Implanted system for orthostatic hypotension in multiple-system atrophy

Thank you for joining us.

[00:01:03] Dr. Gregoire Courtine:
Hello.
 

[00:01:03] Dr. Jocelyne Bloch:
Thank you. Hello.
 

[00:01:05] Dr. Sara Schaefer:
So for anybody who may not be as clinically oriented in movement disorders, I wanted to start by just doing a basic overview of multiple system atrophy and the particular issues with orthostatic hypotension and supine hypertension that these patients face, as well as the current strategies for treatment of those problems.
 

[00:01:31] Dr. Jocelyne Bloch:
It's often a sign of this disease, a neurodegenerative disease, that is concerning many systems, among them the sympathetic system is degenerating. And interestingly, it's degenerating from proximal to distal from the brain to the periphery.

So that's what we found interesting. So in most of these patients, they have these classical medicines that they get in order not to have hypertension orthostatic hypertension, but it's not working so well, especially in the patient that we present in our case reports. She could not stand up. For more than a year, she was bedridden.
 

[00:02:11] Dr. Gregoire Courtine:
So every time I remember when she would stand up, after one or two minutes, she would have such low blood pressure — like like below 60 systolic blood pressure— and she would go into the syncope. So she experienced ,what two or three syncopies per day, more or less?
 

[00:02:27] Dr. Jocelyne Bloch:
Even more. Even each time she wanted the bathroom. She, for example, she had a syncope.
 

[00:02:32] Dr. Gregoire Courtine:
And this is really due to the interruption of a specific pathway from the brain stem, coming from vasomotor center. So that normally regulates the tension in alter. So when there's a orthostatic challenge, meaning the gravity will pull the blood down, when standing up, for example, this pathway will contract the artery to increase the blood pressure and then stabilize the body at the correct valve of blood pressure. But of course there is a degeneration of not only in the brain stem, but also in the spinal cord, as Jocelyne said, this pathway, this bowel reflex, basically, is not efficient anymore.
 

[00:03:13] Dr. Jocelyne Bloch:
So we may have to remember that these neurons are in three parts. The first part is from the brain to the spinal cord. The second part is from the spinal cord to the ganglia, and the third from the ganglia to the vessels, actually. And so there are three nerves.

And the one that is mainly degenerating is the first one, but also a little bit of the second one.
 

[00:03:38] Dr. Sara Schaefer
So related to that anatomy that you just described, can you talk a little bit about the spinal cord stimulator and how it interacts with that anatomy?
 

[00:03:48] Dr. Gregoire Courtine:
So it started for us with spinal cord injury, actually. Also people with spinal cord injury have the same point of interruption of this pathway coming from the brain stem. So they experience orthostatic hypertension as well. And, originally, we used epidural electrical stimulation to reactivate the lower thoracic spinal cord to restore walking.

And then we realized that we could modulate blood pressure with this approach as well. And what we found is that the highest concentration of the circulatory facility with blood pressure modulation, so the second neuron Justine was mentioning, is actually located in the lower thoracic region of the spinal cord.

So what we did is use electrode array to really target the last segment of the thoracic spinal cord. And by this mean, what you achieve is one activation of large diameter F1 fibers that connect to one internal that is catecholaminergic. That then go on this node, that degenerate, which is a preganglionic sympathetic neurons and, and then will lead to the modulation of blood pressure.

So basically the stimulation will compensate for the lack of activation of this so called C2 neuron that is normally responsible for increasing blood pressure.
 

[00:05:05] Dr. Sara Schaefer:
So you mentioned a little bit about the evolution of use of this technology from spinal cord injury patients. How did the two of you become interested in using this for multiple system atrophy, given that neither of you are neurologists or specifically movement disorders neurologists? Where did this idea come from?
 

[00:05:27] Dr. Jocelyne Bloch:
Yeah. Even if we are not neurologists, we have a little bit of medical knowledge. And so we knew about this disease and knowing more about it, we thought about other applications and we thought about first Parkinson's disease, because there are a lot of people with Parkinson's disease with orthostatic hypotension.

But then going more in the field, we saw that in Parkinson's disease in general, the neuron that is degenerating is the last one, the number three. And it starts from the periphery. So we knew that it would not have been a good target.

And then, looking at it, we saw that multiple system atrophy, it goes the other way around. It starts at the brain level. So we thought that it could be a good target. If we had to start with one disease, one neurodegenerative disease, it would have been this one.

So that's why we tried, still not knowing so well what was happening with this second neuron. And if it was degenerating completely lost, it could not have worked too. It was difficult to guess in advance. So in this patient, we spoke to a neurologist and they confirmed what we, we had read and what we knew.

 We first did a heart sonography to see if there was a cardiac denervation, which would have told us that the third nerve was also compromised, but it was not the case.

So we thought, our theory is right. It started at the brain level. And we'll try to stimulate. So we did it. We were expecting results that were probably not exactly the same as for brain injury, because for the brain injury, the second neuron is intact. And we saw that we could modulate the pressure, but probably not as well as, and acutely as what we do normally, when we have a spinal cord injury.

So it means that the second neuron is also probably partly affected.
 

[00:07:28] Dr. Sara Schaefer:
That's so interesting. You know, we classically learn about cardiac imaging to try to differentiate between Parkinson's disease and multiple systems atrophy, given that the post-ganglionic neurons in MSA are spared, as you described. But in terms of using that anatomy to figure out where the stimulator might be helpful and where it might not be helpful that really put the pieces together for me. Thank you.

Dr. Bloch, can you explain the actual surgery itself?
 

[00:08:03] Dr. Jocelyne Bloch:
So the surgery is very similar to pain surgery. For pain surgery, we implant paddle leads, so electrode arrays, on the dorsal aspect of the spinal cord, and that we link to a neurostimulator that is located subcutaneously in the abdominal region in general. So we did the same. So with the paddle leads that was located this time at the lowest part of the thoracic spinal cord and with a little laminectomy, we could push this electrode array over the posterior part of the spinal cord. And then we tunneled the cable toward the abdomen and plug them into the, into this IPG. It's quite an easy, I would say, surgery. The only thing that we do during the surgery is that we checked, at least for the first few patients and we continue checking that it had, we could influence the blood pressure when we stimulated. And already during the surgery, we saw some modulation.
 

[00:09:02] Dr. Sara Schaefer:
And the postsurgical course sounded extremely involved. It looks like the patient had some tilt table tests prior to surgery, just to confirm the amount of change in blood pressure that you saw and how quickly it dropped. And then had many, many tilt table tests, post surgically, and am I correct in that she stayed in the hospital for the first seven days with an intra arterial line in order to measure her blood pressures very precisely? And then was sent home with very, very close follow up? Can you describe that whole process?
 

[00:09:43] Dr. Jocelyne Bloch:
Yes, this is correct. So she was first in the hospital with this arterial line in order to be able to follow the blood pressure bit by bit, and to be very precise and to see the evolution of the blood pressure with the stimulation.

And if I compare it, because we've done it with the spinal cord injured patient, with the spinal cord injured patient, when you stimulate, it goes up very quickly. The blood pressure goes very quickly up. In her, it took more time.
 

[00:10:13] Dr. Gregoire Courtine:
Well, the point with her that it's more like we support the blood pressure meaning that it does not go down as fast as it would normally. In people with spinal injury, we just stabilize it for like hours. Yeah. Like with her it is just that instead of collapsing in two minutes, It takes 10, 15 minutes before she collapses.

But then as you say, we are repeated test and we use this almost as a training. So she went into what we would call autonomic neuro rehabilitation in the sense that she was doing several tilt tests with a stimulation every day as a rehabilitation technique.

And what we realized after a month, is that she was getting much better. So the sympathetic system somehow was reorganizing to improve capacity to modulate the blood pressure to the point that she really wanted to use the stimulation at home. There's a challenge though, when you use it at home, that you need to detect the orthostatic challenge, to adjust the amplitude of the stimulation based on basically the body posture.

So here, what we use is an algorithm based on accelerometers and gyroscopes that are embedded within the stimulator that Jocelyne implanted in the abdomen, to detect the posture, whether she's lying, she's sitting or she's standing. And then we adjusted the amplitude of stimulation on these basis, which allow her to use a stimulation like 12 hours per day. So she would turn on the stimulation in the morning and turn it off at night.
 

[00:11:38] Dr. Sara Schaefer:
I see. And is that use of accelerometers and gyroscopes something that's used in spinal cord injury, or is that novel to this particular patients approach?
 

[00:11:49] Dr. Jocelyne Bloch:
It's already used, I would say, in pain therapy. It's not something we've invented. It's already existing to adapt, because people with no spinal cord injury, nothing, no hypertension, when they change position the contact of the lead with the spinal cord changes. So that's why the big companies have embedded these accelerometers in the IPG. So we we've taken the benefit of this invention, we don't use it yet, but we would like to use it also in the patient with spinal cord injury.
 

[00:12:19] Dr. Sara Schaefer:
So you mentioned that she improved over the course of weeks and months. And I did wanna ask about that. You mentioned that you think that it's because of a reorganization of the sympathetic nervous system. I was also wondering if over time she was able to tolerate higher amounts of stimulation. And if you think that could partially be responsible for that effect?
 

[00:12:43] Dr. Jocelyne Bloch:
Maybe, what I can tell you is that this lady first is still alive. Now it's one and a half year. She's getting worse for many other symptoms. She cannot talk anymore, for example. But she has not had, in the last year, one syncope. So in terms of sympathetic system, she's improved. She's really improved. But the rest of the disease is progressing. So we are not as good for the rest.
 

[00:13:10] Dr. Gregoire Courtine:
So we conducted a lot of experiment in rodent models. So our speciality is really spinal cord injury and Parkinson's, then, and multiple system atrophy. But because of this observation, it really compelled us to start a new resource program to really understand. So this time in mouse model, what could happen when you stimulate, chronically, every day like this, this what is the degeneration of neurons in the brain stem.

We really want to understand the underlying mechanism because we became more and more convinced with this patient, also our experience with a few person with spinal cord injury, were also showing some reorganization of the sympathetic system that the stimulation really changes the way the spinal cord is able to manage this blood pressure, maybe to be more efficient in the way it will adjust the blood pressure in response to the stimulation.
 

[00:14:03] Dr. Sara Schaefer:
That's so interesting. That's something that has been on the radar in DBS as well, given the delayed response in things like dystonia, is it stimulating some kind of reorganization within the brain?
 

[00:14:17] Dr. Gregoire Courtine:
Absolutely. In the case here of the stimulation of the spinal cord, of course, it's clearly a different mechanism. Also because we are going clearly should not degenerate know they are delayed in that degeneration. Like, its almost because they are generated from from the neuron in the brain stem, the first one that degenerate, it looks like that tends to degenerate as well.

And maybe by stimulating you reinvigorate this neuron and probably increase the efficacy of the synapses, et cetera. So probably a different mechanism compared to what have been thought to be a mechanism of deep brain stimulation, and some neural protection.
 

[00:14:58] Dr. Sarah Schaefer:
You mentioned a little bit about how she did, and it sounds like in terms of her quality of life, this made an enormous impact because she was actually able to ambulate without syncopizing. I also wonder how her meds were able to be changed over time. Are you aware of, were they able to increase the Parkinsonism medications, the levodopa, because the blood pressure was less of a concern? Was she able to come off? She had been on three blood pressure increasing medications, right? Fludrocortisone, midodrine, and droxidopa. Do you know what happened over time in terms of those medications?
 

[00:15:41] Dr. Jocelyne Bloch:
I cannot give you the exact details of how she's now. But I know that she decreased all the medicines she was taking for to increase the blood pressure, for sure. The levodopa, she gets some, but not that much. And I should do another update now because, and talk to the neurologist to tell you exactly how far she is. But probably her most severe symptom now is more at the level of the degeneration and the talking, as she has trouble talking and expressing herself. That's the major concern now.
 

[00:16:17] Dr. Sara Schaefer:
And what about supine hypertension, which was an issue to her preoperatively that I know that was partially, at least, attributed to the fludrocortisone. Because of this accelerometer that allowed the device to automatically change, depending on her position — was supine hypertension, did that continue to be an issue for her, or did the device also help with that in some way?
 

[00:16:46] Dr. Jocelyne Bloch:
So I think the fact that we could decrease quite a lot of medicine to increase the blood pressure, it helped. But the last time I talked, the people who evaluated more recently, the blood pressure, they say she has a tendency to be quite high all the time.

She has a superior mean pressure, but not completely hypertensive.
 

[00:17:08] Dr. Sara Schaefer:
Now you mentioned next steps that you are excited about this, as I think we all are, which is why I'm interviewing you today, and that you're looking at mouse models and things like that. How do you see, the next few years of research in this area?
 

[00:17:27] Dr. Gregoire Courtine:
So two aspects. One, as you mentioned, is we really want to understand the mechanism. We know the immediate effect through which mechanism they take place, as I described to you, but we want to understand the long-term effect when you stimulate on the degeneration process, absence of degeneration or reorganization of the that despair at this moment. So we want to understand this.

We also do this in mice, also we have a collaboration with a one special specialist of non-human primate model of neurodegenerative disease. So we're gonna explore this aspect also in non-human primates and also in human anatomy to see what is really the dynamic of the degeneration of this different neurons, which is not well known. Only data from the seventies are available so far.

And also, what is really exciting for us in term of research, is to develop the optimal technology to implement this type of treatment. So we work with a company, Onward Medical, that is developing a a purpose-built technology to modulate blood pressure and people with spinal cord injury, but the same can be used in people with multiple system atrophy and maybe also type of neurological disorder affecting blood pressure, people related to this orthostatic hypertension . And maybe for example, people with Parkinson's disease, although in their case, there might be a degeneration of the third node, in which case it will not be effective, because the stimulation need this known to be spared.
 

[00:18:57] Dr. Jocelyne Bloch:
And we are also very much aware that we only had success with one patient. And we don't know if the other will respond the same. So we need to implant a few others in order to make sure to understand the process, the therapy and who is responsive to it.
 

[00:19:14] Dr. Sara Schaefer:
Is that also planned at your institute?
 

[00:19:17] Dr. Jocelyne Bloch:
Yes, it's planned. So it's pretty rare. We are in a small country. We don't have so many cases, but it's planned. It's planned that we should get a few other patients, and I'm pretty sure that other people will try it over the world. 
 

[00:19:34] Dr. Gregoire Courtine:
It would be so interesting, you imagine, to start this intervention early?

With the early sign about orthostatic hypertension, to prevent the occurrence of this severe degeneration. So a lot to do still in the coming years, but we're gonna put some energy in trying to develop a treatment to at least alleviate this aspect of the condition of MSA.
 

[00:19:57] Dr. Sara Schaefer:
Well, as a clinical movement disorders neurologist, and somebody who finds these patients to be very impaired and, very difficult to manage, I'm extremely glad that you are both interested in this and putting your energy into it. And, thank you very much.
 

[00:20:17] Dr. Gregoire Courtine:
Oh, we appreciate your support.

[00:20:19] Dr. Jocelyne Bloch:
Yeah. Thank you.
 

[00:20:20] Dr. Sara Schaefer:
Anything else you wanna add before we sign off?

[00:20:23] Dr. Gregoire Courtine:
No, we did not talk that she was able not to walk like long distances, which she couldn't walk at all before the intervention.

Yeah. You had said that she was only able to walk five meters and then was able to walk, I think, did it say 250 meters by the end? Without any significant symptoms? All right. All right. Well, thank you very much for your time. I appreciate you telling us about this very unique and very exciting, Very exciting case.

 Let's put it this way: it feels a very exciting treatment in particular, for people with spinal cord injury it is clear, we are very confident that it will become a treatment. We feel also quite confident that we can bring this to people with MSA. But here is our limitation that I'm just going to put it out there also because it's evolving, it's evolving, but know this electronic medicine is gonna come to be available in all the neurological clinic for people, at least with spinal cord injury.
 

[00:21:23] Dr. Sara Schaefer:
Wonderful. I look forward to it.

[00:21:26] Dr. Gregoire Courtine:
Thank you so much for your enthusiasm
 

[00:21:28] Dr. Jocelyne Bloch:
And have a very nice day.

[00:21:31] Dr. Sara Schaefer:
You as well.