetic causes of epilepsy and we have to update this workup and perform more genetic testing.
So this is all I wanted to conclude with this: epilepsy is one of the main features of SYNGAP1-related disorders. Some characteristics are very specific very, very typical like the chewing epilepsy the Jeavons and those overlapping syndromes but sometimes the patients have not a really specific epilepsy. They have myoclonic seizures for example and this is quite typical for other genetic diseases and I think video EEG is really important to be more in deep in our patients, to study them better and to give a better decision-making for drug choosing. So this is all. Thank you all for your attention and I’m happy to answer any questions you have.
Mike: Thank you very much. Now I can tell you already this webinar will become one of our greatest hits and I think it’s important for people to know the story of this webinar. We had a Congreso Cienífico in February where you were one of the speakers and you gave this presentation there and it was so popular we asked you if you would give it in English. So that’s why we’re here. We knew this would be good. Thank you so much for that and thank you for all of the care you give to our Syngap kids and all the other kids with with these genetic diseases. Our patients are lucky to have you. I have a lot of questions and I want to encourage the audience. I know we have clinicians and researchers and parents and please just everybody ask your questions put them in the Q&A. Can you talk more… so there’s one question that’s already from in from Mr Sachin and he says: How can we treat genetic epilepsy? Please advise first line drug? And in addition to answering that question I wanna add two things on the Syngap flavor: I see a lot of patients who are on… not a lot… some of our patients present with eyelid myclonia. Somewhere in the literature it says eyelid myoclonia or absence seizures, I think it says absence seizures: ethosuxamide. So they start ethosuxamide, it doesn’t work or the seizures get worse, add lamictal, doesn’t work, seizures get worse epidiolex… So I literally, two days ago I was talking to a family on these three drugs epidiolex, ethosuxamide, lamictal. And they’re like “maybe we should add Onfi” and as somebody who is… and I recognize your job is very hard and I’m glad you’re doing it but my question for you and neurologists is always… and this is related to your prescription cascade point… Neurologists seem to be very good at adding another drug. How much do you guys talk about (maybe quietly in the corners at conferences) about taking away drugs that seem to have done nothing but are still flowing around these little kids and you know, doing something, you know? Sorry that’s a hard question but…
Dr. Aledo-Serrano: Yeah, no, no, we have to be self-conscious about this all cognitive bias and all the, all our psychological aspects you know. When we do our decision making during clinical practice and yeah, you are completely right, yeah. It’s very difficult for us to go back, to take perspective to, I don’t know, to destroy your own narrative in your case. It’s like you are having decisions and it’s difficult to change them. But for sure this is a direction we have to go through. We have to decrease the medication in general because sometimes we are treating electrocephalography and we are not treating patients. We are not treating families and we have to change it and think more about quality of life, think more about sleep, think more about behavior, because this is something the other side sometimes you are treating seizures and you are improving seizures but the behavior is worse. So that’s… that does not make sense. So yeah.
Mike: So then, we agree. We agree and of course you know my opinion is unwelcome because i am not a doctor unlike yourself or Marta but I still ask them I think are we sure this is not too many drugs? Anyway but Mr Sachin’s question is interesting and I think a lot of people have it. Is there a first-line drug for a genetic epilepsy? In general for genetic epilepsy? That’s the question, yeah.
Dr. Aledo-Serrano: Yeah really, really hard question. So I would say when you don’t know how to treat your patient normally you start with Valproic. Valproic because there are really few genetic causes which could worsen with Valproic. There are some of them like mitochondrial, some metabolic diseases, could worsen with Valproic but it’s yeah, the less, less bad in general. So if I have to to start with one drug at the beginning I would start with that. But I would perform fast genetic testing and this is something we have to ask for. Now we in our hospital we have the possibility to have the genetic testing in one week and a half, the results. So I think this is something we have to fight for.
Marta: Yeah then extrapolating that to Syngap. Are you still thinking of Valproic for Syngap?
Dr. Aledo-Serrano: What is my experience on Valproic? Yeah. Yeah, so didn’t have really really good experience with with Valproic but again maybe it’s because when you have a drug which you are starting with this drug always like Valproic acid, you know very well the bad side of this drug. So because I’m a second opinion center so I always see the bad side of Valproic. Patients normally come to me after Valproic. So because of that I have that bad experience. So maybe it’s not a bad drug.
Mike: Ángel do you mind if I? Can you stop presenting just so we get more faces and less screen?
Dr. Aledo-Serrano: Oh yeah. So yeah.
Mike: That’s that’s great, thank you. So a lot of questions are coming in and I’m thrilled to see three, at least three SRF board members here. If anybody wants to talk live please just let me know but I wanna go to Hans’ first question because it’s a really good one. Do any other genetic epilepsies have a similar EEG profile to Syngap? How (related question because Hans thinks about biomarkers) unique is EEG in Syngap?
Dr. Aledo-Serrano: So I would say it is not unique. So for example CHD2 which is also another genetic epilepsy quite “common” among the rare epilepsies, you can see really, really similar EEGs. Also we had the last week another patient with this kind of EEG patterns and he had a TBR1 mutation so we have some genes which could show like SYNGAP1 but you know it’s more about probabilities. If you have this syndrome you have the probability to find this and this and this and this. So it’s not a the whole spectrum of genes.
Mike: Got it and then Nancy’s asking two great questions too. First is does the video EEG pick up on the eyelid myoclonic seizures and I’ll just add to that personal editorial we get a lot of parents who go into the hospital with the button and they press the button and I can’t tell you how many doctors say to the parents “when you pressed the button nothing happened” and the parents were like “no, I pressed the button because there was stuff” and the doctor’s like “no, when you pressed the button and when the stuff was happening, different times” and so I wonder if that’s real- I don’t know what’s behind Nancy’s question but does the video EEG always pick up on the eyelid myoclonic seizures is what she’s asking.
Dr. Aledo-Serrano: I would say yes in my experience. I cannot tell my colleagues’ experience. I don’t know but yeah. No but I think it’s a like a very typical signature. So it’s difficult to lose eyelid myoclonia. Yeah.
Mike: And then maybe it’s more of the absence that I’m thinking about because I we also have like when a child starts showing delays and having absence seizures ages two and three, you know, something happens, somebody orders an EEG, they go to the hospital and then this is a conversation I know a lot of people have had: the doctor says it wasn’t a seizure. There was some abnormal activity but it wasn’t a seizure and the parents are like… I’m still not sure what that means. So how would you explain and then what I say to them is come back in six to 12 months and suddenly it’s a seizure, right. It’s almost like it’s slowly progressing from okay to seizure but because what Nancy’s second question is you know her first one was like what Marta said what is the best recommended medication and how do you convince people that your kid’s actually having a seizure? Sorry… all these hard questions.
Dr. Aledo-Serrano: Yeah, no, no, it’s nice and it’s also a teaching for me to have these questions. I certainly I don’t know. I think we have to rely more on families in general because for rare diseases you know more about your kid than we know. So that’s for sure. My professor when I started in the world of of epilepsy he told me that at the beginning, you know, Dravet Syndrome is very famous is the most popular among the genetic epilepsies and Dravet Syndrome is very typical for excitation-triggered seizures and also to febrile (fever) triggered seizures. So my professor told me Dr Hilario my mentor he told me that at the beginning they didn’t believe the families. They thought the families were creating that relationship between fever and seizures or excitation and seizures. So yeah, at the beginning you have to, I don’t know, to fight to do things like this, to create meetings among doctors and families and yeah in the end we have to be more horizontal in our relationship with families. I think that’s something which is changing with the new generations of physicians of neurologists. I hope so.
Mike: Me too.
Marta: Extending to that Ángel then we’re talking about a family that got reported an abnormal EEG, that means that the lower- the threshold for seizures is lower but they don’t report seizures and then how do you deal with that because that’s the question we get all the time because you know that kid is a has I mean it’s increased at risk for seizures. Do you treat that in Syngap knowing that 90% of the patients are going to finish having true seizures or how do you deal with that?
Dr. Aledo-Serrano: Yeah. So there is also a cognitive bias for doctors. We call it the “tool bias” that for a hammer you only see.. how you call, nail or…? Yeah. So for physicians we only see seizures because we only have anti-seizure medication. So we we don’t have medications for the underlying cause. So because of that we are like very concentrated on seizures so because of that sometimes we we want to look to other side and don’t see the EEG abnormalities. This is something also which is changing because for example in tubular sclerosis, which is another genetic epilepsy, for the first time in history we have proved that if you have an abnormal EEG and you start medication you can prevent epilepsy. This is something which is the first time in in the history of neurology because we couldn’t prove this before but this is only for tuberous sclerosis. We don’t know if we could make it for SYNGAP1. We need more research on that.
Marta: And to extend to that point Mike and I were talking. The older kids there are few of them. Of course we don’t have many teenagers that are transitioned to adulthood but we have at least two patients and I think three thinking about the people that I know in Spain that when they turn 16, 17, 18, they got worse. Yeah. They start with the epilepsy then if there is any thought maybe of something that will protect the brain to progress to that.
Dr. Aledo-Serrano: Yeah. Do you mean people who didn’t have epilepsy and start during teenage?
Mike: They had absence. They had pretty mild seizure phenotype and then right around 16, 17, 18, 19, they presented with a big tonic-clonic and they had to up all their meds a lot.
Dr. Aledo-Serrano: Yeah. Yeah sometimes we see that. For sure this is something we have to describe like the “adult phenotype” of SYNGAP1. Yeah.
Marta: And just for curiosity what they are using for tuberous sclerosis for prevention?
Dr. Aledo-Serrano: Vigabatrin. Yeah, I don’t think it could work well for SYNGAP1. It’s another physiopathology yeah.
Mike: Yeah I’m gonna… there’s so many great questions here. So Nancy Kessler is asking another one and just so you know, I hope you’ve seen that movie about Caren the 65 year old patient. If you haven’t we’ll send you a link but we have a 65… You have?
Dr. Aledo-Serrano: No, no I haven’t.
Mike: We’ll send it to you. It’s very, very good and her sister Nancy who’s been caring for her for 65 years so you could argue Nancy is probably one of the world’s leading Syngap experts at this point and once she was diagnosed with Syngap only last year at the age of 64 That diagnosis helped them get into the care of Dr Devinsky who sees most of our patients in New York area and and she’s saying Dr Devinsky said that the activity can be very deep in the brain and may not always show. Caren shows abnormal activity and slowness. So just staying with this theme that we’re hearing from patients of like they don’t know… the Syngapians don’t always present seizures on the EEG but there’s a certain kind of abnormal activity and slowness and is that just normal for all encephalopathies or is that, could that be something that is, that we can agree is as a Syngap signature? Because it’s just… and I’m only asking this because parents come out of meetings with neurologists confused. You know the neurologist said there was no seizure. I know my kid has SYNGAP1. I know stuff is happening. I’m seeing eyelids move and they said it was abnormal and slow but no one understands what… I don’t know other people do I’m sure. I don’t understand what abnormal and slow means.
Dr. Aledo-Serrano: So yeah, again so normally in electroencephalography we see like three different things: one thing is the background, which is could be normal or with a slowness as as you were saying, one is epileptiform activity with or without symptoms, and the third one is seizures. So eyelid myoclonia, absences, tonic-clonic, whatever. So the background slowing this is something where we see in a lot of different diseases so it’s not anything which is specific. This is something which is a little bit frustrating as well for doctors because is we know there has to be something more specific for every genetic cause and for example we are starting a new research with our with a university here in Madrid which is trying to use artificial intelligence you know deep learning processing to see some signatures in the EEG that we cannot quantify with the neurologist’s eye. So this is something which could have could give us an answer on this. The problem with this kind of research is that you you have to have a lot of EEGs. So you you need like 30 patients with SYNGAP1 and it’s difficult to get so many EEGs on a rare epilepsy like SYNGAP1. That could be a project for the future.
Mike: Yeah. I wanna… I invited Sydney up from our board to ask a question. She can tell you about her son but he has a- I would love it actually Sydney if you could spend a minute talking about Emmitt’s presentation and all of the medications he’s been on because he’s one of our serious cases. Go ahead Sydney.
Sydney: Sure, okay. Hi Dr. Serrano thank you so much for the really informative webinar. Can you guys hear me okay?
Sydney: Okay great.
Dr. Aledo-Serrano: We cannot see you. We can hear you but not see you.
Mike: Okay I’ll move her over to panelist and then we can see her. She has a lot of questions she should pepper… there we go.
Sydney: Hey. My child Emmitt he’s three and a half now but I think Marta and Mike will agree with me that he’s way on the severe side for epilepsy in SYNGAP1 and much like you described the progression of epilepsy type and frequency that’s seen in adults, I actually believe I’ve seen that in him already. From the time of six months he was definitely having eyelid myoclonia and by the time he was 12 to 14 months the myoclonia went from several times a day (where I thought I was crazy) to being you know, one to two hundred times a day and having full body atonic drops, head drops, clonic jerking of the limbs as well and all of this progressed within like six months from six months to about 12 months. And at this point I think we’ve been through seven meds with having five of them at a time even as well as keto diet plus meds and in every situation I find he’s just incredibly medication resistant. Currently on five meds he is still having at least 100 myoclonia a day with probably a dozen to 30 head drops as well and we just feel like we don’t know what to do but it brings me to my question of do you have a best guess for what mechanism or mechanisms are responsible for some of our kids being so resistant to medications and others who are treated with valproic acid and that’s it.
Dr. Aledo-Serrano: Yeah. So for sure we don’t know yet but some hypotheses we are exploring are other genetic variants. You know, like, there is there is something which is being studied which is the polygenic risk score. I don’t know if you know it. It’s something which is not applied normally in clinical practice but we know if that probably if you have a high genetic polygenic risk score probably your monogenic disease SYNGAP1 or whatever it could be more severe. So sometimes we are we are speaking about the myth or the legend of a monogenic disease. So it’s not that there is no monogenic disease. So you have a mutation in SYNGAP1 but you have a lot of other genetic traits which are modeling and changing the the expression of this and also other environment factors like but we don’t know right now. For sure for example the brain-gut axis some behavioral aspects, educational, family aspects but we don’t know. Sorry my answers are not so precise but this is what we have now.
Sydney: No that’s okay it’s understandable there’s definitely a lot of pieces to the puzzle so we’re thankful for scientists who are doing what they can to help us understand how they all fit together. My second question for you is my neurologist has described my child’s eyelid myoclonia sometimes as atypical absence and then other times like as an eyelid myoclonia and I’ve just been so confused by that and I want to understand why is he calling it two different things how do they overlap and in that case where an eyelid myoclonia might be considered some kind of atypical abstinence does that mean we should consider medications like ethosuxamide which are obviously useful for treatment of absence seizures.
Dr. Aledo-Serrano: So sorry I did not understand eye- eyelid myoclonia and what is the other?
Sydney: Absence, yeah
Dr. Aledo-Serrano: yeah so yeah eyelid myoclona is just the jerking of the eyelid which can be associated or not with the the absence seizure so the problem is sometimes for all of the diseases expressed with eyelid myoclonia we know that they are going to be refractory so even people with mild syndromes with eyelid myoclonia without intellectual disability and without any other seizures we see that they are really, really refractory.
Dr. Aledo-Serrano: So we we have not good medications for for eyelid myoclonia. Sometimes we, I have a good experience with perampanel in some patients, with valproic in some patients, with brivacetam or levetiracetam in some patients, Stiripentol maybe in some patients but they are yeah, mostly refractory.
Sydney: Okay. Yeah, I mean that’s definitely been our experience. So maybe I’ll just go out on a limb and ask you another hard question and see what has your experience been recommending VNS or corpus callosotomy for your patients who are just so incredibly medication resistant.
Dr. Aledo-Serrano: So… yeah, definitely is not… we don’t have really really great experience with VNS and callosotomy. Callosotomy you have to choose very well the patient because you can decrease the cognitive profile and it’s only useful for atonic, for drop attacks. This is the only efficacy and the VNS, the good point is that it’s not very harmful. So if it’s not working it’s not very harmful and yeah, the efficacy can be as one of the other medications. So sometimes it’s working, sometimes it’s not working.
Sydney: Okay. I really appreciate your honest and thoughtful answers and thanks again so much for taking time to share with us hey.
Mike: Thanks for your question. Yeah this is this is great. This is great. Thank you Sydney. So Raymond Holden if you’re if you’re reading along and he’ll- and then-
Dr. Aledo-Serrano: I have like five minutes more because they are calling me from the video EEG monitoring.
Mike: Okay so let me be quick. Yeah. Ray Holden says we have a 12 year old diagnosed nine years ago with drop and eyelid. Sodium Valproate worked but we still have myoclonic eyelids due to growth and puberty. Question: do you have any other ideas on adjuvants that might help cognition? And they’ve used Keppra and they also use CBD. So this is the, if I can extrapolate Ray, this is one of the challenges we have as parents, right? We pile on the- we fight the seizures. We pile on the drugs. We see cognition slip and then people start saying is there any way to facilitate the cognition? Because ID is you know, one of the underlying characteristics.
Dr. Aledo-Serrano: So… yeah, the best tool for cognitive is to have the lowest medication. So if you see that with 400 milligrams per day valproic acid is the same for seizure control as 800 per day, go down to 400. So the minimum, the minimal dosage that’s one of the the main points. The other is to try new medications. We are trying, this is something which is starting now and we are in the middle of bureaucracy war, you know, but we are trying to perform a clinical trial with Fenfluramine which is a new anti-seizure medication and we have really good experience with it in Dravet Syndrome and in Lennox-Gastaut. So this is also a new tool to try new medications.
Mike: Is that going to be a basket trial? I heard from that company…
Dr. Aledo-Serrano: We are going to, no, we are going to perform a specific trial in SYNGAP1 but with really few patients is, someone maybe I shouldn’t talk about this but because it’s something which is yeah, in the… we are working on that but I hope we can start that in some months. So it’s a specific trial in synaptopathies STXBP1 and SYNGAP1.
Mike: Please let us know if we can help. We we work closely with STXBP1 here in the states and I know exactly the company you’re talking with and we are very excited about that drug. So that that study is important.
Dr. Aledo-Serrano: I hope that’s working.
Marta: And before you go I really want you to answer the question of Encarnación. She has a hard case of her daughter. She’s from Spain and her daughter started having bad seizures at 18 and she really lost. She used to walk and everything and be very active and now she’s in a wheelchair and care question is how much she will recover or what is your question about recovering?
Dr. Aledo-Serrano: About recovery after motor worsening or…?
Marta: Yes. After, yeah.
Dr. Aledo-Serrano: But the motor worsening was after seizure onset or…?
Marta: Yes I understand that she got worse and and yeah I may connect you later on with Encarnación but yeah she has been very worried because her daughter used to walk and be very functional and now she’s in a wheelchair.
Dr. Aledo-Serrano: So there is always hope when something was in the past and it has been lost because of seizures because seizures can be treated. So we have some experiences with coming back to walk, coming back to talk and all of that with better seizure managing. So there is always hope if the problem is seizures, yeah.
Mike: Thank you there was one last question and it says: How important is genetic testing? Is it useful?
Dr. Aledo-Serrano: Yeah for sure! We need it. We need it. We need to perform genetic testing and all genetic testings are not created equal. So we need good genetic testing. So because now we have the problem that a lot of patients come to our clinic with genetic testing but you look at them and they are really bad testing. So we have to update the genetic testing each two or three years. So if you have a negative genetic testing, you you should repeat it after two or three years.
Marta: And linking to that question: what about we get parents that get the night EEGs and the MRIs for a long time after diagnosis. How often do you recommend that you get EEGs? And how often do you get MRIs or just the studying MRI and then no more?
Dr. Aledo-Serrano: So for MRI if it’s SYNGAP1 or a genetic epilepsy…?
Marta: For SYNGAP1, yeah.
Dr. Aledo-Serrano: It’s not necessary to repeat it. I would only repeat it if something really different happens. So in that situation I would repeat it but normally it’s okay with one MRI. We don’t need to repeat it. For EEG monitoring I would repeat it quite often. It could be once a year or once per six months or once per seizure change. So if you have a cognitive worsening, if you have a seizure change you should repeat an EEG. And as long as you can. One hour is better than 30 minutes. Two hours is better than 30 minutes. Four hours is better than two hours.
Mike: Thank you. I know you’ve got to go. Yeah so…
Marta: Thank you so much!
Dr. Aledo-Serrano: Thanks for having me. I’m sorry for my English. I know it’s not so fluent but I try my best.
Mike: This is great. This has really been valuable and I think a lot of families will watch it and benefit, so thank you.
Dr. Aledo-Serrano: Thank you all. Hope to see you soon. In person!
Mike: Yeah and good luck with that trial. Anything we can do. That’s an important trial.
Dr. Aledo-Serrano: Thank you Bye.
Marta: Thank you Ángel.