Bilateral focused ultrasound thalamotomy for essential tremor, is it safe?

[00:00:49] Professor Andres M. Lozano:
Thank you. It's a pleasure to be here.
 

[00:00:51] Dr. Michele Matarazzo:
Let me just start with the very basic question on the functional neurosurgery for essential tremor. What options do we have and when do we need to think about them?
 

[00:01:00] Professor Andres M. Lozano:
Well, despite medications, about 40% of patients with essential tremor are disabled by their tremor. And it is for these patients that no longer respond or have intolerable side effects and are disabled by their tremor that we consider surgical intervention.

We've had a number of surgical interventions historically for the last 50 to 70 years to treat tremor surgically. And the oldest operation is called a thalamotomy. And that involves making a Burr hole and introducing a needle and coagulating the neurons or the pathways that lead to colonic relay nucleus that causes tremor, the ventral intermediate nucleus. So a radio-frequency is usually the way that was done. And I was the oldest operation that was done.

Then more recently, other operations have come into play, in particular deep brain stimulation is also quite effective for treating tremor and DBS has done exactly at the same target, and it has the advantage of being reversible and adjustable. A third option is radiosurgery — that is to use gamma knife, for example, to noninvasively make a radio necrotic lesion and the thalamus.. And that has certain advantages in that it's non-invasive, and yet, there's a delay in the clinical response and you're never quite sure that you've aimed in the right place.

So the most recent addition to our toolbox has been the use of focused ultrasound. And this has a number of interesting properties in that it is a non-invasive procedure. We don't do any incisions on the skull. We shoot ultrasound waves through the skull, usually about a thousand waves. We focus them on the nucleus VIM, nucleus of the thalamus, and we get an instant result and we're able to adjust lesion in real time.

And we're able to get an effect that is immediate. And so because of that since 2012, for the last 10 years now, this technique has started to gain some influence and in fact is now the dominant technique to treat tremor of all surgical techniques. It has overtaken DBS. And it is now the most common surgical procedure to treat tremor.

Now, the difficulty is of course, and where the paper comes in, is that tremor affects both hands. And until now, we know that there's a very high incidence of side effects if we were to treat tremor bilaterally, if you do bilateral thalamotomy or even bilateral DBS. The adverse effects can be quite high in the order of 30, 40, or 50% when it comes to speech disturbances, gait disturbances, paresthesias, weakness, et cetera.

And so until recently, people have been extremely reluctant to do bilateral lesion surgery. And our paper really challenges that dogma, that bilateral surgery is not safe. And in this paper, we show that indeed it is possible to do bilateral surgery in a staged manner using focus ultrasound, and that the results are clinically very significant benefit and that the adverse effects are relatively minor and well-tolerated.
 

[00:04:07] Dr. Michele Matarazzo:
Well, thank you very much for this overview of the past and current clinical options for treating essential tremor. Actually in the paper, I really enjoyed also the discussion on the history of neuro functional interventions for tremor.

Now, let me ask you something: knowing the relevant side effects that there used to be with surgical, but other thalamotomies, what made you think that with focused ultrasound, things would be different — better?
 

[00:04:34] Professor Andres M. Lozano:
Well, I think it's always important to challenge dogma in neuroscience and neurology, neurosurgery, and in particular, the dogma was that it was unsafe to do bilateral lesions. But then we dove into this and why is it unsafe? And it's because of the side effects. So then the question is: why do you get side effects when you make bilateral lesions?

And what we did was we made an analysis about lesion location and size and map out the optimal site for tremor relief. And also importantly, what are the sites that lead to side effects? What are the sites that lead to gait disturbance, speech disturbance, et cetera. So we were able to map this out volumetrically in three dimensions, and we were able to map out the sweet spots where we can get and dissociate the benefits from the side effects.

So with this in mind, we discovered for example, that the lesions that are below the thalamus into the dentatorubrothalamic tract, below the thalamus cause gait disturbances. So as a consequence of this, when we did a unilateral surgery and we discovered this, we said, aha. When we're going to do bilateral surgery, we're going to avoid lesioning these fibers at all costs.

And because of that, when we do bilateral surgery, we do two things differently. On the second side, I should emphasize that we stage them. So the first side is a routine focused ultrasound thalamotomy, but for the second side, we make two changes. Number one, we make the lesions smaller, so as to avoid the possibility of a side effect, because we know that the bigger the lesion, the more side effects, there is. And number two, we adjust the position of the lesion so that it is higher up in the nucleus. And we avoid the axons as they enter the base of the thalamus, the cerebellar axon. So with these strategy in mind, we were able to show that it is safe and reasonable to do a bilateral surgery in this staged manner in these patients.
 

[00:06:23] Dr. Michele Matarazzo:
Perfect. Now let's focus on the methodology of the study. How many patients did you include and what were the main outcomes?
 

[00:06:31] Professor Andres M. Lozano:
So this particular trial is an interim analysis after the first 10 patients. So these were patients who had unilateral focused ultrasound thalamotomy on one side, and who continued to have disabling tremor on the second side.

And so these are patients who wanted the second side treated. So that was an inclusion criteria. They continue to take their anti tremor medications as before, because we had only treated one side and they still needed their medicines. And so that was the inclusion criteria. And the point of the surgery was whether this would be safe and whether it would be effective.

So the main outcome measures were issues related to the tremor scores: can we improve the tremor scores on the unoperated hand. And number two, is it safe? What is the profile of side effects and what's the impact on quality of life?

And one of the interesting questions that we answer, we asked the patients is: given what you know now, after the second side, would you have done again? And, and all 10 out of 10 of them said that they would have it done again because they felt that they received sufficient benefit from having the second side done and that the side effects were minor or tolerable.
 

[00:07:43] Dr. Michele Matarazzo:
Good. And do you want to comment on the side effects that you had in the trial? Anything that you did not expect or anything that you did expect and didn't find in the patients?
 

[00:07:53] Professor Andres M. Lozano:
As expected, we found some transient disturbances in gait. And these disturbances are often mostly subjective. So when we measure gait it's actually, we actually don't see any, any deficits, but the patients feel sometimes unsure of themselves or less common in their gait, and these are usually transient in nature. And by one year, it goes away in all the patients. So this usually last for several weeks. And then it usually goes way. So overall there are transient, adverse effects. Mostly the gait is the most common adverse effect, but other issues, for example, paresthesias, loss of sensation, can also be a transient side effect. And also hemiparesis if the lesion encroaches or has edema on the internal capsule.

So these are the known side effects, but in all cases at one year, these side effects resolved.
 

[00:08:40] Dr. Michele Matarazzo:
Now we are approaching the end of the interview, so let me ask about the future. What do you plan to do in the next years? Are you happy with the results as they are, or do you think there is any room for improvement of the, maybe the target location, or even changing the target?
 

[00:08:54] Professor Andres M. Lozano:
Well, I think, I think that the number of patients that have had bilateral that are published in the world is still a very small, less, less than 20. And so I think that it's important to accumulate more experience and to refinethe target. But in the future, I think that we will have to decide whether it's indeed safe to do these procedures, whether it is possible to do them not staged, but in one session — that is another interesting thing. And whether the BIM target is the only target that could be treated. Could we also expand focus ultrasound to treat Parkinsonism by choosing other targets, whether it be the Sophonic nucleus, the Globus pallidus, et cetera. So I think we're going to see an expansion of the possible targets or ultrasound in treating not only essential tremor, but indeed other forms of tremor.

But also to treat Parkinsonism. To treat akynesia, rigidity and bradykinesia, et cetera. So I think, I think that in the future we will see more bilateral surgery BIM. We will see an expansion to novel targets within the basal ganglia, and we will see an expansion to novel indications within movement disorders and indeed beyond movement disorders.
 

[00:10:06] Dr. Michele Matarazzo:
Is there anything else that you want to share with our listeners?
 

[00:10:10] Professor Andres M. Lozano:
No, I think, I think that we now have another tool in our armamentarium. And I think that it is very important to discuss with patients the pros and cons of all four of these surgical options. Radio-frequency thelamotomy, gamma knife, DBS, and focus ultrasound, and to give the patients a say, give them awareness that these procedures are available, and to get them involved in the decision process.

I have equipoise in that I feel that all of these procedures can produce significant benefit. They each have their pros and cons, but I think that we now have more choices, more options for the patients. And I think this is a good thing. For the field and for the patients.
 

[00:10:47] Dr. Michele Matarazzo:
Well, thank you very much for your time. It has been a pleasure to have you on the MDS podcast.
 

[00:10:52] Professor Andres M. Lozano:
Thank you so much. It's wonderful to be here.
 

[00:10:54] Dr. Michele Matarazzo:
We have had professor Andres Lozano and we have discussed the article "Bilateral Focused Ultrasound Thalamotomy for Essential Tremor Phase Two Trial," from the Movement Disorders journal. Don't forget to download and read the article from the website of the journal, and thank you all for listening.
 

MDS disclaimer:
The views and opinions expressed by the participants in this podcast do not necessarily reflect those of the International Parkinson and Movement Disorder Society or their affiliated journals, Movement Disorders, and Movement Disorders Clinical Practice. Any disclosures of the participants can be found within the episode description located on the MDs website.