Biological Mechanisms of SUDEP
1:00 pm - 2:00 pm CST
Background: Sudden unexpected death in epilepsy (SUDEP) is the most important epilepsy-related cause of death, occurring in at least 1:1000 people with epilepsy each year. The risk of SUDEP increases dramatically in uncontrolled epilepsy. The events leading to SUDEP are thought to be caused by a destabilization of autonomic cardiorespiratory compensatory processes. Dr. Simeone’s research has focused on determining progressive changes in cardiorespiratory function that could increase the probability of SUDEP in preclinical animal models. Identification of temporal biomarkers that can be monitored could lead to opportunities for intervention to postpone or prevent SUDEP.
You Will Learn: Dr. Simeone discusses the progressive cardiorespiratory dysfunction seen in the Kv1.1 knockout mouse model of SUDEP and the potential role of orexin as a central regulator of SUDEP.
Speaker Bio: This webinar was presented by Dr. Kristina Simeone, Associate Professor and Director of Master’s in Neuroscience Program at Creighton University’s School of Medicine.
Audience Q&A with Dr. Simeone
Did you notice in your knockout mice, were the animals having more frequent seizures during the sleep period as they neared SUDEP, or was that not related at all, the sleeping seizures?
So, that is a fantastic question. That is a study that we haven’t done yet. So, the study that looked at the hypnograms, that looked at sleep architecture, we analyzed the data. And then after the study was done, we sacrificed the animals for histological studies. So, we didn’t let them live until they died naturally. That study was actually conducted before we started doing that with our endpoints.
So, we know that the animals that had very disrupted sleep that they were a higher risk. They’re I think probably SD70, at the age of SD70, where 70% of the knockout colony had passed away or died of sudden death. So, I think that would be a great study. Are there more seizures that are coming out of sleep? Is the sleep architecture disrupted more as within subject as they approach sudden death? We haven’t done that. That is a fantastic question.
How do you actually calculate disruption in sleep when how much sleep does a wild type mouse get and then they’re going through these bouts of sleeping, waking, the much minimum amount of disruption that’s required to increase to SUDEP risk?
So that’s a really great question. Because, yeah, these animals, they’re rodents, so they don’t sleep for eight hours at a time, right? So, how do you measure sleep deficiency? So, that was a hard question. We analyzed it several different ways. What we ended up with is using actigraphy. So, actigraphy is a non-invasive way of looking at rest and active states. So, these animals were video monitored. They were put into an actigraphy cage, which is an infrared beam that measures activity and rest. They were in that for their entire life. So, we took all of the wild type data.
We found that at the ages we were looking at, there were no changes. It was really, really robust with how many rest EPICs they had during their rest period, during the 12-hour rest period in their light-dark cycle. So, it was constant throughout every single age. So, we took that wild type value of what is standard rest. We compared it to the epileptic animals. We found that as they got closer to death that they had, they had more…
Sorry, I know my arm was not a great line graph. If this was wild type rest, every single day, there was very little variation. If this was the younger knockouts, they look just like the wild type and they had the same amount of rest. And then as they got closer to SUDEP, the rest started to go like this. So, the rest efficiency was this difference between the average all of the wild types together and then each knockout.
If you started treating chronically with DORA starting at, say, P30, and then did you happen to see it enhance survival in very large manner, say up to P20 or P50?
So that’s the study that we still need to do is give a DORA… There’s lots of different doors out there but give a DORA early on at a much younger age and then see if it can prevent everything from happening and if it can postpone SUDEP…
[I will] expand on that just a little bit is that for research purposes, if you give it before the onset of epilepsy, that’s not clinically relevant, right? So, you want to wait until some of the problems have started before you give a drug, so that it’s more clinically relevant. But I do think both of them need to be done, both studies need to be done, where you wait for the onset of some of the pathophysiologies to occur and then you give it as a treatment, but then you can actually start a treatment maybe earlier more as a proactive measure.
Now, it’s important to know that the DORAs improved sleep. So, you don’t want to give it during the period of the day that you’re supposed to be awake, because it’ll just knock you out and put you to sleep. So, this is really restricted to things that we can only do during the sleep. You can give it at lower doses to help protect against some of these pathologies, and it won’t induce sleep, but those are again nuances that we still need to figure out.
Are there any side effects to doing this chronic treatment with DORA?
So, DORAs are really safe. So, in 2009, when we first started working on these studies, we were using Almorexant, which was just about to be approved by the FDA. It has since been pulled from the market. Suvorexant and Lemborexant are now FDA use drugs. So, now we’re using drugs similar to those. So, the benzodiazepine and benzodiazepine-like drugs, when you give them as hypnotics, as a sleep aid drug, they do improve sleep, but they also can cause daytime drowsiness the next day. It can cause other kinds of side effects as well, like cognitive problems the next day and that kind of thing. So, the DORAs are really safe. They’re very well tolerated. You don’t end up with that next day drowsiness during the day.
So, in terms of their safety profile, clinically, these are very safe drugs so far. They’re still relatively new. So, let’s wait 5 to 10 years and see what happens. There is something interesting that we just recently found out. We have a study that’s actually under review right now, I didn’t have time to share this data. But we looked at sleep architecture and EEG of the epileptic animals that had been treated with many different anti-seizure drugs, traditional anti-seizure drugs.
So, in that study, we were able to separate out effects of a drug on sleep versus effects of a drug on a seizure. Because I know a lot of basic scientists and clinicians want to know, “Do the seizures arise more out of REM or non-REM?” We’re finding that for at least in our animal model, that the seizures arise both out of non-REM and out of REM just at baseline, and then the drugs change that up a little bit. Hopefully, that paper will be coming out soon.