Genetic testing for epilepsy surgery: Dr. Pat Moloney

In the second episode of our genetics and epilepsy series, Sharp Waves explores how genetic insights can inform considerations and outcomes of epilepsy surgery. Dr. Alina Ivaniuk interviews Dr. Patrick Moloney, currently an epilepsy genomics fellow at the Chalfont Center for Epilepsy at University College London.

Selected publications:
Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy? Epilepsy Res 2024

Genomics in the presurgical epilepsy evaluation. Epilepsy Res 2022

Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.

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The International League Against Epilepsy is the world's preeminent association of health professionals and scientists, working toward a world where no person's life is limited by epilepsy. Visit us on Facebook, X (Twitter), Instagram, and LinkedIn.

Transcript

[00:00:00] Dr. Alina Ivaniuk: Welcome to Sharp Waves, the official podcast of the International League Against Epilepsy. I am today's host, Dr. Alina Ivaniuk, and today we are delving into a hot, promising, yet still under investigation topic. We'll discuss the considerations and outcomes of epilepsy surgery in patients with genetic epilepsies exploring how genetic insights can inform surgical decisions and improve patient care.

I have a fantastic guest with me today. Joining us is Dr. Pat Moloney, a neurologist and an epilepsy genomics fellow at UCL, University College London. He has extensively studied the genetics of focal epilepsy and precision management of those cases, with particular focus on encephalopathies, which we'll also discuss today.

[00:00:52] Dr. Pat Moloney: Hi, Alina. Thanks very much for inviting me to chat with you today. So, as you said when I was working on this topic, I was actually based in Dublin, working as a clinical research fellow at Beaumont Hospital and the Future New Research Centre. Now I'm based in the UK working as an epilepsy genomics fellow at the Chalfont Center for Epilepsy at UCL. And I'm actually returning to Ireland next year to take up a position as a consultant neurologist in Dublin, so hopefully I'll get to continue my research there. 

[00:01:22] Dr. Alina Ivaniuk: Fantastic. Congratulations on all your career achievements so far, and we are looking forward to see how it evolves further. 

I think you are a very good person to give us insights into the topic. Let's start with more of a general overview of epilepsy surgery in a general population. Could you summarize which clinical factors are associated with the decision to perform epilepsy surgery? Who is a perfect epilepsy surgery candidate?

[00:01:55] Dr. Pat Moloney: Yeah, sure. So I think there are generally three main factors to consider when we're evaluating someone on whether they might be a good candidate for epilepsy surgery.

So first, we have to assess whether the individual truly has drug-resistant focal epilepsy. They must not have achieved adequate seizure control, despite having multiple trials of appropriately chosen and used anti-seizure medications.

And then if they meet this criterion, then the next step is performing a comprehensive pre-surgical evaluation. So this includes a period of video EEG monitoring, high-resolution MRI scanning, neuropsychology and neuropsychiatric assessments, and then possibly other investigations like PET, ictal SPECT, MEG, depending on the initial findings of the evaluation.

And once these assessments are completed, a multidisciplinary team review and meeting happens where the clinical EEG and imaging data are all evaluated to determine if there's a single focal area responsible for the seizure activity. They also assess the likelihood of whether removing this particular focus, what's the likelihood of it leading to seizure freedom or a significant improvement.

And then I guess the third, resection poses a risk of neurological deficits, particularly in areas affecting motor skills, vision, cognition, or language. So the potential risks of surgery are carefully weighed against the expected benefits. And then in some cases, after the initial evaluations, the team may recommend intracranial EEG monitoring. This is done to further refine the localization of the seizure onset and to assess if there's any potential risks to eloquent brain regions. So I think that's the general process and the different things that are considered in the surgical evaluation. 

[00:03:54] Dr. Alina Ivaniuk: Thank you so much for this very comprehensive, brief, but very comprehensive overview.

And I guess it all boils still to the area, some focal area that is responsible for the seizure generation. Yet, if we are talking about genetic epilepsies, stereotypically, they are considered by many people as either multifocal or generalized. Is it always true? And if not, could you give some examples of genetic epilepsies, or rather, we'll be talking I guess about monogenic epilepsy, yeah, those caused by single gene disorders, which would have focal presentations.

[00:04:34] Dr. Pat Moloney: Yeah, sure. So yes, I agree totally with you that the monogenic focal epilepsies receive less attention compared to the genetic developmental and epileptic encephalopathies.

And the way my brain thinks about them is that there's primarily three focal epilepsy phenotypes that are known to have monogenic causes. So the most well-known of these is sleep related hypermotor epilepsy, which was previously called autosomal dominant nocturnal frontal lobe epilepsy, and this can be caused by mutations in the nicotinic receptor subunit genes and also the potassium tunnel gene KCNT1.

The second phenotype is epilepsy with auditory features, which is also called lateral temporal lobe epilepsy. And this can be caused by mutations in the LGI1 gene. And then finally, there's a phenotype known as familial focal epilepsy at variable foci. And this is a syndrome where relatives experience focal epilepsies originating in different brain regions. So, for example, the proband might have temporal lobe epilepsy, while his affected brother might have sleep-related hypermotor epilepsy originating in the frontal lobe. So these are the three kinds of syndromes. Obviously, there's other presentations, but I think these are the classical syndromes you see with monogenic focal epilepsies.

[00:06:01] Dr. Alina Ivaniuk: Excellent. Thank you so much for giving those examples. So not all of them, indeed, are those severe, multifocal, or generalized phenotypes as everybody tends to think about. And that's something insightful, and I think we could probably dive deeper into some of the etiologies that everybody talks about because it's a hot and recent discovery or development.

And I'm talking about the GATOR complex associated disorders. Yeah. NPRL-2 and NPRL-3, DEPDC-5 related epilepsies. They recently emerged as ones causing primarily focal epileptic phenotypes. Do you mind talking more about those specific phenotypes and if epilepsy surgery could play any role in treating those epilepsies?

[00:06:49] Dr. Pat Moloney: Sure. Yeah. So as you know, a lot of my research was done looking at this area and the GATOR1 protein complex is encoded by three genes. As you mentioned, DEPDC5, NPRL-2 and NPRL-3, and the GATOR1 complex acts as a negative regulator of the mTOR or the mechanistic target of rapamycin pathway, which epilepsy clinicians may recognize from its involvement in the pathogenesis of tuberous sclerosis complex as well as focal cortical dysplasia type 2. So, as I mentioned, the classic epilepsy phenotype associated with GATOR1 gene mutations is familial focal epilepsy with variable foci. There are other phenotypes that have been reported, including sleep related hypermotor epilepsy, temporal lobe epilepsy, and Rolandic epilepsy.

Interestingly, around 20% of people with GATOR1-related epilepsies have focal cortical dysplasia on their imaging and importantly, more than 60% have drug-resistant epilepsy. One of the interesting things about the GATOR1-related epilepsies is that they display reduced penetrance. So in roughly 60% of the cases in the literature, individuals with GATOR1-related epilepsies inherited the pathogenic variant from an unaffected parent, which complicates genetic counseling in these individuals. And as you mentioned, the research indicates the people with focal GATOR1-related epilepsies may benefit from epilepsy surgery. And in the published literature, around 60% of those people with this type of epilepsy who went for epilepsy surgery had positive outcomes.

However, it is important to note that there may be a publication bias favoring the reporting of cases with successful surgical outcomes. So we do need to keep that in mind. 

[00:08:44] Dr. Alina Ivaniuk: Yeah. And that's a fantastic conclusion and something that indeed we need to keep in mind that usually reports tend to talk about successful cases. And some of the cases that were not successful may remain in shadows and we just don't know about them. 

Can I also talk about some epilepsy phenotypes or disorders usually associated with classical epilepsy because they are, the reports are less frequent. Individuals with channelopathies, for example, or synaptopathy, but still there are different reports reporting different results. Some of them are successful, some of them have less of a success. How much do we know about epilepsy surgery outcomes in those cases and what are possible explanations for efficacy or non-efficacy of surgery in those cases?

[00:09:44] Dr. Pat Moloney: Sure. Yeah. So I was thinking, I think maybe a good way to approach this question would be using an example of a particular gene. So pathogenic variants in the sodium channel gene SCN1A are known to lead to a range of phenotypes. The most recognized phenotype is Dravet syndrome, which is marked by early-life febrile seizures, developmental regression, intellectual disability and then treatment-resistant multifocal epilepsy.

However, SCN1A pathogenic variants can also cause a multitude of phenotypes, including genetic epilepsy with febrile seizures plus, or GEFS+, focal epilepsy and even hemiplegic migraine. So in a systematic review of the literature, which I published in Epilepsy Research, I examined the outcomes of surgery in patients with SCN1A mutations and those who presented with Dravet syndrome, particularly if they were characterized by multifocal or generalized discharges, they generally had poor surgical outcomes. However, cases in the literature with milder phenotypes and unifocal seizure onset tended to fare better. 

Though again, it's important to note that the number of cases in the literature was very small. And we further investigated this in a retrospective study of surgical outcomes and monogenic epilepsies across a number of international centers, including our own in Dublin. This was also published in Epilepsy Research. And in general, individuals with channelopathies who underwent surgical evaluation generally did not go on to have surgery, probably because of the outcomes of their investigations, but there was a single case of Dravet syndrome who did have surgery and his outcome was unfavorable. I would say that the SCN1A variant in that case wasn't identified until after surgery, and so maybe the decision to proceed may not have happened if it was known about. 

So I think the message I take from this is having an SCN1 mutation is not a contraindication indication for surgery. However, if a person's phenotype is consistent with Dravet syndrome, the surgical outcome is likely to be poor and pharmacological and neuromodulatory treatments potentially should be considered as opposed to surgery in these cases. 

[00:12:09] Dr. Alina Ivaniuk: Thank you so much for sharing this overview and pointing to the research in the topic.

And indeed, I think one of the most important things that you mentioned that we are still accounting for the phenotype and how it feeds into the overall framework of epilepsy surgery candidacy, and if the phenotype is potentially amenable to surgery, then there could be some sort of positive outcome, whereas if the phenotype is generally less amenable than we are talking about, possibly not proceeding to surgery. This is another important outcome or consideration.

 There was one question that I think lots of people are asking in this regard and we still don't have a good answer. We know that in long-standing seizure disorders, people are at risk of development of hippocampal sclerosis. And if it happens, potentially that lesion is amenable to surgery, but especially if it happens on the non-dominant side. Do we know if the outcomes of epilepsy surgery in people with genetic epilepsies with concomitant hippocampal sclerosis are favorable or not?

How should we approach that? Do we have enough data to judge on that or not at all? 

[00:13:30] Dr. Pat Moloney: Yeah, so yeah, no, that's a great point. So there are some monogenic epilepsy disorders that cause febrile seizures in early childhood and then subsequent development of hippocampal sclerosis. So this phenomenon has been described with both SCN1A and SCN1B variants and several reports, including our own retrospective multicenter study report cases of epilepsy surgery in individuals with SCN1B related temporal lobe epilepsy due to hippocampal sclerosis. And generally the seizure outcomes in these cases have been very positive. So I think SCN1B related epilepsy, if there's evidence of hippocampal sclerosis and a unifocal seizure onset, this is an example of a monogenic epilepsy that can be a good surgical candidate provided all the other investigations point to a single focus. I think that's the important factor.

[00:14:27] Dr. Alina Ivaniuk: Another question, sometimes there are concomitant focal cortical dysplasias or something regional that can be on the MRI. And there is an FCD on pathology. If that happens in people with monogenic epilepsies is there any data to support surgical intervention?

[00:14:48] Dr. Pat Moloney: Yeah, so, as I mentioned earlier, FCD type 2, which is classified as an mTORopathy, patients with tuberous sclerosis, DEPDC-5-related epilepsy, and other forms of mTOR-related epilepsies, they may present with focal cortical dysplasia type 2. And in general, these patients seem to respond well to surgery. Provided, I keep on going back to that statement, provided all the investigations align well and the lesion doesn't involve eloquent brain regions. However, I guess, FCD type 2 is a very well characterized lesion and it's generally well circumscribed and we've known for many years that this is a lesion that does respond well to surgery.

FCD type 1, on the other hand, is a less well defined lesion. And in very rare cases, it has been associated with genetic variants in SCN1A, KCNT1, PCDH19. And in the very limited cases documented in the literature of people with these genetic variants having surgery for focal cortical dysplasia, the results have generally been poor. I'm not aware of any cases that have had seizure freedom from surgery with these disorders. I guess the other question, there have also been cases of FCD type 2 being reported in people with channelopathies and other genetic epilepsies and I guess in those cases, the consideration is whether the FCD is an incidental finding in somebody with an additional monogenic disorder and whether you treat the lesion separately from the other genetic disorder. I don't think we know the answer to that. And I'm not sure if there's enough cases out there for us to make conclusive kinds of conclusions about how to manage these and what are the outcomes in these cases.

[00:16:53] Dr. Alina Ivaniuk: That's excellent. Let's then go from the opposite. Do we know anything about the genetics of most common lesions that cause epilepsy, such as FCD or epileptogenic tumor, and does it matter to know if those lesions bear any genetic variants or not? 

[00:17:13] Dr. Pat Moloney: Yeah, so I guess up to now, we've been discussing germline genetic variants; however, we now know that many of the common lesional epilepsies like FCD and gangliogliomas, they're caused by somatic or post-zygotic mosaic mutations involving populations of cells. For example, the somatic mutation BRAF V600E is one of them. the most common genetic driver of gangliogliomas of somatic mutations, and mTOR are probably the most frequent cause of FCD type 2.

And recently, somatic variants in SLC35A2 have been identified as a cause of the neuropathological entity known as MOGHE [mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy]. Don't ask me to recall what that stands for, but these types of lesional epilepsies can often be treated effectively with surgery, once they're supported by aligning investigation results.

I think we're still in the early stages of understanding the genetic influences in these cases, but I think much will be revealed in the coming years. One major challenge is that these brain-restricted somatic mutations can only be detected currently by sequencing the actual brain tissue. So it's difficult to make pre-surgical judgments based on these lesions and their genetic cause.

However, there are new approaches, like CSF liquid biopsy of cell free DNA to help address this challenge, but I understand that they remain some distance away from being applicable clinically.

[00:18:59] Dr. Alina Ivaniuk: Let's circle back to something I mentioned, but I would like to discuss it a bit further. What are your thoughts on whether or not candidates with epilepsy overall should be tested genetically and if yes, when and how to be incorporated in the surgical assessment workflow?

[00:19:20] Dr. Pat Moloney: Sure, yeah, so I think there's three categories of potential epilepsy surgery candidates who potentially should undergo genetic testing. So firstly, I think as with genetic testing in epilepsy in any context, those with intellectual disability or developmental delay I guess the outcomes of genetic testing in these individuals may not influence the decision to proceed to surgery, but it may be helpful in determining the next steps in their treatment, particularly if surgery is not performed, because in rare instances, there may be a precision treatment option. So I think it's good to be thinking about all of these things during the pre-surgical evaluation. 

Secondly, patients with non-lesional focal epilepsies, particularly those with multifocal or extratemporal epileptiform discharges. So in these cases, the detection of an mTOR pathway gene might raise the suspicion of an underlying focal cortical dysplasia and support further investigation with intracranial EEG or potentially other non-invasive tests.

Alternatively, the detection of an ion channel or synaptic function gene might dissuade further investigations. Although I don't think this rule is set in stone but I think having this information can help inform our decisions. 

And then lastly, I'd recommend genetic testing for patients with specific epileptogenic lesions. So patients with focal cortical dysplasia, gray matter heterotopias, polymicrogyria, cavernomas. I think if we're seeing these lesions in people who are being considered for epilepsy surgery, we should be doing genetic testing to perform a comprehensive evaluation on their etiology.

[00:21:14] Dr. Alina Ivaniuk: Thank you. That was a fantastic discussion. And I think we're coming to the end of it. So is there anything else that you would like to bring to our listeners’ attention before we conclude our talk today? 

[00:21:27] Dr. Pat Moloney: The main point I want to emphasize is that the patients who are considering epilepsy surgery suffer from severe and debilitating forms of the condition. And for these complex, difficult-to-treat cases, I think gathering as much information as possible about the underlying cause of their epilepsy, including their potential genetic factors, is essential because these genetic insights can help guide treatment strategies and provide valuable information about their prognosis.

I think we're still uncovering how genomics can influence surgical outcomes. There is some evidence that epilepsy caused by GATOR1 mutations respond well to surgery. However, beyond this, I think the data is limited and it's difficult to draw conclusions. Ultimately, the clinical EEG and imaging findings remain central to our decisions.

Though I think we're continuing to explore and learn more about the role of genomics in this context. 

[00:22:27] Dr. Alina Ivaniuk: Yeah, that was fantastic. Thank you so much for your time and talking to us. We appreciate your insights and those are invaluable. Let's see how the field evolves and what it will bring to us in the future. And maybe we'll do another interview in a couple of years and see where we went. 

[00:22:44] Dr. Pat Moloney: I'd look forward to it, Alina. Sounds great.