Melanie Cole, MS (Host): Welcome to GW Hospital DocPod, a peer-to-peer podcast for medical professionals with the George Washington University Hospital. I'm Melanie Cole. And joining me today is Dr. Mohamad Koubeissi. He's a professor and Interim Chair in the Department of Neurology and Rehabilitation Medicine, and he's the Director of the Epilepsy Center at the George Washington University School of Medicine and Health Sciences, and he's affiliated with the George Washington University Hospital. He's here today to highlight the relationship between stroke and epilepsy.

Dr. Koubeissi, thank you so much for joining us today. I'd like you to start by telling us a little bit about the prevalence of epilepsy in the general population. We're going to put these two things together, but tell us a little bit about what you've seen in the trends for epilepsy.

Dr Mohamad Z. Koubeissi: Epilepsy is one of the most common neurologic disorders. In the United States, epilepsy affects about 3 million individuals and two-thirds of these individuals tend to be treated successfully with good seizure control by using anti-seizure medications. But the remaining third, estimated 900,000 individuals in the United States, continue to have seizures despite medications, which will necessitate other interventions.

Melanie Cole, MS: Well then, let's talk about this very interesting topic. Explain the connection, doctor, between stroke and epilepsy. How does one condition increase the risk or influence the development of the other? What indeed is this relationship? And how common is it for someone to have suffered a stroke, and then develop epilepsy, or vice versa? Is having epilepsy considered a risk factor for stroke?

Dr Mohamad Z. Koubeissi: For millennia, it was thought that stroke increases the risk of subsequent seizures. And people thought that seizures will not increase the risk of subsequent stroke. However, if you go back to Hippocrates, 500 B.C., he wrote that the causality between the two conditions is indeed bidirectional. But people did not believe that until studies recently have disclosed that older individuals who have stroke will have higher chances of developing seizures, but also late-onset seizures will increase the chances of later strokes.

If you look at the causes of unprovoked seizures in individuals who are 60 years of age or older, you will find tumors as the likely cause in about 14%, dementia in about 7%, and some other causes in about 29%. But interestingly, stroke is the cause of new-onset seizure in older individuals in 50% of these seizures.

Melanie Cole, MS: This is so interesting. So, are there specific risk factors, and as we look at the population in general, the likelihood of developing epilepsy following a stroke or vice versa?

Dr Mohamad Z. Koubeissi: So in the medical literature, we differentiate between early seizures and these are further differentiated as immediate seizures within 24 hours after stroke and early-onset seizures within seven days. And on the other hand, you have the late-onset seizures, which occur after the first week. So if you look at the early seizures, we believe they are related to acute biochemical and metabolic disturbances in the brain because of the stroke. But later seizures, which can occur a year or two after stroke, they are believed to be due to permanent alterations. So, it is important to look at the risk factors as you mentioned. If you look at early seizures that occur within the first week of stroke, they do increase the risk of post-stroke epilepsy, which means later seizures that will necessitate treatment with anti-seizure medications.

But among the strokes, what increases the chances of seizures in general is severe strokes, large volume strokes; cortical involvement, which is involvement of the outer layer of the brain; hemorrhagic transformation, which means that sometimes the stroke starts as ischemic, which means blockage of a blood vessel and compromising the brain cells that are supplied by that particular blood vessel. But then later, it transforms into hemorrhagic, so a bleed occurs within the stroke. All these are believed to increase the chances of subsequent seizures. Strokes that involve blood in particular, such as what I mentioned, hemorrhagic transformation or subarachnoid hemorrhage are particularly risky in terms of seizures, because blood factors have oxidant activity and disruption of the blood brain barrier increases the seizure risk because of delivering iron-carrying blood proteins such as hemosiderin, transferrin, and also albumin to brain tissue. And experiments in animals have shown that direct application of albumin on brain cells could increase the chances of seizures, as does the application of iron-carrying blood proteins.

Melanie Cole, MS: Doctor, are you looking then at strength and type of stroke as predictors? Are we using that as a predictor for patients? And if so, is there any treatment post-stroke that differs if you suspect this might become the case? And I imagine that there are still studies being done on that.

Dr Mohamad Z. Koubeissi: Precisely, we and other authors tried to study for a long time the most robust predictors of post-stroke epilepsy in order to assess whether prophylactic treatment is necessitated. The main take-home message now is that anti-seizure medication treatment is not indicated for a big stroke or for any stroke that is believed to carry a high risk of epilepsy until the seizures emerge.

Studies have shown, as I said, cortical lesion, initial stroke severity, in addition to early seizures and young age to be important risk factors for post-stroke epilepsy. However, other studies have found conflicting results. For example, it is still debated that cardioembolic mechanism increases the risk of seizures or the territory of the circulation that is involved in the stroke increases the risk of seizures. But regardless, we still think that prophylactic treatment or preventive treatment of seizures based on the risk factors studied so far is still not indicated.

Now, that said, I have to make a very important point. Although treatment with anti-seizure medications may not be indicated prophylactically after stroke, but sometimes, and depending on the patient's condition, monitoring with EEG could be very important because some studies have shown that up to 28% of patients after hemorrhagic stroke if monitored by EEG within the first few days after their stroke, 28% of these patients will have some electrographic seizure activity on continuous EEG monitoring compared to 6% patients after ischemic stroke.

So, these are high numbers, and it's important to capture those electrographic seizures on continuous EEG monitoring because if this is the case, then treatment becomes indicated. In other words, sometimes the seizures may not show clinically. They may be just electrographic in the acute phase, but still detecting them is very important to improve outcomes.

Melanie Cole, MS: I'd like you to speak as we wrap up, Dr. Koubeissi, as you just mentioned monitoring and you got to my next question before I even had a chance to answer now, as we know that stroke increases the risk of another stroke. And now, we're looking at seizure activity as well, and you're talking about EEG. Tell us a little bit about long-term monitoring. And as you're speaking to other providers to assess the risk of a future stroke, along with the epilepsy, considering the patient's quality of life, put this all together and what you would like the key takeaways to be for other providers as they're looking at this relationship that is still being studied.

Dr Mohamad Z. Koubeissi: I would like to talk about a couple of other points as part of the answer to your question, sort of like in a bullet point format, separately. So first, I would like to talk about why is it important to prevent post-stroke epilepsy. There are numerous studies that have been done in the past decade and many others even before that have shown that post-stroke epilepsy worsens the recovery from stroke. Mild to moderate cognitive impairment have been reported in up to 69% of individuals who have seizures after a stroke, among other neurological impairments.

Additionally, a meta-analysis of about 178,000 post-stroke survivors for a followup period of about four years found that post-stroke epilepsy is an independent predictor of all-cause mortality after the index stroke. So, not only neurological impairments, but even mortality is higher among those who have seizures after a stroke. Again, recurrent stroke is more likely in those who have seizures after the first stroke and dementia.

It's important to answer your question about EEG, that continuous EEG monitoring within the first 72 hours after the stroke reveals association between post-stroke seizure and significant neurological deterioration. And this highlights the importance of detecting early seizures, even ones that do not have clear clinical manifestations, and they will appear only electrographically on continuous EEG, because early treatment potentially can improve outcomes.

The other point I would like to mention is we have talked about how stroke increases the chances of seizures. But now, I would like to say how seizures increase the chances of stroke. The medical literature includes five-case control or cohort studies that directly compared the incidence of stroke in late-onset epilepsy to that in controls. And combining all these studies together, the risk of stroke after seizures was associated with an odds ratio of 3.88. All the studies were consistent in that finding. The odds ratio is stable across a range of followup intervals and geographical locations. And the effect was observed not only in those who had their first seizure after the age of 60, but even as low as their 30s. So, seizures that occur even in midlife as well as in late life will increase the chances of subsequent strokes.

A very important point here is that most of these studies did not differentiate between ischemic stroke and intracerebral hemorrhage. However, the one study that did found that intracerebral hemorrhage is more likely to occur after the first seizure in late age. So, it is important to remind the neurologist that the first seizure that occurs in late age, although it increases the chances of future stroke, will not in its own right necessitate the initiation of blood thinners to prevent the stroke, such as aspirin, because intracerebral hemorrhage is even more likely than ischemic stroke to occur as a subsequent event to late-onset seizures.

However, one thing that could be very helpful to the patient is institution of a statin or HMG-CoA reductase inhibitor, which is a lipid-lowering drug, but not only lipid-lowering, it's also neuroprotective and anticonvulsant. And statins after a stroke have shown reduced risk of post-stroke epilepsy, and also they improve long-term outcomes, reducing mortality, reducing risk of recurrent stroke, and even potentially neurodegenerative disorders.

There are some strokes that have higher risk of subsequent seizures, and these include ones that involve the cerebral cortex, hemorrhagic strokes or ischemic strokes with hemorrhagic transformation, strokes that occur at an earlier age. All these should necessitate vigilance regarding the possibility of subsequent seizures. And in many patients, continuous video EEG monitoring in the first few days after the stroke will reveal electrographic seizures whose treatment can be very beneficial on the outcomes.

On the other hand, late-onset seizures can increase the risk of subsequent strokes. When late-onset seizures occur, they may not specifically necessitate the initiation of an antiplatelet agent, but should warrant a prompt assessment of vascular risk factors.

Melanie Cole, MS: Great information. Thank you so much, Dr. Koubeissi, for joining us today and sharing your incredible expertise in this interesting topic. And to refer your patient, please call 1-888-4GW-DOCS. That concludes this episode of GW Hospital DocPod, a peer-to-peer podcast for medical professionals with the George Washington University Hospital. I'm Melanie Cole. Thanks so much for tuning in today.

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