Transcription:
Focused Ultrasound for Essential Tremor and Other Movement Disorders

Melanie Cole (Host): Welcome to Back To Health, your source for the latest in heath, wellness and medical care; Keeping you informed so you can make informed healthcare choices for yourself and your whole family. Back to Health features conversations about trending health topics, and medical breakthroughs from our team of world-renowned physicians at Weill Cornell Medicine. I am Melanie Cole and our topic today is Focused Ultrasound for Essential Tremor or other movement disorders and my guest is Dr. Michael Kaplitt. He’s a professor of neurological surgery and the vice chair of research in the Neurological Surgery Department at Weill Cornell Medicine. Dr. Kaplitt let’s start with a little definition. What are movement disorders?

Michael Kaplitt, MD, PhD (Guest): Well movement disorders as the name implies are disorders of movement. So, they can be for example tremors which a lot of people think of as a movement disorder and they can occur for a variety of reasons. They can be difficult with making of movements, so you are slow, you are stiff, and these can occur due to a variety of diseases, often caused by abnormalities in one or more brain circuits. So, as human beings we need to move smoothly and efficiently and without tremors and without stopping or starting so we can walk, we can grab things, we can use our hands, utensils. And movement disorders in general, are a group of diseases that affect that ability.

Melanie: So, how are they classified and what disease or conditions are typically associated with movement disorders?

Dr. Kaplitt: Right, well the main diseases that are associated with movement disorders first and foremost the one that most people think of is Parkinson’s disease where there is a specific loss of certain types of cells in the brain. We don’t know why they are lost. We don’t know why they die, but we do know what the consequence of that is. That leads to abnormalities in brain function that could lead to a variety of symptoms including what we call a resting tremor which is a tremor when you are not even moving, a freezing or inability to start a movement, and stiffness or rigidity where the muscles are very stiff, among many other symptoms. So, that’s a very complex disorder. It is inherited in a small number of families; but the majority of patients with Parkinson’s disease are not inherited. And as I said, we don’t know the exact cause and there is a medication that is designed to help Parkinson’s that most patients respond well to called Levodopa or that tries to replace this lost chemical dopamine in the brain. But ultimately, as that disease progresses; about 15-20% of patients may go on to need other therapies when the medicines aren’t working so well and so we can do certain types of surgeries such as put electrodes in the brain and that’s one of the things I specialize in so-called deep brain stimulation to help those patients with Parkinson’s. So, that’s one class of diseases.

The other major movement disorder that a lot of people have not heard of is called essential tremor. Essential tremor is really a tremor disorder without any other symptoms. So, unlike Parkinson’s as I said, that has a variety of symptoms; essential tremor patients look completely normal when they are sitting or walking etc. but when they go to move, they suddenly have uncontrolled shakes and tremors of usually their hands, sometimes, their voice or even their legs or their head, but most commonly the hands and arms; which makes it very difficult to eat with a fork and knife. It makes it difficult to write. It makes it difficult to use keyboards on a computer, etc. And so, that is a different type of tremor than Parkinson’s. That is a tremor with movement or what we refer to as an action tremor. So, when you move you get a tremor, when you are sitting there, you don’t see anything. That’s different than Parkinson’s where you have a tremor at rest when you are not doing anything. And as I said, there are no other associated symptoms.

One of the interesting things about essential tremor is that it is also often runs in families, about 50% of patients will have some close – one or more close family members that have the disease; but unlike genetic diseases like say Tay Sachs disease or cystic fibrosis where we know the gene that causes it; we don’t know the specific gene that causes essential tremor. We just know that it runs in families more often than Parkinson’s and I think the most interesting thing to patients that they don’t realize until they have learned more about this disease is that it is actually much more common than Parkinson’s. Even though most of us have heard of Parkinson’s disease particularly because of some high-profile individuals that had it; many people have not heard of essential tremor, but it can be five times more common than Parkinson’s and some estimates have it even higher than that. So, it is a very common movement disorder that can be very disabling to people.

Melanie: Dr. Kaplitt as you spoke a little bit about Levodopa and dopamine as treatment options for Parkinson’s and now you are discussing essential tremor. Speak about some of the current treatment options for movement disorders. Tell us what’s going on in the field today.

Dr. Kaplitt: Right, so for Parkinson’s disease as I said, most of the treatments are designed to replace or augment the lost dopamine that occurs in the brain. So, that’s the range of medical options for Parkinson’s disease. There’s a lot of research going on trying to figure out ways to actually stop cells from dying in Parkinson’s disease or to come up with new approaches to improving brain function in Parkinson’s disease. For example, one of the things that we have pioneered for decades is an application of a new type of experimental therapy called gene therapy where we can actually put new genes into the brain, give cells new instructions and try to improve the functioning of those cells in a way that’s very different from the way drug therapy occurs. And so we have been doing that for years in both not only in the laboratory but in patients and we pioneered this in patients and now it’s being tried not only for several approaches to Parkinson’s disease but a lot of other brain disorders are being tested using this gene therapy approach.

And then of course, there are cell therapies that people are always interested in to try to replace the cells that are lost in Parkinson’s disease and some of that is now making its way into the clinic as well and we were involved in some patient studies with that as well. So, all of that is going on to try to improve the brain, repair the brain using both drugs as well as novel experimental therapies all in Parkinson’s.

For essential tremor, the treatment options are actually much more limited in part because we don’t really understand what causes the disease. We know that in essential tremor there is an area deep in the brain, in the middle of the circuit that controls movement and it’s a region of a structure called the thalamus. This particular region is called the VIM or VIM nucleus of the thalamus and that is kind of a relay station between different parts of the brain that control coordination. And so, we know that in essential tremor that area is not functioning normally. We do not know why, but we know that that’s what’s happening in essential tremor. So, people try certain drugs for essential tremor that are mostly designed to quiet down the brain, to stop this particular area from firing abnormally, from being overactive.

And so, the drugs that are used are either drugs that are often used for heart rate and blood pressure so-called beta blockers which people use when they have hypertension, or their heart rate is too high. Well, that can lower essentially the adrenaline response in the body and therefore reduce some of the activity of the brain. That can help a bit with essential tremor. There are other drugs that act sort of like epilepsy drugs that are designed to quiet the brain down and prevent it from being overactive as well. Another gold standard drug for essential tremor is called Primidone. That’s in that class and there are others. And these can work for some patients. But because they are not directly addressing the problem the way that Parkinson’s medicines are trying to directly address the problem of lost dopamine in the brain; over time, patients develop problems from that. But at least initially, it is directly addressing the problem whereas in essential tremor, we are sort of just generally trying to quiet the brain down and of course, for most people, even if you have a tremor; you need the rest of your brain to function normally. So, one of the problems with these drugs, is that not only do they not work very well for a lot of patients; but they also can cause a lot of side effects because they can make it very difficult to stay awake, to concentrate, to function, to work; because you are quieting down the whole brain and not just the area that’s needed to be worked on.

So, that is kind of the drug landscape for essential tremor as well as for Parkinson’s. For both of these diseases when drug therapy doesn’t work; then as surgeons, or when there is complications of drug therapy; then as surgeons we can target some of these very specific regions of the brain, these nodes within the circuitry that regulate the responses and the movements of the body and we can try to target them very precisely so that we do not affect the rest of the brain and we can specifically improve these abnormal circuits surgically. And as I said, the traditional surgery for both Parkinson’s disease and for essential tremor has been so-called deep brain stimulation where we would put an electrode into the middle of one of these nodes that is critical to the functioning of the circuitry and try to use that to improve patient’s symptoms. And we have many patients – I have been doing this for almost twenty years. We have many, many patients walking around with these devices in their body where they are clearly much better than they were before the surgery.

Melanie: Then speak about focused ultrasound because this is a newer procedure that takes advantage of newer technology and had been successfully used in the past, correct, to treat things like uterine fibroids and breast or prostate cancer. Speak about this treatment and how you are using it for movement disorders.

Dr. Kaplitt: That’s correct. Well the idea behind ultrasound or focused ultrasound is that you can have ultrasound go through the body and have many beams of ultrasound target the same spot from different angles so that any given beam goes through tissue is fairly low energy and does not damage that tissue. But when all of those beams converge on a particular spot; you can deliver a very high amount of energy because you are adding up the energy of all of these hundreds of thousands of beams of ultrasound at that one spot that they are all targeted on without affecting the surrounding tissue because each individual beam is fairly low energy and they only add up to a high amount of energy at the spot that you are targeting. So, you can deliver enough energy to actually burn or destroy the area of tissue that you are targeting. It has historically been used for certain types of tumors such as uterine fibroids and prostate cancer with the idea being that you can burn or destroy some of this tumor tissue while trying to leave some of the important normal tissue. So, for example in the case of the prostate; some of the nerves and other things, leave them intact. So, that’s historically been the idea.

But of course, the uterus and the prostate don’t have the problem of the skull in the way the way the brain does. And so normally, the only way to get deep into the brain was to make at least a hole in the skull and pass things deep into the brain the way we do with deep brain stimulation. However, in recent years, it was discovered that ultrasound could pass through the skull and into the brain and you could generate a helmet that has roughly 1000 sources of ultrasound in it, all of which are targeted on one spot and so by combining that with some new technology on the MRI side, so that we could actually measure the temperature of all of the tissue in the brain including the spots we are targeting, so-called MR thermometry where we measure the temperature in the brain. You could combine that with the ultrasound helmet delivering 1000 sources of ultrasound from different angles to one spot so that you could adjust the amount of energy that you are delivering to try to achieve the desired temperature only in the area of the brain that you are interested in.

So, in this case, what we are doing is taking advantage of our understanding of the circuitry that I mentioned earlier and the targets that we are interested in. That understanding as a surgeon, I’ve had for twenty years, it’s been out there for 30-40 years and so we well know what the areas are that we want to target, and we know that if we can stop them from functioning abnormally; then patients should get better. We also understand the structures that are near by that we do not want to hit, again because we are used to working in this area and so we know the consequences if you were to do something to these surrounding areas that could affect say sensation and cause numbness, that could affect speech and cause slurring of your speech, etc. And so, we try to avoid those areas that we don’t want to hit and try to target exclusively on the area that we do want to hit by sending the ultrasound energy to target that area of the brain. And so, in this case, the target for essential tremor which is what the ultrasound is now FDA approved for; is the same target that we used for deep brain stimulation, which is the same area of the thalamus.

But this time, without any open surgery, without making a hole in the head, without making an incision in the skin; we can send this ultrasound through and on the procedure table; this is done in the MRI suite; we can monitor the change in temperature until we get to a point that we know is high enough at that spot to destroy that area. And we are constantly testing the patient. So, if the patient is not having any side effects, any problems with speaking, any numbness etc., then we send more and more energy through and we will see on the table, in real time, their tremor disappear. And so, the tremor will get better and better until it’s essentially gone. And we will be testing the patient, have them upside down on the table writing and drawing circles and drinking and doing other things and we will see it get better right away, so that we know that both what we see on the imaging, on the MRI console and based on the patient’s clinical response where they are better with hopefully without much in the way of side effects; then we know that we are in the right spot and we send enough energy to make this thing permanent and with that we can send patients home an hour after the procedure. So, it becomes a totally noninvasive procedure. You are not left with any wires or batteries in the body. And you get to go home an hour after the procedure which is just not true for brain stimulation. So, that’s why it’s been such an exciting technology to work with.

Melanie: Wow. That’s absolutely fascinating Dr. Kaplitt and as far as patient selection criteria; are there some people for whom this is not going to be an option?

Dr. Kaplitt: Yes. So, there are a few limitations. Number one for the focused ultrasound we have to shave the whole head. Now hair grows back, but for those who simply do not want that, then that is a problem. Most patients who have said they don’t want that, ultimately have been okay with it because they realize that it will grow back, they can wear wigs. Some of my patients really like it once their hair is short or shaved and they have kept it that way. So, it’s been an interesting outcome.

More seriously, however, there are a population of patients where their skull is not favorable for this. So, it’s actually a bit counterintuitive. The ultrasound will go through very firm thick skull quite well. The problem is when the skull is very soft. It acts almost like a pillow. If you scream into a pillow; you won’t hear it come out the other side because all the sound gets absorbed in the pillow. So, if the skull is too soft; the ultrasound energy will all get absorbed in the skull and not really get into the brain very well. So, we do a CAT scan in advance whenever we have a patient who is a candidate and interested in this procedure, just to make sure before we go any further that their skull is favorable for this. And so we have a measurement where we actually measure the density or the firmness of the skull and about 10-15% of patients unfortunately will not be candidates for this procedure because of that. But that still leaves the vast majority who are candidates.

And then the final group of patients that cannot get this are patients who simply can’t get an MRI or stay in the MRI for a long period of time. This is not an open MRI. It’s a closed MRI and it takes several hours to do this procedure. You are not in the MRI the whole time, but you go in and out repeatedly and so if you cannot tolerate that because of severe claustrophobia, it’s very difficult. We can’t really sedate people because as I said earlier, we need to interact with them and see how they are doing during the procedure. And if you have a device in your body like certain types of cardiac pacemakers or others; that prevents you from getting an MRI; then we can’t do this procedure. All of those patients are still candidates for brain stimulation, so there is still an option for patients and it’s a good option that we have been doing for years. They are just not candidates for this newer noninvasive procedure.

Melanie: Then wrap it up for us. You’ve explained it all so very well Dr. Kaplitt but tell us a little bit about as you are pioneering this and other surgeons around the country are learning this; tell us a little bit about what it’s like for you and what you see on the horizon. What do you see happening with this? How far do you see this type of treatment going?

Dr. Kaplitt: Well obviously, it’s a very exciting therapy. It’s something I couldn’t possibly envision when I finished my training about twenty years ago and so that’s one of the nice things about being in this type of field is that we see the evolution of these newer technologies that are almost like science fiction. I mean if you remember some of the old science fiction shows like Star Trek; they would do these things that seemed fanciful when they would pass something over a patient’s head and then all of the sudden they are better. And while this isn’t quite at that level, it’s getting there. So, it really is quite remarkable to have these as options for ourselves. Obviously it’s one part of an armamentarium where we have a whole host of new technologies that are coming available for patients, not only with movement disorders but potentially other neurological and psychiatric diseases as I mentioned, gene-based therapies, cell-based therapies and other things and so we have this range of things, some of which are experimental, some of which are now approved like the ultrasound for essential tremor. On the horizon, what I’m very excited about with the ultrasound is some of its newer applications. So, using it to burn or destroy this particular target in the brain for tremors is quite effective but obviously, that’s somewhat limited because it may not apply to other diseases. Most neurological diseases are not necessarily well treated by destroying part of the brain, you actually want to fix it or make it work better. There are some, like epilepsy; this could have a nice application for to destroy an area that you could identify that is the source of the seizure and we actually have a study going on right now to try this in Parkinson’s disease patients. It’s not for their tremor, it’s actually for the other symptoms of Parkinson’s, the stiffness, and the complications of medication, but there are newer studies that we are doing.

But one of the things I’m very excited about is the ability to use this not to destroy an area of the brain; but to actually deliver things into the brain that could help improve brain function. There is a thing called the blood-brain barrier that protects the brain by preventing things like bacteria and viruses etc. from getting into the brain. But that also prevents us from delivering new therapies like gene therapy agents, cell therapies etc. into the brain without surgery. We can’t just inject it into the blood stream because it won’t get in. So, this technology allows us to use it in a slightly different way so instead of burning or destroying an area of the brain; we can actually open up temporarily, for only a few hours this so-called barrier, this blood-brain barrier so that now with a simple intravenous injection; we could potentially deliver things into target areas of the brain with no surgery that could actually improve brain function. And we have been doing this and we have published some of this in the laboratory and now we are starting to do this hopefully in patients in experimental trials that are upcoming at our site for brain tumors, for Alzheimer’s disease, so this has a wide range of potential applications if we can broaden it out using this additional approach.

Melanie: That is so fascinating. Dr. Kaplitt, wrap it up for us, just what you would like people to take away from this segment about movement disorders and focused ultrasound for essential tremor and other movement disorders such as Parkinson’s as you have mentioned. What would you like the listeners to know?

Dr. Kaplitt: I think the most important thing is that people should remember that medication is still the first line therapy for these things because some patients respond extraordinarily well to medicines. However, if you are not responding well to medicine or if patients have taken medicine for years and now they are having complications, or they are not responding as well as they used to; there are a lot of options for them. And some of those options we have great experience with over twenty years which includes deep brain stimulation which has been a great option for a lot of patients and will continue to be a great option. Now we have less invasive approaches such as the focused ultrasound that can actually help improve patients who have some of these diseases particularly essential tremor where it’s FDA approved and so, we are increasingly providing patients with newer options. And I think it’s important that when patients feel that they are no longer doing as well with simple medications as they used to; that they seek out expert advice, expert help and that they go to places that have the full range of options available to them, both traditional and newer options because then they will get the most complete advice, the most honest advice so that that way they can then choose what would be best for them.

Melanie: Thank you so much Dr. Kaplitt for being with us today and for sharing your expertise and explaining what we need to know about focused ultrasound for essential tremor and movement disorders. You’ve explained a complicated topic so very well for us. Thank you again This concludes today’s episode of Back To Heath. We’d like to thank our listeners and invite our audience to download, subscribe, rate and review Back To Health on Apple Podcast, Spotify, and Google Play Music. For more health tips go to weillcornell.org and search podcasts. Parents – don’t forget to check out Kids Health Cast!