Dr. Ramon Diaz-Arrastia, Professor of Neurology, University of Pennsylvania
CURE presents a leading expert on Post-Traumatic Epilepsy

In CURE’s Leaders in Epilepsy Research webinar, participants hear from a leading expert on Post-Traumatic Epilepsy (PTE), epilepsy resulting in physical trauma to the brain. The webinar reviews efforts underway to advance our understanding of PTE, as well as the exciting new therapies being developed that may one day result in a cure.

It is presented by Ramon Diaz-Arrastia, MD, PhD, of the University of Pennsylvania. Dr. Diaz-Arrastia is an expert on the molecular, cellular, and tissue level mechanisms of trauma-induced neuroregeneration and injury-related synaptic plasticity. He works to develop effective therapies for Post-Traumatic Epilepsy.

Plus, hear more about the history and current state of PTE research from this episode of our Seizing Life podcast.

Audience Q&A with Dr. Ramon Diaz-Arrastia

What strategies may be developed to help prevent post-traumatic epilepsy?

Through our work on understanding the mechanisms, I did point to some strategies that may be very attractive. So, I do think we now know that anti-epileptic drugs are not epileptogenic necessarily, and we rather need drugs that are going to promote the integrity of the axonal connections into the hippocampus. We may also need drugs that promote the repair of the blood brain barrier and perhaps block some of the long acting or long duration inflammation that occurs in the brain. So, the goal of developing or the mechanism of developing anti-epileptogenic drugs is really going to be tied in to these strategies to promote the integrity of resilience and recovery of these particular neural structures.

If you have decades of seizures and epilepsy and you’ve had multiple brain surgeries, would you say that you have a brain injury? Would that be an accurate statement? Obviously, it’s not a TBI, but would you call it an ABI?

Of course, I mean, I think obviously epilepsy can occur from many different consequences, but certainly anything that injures the brain, be it a traumatic insult to the head, or be it an ischemic insult or an inflammatory insult or an infectious insult can result in epilepsy. Now, many cases of epilepsy, such an insult is not recognized, which is not to say that it wasn’t there, right? It may have been a subclinical or a subtle insult, but nonetheless resulted in an injury. So, now, I do think the answer to the question is right, that in most cases epilepsy does result from some kind of injury and that discovering how that happens is potentially a value in preventing the development of epilepsy and also potentially treating the seizures after it already develops.

Are there specific symptoms that indicate if epilepsy is due to a brain injury as compared to other epilepsy causes?

Most patients who develop epilepsy after brain injury develop a focal epilepsy syndrome although it can be anywhere in the brain, right? It turns out that temporal lobe epilepsies appear to be the most common. There is something about the temporal lobes, particularly the mesial temporal structures that make it uniquely pro epileptogenic, but we certainly can have frontal lobe epilepsy, parietal lobe epilepsy, occipital lobe epilepsy. It can start from anywhere where there is an injury and the manifestations of the seizure obviously depends on where in the brain the seizure is starting. So, the manifestations of the frontal lobe seizure are going to be different from a temporal lobe seizure, or an occipital loop seizure. So, it’s the kind of stuff that requires careful evaluation, and in most cases require admission to an epilepsy monitoring unit for video EEG monitoring. But yes, one can determine what kinds of epilepsy develops from what.

We have a question about veterans and the prevalence post-traumatic epilepsy in the veteran population to other types of populations with head trauma?

Veterans are at a particularly high risk of suffering traumatic brain injury, and this is a consequence of their military service. Veterans or military personnel are at high risk of traumatic brain injury, obviously in combat settings but even during practice or during training and just living in a harsh environment is risky and there’s a high incidence of brain injury from that. Brain injuries are very common in a general population, but individuals who have served in the armed forces are at approximately a three to four fold increased risk of having a brain injury and a correspondingly increased risk of developing post-traumatic epilepsy. So, this is a major problem to the Department of Defense, Military Health System, as well as for the Veterans Administration Health System. A lot of the research in this area historically has been funded by the DoD and the VA.

Do you happen to know the percentage or approximate percentage of post-traumatic epilepsy patients that are candidates for brain surgery?

Unfortunately, that’s a very hard number to know. It’s certainly not the majority, but it could be as much as 10, 20%. I think everyone who has epilepsy that is refractory to medications, which means that they have been on good doses of at least two anti-epileptic medicines and they continue to have frequent disabling seizures. That is someone who regardless of the etiology of their epilepsy, regardless of the cause of their epilepsy, should be referred for Epilepsy Monitoring Unit Admission and Video EEG Monitoring to determine if they are surgical candidates. I think surgery remains an underutilized therapy option in post-traumatic epilepsy, as well as in many other causes of focal epilepsy.

What are your thoughts about the predisposition to Alzheimer’s after one has had a closed head traumatic brain injury?

This is another area my laboratory is very busy in investigating. So, it appears that individuals who sustain a moderate to severe traumatic brain injury are at greater risk of developing late life dementia. That risk is somewhere in the order of about three to four fold for severe traumatic brain injury. But then even mild traumatic brain injury increases risk of late life dementia modestly, but probably by around 30 to 50%.

Now, that doesn’t sound like much. On the other hand, given that late life dementia is so common, even a modest increase in relative risk does translate into a large number of cases. Now, whether that dementia is Alzheimer’s disease or whether it is some other kind of late life dementia, that remains to be proven, right? Again, that’s one of the things that we very much need to investigate is if we can identify what is the mechanism of that risk of late life dementia after a TBI, what can be done to prevent it? Do we have any strategies that could help in promoting the resilience or promoting the recovery of the brain after a brain injury? And we just don’t know yet, but it’s an area of very active research.

Do you feel that there is an ideal anti-epileptogenic drug profile?

The ideal anti-epileptogenic drug profile is one that controls the seizures 100%. It doesn’t produce significant side effects, right? Now, that ideal drug is going to be different for every patient, right? But many patients are able to find a drug or drug combinations that is ideal for them, meaning that it controls the seizures and allows them to continue their life without significant side effects.

Unfortunately, that only happens about 60% of the time. So, that is a significant number of people and many of the drugs that we have are good drugs, but that remains that about 40% of patients with epilepsy and that includes post-traumatic epilepsy as well as other causes are unable to find an ideal drug or drug combination that works for them. That remains a big problem, which certainly stimulates our work in the area trying to develop preventative therapies and also trying to develop better symptomatic therapies.

What about starting a ketogenic diet post TBI as a possible seizure prevention protocol?

I think that’s a potentially good strategy, right? There are some work primarily so far in animal models that a ketogenic diet appears to be neuroprotective, appears to prevent the death of neurons in some of the aberrant synaptic plasticity. Research in this area is very, very early, I must say. It’s so far mainly in animal models, but it certainly looks promising. Not an unreasonable approach to try.

What about researching the space dealing with devices such as brain cooling?

Likewise in animal models, there is very good evidence that cooling the brain soon after the injury prevents the development of post-traumatic epilepsy. In fact, helps in preserving neural structures and preventing neuro degeneration. So, I think that is likewise an attractive strategy. So far, it’s really only been tried in preclinical models. It appears that focal brain cooling is what’s important. There have been several studies in patients with TBI doing whole body cooling, and that does not appear to work as well. It’s mainly because cooling can have deleterious effects on pulmonary function and cardiac function and renal function. But focal brain cooling is certainly a promising strategy.

Do you feel that preventing hippocampal neurogenesis after TBI is a viable therapeutic direction for preventing mesial temporal lobe epilepsy?

So, there is neurogenesis in the hippocampus after TBI. In most cases, that is a good thing because that allows the recovery of memory function and attention and things that the hippocampus does. So I think one would have to be very, very careful about a strategy where one tries to prevent the normal healing pathway.

On the other hand, it is likely that as I mentioned earlier in my talk that post-traumatic epilepsy may result from those attempts of the tissue to rewire and repair itself, that some of those repairative processes may not be totally perfect and result in a circuit that is epileptogenic. So, I would say that one has to be very careful and one has to be very precise on strategy, such as this, and obviously develop strategies that target the aberrant neurogenesis and the aberrant synaptogenesis while leaving the neurogenesis and synaptogenesis that are important for more recovery in place.

Are sodium channel blockers therapeutic in post-traumatic epilepsy?

Dilantin for examples is one of channel blocker and it does not appear to be effective, although it blocks the early seizures, does not appear to be effective as an anti-epileptogenic agent. I would say that although not every sort of general blocker has been tested, more likely we are going to need alternate strategies to come up with a truly anti-epileptogenic compound. Those alternate strategies are going to have to rely on things like blocking inflammation or promoting repair of the blood brain barrier, or perhaps promoting integrity of the external pathways that become disconnected. I’m personally not that hopeful that just because a drug is anti-epileptic, that it will be anti-epileptogenic. I think the data we have so far seems to indicate that it’s not the case.

Are there any specific group of neurons implicated in post-traumatic epilepsy?

I think that there’s not any one specific group. I think that depends a lot on the location. I think what tends to happen is that when you have a brain injury, many neurons are lost and are damaged, and then the neurons that remain attempt to rewire in order to repair the function of the circuit. But that rewiring is sometimes not perfect and that’s how an epileptic circuit presents itself. So, it appears to be mostly the neurons that are relatively resilient to injury that may be responsible.

Again, I think it’s a two-edge sword. You would not want to prevent epileptogenesis with a strategy that also prevents the repair and recovery. We would have to be a lot more precise and a lot more clever to come up with strategies that prevent the aberrant synaptic plasticity while allowing the functional or the positive synaptic plasticity to persist.

Can seizure type after a traumatic brain injury be a basis for predicting the risk of recurrence?

I don’t think we know the answer to that yet, right? I think what very frequently happens that it often takes a while for the diagnosis of post-traumatic epilepsy to be made. When we talk to patients who have developed epilepsy after a brain injury in reality, they often have subtle behavioral problems or subtle memory problems that proceed the development of clinically apparent seizures. In retrospect, those were probably very small, very focal seizures that were occurring before the clinically apparent seizures presented themselves. So, I think the answer is that we’re going to need strategies that allow the diagnosis of post-traumatic seizures very early on in many cases before it’s very clinically apparent in order to develop effective therapies.

Are you hopeful about the near term future for patients with TBI?

I’ve been working in this field for about 25 years and we have had great progress. On the other hand, when I started working on it, I certainly would have hoped that we would have been further ahead by now. So, I have long accepted and I’ve told my wife and children this that optimism is one of my personality flaws. So, I do believe that we will develop some effective anti-epileptogenic therapies before I retire, right? Obviously, that’s only a belief in terms of having very solid therapies.

I do know that the amount of research in this field has skyrocketed over the last several years. This is mainly through the support of the Department of Defense, but also through the CURE Foundation and many others. We now have much better animal models. We have much better understanding of what’s going on at a cellular molecular level. We have much better biomarkers, be the imaging biomarkers or molecular biomarkers. So, I do think we have the tools in place, and we certainly have some strategies that appear to be successful in animal models. Obviously, translating those into humans is not necessarily an easy or even a linear proposition. But I am an optimist, and I think the answer is that we will have something in the next 10 to 15 years or so.