Neurosurgeons Christopher P. Kellner, MD, and Fedor E. Panov, MD, present results of a clinical trial on paired vagal nerve stimulation (VNS) for patients recovering from stroke who experience upper-extremity weakness. The implantable device, when activated during rehab, stimulates nerves in the brain that then prompt patients to move their arms, hands, or fingers when performing an activity.
Chapters (Click to go to chapter start) Review of the stroke recovery curve for patients who experience upper-extremity weakness and an introduction into the concept of using VNS for stroke recovery Past, present, and future of enhanced stroke recovery and overview of a paired VNS system and how to implant the device Evidence showing how paired VNS works in aiding recovery for stroke patients with upper-extremity weakness and a review of the multidisciplinary process each patients undergoes when receiving this treatment Eligibility criteria Program goals and future direction Q&A/Discussion
Why don't you give it in? Why don't you give a start? Thank you chris We were going to keep that a secret but I guess we'll just let everyone know ahead of time. This has nothing to do with our personalities. We are so excited to introduce this program to the department for what it is now for. What is the potential for a program like this in the future? And other programs like it. Next slide here. You can see our disclosures next slide. So what we'll do today is we will review the enhanced stroke recovery as it exists today in the Mount Sinai System. We will look at the pilot trials that we're trying to perform here. We'll also take a look at the BNS rehab pivotal trial that just received FDA approval. We'll take some time to review the system device as well as the implantation of it and then the enhanced stroke program recovery in action and the possible future directions as this program takes off. Thanks a lot. This is a standard stroke recovery curve for patients who have had a scheming stroke. And we're looking at upper extremity armed function here. And so um patients uh suffered a stroke and they get worse for a few days as they suffer the initial ischemia and then the swelling associated with the ischemia. Uh then they initiate rehabilitation and they have some improvement in function and then they reached a plateau phase thought to occur around the 3-6-month period. Um and then depending on their activity and the treatment they're receiving some of them continue to plateau, some receive treatment that aids them in continuing to improve and some actually start to worsen after that. In that chronic phase, entire careers have been built around the recent discovery of treatments in this phase. Specifically thrown back to me and there is a lot of device development and drug development around treating patients in this window. Um There is not much that we're aware of in our space in this window here. We have heard a little bit about stem cell injections um being done at stanford um and we have also heard a little bit about other forms of stimulation that can be done here. Um And last week we heard about a potential digital bypass that can help augment function in the chronic phase of stroke. But today what we're going to focus on is vagal nerve stimulation to treat patients in the chronic phase of stroke to improve upper extremity function. And this is work that's been going on for quite a few years. Although I was previously unaware of it. It was a little bit under the radar um in the neurosurgery stroke space at least This pilot study was published in stroke in 2018 and this used a very specific form of vagal nerve stimulation called paired Vagal nerve stimulation. And in this specific uh strategy a vagal nerve stimulator is implanted in a patient who has had an ischemic stroke and that ischemic stroke occurred at least six months prior to this training and treatment paradigm. Then while the patients performing the movement, the therapist presses a button and activates the stimulator. So each time the movement is being made the stimulator is activated. It's not that the patient has the stimulator activated, performs a lot of rehab and that has it turned off. This is paired with every single movement. The real rotation Paradigm that this team developed includes three rehabilitation sessions per week for six weeks. And in each session they do approximately 300 repetitive movements that are task specific. Um So in this trial that I just mentioned the pilot study first the treatment arm Engaged in paired rehabilitation for six weeks. Then they engaged in home based rehab in which the VNS was turned on, They did their home rehab and then it was turned off and when it was turned on it would give a pulse every 10 seconds. So in this pilot study, 22 patients, participants were Consented, 17 were randomized and then it ended up that there were eight in each group given some exclusions and people who exited from the study patients who were in the VNS group mm hmm. Um underwent paired rehabilitation which was in clinic and then they went home, they got an assessment, then they went home Uh and they had a 30 day ramp up period at home. Then they started engaging in at home therapy with the VNS turned on. Um And so here you can see the change in the patient's fuego meyer assessment and I'll go into exactly what that is. And you can see that there was a notable improvement in patients who had the VNS turned on and then this is the control group, patients who did not have DNS turned on. So you can see that rehabilitation is improving both groups. Um But is it improving the active DNS group more? There was no statistical difference in this pilot study at this level, but there was statistical significance at this later time point after both the in clinic therapy and the at home therapy. Then the groups crossed over and so the group that did not have the VNS turned on but they did have it implanted then crossed over and then underwent in clinic therapy. Um And that group then did show an improvement at that point, I'm just gonna talk a little bit about what the future minor assessment is, this is a much more complex scale than what we're used to performing for the NIH stroke scale. Um This is a test in which uh each item is scored on a zero to scale zero is the the person cannot perform it. One is, they could perform it partially and two they could perform it fully. Um And then there are five domains, there's motor sensory balanced joint range of motion and joint pain. Um And this study and what we're going to talk about today is motor function specifically in the upper extremity. This can be divided into upper extremity and lower extremities. So that just gives you a sense of what this outcome measure is, that these studies are looking at. That led to a pivotal study being performed that was published in Lancet in April of 2021. And that inspired uh this talk here and uh and a lot of the work in this field that people are now implementing programs implanting DNS and treating patients who have chronic stroke. and so in this study there are 195 patients Who were assessed for eligibility. 108 underwent implantation were randomized and so there were then 53 assigned to the active DNS group and 55 assigned to the control group with the same paradigm as the um paradigm I previously described. Um And there was also this study showed that the control group Had a few Kohlmeier assessment, upper extremity improvement of 2.5. And then the VNS group had an improvement of over five on average. Um And this was after they had their in clinic therapy and then they started doing their at home therapy and it appeared that the patients who had the VNS implanted did continue to have a slight improvement. Um while the control group also had a slight improvement and they remained a statistically significant difference between the two groups with far more improvement in the VNS group. The group also looked at which patients, what percentage of patients were responders and they defined a responder as somebody who had a clinically meaningful response of six points or greater on the upper extremity fuel my assessment. Um And that was based on prior literature In which patients who had a 5.25 point change were considered to have had an excellent improvement With greater than 50% improvement in armed function. And so this prior literature unrelated to this group gave them this definition of 5.25. Um So they used six and 50% of patients in the DNS group had a six point change or more. Mm hmm. Thank you. Chris. So quick review of, you know, the past, past, the present, the future and then hand stroke recovery options as we go forward. Um Go ahead and click. So in the past, even going further back Well, years ago, people have been trying to apparently stimulate the nervous system to affect the brain one of the mentors of Galen and sample apps used to painful stimuli with ligatures to try to stop seizures. Um and that would be just kind of tying people's fingers and using that painful stimuli to trigger the system. Um Beyond the scope of this talk would be the research that is out there. Noninvasive modes. Tms. Transcranial direct current stimulation. Some exciting work has been happening in the DBS domain. And here we want to mention under Machado's trial from Cleveland clinic, it's more than a decade worth of work where they're stimulating in the cerebellum and are able to get right now in you know, open label just beginning of that research Hugo Meyer improvements of up to 10 points but we're still at least five maybe 10 years away from actually coming to fruition. So in the present right now the best way to enhance these patients and their outcomes would be big enough stimulation in the near future as the DBS really takes off and we have these other incredible options as we discussed before the stent road woman trials stem cell injections. Next uh in the future we're hoping that each specific patient will have therapy that is designed for them. And this will include everyone from neurosurgery to neurology to rehabilitation doctors um and we will get to that it's just a significant process and where I think the strength of this program does rely. So this right here is the FDA notice of approval for protestant that just came out earlier this year. The micro transponder system and from this point on insurance companies should be approving this device and that really has triggered the push at Mount Sinai to proceed with this program. Next slide. So a little bit of a background and I apologize if this is too low brow for some of us who do vagal nerve implantation but it will be helpful for the residents and others listening in who are not neurosurgeons. So the the system system is similar to what we classically called vagal nerve stimulation. It's a device that is a two part incision implanted in the neck as well as usually subclinical er or pre auxiliary. For the incision. It has uh usually two contacts and another little stay wrapped that gets wrapped around the bagel nerve itself and then tunneled over to the lower incision. Next slide. So here you guys can see a fairly standard approach to this um for all of us who use spine a little bit more. This is akin to an A. C. D. F. Incision for C. Five C. Six. For those of us who do more carrot approaches. This is a smaller kind of a mini carotid endarterectomy approach and the pocket is done either in the auxiliary, close to the villa or more of a classic dbs battery approach to fingerprints below the clavicle. After that the dissection happens down to the charity chief itself. Next slide and here you can see the outline of the opening. You can see the carrot immediately you can see the jugular vein laterally and the nerve usually lies in between them and deep. Sometimes there's an anatomical variation which would be more superficial and at this point this is an incredible exercise in manual dexterity and patience where you are wrapping the small coils around the vagus nerve itself. There's a couple of tricks that help Eddie chang at UCSF used to put a small cut rubber gloves underneath it to isolate the nerve. Some folks will use vessel loops to gently lift it up to make that part of the process easier. There's some great training that residents can do before these cases on a model that simplifies this a little bit but really gets them into the right approach as to how to do this. Using the correct instruments and surgery after the vagal nerve stimulator itself was implanted, they secure it with some tension relief sutures to the SCM fashion. And then you tunnel into the pocket and connected to the I. P. G. The most common complications from this case hoarseness of the voice. We are dealing with the vagus nerve, uh some discomfort in the area um and a very low chance of larger possible complications including vascular injury. Next slide. So why do we think this works? And as chris stressed, This is decades and decades of work. And actually for this one chris, let's just go to the next slide right away. It shows it as well. But overall again, we're increasing global neural plasticity and we are accentuating the extensive synaptic reorganization that happens with rehabilitation. So, as you can see here on the left task specific practice as chris described together with relevance from the behavioral perspective, the patients need to understand and need to know that this is getting them better. The lower left hand side shows you just how many theories there as to how DNS works. Some of the most recent literature is the simulation of locus Aurelius and the northern arctic spread through the brain. That happens after that. That contributes to the synaptic reorganization. You guys can see in the middle here the sensory motor neuron activity together with neuromodulation, it gives you this long term neural plasticity and you can see the graph here from the 2016 study that shows that the VNS plus we have does better than DNS itself on the right hand side. You can see mice and rat models that show that there's going to be greater nerve recruitment on both sides of the hemispheres with DNS parent rehabilitation versus just intense rehabilitation without the neuromodulation. Next slide. So this is the uh this is the paradigm that was used in the in the in the study. And the most important thing to emphasize here that was even emphasized in jeremy's talk is that this is a multidisciplinary program in which you need close collaboration between neurologists, neurosurgeons, rehabilitation, doctors, patients of course and industry. Um And so in this protocol, the patient undergoes the surgery, has the device placed um then undergoes baseline testing, then has there in clinic rehabilitation 42 days where they're going three times a week and they're having in person paired VNS where the therapist is pressing the buttons, you've got to have therapy team who's highly engaged and performing this rehabilitation. Um We've been working with the abilities research center with the rehab department here at Mount Sinai developed this paradigm um and that state Petrino's group then they undergo their post in clinic rehab testing. Then they continue performing their at home rehab as they did in the study. We're also adding because of the cost, the upfront cost and the challenge of making sure patients will comply with this long and arduous paradigm. We're mandating a pre debilitation one month period where they meet the rehabilitation team And they go to rehab in the same way they will in this in clinic rehab for four weeks during this period of time. They're also enrolled in the precision recovery program. Uh And they're entering their data at home and they're having their examination recorded on a weekly basis. Um Here's that app that we've developed a little bit since the last time you heard about it. Um And so this has um because I kind of some basic features were able to um link up some physiologic monitors and we're able to have the patient fill out the survey just a few questions each day and then the clinician is able to monitor how that patients doing. So each patient will be uh logging high resolution physiologic survey and uh and neurologic function data. Um here's that automated app we've been using for monitoring the patient's movements. Uh And the patients will be recording themselves. So we have a highly um resolved method of tracking the patient's movement over time. That's going to be more we think better at detecting improvement than even the few Lemire which as you heard Was either a 01 or two for each muscle group. Um The specific eligibility criteria for patients who are who could potentially have this done. Um These are for patients at least the FDA indication is for patients who have a scheming stroke. That could change in the future. If another trial um focusing on I. Ch. Or other diseases shows benefit the animal studies suggest that there probably will be benefit for I. C. H. That's similar to the benefit for a scheming stroke. So that's going to be an exciting area of research. Um If a patient has a patient has to have some upper extremity weakness of course because that's the target um improvement. And so the patient has to have an NIH stroke scale of 1 to 3. If they have a zero they're not bad enough and if they have a four uh they're unlikely to benefit because they're not able to perform the tasks necessary to engage in the task based period rehab patients also need to have some sensation and that was described in the study and that's so that they can also maximize their participation in task based rehab. Of course they can't have a prior of the economy. We have already developed a prospective registry. So just emphasize what we're talking about today is clinical practice. But we want to monitor outcomes in this program. And so we will have a parallel quality assurance database in every patient that provides their consent will also have their data prospectively recorded in a research registry. Um, we estimate that this will, there will be a large number of patients in our system eligible for this annually. We have 1900 ischemic stroke patients in the Mount Sinai health system annually. 66% of those patients have arm weakness um by the data. Uh and after six months, about 10% of those completely recovered. And so therefore would be ineligible. So there are about 60% of patients just kind of looking at the broad group and that leads to about 1140 40 broadly eligible patients. Of course, you would have to look in more detail um about whether or not those patients can really undergo this procedure and they have the social support to engage uh and comply with the rehabilitation program. Um Dad. Mm hmm. Sorry, I took your last slide slide there. No, no, It's all right. We made it work until the end. So, the goals and future directions And to us, this is the most exciting part. We can really improve the stroke recovery of patients for whom really not. A lot has been available. Once. As chris pointed out, they reached a plateau. We are set up here as the Senate to perform this perspective high quality research and this is leveraging the work that chris and Dave Katrina have done in the past. And really building on the fact that it's a cohesive team that works at Mount Sinai together. We most certainly can have this grow into an enhanced stroke recovery program in the future. That includes everything that we mentioned so far in this talk. I think that all of us do think that the creation of future cyborgs is easier than regrowing the nerves but we will be approaching this in combination. So we will be bypassing neuronal circuits that no longer work with creation of brain machine interfaces. But at the same time we will be stimulating whatever recovery can still happen in the circuits that are intact or can take over. And of course, you know, interest cerebral hemorrhage is a big question mark at this point. But all that we've seen so far would point us to the idea that those patients will benefit another stressor to place here. Is that the way that the trials are designed for them to take away the placebo effect and natural recovery. They had to wait for the chronic phase. Whereas we really go into the real world, both chris and I and some of the other people in the field do think these patients may benefit from implantation earlier, from rehab earlier from stimulation earlier and that can potentially even improve their down the road outcomes. Uh And I want to make sure that we both also thank rasheem Nikola Gara and to generate he who helped with the slides in the preparation list. There are excellent medical students that work with chris on these projects. So with this we want to thank you guys and we want to leave some time for questions. This is an exciting opportunity for the center and we think that the amount of patients coming through potentially will be a lot. So we will need the help. I see Sharon McGee has a question here. Thank you very much. Really exciting program, congratulates both of you because we really put our program forefront of stroke recovery. He said two questions. One as we know that neural plasticity is time dependent. One of the critics of this mass general a pilot study and subsequent clinical child was included patients 5, 4, 4 months after a stroke. Up to six years. So what would be the timeline that we will be using in this program According to the studies that they did not have the power to evaluate if there was a difference in improvement based on the complexity of the stroke. Um but they comment that they they think that there is a benefit even for patients with severe chronic stroke. So, you know, up to and I think the latest patient in the study was up to nine years as you mentioned. Um So I think that's one reason to very carefully monitor outcomes to see if there's a difference in the amount of time until implantation and treatment. Um But according to the study chronic stroke, his chronic stroke so that's any patient after four months in the pilot and then six months in the uh in the trial. Some some people argue that there might be even role for venus in acute stroke ah taking into account anti inflammatory and I glutamate uh potential of DNS. But that's it. Different topics. Yeah. You know as we were discussing offline there's there are simultaneous methods of stimulation but those really haven't panned out uh in animal models to be as effective as the implanted paired VNS. Um and so uh it might be that you just can't stick to the paradigm enough. You can't get those 300 repetitions if it's not implanted. Um Or it's not getting to the right part of the nerve and getting as robust a stimulation hasn't implanted stimulated and follow up as well here. So yeah from the perspective of doing acute urgent V. N. S. The center has experienced with that you know we run into that when somebody is in status and nothing else is working. Um So we are able to do this on a more acute basis and I think that eventually the program will head in that direction as you said to stress the fact that it's not just nerve elasticity neuromodulation but also that it's potentially inhibition of the inflammation that's happening. Um That would be outside of what's recommended right now. But to me Sinai is the place to potentially try something like that and to keep that going as a project. That's great. Uh Last question um ted any any potential role for para cutaneous cns in future. Well I think who was it? Chris got chris got stimulated like this by Dave Petrino at some point when he was going through his bout of clinical depression after call. Uh Most certainly I think that the whole the whole field is moving from being able to get good enough intracranial e at the source and then slowly reverse engineering approaches that will become more and more minimally invasive. We're trying that in epilepsy. Were trying that in neuromodulation. It's been tried in depression and for sure eventually we're thinking that the stimulation can happen targeted and without the invasive procedure. But I think we have to go through the building blocks of getting there. Thank you dr harry pinatas. Yeah my connection maybe off here. Can you guys hear me? Okay? Yeah we can hear you okay. Um You know one of the things I was thinking about chris and ted I don't know if you guys were part of the grand rounds we had with mike sri guru with connect oh mix and you know chris you and I have been communicating about this but it may be nice to somehow incorporate some resting stand em or I data into this uh and then look at you know some of the recovery data in terms of connect atomics and the other thing too is you know transcranial magnetic stimulation is another area kind of rapidly growing and parallel here um with some of these recovery efforts and patients with brain tumors with strokes and other issues. Yeah absolutely agree both tms um direct transcranial as well. Um I think all these things will grow together. We're just we're starting out in different spots. We as neurosurgeons are focusing more on the invasive procedures that we know well and we're taught that there's a lot of the neurologists and rehab physicians will be pushing the tms chronic comics is a great idea and I think that downstream the goal is to have this bs patient specific as possible. And maybe the comic comics analysis will rule out some cases where we see that they will not benefit long term and actually will help us even further delineate the stimulation that we need to provide. All of that is still to be to be learning to be discovered. Are we nearing the end? If so I wanted to ask a question that gets back to how we started with cherished corner this morning. No are you still on the line? It looks like No I had to step out so Brandon along the lines that we discussed. You know how to evaluate programs. What do you think would make me the happiest about this fantastic presentation that we just heard. What do you think that makes it stand out? I think 11 thing that stood out to me is that there's a lot of um uh collaboration between different different um people in a in our department, within the different sectors of functional neurosurgery and vascular neurosurgery and and uh you know, design and innovation and working with ways to create new therapies and um you know, bringing a lot of bright people together and having them, you know, in close proximity. You can really spin out a lot of a lot of fantastic projects. You hit it right, you hit the nail right on the head. I mean that's just so great, you've got a vascular guy talking to a functional guy. They don't even speak the same language, they don't even understand each other half the time and yet um you know, got a little bit of a seniority issue thing, but they're both collaborating together. So I just want to congratulate you, I'm sorry I had to step away during that part. I would love to see the other part of the slides I've seen a little bit but I want to see more. Um it's great, it's great how can we amplify? My only real question is how can we amplify this? What sort of resources are needed and how can you amplify the effort beyond what it is now? Yeah, I think at this point the next step will be, we've had some offline discussions with the neurologists. You're really taking this presentation to the neurology grand rounds. I know some of the neurologists actually on this, on this conversation right now. Um, and getting the word out, you know, a few patients will come back year after year, after year, even nine years out from their stroke, Who can still now benefit from this? As we said, the trial goes out to 10 years, they can get benefit, but a few folks have given up and it's really working through the system and finding people who are 67 years pastor stroke who think they can not get better and we want to get them to change their mind. And the other really important aspect here, I think this is Mark Carney from Canada who stated, uh, you know, the financials are always important. It's always important for us to be able to sustain this program. From the perspective of administration in the hospital, He phrases it as you know, breathing is not the goal of life, but breathing is pretty important to living. Um, and we're happy to report that the initial financial analysis and do seem favorable from the perspective of what insurances will be reimbursed for this. And while the margin may not be great, the volume of the cases will most certainly amplify that. So I think that we are in good position and again we welcome anyone and everyone who is willing and able to collaborate on this because this will be a big project. How do you think this relates to intention? You know that late curve with the chronic rehab phase uh plateau door improving or or decreasing? Um you know I've usually said 18 months as my limit for when I'm expecting continued improvement on someone who suffered a deficit, whether it's surgical or stroke. Um but we find that there's some highly motivated people who forced themselves to get better even after they've reached what should normally be the plateau. I wonder what that mechanism is and how that relates to stimulation. That is. It's another type of stimulation, isn't it? Intention motivation that are self generated are is another type of stimulation. I wonder how that relates to VNS and other types of activation. Yeah, I mean this is the neuromodulation concept of resilience and there's some great research in that and Helen may burgers at our center. Uh not necessarily complete. Um You know, defense from stress resilience is not a resilience is actually undergoing the stress undergoing the trauma but being able to long term to continue to push for it. We have some incredible research where a singular stimulation, a little bit more mid singular and posterior actually creates this concept of increased resilience where patients are able to undergo awake brain surgery easier, Better if those areas are stimulated. So what do you think the mechanism is chris of that motivation versus stimulation? If there is any type between the two, the activation of the of the motion um you know, engages multiple areas in the brain and that system improvement is far more robust than uh direct direct cortical stimulation. Um And that that recruitment of the system and building the network is is critical without being without able to be more specific. I mean that that to me is intuitive and and the data has shown that that um it's a circuit rather than a direct stimulation of the motor cortex. Yes. Um I think also that just psychologically these patients um they basically have no hope when they get to this plateau phase and I have hundreds maybe, you know at this point thousands of patients who are in that phase and they really don't have many options because insurance has run out and is no longer giving them rehab. So if they did get rehab as you saw from the control group, they would still make some improvements but they're unable to get that dedicated rehab. And so this is an opportunity to re engage patients in the rehabilitation system um in a way that benefits them whether they're getting stimulation or not and kind of rallies forces behind them in this, a new hope of another phase of their recovery. So I'm I'm excited about this because of that opportunity as well as introducing a new treatment that's going to make it even better. Um The rehab department um has some funding to fund these patients in this phase of recovery even if insurance does not cover their uh their rehabilitation three week three times per week session. So we can guarantee patients that they're going to get that intense recovery after having the implementation. The other question I had was about things that do not have such a discrete event. Um you know my dad just turned 100 and he's lost a little bit of function but he would like to have more function and would like to have some function come back. He never had an acute massive event that you would justify putting one of these in but there are probably focal uh there is loss and there's lateralization. Um What about the general, what about the population that's just getting older and is losing function? How is it possible? This could help? Yeah, I think so. Um And I think this is where the noninvasive approaches probably are going to be tried first in patients with no severe significant stroke deficit. This is where TMS transcranial or potentially transportation's big winner stimulation. Probably the will be the way that the community goes first. Alright well when let's schedule the follow up. When is the follow up talk? We're getting approval for the device? We hope in early january um and so shortly after we will be able to give you an update. Alright, so 9-12 months from now, maybe? Yeah. Okay. Great. Thank you. It's very exciting, correct. Thank you. Thanks everybody.
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