Advances in Treatment for Epilepsy-Use of Neuromodulation in the Management of Refractory Status Epilepticus

Video Transcription

Thank you very much for this very kind invitation and it's my pleasure too to speak about my favorite topic in my life, neuromodulation, although it may not be in refractory status  epilepticus because there are certainly still a lot of challenges for neuromodulation in status epilepticus. These are my disclosures for today.  My learning objective, I'm going to try and provide you with some preclinical background, some rationale for thinking of neuromodulation in status epilepticus, and maybe provide  you a little bit of guidance on how to proceed in this topic. Now neuromodulation in the field of epilepsy, I can speak I think about neurostimulation,  concerns the administration of electrical or magnetic current in the vicinity of neuronal tissue in order to try and modulate neuronal activity, this in adjunct to what we have  been trying to do and changing the brain with chemicals. We all know that physiologically our brain also works with electricity action potentials,  so neurostimulation is actually targeting that part of our normal brain functioning. In epilepsy, because it certainly didn't start out in epilepsy neurostimulation, primarily  in specificity and movement disorders, but in epilepsy when we started thinking about neurostimulation we have realized in the meantime that there are various strategies  that you can try and think about when you think about neurostimulation and epilepsy. There's bottom-up and top-down strategies, meaning that you can perform transcranial  magnetic stimulation and trying to interfere with cortical, subcortical networks. Bottom-up is what we preferentially do with, for instance, cranial neurostimulation, where  you target the brainstem and then inputs towards the rest of the brain. You can try and work for a neuromodulatory approach, which typically takes a while to  install itself, or in epilepsy you can try and actually immediately, acutely intervene with seizure activity.  Maybe that's most relevant to what we are talking about today with status epilepticus. You can try and target the seizure focus and try and place an electrode somewhere in the  brain when you know where the seizure focus is. Or maybe also more relevant here, in the case of status epilepticus, try and interfere with  what we call epileptic networks, or at least regions in the brain that we know are involved in epileptic networks, such as the hippocampus, the thalamus.  We have randomized controlled trials and long-term follow-up available for efficacy and safety for three modalities of neuromodulation in epilepsy.  That's vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation.  My talk will focus today on vagus nerve stimulation, because basically only for vagus nerve stimulation we have case reports and even case series available in status epilepticus.  Vagus nerve stimulation has become an old therapy already. It's certainly not new anymore.  It has been approved as an adjunctive treatment for drug-resistant epilepsy many years ago,  and it is indicated in unsuitable surgery candidates or patients who underwent unsuccessful epilepsy surgery.  The long-term open data demonstrate that up to 60% of patients can become responders if we use vagus nerve stimulation as part of their total treatment regimen.  Now we have seen all the devastating results of treating or just the occurrence of status epilepticus, and as there is a very high case fatality, often off-label products are  tried in this condition. And of the neuromodulation therapies that we have available, we can certainly state  that VNS is least invasive and that we have long-term experience with this therapy in many epilepsy centers.  Also there are some reports on the fact that patients that are being treated with vagus nerve stimulation for their drug-resistant epilepsy tend to have a lower incidence of  breakthrough status epilepticus. So in that sense, we start thinking about VNS in status epilepticus, but of course there's two big groups.  And we are talking here about treating patients with an expensive implantable device. So if you have a patient with drug-resistant epilepsy, that may be not such a big challenge,  as maybe later on you can continue the treatment with vagus nerve stimulation. But of course there's also patients with NORS, and there you are starting out with a relatively  invasive therapy. In a patient who never had epilepsy before, assume that you can stop the status.  The question still is, are we going to continue this therapy with this implantable device? Potentially also these have different effects based on different mechanisms of action or  different mechanisms may be required in both conditions. Certainly we don't know exactly the mechanism of action of vagus nerve stimulation, certainly not in status epilepticus.  Hopefully there is a way to induce desynchronization in a hyper-synchronized state. Now many years ago, previous to bringing the therapy to the market, there were many preclinical  studies in animal models, and I give you a brief overview here, where basically most of the studies were performed indeed in relatively acute seizure situations.  Most of these animals were under anesthesia, so it's quite difficult to extrapolate this to humans in the first place, and also to awake humans, or for instance humans in status  epilepticus. And here for instance you see a very nice example of one of these preclinical data demonstrating  that VNS, if you deliver it at the onset of seizures, was able to reduce the seizure duration significantly, in this case from 30 seconds to 5 seconds.  So demonstrating that most likely, if we believe this data, that indeed VNS is able to have a relatively acute effect on seizure activity.  Now in the past years we have performed a lot of translational research in this context in Ghent University Hospital, and we certainly designed optimal or more optimal vagus nerve  electrodes to be used in our rodent models compared to the initial preclinical trials that were often done in an acute setting with an open surgery situation, and for instance  also with preliminary designed hook electrodes, where electricity can go anywhere in the vicinity of the electrodes.  So since the design of these more miniaturized and more improved electrodes, certainly research has also improved.  But if I checked all the research that we did in relatively acute seizure models in our lab, we found very conflicting results.  For instance, one of the first preclinical studies that we did was deliver vagus nerve stimulation in the absence model in rodents, and basically what we saw, if we really acutely  deliver it, immediately after the onset of the seizures in these absence seizures, that basically we even were able to increase the duration of spike and wave discharges.  If you have a continuous and, for instance, weekly treatment of these animals, they do tend to have a decrease in their seizure activity.  We also looked at the motor cortex stimulation model, where basically we could demonstrate  a relatively acute effect on cortical excitability, where we had to deliver more electrical activity  to the cortex when the rats were treated with vagus nerve stimulation to induce cortical excitability and seizure activity.  And then we did an amygdala kindling model, where we also investigated where the relatively  acute effect of vagus nerve stimulation was able to affect the kindling process, and basically  we were not able to do that, and even found, again, in some rodents pro-convulsant effect when VNS was administered prior to the kindling pulse, and an anti-convulsant effect when  VNS was applied immediately after the kindling stimulus. So it's not a straightforward question where you can just deliver VNS in acute situation  and hope that you will be able to stop a seizure. We also performed VNS in a pylocarbon model, when we nicely demonstrated a decrease in  total seizure severity, and we also investigated the effect of stimulating the vagus nerve in the cervical region on potential intracranial networks, like the hippocampal network.  This was work done by Lars Larsen in our laboratory, investigating both EEG and evoked potentials,  and just to demonstrate to you that he found significant effects in the hippocampal network, but highly dependent on the type of VNS paradigm that we used.  So depending on the type of stimulation parameters that you use, you have a different effect intracranially. This brings me to patients. What do we know?  Well, there's very little information in the literature, or only from anecdotal information,  demonstrating that truly while, for instance, a patient is receiving EEG and having a seizure,  and you acutely administer VNS, for instance, by using the magnet that patients can use, that you are able to acutely desynchronize the EEG.  There were a couple of case reports on that, and more recently, due to the fact that we  performed a study with a closed-loop approach, indeed there were some cases of patients demonstrating  when you acutely are able to deliver VNS, that you are able to shorten seizure activity. I briefly want to share with you one of our cases that, of course, triggered our interest  in vagus nerve stimulation and status epilepticus. This is Sarah. She is part of a twins, and basically had in her medical history a serious pneumonia  with pulmonal hypertension, and a thrombosis of the right vena cerebrae interna, and a thalamic bleeding shortly after she was born.  And since the age of about one year, she was repeatedly admitted to the hospital with nonconvulsive status epilepticus.  And again, in 2006, a similar thing happened, and here you see her EEG, which is quite clear. And basically, this is a patient that was treated in the pediatric intensive care unit  with all the typical progression of anti-epileptic drugs, and eventually also anesthesia, resulting  into a EEG like this, a burst suppression pattern with bursts that are clearly still quite epileptic. And we are now almost two weeks later.  Any type of anti-epileptic drug has been tried, and eventually the adult department was consulted  for a multidisciplinary meeting to investigate whether this patient could be a potential candidate for surgery, despite the fact that she had generalized abnormalities on her EEG.  And basically here, what you see is indeed the sequelae of her post-natal right thalamic bleeding.  So it was decided that the only option for this patient would be vagus nerve stimulation, and we did perform vagus nerve stimulation in her.  She was under continuous EEG monitoring, and we had over a one to two day period, a stepwise increase in vagus nerve stimulation parameters, up to one milliamp.  The theopental at that time was stopped because she was going into multiple organ failure, and we further increased her output current up to 1.75 milliamps.  And this is the EEG that occurred after six to seven days of vagus nerve stimulation. And of course, I'm showing you one of our NICE cases.  And in the following days, this patient gradually regained consciousness and was extubated. And actually, we have been following her up now for 15 years, and this patient is still  seizure-free on VNS and three anti-epileptic drugs. So basically, we regularly get this question in refractory status epilepticus.  And a couple of years ago, together with Maxine Gibouet and Professor Strinka, who is here  in the audience, we performed a review on all the cases that were published in the literature.  And we came to 28 patients and found a success rate in generalized epilepsy in up to 76 of the reported cases, and for focal epilepsy or partial epilepsy in about 30% of the cases.  So we did an extensive literature research. Studies were included reporting the use of vagus nerve stimulation for both refractory  and super refractory status epilepticus, and the primary endpoint was the cessation or not of the status epilepticus episode.  We also had a positive outcome definition that you can see here. And we did a lot of, or tried to do, a lot of data extraction.  And most importantly, of course, on, for instance, time, duration of the status epilepticus prior to VNS, and then time to cessation, which is, of course, quite important.  We eventually got 25 manuscripts, clearly all class four evidence, 44 patients. We excluded these patients who had epilepsy of partialis continua, eases, or repetitive  seizures following acute encephalitis. And that gives us the result in 37 patients where, indeed, cessation of status epilepticus was reported in the magic 73%.  And in 20% of patients, there was no cessation. There were three fatalities due to the underlying condition.  And then also very nicely, for most of the patients, we had information on duration of a status epilepticus.  And if you compare that pre and post VNS implantation, it was decreased from 21 days to eight and a half days.  So if we consider the positive outcome that we defined, these numbers were even higher. And the VNS parameters were reported in these publications in 20 patients.  And they were typically what we see in regular treatment of patients with epilepsy and vagus nerve stimulation.  So in conclusion, due to the high case fatality in refractory status epilepticus, off-label treatments are typically, that are approved in drug-resistant epilepsy patients, are  tried in patients, even if there's no proven efficacy for refractory status epilepticus. VNS seems to have the potential to interrupt these episodes in a high number of patients.  But we have to realize that this is data, of course, from class four studies. And our major issue probably lies here.  There is a higher risk of reporting bias, in the sense that certainly VNS has been tried  in refractory status epilepticus unsuccessfully, but these cases are most likely not reported. There were certainly also missing data in our analysis, and primarily, for instance,  with regards to EEG outcome. There is limited knowledge for other neurostimulation modalities.  There are a couple of cases with responsive neurostimulation, with deep brain stimulation, and also the non-invasive approaches like high-definition transcranial direct current  stimulation is being tried. But really, it is too early to see whether this can help these patients.  So it's clear that there is an urgent need for prospective studies to investigate the role of acutely delivering VNS in status epilepticus, to identify optimal stimulation paradigms  for this acute effect on the brain, also to identify the timing of the implantation. Should we wait until we are speaking about refractory status epilepticus?  Should we first try the ketogenic diet? Should we do it together? There were initially some publications that they have a synergistic effect.  Can we identify potential synergies with pharmacological agents or non-pharmacological treatments? And very important also, we are speaking here about an expensive therapy.  We need to think about cost-benefit. Of course, if you realize that a patient in intensive care unit per day in Belgium, and  most likely in most countries, is extremely expensive, and we once calculated that in three days, three days of the intensive care unit pays back one device for treatment.  So I'm not advocating that we have to do it in all the patients, but this, with regards to cost-benefit, these are expensive patients already.  Of course, sufficiently powered randomized control trials are difficult in status epilepticus, and maybe even extremely challenging when we'd want to try implantation with devices  and therapies with devices. The impact on clinical care and practice, currently I can only say that there is no  true evidence for the use of neurostimulation to treat refractory status epilepticus. We have positive reports of many cases for vagus nerve stimulation, but these are class  four studies just demonstrating that there is a potential. Thank you very much for your attention.

Video Summary

The speaker discusses the potential and challenges of using neuromodulation, specifically vagus nerve stimulation (VNS), in treating refractory status epilepticus. Neuromodulation involves administering electrical or magnetic currents to modulate brain activity, usually supplementing traditional chemical treatments. Despite advances in using VNS for drug-resistant epilepsy, limited evidence supports its efficacy in status epilepticus. However, some case reports and studies suggest VNS might decrease seizure duration and severity acutely. The speaker emphasizes the need for prospective studies to establish optimal stimulation parameters, investigate potential synergistic effects with other treatments, and weigh cost-benefits, considering VNS's relatively high expenses. While some positive outcomes have been reported, current evidence largely comes from class four studies, highlighting a need for rigorous clinical trials. Overall, the presentation underscores a cautious yet hopeful approach to advancing VNS applications in status epilepticus.

Asset Subtitle

Presenter:

Kristl Vonck, MD, PhD, FEAN, is Assistant Professor of Neurology at Ghent University Hospital, Ghent, Belgium. Her medical training was carried out at Ghent University and her PhD thesis was entitled ‘Neurostimulation for refractory epilepsy, clinical efficacy and mechanism of action’. She has held international training positions at Guy’s Hospital, London, UK; Yale University School of Medicine, New Haven, Connecticut, USA and the University of Stellenbosch, South Africa. Her research interests include neurostimulation, bioelectronic medicine and neurophysiological homemonitoring of neurological disorders.

Keywords

neuromodulation

vagus nerve stimulation

status epilepticus

clinical trials

treatment challenges