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Decoding epilepsy: a precision approach to management · VJNeurology Podcast

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  Hello, and welcome to today's podcast from the Video Journal of Neurology.
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  We are an open access video journal sharing the latest neurology news across all major disciplines.
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  Our regular podcast will bring you exclusive insights from renowned experts
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  on hot topics in their fields.
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  In today's episode, we delve into the fascinating world of precision medicine
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  and genetics in epilepsy.
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  Our experts will shed light on how genetic factors are shaping our understanding
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  of epilepsy syndromes and paving the way for personalised treatment strategies.
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  Four international experts will share their perspectives on the vital need to
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  integrate our expanding knowledge of epilepsy genetics into our treatment plans
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  for diverse patients to ensure more informed decisions are made.
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  Although new targeted therapies are being studied for certain syndromes,
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  precision medicine enables the strategic use of current drugs,
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  selecting agents most likely to be effective based on our understanding of the disease.
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  During the podcast, the experts will delve into this capability,
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  highlighting the immediate applicability and potential of precision medicine in epilepsy care.
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  First, we hear from Kristen Park from the University of Colorado,
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  who will delve into how we can use precision medicine principles to guide the
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  selection of anti-seizure medications in order to optimize seizure control and
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  minimize side effects in patients.
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  This approach emphasizes the optimization of existing drugs,
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  extending beyond the focus of developing new genetic therapies.
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  The ability to use current anti-seizure medicines in a more kind of precise
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  way for epilepsy, especially related to the genetic epilepsies.
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  So I think the current state of all of precision medicine is a bit of a broader
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  topic that has a lot more to it.
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  So basically, I talked about a number of more common genetic epilepsies and
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  what therapies we have that can be used in a more more targeted way to treat them.
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  So one of them was KCNQ2, which has been associated with both self-limited neonatal
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  seizures, as well as a more severe epileptic encephalopathy phenotype.
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  I talked a little bit about some potassium channel blockers that are in the
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  pipeline, because our prior potassium channel blocker has been removed from
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  the market. That was Patiga or Izogabine.
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  But there is some evidence that children respond to sodium channel medications
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  because the sodium channel and potassium channel are localized together on the exon initial segment.
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  And so a lot of these children will respond to sodium channel blockers as well.
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  So we discussed the kind of case reports and literature that is available in that situation.
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  We also talked about the use of vigabatrin and tuberous sclerosis.
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  That's a relatively common neurogenetic diagnosis.
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  And I think there's been a lot of interest in using that as kind of true precision
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  medicine to alter the disease course,
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  and there have been some promising trials, although the recent PREVENT trial
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  that came out in August did not necessarily show benefit to preventing the development
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  of epilepsy in children who were pre-treated with vigabatrin.
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  They did have a lower incidence of infantile spasms that started a bit later,
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  but none of the other endpoints were significant.
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  That may have been because they had a low number of patients or their enrollment
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  was not as, I guess, robust as anticipated.
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  So I think that was a second one. We also talked about the use of parampanel
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  in GRIN disorders, so disorders of ionotropic glutamate receptors.
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  And those come in a number of different flavors. There's not much evidence.
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  There was only two single case reports.
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  And that medicine is positive allosteric modulator of AMPA receptors.
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  And was used in a couple of children with some benefit.
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  Most of these are not robust studies that are done with randomized controlled
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  trials, but are, you know, small series of patients from either a single or
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  a number of different institutions that have shared data.
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  The first key factor is to understand whether the patient actually has the diagnosis
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  that you think they do, right?
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  So our genetic testing can be quite complicated to interpret.
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  And so a lot of times people will have variants that are not quite clear and
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  they get that diagnosis even though it may not actually fit.
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  So I think the first is to clearly establish that they have the diagnosis.
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  I think second is that a number of the genetic conditions that I talked about
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  have mechanisms of disease that exist in both overactive forms and underactive forms.
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  So So haploid insufficiency, loss of function, so to speak, and then also gain
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  of function or overactive channels or receptors or whatever it may be.
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  And that creates a very different landscape for the use of medications, right?
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  You wouldn't want to give someone who has already a low functioning sodium channel
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  additional medication to block that sodium channel further unless you really
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  understood the mechanism at a precise level and that was indicated.
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  So I think that is where the intersection of functional studies and a really
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  in-detailed assessment and understanding of the mutation is necessary before selecting the agent.
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  One final thought would also be dosing. So I think a lot of these kids,
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  at least with some of the sodium channel blockers and sodium channel disorders,
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  need super therapeutic doses sometimes to have the effect that we think they will.
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  So I think it's important to review what literature there is to kind of get
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  a handle on what to do in each situation.
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  Simona Balestrini from University College London talks on the importance of
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  looking at the entire genome to gain a better understanding of epilepsy phenotypes.
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  She emphasises a holistic approach that goes beyond the idea that a single mutation
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  is the sole cause of the disease phenotype.
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  So in fact actually we are moving more and more from the monogenic concept of
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  epilepsy epilepsy to a kind of more complex architecture background of each
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  individual with epilepsy.
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  And I think one way is to fully understand the phenotype.
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  So not to stop the epilepsy presentation, but see, for example,
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  what are the comorbidities?
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  What is the course of the disease over time?
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  So really focus on the single individual presentation. presentation
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  and then an important tool of course is
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  genomics because genomics often give us a
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  monogenic cause but for example we recently showed how
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  in Dravet syndrome also the rest of the genome
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  can play a role in the clinical presentation of the disease so it is definitely
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  important to recognize a monogenic etiology when that is present but then I
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  think more and more we are going towards the whole genome characteristics to
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  understand the phenotypic variability.
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  The variability in treatment response, the variability in the outcome,
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  the variability in the comorbidities presentation.
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  So I think that the more we will understand the genome in terms of gene expression
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  at different ages, in terms of role of gene modifier,
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  in terms of regulation of the genome in general, the more we will be able to
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  tackle the complexity of rare disease presentation and rare epilepsy in this context.
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  Reetta Kalviainen from the University of Eastern Finland rate how genetic testing
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  is fast-tracking progress in epilepsy by helping confirm clinical diagnosis
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  and allowing disease identification at earlier stages.
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  Her clinic has been meticulously documenting patient outcomes to explore the
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  relationship between epilepsy phenotypes and genotypes.
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  We caught up with her on the importance of this work.
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  Already now, it's very important to understand that, for example,
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  in these monogenic diseases, but also in mitochondrial diseases,
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  when we recognize the genetic disease, we can modify the treatment.
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  So we know already that there are some drug treatments that we should use and
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  then some drug treatment,
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  drugs and disease medications that we should avoid.
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  And the list starts to be quite comprehensive already now.
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  And of course, when we do this work more and more, then I think the list will
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  start to be really comprehensive and we are going to be having a huge amount of more data.
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  And this is also really important that we do the research.
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  So personally, what we are currently doing in my clinic, we take the consent
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  of every epilepsy patient, whether they have a severe epilepsy or common epilepsy, mild epilepsy.
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  And we try to also find new things.
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  And that has been very promising that we have really found out also new ways of thinking.
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  And surprises that explain why this patient reacts to this drug like he or she does.
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  And that's the way to learn more. But already at this point,
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  we can adjust the medication according to the genetic findings.
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  And therefore, it's important that people start to use genetic etiology determination
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  determination better and better and more than they used to be.
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  Of course, I understand that not all patients want to do it.
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  And we need to also, of course, take into account the content of the patient
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  and how they react and perhaps inform them better to understand the benefit.
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  The scene of genetic testing has rapidly changed.
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  And I think every clinician a season, doing diagnostics of epilepsy should be
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  now more and more aware of the possibilities of genetic testing.
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  So I think we rarely use that.
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  But now I think more and more we should be aware of the possibilities and especially.
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  Of course, early one-set epilepsy. So earlier the one-set is,
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  the more possibilities there are to be found genetic reasons and etiologies
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  for the epilepsy. That's for sure.
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  But then, of course, also later on, if the person has intellectual disabilities,
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  for example, any kind, not only severe ones, but also milder ones,
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  some cognitive developmental problems, learning difficulties,
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  that's a sign that we should already start to think about genetic testing.
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  Then dysmorphic features, of course, could be a sign of possibilities to find something.
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  And so these are signals of genetic things. And we must remember that genetic
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  is not equal to familiar.
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  So we are not talking about epilepsies that you should find in the family.
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  That's of course an indication to do genetic testing, but majority of the mutations
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  that we currently find, they are de novo mutations,
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  so new mutations in the patient that we are looking at.
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  Then personally, I'm really interested in progressive myoclonic epilepsies,
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  which do not start early.
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  Many of them do not start early. Some of them do, but many of them start in
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  perfectly healthy child or teenager later on.
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  And then you start to have tonic-clonic seizures and then myoclonic seizures.
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  And then you start to have also other neurological symptoms like cognitive problems
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  or ataxia or other things.
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  And that's, again, another field where we currently have many,
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  many, many new genetic diseases.
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  So, for example, these are some of the very interesting areas where more and
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  more genetic testing can be used and new diseases are found.
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  Finally, Guido Rubboli from the University of Copenhagen introduces the use of
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  precision medicine to correct genetic defects in epilepsy, addressing its challenges,
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  such as dealing with small group sizes and limited data.
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  Additionally, he discusses emerging strategies in precision medicine,
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  highlighting the importance of optimizing existing compounds by leveraging our
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  growing understanding of epilepsy genetics.
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  Well, in the last decades, two decades, I would say, genetics has entered the field of epileptology.
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  And we have found a certain number, significant number of epileptic conditions,
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  particularly with onset in childhood, that can be caused by variant,
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  pathogenic variant in some genes.
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  So we know now that a certain number of these conditions have a genetic cause.
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  This is extremely important because, of course, we can provide a diagnosis to
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  the families or to the patients, but also we can try to find out treatments
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  that can try to correct the genetic defects.
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  This is what we call precision medicine, and we have developed a certain number
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  of studies that have tried to address these issues.
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  So, how drugs are already available in the market or how we can develop new
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  drugs or other strategies that can try to rescue the genetic defect.
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  The issue is that the conditions that I just mentioned, so these epileptic disorders
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  with the genetic cause, most of them are rare diseases.
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  So the number of subject effects are quite few. And so, the studies that have
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  been done so far have been done in a limited number of patients.
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  And this provides a limited number of data. So, most of the data so far are
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  anecdotal or in very small cohort patients.
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  So, we need to expand the population of the patients that have been subject
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  or treated with the precision medicine.
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  This is one of the main hurdles. Another one is that even when we have some
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  studies, or when some studies have been attempted but the results have not been
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  good, results have not been obtained, negative results usually are not published.
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  There have been no systematic search of which genes to study.
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  So this I would say that the precision medicine approach to epileptic condition
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  is still there in its infancy.
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  We are just starting. We need to have better studies, larger cohorts,
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  longer follow-up, we need to have also the natural history of this condition
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  to identify better endpoints and better outcome measures.
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  These are the challenges that we are facing now when we are talking about precision
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  medicine in rare genetic epilepsies.
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  We have several compounds.
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  What has given us precision medicine is also how to better use compounds that
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  we had already in the markets, because we know that these compounds act particularly
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  well in that genetic defect.
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  But also, there is a new line of compounds under development.
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  Several new molecules have been under development, much more specific,
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  much more selective than the older compounds that are more larger population of patients.
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  In addition, we have also new strategies, for example,
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  the antisense oligonucleotides, which are small pieces of DNA that try to match
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  the RNA to modify or suppress the production of abnormal molecules.
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  And this is a quite new approach with very, very few studies in humans.
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  I would say we are still at the beginning.
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  And then in the next future, what we expect is to use gene therapy.
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  So, to replace a defective gene with a gene that works properly.
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  There are no studies in human, in epileptology. We are having the first studies
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  in animal models, which are quite promising.
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  But still, this is, I would say, the next frontier in precision medicine and epilepsy.
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  We hope you enjoyed tuning into today's podcast on this very important topic.
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  From correcting genetic defects to understanding entire genomes,
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  our speakers have illuminated the path towards more informed decisions
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  in epilepsy care if you found this episode useful we would
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  love it if you could leave a review to make sure you don't miss any episodes
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  join in the conversation and visit vjneurology.com for the latest updates in
• 17:39
  the field until next time,
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  you.