View complete transcript
[00:00:54] Dr. Giovanna Zorzi: Hello, and thank you very much for this invitation. It's really a [00:01:00] pleasure.
[00:01:00] Dr. Sarah Camargos: Thank you. Could you please tell us the objectives of your study and the gaps it intends to cover?
[00:01:08] Dr. Giovanna Zorzi: So the aim of this study was to evaluate the efficacy of pallidal DBS in a cohort of pediatric patients affected by idiopathic genetic non degenerative dystonia. We know that these diseases are usually severely disabled condition and DBS has been used to treat these patients since late 90s. But analyzing the literature, in my opinion, there are this critical issue.
First, we know that primary genetic dystonia responds better than acquired dystonia, but in this group of patients with genetic dystonia, the degree of the response is highly variable. Attempts have been made to correlate certain factors such as age of onset, [00:02:00] disease duration, type of dystonia, but without ethnic reconclusions.
And more recently, Some authors suggested that maybe the specific genetic causes may be important factor for the prognosis. The second important consideration is that from the analysis of the literature, the results of the efficacy of DBSs are mainly reported in very short and medium term. But what happens in long term?
So with this study, we intend to answer these main questions. So, Evaluate the outcome in specific type of dystonia and report the long-term results.
[00:02:41] Dr. Sarah Camargos: Yes, it is really important. And tell us how did you select your patients and how was the study design?
[00:02:50] Dr. Giovanna Zorzi: So we include, this is a retrospective study, so we include all the consecutive patients affected by [00:03:00] genetic, idiopathic, so we exclude the generative and acquired dystonia. The second criteria was they underwent bilateral different stimulation at our institute. So we exclude in those cases with unilateral or that underwent DBS post status ..
But to increase the numerosity of the population, we also apply the same criteria with all reported patients. So we were able to select from the literature with individual patient data a cohort of 224 patients. So our study is made by our cohort that include 25 cases. And a group of patients from the literature of, as I said, 224.
And we reported the outcome as the primary outcome, the change from baseline using the [00:04:00] Burke-Fahn-Marsden Dystonia rating scale.
[00:04:02] Dr. Sarah Camargos: And how long was the follow up from your patients?
[00:04:05] Dr. Giovanna Zorzi: So from our patients, the mean post surgery follow up was 11.4 years, and this was a big difference compared to the meta analysis cohort in that the mean follow up was only three years.
[00:04:20] Dr. Sarah Camargos: Yes. So I think you covered a very interesting gap on the field. And what were the outcomes of your study?
[00:04:31] Dr. Giovanna Zorzi: So overall, we can say that we show that both in our cohort at one year, we had a mean improvement of around 40 percent of the scale. And the last follow up, the main improve was 33%. We observe improvement at each time point of the follow up, but there was a tendency to decrease over time. But also we [00:05:00] show a great variability among patients with different phenotypes.
Patient with the DYT1 dystonia showed the best and most stable improvement, both as short and long term follow up. Also, patient with DYT6 dystonia in our cohort showed a very nice improvement at one year, but there was a tendency to decrease over time. Let's say that at the last follow up, the improvement was around 30%.
KMT2B dystonia showed a less spectacular improvement at one year, but a little more improvement at the last follow up. If we consider the patient with idiopathic dystonia, so the improvement was at one year about 33 percent, with a little decrease at last follow up. There was a proportion of side effects that was comparable in the literature compare the rate, of infection. It was around [00:06:00] 80%. But we had unexpectedly two patients with the serious side effect of lesioning during surgery. But we have to consider that those two patients had the lesion because they had to be re operated for the rupture of one electrode in a situation of emergency. So we consider that this relatively high rate of infrasurgical effect was due to this particular situation. So overall, in our cohort, we demonstrate that DBS was effectiveness at short and long term follow up with relatively safe procedures.
[00:06:43] Dr. Sarah Camargos: Yes. And when. You compared the second part of your study, you performed a very interesting meta analysis. So when you compare your cohort with your literature meta-analysis, and [00:07:00] what were the main differences or similarities?
[00:07:04] Dr. Giovanna Zorzi: So the two cohorts were comparable in terms of age of onset, age of surgery, and baseline dystonia severity, but the two main difference was first, the relative frequency of the single genetic phenotype. That means that in the cohort, there was the major of patients had DYT1 dystonia, followed by DYT11 dystonia.
YKMT2B and DYT6, they were relative frequency in our cohort, were very low. In the meta-analysis cohort, and I think this was due because the genetic screening protocol in our study compared to the literature was very different. Many patients in the literature were only screening for DYT1, and that means also that the idiopathic group of of dystonia are not really comparable.[00:08:00]
Because while we know that in our study, our idiopathic, a really true idiopathic, we cannot say the same for the literature because the genetic screening was not complete. The second difference was that the outcome in the meta-analysis at short follow up was better than our. But this, again, is probably due to the fact that it's a higher proportion of the DYT1 that we know have a pretty spectacular response to DBS.
And also, the outcome at the last follow up was of course better in the meta-analysis, but as we said before, the length of the follow up is completely different, so they are not comparable. But if you consider the single response in the genetic group, I think the results are comparable. Overall the rate of improvement is comparable in our cohort and in the meta-analysis.
[00:08:56] Dr. Sarah Camargos: I understand it is comparable in [00:09:00] one year follow up because yours is longer than the literature, right?
[00:09:05] Dr. Giovanna Zorzi: Exactly, yes.
[00:09:07] Dr. Sarah Camargos: So if I understood correctly, your follow up is one of the most larger follow ups that we have regarding non degenerative genetic dystonias, actually.
[00:09:19] Dr. Giovanna Zorzi: Yes, say that in the meta-analysis there are only 20 patients reported with the follow up longer than five years. We have a mean follow up of 11.4.
[00:09:32] Dr. Sarah Camargos: It's really different, of course. And is the long term outcome in your cohort associated with phenotype or genotype?
[00:09:44] Dr. Giovanna Zorzi: I think this is a very crucial question, and I think the answer is not really clarified. So I believe that our results demonstrate that etiology is probably one of the most important [00:10:00] factors for predicting outcome of DBS, not only a long term, but also a short and medium follow up. But also we see that there was a tendency in all category of decrease of the beneficial effect of DBS.
And the reason of this is not really known. One reason could be that there is a progression of dystonia in all cases with the appearance of the worsening dystonia that we know is less responsive to DBS and one could be the reason. But the second reason could be also due to local effect where the electrode of gliosis or are due to the long electric stimulation of the globus pallidus.
And it can be that there is a loss of efficacy due to the surgical aspects. So I think that we need to have more long [00:11:00] term study to assess the efficacy in a larger group of patients to address these questions.
[00:11:06] Dr. Sarah Camargos: Yes, thank you. I was especially interested in the idiopathic dystonia cases. How this cases, your case is different in the phenotypes from DYT1 or actually DYT TOR1A or DYT TAP previously DYT6 patients.
[00:11:29] Dr. Giovanna Zorzi: So I can say that overall the phenotype was not different. So according to the inclusion criteria, all these cases have dystonia as the only feature. There is no myotonicity, but there is no other neurological symptoms. We had some patients who had a phenotype similar to DYT1 and others similar to DYT6, which means with a more cranial and axial involvement.
We also try to identify in the part [00:12:00] of the dystonia population, some clinical factors predicting of the response to DBS, but we were unable to. So, unless we don't know the genetic status, I think that the idiopathic cases remains a population where response to DBS is really unpredictable.
[00:12:17] Dr. Sarah Camargos: And what about the non motor symptoms such as pain or quality of life? Did you notice some change on those patients? I understood also that some of them had less need for anticholinergic or other drugs. Do they have less need for botox?
[00:12:40] Dr. Giovanna Zorzi: So I have to say that our study, since it was a retrospective study, was focused on the motor outcome aspects, so we did not specifically address quality of life or pain. Okay. Thank you. But I can say that normally pain is not a big issue in neurodegenerative [00:13:00] dystonia. So I would say that there was not such a big change because pain is usually much more important in other type of dystonia.
Quality of life. I would say that overall clinical, there was a great improvement. The quality of life that reflects the motor improvement, that children that were able to gain some function that was not there before surgery, like walking. Feeding, writing. So it was a very strong improvement, but I have to admit this great limitation of our paper.
I think that assessed quality of life may add important aspects in considering the effectiveness of DBS in children and also in parents. So I think for the future and I see that recent work are always addressing the aspects that I think is [00:14:00] very important.
[00:14:01] Dr. Sarah Camargos: And let's talk a little bit about the future. You have mentioned, and please tell us what are your next steps in this field.
[00:14:13] Dr. Giovanna Zorzi: I think that pediatric DBS is really evolving and fascinating field. First, there are new technology on the field, so we know that there are new technology that allow us to be much more precise in targeting the brain. There are new devices that we allow us to record also from the brain for the Parkinson.
So we were able to record some electrical activity that hopefully will correlate with dystonia symptoms and, with the aim to have an adaptive stimulation. I think the other step is to not only continue to follow patients, but also to search for new targets. [00:15:00] Because it's my opinion that we see that some genetic dystonias are not really responding to palladal DBS, and in my opinion, this means that the pallidum may not be the right target.
For every type of dystonia most, probably the neuronal circuitry underlying the dystonia are different among different. So the future is, how can I target better this specific brain area to have the optimal response. So the, I think the field is to look for new target in genetic dystonia that are not responding to palladal DBS.
[00:15:42] Dr. Sarah Camargos: So, you think, maybe, you think of cerebral target, too.
[00:15:49] Dr. Giovanna Zorzi: Exactly Yes.
[00:15:51] Dr. Sarah Camargos: Yes.
[00:15:51] Dr. Giovanna Zorzi: Neuromodulation units like you do in epileptic surgery, when you look for the focus [00:16:00] with temporary recording from the brain, I think the future can be that.
[00:16:06] Dr. Sarah Camargos: And we're gonna see you again in these next steps, for sure.
[00:16:11] Dr. Giovanna Zorzi: I hope.
[00:16:12] Dr. Sarah Camargos: Professor, thank you so much. We appreciate all your collaboration in the field and with this podcast many thanks for your time and please stay with us and tell us a little bit more in the future about your next studies. Thank you so much.
[00:16:32] Dr. Giovanna Zorzi: Thank you. Thank you very much. Goodbye.
[00:16:36] Dr. Sarah Camargos: Goodbye. [00:17:00]