Diagnosis, Treatments, PreventionsCauses of EpilepsyResearch & Innovation
Written By Torie Robinson

Accelerated Brain Ageing and Neurodegeneration in Epilepsy - Dr. Marian Galovic, University Hospital Zurich, Switzerland

Accelerated brain ageing is increasingly understood as part of epilepsy. In this conversation, Dr. Marian Galovic, Adult Neurologist and Epileptologist, explores neurodegeneration beyond seizure activity, the impact of status epilepticus, and why disease-modifying treatment may help protect long-term brain health.

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This episode is sponsored by EASEE® by Precisis and had no influence over the editorial content or discussion. Learn more about EASEE® here.

 

Episode Highlights

  • Epilepsy causes accelerated brain ageing

  • Neurodegeneration may occur even without frequent or ongoing seizures

  • Status epilepticus causes rapid and severe brain injury and is a true emergency

  • Early, disease-modifying treatment may help protect long-term brain health


About Dr. Marian Galovic

Marian Galovic is a neurologist and epileptologist based in Zurich, Switzerland, and the Head of the Epilepsy Unit at the University Hospital Zurich. He has a strong research interest in the topic of acquired epilepsy, neuroimaging, and brain aging - so-called neurodegeneration. This includes the crucial question of whether seizures actually damage the brain.

Full profile: marian-galovic


Topics mentioned

  • neurodegeneration

  • structural change

  • cortical thinning

  • accelerated brain aging

  • status epilepticus

  • disease modifying

  • hippocampal sclerosis

  • neuroprotection


Related papers

  • Trailer & intro

    00:00 Marian Galovic

    Status epilepticus really is an emergency. And the longer status epilepticus persists to higher the risk of developing brain damage. And we measured this. We looked at, well, actually the most severe forms of status epilepticus that can take weeks or months and we see that during this time the rate of brain damage or brain shrinkage was 80 times that of normal aging. So 80 times!

    00:26 Torie Robinson

    I’m Torie Robinson, and I’m joined by Dr. Marian Galovic, adult neurologist epileptologist and researcher, to explore whether seizures damage the brain and what we now know about neurodegeneration in epilepsy.
    This episode is presented in partnership with EASEE®, by Precisis GmbH. 

    Do epileptic seizures damage the brain?

    00:42 Torie Robinson

    For a long time, epilepsy has been framed as kind of like a conditional disease of intermittent seizures - and almost seizures alone, to be honest - but your work suggests something more fundamental and that epilepsy is a dynamic brain disease, brain as a whole, with progressive structural change. What is actually progressing and why does that matter clinically?

    01:02 Marian Galovic

    Yes, that is an excellent question and one that has been really challenging clinicians and researchers for more than a century. And it is also something that I am regularly asked by my patients and their relatives, the question whether seizures damage the brain. And it is a deceptively simple question, but the answer is quite complicated, I think, and also quite controversial. So, despite more than 150 years of progress into research into seizures, we still cannot answer this with absolute confidence. So the way we try to approach this is by using brain imaging. So we had a look at people who had more than one brain scan and analyse how their brains changed over time. And this is a pretty good approach because brain scans are widely available and they also allow us to measure the size of the brain and or the thickness of it, you know, and how quickly it shrinks.

    Brain shrinkage in those with an epilepsy

    01:59 Marian Galovic

    So there were many studies showing that epilepsy actually is associated with some sort of brain volume loss, but this also happens during healthy aging. In order to sort of differentiate what is related to epilepsy and what is related to aging, what we did was we compared people with epilepsy and healthy individuals who had several brain scans, and looked how much their brains were shrinking or thinning. So, it seems that this is happening much more quickly in people with epilepsy than in healthy individuals. So it seems that their brains are shrinking at around double the speed of normal aging, which is quite a lot. So there is good data showing that the brains of people with epilepsy look as if they have also aged more quickly. So not only we see that this brain shrinkage is happening more quickly, but also we can estimate the brain age. So you, Torie and I, we have our biological age, which we won't tell anyone, right? Because it's a…

    03:07 Torie Robinson

    No! Haha.

    03:08 Marian Galovic

    Yeah, exactly! Haha! But we can estimate or measure our brain age. So what's happening there, we can look at the brain scan and then use an artificial intelligence or machine learning approach to tell us how old does our brain look like. And what this tells us consistently is that the brains of people with epilepsy look around four to five years older than their biological age. So they age slightly more quickly than healthy individuals.

    03:37 Torie Robinson 

    Does this relate to seizure frequency, seizure severity? And do we know if the thinning continues when people have seizures controlled? And do we know why? Why is this happening?!

    Causes of brain shrinkage

    03:50 Marian Galovic

    Here it's when it becomes interesting. So in the past, obviously we thought, well, this is driven by seizures. But what we are starting to see, is seizures are possibly not the only or not the main driver of neurodegeneration or accelerated brain aging and epilepsy. And so there are several reasons why I think that seizures are not the only driver. So first of all, we saw some accelerated brain aging also in people who were seizure-free. So this seems to happen also in the absence of observable seizures. And next, there is also good evidence from the brains of people with epilepsy who died at certain point or who were operated and we can analyse their brains and we can see that even in people who had many, many seizures over decades, we may not find areas of clear damage to nerve cells, right. So seizures may not be the only drive of this, but that's something else happening in the background. And, you know Torie, how I like to describe this to our patients: so I like to tell them, you know what, epilepsy is like a storm in the brain, which is happening in the dark, you know. I'm sure you saw a storm in the dark, so you don't see anything really, unless there's lightning. And so the seizures are the lightning strikes. And why I like this is because seizures are just as unpredictable as lightning so we don't know when and where it's going to happen and that's also what's really, really tricky for people with epilepsy. Now, so what does this mean? Bear with me! What does this mean is that we can only see really the lightning or the seizures but much more is happening underneath it, much more is happening in the background and that's the storm but that's much more difficult to measure and I really think that it's not necessarily just the seizures, but it's really the storm in the background that's driving all this process and it's important for healthy brain aging in people with epilepsy.

    Sponsor mention

    05:50 Torie Robinson

    Before we move on - with thanks to EASEE®, by Precisis GmbH. 

    Impact of status epilepticus

    05:54 Torie Robinson

    Seizures differ a lot. We have different types of seizures and we have some seizures that last a lot longer than others. Hopefully it will last, like, a few seconds, but sometimes it can last even over an hour. We have status epilepticus. So what is the impact on people's brains as a result of something like that?

    06:09 Marian Galovic

    That's a great point. So, the seizures I've been talking [about] so far about are brief seizures. So these are seizures that usually take a couple of seconds or maybe one to two minutes. But then we have status epilepticus, which is really an extreme form of seizures that just usually don't stop themselves and they can take anything from around five to 10 minutes to days, weeks, or even months. And these are really, really dangerous. So we know from animal research that really long seizures (called status epilepticus) cause brain damage in animals, but we didn't have much evidence on this in humans. But now there is really robust data from imaging coming in and also from blood biomarkers of neurodegeneration, where we see that status epilepticus really is an emergency. And the longer status epilepticus persists the higher the risk of developing brain damage. And we measured this. We looked at, well, actually the most severe forms of status epilepticus that can take weeks or months and we see that during this time the rate of brain damage or brain shrinkage was 80 times that of normal aging. So 80 times! And even if you compare it with diseases like Alzheimer's disease or dementia (which we know that they cause a lot of brain damage or which happens quite quickly) and status epilepticus is still 20 times quicker. So this is really an emergency. And I've done quite a few brain imaging studies during my research and I've never seen anything like this! The brain during status epilepticus really tends to melt away. So I think this is really an emergency and it tells us we need to act quite quickly and aggressively to stop status epilepticus as soon as possible. So, to summarise, brief seizures: probably not terribly bad for a brain or just a minor issue, but very long seizures are very bad and you need to act very quickly to stop them.

    Surgery as disease modification

    08:10 Torie Robinson

    What is interesting - and I have personal interest in this myself due to my own epilepsy surgery - when we see the epileptogenic focus being removed, that progressive cortical thinning appears to stop and in some regions of the brain even reverse. And does that change how we should think about epilepsy surgery - from symptom control (so the seizures and other things that can occur as a result of epileptogenesis), to something closer to disease modification or neural protection?

    08:39 Marian Galovic

    Oh, absolutely, that's how I think about epilepsy surgery. So because anti-seizure medications, mostly just really suppress seizures. And what we see in our research is that probably suppressing seizures wouldn't do the full job, you know? So you may still have some additional brain shrinkage or brain damage, even in the absence of observable seizures. But what happens during epileptic surgery, it's clearly disease modifying because many patients who have successful surgery, they can stop their medication and their seizures just won't recur. And that's different. If you stop your anti-seizure medications, then in a patient who has ongoing epilepsy, then the seizures wouldn't necessarily stop as well, but they would reoccur and continue again. So this is also what we see in our research. So when we can clearly see before epilepsy surgery, there is this ongoing process of brain shrinkage, around double the rate of normal aging. And after epilepsy surgery, particularly if this was effective (so if you stopped all the seizures), it normalises! It goes back to the rate of healthy aging. So what does this tell us? At the moment, many, many patients wait for epilepsy surgery, even for decades. I think one study estimated around 17 or 19 years delay between the diagnosis of seizures or even drug-resistant epilepsy and when they underwent surgery, and this is really time lost and you can imagine what's happening to the brain due to the accelerated brain aging in this time. we should get epilepsy surgery as much available as possible and as early as possible to people with epilepsy.

    Inherited risk vs acquired damage

    10:19 Torie Robinson

    Could not agree more. So tell us about “inherited risk” versus “acquired damage”. So I know you did some studies in two siblings and so tell us about them and their hippocampal volume loss.

    10:34 Marian Galovic

    So this is very fascinating and thanks for bringing it up. So we were looking at siblings of people with temporal lobe epilepsy. And these siblings, they were unaffected. So they didn't have epilepsy, they never had seizures, they had a normal EEG, and they never took anti-seizure medications. But, they were genetically related to people with temporal lobe epilepsy. So they shared around 50% of the genetic information together. Right, so now what we saw was the hippocampus, was smaller in siblings than in healthy people. And this is the part that's usually affected very, very early in temporal lobe epilepsy. So in people with epilepsy, it's very small frequently, we call it sclerotic, but even in the unaffected siblings, it tended to be slightly smaller than in normal people. So what does this mean? And I believe this shows that there is a genetic contribution to these things. I don't say that genetics is the only cause for developing epilepsy, but there is some predisposition or contribution of genetics. And there is good evidence showing that at least for temporal lobe epilepsy, the MRI changes that we see that I was describing frequently start within the hippocampus. So that the hippocampus is at the very start of this process, and then it sort of spreads into other areas. And where does it spread to? It's mostly areas that are highly connected with the hippocampus. So the brain is like a network. And in temporal epilepsy, at least, the most vulnerable areas are those that are connected with the hippocampus. So now, and what can we take away from this? So, we can see that the hippocampus is at frequent at the very beginning, but in siblings, we don't see these other distributed changes. So that means that these distributed changes are likely acquired and they may be preventable. I think this is the most important thing, right? So what I believe is happening that in cases with temporal epilepsy and hippocampus sclerosis, it probably starts in the hippocampus and then this process may be spreading over networks to other brain areas which may be affected, they shrink over time, and this can then cause cognitive problems or other issues or even psychiatric problems and so on.

    So this is a window of opportunity really, because these areas in the rest of the brain seem to be acquired. Again, we could use some neuroprotective measures or epilepsy surgery really is the only and best studied neuroprotective measure that we have at the moment to stop this process early before any big damage occurs.

    What should change?

    13:07 Torie Robinson

    As a result of what you've learned so far - and I've no doubt your research into this will continue - what should the neurologists listening now, what should they do differently?

    13:15 Marian Galovic

    First of all, I think we can mostly reassure our patients that a few brief seizures probably do not have a huge impact on the brain and do not do a lot of damage. You need to be very careful about status epilepticus. That's dangerous, of course, but brief seizures are mostly okay. I think that nevertheless, we need to make clear that epilepsy itself has an effect on brain networks and brain health. And interestingly enough, this effect is mostly pronounced during the early stages of epilepsy, so not during the late stages but in the early stages. And so if we want to prevent additional brain damage accumulating over the course of epilepsy, we need to act quickly. So don't just wait and see how seizures develop but use the most efficient treatment and the best tolerated treatment and also think early about epilepsy surgery. And I believe that using these measures we can prevent additional brain damage in our patients and also maintain their brain health, which I believe is really, really important. And it's also something that we can contribute, which is besides sort of suppressing seizures, but really improving the brain health of our patients in this manner.

    14:26 Torie Robinson

    Thank you so much to Marian for unpacking whether seizures damage the brain, and for explaining how epilepsy can drive accelerated brain ageing - even beyond seizures.

    With thanks again to EASEE®, by Precisis GmbH, for partnering with Epilepsy Sparks.

    If you found this conversation helpful, please give it a like and subscribe, and hit the bell so that you are notified when new episodes drop. I would love to hear your thoughts or experiences in the comments below. Thank you for joining us, and see you next time.

Torie Robinson
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