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Today, I have the pleasure of interviewing Professor Elena Moro, who is Professor of Neurology at the Grenoble Alpes University and the University Hospital in Grenoble, France. She will be discussing management of chorea, with a special focus upon Huntington's disease, and the role of deep brain stimulation and other surgical interventions.
So, hello. Elena, thank you again for taking the time to discuss this topic. So my first question, so many patients with choriac disorders, especially those of a [00:01:00] neurodegenerative etiology, present with a spectrum of neuropsychiatric symptoms. How do you approach them from a management point of view and how and when do you decide to treat the chorea specifically?
[00:01:12] Prof. Elena Moro: So first of all, thank you very much Ruth for inviting me to this nice beautiful series of podcasts. So to go directly to your question, indeed you are right, right? So patients with hereditary neurodegenerative disorder, like Huntington disease, as you mentioned, the Huntington like SCA17. C9orf72 neuroacanthocytosis, but also patient with autoimmune chorea like lupus induced, or the pseudonym chorea.
They present with several neuropsychiatric symptoms, especially anxiety, depression, OCD. Apathy, suicide attempts, unfortunately, frontal [00:02:00] behavior, agitation, irritability, aggression, hallucination, psychosis, cognitive decline, and dementia. We have this really broad spectrum of, as you said, the neuropsychiatric symptoms, which sometimes, and I will say, often in Huntington disease are a big issue, much more than chorea, as as we know, right? We can manage, as a neurology, chorea much better than all the other neuropsychiatric symptoms. So what I, and especially Huntington disease in the young people, the, the neuropsychiatry part is, is really very strong.
And so in the ideal world where we can have a very nice colleagues And the very nice team. The idea is to have a psychiatrist first who is involved in the team, and then a psychologist, a neuropsychologist, [00:03:00] people who can really help in a multidisciplinary management of the patients.
This is in the idea world. Very often we know we lack of psychiatrists everywhere, so it is very difficult to have them. helping us also because they don't think that Huntington's disease belongs to them. So what I do, I try to manage by myself mild or relatively simple symptoms. For example, depression, if it's not not reach the severity of a suicide attempts, of course, very severe one with usually a SSRI.
In Huntington, especially venlafaxine because of the interaction with the other drugs, I can use mirtazapine, especially if we have a sleep issues. Some tricyclic antidepressant with the caution and also benzodiazepine and neuroleptic, we will go through. [00:04:00] This mood stabilizer agents, but again, often in some patient, really, we need to get them hospitalized in some psychiatry ward, right?
Especially if the depression is severe as I said, the suicide attempts, we can't do this in neurological wards because we are not equipped for the safety of these patients. So what you said really stresses the need of having a multidisciplinary team in treating especially Huntington's disease.
[00:04:36] Dr. Ruth Walker: Absolutely. These you know, obviously critical points. And yes, definitely. I'm often more, much more often called because my patients with Huntington's have been admitted to psychiatry with some issue. And yes, we often end up managing the psychiatric aspects. So let's focus a little bit more on the, the movement disorder, the chorea specifically.
And so how do you decide when the [00:05:00] chorea needs to be treated and what do you use? How do you approach that patient?
[00:05:05] Prof. Elena Moro: So because what we said before, often it depends also on the age, this neuropsychiatry issue can be the most relevant for the patient, the family chorea becomes relevant when really affects. The quality of life of the patients, the activity of daily living. So when really there is a disability induced by chorea, , we can say when the severity of the movements, they interfere real, the abnormal movements in the management of the ordinary quality of life.
So that. I think also for dystonia is not for chorea is the trigger, right? Which tells a neurologist, maybe we need to start the treatment for chorea. And we have to balance also all the side effects of the treatment, right? Because we, we know that when we started any kind of treatment, we [00:06:00] have to be sure that we don't make the the patient more miserable of what he is or she is already.
So this is just when I start and then the classical management for Huntington's disease, you know, there are some guidelines that in some in Europe are available in Germany. We know that the movement society has just an evidence based recommendation. It was in 2021. And then if we use this recommendation, what we see right away, that actually a specific treatment i s, is rare.
We have just tetrabenazine, this presynaptic The vesicular monamine transporter too, which are well recognized by, this paper has the most effective treatment for Huntington's disease for the motor point of view. I think you know, Ruth, [00:07:00] that in Europe. We only have tetrabenazine. In the, the FDA has approved in the United States, deutetrabenazine Tetrabenazine. You have also valbenazine, so we don't have, unfortunately, these drugs and as far as they know these are as as good as tetrabenazine. And also you have a less. Severe side effect profiles, especially depression, right? So you have a little less depression as a side effects compared to tetrabenazine.
So my experience then is most focused in tetrabenazine. But it's interesting also to know that the German recommendation, they also value tiapride has, which is a post synaptic inhibitors of D2 and D3. receptors. For the profile of the side effects. Compared to tetrabenazine, there are [00:08:00] less depression, akaitesia, and parkinsonism.
So some countries, they really prefer also to use tiapride. Or to use both the combination of tetrabenazine and tiapride but a lower doses to minimize the side effects of tetrabenazine. I, I have to say that I personally like
Aripiprazole. Because also has this mood stabilizer effect. So patients are a bit more relaxed and less anxious.
They can function a little better. And I'm also a fan of Haloperidol because we know this drug very well. And I think the side effects are acceptable. Maybe doesn't have all the depression of Olanzapine of tetrabenazine, but also can use olanzapine, risperidone benzodiazepine if.
You have all the side effects of tetrabenazine. [00:09:00] The other thing that I would say tetrabenazine usually is three times a day, right? So not all the patient they like, or they don't have an environment supporting, three times a day, a regular prescription of this drug. This is for Huntington.
Then of course, it depends on the etiology of chorea. Then if you have autoimmune, of course, you do more the anti immune treatment. Or also in Sydenham chorea you can use risperidone, tetrabenazine, valporate besides the prophylaxis. So these drugs are quite well known and used in the majority of the world now.
[00:09:43] Dr. Ruth Walker: Thank you. That's really interesting. Yeah. We don't have tiapride in the US as you probably know. And I mean obviously we're very nervous about people, worsening the movement disorder, making people Parkinsonian with the dopamine D2 blocking agents.
And I'm kind of a fan of [00:10:00] clotiapine, I have to say, even though it shouldn't have D2 blocking. Features especially when people have like a lot of agitation at night. I find that quite useful. we have several options and it really is a matter of weighing the comorbidities, how much mood, agitation, psychosis, there is, and depression. And it certainly would be great to have more psychiatrists on board to help us fine tune these. But yeah, the choice of whatever we use for the chorea is balanced with the risk of side effects and the other, the other symptoms. So obviously you are an expert on deep brain stimulation.
And so I would love to hear like what your experience is. for deep brain stimulation in the hyperkinetics, the choreic disorders in Huntington's disease in other entities.
[00:10:49] Prof. Elena Moro: Thank you Ruth. If I can tell you a story do you remember SARS, the first SARS, SARS 1 in Toronto and not only in Toronto, but I was [00:11:00] just arriving in Toronto, it was in 2003 when we started, I had a patient with Huntington Disease, very severe chorea and an dystonia gait impairment. But cognitively, and from the psychiatry point of view, he was relatively preserved.
And the Toronto group at that time was the first one. In the world who had already operated another woman with Huntington disease and bilateral pallid GPI, the pallidum internum stimulation with some mixed results. And so I, I ask Andres Rosano, why we don't operate this person because it doesn't have a major contraindication from the neuropsychiatric point of view.
His major problem is chorea. Why we don't do it. And during that period, he got stuck in the hospital. So I had all because of [00:12:00] the SARS and so I had all the time to try different parameter stimulation and which was a paper that we published after one year of follow up in 2004. And we discover a few things because you have to know that in the literature.
Before DBS, they did some palidotomy in, in Huntington, but the results were a disaster because the patients worsened. They became more Parkinsonian. And I always thought, what was the reason why they became more Parkinsonian? And indeed, When we started the stimulation, it was super interesting because the Chorea, swoop, disappeared completely.
Dystonia also improved, but if I use high frequency, the 130 which we use for Parkinson's disease and [00:13:00] dystonia, I made the poor patient parkinsonian, more parkinsonian it was under Haloperidol also, but it was very mobile. If I use the frequency of 40 hertz the chorea was still very well improved and it was much less Parkinsonian and also gait improved. So I think that lesion, this is the reason why stimulation is not the same as making a lesion, was probably alterating much more all this oscillatory activity of the basal ganglia. And reducing the frequency, probably the networking was much less affected. The networking for bradykinesia and, and the rigidity was much less involved.
So that opened the eyes also for doing other patient with Huntington disease. And that's also, if you read the [00:14:00] literature. After there were several cases published with different results in the STN also, in the external part of the pallidus, there's been also some clinical trials in Germany with the pilot study with the mixed results and a clinical trial just finished, but in almost 50 patients.
We don't have the result published yet. But I think as, as much as I know that they found an improvement in chorea
[00:14:32] Dr. Ruth Walker: So
Dual electrodes, so both.
[00:14:35] Prof. Elena Moro: Yeah, but
I think probably in one electrode, it should, if it's in the right place which is always the posterior ventral lateral part of the pallidum internal, it should work because it works for dystonia.
It worked for chorea in the first case that I was talking to you. But the pallidum is not. The best target for, [00:15:00] for many surgeon because they're used to the STN, the pallidum is very big. So you need a good micro recording. So it's not actually an easy target. So there is still currently patients.
We had one done here who can benefit. But as I said, you have to operate people who are not so cognitively impaired. And stable from the psychiatry point of view. If they have a suicide attempts, you know one month before the surgery doesn't work very well, right? They are at risk of having not for the surgery, but or keeping this behavior.
So this is the caveat. You have to select. patients who are not so cognitive and psychiatry impaired, but otherwise this GPI DBS has been used also in chorea, acanthocytosis in ADCY5, GNO1 for chorea and [00:16:00] in most of the cases a good benefit in chorea has been reported.
[00:16:06] Dr. Ruth Walker: And you would say this is with, so GPI, the posterolateral ventral part and low frequency stimulation, you would say would be the choice.
[00:16:15] GMT20240328-151339_Recording_separate2: Yes. Then I think probably depends on the severity of the disease. So how much is the, basal ganglia damaged probably right all the Huntington stuff, how many triplets, all these thing. But we don't have studies on that. Right. We don't say study which can predict which patients can improve more.
But probably there are some other characteristics besides this neuropsychiatry profile, which might also not have an impact on the benefit you have in this patient.
[00:16:51] Dr. Ruth Walker: Yeah. Yeah. I mean, and there also can be some other factors, in the, chorea acanthocytosis, GPS13A disease, people can [00:17:00] have like, have lots of obsessive compulsive behaviors. And so it'd be really interesting to, I mean,
[00:17:06] Prof. Elena Moro: They improve.
[00:17:07] Dr. Ruth Walker: talk about two, two targets
[00:17:09] GMT20240328-151339_Recording_separate3: Yeah.
[00:17:10] Prof. Elena Moro: You know, the, in the patient that we did with the GPI, they improved also this obsessive behavior and tics and also this classical posture and the rubber gait. So the problem that is a neurodegenerative disease, right? So they might lose some benefit and other problem they arrive, but I think if we can, is like the new treatment for Alzheimer's, right?
So if we can give this patient one, two, three years of good quality of life, I would go through because the serious side effects, they are relatively rare. Right? So I think it's the same concept we should give these people the possibility to have an improving quality of life, even if it's two, three, four [00:18:00] years.
[00:18:00] GMT20240328-151339_Recording_separate3: You mentioned briefly the issue, people are losing neurons in the basal ganglia throughout the disease course. Now, what about the issue of, the electrode is obviously staying, staying in place and the brain is kind of shrinking around it. What are your concerns in that area?
[00:18:20] Prof. Elena Moro: Well, as I said, we don't have a lot of data. The patient who I told you before, we had the follow up after five years. And in five years, you know, this disease is running fast, he was still having the same benefit. In chorea, not in, in gait. The gait disorders, the balance, they progressed so , the GPI was not effective anymore.
but there was still some reduction because the pallidum is big. So I think even if there is some shrinking is not as big as you know, if you lose the benefit. [00:19:00] So I think this can explain why in that particular patients there was still a benefit, but as I said, we don't have a lot of data about a long term very long term so which can eventually support what you say
[00:19:16] Dr. Ruth Walker: I remember seeing some case reports with lead migration. I think,
[00:19:21] Prof. Elena Moro: but a lead migration can be a link, can be related to other because you have to fix very nicely the electrode to the skull. You know, it might be also a problem and related to the technique that the neurosurgeon used, right? So because we, I, I really see this problem very rarely also in children with dystonia, which, you know, they, they move a lot.
So the electrode misplace, misplacement usually is a problem that they didn't fix. It's it very well.
[00:19:54] Dr. Ruth Walker: Mm. Okay. And then I know there was some successes reported in people [00:20:00] with ADCY5 mutations. This is not as far as I know, a neurodegenerative disease. So certainly, people who are, in that situation, you would expect more sustained benefits. But as you say, we really need more long term follow up, in these people.
it's definitely something which you would consider in somebody with Huntington's disease, with the neuroacanthocytosis syndrome, where the chorea is very, prominent. Now,
[00:20:30] Prof. Elena Moro: Post stroke, right? Usually, they go away, you know, there is an improvement, spontaneous improvement, or with the medication that you use. But often, you know, in some patients in whom Chorea can persist in being disabling GPI stimulation has been used also thalamic, but especially GPI-DBS has been used in some cases you know, like induced by maybe bleeding, oma, [00:21:00] all this kind of much rare issues has been reported in one side of course, but been reported.
[00:21:10] Dr. Ruth Walker: Right. As you mentioned, chorea following a structural lesion tends to get better with time. Unlike with dystonia. But actually one thing I, didn't think of previously, it was like the Tardive syndromes, Tardive dyskinesia, which is often technically choriac.
Is this something where you've done a lot of DBS?
[00:21:27] Prof. Elena Moro: We are lucky that we have a tetrabenazine which works and all your drugs and also botulinum toxin, right? Sometimes it works especially in the cervical part. But yes the beauty of Having a patient with tardive chorea or dystonia, who does not improve with the medication botulinum toxin, is that they respond really very nicely to bilateral GPI DBS.
Like a [00:22:00] DYT1 population, they have a brilliant and longstanding response to bilateral GPI DBS. We don't see them very often now because, you know, psychiatry, they change their way to treat patients, but they respond very well. Yeah. This patient responds very well.
[00:22:17] Dr. Ruth Walker: Yeah, that's nice. Now, what about other surgical interventions? I know there's been some work on, stem cell transplantation in Huntington's disease. I haven't heard anything on that in a while. What's your experience?
[00:22:30] Prof. Elena Moro: But you, you remember very well this 20, more than 20 years old paper from France actually, with the transplantations, it's a neural stem cell transplantation, which failed. Right. So it was a big hope and unfortunately there was no major improvement in this patient. So as you said, there's been a bit abandoned, right?
But there is an ongoing clinical trial using bone marrow stem cells [00:23:00] and another one using autologous stem cell from adipose tissue. So we don't know the results yet. We hope and we wish to see a benefit, maybe in the progression of the disease, right? Because there's some studies that they show, you know, there is less atrophy, less progression of the disease with the MRI.
We don't know if clinically we have a big advantage. But personally, I don't know, this is a genetic disease, right? So we know that the protein is the dysfunction is accumulating and the toxic, the mutated protein. So should just insist on gene therapy and you know, found a better way to not to cut all the, the wild protein, but just to target the toxic one.
So I, I don't believe that this [00:24:00] is a major area where to go because as we have been failing for 20 years in this area. So probably with the new technique, gene therapy, it might have more hope or success in the next future.
[00:24:15] Dr. Ruth Walker: Yeah, but I imagine one would translate striatal fetal tracts, you know, convert the neurons to striatal cells. But then again, that wouldn't be ideal because you said that, the Mutant protein is everywhere.
It's in the cortex and so that's probably accounting for a lot of the symptomatology. So,
[00:24:35] Prof. Elena Moro: And probably Ruth, we have to target these patients much earlier. As we know, since when they are in the womb of the mother, they have already , red acted cortical, you know thickness. We know this study actually was done here in Grenoble right by the first author. So I think that we should intervene [00:25:00] much earlier with this kind of treatment.
So we don't know. Maybe it's too late, right? It's too late when we do this kind of treatment.
[00:25:10] Dr. Ruth Walker: So, very interesting. So you're actually a lot more positive about the role of DBS for GPI in diseases like Huntington's. I'm actually a little surprised by that because, it seems obviously you need to select the correct patients very carefully. Those who are going to be able to tolerate it, without significant cognitive or psychiatric issues.
And obviously the, the appropriate situation where the family is going to be able to manage it. And then GPI and low frequency stimulation is the way to go. So it certainly sounds like a good option for the right people buying them a few years of benefit when optimal medical management doesn't work so well.
[00:25:51] Prof. Elena Moro: Yeah, this is my impression. This
[00:25:53] Dr. Ruth Walker: No, no, you're, you're the expert in this area. It's actually something I, I've not done, not so, so much [00:26:00] myself for whatever reason, but yeah, my experience has mainly been somebody with chorea acanthocytosis who had like a benefit for a couple of years and then it wore off.
And that seems, that seems to be the way. So
thank you so much. It's a really interesting discussion and we look forward to learning more about the role of DBS and other therapies in these disorders. So thank you.
[00:26:24] Prof. Elena Moro: Thank you. And bye. Goodbye. Goodbye.