This transcript has been edited for clarity.
Andrew N. Wilner, MD: Welcome to Medscape. I'm your host, Dr Andrew Wilner. Today, I am interviewing Dr Christopher Gibbons about his research presented at this year's American Academy of Neurology meeting. Dr Gibbons is a clinical neurophysiologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts. Welcome, Dr Gibbons.
Christopher H. Gibbons, MD: Thank you very much for inviting me on. It's a pleasure to be here.
Wilner: Thanks for joining us. I looked through many of the abstracts and yours caught my eye. I am an epileptologist and not a movement disorder specialist, but I keep hearing about alpha-synuclein. I know a while back there was some testing available in the skin for small-fiber neuropathy. I saw in your abstract that you were using skin testing for alpha-synuclein, and that was definitely new to me.
Please tell us what you did and why you did it, and then we'll get to what it means.
Gibbons: Absolutely. To give you a little bit of historical background on how we got here, the skin, as you suggested, has been used for small-fiber neuropathy testing for several decades. I've been involved in a large amount of that research myself at Beth Israel Deaconess Medical Center. One of my areas of interest is in autonomic disorders.
We knew that many of the autonomic disorders were tied to these groups of disorders called synucleinopathies, characterized by the presence of phosphorylated alpha-synuclein. This misfolded protein is alpha-synuclein — which we all have, but when it's phosphorylated and misfolded, it begins to accumulate in places throughout the brain and the nervous system and causes damage to the various neurons in those regions.
We've known for some time that some of these disorders have peripheral features as well. The synucleinopathies include Parkinson's disease, which is the most well-known; multiple system atrophy (MSA); pure autonomic failure; dementia with Lewy bodies; and even the prodromal condition REM sleep behavioral disorder, which many of us now think about as the fifth synucleinopathy.
We all know that there are nonmotor manifestations of disease — gastroparesis, constipation, and other features of the kind of diseases that are not kind of clinically the parkinsonian tremor that we think about. This had really sparked our interest to dig into why this was happening. We began looking at peripheral tissue a long time ago to see whether there was some damage to the peripheral nervous system that might explain this.
In 2013, we started looking for alpha-synuclein in the skin and we published our first paper on that many years ago at this point. This has evolved over the last decade with other groups publishing this as well, and many people have an interest in detecting this phosphorylated alpha-synuclein within nerves in different systems.
Whether it's in submandibular gland biopsies, colonic biopsies, or skin, all of these sources of tissue have nerves within them. In fact, alpha-synuclein can be detected within all of those. Of those different sources, skin is the easiest to access because it's just a simple punch biopsy.
This is something that's evolved to the point where it is now commercially available. This study that we're doing at the moment is a retrospective review of several hundred cases that were referred in for clinical testing, using skin to evaluate for the presence of phosphorylated alpha-synuclein.
Wilner: You looked at about 100 patients with a variety of movement disorders. I guess the question would be, If you have a patient, how useful is this test? Did it tell you anything you didn't already know?
Gibbons: From the time the abstract was submitted to when we were able to present, we did get additional patients in. Our total number that we looked at was 207, and then we excluded those patients who didn't have complete medical records.
We reviewed the complete medical record and had a panel of physicians review the cases to determine, in their expert opinion, what was the most likely diagnosis. Did they think it was Parkinson's disease? Did they think it was dementia with Lewy bodies, MSA, or something else that was not a synucleinopathy? We gave the expert panel the task to make the best decision, and then we matched that up to what the results showed.
We categorized the groups by whether we thought they were "probable diagnosis": in other words, they met the criteria at that threshold for Parkinson's disease, MSA, pure autonomic failure, or dementia with Lewy bodies, with consensus criteria to get to that probable threshold, which is the highest clinical one we can make. They were given a possible diagnosis if we couldn't find any other disease to explain this that was more likely, but they didn't achieve that probable diagnosis threshold.
We found that for all-comers, the diagnostic accuracy was roughly in the 65% range. In other words, of all patients who were thought to have synucleinopathies, about 65% had phosphorylated alpha-synuclein in the skin. However, if we looked at the probable diagnosis, this went up to roughly 80%, but the possible diagnosis was roughly about 50%.
We found that with increasing diagnostic certainty, the likelihood of finding phosphorylated alpha-synuclein went up. These numbers are remarkably similar to the autopsy studies, where we see that in the best hands — movement disorder specialists or other specialists — the highest diagnostic accuracy they can get in life is about 80%. Autopsy confirmation shows that the other cases are progressive supranuclear palsy or other diseases that aren't synucleinopathies. This is very similar to what autopsy cases were showing previously.
Wilner: Let me clarify a couple of things. First, the test doesn't differentiate between the different synucleinopathies, right? It wouldn't tell you if this is Parkinson's disease or MSA. It doesn't make that distinction. Is that correct?
Gibbons: That is correct. We have a very large ongoing prospective trial looking specifically at that question. We have a fairly robust hypothesis that we can, in fact, differentiate that. This is an ongoing trial, so it'll be available next year.
Wilner: That's next year.
Gibbons: Hopefully, next year. Exactly.
Wilner: My other question is about the 80%. Does that mean that 20%, roughly, of the patients who were thought to have a synucleinopathy did not have a synucleinopathy based on the skin test?
Wilner: The question is, was the skin test wrong for that 20% or was the diagnosis wrong? In other words, is the skin test the gold standard in this scenario?
Gibbons: In this particular study, we made no presumptions as to which was the gold standard. This was based on what is the concordance between clinical diagnosis and skin testing. We know from prior validation studies that sensitivity is roughly 95% for the skin test in patients with an established diagnosis — so in other words, not prodromal cases such as REM sleep behavioral disorder, where sensitivity will be lower, depending on how early the disease is. In patients with established diagnostic confirmation, this is roughly around 95% and then specificity is approaching 100%.
Wilner: In that case, roughly 15% of the clinical diagnoses were not accurate, is that correct?
Gibbons: That's what we're presuming, yes.
Wilner: That's pretty interesting. I have two questions. One, do you have plans to continue to follow these patients in case you have the opportunity to get some postmortem material and then compare that with your skin biopsies? Is that going to be possible?
Gibbons: We are absolutely going to be continuing to look at that information. I think the more data we can gather over time, the better. We do know that the clinical diagnostic accuracy always improves with additional information. Again, end of life is much more accurate than early diagnosis. We definitely understand that things move. In fact, if we can get postmortem diagnosis, that's obviously the best option. I think we're going to optimally continue to follow this for as long as we can.
Wilner: There was another observation in your abstract that I thought was very intriguing, which was a high prevalence of small-fiber neuropathy. What is that doing in there?
Gibbons: It's an interesting question and one of the things we've been following for some time in the peripheral nerve field, because we've identified that many patients with Parkinson's disease will have reduced nerve fiber densities, although they may be clinically asymptomatic. They don't report any clinical symptoms of small-fiber neuropathy, but in density analysis of intra-epidermal nerve fibers, they're always reduced substantially compared with healthy people.
This was a very similar finding, and we found some differences between the groups. For example, Parkinson's disease tended to have a mild small-fiber neuropathy by pathology, not necessarily by clinical diagnosis, whereas dementia with Lewy bodies actually was more severe. Those patients had a more severe loss that tended to involve more territory of distribution, whereas MSA tended to be less affected. Of course, those were much younger patients as well, on average.
There is this interesting kind of breakdown of pathology that we seem to differentiate to some way based on the small fiber as well. I think that's going to play a role in some of our separation between groups, for example. This, I think, will be an interesting way to help distinguish between these cases.
Wilner: These disorders are far more complex than we learned in medical school, it sounds like.
Gibbons: Always continue to learn. Yes.
Wilner: At least when I was there. Lastly, you mentioned that this test is commercially available. When, if ever, should a clinical neurologist use it?
Gibbons: Just to be clear, I have a disclosure to make regarding that. I was a founder of the company that started this diagnostic testing. This is based on work that's come out of my lab and other labs as well. We've developed this test because people were asking us to run it out of a research lab, saying, "Hey, could you do me a favor? I've got this confusing case." Generally, you can't do that, of course, for many pathology-based reasons and diagnostic requirements.
These questions kept cropping up. The tough cases, the ones where you're not sure what it is. Is it a complicated essential tremor case for Parkinson's disease? Is it a case of MSA or something else, such as progressive supranuclear palsy. Is it a case of dementia with Lewy bodies or something else?
In many cases, having that knowledge will make a difference in your clinical treatment and your planning, quality of life, and everything else. Those are the questions we want to try and help people answer.
Is this a situation where knowing that information would make a difference to your clinical treatment plan? That's largely what we've been recommending, that when people get stuck not knowing what this is, can this be helpful?
In my own clinical practice, I see a large group of patients with diabetic autonomic neuropathy. Of course, they're a bad disease case, but I've been following them now for many years and some of them suddenly get worse. And the question is, is this somehow due to the diabetes, or is this in fact due to them getting older and developing a degenerative disease on top of their diabetes?
Unfortunately, to follow Occam's razor, they always have more than one disease. In fact, I've discovered quite a few are developing synucleinopathies on top of their diagnosis of diabetic autonomic neuropathy. That creates a challenging treatment paradigm, but it means that you don't have to focus on the diabetes as much and tighten up glycemic control. I can focus on the autonomic disorder as a separate issue now.
Wilner: Wow. That's really helpful. It sounds like it's not for everyone. It's sort of a second-tier test if you're struggling with the diagnosis, you've got a pretty good concept of what's going on, but you need some refinement. Is that fair?
Gibbons: Exactly, yes.
Wilner: Is there anything you'd like to add that we didn't cover?
Gibbons: No. I think there's a large amount of great and interesting stuff going on in synucleinopathies these days. Our hope is that the combination of testing and early diagnostic accuracy may help with some of these treatment trials going forward. There are many pharmaceutical companies interested in developing treatments for Parkinson's disease and other synucleinopathies. I think that would be a huge leap forward for all of us if we can begin to treat some of these degenerative disorders. This will be an enormous success.
Wilner: That's exciting. Dr Gibbons, I want to thank you for telling us all about your research that you presented at this year's American Academy of Neurology.
Gibbons: Thank you very much for having me. It's been a pleasure.
Wilner: Thank you. I'm Dr Andrew Wilner, reporting for Medscape.
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Cite this: Skin Testing May Help Detect Movement Disorders - Medscape - May 18, 2022.