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And we will focus on the focused ultrasound mediated ablations as a therapeutic option for our patients. Hello Raul and thank you for joining.
[00:00:35] Dr. Raul Martinez Fernandez: Hello, and thank you for the invitation.
[00:00:37] Dr. Michele Matarazzo: So let's start by explaining how an ablation, or in other words, a lesion in the brain, can have a positive effect on the symptoms of our patients. Wouldn't you expect the opposite?
[00:00:49] Dr. Raul Martinez Fernandez: Yeah, that's an important point, because it's quite contraintuitive that a lesion in the brain could provide a benefit on a condition, on a disease. In fact, well, ablation has been performed for decades. [00:01:00] It started in the forties of the last century. At that time, it was based on empirical observations, which means that patients who had had a lesion in the brain improve specific symptoms such as tremor, but not only tremor, also rigidity or bradykinesia in the case of PD.
And it was performed for thousands worldwide. With the advent of deep brain stimulation, lesions were practically relegated. They were continuing to be done, but deep brain stimulation prevailed. For different reasons. We can discuss about this afterwards. What we know now is that a lesion and ablation in the brain is therapeutic because it sort of reverses a network which is malfunctioning in the context of disease.
Parkinson's disease is a circuitopathy, essential tremor, same there, there is abnormal activity in the brain that is producing the clinical signs or symptoms. And by doing a lesion, we reverse [00:02:00] this abnormal activity. And we, sort of lead the brain to a more physiological status. So in the end, this is a neuromodular modulative technique by disrupting abnormal activity, which is underlying the disease or the symptoms of the disease.
[00:02:17] Dr. Michele Matarazzo: Great. Now, can you explain in just a few words, how can you do lesions with Focused Ultrasound? I mean, we do use ultrasound as a diagnostic tool. Now, how can you use it or, or play with it to, to make it produce lesions in the brain?
[00:02:33] Dr. Raul Martinez Fernandez: Yeah, well, focused ultrasound lesions or ablation are based , on increase of temperature. These are thermal ablations. It is not that one, as you well know, ultrasound energy does not increase independently temperature, but if you have like in the case of focused ultrasound, 1000 ultrasound beams that have a confluence on a specific region, in this case, specific brain [00:03:00] region.
The confluence of these hundreds of ultrasound beams increases the temperature on, on target. And this increase of temperature is what is produced in the lesion. In other words, lesions are produced by the focusing of hundreds of ultrasounds, beams in a selected brain region.
The the energy of ultrasound is converted into a temperature, into increase of temperature, and that is the, the mechanisms by which ultrasound energy produces ablation.
[00:03:30] Dr. Michele Matarazzo: Okay. So, and you were mentioning before that lesions have been done for years or decades. What is the advantage of focused ultrasound and what are the differences compared to other techniques to produce these lesions?
[00:03:42] Dr. Raul Martinez Fernandez: I have to say that the history of ultrasound to produce lesions is not recent in the forties and fifties, it was tried as well. But at the time the limitation was the most of the energy was absorbed by the skull and therefore it could not penetrate into the brain to produce a lesion.
So [00:04:00] previous techniques, the classical techniques were surgical techniques. And these techniques require craniectomy and required electro penetration into the brain to produce the lesion, to produce ablation. The main advantage, and in my view, the factor that has made of focused ultrasound game changer in the field is that we do not need anymore incision.
We do not need anymore penetrating into the brain to produce those ablations. And that, that it's a completely different approach because you avoid all complications related to the surgical art, per se, and the impact, the, the global impact on the brain is lower than that of the previous surgical ablative techniques.
[00:04:43] Dr. Michele Matarazzo: And what about gamma knife?
[00:04:46] Dr. Raul Martinez Fernandez: gamma knife is indeed a good option. It has been used for 20 years. If I had to say, which is the main limitation of gamma knife as compared to ultrasound is that ultrasound, the effects, the clinical effects of ultrasound [00:05:00] are immediate.
So you can monitor in real time. Where are you impacting through the MRI. And which effect is it having? So you can see whether there is a beneficial effect and if there is any side effect and you have to correct the target. On the contrary, gamma knife. The effects are delayed. It, it, it take a few months, three to six months to have the permanent lesion done.
So you have less control on what is happening on where, where are you impacting? This is a good technique as well. As I said, it has been used, but in comparison to ultrasound, these limitations in my opinion, make focused ultrasound. A better option. I would not say that is a better treatment because each one might have suitable candidates, but in general, overall I see ultrasound as a, as most reliable option to be sure of the kind of impact that you are having.
[00:05:55] Dr. Michele Matarazzo: Now you were mentioning that focused ultrasound is a more [00:06:00] commonly available option recently for doing ablations in the brain. So let's talk a little bit about the recent history of focused Ultrasound for doing these lesions in the brain. And probably it's easier if we go disease by disease.
And let's start with essential tremor, which if I'm not wrong, was one of the, the main disease that targeted with focused ultrasound for improving symptoms in, in our patients. What happened and what is the evidence that we have for using focused ultrasound ablations in essential tremor?
[00:06:31] Dr. Raul Martinez Fernandez: Yeah essential tremor was the first firstly approved application, and it's the most widely applied. It was not the first application of ultrasound. In fact, there are a few studies, a case series of ultrasound thalamotomy to treat neuropathic pain. Although that has not been approved so far.
And in case of essential tremor, we ultrasound received regulatory approval in 2016. That was based in a few trials [00:07:00] initially, 2013. Two milestones occurred that were two open label trials in one in the New England and the other in Lancet Neurology, which show that unilateral thalamotomy was effective to treat essential tremor and it not only essential tremor, but also the disability related to tremor and quality of life that was followed by a randomized control trial in 2016, which was the 1 that lead to the to the approval on the indication. I need proof with class 1 evidence that ultrasound as compared to a sham procedure was superior improving tremor and disability related to tremor. And this is an important point in my view, because we don't do not treat tremor. What we treat is tremor related disability, because if a patient does not have disability it does not need to undergo a relatively invasive treatment, because in the end, ultrasound, Might not be as invasive as previous techniques, but it's invasive.
We're doing a brain lesion, so we have to [00:08:00] select appropriate patients. In 2016, as I was saying, this randomized control trial lead to the approval of the indication. And since then we have had more evidence, mainly long term follow up series showing that the ethic of a lesion is permanent. If you have a good effect initially, it lasts at least for five years.
At least because that's the follow up that we have and that in general, lesions are safe and there are a few collection of the pilot that by both studies showing that most side effects are either mild or transient permanent side effects cannot cure because we're doing the lesion, but it's quite unfrequent.
It's very infrequent. In fact, and there's more evidence showing that we can even consider performing bilateral treatments, bilateral lesioning. There was a reluctance in the past of to perform bilateral [00:09:00] treatments because well, the experience from surgical techniques showed that bilateral ablation might be associated to a high rate of, of side effects.
However, as this technique is, as I said, less invasive, the global impact is, is lower. Then a few series has showed that ultrasound bilateral ablation in essential tremor might be feasible and might be safe. And of course, might be effective to treat both sides of the body. So this, I would say that the most relevant evidence that we have had in the last.
10 years.
[00:09:34] Dr. Michele Matarazzo: Perfect. And so you were discussing about thalamotomy first unilateral thalamotomy to treat the contralateral side, and then that there is some evidence that also bilateral thalamotomy is a possibility. Is thalamotomy the only option we have for essential tremor or are there other targets that could be targeted for, for essential tremor?
[00:09:55] Dr. Raul Martinez Fernandez: That's a great question because the target discussion has last [00:10:00] also decades. The universal target for central tremor is the VIM, the thalamic VIM. However, in the past with radio frequency, surgical ablation, it will show that also the cerebellar thalamic tract might be a good target, that also the posterior subthalamic areas might be beneficial.
to treat essential tremor. And we're in a similar situation with ultrasound ablation. While the VIM continues to be the universal target, some evidence is showing that there's an impact on the cerebellar thalamic tract might also be an option. And in fact, might be a superior option than the VIM.
There are no direct comparisons between targets, so we cannot Confirm which one is superior to the other, but in my opinion, it's an ongoing discussion, an ongoing debate. I have to say that in the case of essential tremor, both locations, the VIM and the CTTs, the cerebellar thalamic tracts, both are very [00:11:00] effective.
[00:11:00] Dr. Michele Matarazzo: With the essential tremor with thalamotomy and essential tremor, what are the main side effect? You were mentioning that in general is quite safe, but what should we be worried about? And what are maybe the patients that are less good candidates for this treatment because of any underlying condition that that might worsen after the thalamotomy.
[00:11:23] Dr. Raul Martinez Fernandez: that's, of course, and very important point, because I said that. Permanent side effects are rare, but practically all patients who undergo thalamotomy for ET, they, they present side effects. I would say that 80 percent of patients have side effects. However, these side effects are generally mild.
And they are transient because they are not related to the lesion itself, but to the edema, to the inflammation surrounding the lesion, which is very typical in the first weeks after treatment. Therefore, when this edema disappears, side effects usually [00:12:00] recover and disappear as well. The most frequent side effect, by and large, in the case of a thalamotomy or ET is gait and stability.
In that regard, we always tell patients to be very careful that they, they are going to be unstable for a few days or weeks, and they have to be very careful of within the first few weeks after treatment. Those patients who have gait instability pre treatment, can be considered for thalamotomy if they have disabling and medically refractory essential tremor, but you have to be more careful with those.
You have to be maybe more conservative when doing a lesion, doing a smaller lesion and inform very much the patient that pre treatment gain instability can impair afterwards. So I would not exclude a patient because of previous baseline and stability, but I would be more careful. Other less frequent side effects are speech disorders, which are usually mild.
[00:13:00] And sensory disturbances like paresthesia in the mouth or in the fingertips, these are the most frequent, although my impression and what shows the literature is that with time and experience, the rate of these side effects is decreasing as expected, we needed the learning curve. So I will not see.
Those as a, as a problem in general.
[00:13:26] Dr. Michele Matarazzo: Perfect. Now let's move on to Parkinson's disease. Well, you between others have have showed and have lead the way. Towards a treatment with focused ultrasound for Parkinson's disease. Now, can you guide us through what are the options of a focused ultrasound treatment for Parkinson's disease?
What are the targets? What are the possible side effects? And also what, what is the, the expectable outcome of a patient who undergo a focused ultrasound treatment with Parkinson's disease.
[00:13:53] Dr. Raul Martinez Fernandez: Well, that's a very wide discussion. If the target discussion in ET [00:14:00] was debatable, this one is, it's very complicated because we have more options in PD and also because PD is a more complicated condition and we have to consider that it's, it's much more diffuse.
You have the level of induced complications where you have non motor manifestation. So. It's not as easy the management the patient selection and the post treatment management is not as easy as with essential tremor, but essentially because the disease is more complicated having say that so far with PD, most of the studies have been unilateral as well.
So, to treat one side of the body only. And in that regard, I would say that a good patient for the therapy would be a patient with very symmetrical condition, regardless of the target that we are, we're approaching because by improving one side of the body, you are going to provide a better motor statute.
Generally, if you have a patient with marked bilateral [00:15:00] impairment. Which is not optimally controlled with medication that patient, in my opinion, should undergo deep brain stimulation that on one hand, on the other hand, the target discussion. Well, what do we know? And we know that from a previous ablative surgical interventions, and also from the DBS experience is that the STN, the subthalamic nucleus is the most effective target for Parkinsonian manifestations, not only tremor, but also rigidity and bradykinesia.
The thalamus. Might be the most appropriate target only For Parkinsonian tremor, it does not improve really bradykinesia and very slightly rigidity. And the, the pallidum is a very good target for hyperkinesia or for motor fluctuation for dystonia or dyskinesia.
We also have. Experience with the pallidothalamic tract, which is a quite promising target, but still we don't have a controlled study to show the benefits properly. The target decision [00:16:00] would depend on specific clinical manifestations of the patient. If you have a patient with Asymmetrical dyskinesia or dystonia only one side of the body for that patient, I would target the pallidum without a doubt, because the STN is not as effective with those manifestations of the pallidum.
If you have an asymmetrical patient with rigidity by the bradykinesia tremor, then I would target. Then to subthalamic nucleus, that is still not well defined in the field. I think consider that we have been discussing the target for DBS for 20 years. So we're still, this is a new addition. The ultrasound is a new addition to the, all these armamentarium for PD.
So we are. still defining which are the more suitable candidates. But if I had to say something in general, I would say asymmetrical patients. And depending on the many, specific manifestations, you could select one target of or the [00:17:00] other.
[00:17:00] Dr. Michele Matarazzo: Okay. And what about the side effects specifically for each of those targets? You discussed already about the thalamus and the VIM, which I suppose does the risks and side effects would be the same or similar As the one that you were mentioning with essential tremor, but what about a subthalamic nucleus or pallidothalamic tract or, or the globus pallidus pars interna.
[00:17:24] Dr. Raul Martinez Fernandez: That is correct. In fact, side effects are, are target dependent, some of them, at least. And as I said, with the essential tremor, the VIM is more associated to sensory disturbances. And gait and stability, which is not the case with the STN or the GPI it, they can occur, but they are not frequent at all.
The STN is is related to dyskinesia associated to the subthalamic lesion. This is also feel of debate in our experie. dyskinesia after subthalamic lesion have a good prognosis. In fact, they, they resolve within weeks in most of the cases. And [00:18:00] in fact, and that is important, they are related to a very good anti Parkinsonian effect because you have to consider that these are the two sides of the spectrum, Parkinsonism and dyskinesia.
As far as after subthalamotomy, you can decrease levodopa. Dyskinesias are never a problem and you can decrease levodopa in those patients who are markedly asymmetrical because the other side does not need as high doses as the the initially treated side. And in the pallidum, I would not say that there are specific side effects, but there are also the general side effects, regardless of the target.
My main concern is impacting on the internal capsule, because if you impact on the internal capsule, you have you can have dysarthria, can have a motor weakness and that that can happen with any of the targets and that is in my opinion What we have to avoid the most to be careful during the treatment to avoid kind of weakness, motor weakness Because [00:19:00] that could be the more disabling in the midterm we have had, I mean, all teams and the study shows that, that you can have a motor weakness in general, they improve progressively as well.
But if the lesion has grown and has impacted on the, not only TV, but the lesion has impact on the internal capsule. Well, that can be sustained. That can be permanent. In general, it is, as I said, is infrequent to have a severe or any that is very, very infrequent, but conceptually that could happen.
So you have to be very careful of not impacting on the internal capsule. That would be, in my opinion, the most concerning adverse events.
[00:19:40] Dr. Michele Matarazzo: Great. Now you were mentioning in that one of the, the main selection criteria is the asymmetrical features of the motor features of PD. What about bilateral treatment? Is that something feasible or is there something that you are working on?
[00:19:57] Dr. Raul Martinez Fernandez: Well, it's similarly to essential tremor. There are [00:20:00] concerns which come from the classical radiofrequency ablation era. Because it was shown that bilateral ablation for PD also was related to neurological complications, mainly to speech and gait complications. Again, as this is a new and less invasive therapy, if this Concept has been revisited.
We were behind essential tremor. There is only one published series of bilateral ablation in the palliadothalamic tract for Parkinson's disease. It seemed to be pretty well tolerated. That was an open level series. We need more evidence. And while this evidence is underway, there are a couple of studies.
One with bilateral STN lesion that will be soon published. And there's another ongoing study with bilateral pallidothalamic tract, but with a larger sample than the previous one. And our experience, it is better tolerated that [00:21:00] radiofrequency ablation. It might be in our, in my opinion, it might be feasible and effective in selected patients.
Not all patients could undergo bilateral ablation, in my opinion. And something which is important is that at the time ablation must be done not in a stage manner, not at the same time, not simultaneously, but with a few months apart one side from the other. And this is because the edema after treatment, if you have edema on one side that is well tolerated, you can have side effects, but in general is well tolerated by the brain.
But the impact of edema in both sides at the same time might be related to transient, but probably relevant adverse events. So I will not perform at the time being bilateral ablation simultaneously. We need more evidence, of course, to to draw conclusions. And we're going to have more evidence in the near future.
And it's something that needs to be [00:22:00] explored again. My opinion, it would be feasible and useful for selected patients, not to the general population. Well, not even DBS is applicable to the general population of PD, but and with ultrasound would be similar. In selected patients, that would be definitely an option in the future.
[00:22:20] Dr. Michele Matarazzo: Perfect. Now we have discussed about the two main diseases, which are essential tremor and Parkinson's disease, but do we have any evidence in in other movement disorders that the focused ultrasound is a viable option as a treatment?
[00:22:34] Dr. Raul Martinez Fernandez: Absolutely, I mean, PD and essential tremor are the 2 main indications and worldwide approved, but there's evidence on other conditions. There are case series of focal dystonia. That would be a very, I think, ultrasound ablation is a very good option for focal dystonia, although we still don't have Control trials.
Neuropathic pain it's also been explored so far. Not enough evidence to, to [00:23:00] confirm whether it is effective or not. The last study from the Virginia group was a bit disappointing, although it needs to be explored further And and well, one indication which goes a bit beyond neurology is neuropsychiatric conditions.
So you probably know that in the past psychiatric conditions were treated with ablation as well. That was a completely different scenario. Now, there are a few studies showing that bilateral ablation of the anterior internal capsule might be good option for OCD, obsessive compulsive disorder, also for depression.
And that's a field that in my opinion, needs to be explored further. Absolutely. Because psychiatric patients are complicated. Sometimes deep brain stimulation with those patients is well, they cope not very well with deep brain stimulation. And in that regard ultrasound ablation is more clean.
I mean, it's more easy going for those patients. So these are the, the main I think ongoing [00:24:00] indications that have been studied, but in general, anything which is treated with DBS conceptually can be treated with ablation. So I think the, in the years to come, we're going to see more diseases approach with ultrasound ablation.
[00:24:16] Dr. Michele Matarazzo: Well, thank you very much. Now, before we approach the end of the interview, can you just guide us through the whole process of a treatment? So from the patient selection to the final outcome of the treatment itself?
[00:24:29] Dr. Raul Martinez Fernandez: Sure. So the first thing is visiting the patient on your clinics. You have a patient with, I don't know, ET, PD, with medical refractory manifestations. Then if the patient is a good clinical candidate, you perform a CT scan. The CT scan is to calculate the skull characteristics, because there are some patients who have skull characteristics that do not allow The ultrasound energy to penetrate into the brain.
It's only 5 to 7 percent of patients, but this can happen. So it's performing this CT scan. If the [00:25:00] CT scan is switchable, then in our case, that's not a generalized probably, but in our case, we perform an MRI to see any structural abnormalities. Neuropsychological testing just to see that the patient is cognitively well enough to tolerate the treatment itself.
At this visit, it was like a presurgical visit. Although we do not consider this techniques as surgical, we want to have this pre evaluation by the anesthetist for, for comorbidities, et cetera. And also blood test to check the platelets et cetera. If everything is fine, then the patient is a good clinical candidate, has no contraindication, and the patient can undergo the treatment.
[00:25:42] Dr. Michele Matarazzo: And how is the treatment itself? So the patient, how long does he stay in the hospital? How long does he take the treatment?
[00:25:49] Dr. Raul Martinez Fernandez: Well, patients need to get admitted and shave their heads because the hair can interfere with the ultrasound beam. So they need , to have their head shaved. Then we placed the [00:26:00] stereo static frame. We place the patient in the MRI and attach the stereo frame to the ultrasound transducer in the case of essential tremor.
It lasts about two hours, two to three hours. In the case of pd, as it is a bit more complex, it can take three to four hours sometimes, and after that the FX permanent. We keep the patient in the hospital for one night, nothing has happened, but nothing has ever happened with our patients that night, but we prefer to have them in the hospital and the day after we perform an MRI to see the final lesion and have an idea on how he's going to evolve in some centers.
I know that it's made as an outpatient clinic application, which. I think it is okay. But in general, they do not need more than one night in the hospital afterwards. The follow up. Well, it's it depends on the condition essential tremor patients. You can visit them [00:27:00] twice or three times within the first year.
And with PD, you have to adjust medications, et cetera. Sometimes you need a few more visits, but well, in general, the, the followup is quite straightforward.
[00:27:14] Dr. Michele Matarazzo: Well, thank you very much. Is there anything else that you want to share with our listeners?
[00:27:18] Dr. Raul Martinez Fernandez: I just want to, to say that in my view because there was some debate and controversy when ultrasound came out, because we already had deep brain stimulation, which is a very effective and highly proven therapy. And I want to say that for me, ultrasound is just a new tool. a new tool to treat these conditions.
The ultrasound and DBS are not competitive. They are complementary and we just have to learn which patients are more suitable for one technique and which are more suitable for the other. And this is an advantage. We have a new tool and we have to To learn properly how to, how to apply it. So I would not, I would never make a competition with with DBS on which one [00:28:00] is better because I don't think there's a better one.
There is not the best one but, but both are valid and are tools that we can use to improve our patients quality of life.
[00:28:12] Dr. Michele Matarazzo: Perfect. Well, thank you very much. Thank you very much, Raul, for being with us today.
[00:28:16] Dr. Raul Martinez Fernandez: Thank you.
[00:28:17] Dr. Michele Matarazzo: We have discussed the fast mediated brain ablations and their applications in movement disorders with Dr. Raul Martinez Fernandez from the HMCNAC in Madrid, Spain. Thank you, Raul, for your insights and your contributions to the field.
And thank you all for listening. [00:29:00]