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[00:00:00] Nancy Volkers: Some people with epilepsy also experience memory and learning issues, as well as depression or anxiety. A study in Australia screened people for these conditions at a first seizure clinic before any anti-seizure medications had been prescribed. Compared with the control group, the people at the first seizure clinic had higher rates of all of these cognitive and neuropsychological issues. The study appears in the April 2024 issue of Epilepsia Open.
[00:00:32] Remy Pugh: So my name is Remy Pugh. I'm a final year PhD candidate at the Florey and Monash University in Melbourne, Australia.
[00:00:42] Dr. Chris Tailby: Hi, my name's Chris Talby and I'm a clinical neuropsychologist. I'm a research fellow at the Florian Institute and a neuropsychologist at Austin Health, and I'm the cognitive stream lead on the Australian Epilepsy Project.
[00:00:54] Nancy Volkers: Can you talk a little bit about why you did this study and why it's important to discern if these cognitive and psychological issues are happening before a diagnosis of epilepsy rather than after?
[00:01:13] Remy Pugh: Yeah, sure. So I guess in recent years, there has been a bit of a push to understand the neuropsychological problems of epilepsy. We know they're multi determined, but most of the research is done in chronic epilepsy cohorts, and it is really difficult in those cohorts to separate the risk factors for cognitive or mental health problems.
So our primary aim really is to capture the true effect of the underlying epilepsy pathology on neuropsychological functioning to obtain a bit of a baseline effect of the condition, if you will, and to do this, we chose to assess people as close to disease onset as possible, or after the first seizure was first brought to clinical attention. Because for the safety and well-being of people with epilepsy treatment and lifestyle changes occur as soon as possible after diagnosis. So, already from then on, there's risk factors accumulating. You know, things like anti-seizure medications and subsequent seizures and also like a psychological cascade of adjustments to this diagnosis. So we felt that it minimized these factors as much as possible.
[00:02:33] Dr. Chris Tailby: And then another, another issue that we didn't really talk about it in the paper, but it's an issue that's driving the research that we're doing is we're interested in can some of these neuropsychological measures, if we collect them early in the patient journey, do they provide some kind of signal about risk factors for things like seizure recurrence or medication refractoriness?
And so we already know that severe intellectual compromise, like intellectual disability or dementia, that those already carry elevated risk of things like seizure recurrence and refractoriness but we're interested in this more moderate degree of cognitive or psychological compromise. Is that a risk factor?
So that was another motivation for the study there and some of those selection criteria.
[00:03:16] Nancy Volkers: Got it. Yeah, that makes sense. Could you maybe tag team and walk through your results?
[00:03:23] Remy Pugh: Sure, absolutely. I suppose as a whole, the study found that people with new onset epilepsy did have poorer cognition and elevated rates of clinically significant mental health problems than neurologically healthy peers.
We found that the greatest deficits were actually in learning and memory, but the attention, working memory, and executive skills were also reduced in this cohort, and these problems were present over and above the effects of mood and anxiety symptoms, as reported. In terms of the psychological problems, they were fairly high. The average symptoms of mood and anxiety weren't significantly different to controls, but it was more that there were more people with symptoms in the clinical range.
So about 1 in 3 of the people with epilepsy were at high risk of either major depression or an anxiety disorder, which is pretty high, but also pretty consistent with other epilepsy literature. But I suppose that all of these findings are present and apparent at disease onset, or maybe even before, suggests that these comorbidities are primary attributes of the underlying epilepsy.
And that was kind of the, the main finding out of our data.
[00:04:48] Dr. Chris Tailby: Yeah. And I think, you know, just to reiterate what Remy's said, you know, one of the key things that we think is important about our study is, I mean, we really have captured people as early as is feasibly possible after the index event, before medication has been introduced, and in most instances before seizure recurrence can have occurred.
So, you know, short of a community-wide study where you're tracking people and seeing who develops a seizure for the first time, we think this is realistically as early as possible as you can catch people.
[00:05:19] Nancy Volkers: So you assess these people at the first seizure clinic, you assess them for depression and anxiety and learning and memory issues. Did you ask them if they'd already been diagnosed with any of these, or were you just testing them without asking, you know, are you aware that you have dyslexia or learning difficulties or, or any of that?
[00:05:45] Remy Pugh: Yeah, no, we, we didn't as Chris said earlier, we kind of kept a routine and blanket kind of referral for people. So we assessed everyone coming through whether or not they had issues. And so we weren't specifically asking whether they had those.
Most often it seems in the literature anyway, that a lot of people underestimate the cognitive problems at this stage of the disease. Sometimes people aren't aware or there's other things going on. So we just kind of captured the symptoms or captured the functioning without asking.
[00:06:21] Nancy Volkers: I was thinking about how learning difficulties and anxiety and depression can kind of co-occur because if you have learning difficulties, it can cause social issues, which can make you feel anxious.
[00:06:33] Dr. Chris Tailby: So we're getting into a really interesting area, right? Because we know that learning disorders are elevated in this population and often unrecognized. That’s something we've seen in our practice here. I think one of the points of again, I'm just reiterating what Remy said, was that we're actually seeing people before they come to the first seizure clinic, even like, as soon as their referral comes in, we're contacting them and that's enabled us to get on the radar very early for patients if there are psychiatric issues at play. As well as, the seizures aren't just the sole focus of what's going on here. And then when they come into the first seizure clinic, the clinic is already armed with this information about well, there's some cognitive issues we should be thinking about. There's some psychiatric issues we should be thinking about to hopefully get a rounded picture of the patients when they are seen in that first seizure clinic setting.
[00:07:22] Nancy Volkers: So what I appreciated about your study, and I know this is there've been a couple of other studies that showed that you know, learning and memory issues and neuropsychiatric issues are present when epilepsy is diagnosed and you're even taking a step back even before it's diagnosed.
But I feel like there's sort of another narrative that both of these can be true, right, that epilepsy leads to these things. So having chronic seizures, being diagnosed with epilepsy can cause anxiety, it can cause depression, it can, or it can contribute to anxiety and depression, and then, repeated seizures can also lead to, to memory issues.
So it seems like the study sort of suggests there's this underlying, you know, base of the iceberg is this process that's sort of causing all of these symptoms and seizures are just, just one of them rather than the seizures come first and then all these other things are consequences. Is that kind of how you're looking at it?
[00:08:28] Dr. Chris Tailby: Yeah. It's this idea that there's some kind of underlying fundamental network disturbance of which the seizures are a symptom and of which the cognitive and the psychological issues are a symptom as well.
And so it's that underlying process that gives rise to both. Yeah. I mean, we think our data certainly support that there's an element of that, but, you know, as you also alluded to, there's this interesting dynamic between, you know, if there is this underlying network disturbance that's causing these problems, and there's some other evidence out there that it almost seems like the brain's trying to adapt to that disturbance to keep it contained or keep it controlled, almost firewalling it off.
But then that may have, in turn, have secondary effects on how efficiently information can move around the brain. And so the kind of adaptive response, if you like, could also have secondary effects on cognition, on mood. So there is this interesting dynamic or this interplay back and forward between the fundamental problem and the response to the problem.
[00:09:32] Remy Pugh: And it is really hard to separate it at times. I think the advantages of separating it is that you can work out certain risk factors that might make you more or less prone to these.
So you can kind of anticipate or avoid any extra burden. And in the end, that outcome is what matters and that's what will be treated.
[00:09:52] Dr. Chris Tailby: And then the first step is, you can't manage it or treat it until you've identified it.
[00:09:58] Nancy Volkers: And do you feel like it’s more on the radar, that these issues are more on the radar now than they were say 10 or 15 years ago, as far as people being diagnosed with epilepsy and being screened for these sorts of comorbidities?
[00:10:14] Dr. Chris Tailby: There's certainly greater awareness. And then one of the big, just speaking locally, I think one of the big benefits that we've seen through running and initiating this project is that we've now got neuropsychology deeply embedded in the first seizure clinics, at our local health at Austin Health. And so now, you know, these issues, we're part of the discussion and we're part of the conversation. And so it's broadening the scope of what's dealt with and thought about in the first seizure clinic. So there's, it's definitely on the radar there. Yeah.
[00:10:49] Remy Pugh: You know, historically there has been a more seizure focus when coming through a medical clinic. And I think, assessing things like cognition, but also mental health, improves both the formulation of the patient, but then yeah, also gives a wedge where we can intervene with those things too.
[00:11:09] Nancy Volkers: So is the group planning any further studies in this area and if so, what sorts of things are you working on?
[00:11:17] Remy Pugh: Yes, we are. Within the same project, we have obviously noticed how much memory can be affected. So we are also exploring memory function at extended intervals in new onset epilepsy and looking at the possibility of accelerated long-term forgetting, which is a phenomenon increasingly found in chronic epilepsy. And we're also screening neuropsychological function in other patients attending the first seizure clinic. So this could be things like provoked seizures or seizure mimics like a syncope or migraine, for example. And how the outcomes compare to people with epilepsy.
But we, I mean, more broadly, are really hoping to explore, like Chris said, if there is a signal in the cognitive data, given that there is quite a lot of issues detected early that is a useful predictor of seizure risk, subsequent seizure risk, or medication refractoriness, or other clinical outcomes. But our data at this point is a bit too small for that, so it would require a bit of a multi-center study or have a bit more integrated methods to answer those kind of big questions.
[00:12:31] Dr. Chris Tailby: Yeah, but this kind of gets to, going beyond the study under discussion here, but the Australian Epilepsy Project that I referred to earlier, this is a large federally funded nationwide project. And one of the cohorts that we're targeting is people with a new diagnosis of epilepsy and then we are also recruiting people with a first unprovoked seizure, as well as those with drug-resistant epilepsy and we get broad coverage of cognitive function, genetics imaging, and then we track people over two years to see what happens with their epilepsy.
And the idea here is really to develop large-scale uniform data sets that we can use to apply AI and machine learning to, to try and develop decision support tools to deal with questions like, you know, is this first unprovoked seizure, is there likely to be a recurrence or is this person going to be medically refractory or can we identify a surgical target where we could intervene with this person?
So there is this broader scope of research that's going on in the background that's targeting exactly the questions we've started scratching the surface of in this study.
I might add one other thing if I can. One of the challenges we found in this project was, it was really hard over the telephone environment to derive a good measure of processing speed. This is something we know, this is key in epilepsy. It's key in many neurological conditions. But it was one of the biggest limitations if you like. But what we've developed through the Australian Epilepsy Project is we built our own video-conference-integrated cognitive testing tool so that we can reach people remotely and we can cover all the relevant cognitive domains to epilepsy.
And so we think this is a way that we'll be able to reach people anywhere. Then we can use this to track people longitudinally as well. So we could get a baseline assessment, then we can get a quick follow up when a medication is introduced to see if there's a change. And then people can do that from their home anywhere. This is going to be really important for how we manage things in the future.
[00:14:29] Nancy Volkers: So the last question I had was sort of a little bit off topic, but it has to do with an index event, you know, what is the first seizure?
And it's probably because I've been reading a couple of papers that talk about how many seizures are missed and how many times people think they have a seizure when they really haven't. But you know, I think you said that about a third of the people in your study knew they had seizures before the index event that brought them into your study. So the number could be higher than that.
Does that have any impact on your line of research? Because if there is some underlying dysfunction and everything kind of starts at once, then you're kind of catching these people further along the line than you'd really want to. Because some of them have already been having seizures for months, and they just didn't know it. And so this other, all these other comorbidities have also been developing. So, is there a way we can catch it earlier?
[00:15:26] Remy Pugh: There's often a dramatic clinical event, like a motor seizure or a tonic-clonic seizure is what brings people to clinical attention. And that's kind of where the care or the management tends to start. I mean, our data can't specifically speak to this, but I guess the third that seemed to have the prior unrecognized seizures were really elucidated from a very thorough clinical interview.
And I think probably a very minority of patients will have come and said, I've had these events before. It typically you know, might have been things that they barely recognize or that look a little bit different, or especially if it was a focal seizure that was very different or some auras or things to the tonic-clonic that they experienced when they came to the doctor.
[00:16:15] Dr. Chris Tailby: Thinking about your question it seems to be, you know, I feel like I'm talking outside my knowledge area a little bit here, but the question is how do you increase community awareness of the different manifestations that seizures can take?
And there's some evidence, I think, from stroke, for instance, about public campaigns about recognition of the symptoms that stroke can take, and that's increased awareness of in the community about what to look for. And then, you know, so there could be parallels there with epilepsy education.
I know that in Australia, there's a program called, I think it's called Smart Epilepsy or Epilepsy Smart. It's run through the epilepsy advocacy groups. And that's really targeting, they've got programs for things like the education sector or the disability support sector or aged care sector, where there is a high risk of seizures amongst other things, to raise awareness about how not all seizures are convulsive in nature. They can have these other presentations. It’s to try and raise that awareness so that these issues are picked up earlier in the community and dealt with earlier. So that's a great example of how this can be addressed.
[00:17:22] Nancy Volkers: Yeah. Great. Thank you. I didn't know if you either of you had anything else you wanted to add about the significance of the study or the impact how you hope it's going to help with management or any of those things?
[00:17:38] Remy Pugh: I think together with other similar research in the field, it really does highlight how important neuropsych involvement or neuropsych screening can be for the benefit of these patients.
People often say in the literature that cognitive or psychological problems can really affect quality of life more than the seizures do. And so by identifying and bringing those issues to the forefront at the very earliest time point. again, it can kind of change the way you formulate patient management planning, but it also allows us to refer for more comprehensive assessment, get people the support and the intervention they actually need that they wouldn't have otherwise had, or maybe had only years into their epilepsy journey.
But it also has other benefits, like the neuropsychological profile might influence the choice of anti-seizure medication. You know, there's certain medications with side effect profiles for cognitive and psychological risk, but there's also anti-seizure medications that have mood stabilizing properties. And that might be important for someone with high depressive symptoms or things like that.
So that's kind of another benefit. It in the clinical world, as well as establishing a bit of a baseline for that person about how they're functioning from the start for which future change can be indexed. So, if people start new medications or cease medications, or a patient's reporting any changes in their cognitive or mental health status, that might be a prompt for another assessment and you can kind of see and capture that change.
[00:19:24] Nancy Volkers: Well, thanks to both of you for, for joining me and walking through your study.
[00:19:30] Remy Pugh: Thank you for having us.
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Founded in 1909, the International League Against Epilepsy (ILAE) is a global organization with more than 125 national chapters.
Through promoting research, education and training to improve the diagnosis, treatment and prevention of the disease, ILAE is working toward a world where no person’s life is limited by epilepsy.
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