Corneal confocal microscopy as a novel biomarker of neurodegeneration

Pain isn't nice, but there are times when it’s necessary - If you don’t feel the pain you should, you’re at risk of doing yourself greater damage. If you feel pain you shouldn’t, that could the first signs of a deeper issue. 

Professor Rayaz Malik and Dr Ioannis Petropolous talk about their work on a new, non-invasive, inexpensive way of detecting early stages of neurodegeneration that could be as easy as an opticians appointment. 

Read their original research: https://doi.org/10.2337/dc20-2012 

Transcript

00:00:04 Will Mountford 

Hello. I'm Will. Welcome to researchpod. 

00:00:08 Will Mountford 

Pain is rarely a welcome thing in life, but there are times when it is useful to prevent any further accidental harm. If you don't feel the pain, you should at risk of doing yourself greater damage. If you feel pain, you shouldn't. That could be the first signs of a deeper issue, including but not limited to, some neurodegenerative conditions. 

00:00:27 Will Mountford 

Today I'm speaking with Professor Rayaz Malik and Doctor Ioannis Petropolous about their work on a new way of detecting those early stages of degeneration that is non invasive, inexpensive and as easy as an optician's appointment. And if all that sounds too good to be true, just wait till AI gets applied to it. But First things first. 

00:00:50 Will Mountford 

And joining me to talk about their work, Professor Malik and Doctor Petropolis. Hello to both of you. 

00:00:54 Prof Rayaz Malik 

Hi, this is Rayaz Malik, professor of medicine from Weill Cornell medicine in Qatar. I'm a clinician and an academic. 

00:01:01 Dr Ioannis Petropolous 

Hi, I'm Ioannis petropoulos. I'm an assistant professor of research and medicine at Weill Cornell Medicine in Qatar. I'm an optometrist. 

00:01:08 Dr Ioannis Petropolous 

By training and I've joined Prof Maliks team back in 2009 to work on the cornea confocal microscopy project. 

00:01:16 Will Mountford 

What is it about the field? The research that is, I mean, drawn you to it in the 1st place and kept you invested all these years? 

00:01:23 Prof Rayaz Malik 

I think it boils down to my I suppose previous life working in the field of nerve damage in patients with diabetes, which is a highly prevalent disease, has major issues in patients in terms of pain, in terms of foot ulcers, in terms of amputation really the. 

00:01:44 Prof Rayaz Malik 

Lack of a sensitive measure to assess nerve damage. 

00:01:49 Prof Rayaz Malik 

One aspect which would profoundly change how we deal with this condition because at the moment what we do is we wait for the patient to develop these complications and then it's too late and the other aspect actually is a really important feature of corneal confocal microscopy, which is that we believe that this could be. 

00:02:09 Prof Rayaz Malik 

A test that the FDA, if they approved it, could use it in clinical trials to enable a drug or new drugs to be approved for the treatment of diabetic Nope, which unfortunately we do not have at the moment. 

00:02:22 Prof Rayaz Malik 

We have 100% failure rate for clinical trials and it's the frustration of that that has really kept me carrying on with this research. 

00:02:31 Will Mountford 

Doctor Petropolis, you said that you joined the team. Could I ask you to tell me a bit about the landscape for those failed trials and what has led to some of what we're talking about today, if we may be? 

00:02:41 Will Mountford 

On the cusp of a breakthrough. 

00:02:42 Dr Ioannis Petropolous 

So basically back in 2009, as I was doing my post. 

00:02:45 Dr Ioannis Petropolous 

The studies I got fascinated by what we call structure to function relationships, and I came across Prof Malex project at the time. What was, let's say, extra fascinating was the fact that it was going away from the classic ocular disease and it was looking at the systemic landscape. 

00:03:05 Dr Ioannis Petropolous 

Of diabetes and the effects. 

00:03:08 Dr Ioannis Petropolous 

The guy. So it was when I spoke to Professor Malik for my interview that I realized how important it is for the patients for drug discovery to have a new biomarker like this and versus history. I joined the team I worked on this project and we found really interesting data that. 

00:03:28 Dr Ioannis Petropolous 

Support the use of Conoco microscopy in diagnosis of diabetic neuropathy. 

00:03:32 Prof Rayaz Malik 

And well, I just want to add, I think it was the exact opposite for me even still now there are, I would say, dinosaurs in the world of neurology, even endocrinology, who who are not accepting of this complete. 

00:03:46 Prof Rayaz Malik 

Paradigm shift, where we're going to use the eye to look at neurodegeneration in the feet. How could that be possible? You know it's impossible. Or as we've now begin to show, that actually we can use what is going on in the eye to look at what's going on in the brain. 

00:04:06 Prof Rayaz Malik 

Sometimes I call this dogma, which is people are set in their ways. They will not change, you know, and even if you present them the evidence, they will still say but but, but. And that bot is the thing that is holding us back. 

00:04:26 Will Mountford 

The lookism of the received wisdom textbook knowledge at the. 

00:04:29 Will Mountford 

Moment. 

00:04:30 Will Mountford 

What is peripheral neuropathy in terms of how it comes about, who it comes about in and by the time it reaches you or any other clinician, what the standard current practice is? 

00:04:43 Prof Rayaz Malik 

OK, so peripheral neuropathy is essentially damage to. 

00:04:48 Prof Rayaz Malik 

Nerves. Now what are nerves? Well, they are the structures that. 

00:04:55 Prof Rayaz Malik 

Communicate you to the outside world because if you didn't have nerves, you will not perceive any sensation and that's actually what's called the somatic nervous system. Then there is the autonomic nervous system, which regulates how we breathe, how our heart kind of beats. 

00:05:14 Prof Rayaz Malik 

Whether we feel hungry, whether we are full enough, when we've eaten too much, all of these signals are intrinsically controlled by the nervous system, and peripheral neuropathy is a manifestation of damage to actually both the somatic and autonomic nervous system, and so you can imagine, you know, the patient who has. 

00:05:33 Prof Rayaz Malik 

Neuropathy when that Dems are being damaged, they will feel pain, but when their nerves are completely damaged, actually they lose sensation and you have people who literally cannot. 

00:05:44 Prof Rayaz Malik 

Feel when a pan is hot or when they put on a tight pair of shoes. You know, you and I we put on a new pair of shoes. We're uncomfortable for the first few days until you wear the shoe in those people, they just carry on. And what is that uncomfortableness telling us? Well, it's telling us your tissue has been damaged. And if you can't perceive that. 

00:06:05 Prof Rayaz Malik 

You can imagine how the patient can then develop an ulcer complications and they don't know about it. In fact, last week I was speaking to somebody very. 

00:06:14 Prof Rayaz Malik 

He I would say a business person who, you know the world, I mean the guys doing deals with companies, you know, mega companies and he's also a Manchester United fan. But he developed out of the blue painful neuropathy and we're actually trying to work out what the cause of that is. But honestly what he said to me really resonated because you hear these stories. 

00:06:35 Prof Rayaz Malik 

And he said, look, there was a point in my life where literally I would have been happy for people to have amputated my legs, then continue with. 

00:06:44 Prof Rayaz Malik 

His pain, and that's how bad he was. And he was on multiple drugs. It's getting better now. So that's the painful side of it and story. And you know, you get patient after patient who will tell you this. Of course not what every patient gets such severe neuropathy, but certainly a small but significant proportion do. And then the other side of it is the patient who walks into my clinic. 

00:07:06 Prof Rayaz Malik 

Whose husband is complaining of a funny smell. 

00:07:09 Prof Rayaz Malik 

Right. And they've got a ulcer that has developed on their foot and honestly this is a story that I heard a while ago when I was still a junior doctor. A patient, had a nail sticking through the bottom of their literally the shoe and they developed an ulcer and didn't feel it and had no idea that they had this horrible ulcer. 

00:07:29 Prof Rayaz Malik 

That was now becoming, you know, infected. Those are the two extremes that you see. And I've had people who have, you know, had local amputations, without anesthetic. 

00:07:40 Prof Rayaz Malik 

That's how you know you could lose sensation. 

00:07:43 Will Mountford 

Well, you'll forgive the pun, but from now we are onto the sensitive issue of pain. Doctor Petropolis, if you could tell me a bit about that in terms of not just the clinical presentation, but maybe some of the, the neurochemical that's signalling of how the body feel as manifests does pain. 

00:08:00 Dr Ioannis Petropolous 

When it comes to pain, there's a whole range of reactions that happen, and as Prof Malik said, pain is essentially a sensation that allows you to feel, understand what is happening around. 

00:08:12 Dr Ioannis Petropolous 

And with that you have, I guess secretion of proteins, neuropeptides that connect the nerves and they generate the signal which is essential to feel pain. So basically the way that pain is transmitted is through the sensory fibers. And that has been the focus of our research in, in, in profile. 

00:08:32 Dr Ioannis Petropolous 

Lab over the past many years, so this sensory fibers, they're very small in size and they're located in the feet. 

00:08:40 Dr Ioannis Petropolous 

And they connect to other, larger fibers. And those fibers, they're supposed to send the signals up to the brain and feel sensation of pain. And it is the point when these small fibers get damaged. I guess secretary doesn't work well anymore. 

00:09:01 Dr Ioannis Petropolous 

Which is something unfortunately very common in in diabetes. 

00:09:05 Will Mountford 

I mean, I was already flinching by the time you got to the ulcer, because, I mean, just the idea of the smell. But when pain is a symptom, how does that connect to other related diseases? Because there's a lot of things that can cause pain. But knowing when pain is mediated by nerve damage or diabetes. 

00:09:25 Will Mountford 

Chemotherapy HIV. What is the kind of wider implication for pain, clinically speaking there? 

00:09:31 Prof Rayaz Malik 

So pain actually is what brings the patient to the doctor. 

00:09:35 Prof Rayaz Malik 

And a lot of pain can of course be inflammatory. You have damage to tissue and is an inflammation and it is going to give you pain and it's actually what I would somebody famous once long ago said pain is God's greatest gift to mankind because it alerts us to damage to tissue, to our bodies, the type of pain that we're talking about is. 

00:09:57 Prof Rayaz Malik 

Something called neuropathic pain, which is. 

00:09:59 

Driven. 

00:10:00 Prof Rayaz Malik 

By damage to nerve fibers, and that is a different type of pain in the sense that it is because of an intrinsic damage, not to the tissue around the nerves, but the nerves themselves are damaged and the signaling becomes abnormal and. 

00:10:20 Prof Rayaz Malik 

The nerves themselves can be damaged due to a variety of conditions, so the commonest is diabetes. Why does that happen? Well, because in diabetes you have this multi. 

00:10:31 Prof Rayaz Malik 

Full metabolic abnormalities, high glucose levels, high lipid levels, abnormal blood flow from blood pressure, loss of abnormalities going on in the diabetic patient that can drive the nerve damage, and then once those nerves are damaged, they will signal abnormally and the patient will then perceive pain. But pain is a kind of a. 

00:10:51 Prof Rayaz Malik 

Complex phenomenon because you know one you can have pain. I can have pain, but the effect that it has on us in terms of how we deal with it and how do we deal with it? Well, it's actually to do with how our brain deals with it. You know, so there are multiple. 

00:11:05 Prof Rayaz Malik 

I would say gating points, whether it's in the spinal cord or in the higher center of the brain, which can amplify or can nullify the pain signaling and depending on that, you can then have different people will react differently. So you can have some people like this guy that I've talked about, you know, said literally. 

00:11:25 Prof Rayaz Malik 

Cut my amputate. Right. This is just too much. And there are other people who could probably maybe have similar degrees of pain who can and nice to deal with it. And then of course, you've got people who lose sleep, become depressed. So complicated. 

00:11:40 Prof Rayaz Malik 

Which is why we need an objective test. 

00:11:42 Will Mountford 

That leads me on to my next question there that with all of these centers that are activated, is there anything like a scale for pain in a chemical sense, useful biomarkers perhaps from outside of peripheral neuropathy now what's informing research for corneal confocal microscopy to develop the tests that you are? 

00:12:02 Will Mountford 

Looking on. 

00:12:03 Dr Ioannis Petropolous 

So there are scales to measure pain. There are scales where patients can respond to what extent they feel pain, how much pain they feel, what kind of pain they feel. But through my research, improved Malex lab. What I've seen is that these scales are highly subjective. 

00:12:20 Dr Ioannis Petropolous 

So one day the patient can refer to one type of pain and then at the follow up appointment, the patient can refer to a different type of pain. That subjective element doesn't help very much to understand what is really happening, apart from realizing that the the patient suffers from. 

00:12:38 Dr Ioannis Petropolous 

Now, and this is where corner confocal microscopy comes in. As an objective test which can help us understand if there is any structural damage. 

00:12:50 Dr Ioannis Petropolous 

To the net fibers to the small fibers, which are crucial in terms of sensation, and then check if this damage is associated with the symptoms that the patient is referring to. 

00:13:05 Prof Rayaz Malik 

Yeah. And you know, that's really where I get excited about corneal confocal microscopy. 

00:13:10 Prof Rayaz Malik 

Because we have other tests so-called objective tests, and they've never really been able to, I would say. 

00:13:16 Prof Rayaz Malik 

Correlate with a the presence of pain or the severity of pain, but we have shown in studies that in diabetes and also in chemotherapy induced neuropathy that actually the extent of corneal nerve damage detected by corneal confocal microscopy is related directly to the presence of pain. 

00:13:38 Prof Rayaz Malik 

So if you have a cohort of patients with pain compared to those without pain with diabetes, they have more damage in those with pain. And if we furthermore grade that severity of pain into mild moderate severe, the more severe the pain, the more severe the damage. 

00:13:58 Will Mountford 

Now focusing on corneal confocal by can I say CCM for short. 

00:14:03 Will Mountford 

I hope so. 

00:14:04 Will Mountford 

Could you talk me through some of the process of the you know the steps of the operations? 

00:14:08 Dr Ioannis Petropolous 

So CCM is effectively a camera for the cornea. You've probably come across during an examination of the ophthalmologist, an instrument that they use where it flashes white light and with that they can check your eyes. So basically, cornucopian microscopy can take this examination to the next level. 

00:14:26 Dr Ioannis Petropolous 

It provides very high magnification in. It can check the cells and the nerves of your cornea and check for any signs of damage, so the process is basically very simple. All we have to do is that we have to apply a drop of anesthetic to prevent too much blinking during the examination. It doesn't dilate the pupils and that means that the patient. 

00:14:47 Dr Ioannis Petropolous 

Is free to do any activities immediately after the test. 

00:14:51 Dr Ioannis Petropolous 

It has no pain, so basically all it does is to come very close to the eye with minimal contact and capture very high resolution and high magnification images. We're talking about 600 times magnification of all the layers of the cornea, starting from the very first layer which is full of cells down to the nerves and then. 

00:15:12 Dr Ioannis Petropolous 

More cells until the endothelium and that can help us really understand if there's anything particularly in the nerves that are are associated with the symptoms of neuropathy that we spoke about before. 

00:15:24 Will Mountford 

Should one hope for a a high score there low score? Is it more like tennis? 

00:15:28 

Golf. 

00:15:30 Dr Ioannis Petropolous 

I think it would be more like tennis, so you're hoping for high score. The higher density of nerves, the more normal that it is for the patient. Of course we know there is a threshold and anybody who has above that threshold is within what we call the normal area and everybody. 

00:15:49 Dr Ioannis Petropolous 

Below that threshold, it can be either a suspect for neuropathy or if it is too low, it can have confirmed neuropathy. 

00:15:57 Will Mountford 

And to put all this in the context of diabetes care, I mean, could be focusing particular on diabetes, what's useful in terms of pure rather than just management. I've got notes here on pancreatic transplantation, bariatric surgery, if I could walk through some of those interventions then leading up to CCM as an. 

00:16:17 Will Mountford 

Outcome. 

00:16:18 Prof Rayaz Malik 

OK. So I mean essentially the reason why we did these studies is it was the proof of principle to show that if we can improve care in different ways of the patient, what impact will that have on the nerves in the cornea? And the first proof of principle. 

00:16:39 Prof Rayaz Malik 

That actually we were, I I think kind of almost forced to do it by the National Institutes of Health where we applied for a grant and they said, well, you know, you really need to show us what you're measuring changes or improves after you do something that's almost a cure for type one diabetes and which your pancreas transplantation. 

00:16:58 Prof Rayaz Malik 

And we just happened to be in a, I would say one of the best places in the UK. Certainly the Manchester is is up there in terms of pancreas transplantation and kidney transplantation. We had a big diabetes center type one diabetic patients who were at end stage kidney failure need a new kidney to for transplantation. 

00:17:18 Prof Rayaz Malik 

Also, they were undergoing pancreas transplantation. So in essence, in the words of one of my colleagues is a surgeon said you know. 

00:17:24 Prof Rayaz Malik 

As you physicians, you know you kind of play with these patients, you don't really cure them, we cure them and which is what they were doing. They were giving a new pancreas and essentially curing the underlying problem. And of course that gives you the basis on which you can say, well, if you cure the diabetes cure, the blood glucose, then the nerves should repair. And that's what we did. 

00:17:45 Prof Rayaz Malik 

We did this study where we took patients before transplantation and then followed them up over time and we showed very clearly that corneal confocal microscopy as oppose. 

00:17:55 Prof Rayaz Malik 

To a bunch of other what we call FDA approved measures, which is symptoms, signs, nerve conductions didn't improve corneal components within six months. It was starting to repair showers repair. We could objectively measure it and then it continued to improve and it was about 36 months before the other measures started to improve. 

00:18:15 Prof Rayaz Malik 

And you know that gives us huge insights into. 

00:18:18 Prof Rayaz Malik 

How sensitive this test is to look for nerve repair, and similarly with bariatric surgery, you know, biometric surgery, people who are overweight, actually people used to think that ohh, they're OK, you know, they're they're overweight, they're uncomfortable. But we actually showed that in people who are overweight or morbidly overweight, they actually already have a neuropathy. They have no damage. 

00:18:38 Prof Rayaz Malik 

Which they're not aware of, and when they undergo bariatric surgery of cause, diatric surgery, you lose huge amounts of weight. But if you've got diabetes, you cure your diabetes. Blood pressure goes away, lipids improve, and you'd expect that to have an impact on the nerves. And it did. And we were able again able to show within 12 months that the nerves were starting to repair. 

00:18:59 Will Mountford 

As well as being a score or scale for after treatment, where could CCM fit in terms of early detection prevention even for some of these conditions? 

00:19:09 Prof Rayaz Malik 

So again, you know this is a loaded question in the sense that it was the question that I was often asked by uh by the dinosaurs in the world of neurology, you know? Oh, yes. But you're measuring all these things. It's abnormal, but does it really predict what happens clinically? And so we actually we've done studies several studies that all have taken people. 

00:19:30 Prof Rayaz Malik 

With diabetes without neuropathy clinical neuropathy as they would measure it with their nerve conductions with their symptoms. 

00:19:36 Prof Rayaz Malik 

The science, and we've then followed up and this is actually a big NIH. 

00:19:41 Prof Rayaz Malik 

Sodium study. We've followed those patients over four years and a proportion of those patients developed neuropathy, no surprise. And then what we were able to show is that actually corneal nerve, the extent of corneal nerve damage at baseline. 

00:19:56 Prof Rayaz Malik 

Could predict those people who develop neuropathy develop diabetic neuropathy with really quite high sensitivity and. 

00:20:04 Prof Rayaz Malik 

City and we've done exactly the same. Actually. It's a separate disease, but dementia. We've taken people who've got mild cognitive impairment and we've followed them up over three years and we know that for sure. Uh, proportion of those people with mild cognitive impairment will develop dementia and guess what? Nerves were lower in those people. 

00:20:24 Prof Rayaz Malik 

With mild component who developed dementia compared to those who weren't. 

00:20:28 Will Mountford 

And to see this fitting into wider clinical design as well to expand the utility you mentioned about cohort selections for go, no go is just a kind of way to get a lot of information as early as possible. How many doors does this open for the medical practice outside of just what we've talked about today? 

00:20:47 Prof Rayaz Malik 

Yeah, honestly. In fact, yesterday I got an e-mail from a rather big pharmaceutical company who were frustrated with the amount of money they've spent over the last 30-40 years and the number of times they've failed in their clinical trials and they were asking, you know, what can we do? 

00:21:03 Prof Rayaz Malik 

To to try and help improve the design of our clinical trials and I said, you know, one thing that you can really do is incorporate corneal confocal microscopy because you know you you can think. 

00:21:13 Prof Rayaz Malik 

You've got this. 

00:21:14 Prof Rayaz Malik 

Drug and you're going to do a clinical trial for are you going to do it for 4-5 years before the current endpoints start to improve? No, because most. 

00:21:23 Prof Rayaz Malik 

Pharmaceutical companies will want to do the trial within 18 months, two years and they say, you know, if it hasn't worked by then, forget it. The drug doesn't work. But that's actually not what they should be doing. Maybe they should be doing having CCM as as a kind of a a starting point alongside the other test. 

00:21:38 Prof Rayaz Malik 

If CCM within 12 months is starting to improve, then you know you could invest for a longer period of time and you know, show that it's in effect. If it hasn't, then I suspect that you're on a drug that isn't going to work, so that's where the go. No go signal comes in. That is really important because otherwise you end up doing this. Repeat, rinse, repeat, rinse, repeat which is. 

00:21:59 Prof Rayaz Malik 

Go into these trials, fail and then say oh. 

00:22:03 Prof Rayaz Malik 

The drug doesn't work. 

00:22:05 Will Mountford 

And Physiology underlying those central conditions. Is there anything to look at? You mentioned dementia, but we've also had concerns about long COVID over the last fourish years. Is there anything that unites this kind of a body of central diseases that might be something that CCM gives us an earlier insight into? 

00:22:23 Prof Rayaz Malik 

Yeah. So specifically with regard to lung COVID, we actually did a study in Turkey and we showed very clearly that people who develop long COVID have less corneal nerves compared to people who've had COVID but didn't have long. 

00:22:40 Prof Rayaz Malik 

Little bit. 

00:22:41 Prof Rayaz Malik 

And actually for this study, you know, as an academic, you're kind of like, you're bothered about impact factors and stuff, but there's something called an altimetric score, apparently, which is supposed to be good. And we were astronomical. We were like 1600 or something. We scored in that, you know, most papers scored about 20, but it's because of the interest that we got because genuinely. 

00:23:02 Prof Rayaz Malik 

There are many people out there who have got long COVID and they are ignored by their physicians because it's not an entity we recognize. But there's a lot of, I would say, otherwise, normal driven people who suddenly their lives have been upturned, you know, destroyed because they've got this thing. 

00:23:20 Prof Rayaz Malik 

Long COVID. And you think, well, why should you be having this? But it's because there is evidence of neurodegeneration. 

00:23:32 Will Mountford 

From where I'm sat, I can see only upsides to this and without getting into uh, let's say wider reforms of the healthcare sector, what stops this being for everyone everywhere? Is it the technology thing? Research, validation. What would it take to make the world? 

00:23:50 Will Mountford 

Fit CCM being used all these kinds of possible. 

00:23:54 Will Mountford 

Patients. 

00:23:55 Prof Rayaz Malik 

First of all, without being wanting to be upset anybody, I'd say we need to get rid of the dinosaurs. Once that happens, then you know, we actually genuinely move and we make progress. Secondly, the company themselves, Heidelberg, need to make a cheaper, more rapid, more effective non contact call, new confocal microscope. 

00:24:15 Prof Rayaz Malik 

And if they don't, somebody else needs. 

00:24:17 Prof Rayaz Malik 

Too, and that would, I think would be a kind of a major game changer because you know it's access. Ideally I would love to see this on every High Street, right people walking around. You're worried about whether you've not, you've got neuropathy from diabetes or from chemotherapy or whether you're not, you might get dementia. You have this scan, it's. 

00:24:37 Prof Rayaz Malik 

Nice scan and especially with the current use of AI and now we've got some amazing data. Now with AI that shows that we can not only pick up earlier changes with much better sensitivity but also predict or differentiate different diseases. And that's always one of the kind of things that people come back to me and say, oh, you know you've done colonial confocal microscopy and diabetes. 

00:25:01 Prof Rayaz Malik 

And this and that you find an abnormality. But now, actually what we're showing with AI, we can actually differentiate different diseases. So with 100% sensitivity I can tell you whether or not somebody's got nerve degeneration. Parkinson's disease for example. 

00:25:17 Prof Rayaz Malik 

And for multiple sclerosis is about 95% for dementia, it's about 95%. That completely changes what we're doing. 

00:25:25 Will Mountford 

Yes, that was in one of your newest papers, I think Doctor Petropolis, if I could ask you for maybe a quick run through in terms of where you see AI in terms of that paper now and maybe the next five years, what's happening and what could come next, your ramp up from there? 

00:25:44 Dr Ioannis Petropolous 

Before I send my view on a I, I would just like to say that the way it started is as a lot of these tasks we try to automate the analysis process and save us time so that we can perhaps look at more diseases, more patients and in general make things a little bit more efficient so. 

00:26:04 Dr Ioannis Petropolous 

In the last few years we've seen, I would say, an explosion of AI applications, and that includes the field of cornea, confocal microscopy, the field of CCM, and. 

00:26:15 Dr Ioannis Petropolous 

AI has this almost, I would say magical power to allow us to look at the images in ways that was simply not possible before, and this is because AI can analyze parameters that we as humans cannot. It can do complex calculations in the background. 

00:26:35 Dr Ioannis Petropolous 

And I think with the development of explainable artificial intelligence, we can now see how the algorithm is making these decisions. This is definitely a game changer in terms of diagnosing early screening, patient populations and of course. 

00:26:55 Dr Ioannis Petropolous 

Predicting outcomes, so I could honestly say that if we managed to integrate AI algorithms with the current hardware that we use to scan patients, that could be definite. 

00:27:08 Dr Ioannis Petropolous 

The I wouldn't say the $1,000,000 question, but the $1,000,000 answer in a sense that we can combine two very powerful techniques to help us at our goal, which is to diagnose earlier and prevent disease or treat disease. 

00:27:23 Dr Ioannis Petropolous 

To add to that, apart from helping us look at the images in ways that we explained are not possible currently by humans, it can also help us differentiate between diseases, which is very important in the context of applying a diagnostic test, a biomarker, and be able to tell the physician that. 

00:27:43 Dr Ioannis Petropolous 

X findings come from said disease or why findings come from a different disease, so this is definitely something that us and perhaps other groups are working on. We've been trying to answer this question and I'm hopeful that we will. 

00:27:59 Will Mountford 

Thing that puts the two hurdles there of someone coming up with a non contact version, Heidelberg or anywhere else and then. 

00:28:06 Will Mountford 

Having an AI suite to access that, you know, make the things work, the kind of scale you're talking about. We've been talking a lot about how well this is going and how useful it is for a lot of applications, but I know there have been some negative findings as well around neuropathy and how it compared with other measures. What does that mean in your eyes as to how this is useful as a biomarker for? 

00:28:27 Will Mountford 

Generation. 

00:28:28 Dr Ioannis Petropolous 

Thanks for bringing up this important question. So we are aware that some recent studies showed some negative findings in a sense that they either show that CCM is not performing as good as other diagnostic test. 

00:28:41 Dr Ioannis Petropolous 

Or that it doesn't correlate strongly with other measures like skin biopsy symptoms and signs. 

00:28:49 Dr Ioannis Petropolous 

This is important for for CCM because it is telling a story. It is telling a story about situations where CCM might work or may not work as this is the case for all diagnostic test. 

00:29:02 Dr Ioannis Petropolous 

We also need to take a closer look to these studies and understand what led to these results. Is it the specific study population? Because we know that variables like diabetes, duration, control of diabetes medications, the age of the patients, the specific painful symptoms that they get. 

00:29:21 Dr Ioannis Petropolous 

Can affect the outcomes, or perhaps is the analytical approach that we use, which might have led to these results in terms of the analytical approach, we are more capable than ever with the use of artificial intelligence. 

00:29:37 Dr Ioannis Petropolous 

To quantify additional metrics, so a question that arises is whether by quantifying these additional metrics, perhaps we can look at these results from a different angle and better understand more about the situations where CCM didn't work. 

00:29:54 Will Mountford 

So something of a silver lining that most ending is all the same. 

00:29:57 Prof Rayaz Malik 

And and actually, well, you know, I I would welcome all data right. Because, you know, sometimes if you just see positive positive positive then actually that's not to me science is not discovery. It's about having those challenges and then providing an explanation for why. 

00:30:18 Prof Rayaz Malik 

It may have worked or may not have worked. And when I look at those studies, there's one particular study that got published in a highly prestigious journal of Neurology. When I looked at the numbers, I honestly thought they'd made a mistake and a a decimal place mistake because they were coming up with. 

00:30:33 Prof Rayaz Malik 

Say for example a sensitivity for corneal confocal microscopy of 14%, which is unheard of compared to 99% of the data that's published out there, which all shows it's above 80%. But then the other counter bit of that was actually that specificity for CCM. 

00:30:53 Prof Rayaz Malik 

That's corneal nerve fibre length in that study, it's the best I've ever seen. It's 98% something close to that. So that makes. 

00:31:00 Prof Rayaz Malik 

You think that there's something not quite right about that study? We need to ask questions as to as to what was the design of the study. You know, how did they measure neuropathy but. 

00:31:11 Prof Rayaz Malik 

As I said. 

00:31:13 Prof Rayaz Malik 

I welcome negative results as much as positive results. 

00:31:16 Prof Rayaz Malik 

That's how we move forward. 

00:31:24 Prof Rayaz Malik 

Ultimately, people need to be aware that you've got this potentially powerful technique which is not going to be inflicting any pain. Any taking any tissue out or whatever, but it's going to give you a very sensitive measure of neurodegeneration. So people patients need to know about it. 

00:31:43 Prof Rayaz Malik 

Other specialties, you know, neurologists need to know about it. Ophthalmologists need to know about it. Endocrinologists need to know about anybody who deals with neurodegenerative disease needs to know about this technique because it really is, I believe, such a powerful way, an easy way. 

00:31:59 Prof Rayaz Malik 

Of. 

00:32:00 Prof Rayaz Malik 

Addressing the issues, the day-to-day issues that as doctors we face, which is about being able to diagnose a disease, being able to actually predict what's going to happen to that disease over a period of time, and if we have got therapies already seeing if those therapies are working. 

00:32:20 Prof Rayaz Malik 

To help improve the underlying neurodegeneration, and if we have new therapies that where we think they're going to work, we can use it to test, evaluate whether or not they're. 

00:32:31 Prof Rayaz Malik 

Going to work. 

00:32:33 Prof Rayaz Malik 

Honestly, the technique is just beautiful. I mean, it's like it's simple, it's non invasive and it has so many applications in terms of not just what we've kind of folks on diabetic neuropathy but multiple neurodegenerative diseases. And to me, you know, when I look at that, I think wow, if I was a person. 

00:32:54 Prof Rayaz Malik 

Walking along and I had a worry or concern about maybe having a new. 

00:32:58 Prof Rayaz Malik 

Would you advise what would I like? I would like to just walk in to my High Street optometry shop. You know, optometry place and just have a scam. Right? Rather than wait, which at the moment in the NHS, you're gonna be waiting two years minimum to even get to see a neurologist. 

00:33:18 Prof Rayaz Malik 

Right. So you know, this could actually open the door in terms of you have a quick test and then if it's positive you then get you know, fast tracked in terms of referral. Otherwise you're waiting, you know you got these symptoms and and people are just not able to access. 

00:33:35 Prof Rayaz Malik 

You know the the medical system. 

00:33:37 Dr Ioannis Petropolous 

I would have to agree with Professor Malik on the use of CM. I think it is wonderful, really that ophthalmology comes to meet neurology and address a major challenge when it comes to diagnosis of diabetic neuropathy. I think we are proposing and not just we. I think there's a lot of centers around the world that are using. 

00:33:57 Dr Ioannis Petropolous 

This technique with great enthusiasm and we are proposing a test which is easy to use. It gives instant results. 

00:34:06 Dr Ioannis Petropolous 

It provides a view that wasn't possible before in the nervous system. We are hopeful about the future of this diagnostic test and what kind of changes it might bring to the way diabetic neuropathy and other neurodegenerative diseases are diagnosed. 

00:34:24 Dr Ioannis Petropolous 

And I would like to add to what Romalic said that apart from patients and doctors, I would like to add to that list funders and policymakers because we can generate the data and we have generate the data. I have joined this journey from 2009 and I have seen a lot of the data around CM changing. 

00:34:44 Dr Ioannis Petropolous 

In a positive way. 

00:34:46 Dr Ioannis Petropolous 

And we have validated the findings, but only if funders. 

00:34:50 Dr Ioannis Petropolous 

Fund these larger studies and policymakers decide to make CM conical photomicroscopy as a diagnostic test for patients who have potential neurological issues. Neurological complaints only then CCM can really take off. 

00:35:10 Will Mountford 

And for anyone listening to this, who wants to know more about you, your lab, any specific publications? Where can they find more? There's maybe any websites or upcoming papers that you'd like to raise for their attention? 

00:35:22 Dr Ioannis Petropolous 

I would say in two places we are very active on social media and they can check on social media accounts on DNA group, which stands for early neuropathy assessment. 

00:35:32 Dr Ioannis Petropolous 

Group and for anyone who want to have a deeper look, a deeper dive into the numbers, they can always read our papers who are published as Open Access simply by typing our names in a search engine like PUB Med or Google Scholar and a lot of the bibliography will come up. 

00:35:53 Will Mountford 

Thank you so much for your time and I look forward to speaking with you both again sometime soon. 

00:35:56 Dr Ioannis Petropolous 

Thank you. Thank you, will.