Episode Transcript
Speaker 0 00:00:00 Welcome to the Dry Eye Coach podcast series. Click on dry eye. Your insider passed to the most exclusive dry eye topic. The series will raise awareness about the current and future state of ocular surface disease. The podcast will focus on a variety of topics.
Speaker 1 00:00:15 In today's episode, we have the pleasure of speaking with Scott Howorth, whose practices at the University of Colorado and is an assistant professor there. Dr. Howorth is a leader in ocular surface disease with special interest in neurotrophic and neuropathic cordal pain. Welcome, Scott.
Speaker 2 00:00:31 Hey, great to be with you.
Speaker 1 00:00:33 Hey, Scott. Can you tell us a little bit about your practice?
Speaker 2 00:00:36 Yeah, so I practice, um, at the school of medicine. I'm at the Sue an Chuts Rogers Eye Center, uh, where I do, you know, solid four days of, uh, clinical practice, uh, seeing patients, mainly ocular surface and um, uh, cornea patients. A little bit of, um, sort of perioperative care as well. Uh, and then do some research there as well. I'm heading up right now I think for, um, clinical trials. Uh, it's a couple sponsored and then a couple that, uh, we've started on our own. Um, so it's a good mix of, of taking care of patients and then also, uh, you know, trying to stay on the edge for learning about new technologies too.
Speaker 1 00:01:17 You mentioned clinical trials and you do a lot ocular surface. I mean, you're also secretary of the, uh, academy section, the anterior segment section. So I did have to put that, uh, shout out for, for, for that group. Uh, can you tell us a little bit about your research that you're doing at OSD right now?
Speaker 2 00:01:31 Yeah, so there's, there's actually several things. Um, so probably the thing that I'm most excited about is a, uh, two things. There's actually one study from a company called CSUs, uh, where we're working on a kind of a novel mechanism, uh, for treatment of Sjogren's. And, um, the mechanism is, is something called a T R P V1 Receptor antagonist, which is actually working on the corneal receptors. And the, the hypothesis is that it actually ties in with, um, down regulating pain responses cuz it's one of the primary nose receptors involved in pain, but also it can, uh, potentially also decrease inflammation too. So, um, so that's one thing that I'm excited about. Another one is actually on the opposite side of the spectrum, but pertinent to today's discussion, um, utilizing a first inhuman, uh, phase two trial from Claris bio, uh, therapeutics, um, looking at a HEPA growth factor in stage two and stage three neurotrophic keratitis.
Speaker 0 00:02:36 I'm, I'm really excited about the work that you're doing. Um, can you tell us a little bit more about, like, what is your definition of neurotrophic keratitis?
Speaker 2 00:02:43 Yeah, so neurotrophic keratitis by definition, um, is essentially a disruption or, or a interruption, uh, in some cases of the trigeminal inv. That's what innovates the cornea. And what that can result in is, is the hallmark, I guess is decreased sensation, right? It's, that's the easy way to test for it, but it can result in changes to the epithelial health. So stage one neurotrophic keratitis is, um, is kind of hallmarked by, um, a decrease in epithelial integrity. And so we see like a persistent ker that in, in many cases resembles, uh, what we see in dry eye. Uh, stage two, um, is a, essentially a, a persistent epithelial defect, uh, where the epithelium loses its ability to basically repopulate and, and heal the defect. And stage three is accompanied, uh, a persistent epithelial defect accompanied by stromal volume loss. So we see thinning and, and even sometimes melting and perforation of the cornea.
Speaker 1 00:03:44 Hey Scott, what's the prevalence of nk? I mean, how often are we seeing it or do you think we're missing it in clinical practice?
Speaker 2 00:03:51 Yeah, so it's actually classified as a rare disease in the US so that means, uh, it's less than 75,000, um, cases per year. But we're definitely missing a lot of this because there is such a resemblance in, in stage one disease with dry eye. I think a lot of times it gets misdiagnosed and is treated just as a dry eye, uh, type of condition.
Speaker 1 00:04:17 Mm-hmm.
Speaker 0 00:04:17 <affirmative>. So where does corneal sensitivity testing kind of fit into your ocular service workup if you're trying to figure out what you've got?
Speaker 2 00:04:25 Yeah, that's great. So, um, so in learning about a lot of this stuff, right? My, my practice and the way that I approach, uh, patients, it continuously evolves. And if you asked me five years ago was I'd even doing corneal sensitivity and the answer then would've been extremely rarely, and now it's actually a part of the workup on every dry eye evaluation that I see. So it, it needs to be done early. Um, so it's usually one of the first things I'll do after assessing the, the cornea with a slit lamp. Um, and it's after, uh, the technicians do like the other entrance testing like, uh, osmolarity and, and, uh, like, uh, interferometry to assess like my boing glands and those sorts of things. But, but it's done fairly early before we put any drops in the eye before we put any stains in the eye. You need to, you need to check sensitivity at that time
Speaker 0 00:05:18 And how are you testing it?
Speaker 2 00:05:20 So, um, so for a long time I was using a cotton wi. Uh, but because we're involved with a little bit more research now, I do have ANet, um, which is a, it's, it's kind of a pen like device that has a filament in it. And um, basically you just measure the length of the filament. Um, and the longer the length, uh, the more sensitive the cornea is, the shorter the length, the more force it applies to the cornea. So the less sensitive it's,
Speaker 1 00:05:47 Hey Scott, when, when you're, when you're testing it, are you testing one zone or are you testing five zones and, uh, what, what are you marking down? How are you great with
Speaker 2 00:05:56 That? Right, that's a great question because there isn't really a standardized way of doing it. Um, so I test the central zone first, and then I've been testing the superior zone, uh, because from a reliability standpoint, that has a, a greater degree of reliability than some of the others. Um, and I do that as part of like, say the dry eye, uh, evaluation workups. Uh, but it depends on the patient too, because if they come in with like, say a history of prepare that keratitis or some other type of, you know, corneal, uh, disease mm-hmm. <affirmative>, typically I'll do more zones, especially if there's like a, a scar or something else that's, that's anatomically a little different or physiologically a little different than a normal cornea.
Speaker 1 00:06:42 And so, so what are you grading? Is it absent, reduced or?
Speaker 2 00:06:46 Yeah, so it depends on what you're using. With a cotton wsp, you can, you can basically just get a rough sense for it. And again, if you twist out the, the cotton filaments to form like just a few tiny filaments at the very end of it, and if the patient can detect that, that's pretty much normal. Um, but you know, the thicker the, the bulk of filaments are the less sensitive they are. So then you can, I used to just go from basically normal to like a negative three. Um, and that was the grading system I used, which was, which was pretty rough, but I mean, it still denotes decreased sensitivity with a kche bene, you're, you're essentially marking down, uh, in centimeters the length of the filament in half centimeter steps.
Speaker 1 00:07:27 Tracy, what are you doing?
Speaker 0 00:07:30 Um, right now I just have the cotton list, so, and I tend to do that particularly in cases where there's a lot of assymetry sensation or somebody tells me that one eye is really a lot drier than the other feel more sensation where, again, in history, especially with her pet cases.
Speaker 1 00:07:44 Mm-hmm. <affirmative>, that's a great point you just brought up with the asymmetry. I mean, how many times have we seen that eye, that al tread looking dry eye? It looks like a mess. The other eye was like one plus diffuse s pk, you're like, wait a second, that's a flag, uh, flag right there. So Scott, you diagnose the nk, so what is your typical treatment protocol? What do you use? Because oftentimes, as you mentioned, we're we're diagnosing a dry eye first.
Speaker 2 00:08:09 Right. So I, I use a lot of serum tears. I think that's my, my first go-to. Um, just because it's something that we can acquire pretty easily, uh, for the patients. I can get it within a few days. Um, the hospital has their protocol, uh, for, for drawing it up. It's relatively inexpensive even though it's not covered by insurance. And so that's generally my first step and if they don't respond to that, then I'll use, uh, something like center German or if they're a stage two, stage three, then we have a, another sort of research opportunity for them to participate in the claris bio trials. So, so that's kind of the order of, of preference, I guess, from a treatment standpoint.
Speaker 0 00:08:46 Mm-hmm. <affirmative>. So are you using amniotic membranes at all?
Speaker 2 00:08:50 Um, I, I do, but it also depends on why they're neurotrophic, right? So because you only have the membrane on there for a limited amount of time, and depending on the nature of the disorder, if it's something that really has more of a chronic timeline, then they probably need to be on things a little bit longer. So an amniotic membrane's great if you just need to have something in the eye for a few days and if it's a small defect or something you think you can manage it afterwards. But what I'm finding is more frequently we have to have, uh, you know, treatment that's ongoing at least for, for a bit longer and that's where the other two options come in.
Speaker 1 00:09:27 So, so you did mention actually autologous serum. Let's stay on that, the serum tier first. So what concentration are you utilizing for this?
Speaker 2 00:09:35 Yeah, so for neurotrophic disease I'm using 25% most frequently. Um, in a few cases I've gone up to 50%. Um, but usually those higher concentrations I'm applying those on and otherwise a cornea that's otherwise free of epithelial apathy and then that's where we start to use it more frequently in pain patients.
Speaker 1 00:09:58 Mm-hmm. <affirmative>, well, don't you worry, we're gonna get there here shortly.
Speaker 2 00:10:01 <laugh>.
Speaker 0 00:10:01 Have, have you ever prescribed the platelet rich plasma? Have you tried that ever instead of,
Speaker 2 00:10:06 You know, I, I have not. It's, it's been something that I'm hoping that we can develop a protocol because it's really not that much different. I mean, it's still a blood derived product and, and the processing and the handling of it is a little bit different than serum, but not terribly so. So I'd, I'd really like to get that going. It just takes a while sometimes to get, um, protocols like that, uh, developed and pushed through the, uh, the institution sometimes,
Speaker 0 00:10:30 Right, <laugh>?
Speaker 1 00:10:33 Yeah. So, so you, so, so we have the serum tier, we have the, the theen, uh, the biologics. So we use one course. So then what do you tell your patients? They come back after eight weeks? They do it actually. Can you talk about the treatment itself for those that aren't familiar?
Speaker 2 00:10:50 Yeah, yeah. Soen German, um, trade name is ox. It's produced by a, a private company, um, called dpi. They're out of Italy. Um, but essentially what it is, is, is a recombinant nerve growth factor, human nerve growth factor. So they've programmed essentially a bunch of bacteria to produce, you know, larger amounts of growth factor, harvest it, um, and then it's applied directly to the eye and it's a typically an eight week course, um, six times a day. Um, and so it is a little bit, you know, time consuming for the patient, but oftentimes they're using a lot of different drops anyway, but, but because we're reapplying nerve growth factor, of course we expect to see, you know, increased sensation increase, uh, stable sub basal nerve plexus density, um, those sorts of things. To answer your question though, like what, what does that look like when you apply it clinically? Um, so I have the patient start it. Um, I usually try to visit with them at around four weeks, so when they're halfway through their treatment to see if we're making any progress. And then at eight weeks, if the defect isn't healed, um, I will apply for them to, to get a second treatment. Um, and more often than not, we're able to do that.
Speaker 1 00:12:00 Yeah. Yeah. And that's, that's what I wanted to get at is because we know the data shows that 72%, uh, do complete, get complete corneal healing after the treatment. 80% are still, uh, uh, no recurrences within a year, but sometimes the eight weeks isn't enough, so you have to do it again, whether it's at that time or down the road, uh, many months later.
Speaker 2 00:12:20 Yeah, exactly. And, and it really again comes down to why are they neurotrophic in the first place. Like, you know, I can think of one case in particular, uh, where a patient had LASIK surgery and um, she developed keratopathy following that, but she was also a poorly controlled diabetic, had been for many years, um, contact lens wear for many, many years prior to that. And so those are other risk factors that play into it. And again, we're not curing their diabetes and so it's likely that she'll need occasionally some support for the ocular surface going forward. So, um, so in that particular patient, um, yeah, we did two rounds, but she was able to get pretty much complete corneal healing after the second round and envision correctable to 2015. So she was really happy.
Speaker 0 00:13:05 Do you find that patients have, um, easy access to it from a standpoint of paying for or through their insurance for obtaining this growth factor?
Speaker 2 00:13:14 You know, it, um, it sometimes can take a little bit of time and it depends on the insurance that the patient has to, to begin with, but I don't think that I've ever had a patient really pay an exorbitantly high amount for it. Um, one patient who's already pretty wealthy to begin with, he might be the only one that's ever paid money for it. They have a pretty fantastic, um, like grant and support system for patients to improve access and, and make sure the medication remains, uh, reachable for them from a cost standpoint.
Speaker 1 00:13:45 So, so Scott, another question that I have cuz as you know, I always have many for you, let's talk about neuropathic pain and you know, what's going on there because we always have that patient, the pain without stain, and you know, what, what, how should we go about identifying it and treating it?
Speaker 2 00:14:01 Yeah, that's a, that's a great question, Wal and the, the clinical signs don't match up with the amount of discomfort that they're in. So you might find a, like a fairly rapid tear breakup or maybe just a little bit of staining, but the patient is in, uh, you know, particularly, particularly distressed, you know, because they're, they're very uncomfortable. And so, so looking for that disconnect is, is the first step that we can do and trying to identify them. Mm-hmm.
Speaker 0 00:14:29 <affirmative>, what's different about your treatment protocol for somebody with, um, I call it almost like a fibromyalgia of the eye, if you will.
Speaker 2 00:14:37 Mm-hmm. <affirmative>? Yeah, so the first thing is, um, there have been a number of papers that have come out showing, um, that autologous serum is extremely beneficial for them. And usually they're, they're getting higher dose serum, as I mentioned previously, and in my practice I use 50%. The other thing is we're looking at, and again, it, it depends on the severity, um, but we're looking at other options. Um, sometimes systemic medications, uh, collaboration with, uh, pain management and pain psychiatry. Um, many of these patients are emotionally distressed and do need to have, um, you know, emotional support as well. So making sure they have, you know, a good spouse that's supportive of them, if not, you know, someone they can talk to within the, within the medical professions to, to manage some of those stresses. Um, I think those things are very different. That's a particularly challenging disorder to deal with when we, especially when we get into the more severe and centralized cases.
Speaker 1 00:15:39 So other than autologous serum, and I know I asked asked you before for 70%, you know, I've, you know, even the cornea docs that I've worked closely with, they, they're not aware of any study that 70% is effective for neuropathic pain. Um, any comments on that?
Speaker 2 00:15:57 Uh, yeah, I mean, I, I can reference a paper by, um, well, one of the co-authors on it was, was Dr. Hamara and they looked at, um, light sensitivity or AIA and response to serum. And actually over a six month period, I believe the statistics are like 80% of the patients had, um, some level of improvement and 60% of them had like 90% or better improvement to their symptoms. And that's one of the facets of, of neuropathic pain. Um, I can't remember if that study used 50% or if it used 25% though. I'll have to go back and and reference that.
Speaker 1 00:16:36 Yeah, I mean I had that patient that I asked you about cuz I mean, she was a 29 year old, otherwise young and healthy, uh, but she did have that significant pain and she goes, Hey, can you write 75% for me? And I, I've never used it, uh, before. So
Speaker 2 00:16:51 Yeah, so they've, they've also looked at, you know, if we're talking about serum, they've looked at higher concentration serum for more severe, um, ocular surface diseases anyway, things like graft versus host and Sjogren's. And I found that those, um, have been more effective. I can tell you anecdotally too, I had a patient that I diagnosed with, uh, neuropathic pain that did not respond to 25%, but when we bumped her up to 50%, um, she actually got significant improvement from that. So just speaking from my own experience, I think, uh, I usually start with the higher concentrations now.
Speaker 1 00:17:25 Yeah. Scott, you mentioned systemic, uh, systemic medications and co-managing with primary care and pain specialist. So that patient of mine, she was on nortriptyline and there was a study outta Tufts looking at, I think it was 53 54 patients that got about 40% improvement in their pain neuropathic by treating it, uh, systemically as well. So, so any final pearls that you have when it comes to either neuropathic or neurotrophic pain? Uh, for our
Speaker 2 00:17:51 Patients? I think that the whole area of, you know, what the nerves contribute to the ocular surface, both from a sensory standpoint, a regulatory standpoint, and, uh, just a, a main maintenance standpoint of corneal health. I think it's pretty amazing. I think we've really underappreciated the value that the innovation system really brings to, to the cornea. And boy, just make sure that you're aware of these things. Like, I guess, um, you know, for a long time I think it's been underappreciated, but, but the more we learn about it, the more we find that it's ex an extremely critical part of maintaining a healthy cornea.
Speaker 0 00:18:29 Thank you for, um, helping our colleagues to identify and treat these kind of more advanced or atypical ocular surface, um, disease and dryness patients. We'll be really excited to see what the outcomes of your future research will be.
Speaker 2 00:18:41 All right. Thanks for having me guys. It's been fun.
