Focused Ultrasound: Current & Future Neurological Use

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD: In the neurological field, focused ultrasound has proven that combining high frequency ultrasound with magnetic resonance imaging can treat medication resistant essential tremor, and tremor dominant Parkinson's disease. Now researchers and clinicians are eager to investigate additional applications of this technology for other neurologic diseases. In this episode of Neuro Pathways, we're discussing current and novel uses of focused ultrasound. I'm your host Glen Stevens, neurologist/neuro-oncologist in Cleveland Clinic's Neurological Institute. I'm very pleased to have Drs. Sean Nagel and Dan Lockwood join me for today's conversation. Dr. Nagel is a stereotactic and functional neurosurgeon in Cleveland Clinic's Neurological Institute's Center for Neurological Restoration. And Dan is a neuro-radiologist in Cleveland Clinic's Imaging Institute. Sean, Dan, welcome to Neuro Pathways.

Sean Nagel, MD: Thank you.

Dan Lockwood, MD: Thank you for having us.

Glen Stevens, DO, PhD: We mentioned in the lead that high intensity focused ultrasound, or what we call HIFU, is approved for use in patients with essential tremor and tremor dominant Parkinson's disease. Your team has been using this technology now for several years. Sean, can you explain to our audience what HIFU is and your results to date?

Sean Nagel, MD: So as you mentioned, we acquired our device back at the end of 2018, and we have thus far treated about a hundred or so patients with either essential tremor or dominant Parkinson's disease. The treatment couples an ultrasound transducer to an MRI. And in these cases, I like to explain to the patients, the MRI both is used for visualization, but it also can record temperature changes in the brain. And we are intentionally trying to create a small lesion in a part of the brain called the thalamus. And this has been known for many decades to be an excellent site that we can use to control somebody's tremor that's been refractory to medications. Most of the procedures take on average about two hours. We do consider this incision-less, but it's not noninvasive. In other words, we are, as I mentioned, making a small lesion in a select part of the brain. The treatment does include placing a small head frame as well, and that does cause some discomfort for the patients, but short of that, most patients find this pretty well tolerated.

Glen Stevens, DO, PhD: And my understanding is that you actually get real time information back from the procedure. Why don't you tell us a bit about that?

Sean Nagel, MD: Yeah, that's right. So each patient who we are evaluating, they undergo some pre-planning imaging. At that point, they are fitted with this head frame and then secured to the transducer helmet. And then we usually proceed in three phases. One's an alignment phase, followed by a verification phase, and then a treatment phase. And so what's unique about this procedure is during the verification phase, we can turn the ultrasound on and use it at lower energies before we create a lesion, but enough that we can start to see some benefit in the patient's tremor. And this helps us really effectively control their tremor by delivering the high energy at the correct spot. And so usually at on average we... an estimate, maybe eight to ten sonications were required to complete the treatment, but the bulk of the sonications are really used both to align and verify the location before doing the final sonication.

Glen Stevens, DO, PhD: And how do you determine if a patient's had a response to the treatment?

Sean Nagel, MD: We generally put them through several manual tasks that we would normally use to evaluate their tremor. These include things like holding a cup and bringing it towards their chin. We have them participate in some manual tasks like handwriting, drawing a spiral, or drawing a line from one point to another. This is all while kind of in a supine position. We also assess their finger to nose testing as well.

Glen Stevens, DO, PhD: So one of the unfortunate things of an audio podcast is that we can't show you nice pictures of an improved tremor, but tell us about your results. What are you seeing?

Sean Nagel, MD: Most of the patients who we've taken care of end up with excellent improvement, and by that, I mean usually we aim for about 60 to 80 percent benefit. And so the patients at the conclusion of the procedure usually have a very steady hand and are pretty impressed overall, as we are each time we do this, with the outcomes.

Glen Stevens, DO, PhD: As a neurologist, when I first started training for multiple sclerosis, we could give patients steroids. And then when they failed that, we could give them some more steroids. There weren't a lot of options. And now of course, there's 20 drugs that you can give patients. So clearly not all of the patients that come to see you, you probably just discuss focused ultrasound. You probably also discuss deep brain stimulation. How do you decide?

Sean Nagel, MD: So some of the patients that we've taken care of do come to see us initially pretty upset on having the focused ultrasound treatment. This is primarily because it's, again, considered less invasive overall than deep brain simulation, there's no hardware, and really there isn't any specified follow up. Although we do want to see how our patients are doing for several months or several years. All the patients who we see here at the Cleveland Clinic do go through a comprehensive evaluation, where we want to just verify the diagnosis and then try and give them a general recommendation about what treatment we think would benefit them the most. One of the other main deciding points for a lot of our patients is whether or not they want to have both hands treated. So obviously a central tremor, many of the patients have symptoms that bother them at both sides of the body.

And right now the focus ultrasounds' only FDA approved for unilateral treatment. So often that can be an important decision point before deciding on which approach we want to take. Patients who do want to have both hands treated at this point really would still be best served if they're a good candidate for deep brain simulation. The other factors obviously that come into play are comorbidities. So some of our patients who have other preexisting conditions, especially heart and lung issues, or may need to be on anticoagulants for extended period of times, are maybe less inclined to be good candidates for deep brain simulation.

Glen Stevens, DO, PhD: So other than tremor in the movement disorders field, are there other symptom management techniques or processes that you're using, or interested in?

Sean Nagel, MD: For the focused ultrasound?

Glen Stevens, DO, PhD: Yes, for focused ultrasound.

Sean Nagel, MD: So the FDA is, they approved this initially for a central tremor in 2016, and then they expanded the indications for Tremor-Predominant Parkinson's disease. And then in 2021, they did approve it, a pallidotomy, for more severe motor symptoms for Parkinson's disease as well. We have not started using that approach yet in our patients, although we do expect soon that that will be available. And there are a number of other areas that people are investigating to see if we can use the ultrasound to treat other diseases.

Glen Stevens, DO, PhD: So we'll shift over to Dan. We know the neuro-radiologists are always doing the heavy lifting. So Dan, let's talk about some novel uses outside of movement disorders. And we talked a bit about HIFU, there's also a technique called LIFU, low intensity focused ultrasound, that is currently being used to open the blood-brain barrier. Why don't you just tell us a little bit about that technique and how it's different than HIFU, since I know you're involved with both.

Dan Lockwood, MD: So there are many different ways to use ultrasound energy in conjunction with the MRI guidance that we use, and a good way to think about the different ways to use the focused ultrasound is how you deliver the energy. What's the frequency of the sound energy, and how much energy are you delivering? And at higher frequencies and at high levels of energy, we can make really tiny lesions and essentially burn a tiny little hole in the brain, like we do with Sean for the tremor treatments. But at lower energies, a wider variety of effects are possible. And these range from slightly lower energy levels, where you might mechanically disrupt something, to even lower energy levels where really the effects are less well understood on the brain, and referred to collectively as neuromodulation. In our blood-brain barrier study, though, we use a very specific effect of a lower energy of ultrasound and a lower frequency level, in conjunction with micro bubbles that are commonly used in ultrasound imaging applications, to see the blood vessels well.

These micro bubbles will resonate with the ultrasound energy, and at exactly the right frequency and the right energy levels, they will cause the blood-brain barrier to predictably open in the location of your choosing, the target location for the procedure. And by doing this, by opening the blood-brain barrier in selected locations, we can essentially deliver medication that would otherwise not cross the blood-brain barrier to that location in the brain.

So our study that we're conducting right now at the Cleveland clinic is a study where we are treating patients with recurrent glioblastoma who have already had everything that conventional therapy can offer them with radiation, chemotherapy, and surgery, and their tumors have recurred. And we are taking them into our ultrasound unit, and opening up the blood-brain barrier in and around all the areas as close to their tumor resection site as we can. And then after we have successfully opened the blood-brain barrier, we send them to the chemotherapy suite to receive carboplatin intravenously, and carboplatin is a chemotherapeutic agent that doesn't normally cross the blood-brain barrier. And we're able to, with the focused ultrasound, choose exactly where we want in the brain to essentially deliver the carboplatin therapy to.

Glen Stevens, DO, PhD: So Dan, as a neuro radiologist, why don't you tell us what you see when Sean gives the HIFU, versus what you see with the LIFU. Is it different?

Dan Lockwood, MD: Yeah. So in terms of what you can see on imaging after these two different procedures, it's actually completely different. After the high intensity focused ultrasound, where the goal is to ablate a tiny, very specific area of the brain, essentially the imaging findings are very similar to someone who's had an acute lacunar infarct in that area. You'll see restricted diffusion on diffusion weighted imaging, you will probably see some susceptibility changes from tiny amounts of hemorrhage in that location. In the immediate post-procedural phase, you'll see different layers of edema around the lesion that tend to recede. Similar to the recession of edema and mass effect from a stroke. And months after the procedure, it can actually be very hard to find the lesion, and you may have to scrutinize your susceptibility weighted images to look for a tiny bit of residual old hemosiderin at the site of the lesion. But otherwise, it might be very difficult to see the effects of what you've done.

In our blood-brain barrier procedure, it's completely different. With the blood-brain barrier opening, there are two main imaging findings that you can see. One is sort of a transient increased vascular permeability to intravenous contrast. And that's how, actually, the company who is developing this technology measures the efficacy of opening the blood-brain barrier, is by comparing the intensity of the pre and post contrast images on your MRI scan that you do right after the blood-brain barrier opening procedure. And the other effect that we see that is less well understood are tiny little dots of susceptibility change that show up sort of in a grid-like pattern that mimics the pattern of our energy delivery to the area around the brain tumor. And these may be tiny foci of micro hemorrhage, or they may be susceptibility changes for other reasons that we don't fully understand. And those tend to be less transient and more of a permanent feature of imaging after the blood-brain barrier opening.

Glen Stevens, DO, PhD: So I'm glad that you were able to say that, and I didn't have to explain all the workings of the MRI. So if we go back to Sean here for a sec. Sean, side effects that you can see from the treatment? Obviously we want the tremor to get better, but what potential side effects can we see?

Sean Nagel, MD: Yeah, that's right. So side effects are actually relatively common and expected in some sense after this treatment. And this was, what I mean by expected is we sort of anticipated this based on the randomized controlled trial that was published in the New England Journal of Medicine, where they reported essentially about 33%, or a third of the patients, were describing some side effect. Most commonly, these include gate disturbance, sensory changes in the extremity that was treated, or up in the face or tongue. Some patients will describe difficulty with swallowing. Other patients might have some nausea, headache, things like that.

In general, these side effects do wane relatively quickly, but in rare cases, they can be persistent. And it's been really important as we've gone along is to emphasize with the patients during the preoperative visit to potentially expect some side effects. That's not to say everybody experiences a side effect, but because it's relatively common and especially in somebody who might be a little more susceptible, they might notice it more. And so we just want to be sure that they're aware that this could happen and can take some precautions to ensure maybe they're not falling, or things like that.

Glen Stevens, DO, PhD: Sean, do you put the patients on steroids?

Sean Nagel, MD: We do consistently start patients on steroids immediately after the treatment. Most patients, it's usually a short course, seven to ten days or so. I think it remains to be seen how important that is in sort of reducing the swelling, or reducing the side effects. But at this point that's been sort of the standard approach in our group, and I think other groups worldwide.

Glen Stevens, DO, PhD: So Dan, if we come back to you with the HIFU, we see some edema swelling. What about with the LIFU? Are you seeing any edema from opening the barrier with these susceptibility changes?

Dan Lockwood, MD: We really don't see any change in what we think of as edema, that is T2 and flare changes around the brain tumor, after opening the blood-brain barrier. It's really confined to the post contrast imaging and the susceptibility weighted imaging. And I think when we're thinking of the side effects in the high intensity focused ultrasound procedures that we do with Sean, we think of some of the effects that we're causing that we want to cause, i.e. the tremor relief, are there because of where the lesion is. And most of the side effects, many of the side effects happen because of the swelling that happens around the lesion right after we place, similar to the swelling that happens after somebody has an infarct.

And those are things that, throughout the procedure, Sean and his team are doing repeated neurological examinations on these patients and looking for these effects during the verification phase. And immediately after the lesion is placed, you may not have any issues with your balance. But a few hours later when the swelling has started, and when the edema would be there and might be visible on an MRI scan, for example, our post-op day one MRI scans, that might be when some of these side effects were at their most severe.

Glen Stevens, DO, PhD: So Dan, to stay with you just to help our audience understand, what's the volume of a lesion you would treat with HIFU, versus the volume of a lesion you would treat with LIFU?

Dan Lockwood, MD: So in high intensity focused ultrasound for tremor, now the goal is to treat as low a volume as you possibly can, and get symptom relief from the tremor. And the idea is you want to cause the lesion that relieves the tremor and doesn't do anything else, and doesn't disturb any of the other neurological systems in areas that are adjacent to where you're putting the lesion in. That's in contrast to the blood-brain barrier opening, where we might treat... with our current patient for example, I just did a treatment plan yesterday for him. And we're looking at a treatment volume of about 90 cubic centimeters of brain, where we're going to be trying to open the blood-brain barrier. And that can be contrasted with a high intensity focused ultrasound where our initial lesion, we're really looking at maybe a sphere or an ovoid ellipse that is maybe three to four millimeters in diameter. And we want, again, the smallest possible lesion we can get that will give us a good tremor relief, and a durable response from the treatment.

Glen Stevens, DO, PhD: Excellent. So what about other areas of neurology applications elsewhere? New technique, new technology, there's going to be a lot of interest in things such as epilepsy, Alzheimer's disease, psychiatric disease pain. Sean, do you want to start for the HIFU part, other applications that you see, or that your interest in, or have started looking at?

Sean Nagel, MD: Sure. There's, kind of worldwide there's a number of ongoing investigations, both preclinical and clinical, to explore other possible uses for this device. They generally can be largely grouped into thermal ablation type procedures, which is similar to the essential tremor, and then immune activating or even like stem cell homing type procedures. Most of, I think, what has been started so far has used, outside of the LIFU system, is to use thermal ablation to try and treat other areas of the brain. And in some cases, some of the studies I think that have been completed is they've tested safety treating hypothalamic hamartomas in a small number of patients. There's some early testing, I think... also, just to back up, to try bilateral treatment for central tremor. There are epilepsy investigations that are ongoing right now, and then a number of different approaches are people are considering using the LIFU for more neuro-modulatory investigations, to kind of interrogate or study brain function.

And so the advantage here is that this is a reversible treatment, but you can gain some insights into maybe how the brain works. And this includes things like psychiatric diseases or addiction, where you may be able to test low energy or low intensity focused ultrasound, and see if a patient's responding in some particular way. And that, again, may provide some insights for how we can use the device later on. Initially when this was developed, the application was to use this for chronic neuropathic pain by treating the central lateral thalamus. Thus far it's not an FDA approved indication, but that also is potentially an exciting area for research, I think in the future.

Glen Stevens, DO, PhD: So if we had a wishlist, what about intercerebral hemorrhage with clot? Could you use this to bubble up the clot and get it out?

Sean Nagel, MD: Potentially. One of the things that has been explored a bit more is to try and use this almost as an adjunct or as another way to endovascularly destroy a clot for an ischemic stroke. There were some early studies in animal models testing this, as well in hemorrhage, to see if that would help liquefy the clot, and that might be another application where this is useful.

Glen Stevens, DO, PhD: So Dan, with Alzheimer's disease there's been some interest in opening the blood-brain barrier, with the hope that you'll then have the beta-amyloid washout, and you could do imaging before and after to see if it looks better. You mentioned earlier the susceptibility changes. I guess my question is we're seeing susceptibility changes. Ultimately, do you think that's going to have a negative impact on cognitive function, or just too early to tell?

Dan Lockwood, MD: Well, I think that would be something that would have to be monitored very closely during those clinical trials. And there are clinical trials right now with human patients that are looking at opening the blood-brain barrier in the hippocampal formations of Alzheimer's patients. And I'm sure they're going to be paying very close attention to those susceptibility changes, and also to the quantitative plaque imaging before and after those procedures to make sure that they're doing more good than they're doing harm with that procedure. I mean, it's a very new technology and we're just sort of on the doorstep of figuring out all of the different ways that it can be useful. And so the immediate reaction is to try and use it for absolutely everything you possibly can. And it'll take some a while, and it'll take a lot of hard work, and bench research, and clinical research to sort out what the things that will really end up clinically translating are. And what are the things that will sort of... may have seemed like great ideas at first, but not turned out to be as applicable to real life patient care.

Glen Stevens, DO, PhD: So, any other thoughts either of you would like to share with our audience that you feel would be important that I've not asked you so far?

Sean Nagel, MD: I think one of the things that's important to address is for the FDA approved indications, because this is a relatively new treatment. We don't know the long term outcomes, so we're just starting to collect data on patients three, four, five years out to see how they are responding. One of the things that may come to pass is that patients may be eligible to be re-treated. And in fact, in our group, we've actually re-treated one patient as well, who had this treatment several years prior. And so this may become something that becomes standard of care, where patients who recur, similar to gamma knife treatments for trigeminal can come back and have treatment again.

But I think this still remains to be seen if this is the path we go down. Early evidence suggests that there probably will be some wearing off of the benefit. But what we don't know is this just a natural history of the disease of the essential tremor, where it didn't really, it's not so much that we didn't treat the

tremor fully on the day of the treatment. It's just that now that those cells that were causing that patient that problem are now causing their tremor.

Dan Lockwood, MD: There are a number of technical issues that also are being addressed by the company who's developing this technology now, in terms of how large a volume you can treat during one procedure, and what parts of the brain are accessible. The biggest barrier to getting sound energy into the brain right now is the skull. And so they are finding ways to get the ultrasound energy to pass through the skull, treat larger areas of brain, and treat areas of the brain that are very close to the skull. I mean, the initial approval application of treating essential tremor, one of the reasons why that works and was able to get initial approval, is because it's so centrally located. But the more peripheral lesions and things that are deeper down, closer to the skull base, sort of harder to get the ultrasound energy to. And that's another just sort of basic technical feature that is being addressed right now, as we speak.

Glen Stevens, DO, PhD: Well Sean and Dan, it seems like an exciting time to be in the field. Thanks so much for joining us today, and we appreciate your expertise in this area.

Dan Lockwood, MD: Thanks for having us.

Sean Nagel, MD: Thank you.

Conclusion: 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, 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. And thank you for listening.