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Uh So I'm here today with Professor Norman Delonte. It's a real pleasure. Pleasure to have a conversation with him today. Um uh Professor Dante, I wonder whether you could maybe kick off just by, by introducing yourself explaining a little bit about your research interest. And then we're going to dive into some of the really interesting research that's happening in epilepsy right now. Hi, Phil, thanks. Uh Hi, everybody. My name is Norman Delonte. I'm a neurologist with a particular interest in epilepsy. Epileptologist. I'm based uh at Beaumont Hospital in Dublin and also at future research Center, which is based at the Royal College of Surgeons in Ireland where I have an academic appointment. Um So my main interest clinically is in epilepsy and uh epilepsy research, I suppose at this point, primarily in epilepsy, genetics and how epilepsy, genetics might guide uh treatment and future specific, what we call precision treatments depending on uh molecular diagnosis of an individual's epilepsy. So that's me. Um uh Currently, um it's really great to have a conversation with, with you today. Professor. I wonder um we've just had a BM that's happened um in uh in the last month um what were the kind of key topics that were being discussed in epilepsy at ABN this year? Um So I suppose there's a lot of interest currently um in what might be called I mentioned already precision therapy or targeted therapy or niche therapies for individual um syndromes. Um for example, uh grave syndrome, which is severe myoclonic epilepsy of Embassy Lennox Gastaut syndrome, which is a more of a rag bag diagnosis, which includes a lot of severe epilepsies that have different types of genetic causes or no known genetic cause. Um And there's also of course interest in the in the new um with the newer anti seizure medication, see, noble mate, which has now got approval um in, in many parts of the world and just recently approved in the UK and Ireland and funded. Um that's seen Obama is a novel antiseizure medicine which has been available in some other countries for, for a while. It's got a dual mechanism of Axion and it's approved and can be quite useful for a factory focal epilepsy. But in terms of the the niche therapies for Dravet syndrome and Lennox Gastaut syndrome. Uh there was a number of symposia on uh drugs like fenfluramine and another drug Epidiolex, which of course is pharmaceutical grade um kind of a diet. There was no new absolutely novel clinical trials presented at ABN in Belfast. But there was a lot of discussion about, as I say, uh precision therapies and and some discussion about Sinemet. There was also of course, some discussion about the old chestnut of trata Jenness it Ian of sodium valproate uh issues around folic acid dose supplementation. Um uh A and then of course, there was A B and of course, it's not the A B N I N A meeting association, British Neurologist, Irish Neurological Association joint meeting. There was quite a bit of discussion on other topics of neurology such as Myasthenia gravis, uh multiple sclerosis. Of course, there was a guest lecture on chronic traumatic encephalopathy, which of course is very topical given issues around multiple concussions. And then there was some very interesting discussions about emerging novel therapies for Alzheimer's disease and other dementia. So it's not confined to epilepsy. And I would say, as I said, there was no one knew specific trial presented but just discussions about recent trials and recent uh new avenues of therapeutics if you like in epileptologist. E uh really interesting. So you've, you've mentioned about precision medicine uh particularly in, in epilepsy. Um How close are we to, to seeing precision medicine being rolled out in, in epilepsy? Well, to, to a minor degree, it's already happening. And we were uh so it's not obviously um the number of patients and families who are positively affected by, by what we call precision therapy is still small, but it's already happening. It will increase over time. I mean, the basis for precision therapy, of course, is precision diagnostics, you won't understand the molecular basis of somebody's epilepsy. And we should not be using the term the epilepsy's because it's not, it's a whole collection of different disorders. But the base, the starting point for precision therapy is precision diagnostics. And that usually means uh significant detailed genetic testing in, in appropriate patient's where there is a strong suspicion or a reasonable suspicion that somebody might have a genetic epilepsy. So what we're talking about really is early appropriate either whole exome sequencing or gene panel testing. Now, there's issues around resources and I know you're interested in that. Um not everybody has an and every healthcare society is, I won't use the term struggling but but trying to incorporate appropriate genetic testing, whether that's all excellent sequencing or otherwise into the diagnostic paradigm. But there's plenty of studies in epilepsy, for example, that have been published in both pediatrics and adults that early appropriate whole exome sequencing is cost effective because you find in some of these patient's the precise molecular diagnosis and then the so called diagnostic Odyssey etcetera is foreshortened. And you want you, you understand the exact nature of this person's epilepsy and there may, may not be a precision therapy. So to answer your question, that's already happening and gradually it will it will happen more as as more people are tested, but also as more genes are discovered and is more basic science research is translated into clinic. I mean, an example, I suppose the most robust example of precision therapy in the epilepsies is the use of ever alignments in tuberous sclerosis complex. And that's, that has, that has an evidence based in terms of the exist tree trial, wherever alignments was shown to be a benefit in individuals or tuberous sclerosis complex, um who had ongoing refractory seizures. But we've done a recent work using everolimus in patients with non tuberous sclerosis enteropathy. So other proteins with mutations causing a dysfunction of the entire system. For example, the gator one complex that, that involves three proteins. And we've done some preliminary work using everolimus in non T S uh epilepsy with some positive effects. In fact, we just heard recently that uh our case series manuscript has just been accepted for publication. So there's a, there's a lot happening in, in in precision therapies, but I like to use the term to slow drip, drip of progress. It doesn't happen overnight. It just happens by degrees. And uh you'd mentioned there that, that there are some barriers to implementing uh precision medicine particularly in low resource settings. How are we, I guess to start in the high resource setting? Uh What what, what, what, what scale do we face those barriers in high resource countries? And then is there anything that um that can be done in these kind of low resource settings to make this sort of therapy more generalized herbal or more available? Yeah, I mean, that's a difficult question to answer. I mean, it's clearly a problem even in so called high resource countries. Part of that is, um, lack of knowledge and lack of education that, um, you know, if you're a job in general neurologist, it's difficult to think about or even know about all the different genes that are mutated that might, you know, that might cause your patient's phenotype. So, it's, it's lack of information, it's lack of knowledge. It's um it's lack of appreciation of uh the value of a really appropriate testing. Even from an economic point of view. As I said earlier, if you make an early diagnosis, get the patient on the right drug, then not only of course, which is the most important thing there. And the family's quality of life will be better but will be less visits to the emergency department. They will be less injuries, there'll be less use of essentially unnecessary CT scans. So there's a big piece here around pharmaco economic evaluation of genetic testing and some of that was already done. As I said, um, you know, and you need to advocate, I mean, I've told our business manager manager and department that, you know, this is important, this works expect a 10% year and a year increase in maybe the cost of the department's genetic testing bill. And we need national strategies in Ireland. We just had a national strategy for genomic medicine announced on for, for all diseases which is fantastic. Um So it's a constant challenge. It's, it's, it's, it's, uh there's no one answer and then in a, in a so called more resource poorer setting, um I'm not sure what the answer is except for like what you're trying to do, fellas is more education and get the word out there that this kind of medicine makes a big difference to people's lives and it can save taxpayers money as well. No, you don't want, you know, sometimes I'm asked, okay. So for somebody with new onset epilepsy, apart from taking a good clinical history and making a robust diagnosis. Um and apart from obviously routine blood tests and E C G etcetera, the two main tests uh ideally that are used in somebody with early onset or new onset epilepsy as an E G, which is just uh it's snapshot in time. That's not to be all and end all and generally good quality imaging, which usually means an MRI. Although again, important resource poor settings, that may not be the case. It could be a CT. Of course, that's not bad either because the CT is better than an MRI for neurocysticercosis. But that's another story. But I'm asked sometimes, well, should every person with new onset epilepsy have a whole Exxon sequence? I don't think that we're at that stage because um that certainly would not be cost effective, but you would, you would look down the road even in 5 10 10 years time. And again, we may be talking about more resource richer countries will, will neonatal, it's have a whole exome sequence that then is curated for the rest of their life and their health care journey. So this opens up lots of uh different issues and questions. We're not really talking here about epilepsy trials, but we'll get onto that and how genetics can, can lead into more, more uh smaller but but targeted clinical trials as well based on genetic testing. So we come around circle to that to I got to, I got to squeeze in one more question about about the whole exome sequencing and genetic testing. And then, and then we're going to be straight onto to epilepsy trials. But if you are, so you mentioned the jobbing neurologist there. Um what point should jobbing neurologist consider genetic testing? So should everyone be tested? Whose got epilepsy? We've said no. When do we start to think about genetic testing? Yeah, I mean, again, that's a good question. The short answer at the moment still is probably know it depends on the phenotype in the epilepsy syndrome diagnosis. I mean, if somebody has refractory epilepsy because they have mesial temporal sclerosis in their hippocampus. I mean, we've already been disappointed by research sequencing of those large group of patient's and not really coming up with a genetic answer. And but if somebody has so, but then there are more appropriate groups who may well have ongoing refractory epilepsy. These, these would be individuals with epilepsy associated with learning disability, the diagnostic of unknown etiology and the diagnostic him rate. I don't particularly like that term, but it's used to think of a better term. But the diagnostic, we we find a diagnosis maybe up to 40% of those patient's a genetic diagnosis. So, epilepsy associated with learning disability of hit or two unclear etiology. Of course, there could be other etiologies. We there's other etiologies that can be fairly obvious from the clinical assessment. It could be post traumatic epilepsy or somebody might have had encephalitis. So they're generally, we would think that they're, they're, they're, they're the pier causing these patient's. But so learning disability with epilepsy, people with cortical developmental malformations on MRI people with multifocal non lesion, Aleppo Pepsi, people who might have other co morbidities like neuro psychiatric illness, people who might have multi system disease might suggest tuberous sclerosis. So there's a group of patient's but certainly still not everybody because some of the complex epilepsies associated with refractory disease probably are, are probably mixed oligo genic collagenic and environmental. So it's, it's very, we're, we're at this point in time still looking for monogenic disease and not oligo genic apologetic disease. Although we're beginning to make inroads into that now with things like the polygenic risk score. But in terms of therapeutics, that's much more or diagnostics and therapeutics, that's much more difficult. So that's why I suppose I'd frame your question in other ways at what point and with the job in neurologist who's trying, who's seeing patient's with M S and trying to uh seeing patients with dementia, seen patient's with headache, of which there are lots of exciting advances in all those areas as well. But if a non epileptologist, neurologist is seeing patient with epilepsy who's still having very great difficulty with seizure control and a lot of, you know, problems with their epilepsy. I suppose the, the the next thing would be actually referral to a specialist epilepsy center who then can take on things like genetic appropriate genetic testing or video eeg monitoring or more more advanced imaging, for example, got it um makes a ton of sense as promised, let's move on to epilepsy. Trans, we've talked a little bit about A B and we talked a little bit about um advances in genetic text testing and precision medicine for um let Zuma and, and, and think about epilepsy more generally and a global level. What are the most important bits of research that are happening in epilepsy right now? What are the, what are the most important results? Uh You all just should, should know about and maybe we can talk a little bit about the ongoing trials, which perhaps, I mean, I'm just saying there are some ongoing trials all the time, but I I can't give you the details of those from the off top of my head. But um uh the most recent drug that's gone through approval in most parts of the world, I mentioned it earlier seen open it and that was on the basis of a number of international trials. The problem is as I see it with trials for epilepsy and traditionally, that's been trials for a factory focal epilepsy which have been agnostic to cause. So these, these two under group of patient's of temporal of epilepsy, we don't want to worry about cause we just give them drug added to their current drugs. Are we give them placebo added to their current drugs? That kind of trial that add on in refractory focal epilepsy, which is, is the kind of base type of clinical trial that's been used since way back since the decade of the brain in the 19 nineties, since we had all this explosion of new antiseizure medicines. And uh in the last 30 years um is getting harder and harder to do because if you're a neurologist or an epileptologist and you have a patient with ongoing seizures and they've failed six drugs, then you have plenty of other drugs to try. Even though you know, there's a low chance that this, that next drug will work, but it's not zero. So do you try the seven drug from your Armamentarium or do you expose your patient to placebo for at least three months or even longer? And most epileptologists understandably myself included would have a problem with that because we know even from Philip Rivlin's meta analysis of Sudip and clinical trials that there's a higher risk of Sudip in patient's um exposed to placebo in that kind of environment. So these trials are getting really difficult to uh to perform and more difficult for farmers to perform, more expensive and more difficult to justify. So it goes back, I suppose and it is, I suppose my favorite topic to the you, you, you then change your tack and you look at, you, look at etiology, you look at cause. So let's say you have 10 patient's with severe epilepsy, maybe a few centers and they're severe epilepsy is due to pathogenic variants in a particular gene, let's say depth deck five, which is again, an MTR MTR JEAN that's been described over the last number of years has been an important cause of epilepsy. So you then do an end of some trial. If you like or an end of one trial, the patient can even be their own control. Uh But you, you take a small cohort of genetically proven epilepsy involving the same pathway and you give them a drug that you think might be of benefit. And again, I used the example earlier on of everolimus, which is an EMT or inhibitor, those kind of um specific or precision diagnosis driven precision medicine trials, I think is the way of the future in severe epilepsy because we as well understand it more and more but taking a large cohort of two or 300 individuals with temporal of epilepsy and not even thinking about etiology and trying to give them another new compound that's uh that's proving more problematic. Um There, there are some trials, ongoing trials in epilepsy. As I say, I can't. Um there's, there's a number of new drugs that are being developed by different companies but I won't mention companies but I can't and they are happening but they're there because they're so hard to do. They tend to be multinational and sometimes actually interestingly enough and you'd be interested in this fill some of those trials are done in resource poor countries now because resource rich countries and I'm I'm not making value judgments. I'm just saying it as it is in resource rich countries. Then all the 2025 28 anti seizure medicines are available and many of those countries will provide the antiseizure medicines free of charge. For example, I'm lucky enough to live in Ireland and patient's in Ireland don't have to pay for their anti epilepsy. Medications is provided almost called a long term illness scheme because epilepsy is a long term illness. So that's brilliant. Um But so farmers are forced to go to resource poor countries to use novel drugs in clinical trials. Now, that's, that's a problem. I mean, that's what and then your there's issues around. Well, our patient's doing better because their, their medication adherence has been monitored more closely. Is there a greater placebo effect um in different societies? Because they're getting more, they're seeing their doctor or their nurse every four weeks. So there's lots, you know, I'm not, as I say, I'm not in a position at the moment to list out five or six trials that are happening. There are, there are, there are happening but there are, there are issues surrounding them. Super interesting. Um And in 10 to 15 minutes were absolutely brilliant summary of ABN of precision medicine and some of the ongoing trials in epilepsy. Professor Galante. Thank you so much for your time today and we really appreciate it. Thank you, fella enjoyed it.