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Melanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole and today we're offering an update on new applications for DBS and Parkinson's treatments. Joining me in this panel are Dr. Michael Okun. He's a University of Florida Chair of Neurology, Executive Director of the Norman Fixel Institute for Neurological Diseases at UF Health and a Professor at the University of Florida. And Dr. Kelly Foote. He's the Co-Director at the Norman Fixel Institute for Neurological Diseases and a Professor at the University of Florida College of Medicine in the Department of Neurosurgery at UF Health. Gentlemen, I'm so glad to have you join us again today. Dr. Okun, as we're giving this update, and it's such an interesting topic, I'd like you to set the stage for us on the first-line treatment for tremors resulting from movement disorders, such as Parkinson's and for patients that haven't seen positive effects from medication. Give us a little update and some of the history on the clinical indications for use of DBS for referring physicians.

Michael Okun, MD (Guest): Yeah. So, it is a very interesting field and one that is evolving quickly and something that I think is important for physicians that see people with movement disorders within their clinics to pay attention to, because it turns out, that there are a lot of folks with diseases like Parkinson's and essential tremor, and even some others that have these extra movements, we call hyperkinetic movements that might be associated with their particular disorder. So, with Parkinson's disease, it might be shaking or tremor, or it might be something like dyskinesia, which are extra dance like movements. And so we think of these extra movements as hyperkinetic movements.

And of course we do address them first with medications. And so there are over a dozen different medicines that we use to treat Parkinson's disease. And there's three or four first-line medicines that we think about for diseases like essential tremor when people have tremors. And then of course, if you have movements that have been precipitated or caused by the medicines or the progression of a disease, like Parkinson's, those are those dance like movements like dyskinesias we then begin to shift our thinking if we've tried medicines. And of course we try not only a cocktail of all of those different medicines together, but we also think about how we give them.

So, timing of the medications is super important in the management, but if you've done everything that you can do and you're still getting or resulting in a case where you just can't get a hold of the symptoms, these extra movements, then we begin to think about deep brain stimulation therapy.

Host: Dr Foote, can you speak about the clinical criteria and patient selection for DBS? Has anything changed? Is there anyone who this is contraindicated for? Tell us a little bit about the inclusion and exclusion criteria for DBS.

Kelly Foote, MD (Guest): Sure. Sure. I would say that as the safety profile and the efficacy of deep brain stimulation over the last 30 years or so has improved, the indications for DBS surgery have increased. We're less nervous about this procedure than we were in the beginning. And you know, Michael mentioned hyperkinetic movement disorders, but the truth is it's not just the hyperkinetic movement disorders, it's hypokinetic as well. You know, a large percentage of patients with Parkinson's disease don't have tremor. So, I would say the primary indication is a patient who, who has known Parkinson's disease and who suffers from debilitating motor fluctuations. What I mean by that is they spend their day going back and forth between states of hyperkinetic dyskinesias when their medications wear off. When they're on their medications, they have side effects that make them move more than they want to. And when their medications wear off, they may have the tremor, but that they may not, but they may also be stiff and slow.

You know, they have brief episodes during each dose of their medication where they function reasonably well, but as the disease progresses over the years, the efficacy of the medications wanes, you have to take more and more medication as your native dopamine production diminishes, and interestingly, the threshold for stimulation induced side effects like dyskinesia and hallucinations actually decreases as well.

So, the therapeutic window for dopamine in the human brain, in someone with Parkinson's disease, gradually narrows to the point where even a very good movement disorders neurologist is going to really struggle to keep the dopamine levels at a good point with various manipulations of the patient's dopaminergic medications. So, the patients who are struggling to function and variable ability to function throughout the day, tend to be the ones who get the most benefit from deep brain stimulation therapy.

Host: Now Dr. Okun, I'd like you to tell us about the UF research study about home management of DBS settings. Please tell us about your recent trials. I find this so interesting and I imagine for the patients and their families, this is preferable.

Dr. Okun: Yes. So, we have been quite interested over the years in not only the development of the technology. So, our laboratories have been working on what we call neuromodulation. So, you know, we try to change those conversations that are going on in the brain to improve symptoms, but we realize that it is really important to try to address these public health issues in a way in which people can actually get access to the devices. And so, we know that practitioners that are out there in various clinics all over the United States and frankly all over the world, you know, are going to have to manage this generation of people who are bionic.

And we know that they're over 200,000 folks now that are walking the planet that have these types of devices. And so, we've been interested in the development of technologies to help nurses and other practitioners and the individual patients themselves to be able to manage their diseases within their home. And we talk about this in the context of bringing the disease to the home, to the patient. And many of these patients have difficulties traveling. They have dysfunctions that make their lives difficult to get in the car, and it might be difficult to get to the offices. And so having the technologies for people to be able to reach out and either manage from the office to the home or alternatively to have people that go out to the home to help folks to manage these these deep brain stimulation devices, which can have thousands of settings, is really important.

And so we published a study in JAMA Neurology just here in June of 2021. And the way it worked was we randomized people to two groups. Those folks that came to the clinic for all their adjustments, and then we had a group where they were visited a few times by a home health nurse, and then the home health nurse checked in with them by telephone. And we looked at the results and provided this really cool, easy to use tablet to help to manage these folks. And we found out that we could manage them in their homes just as well as we manage them within the clinic setting, meaning that all of the outcomes were the same when we compared those groups. And so figuring practical ways for folks to be able to have really complicated devices implanted and managed and have them stay in the home settings is going to be important.

And then on top of that, our group is also working a lot on the ways in which we can help the practitioners. So, the people that are in the clinic. So, the docs and the nurses and the nurse practitioners and the physician assistants, they need to be able to be equipped with the tools so that they don't have to spend hours and hours adjusting these really complicated devices. And so we work a lot on trying to develop the technology to make it easier to manage people and to make sure that their outcomes stay the same or potentially in the future could even get better.

Dr. Foote: Yeah. I think I can add something interesting to that from a surgeon's perspective. You know, I think many people think of deep brain stimulation as surgical treatment, which of course it is. But the implantation of the deep brain stimulation lead into the appropriate place in the brain and getting the patient through that process and getting the system implanted, I would say is, you know, only half the battle. And of course, you know, we have a bunch of research that's focused on improving our ability to do that well which improves the outcomes. But what a lot of people don't realize isthat the management of the patients after the surgical procedure is done is a huge determinant of the success or failure of that intervention.

So, so, a program like this, you know, a lot of our research goes into how do we optimize these systems once they're implanted? And if you can figure out a way to have this done at home, develop tools that help people do it more effectively and more efficiently, that's really helpful. You know, the other exciting thing that we're working on is trying to teach these systems to program themselves, which I guess would be opening another discussion of closed loop deep brain stimulation that we ultimately hope to be able to do.

Host: Well, that was a perfect segue, Dr. Foote and I find that home adaptation so interesting to make treatment far more accessible really, to people who have difficulty traveling or in remote areas. Tell us a little bit about adaptive DBS, targeting the different regions and modifying this in real time. I find this absolutely fascinating.

Dr. Foote: Well, adaptive DBS or closed loop DBS is something that we think ultimately all DBS will exploit. It just sort of makes intuitive sense. You know, the brain is not a static organ. You know, I mentioned that patients' symptomatic states fluctuate throughout the day. And a treatment that continuously delivers the same therapy is not going to match that dynamic environment in the brain. But if we can find neurophysiologic biomarkers in the signals that we record from the brain, that correlate with the patient's pathology. For example, just to simplify it, let's say, you know, I have a patient who has tremor that is debilitating and that tremor fluctuates throughout the day. Or that tremor is only present when the patient is doing certain things. If I can continuously record the electrical activity from that patient's brain, and I can identify in those signals from the brain a biomarker that says when this signal appears, this patient is about to have a tremor that's debilitating.

We also have an effector loop in that system that says, whenever this appears, deliver stimulation to this area of the brain, which will prevent the tremor then you have a system that continuously monitors the state of the patient's brain and responds appropriately when needed, but when not needed, doesn't stimulate.

And one of the important notions about deep brain stimulation that people don't focus on is, you know, we're excited about disrupting pathologic signals in the brain that are causing problems, but there's always collateral damage, if you will, when you stimulate the brain. If you're really good and you put the electrode in just the right spot, you can disrupt some pathological signal that results in alleviating the patient's symptoms, but there will always be some disruption of normal information flow in the brain say in surrounding circuits. And you know, we focus a lot of energy on trying to minimize stimulation induced side effects and in theory, this adaptive simulation, because it would only be on when the patient needs it would minimize that disruption of normal information flow in the brain and minimize side effects of DBS.

Host: This is such an interesting topic and these updates are so important, really, very innovative. So, Dr. Okun, do you have any updates on non-surgical DBS techniques?

Dr. Okun: Yeah. So, there are a number of really interesting what we call surgical approaches to various movement disorders, including Parkinson's disease that have really reached, you know, the field. And if you're a practitioner in your office, you should always be aware of all of the alternatives from medicines to surgeries to the various different things that we would think about.

And so there are a number of categories that when you're talking to patients it's important to, to not forget. One is a group of therapies that we would think of as pump therapies that have been evolving. And so there's a dopamine pump called a Duopa pump that can provide continuous stimulation. It's kind of a tube that goes into the first section of the intestine into the duodenum and can provide continuous stimulation with sort of a cartridge that you put into a belt and set a flow rate on. There's a pump that's been approved in Europe and in other locales, but not yet, at least that we've seen. And we're following with the FDA on this story called an apomorphine pump. And so that actually goes underneath the skin, it's subcutaneous and provides a drug called a dopamine agonist continuously for the treatment of what we call these off symptoms of Parkinson.

And so when you get tremor, stiffness or slowness, you can get some improvement and both of these therapies can help with the symptoms of Parkinson disease, both the Duopa pump and the apomorphine pump. Now of course, the Duopa is a available in the United States and the therapy's not quite as good as deep brain stimulation and does require management of that tube. And that's where we've seen the most complications there. Remember it's not completely internalized. And so when you have a deep brain stimulator implanted by an experienced neurosurgeon like Kelly Foote, it's completely internalized, meaning it's inside the skin. You can swim, you can do anything that you want.

And these other therapies are sort of from the outside in. And the third therapy that we think about is one called focused ultrasound. And this has been around since the 1950s. And it's where you point sound waves from the outside to the inside of the body. And you can do this, actually, not just in the brain, but in all areas of the body. And it can allow you to destroy tissue. And I say, oh my gosh, well, why would I want to do that? Well, it turns out there's a long history in movement disorder surgery for tremors and Parkinson's especially, but also for other disorders that if you actually ablate or destroy the tissue in the right area of the brain, it changes those conversations, just like the stimulators that Dr. Foote implants called deep brain stimulators. You can change that conversation by actually destroying the tissue. The advantage to the focused ultrasound is you can do it from outside the brain and outside to inside. So, you don't need that surgical incision. The disadvantages are that you can only do it on one side of the brain and the accuracy is not as good coming from outside the brain than when you go in and actually record and listen and map out that region, because millimeters are like miles in the brain. And so this is another option that, that we think about. It was first approved for tremor in essential tremor, but also the tremor of Parkinson's can be treated. But again, only one side of the brain. And we might even think about this therapy in some folks maybe have some things that might make them at higher risk for conventional or regular deep brain stimulation therapy. So, maybe they're on blood thinners or maybe their age is older. They're have fragile skin. And so we think about these as other options that might be on the table.

Dr. Foote: Yeah I'll add to that as well. You know, I think that MR guided focused ultrasound is actually a very exciting therapy and it has the obvious advantage of not having to have an incision. It's you're not going to get an infection. You're not going to have adverse effects of bleeding and things like that. But you know, the interesting perspective that a lot of people miss is that the origin of deep brain stimulation was actually looking for a way. It was one of my mentors Professor Benabid in Grenoble, France in the late 1980s. At the time neurosurgeons were quite good at doing lesion therapy, doing what are called thalamotomys, which is a treatment actually that Michael J. Fox got at one point to suppress tremor. And thalamotomys, were very effective. But the, as I mentioned before, they're all, there's always a little bit of collateral damage and the circuitry that controls speech and walking is closely intertwined with that circuitry through the cerebellum that causes the tremor.

So, Professor Benabid and others at the time were very good at basically burning a hole in the thalamus by implanting a heat probe, an electrode into the thalamus and burning a hole in the thalamus, which would stop the tremor. And occasionally have some side effects that adversely affected speech and walking. And Professor Benabid, at the time, you know, the technique for doing that was you would put the electrode in and before you would heat it up to burn a hole, you would deliver electrical stimulation. And he, of course, like everyone noticed that you know, during the electrical stimulation, that tremor would also abate.

And you could also test for side effects during electrical stimulation to see if the patient's speech or or their movement was affected. And, at the time they determined that making a lesion on both sides of the brain just had an unacceptably high rate of adverse effects on speech and walking. So, he had this idea, well, what if we instead burning a hole on the second side of the brain, let's just implant an electrode and continuously stimulate to have similar effects with controllable side effects. And that was the actually the origin of modern deep brain stimulation. I feel like now we've come full circle and we're going back to burning holes in the brain strategically. But you know, that's a perspective that I think a lot of people miss. I do think MR guided focused ultrasound lesioning is the most elegant and probably the safest way of creating a lesion in the brain, but it's still burning a hole in the brain.

Host: Wow. This is such an interesting and informative episode. And I'd like to give you each a chance for a brief, final thought for referring physicians. So, Dr. Foote, any new therapies such as immunotherapies, cell based gene therapies. Tell us a little bit about anything that you think is exciting coming in the future.

Dr. Foote: Well, I will say I'm very excited about the potential for gene therapy for treatment of Parkinson's disease and the potential for stem cell therapy as well. I do want to temper that excitement and make one important public service announcement, which is there is to date, no evidence that stem cell therapy affects the progression of Parkinson's disease. There are however, many stem cell clinics that are charging high prices to patients who sometimes can't afford it, for stem cell treatment for their Parkinson's disease. And I just sort of want to caution people, that right now, stem cell therapy is not ready for prime time and they should not pay for stem cell therapy for Parkinson's disease.

That's not to say that there aren't some very exciting, there are several exciting trials ongoing for both stem cell therapy and gene therapy for Parkinson's disease that we think may end up being you know, hopefully putting us out of business in the deep brain stimulation world if we can find a therapy that actually cures or stops the progression of Parkinson's disease using some of these other more exciting cellular techniques.

Host: Dr. Okun, last word to you. What would you like referring physicians to know about this update we're giving and your UF research study on home management of DBS settings.

Dr. Okun: I really would like to emphasize that it's an exciting time. And it's really important that we share with our patients, you know, all of the medical therapies and there's nuance too. And so making sure that we are not only using the right drugs, but we're using them in the right way. So, make sure you ask lots of questions and work with some folks that maybe have some experience in that area so they can help to manage your patients.

But if you get to the point where you're having difficulty managing them with medicines, then we would refer them for deep brain stimulation to center that's very experienced, that has a lot of folks that get together and evaluate the people in an interdisciplinary fashion and decide the risk benefit ratio as to moving forward with one of those therapies. I would make sure to, you know, always broaden your discussions to include pump therapies, you know, like the Duopa pump, like the apomorphine pump that's coming, the focused ultrasound and just discuss in a very honest and open way, the risks and benefits of each and what might fit an individual person. And then finally, you know, I always tell folks, ask your doc what's new. And it's, you know, one of the most important questions that you can explore when you're at an appointment.

And so I would just say to the practitioners, be ready for that question. And it's important to be able to help folks to find the information on clinicaltrials.gov, where all of the research trials are listed and to make sure that people know as Dr. Foote talks about, that none of the stem cell therapies have really advanced past research and there's thousands of clinics offering fee for service. And we should be really careful and make sure that we're counseling people to be very careful with that particular therapy. So, that our patients don't get sold down the road of something that they might regret or might cause some harm to them. But we're also moving to a personalized era of medicine and we see this happening in cancer, and we're going to see more and more of this in Parkinson's and movement disorders.

Getting people's genes and their genetics and seeing if they have genetic abnormalities, and for those folks, developing more personalized therapies. And then for others, you know, developing the right way to manage them and to try to manage them at home is going to be important. And so there's a lot of really cool things coming with neuroimmunology and diets and surgeries. And so just keep an open mind and make sure when you're talking to your patients, that you have a complete discussion. And even when you're talking about new things, make sure that, that you can help them to be safe when they're choosing what's right for them.

Host: What an exciting time to be in your field. Thank you gentlemen, for joining us today and giving us this update. To learn more about Parkinson's disease and the Norman Fixel Institute of Neurological Disease, please visit fixel.UFhealth.org. Or to refer your patient or to listen to more podcasts from our experts, you can always visit ufhealth.org/medmatters.

That concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole.