Epigraph Vol. 25 Issue 3, Summer 2023

Statins and epilepsy: Dr. Emilio Russo and Dr. Tony Marson

Reported by Bruna Nucera | Produced by Nancy Volkers

Cite this article: Nucera B. Statins and epilepsy: Dr. Emilio Russo and Dr. Tony Marson. Epigraph 2023; 25(3): 52-57.

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Podcast Transcript

[00:00:00] Dr. Bruna Nucera: Recent data from literature suggest that besides the beneficial cardiovascular effects, statins have also a neuroprotective role in different neurological disorders, including epilepsy. In this episode of the Sharp Waves podcast, we discuss statins as anti-seizure medication: Yes or no. With me I have two speakers, Professor Anthony Marson and Professor Emilio Russo. Please introduce yourself, Professor Russo.

[00:00:33] Dr. Emilio Russo: Bruna, thank you very much for introduction. I'm Emilio Russo. I'm professor of pharmacology at the University of Catanzaro in Italy. I've been working mainly on preclinical models of epilepsy. But also running some clinical trials on the pharmacological side.

[00:00:48] Dr. Anthony Marson: And I'm Tony Marson. I'm an academic neurologist in Liverpool, professor of neurology, leading the epilepsy group there. My track record really is in running clinical trials, trying to answer questions about whether treatments are clinically or cost effective.

[00:01:03] Dr. Bruna Nucera: Okay. Thank you so much for accepting our invitation and Professor Russo, the first question I would like to ask is more in general, what statins are and what are the mechanism of action?

[00:01:18] Dr. Emilio Russo: Well, in the general view in pharmacology, statins are cholesterol-lowering drugs. That’s the way they are usually classified. And that's what they're used for. So they're using primary or secondary prevention of any cardiovascular events on the clinical side. The mechanism of action, the one we know and we usually describe, is the inhibition of one of the enzymes which is leading to the synthesis of cholesterol in our body, which is HMG-CoA reductase.

Obviously in many other experiments and data demonstrated, there are also other mechanisms. From this point of view which I generally call the pleotropic effect of statins, including stabilization of plaques, for example, or other mechanisms leading to this cardiovascular protection.

More generally in the view of epilepsy, for example, or neurogenerative diseases, statins may be anti-inflammatory and have an effect against neuroinflammation.

[00:02:21] Dr. Bruna Nucera: Okay. Professor Marson, when and why did people start thinking that these drugs could be used also for epilepsy?

[00:02:30] Dr. Anthony Marson: Yeah, so there are a number of lines of inquiry there. And I think we need to think about two separate scenarios really. One is around, might statins alter the natural history of epilepsy? Is there something about statins which either reduce the risk of seizures or change the epileptogenic processes in the brain? There's information from a number of animal models which suggests that statins have an antiseizure effect, and also that they might have an anti-epileptogenic effect, so reduce the severity of epilepsy.

And that's really interesting at a time when we're really frustrated, because we've spent 30 years developing a load of drugs which treat seizures, but they really do nothing about the underlying biology of epilepsy. Can we develop new treatments which will affect the biology of epilepsy? And it might be easier to start with trying to repurpose drugs that we've already got, that we know are safe, whilst we're also in the process of developing potential new treatments which can interact with these processes.

The second area to think about is the fact that we know that epilepsy is becoming increasingly common in older populations, and those older populations are more likely to have vascular disease. And we need to think very seriously in the epilepsy clinic whether we're missing an opportunity to improve people's vascular health, because I don't think we do that very effectively in epilepsy clinics. Should we be identifying people with poor vascular health for whom statins should be being prescribed?

[00:04:04] Dr. Bruna Nucera: Thank you. Professor Russo, what are the main preclinical studies on statins as anti-seizure medication and what are the main results?

[00:04:13] Dr. Emilio Russo: Well, I think we have to look back, well, what, 20 years ago, I think, to the initial studies on statins and epilepsy in animal models. The first is one published around 2008 in Neuroscience Letters, in which it was demonstrated that some statins, atorvastatin, would be anti-epileptogenic in a model of epileptogenesis. The one we know, like temporal lobe models mainly at that time. So this was really the first evidence on this side.

Then after that, we have seen many other clinical studies with statins, with all the statins tested so far. There is no one which is better than the other one, I must submit. Since, you know, preclinical research is usually a sort of track of something demonstrating a hypothesis, and then this has to be translated on the clinical side.

We are lucky that actually some research has been running together in the same time. Preclinical research and clinical analysis of results, which we'll discuss later, going together. In the end, what has happened is the fact that moving out of this mainly post-insult model of epilepsy on the clinical side, we also had some evidence of efficacy in genetic models, for example.

So it is not only an efficacy seen in the kind of epilepsy in which you have vascular damage, but maybe the mechanism may spread to, and be applied to, other areas of epileptogenesis. The main outcome is the fact of trying to identify which is the best statin in this area. When talking about clinical data it's not easy to identify the best statin at the time. Also, I've summarized the mechanism of action, but we cannot really say that all the studies share the same identical mechanism of action.

[00:05:56] Dr. Bruna Nucera: And Professor Marson, do you have any comments about the preclinical studies?

[00:06:04] Dr. Anthony Marson: Well, I, think the results of the preclinical studies are tantalizing in that they tell us that statins might have a useful effect and we need to find out whether that is translated into humans. So we need to think about how we might design and undertake some trials in humans to answer those questions.

Professor Russo was talking earlier about which statin do you choose now. I think that's very difficult. Probably the pragmatic answer is you choose a statin which is frequently used and well tolerated and run with that because in terms of effect, they're probably all very similar.

[00:06:39] Dr. Bruna Nucera: Professor Marson, what about human clinical studies?

[00:06:42] Dr. Anthony Marson: We can get some insights from population-based data. We've increasingly got access to big healthcare data sets with information about many, many thousands of patients. So we can effectively look at natural experiments. Do people that are given statins in certain situations have a lower risk of seizures? And there are some insights coming from those data that tell us that statins may be having an effect on reducing the risk of seizures.

But of course, those kinds of studies are only ever hypothesis generating. The only way to answer the question properly is to undertake a randomized controlled trial. Which takes us back to a trial that we ran from Liverpool back in the nineties, the MESS study, where we randomized people with first seizures to antiepileptic drug treatment or not, or as we call them now, anti-seizure medications or not, to identify whether short-term outcomes were any better and whether there was any evidence of a disease-modifying effect. And we were able to answer the question that anti-seizure medications reduce risk of recurrence, but don't actually have any long-term effect on the natural history of epilepsy.  And we could run similar trials of statins or other potential disease modifying treatments. One of the challenges there is that those sorts of trials take about 10 years to complete. So it will take us quite a long time to get answers to those questions. So it's really important that we have a good pipeline of likely potential effective treatments to put into studies which are probably going to take us a number of years to complete.

The other challenge, and I'm really interested in Professor Russo's comments here, is that we don't have any biomarkers or mechanisms that we can look at in humans. And I think funders, our experience certainly in the UK is that funders that might fund a randomized trial also want those studies to include some mechanistic work so that we can demonstrate how statins might be having an effect.

And that feels like a bit of a stumbling block that we really need to come over. What are the mechanistic studies that we could include in clinical trials to help us prove to funders that statins are having an effect?

[00:08:55] Dr. Bruna Nucera: Professor Russo, any comments about that?

[00:08:58] Dr. Emilio Russo: I mean, I agree. I agree. Obviously, there are several aspects we have to consider. Besides the biomarker story, also for simple patient selection based also on the clinical observations. So we would make a difference if we are going to treat post-stroke patients more than any other type of epilepsy. And we need to understand which is the best line to follow up also. Because we have evidence of neuroprotection, for example, by statins, and effects also on maybe disease progression and neurodegeneration and the studies may be protective on this side. So we need to have proper evidence to move on.

I mean, surely what has been done so far is very indicative of potential. But again, population-based studies are not the best in this area.

[00:09:47] Dr. Anthony Marson: Yeah. And I think one of the real challenges for us is to identify the patient populations that we might want to include. And I guess we've embarked on a conversation where we're most interested in finding out whether statins are disease modifying, so whether they are having an antiseizure effect is probably irrelevant because we've got lots of antiseizure drugs. The really tantalizing question is, do they have any disease-modifying effect?

And we could do studies in people with stroke, but they will have already had a statin so we can't randomize people with stroke to have or not have the statin. So that's not an opportunity. People with head injury or some other brain insult might be an opportunity, but they're a really challenging group of patients to run studies in because if they've had a significant brain injury, they've got lots of other things to worry about rather than seizures. And you know, I increasingly think that the population that may be the easiest to study here is actually people with first seizures. We've got people early on in their experience with seizures, there is a process going on that we don't necessarily understand, about half of them are at risk of having future seizures, so is there a cohort of patients with first seizures or early epilepsy that we should be including in randomized trials to identify if these drugs are disease modifying? And even if, you know, even if the effect is small, it's likely to be a substantial kind of health economic benefit, because epilepsy's so common, and because the consequences of epilepsy are so long over an individual's life.

[00:11:16] Dr. Bruna Nucera: And Professor Russo, could you briefly summarize the evidence about post-stroke seizures and statins?

[00:11:23] Dr. Emilio Russo: We have really few data actually on the preclinical side. We do have more population-based studies since as Professor Marson said, you know, statins are very much used around the world and obviously people who are having a stroke might have been taking the drug before.

 We really need to have proper randomized trials to understand whether this is true or not. There are new ways. I mean the new scores we can use to select patients, like the SeLECT score, for example, to be included in this kind of studies. And there are study designs now of 18 months, which is not that long. So maybe we don't really need such longer studies as we thought before for epileptogenesis, even though we don't really have biomarkers. But again, if the effect is strong enough, then 18 months may be enough to understand whether the drugs are really effective or not.

[00:12:15] Dr. Bruna Nucera: Professor Marson, anything else to say about that?

[00:12:19] Dr. Anthony Marson: Following people up for 18 months, the challenge is if you want to generate a cohort of 600, 700, 800 patients and follow the last one up for 18 months. It's still going to take 5, 6, 7 years to complete those sorts of studies, unfortunately. But that's the real world. So we need some surer bets put into those studies, and to go back to a comment that was made earlier as well, because when we were thinking about this a year or so ago, we thought, well, this needs to be a trial of people that are likely to have focal epilepsy. And then there are the data which suggest that statins could have an effect on people with idiopathic generalized epilepsy. So maybe, you know, broad inclusion criteria, and see if there are patient characteristics where the effect is greatest. Assuming that there is a treatment effect.

[00:13:14] Dr. Bruna Nucera: And Professor Marson, what about your personal experience about statins and epilepsy? Have you conducted any studies about that?

[00:13:23] Dr. Anthony Marson: We’ve not conducted any prospective studies. My colleague, Nasir Mirza, has been doing the kind of systems biology and clever things with the literature to identify potential drugs for repurposing, including statins. And we've been looking at the population data, but we've not actually, outside of routine clinical practice, been prescribing statins for people with seizures.

[00:13:52] Dr. Bruna Nucera: And Professor Russo, what about your experience?

[00:13:56] Dr. Emilio Russo: Well I've published a couple of papers on clinical models. We’ve done some experiments in our lab in the beginning of 2010, 2012. The first one was actually on this model which is called DBA/2 mice. They have audiogenic seizures. We wanted to test if there was any direct anti-seizure effect, you know. We saw just a minimal effect on seizures themselves. And then we tested whether the use of statins may potentiate the effects of other anti-seizure medications. We came out with a paper published in Pharmacological Research in 2013.

The second part of the experiments, we focused on the anti-epileptogenic effects, and we moved on a model which we were using in our lab at the time a lot which is the, WAG/Rij rats is the name, the correct pronunciation in the Netherlands. This is an absence model and is seen as an epileptogenesis model. Seizures will appear over time and will increase over time in these animals, and we knew that treating these animals before seizure appearance with all the drugs would stop or prevent development of seizures in the future. And we tested a few statins. Different dosages as well. And we found actually again, that atorvastatin, for example, was quite effective in preventing the development of absence seizures. So also an effect in genetic epilepsy.

And in this same paper we focused attention on comorbidities, analyzing depressive-like behavior and anxiety in rats, as much as you can say a rat can be depressed or anxious. So, opening to all the possibilities and all the effects of those drugs since neuroinflammation is about the many neurological, psychiatric disorders. So if you reduce your inflammation, you may expect an impact on many aspects of the brain.

[00:15:47] Dr. Bruna Nucera: Thank you. I have another question about potential side effects of statins, in particular about behavior changes. Did you, just talking about that, what do you say about this potential side effect of statins?

[00:16:03] Dr. Emilio Russo: This is not an easy field. I mean, if we look at statins, they've been used for a long time now and for very long periods by patients and people around the world. Those are not the most famous side effects. Indeed. As you know, we usually observe muscle problems. And the use of statins has been linked to the development of Type 2 diabetes, for example. Which is something we already know. If we look at behavior, yes, there are case reports or single cases in which some alterations have been observed. This is not surprising to me, I must say, for two different reasons.

It's never easy to correlate an adverse event to a drug above all. When the drug is used in so many people altogether, they're all different. One from the other one. And I'm not surprised that a drug having an effect on the brain may have a side effect in the brain. And as far as we believe that statins may have an effect in the brain, I'm not surprised about the fact that some people may have cognitive impairment or psychosis. Right? But this is, these are very small cases. While we see improvement, for example, in other patients. So we see, for example, cognitive improvement in some patients using statins.

The other problem is the fact that we've been talking about the use of statins and therefore we are talking about adherence in the long term. And we know that adherence to statins is very low when we use them for cholesterol lowering. So this is another challenge on the clinical side to be faced trying to use those drugs.

[00:17:26] Dr. Anthony Marson: Yeah, and, and I guess two related topics there. One is around the age group that we might want to try statins for. And traditionally, we use statins for middle-aged, older people. But if we want to prevent epilepsy, then we might be thinking about using statins in younger people or even in children to reduce future seizures.

[00:17:51] Dr. Bruna Nucera: And Professor Russo. Are there other lines of research on statins and epilepsy or in general that we are not talking about?

[00:18:00] Dr. Emilio Russo: Professor Marson just mentioned children for example. So, encephalitis, all types of encephalitis or developmental epilepsy have not been explored. We believe if the mechanism is inflammation, then there is room for this kind of research. The other side is comorbidities. Comorbidities, again in epilepsy, which may differ from other direct pathologies. I mean, there are studies in Alzheimer's disease, for example, but cognitive impairment will not be identical. It's not identical in patients with epilepsy and Alzheimer's patients. So we cannot really extrapolate data from one group to the other one. So we need to be very much focused and say, okay, we want to see whether statins may have an effect on cognitive impairment in epileptic patients, or depression in epileptic patients, and so on. So this is another area we should look at.

And finally, yes, we need the mechanism. We don't know enough. We don't know enough about cholesterol in the brain. So we know that cholesterol is actually leading to the synthesis in the brain of other molecules which are neuromodulators, but we don't, we don't really understand those mechanisms so far.

[00:19:16] Dr. Anthony Marson: Yeah. So the risk is that lack knowledge of mechanism prevents us from testing what might be an effective treatment. And we didn't really know how valproate worked. We still don't know how many of our drugs work, and yet we know they work and they're used in routine clinical practice.

And I think one of my concerns is that because it's so difficult to pin down the mechanisms that we will be prevented from a testing what might be effective treatments because of a kind of a mental block amongst funders and people making decisions.

I think we need to get on and do some clinical trials with these safe, effective treatments. If this was a high-risk treatment, then obviously we would need to be thinking about a different paradigm. But I think given the millions of patient-years of use of these drugs for cardiovascular disease, the risk to individuals and the potential compared to the potential gain, I don't think there's an argument.

I think we should be getting on doing some simple clinical trials to answer the questions.

[00:20:28] Dr. Bruna Nucera: And finally, Professor Russo, do you think there might really be a possibility that in the future statins could be used as anti-seizure medication? Yes or no?

[00:20:40] Dr. Emilio Russo: We, we need proper evidence. So let's go ahead. Let's go ahead working and let's create evidence to support the use and let's keep our fingers crossed. Hoping that this will change the future of many patients.