Special Series: Why tremor?

[00:00:37] Prof. Elan Louis: Thanks very much, Alfonso. We're happy to be here.

[00:00:40] Dr. Alfonso Fasano: Thank you. So let's get started. And I would like to really start with the question. Why tremor? Why do you think it is important to talk about tremor?

[00:00:49] Prof. Elan Louis: Tremor is one of the most common neurological disorders. It's among the most common movement disorders, and it [00:01:00] affects millions and millions of people, not only in the United States where I am, but across the world.

[00:01:06] Dr. Alfonso Fasano: Indeed, it is very common, and you have done a lot of work in trying to understand the epidemiology of the disease, particularly essential tremor. Can you give us a flavor of how common it is from a number perspective?

[00:01:20] Prof. Elan Louis: Sure. So we know from population based studies that 90 to 95 percent of normal individuals have a clinically evident tremor on examination. That would be considered a normal tremor. But as far as abnormal tremors go, essential tremor is the most common of these. And we know from epidemiological work that in the United States, for example, there are about 7 million people with essential tremor.

Which represents 2.2 percent of the entire U. S. population. Globally, when you look at [00:02:00] people over the age of 50 it's about 4 to 5%, and it goes up each decade. So by the time people are in their 90s and older estimates are that as many as 20 to 25 percent of individuals have essential tremor, making it extremely common.

[00:02:19] Dr. Alfonso Fasano: These are remarkable numbers and I'm sure you agree with me, though, that in spite of this, very high prevalence, not many patients end up being seen by a doctor, not even a movement disorder neurologist, but even just a family physician or a general neurologist. Why so?.

[00:02:35] Prof. Elan Louis: I'll just elaborate on the last point a little bit as well, that we were talking about the prevalence of the disorder, but in terms of the incidence, that is new cases arising each year again in the United States the estimates are that about a third of a million new cases arise each and every year so that's close to a thousand new cases arising every [00:03:00] day.

But getting back to your question about why we don't see all these patients in clinic, and that's because the tremor can range in severity from mild to very severe, and many of the cases in the population have early and or mild essential tremor. And the estimates are that anywhere between about 10 to 15 percent of patients that are seen in population based studies end up coming to medical attention.

So we're just seeing a fraction of these patients.

[00:03:33] Dr. Alfonso Fasano: And do you think that the overall understanding of the public opinion on tremor is good enough or for every person out there with tremor? The only thing that they're interested and is ruling out Parkinson's. If there's a good understanding of what tremor is.

[00:03:48] Prof. Elan Louis: I don't think there's a great understanding in general about tremor in general or about essential tremor more specifically. I also think many [00:04:00] individuals with this have other explanations initially. Maybe they think they're drinking a little too much coffee. Or maybe they think they're a little nervous.

Or maybe they think it's a medication that they're taking. People will try to find rational reasons for why they're shaking more. And if you can find a reason for why you're shaking, You don't need a doctor to tell you why you're shaking. And so you don't necessarily come into medical attention.

[00:04:28] Dr. Alfonso Fasano: Absolutely, so a lot of people actually seek for their own explanations on the Internet, which is very dangerous. And but more in generally speaking, if we looked at tremor, and yes, essential tremor perhaps in the general adult population. Can we look at it? This is a question that I was trying to find a solution to.

Can we look at tremor as an overall sign of brain frailty? Something that is cooking because we know that some of these patients, as you showed end up having Parkinson's disease. So can we look at tremor as a [00:05:00] general and specific sign that something is off?

[00:05:03] Prof. Elan Louis: And here, just to clarify, we're talking about tremor in general, or we're talking specifically about essential tremor 

[00:05:09] Dr. Alfonso Fasano: Given the prevalence that you just outlined, even if we say tremor in general, I guess we need to refer to essential tremor, although, as some epidemiological studies have found enhancement of physiological tremor as the most common problem. So I would say let's lump them together for now and let's have a conversation about it in tremor, essential tremor, enhancement of physiological tremor.

In other words, I'm 60 years old and I start having a mild postural tremor. It doesn't bother me. But do you think it's going to be interesting to neuroscience? Look at these patients carefully because this is going to indicate that something is wrong with their brain. And this may be the beginning of a dementia or Parkinson's or this tremor might be like that forever.

What's your general idea about this?

[00:05:54] Prof. Elan Louis: Right. So the first consideration is looking at that tremor and seeing [00:06:00] whether that meets criteria for essential tremor, which is a disease or a family of diseases, as opposed to just a normal condition. Because if 95 percent of people in the population shake by definition, that's a normal condition.

It can range in severity. Some people can have more of that normal condition and some people less. But you want to see whether you're dealing with the approximately 4 or 5 percent of people out there in this age group who have what we call essential tremor. And yes, I think it is very important to determine that because not only does essential tremor have its own natural history and we know that it worsens over time.

So this will be important for patients to know as they consider treatments over time. But we also know from epidemiological studies that [00:07:00] it appears to be a risk factor for other degenerative conditions like Parkinson's disease and dementia. So I think it's important to know from multiple perspectives.

And given the fact that it's often a familial disorder, it becomes an important question for families to know about do we have something in this family that we're all at increased risk for that is potentially disabling and associated with other conditions.

[00:07:31] Dr. Alfonso Fasano: Well, I'm touching upon what you just said the familial tremor. I heard that some people don't look for medical attention because, oh, no, this is something normal. Everybody in my family shakes. So they don't even. perceive this as necessarily a problem. I don't know whether that's really the case, especially for those high amplitude kinetic tremor.

But that aside, and obviously if you want to comment on that, it's fine. But the question I have is we know that this condition, let's talk about essential tremor in this case, is highly inherited. So there is a high proportion [00:08:00] of people with at least another family member and with the same problem. And we also have large pedigrees sometimes, and in spite of that, it's so difficult to find genes.

How can you reconcile this? 

[00:08:12] Prof. Elan Louis: Right, so I think when I first became interested essential tremor. This is in the mid 1990s the idea back then was that it was highly inherited and that it was an autosomal dominant condition. And I think just given the experience of many of us who have been looking for genes the last 20 years, is that we've come to the conclusion, firstly, that it's less inherited than we thought it was.

And secondly, that it's not often, or less often than simple Mendelian genetics and more likely complex genetics with probably multiple genes each having a very small effect although as a field we [00:09:00] haven't had a lot of success in terms of identifying those genes in more than one or two families.

So there's still more work to do, and we are in a similar situation to autism or schizophrenia, where clearly there's a familial contribution, but we're having difficulty finding what those genes are.

[00:09:24] Dr. Alfonso Fasano: Because of the multiple contributions, I agree entirely. And actually, you briefly mentioned the beginning of your career. And once thing I was particularly interested in asking you today which I asked I don't know if you remember at some point when we were having a conversation during a meeting is the following question.

You've been working on this for many years. You published hundreds of papers on Tremor. Why did you get interested in Tremor?

[00:09:48] Prof. Elan Louis: I got interested in tremor almost by accident. My mentor and advisor asked me to look at a simple question that related to tremor, which was how often it runs [00:10:00] in families. And I told him that everyone knew that 50 percent of cases were familial. And he suggested I look into the literature.

And I looked in the literature and I found two things. Number one, that the data were low quality and all over the place. So that value of 50 percent was probably not a valid one. And secondly, there were so few studies of essential tremor in general that any direction that you turn in there are questions that are unanswered questions, whether it relates to the causes of the tremor, the genes, environmental factors, underlying pathological changes.

, natural history. Anywhere you turn, there are unanswered questions.

[00:10:47] Dr. Alfonso Fasano: Yeah very interesting and these overall emphasizes the role of mentors. A lot of the listeners of the MDS podcast are trainees or young movement disorder specialist. And I think this is a [00:11:00] very important message that just by chance, just because you met, one person, your mentor, that one day asked you a question that you thought it was an easy answer to give that profoundly changed the rest of your career.

And this is really the power of mentors. So that's why I'm really glad that you shared this experience with us. Talking about the role of mentors and educating on tremor. Do you think that more neurologists or even more disorder neurologists should be interested in tremor?

[00:11:27] Prof. Elan Louis: I think everyone should be interested in tremor, and I think all movement disorder neurologists are interested in tremor to some extent, because You really can't be a movement disorders neurologist and not take care of patients, whether they're essential tremor patients or Parkinson's patients or patients with dystonia these all have tremor, right?

 You have to be, but as a central focus, I think more and more people are interested in it now than in the past. I think that as we fill in more and more of the blanks [00:12:00] there is more for people to be immediately interested in and fascinated by. And so I think we see those numbers increasing as we advance our knowledge.

[00:12:11] Dr. Alfonso Fasano: Now, that that's very good to hear. And do you think this is spiraled by an increase in funding? Because I don't know if there's enough attention from an economic standpoint when it comes to tremor.

[00:12:23] Prof. Elan Louis: There are in terms of NIH, there's a relative paucity of studies on essential tremor with the rise of neuromodulation which I know is very near and dear to your heart that many of the publications that relate to essential tremor and now many of the funded proposals center around the role of neuromodulation in essential tremor. That has increased the number, but in terms of non neuromodulation the number is still quite small. I think with associations between essential [00:13:00] tremor and dementia and Parkinson's disease I think the number will likely go up because this adds an additional dimension to the study of essential tremor.

[00:13:11] Dr. Alfonso Fasano: Yeah, I will agree entirely with what you just said. Maybe the only exception to the non neuromodulation piece also gaining attraction and interest is the focused ultrasound option that has led many. Patients who go seek for medical advice. And in my experience, actually, I found that many of these patients don't even have tremor.

They have any sort of disease from myclonus or many have functional tremor. And I know that this mirrors your experience. 

Moving on to another question I have for you. Have just two more. You've been very kind in sharing your time with us. One question is what do you think are the most important discoveries in tremor research?

If you look back on the past, I don't know, 20 years where does your mind go to the question, what is the most important discovery or the most important discoveries in this field?

[00:13:57] Prof. Elan Louis: Well, I think that there are several areas of [00:14:00] knowledge that have advanced. One of these is when I entered the field essential tremor was really just viewed as and regarded as almost just a symptom, almost just a physical examination finding. And now we have a really enhanced understanding of the clinical features and natural history of this disorder.

I think everyone in the field agrees that there's considerable heterogeneity and how we deal with that heterogeneity is a topic for debate and discussion and controversy. So I think there's a richer view of the disease or I think probably a family of diseases themselves. And that's been a big change.

The other is that 20 years ago, we really didn't know where in the brain essential tremor was coming from. There was a hypothesis put forth [00:15:00] that it related to a physiological dysfunction coming from the inferior olivary nucleus. But when one looks more critically at this, it was based mostly on animal studies that were not even directly relevant to the human condition, essential tremor.

So we've really gotten to the point now where we understand the central role that the cerebellum plays in essential tremor, and back then there had been very few autopsies. I could count the number of autopsies back then on both of my hands and now we're at the point where we're dealing with an order of magnitude more.

We're dealing with close to 300 autopsies, and we've gotten to the point where we've identified degenerative changes in the ET brain, numerous of these. And to the point where we can take an ET brain at the time of death and a control brain and tell the difference [00:16:00] between the two with 95 percent accuracy.

So having this understanding of the tissue based changes that occur in patients with the disease then opens the door to understanding the pathophysiology. Which then opens the door to more targeted therapies which we both know we need to do a much better job at devising better therapies for this disorder.

Coming back to the start of our discussion, why aren't there more patients coming into clinic? I think one of the reasons is also that the treatments are limited, and so patients might come to clinic once or hear about others who come to clinic and know that the success rate of the current treatments is pretty modest.

[00:16:46] Dr. Alfonso Fasano: Absolutely agree. Thanks for this. And my last question that builds on what you just said, because you gave us a perspective over the past 2 decades. The question is, where do you think this field is going?

[00:16:57] Prof. Elan Louis: I think that this field [00:17:00] is now heading in a direction where scientists are beginning to think on a more serious level about what the underlying causes are and that the seriousness of research is on par with the research that occurs with respect to disorders like Parkinson's disease and Alzheimer's disease, other neurodegenerative conditions.

So I think it's very hopeful in that regard. And I think the types of research that are going on will increasingly enhance our understanding of the disorder. I can see now, for example, in the last several years, the number of medications or potential medications that are under consideration by pharmaceutical companies has really expanded considerably.

And I think a lot of that is, again, just based upon our enhanced understanding of the disorder. So I'm hopeful that the [00:18:00] pharmacology will get better. And that will keep pace with all of the advances that have occurred over the last several decades in terms of neuromodulation therapy, which I would say has been another major change in the last 20 years.

[00:18:15] Dr. Alfonso Fasano: Thank you Elan these were great insights. This was the 1st episode of the podcast on tremor. You just heard from Professor Elan Louis from UT Southwestern in Dallas, Texas in the United States. These episodes was Why tremor. Once again. Thank you, Elan. It was a pleasure to host you here.

[00:18:33] Prof. Elan Louis: Thanks very much, Alfonso.

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