Thank you for joining us.
View complete transcript
[00:00:39] Dr. Roberto Erro: Thank you, Sara
[00:00:40] Dr. Sara Schaefer: I would like to start by going over the terminology. There are a lot of terms, they seem to be in flux. You hear all kinds of things, essential tremor or pure ET, ET with soft dystonic signs, tremor with dystonia, tremor associated with dystonia, dystonic [00:01:00] tremor, ET plus, et cetera.
I'm sure I'm missing some. Can you go over the terminology and let our audience know what is the most up to date in terms of how they should be describing and categorizing these patients?
[00:01:14] Dr. Roberto Erro: Yes, you're right. Terminology in this regard tends to get complicated. To make it simple, we can say we have ET, which is an isolated tremor syndrome, on the one side, and tremor combined with dystonia, where tremor is in fact associated with another motor sign, that is dystonia, on the other side. The latest tremor consensus published in 2018 further suggested to stratify patients with ET into what I call a pure form in which patients only have the core phenotype of upper limb action tremor and ET plus when patient further display either rest tremor or the so called soft signs.
These are subtle neurological findings with an uncertain relationship with the tremor syndrome. Such as subjective memory complaints, [00:02:00] tandem gate difficulties or indeed subtle dystonia. The reason behind this was to clean up, so to speak, the group of patients with pure ET in order to facilitate research on this group, given previous failure in the field.
When it comes to tremor combined with dystonia, a suggestion stemming from the old tremor classification, which was embraced by the dystonia classification too, was to stratify this group of patients in those with dystonic tremor, in whom tremor and dystonia co localize, and those with tremor associated with dystonia, in whom the two phenomena don't, for instance when we have patients with cervical dystonia and upper limb tremor.
The latter proposal came out when there was still an open debate about the nature of tremor in dystonia, but I think it's outdated now, and we don't have robust empirical evidence to tell dystonic tremor and tremor associated with dystonia apart. One issue here, I believe, is about the use of the term dystonic tremor based on tremor phenomenology, and in the [00:03:00] absence of clear dystonian examination.
This came about because of a misinterpretation of an old paper by Stan Fahn in which he described the phenomenology of tremor in the context of dystonia and reported on the dynamic variation of tremor in relation.
to volitional movements, that is, tremor gets worse if patients attempt to move opposite to the direction forced by the dystonia. Over time, some authors have started using this concept, as well as other phenomenology features being reminiscent of tremor combined with dystonia, to call a tremor dystonic, even in the absence of dystonia on examination.
Although I might agree with this approach, this is currently not formally accepted by either the consensus on tremor or on dystonia. And therefore should not be used in such sense to avoid confusion in the field.
[00:03:49] Dr. Sara Schaefer: All right. Well, that certainly clarifies things a bit. Though it seems like the terminology may continue to change over time as people argue about these various [00:04:00] subtleties.
[00:04:00] Dr. Roberto Erro: Yes, indeed are a lot of debate, especially about ET plus So it might change in the future again. But as for now, this is what we have in our hands.
[00:04:13] Dr. Sara Schaefer: Moving on to your specific study, can you tell us what TITAN is and what's involved in collecting data within the TITAN network? Specifically, how are patients within this network categorized as ET, pure ET, or ET with soft dystonic signs, et cetera? Is it by clinical documentation? Are they videotaped?
Are there multiple reviewers or just one expert reviewer? ET, you know, as a bit of an umbrella in clinical practice with different neurologists and even movement disorder specialists noting various degrees of dystonia or just lumping it all into ET. Personally, I've seen in video rounds, movement physicians argue over whether a little bit of thumb depression, for example, counts as dystonia or [00:05:00] not.
So how were these patients that you used for your study categorized?
[00:05:06] Dr. Roberto Erro: So the the Italian Tremor Network, is a multi centered data collection platform. The aim of which is to prospectively assess the phenomenology and natural history of different tremor syndromes, but Parkinson's disease related tremor, and to serve as a basis for future etiological, pathophysiological, and therapeutic research.
Patients are classified according to current diagnostic criteria, which might be seen as a bias is inherent to any tremor research in the absence of diagnostic biomarkers. The core protocol does not require multiple raters to confirm the diagnosis, but we are also collecting video documentation of these patients so that in the future we can test the reliability of the clinical diagnosis.
Disagreement between experts about clinical diagnosis in the field of tremor is a well known phenomenon, which partly depends on the expertise of the rater. The inclusion of multiple centers with different expertise, namely on [00:06:00] essential tremor or on dystonia, might in a sense mitigate the overall diagnosis of either tremor syndrome.
What has to be considered dystonia is indeed one of the issues in the field, and that's why I think we need longitudinal evaluations of these patients to see whether they go on to develop overt dystonia or not, and this is one of the aims of the title.
[00:06:21] Dr. Sara Schaefer: And what did your group do with the TITAN data?
[00:06:27] Dr. Roberto Erro: As I mentioned, the new tremor classification introduced the stratification in the group of ET into pure and plus forms taken as a whole. The ET plus category might be a gray boxing, which will lump different subsets of patients.
Conversely, there is preliminary evidence that ET plus of dystonic signs might be more similar on imaging to tremor combined with dystonia rather than with ET. The aim of this study was therefore to seek for similarities and differences between ET plus of dystonic signs, thus excluding ET plus with others [00:07:00] signs and both pure ET and tremor combined with dystonia.
[00:07:04] Dr. Sara Schaefer: And what did you find?
[00:07:06] Dr. Roberto Erro: I think the main findings located at the group of ET plus soft dystonic signs were a number of commonalities with group of tremor combined with dystonia, including the tendency for tremor in the soft dystonic signs to co localize, which might support their dystonic nature. However, we also found some similarities with group of pure ET, indicating that in number of cases, what we deem to be soft dystonic signs might be physiological deviations from normality.
This suggests that there is heterogeneity even within this group, and therefore we have to delve into this variability with the use of non clinical markers.
[00:07:46] Dr. Sara Schaefer: A lot of the findings in the paper I found to be not very surprising including that upper extremity predominant onset was found more in essential tremor versus midline symptoms in [00:08:00] tremor combined with dystonia. And that task specificity and presence of sensory tricks was higher. In the tremor combined with dystonia group, as one might expect, were there surprises for you?
[00:08:14] Dr. Roberto Erro: Well, when I first started looking at the data, I tried hard not to have any prejudice, and I remember vividly a strong debate between experts at one conference about the value of research performed before the new classification on tremor was released. What I mean is that the new tremor classification has revised the nosology of tremor syndromes, particularly of ET, so that previously collected information had to be tested again on the new tremor categories.
As such, to me it was not really a surprise that ET, as currently defined, had the lowest response to alcohol. This concept of alcohol responsiveness in ET came from old research comparing ET with PD related tremor, and we know that in PD tremor is not responsive to alcohol, so the implication was made that ET [00:09:00] is alcohol responsive as opposed to PD.
However, in those days, there wasn't much awareness about tremor combined with dystonia, And this feature of alcohol responsiveness has been demonstrated to be inconsistent, and in fact is not anymore considered a supportive criterion for the diagnosis of ET. I think the teaching point here is that within each tremor syndrome there might be variability, and if we take alcohol responsiveness as a clue to the pathophysiological mechanism, And regardless of the phenotypic level, we might exploit it for testing some drugs, like long chain alcohol molecules, or sodium oxipate, in an umbrella type of clinical trial, where you include tremor patients not based on their diagnosis, but on this feature of alcohol responsiveness.
Regarding the midline tremor at onset, you might remember that these patients were often deemed to have essential head or voice tremor, a definition which is not allowed anymore by the consensus . And here are the layer of evidence that they are more [00:10:00] likely to go on to develop a tremor combined with dystonia.
Regarding task specificity at onset, or in other words, task specific tremors, the debate is still open. And they are in fact categorized apart from both ET and dystonic type of tremor in the new classification. We have shown here that these patients may lose their task specificity over time, but do not necessarily progress to develop overt dystonia.
This further emphasizes one of the new aspects of the tremor classification, that is the possibility of patients to change phenotype over time, and therefore diagnostic label. We should be clear, however, that these are all axis one diagnosis based on the clinical phenotype only, with no a priori assumptions on the underlying etiology, which is dealt with according to the second axis of the tremor classification.
[00:10:48] Dr. Sara Schaefer: You touched on a couple of the things that did surprise me as well about the alcohol responsiveness being actually lower in purity versus The patients with more [00:11:00] dystonic features, I didn't know the historical context. So that's very interesting. Thank you for sharing that. And I was also surprised that there was task specificity in some pure ET patients.
And it's interesting to know that they don't necessarily go on to develop dystonic features. So certainly a lot of question marks still. You know, you've talked a little bit about this and, and it's clear in your paper that these seem to be on at least a phenotypic continuum, right? There's pure ET, there's ET with soft dystonic features, and then there's tremor combined with dystonia.
And You know, given that families, even within families, there can be family members that fall into any of these categories with some family members with pure ET, others with, cervical dystonia and dystonic head tremor and even within individuals over time, dystonic features can become more prominent with passing years and [00:12:00] decades. And in your results you found that ET with uh, and tremor with dystonia are more disparate with tremor with soft dystonic features in between in a lot of ways. So you call for the need for biomarkers to help distinguish between these entities. Why do you think it's important to make this distinction given how much overlap there is in, in individuals and in families?
[00:12:26] Dr. Roberto Erro: You are right. But from the phenomenology point of view, there is indeed a continuum. If you think of Parkinson's disease as a reference, you have patients with prominent tremor which overshadows other motor features on the one side, and patients with no tremor whatsoever on the other end of the spectrum.
If you wear the dystonia speculum, the same is found, with patients having prominent tremor, rarely you might even have a patient having a body antenate dystonia gene with an isolated tremor syndrome, and patients with overt dystonia but no tremor. However, we also have evidence that [00:13:00] patients within the same tremor category might be different.
For instance, there are a couple of studies about non invasive cerebellar stimulation, which have been performed in ET and in tremor combined with dystonia, and what was shown is that in both groups, there were both responders and non responders, hinting a different pathophysiological mechanism. I will note some phenomenological features like jerkiness of tremor, irregularities in both space and time domain, were predictive of the lack of response.
Since these features are not reliably collected by the naked eye, I think that the use of biomarkers For instance, advanced neurophysiology, perhaps applying machine learning techniques, can help us in setting from a mechanistic perspective where the tremor is coming from, which might have important therapeutic implications, and this already applies to DBS or ultrasound targeting.
So, I wouldn't necessarily split or lump this syndrome necessarily. I think we have to get used to the [00:14:00] clinical variability of tremor syndromes and phenotype these patients.
[00:14:04] Dr. Sara Schaefer: Yeah, I was going to ask you if you were a lumper or a splitter. You're sounding a little bit like a splitter in your answer, but I, I do understand that it's a false dichotomy. So I guess you're somewhere in between.
[00:14:15] Dr. Roberto Erro: Yeah, sometimes you need to lump together these patients. It depends on the research question, I think.
[00:14:22] Dr. Sara Schaefer: In your view, what are the next steps? Does your group have anything further underway or planned?
[00:14:28] Dr. Roberto Erro: Well, as I said, the TITAN is a research platform designed to collect a wide range of data encompassing both clinical and non clinical information, including biological samples, for instance. It aims to create a large cohort of patients which are characterized at the best possible way today for future research.
Just to mention a couple of ideas, we are particularly interested in the evolution of ET plus patients, especially those having features suggesting an aging related syndrome. Moreover, we are trying to see whether applying computer vision type of techniques on [00:15:00] the collected videos might turn useful for a deep phenotyping of these patients, but there is a lot to come, so stay tuned.
[00:15:07] Dr. Sara Schaefer: Thank you for talking
With us today about your paper and sharing your thoughts. And perhaps we will see you at the Movement Disorder Society meeting.
[00:15:16] Dr. Roberto Erro: absolutely. We'll see you in Philly.