Epilepsy Surgery New Methods to Pinpoint the Right Candidates

Podcast Transcript

Dr. Alex Rae-Grant: Neuro Pathways, a Cleveland Clinic podcast for medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology, psychiatry, neurosurgery, and neuro rehab.

Epilepsy affects three million adults and nearly 500,000 children in the United States. In 2018, the CDC reported that one out of every three adults with epilepsy hadn't seen a specialist in the prior year. Of the 90% reported taking epilepsy medicines, 56% still experienced seizures. In today's episode of Neuro Pathways, we are discussing the implications of medically intractable and uncontrolled seizures, and the indications, candidate selection and latest technology supporting epilepsy surgery.

I am your host, Alex Rae-Grant, neurologist in Cleveland Clinic's Neurological Institute, and I'm very pleased with Dr. Imad Najm join me for today's conversation. Dr. Najm is Director of Cleveland Clinic's Epilepsy Center, and a staff neurologist in Cleveland Clinic's Neurological Institute. Imad, welcome to Neuro Pathways.

Dr. Imad Najm:  Thank you very much.

Dr. Alex Rae-Grant:  Let's start off by telling our listeners about yourself. Where are you from, where did you train, and how did your career lead you to Cleveland Clinic?

Dr. Imad Najm:  Well, I'm from Lebanon. A did go to medical school in Beirut, in the French University. Then I got to Cleveland Clinic through Paris and Los Angeles, where I did my training here at the Cleveland Clinic, both internship residency and my fellowship in clinical neurophysiology and epilepsy. And since 1997, I've been here on staff at the Cleveland Clinic Epilepsy Center and Department of Neurology.

Dr. Alex Rae-Grant:  So today, we're talking about indications and surgical advances in the treatment of epilepsy. But let's start with this kind of major concern, the staggering 56% of patients who have epilepsy but are still experiencing seizures. How does that factor into thinking about surgery for that population?

Dr. Imad Najm:  Well, this data as you mentioned, is really, really concerning. In the past, we thought that only one-third of patients with epilepsy, they fail to respond to anti-epileptic medications. But this recent data from CDC from 2018 tells us that the majority of patients with epilepsy, they continue to have seizures.

Now, we know from the International League Against Epilepsy guideline and their definition of what we call pharmacoresistant epilepsy, that pharmacoresistant epilepsy, it's a failure of two or more anti-epileptic medications. Why is it so? Because it's very well-known from the data from Kwan and Brodie from 2000, that if a patient fails two or more than anti-epileptic medications, the chances for this patient to become seizure free permanently or for long periods of time is less than 5%. And this is exactly why when we fail two or more medications, we start to think about the possibility of other treatment options.

The first treatment option that we should think about in particular for those patients with what we call focal or partial epilepsy, is epilepsy surgery. Epilepsy surgery, as we all know, it is not a new technique. It's not an experimental treatment modality. Epilepsy surgery has been used since the 1950s. And at least in this country, successfully, since the mid-1970s. Now epilepsy surgery in general, whenever it's indicated in the right patient in the right setting, it does lead to permanent seizure freedom for anywhere between 50 and 60% of patients. This is permanent seizure freedom with no relapse. So that's why whenever the patient fails two or more medications, we should think about the possibility of epilepsy surgery.

So what do we need in order to think or to take patients through the epilepsy surgery queue, so to say? First, we need to confirm that this patient has focal epilepsy. Second, we need to find out where these seizures are coming from. And here in order to localize what we call the seizure onset or the epileptogenic zone, we have recourse to multiple tests. The most important one of which is video EEG monitoring. This is an admission, an inpatient admission to the Epilepsy Monitoring Unit, whereas the patient's seizures are recorded and we acquire both interictal an ictal EEG data. This data is used to guide us through the process of where these seizures may be coming from, what area or areas in the brain these seizures are involving, then to take all of this information, put it in context of other tests results. This would include primarily an MRI, magnetic resonance imaging test, that with the highest definition possible to look for a scarred focal cortical dysplasia, hippocampus cirrhosis, a vascular malformation, a tumor, or an area of encephalomalacia due to previous injury, for example.

In addition to that, we may need to do PET scan, which basically, what you call fluorodeoxyglucose PET scan or FDG PET scan, to look for areas of hypometabolism, decreased uptake of the sugar. Then at times, we do other tests that include ictal SPECT to look at the increased perfusion during the seizure. Then at times we may use if we have available, MEG, magnetoencephalography, to further identify the epileptic focus in this three-dimensional space.

When we have all of these results, the next phase will be to have a discussion in what we call multidisciplinary patient management confidence, to identify those patients who are surgical candidate and those patients who may need to do further testing that may include some invasive evaluation, and those patients who may be unfortunate not to be surgical candidates.

Dr. Alex Rae-Grant:  Who else is involved in that? You said radiology and nuclear medicine and obviously, epileptology. But there's got to be other people involved in that management conference, too.

Dr. Imad Najm: That is correct. In addition to the epileptologist, neuroradiologists, nuclear medicine specialists, we have epilepsy neurosurgeons who are part of the patient management confidence. We have psychiatrists. We have neuropsychologists. We have bioethics specialists and a group of nursing and support staff who have access to the social aspect of epilepsy and they give us some input about the possible social constraints or psychosocial constraints for the patient if they are to undergo the epilepsy surgery.

Dr. Alex Rae-Grant: It is really a team sport that you are playing.

Dr. Imad Najm: Absolutely. It's a team sport, and it is basically a decision that is a group decision rather than one person's recommendation.

Dr. Alex Rae-Grant:  Let's say you've determined a person as a candidate for surgery. What kinds of interventions are now available, and how do you determine what's the most appropriate for that individual?

Dr. Imad Najm:  Yes. The traditional type of epilepsy surgery is what we call resective/disconnective surgery, where a focus is identified and the risks of the resection are assessed from a functional standpoint, and that area is removed. That is the traditional, most traditional type of epilepsy surgery. Now more recently, there have been some surgeries done through what we call focal laser ablation. Laser ablation could be quite successful if we are able to localize the epileptic focus and to define the extent. And hopefully, it is a small focus rather than a three, four, five, six-centimeter foci, which probably then become a little bit more difficult to burn or to ablate, so to say, with the laser probe.
And in addition to that, there may be in the future something even less invasive way to do the seizure focus ablation. This would include what we call HIFU, or high intensity focused ultrasound. This would be done for those deep lesions, we think. Also, there are no trials that have been done here, but certainly there are now some centers that are starting to use high intensity focused ultrasound to ablate some very, very tiny deep foci of epilepsy.

Dr. Alex Rae-Grant:  Imad, beside the traditional epilepsy surgery, any other specific interventions that you'd like to mention to the audience?

Dr. Imad Najm:  Yes. There are now three approved interventions in United States. The first one that was approved in the late 1990s is called vagus nerve stimulation, which basically, or VNS. VNS is an electrode adapter around the      vagus nerve and one side of the neck, linked to a stimulator. That is what we call an open loop type of stimulation. Periodically, every four-and-a-half minutes, it sends over 30 seconds impulses to the vagus nerve. VNS has been shown to decrease seizures by almost 50% in around 50% of the patients. With seizure freedom, unfortunately is not as good, probably 5% to 10% of these patients.

A more recent neuromodulation technique is called RNS, or responsive neurostimulation. Responsive neurostimulation is based on the fact that we have an electrode implanted in the brain, where it is as close as possible of the seizure onset. Then there is in that stimulator that is implanted in a part of the skull, a craniectomy is like maybe one-inch in diameter in the thickness of the skull, embedded in the skull. That device has three functions. The first function is to record the EEG. The second function is to detect a seizure. The third function is to send a electrical impulse when a seizure is detected. That's why it's called responsive neurostimulator. Now, same thing, almost same. 50% of patients, they have 50% decreased seizure. Maybe 10 to 15% of the patients will become seizure free.

The last neuromodulation technique that has been approved in United States, it was approved in 2018. It is deep brain stimulation. Not very different to the DBS or deep brain stimulation techniques used in some forms of movement disorders. With this one, stimulating the anterior nucleus of the thalamus. Now, the indications for these patients who are not epilepsy surgery candidates, and whose probably seizures that are involving the limbic system. The results here we know from the trials, the results are almost the same... 50% decrease in 50% patients, maybe around 10% seizure freedom. Now, although these numbers are not earth shattering, but we have to know that in some patients, we really do not have other options. Medications fail. They are not the traditional resective surgery candidates. These patients, we need to do something to decrease at least the number of seizures.

But there is something interesting that recent data has been showing. Either using VNS, DBS, or RNS, it is the fact that with time, it seems like there is an increase in the percent of patients who are becoming either seizure free or more importantly, a decrease in patients whose seizures decrease with time. It is a neuromodulatory effect that we all hoped for, and it seemed like this recent data is quite suggestive of, giving us some hope that these techniques may be helpful in the longer run. But certainly, we don't think at this time and point, the indication for these techniques is as a first line treatment. It's medication that remains first line treatment, then to the additional epilepsy surgery, then consider neuromodulation technologies.

Dr. Alex Rae-Grant:  So let's talk a bit about results and outcomes. You mentioned sort of 50 to 60% seizure freedom. Is it varied depending on the approach that you use, or the type of epilepsy? How do you think about that variability?

Dr. Imad Najm:  Yes. As we all know, epilepsy may affect any part of the brain. It is primarily cortical disease, either the neocortex or the archicortex that is the hippocampus. And therefore, any pathology that affects the cortex or the hippocampus may lead to the formation of an epileptic focus. Based on the type of the pathology and the location of this pathology, we have different outcomes. Historically, the most successful type of epilepsy surgery has been thought to be hippocampal sclerosis or what we call medial temporal lobe epilepsy due to hippocampal sclerosis. In hippocampal sclerosis, the outcome could be as good as 60% to 70% of the patient who would become permanently seizure free. Now in addition to that, the patients who do extremely well are those patients with what we call congenital tumors, such as ganglioglioma and dysembryoplastic neuroepithelial tumors, or DNETs. Those patients with some cavernous angiomas, and some patients with very focal lesions from a trauma, focal trauma, or due to a small stroke.

Now more recently, over the last maybe 20 years now, there has been better identification of what we call focal cortical dysplasias. These are the focal malformation of cortical development that affect any part of the brain. Although there are most commonly seen either in the frontal lobe or the temporal lobe, and to lesser extent, in the parietal lobe... and very rarely, in the occipital lobe. Now these are what we call FCDs. It depends on the subtype. There are what we call FCDs Type 1, and FCDs Type 2. FCDs Type 1 are less well defined, and they typically have worse outcomes than Type 2A or 2B, which are much more focal, much better identified on MRI. Their outcome may be anywhere between 60% to 80%. There is a very specific pathology called bottom-of-sulcus focal cortical dysplasia. These are very tiny lesions, maybe three, four, five, six millimeters in its diameter that affect the depths of a particular sulcus. They are affecting mainly the frontal lobe, either superior frontal sulcus or inferior frontal sulcus. These malformations could be resected very easily and very focally, leading to up to 90% success.

Dr. Alex Rae-Grant:  As you mentioned success, I wonder how do you measure in your surgical population, what's the follow-up and how does that look?

Dr. Imad Najm:  After surgery, typically in our setting here at Cleveland Clinic, we see the patient at 10 days after surgery to remove the sutures. One month after surgery typically, to make sure from a functional standpoint, everything is well. Then we see them three months and six months after. Six months is the visit in which we get typically an MRI of the brain, and we do an EEG at our outpatient EEG. This EEG is very important, because outcome studies showed that it could be quite predictive of the outcome. In particular, if an EEG at sixth month shows any interictal epileptic activity, there is a higher risk for later failures. Then after the sixth month, we see them at one year after surgery and thereafter on a yearly basis, unless there is a seizure recurrence.

Dr. Alex Rae-Grant:  Your practice has a very large clinical population of epilepsy surgery patients. I've heard numbers about 400 or so surgical interventions a year. Even so, it still sounds like epilepsy surgery is not being offered to as many people who could benefit from it. Can you speak to that? Is that so? And if so, why aren't more people being offered seizure surgery?

Dr. Imad Najm:  Yes, that's absolutely correct. The number of surgeries done in the United States is approximately close to 3,000 surgeries per year. It is estimated, and this is a meta analysis study that we just concluded here, that around 150,000 patients are surgical candidate in United States alone. In addition to that, it's estimated that we have another 15,000 patients per year who will become seizure candidates in addition to the 150,000. This data is very sobering because it tells us that even in a country like the United States, where we have access to high level medical resources, epilepsy surgery is not used to the extent it should be.

Now, it is very important for all of us to know that there are these side effects, or the problems from seizures are not limited to the seizure, per se. The known seizure effect lead to injury, lead to disability, lead to fractures, lead to head injury injuries, bodily injuries, skin injuries. In addition to that, seizures that are not controlled, even one seizure per year or a seizure per five years, lead to a significant increase in what we call sudden unexplained death in epilepsy or other what's known as SUDEP, S-U-D-E-P. SUDEP, the risk of SUDEP increases up to 15 times in those patients who have recurrent seizures. In particular, those who suffer from generalized convulsive seizures.

Data showed clearly that the only way we can eliminate the risk of sudden unexplained death in epilepsy is through a complete control of the seizures, not a partial control of seizures. That's why nowadays when we are asked, "What is your goal in treating patients with epilepsy?" The answer is very simple. Zero seizures. It's not like, "Oh, this patient has one seizure per month during nighttime. It's not disabling them." It may not be disabling them, but it's putting their life at risk and at any moment, from what we call sudden unexplained death.

Dr. Alex Rae-Grant:   Let's move away from that for a moment. Are there any new tests or approaches to knowing who to treat with surgery that you want to tell our audience about?

Dr. Imad Najm:  Yes. I think one aspect of the evaluation of patients with pharmacoresistant epilepsy that we did not talk about is, those patients who after the first phase of the evaluation, they do not qualify to go straight to our epilepsy surgery and/or resection of a focus. These patients may benefit from what we call an invasive evaluation.

Now in the past in United States, we have done what we call subdural grid evaluation, where subdural electrodes are placed under the dural and after the craniotomy, and the patient is taken to the epilepsy monitoring unit for another evaluation, now with the electrodes on their brain. Besides this, over the last 10 years since 2009, in this country we've been using what we call SEEG, or stereoelectroencephalography. It's a French technique that has been used since 1959 in Europe, mainly in France and Italy, and that we brought it here to this country in 2009.

This technique basically is using electrodes, what we call them depth electrodes, inserted through a tiny burr hole of three millimeter in diameter, to be inserted in select areas in the brain. The advantage of this technique is less invasive, because we don't do a big craniotomy. But there is another advantage which is it provides us with a three-dimensional map of the brain. Because these electrodes, they don't sample only the surface of the brain, but they sample deeper structures. And they can sample the frontal lobe, parietal lobe, temporal lobe, if needed in the same patient. They could sample both sides, which was not available with the subdural grid technique. Now, invasive evaluation can lead to significant seizure freedom in a large number of patients. For example, we have in our recent data, around 47% of patients will become seizure free after SEEG evaluation that result in surgical resection.

Now from a diagnostic standpoint, there are some techniques that are quite exciting. I think the technique is MEG. I mentioned it a little bit earlier, magnetoencephalography, which is a technique that we have been using here at the clinic since 2007. It does require a machine or a system that is quite expensive. But this system, what it does, it does measure the magnetic field surrounding the electricity in the brain. By itself, it can give us a three-dimensional localization of the potential epileptic focus, and therefore, it could be very helpful. In particular, those patients with what we call MRI negative epilepsy, where there is no lesion that was identified on the MRI. In addition to that and then now in the era of artificial intelligence or machine learning, we benefit quite a bit here from post processing of the digital data that we have. Post processing of the EEG data, what we call signal processing, to identify the foci of epileptic areas in some of these patients. And this is what we call in particular for those patients with depth electrode, what we call the fingerprint of the epileptic area on signal processing of the brainwaves.

Then in addition to that, we can do post processing of the MRI, and identifying lesions that you could not see on a naked eye. And typically, we look at the nonhomogeneity between the gray and white matter. A technique called... One of them is called voxel-based morphometry, or VBM. Which would basically take whatever MRI sequences we've been using, do the post-processing analysis. In some situation, it could be up 20%, 30% of the patients may give us some information about a potentially epileptogenic area.

So in addition to that, we are using more and more what we call multimodality co-registration. So typically when you have an MRI, you look at it. Then you move your eyes to look at the PET scan, move your eyes to look at ictal SPECT, MEG, and so on. By doing so, there is a loss of the spatial resolution of our eyes. To remedy to that, now we are using what we call multimodality co-registration platforms to superimpose all of these tests on each other and see now the brain in a three-dimensional space. And all of your information from imaging... EEG, in particular, depth EEG or the invasive EEG... PET, SPECT and MEG all together, giving us an idea where these data, they converge in identifying the focus. Then they will help us in mapping or planning the location and extent of the resection. The surgeon will take this information, will feed it into any of their intraoperative navigation system, and perform a very well mapped and well planned small resection, leading or optimizing therefore, the results from an outcome standpoint.

Dr. Alex Rae-Grant:  Before we sign off, any closing comments for members of the audience who face this challenge of treating people with uncontrolled seizures? Any advice for them?

Dr. Imad Najm:  Well, this is something I try to remind myself of every day. First, we have to remember that epilepsy when it's recognized, it could be treatable even though the latest data is sobering, about 56% of adult patients tend to not respond to medications. We still have 44% of them, they do respond to medications. Now, in those patients who do not respond to medications, we should never give up. First thing which we did not talk about is the fact that some patients who are labeled to have epilepsy may have what we call psychogenic nonepileptic seizures.

So therefore, a video EEG evaluation in a epilepsy setting, inpatient setting, would give us opportunity to differentiate between those who have epilepsy versus those who don't have epilepsy. Then even amongst those who have epilepsy, it can separate those who have primarily generalized epilepsy, which is they're not surgical candidates, from focal epilepsies which could be epilepsy surgery candidates. You should remember that in these patients, epilepsy surgery, it could be a very good option that could be successful. And as I mentioned, up to 60%, 70% of the patient overall and with minimal side effects and/or co-morbidities.

Then why do we need to pursue seizures to the last one, so to say? Because if we control seizures completely, we eliminate the risk of sudden unexplained deaths. We have always to remember, every patient or any patient with epilepsy whose seizures continue to happen, is at risk of sudden unexplained death. That could be very tragic, affecting mainly the younger patient population. But we can prevent this, and the way we can prevent it... Identify epilepsy, identify these patients who are surgical candidates, and pursue surgery in the right setting.

Dr. Alex Rae-Grant:  Well Imad, it sounds like you're not going to be out of business anytime soon.

Dr. Imad Najm:  Unfortunately.

Dr.  Alex Rae-Grant:  Keep up the good work. Thank you so much for joining us today. It's been a great discussion. Have a good day.

Dr. Imad Najm:  Thank you, to you as well.

Dr. Alex Rae-Grant:  This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast. Or, subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro. Or follow us on Twitter, @CleClinicMD, all one word. That's at C-L-E Clinic MD on Twitter. Thank you for listening. Please join us again soon.