Dr. Paul Fishman, MD, PhD, Clinical Professor of Neurology at the University of Maryland School of Medicine, talks about how a special ultrasound could help relieve symptoms of Parkinson’s.
Interview conducted by Ivanhoe Broadcast News in July 2022.
Can you explain what’s causing the movement trouble when someone has Parkinson’s?
FISHMAN: Parkinson’s disease is a neurodegenerative disease – In a sense its like premature extreme aging. It’s in the same family of Alzheimer’s disease, and it’s the second most common. There are about six million Americans with Alzheimer’s disease, about a million with Parkinson’s disease. It interferes with movement, the ability to use the hands, the feet, dexterity. It causes shaking that can interfere with function and in its later stages can interfere with balance and can cause problems in thinking and memory that are similar to Alzheimer’s disease.
What are some of the signs and symptoms?
FISHMAN: The most common first symptom is just shaking of one hand. It’s an unusual form of shaking in that it’s suppressed with movement commonly and called a rest tremor. So, if the hand is just sitting, not doing anything, it’ll shake. But it may commonly go away if you start to move it. It may come back if you try to hold the posture for a time, like screwing in a light bulb and you have to keep that hand steady. But that’s the most common earliest symptom, which in general is – even though it helps a great deal, in diagnosis – is frequently not functionally interfering. The later symptoms interfere with speed and dexterity of movement in the hands, along with a sense of muscular stiffness that can occur in both the arms and legs and interference with walking. Walking takes on a shuffling quality. There are changes in body posture, such as stooping, which can also interfere with normal day-to-day life.
What are some of the traditional gold standard treatments?
FISHMAN: For better or worse, the most effective and widely used medication for Parkinson’s disease remains Levodopa, which was introduced in the 1960s. It is used in combination with a medication called Carbidopa that allows it not to be broken down in the body but get into brain where it needs to work.
With Levodopa, does it become less efficacious over time?
FISHMAN: As Parkinson’s disease gets progressively worse, Levodopa continues to work but its ability to make patients normal or close to normal becomes less adequate. So, it’s not so much that the Levodopa doesn’t work. It’s that the severity of the disease increases. Also, it tends to act erratically after years of treatment. So, patients commonly describe themselves as having at least three different phases to their day. One where the medications are working, they call it being “on”. The other times when the medications stop working commonly at the end of a dose before the next dose where the stiffness, the slowness, the tremor comes back, and that’s the “off” state. The other part with common use of Levodopa over years, one can become overly sensitive to it so that it induces abnormal movements, fidgety movements, called dyskinesias. They usually happen when the medication dose is high. So patients can be “on” with dyskinesias. It’s kind of like the old joke in football about when you throw a pass, three things can happen. Two of them are bad. Only one of them is good, you know. So, you want to be in that on state without dyskinesias because they can interfere with normal movement.
For patients whom this isn’t working, or they’ve had Parkinson’s for a while and Levodopa is no longer an option, what’s the next state? What’s the next option for them?
FISHMAN: Well, there are certainly other medications that are used along with Levodopa that in general are longer acting. They’ve been available for years. But when even those medications fail to totally control these ons and offs for patients, surgery has been available for Parkinson’s patients for over 30 years. It went through three phases. The first phase was to open up the skull. There was a particular area of the brain, if you put in a probe and usually, like a microwave probe and you destroyed that area, you could relieve symptoms. In the late 1990s and into 2000, instead of destroying a piece of brain, what goes in is a pacemaker-like wire that puts in a jamming signal – that’s called deep brain stimulation. That’s been a huge advance to give patients much better control of their symptoms.
Can you talk to me about the Exablate?
FISHMAN: That’s the third phase. X-rays were used first, with what is called the gamma knife, you can destroy brain tumors without opening the skull with focused gamma radiation. Now, we can use focused ultrasound to destroy a small spot of brain. So, it’s a step backwards to the old days in that it’s destroying a piece of tissue, and it’s not adjustable like DBS is, but it gets away from the most common serious complications of any form of brain surgery, which is bleeding into the brain or infection of the probe within the brain. I think we all know once something is implanted, whether it’s a heart valve or a pacemaker, it’s always susceptible to infection.
Can you walk me through the procedure? How does this work for patients?
FISHMAN: Both deep brain stimulation and focused ultrasound start in a very similar fashion. For better or worse, it does start with head shaving. That’s usually not a nonstarter for most people. They rely on a highly machined steel frame that’s tightly attached to the head. They both rely on MRI imaging to really image that brain target that’s never seen by the surgeon. Now, in deep brain stimulation, the rest is all done in the O.R. where a very small hole about the size of a nickel is made. That probe is driven into the brain – most of the time done with an awake patient. Besides recording from the brain, one then turns on that electrode in the operating room. There are probably 100 YouTube videos that show this from every major medical center in the country, because the improvements that you see most of the time occur immediately. As soon as you turn that thing on, you adjust it. That is what tells us that the probe is in the right place. If we’re not happy with the probe’s location, meaning when we turn it on, we don’t get the benefit or we get side effects from stimulating nearby brain we can change the position of the probe. Side effect depends on what region of the brain is being stimulated. You might get pulling or a sense of pins and needles or double vision depending on where the probe is off target well, and then you could pull it out, move it over and try it again. In a very similar way but without ever opening the skull, focused ultrasound try to target the brain region. On top of that frame goes a helmet-like device that has an array of tiny little sound speakers. There are more than a thousand of them all putting out a very small beam. Like using a flashlight to burn a piece of paper, where all the beams of sound energy come together at the target and hits brain, it’s converted into heat. What’s nice about MRI imaging – not only can you see brain, but MRI imaging can measure brain temperature. It gives you a temperature map pretty much like you see on TV where the hot spots in brain are. The operator can look at the spot on the temperature map and say, I’m not happy that the peak temperature is not exactly where I want it. Instead of pulling the probe out and moving it over, one just dials and adjusts the array slightly. First we raise brain temperature at the target region to a level that can interfere with brain function, about 20 degrees Fahrenheit above normal – at that temperature brain doesn’t function well, but it doesn’t kill anything. Then we evaluate the patient just like in DBS. We look to see if only good things happening. Are their symptoms getting better or is anything bad happening? Do they have any interference with speech? Do they have any weakness? Do they have any funny feelings? If needed, we can adjust the target – the array – to make sure that we don’t do any permanent damage and do it all over again. Then, if patient and operator and the team are pleased with the positioning and what’s happening, we intensify the sound energy and destroy that small part of brain.
Was this approved in 2021?
FISHMAN: No, for tremor, it was FDA approved in a related condition called essential tremor, which has shaking alone and not any other symptoms, it was FDA approved in 2016.
Was it FDA-approved for just for Parkinson’s in 2021?
FISHMAN: It’s been stages – 2016 approved for essential tremor, 2018 approved for tr approved for tremor related to Parkinson’s disease but only for that specific aspect. It turns out that it’s the same brain target that can be used in both situations. The more recent FDA approval in the end of 2021 was for a totally different target that can affect all of the symptoms of Parkinson’s and not just tremor – a target that goes by the initials GPI.
What are the implications? What does this open now that doctors have another option?
FISHMAN: The option is between medical treatment and deep brain stimulation. Some patients may not be good surgical candidates. Some patients may find that the risk of deep brain stimulation is greater than is acceptable for them.
It gives them a middle ground. There have been no direct studies comparing deep brain stimulation and focused ultrasound. But if you look at the studies we have done and compare them to similar DBS studies, one can say – and this is true for tremor as well – deep brain stimulation is more effective but has more risk. So, if you’re looking for that middle ground where you’d like to go for less risk and sacrifice effectiveness to some degree, now you have a middle option.
Can you talk to me about your patient, Mark?
FISHMAN: Mark was a typical patient who came for Parkinson’s surgery. He had a clear diagnosis. This isn’t something for people where they have unusual forms of Parkinson’s that don’t respond to medication. And sadly, it’s not for them. It’s for patients who are in the middle stages of Parkinson’s, like Mark, where the medications work, but at times the medications are working incomplete, meaning they have good quality on. When the medications are working, he’s doing well. When the medications are not working, it interferes with his day-to-day life. If we try to push the medications a little higher, we’re starting to get these fidgety, abnormal movements, which if we push the medications any higher, they would interfere with day-to-day life. So, he would be referred to as having dose fluctuations. That’s the commonest reason someone goes for Parkinson’s surgery. When we him offered this option, to significantly improve those symptoms without open surgery or the physical placement of a electrode, that resonated with him, particularly this new study that we’re currently involved in.
Can you do both sides? Are you limited to one in the study?
FISHMAN: That’s what the study is all about.
Can you talk to me about that?
FISHMAN: Well, the previous study, most everyone did well with one side. Some of those patients were even selected that had Parkinson’s that was much worse on one side than the other. The reason for that is that in the old days, when open Parkinson’s surgery was done, when they tried to do two sides, particularly if they tried to do two sides at once, they got an unexpected complication. So, what we all probably learned in high school is that left side of brain controls right hand, and right side of brain controls left hand. What they don’t tell you in high school is what about all the things in the middle of the body? Important functions controlled by muscles in the in the middle – speech, swallowing, balance. That takes coordination of both sides of brain. There’s a lot of individual variation about how much left and right brain contribute to those things. And that’s why in the old days, some patients did well when they did one side and had lots of problems with speech, swallowing or balance when they did the second side. So, that’s why there’s always safety first ands see that people did well with the first side done. It turns out that in Switzerland, one neurosurgical group had been looking at an unusual target for the last several years. That’s close to but not exactly in the area of the brain that we had been exploring. They had already done probably a dozen people on both sides with a good result. So, it was one of those things where things looked very good, but it was a single center and particularly a single center where people came from all over the world and then went back to where they were, which makes it very hard to have accurate information on long-term follow up. So, the gold standard to see if something is going to be widely applicable is to get a whole bunch of centers to do it and work together and doing something as similar as possible as the Swiss group to approach both sides. It’s important because even though Parkinson’s may start on one side, as the years go on, most Parkinson’s patients are affected on both sides. And of course, for things like walking, you need improvement on both sides. We recently completed a large study treating both brain sides for a different condition essential tremor with good safety, so we were well-positioned to try to explore this new brain target. My feeling about the Swiss study was optimistic but skeptical. And I think I expressed both of that to Mark that very few people outside of that Swiss group had ever had this. That’s why it’s gratifying that so far, the patients are doing well. We still have a ways to go, though.
How many patients have had both sides here at the University of Maryland?
FISHMAN: At the University of Maryland, we’ve only had three that have had both sides done so far. Because one of the things we learned from the old bad experience on treating two sides, is if somebody has problems with the first side, they’re not a good candidate to have the second side done. The worst experience years ago was when they tried to do both sides at once. So, our current research study demands that people do well for a six-month period before it’s a go to do the second side.
How many other centers are together on studying this?
FISHMAN: About a dozen. Both in this country and out.
What’s the goal? How many patients do you want to study?
FISHMAN: The goal is probably about 60 or 70. And then, of course, the next step is really up to the FDA. In the past the FDA has required us to confirm any results with a placebo-controlled study where actually do sham ultrasounds on some patients including shaving their heads – and as many as a third of the patients – they’re guaranteed to get it eventually. They get the frame put on, and they go through the whole procedure with nothing happening. And that the FDA has commonly demanded. Generally, in science, because of placebo effects, we want to have a “placebo controlled.” In that situation, you even need two teams – one team doing the sonication, or in this case, the fake sonication, and another team who’s evaluating the patients. Both they and the patients have no idea if they were treated or not. This study right now is not placebo controlled.
Is everybody getting it?
FISHMAN: Everybody is getting it. Then, we’re just going to have to see what the FDA decides.
Is there anything that you want to make sure that people know?
FISHMAN: I just wanted to mention that this technique has the capacity to do a lot of other interesting things besides destroy brain. When we’re destroying brain, we’re turning up the intensity on it to cook a small spot of brain. But what was discovered in animals more than a dozen years ago is that if you set these sonication parameters correctly, you can disrupt the small blood vessels in the brain. You can disrupt them minorly without killing them so that they allow medications or therapies that are in the blood to get into brain. In general, most medications that we give to people don’t get into brain because the small blood vessels of the brain, are zippered together. It’s what’s referred to as the blood brain barrier. There’s been use of this technique with medium amounts of energy to open up the blood brain barrier. It may only stay open for a few hours, but that’s enough of a time window that you can give a patient medication by vein. This has already been done – is being done here at the University of Maryland to treat brain tumors by Dr. Graeme Woodworth that’s been going on for years. Recently they’re small studies looking at it to treat Alzheimer’s disease and small studies looking at it to treat Parkinson’s disease – one that’s just been completed in Canada just within the last couple of months. So, we’re looking careful at those to see if that’s going to be worthwhile for us joining along with them.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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