 We're going to start, even though I know people are getting their food, I have to get surgery. I'm going to give you an update on collagen crosslinking. I actually spoke about this about two years ago in Grand Rounds. Corny collagen crosslinking was approved in the U.S. by the FDA about two and a half, three years ago. And it's just kind of ramped up pretty slowly in terms of payer reimbursement, so that's gotten better and better. And so the volume of procedures done in the U.S. has really skyrocketed in the last year and also in our clinical practice here at Moran. So I don't have any financial disclosures. And like I said, I did talk about this a couple years ago, and there really is not a ton of new information except for just a lot more clinical experience. Hi, Jane Durkin. We have a guest of honor, Jane Durkin, Moran alumnus. Corny collagen crosslinking, as you guys know, is mainly used for caroticonis, but also can be used for other ectatic conditions. And the next most common one would be post-lasic ectasia, which fortunately is becoming much less common with better techniques. Obviously, we can do cornea transplants on people with ectasia, but they don't always work out perfectly, as you could see in that bottom slide. That's not what it's supposed to look like. So it would be really nice knowing that caroticonis tends to be a progressive and fairly common disease to have some way of, you know, preventing it or minimizing the morbidity from it. And obviously, we want to identify at-risk patients who are much better at that now with more sophisticated corneal imaging. Mainly tomography, which many of you would know the brand names, but Pentacam would be a very common one. Galilei would be another one, which basically gives more 3D data about the cornea and its shape. But also just counseling patients and certainly patients who are at risk not to rub their eyes, because eye rubbing is definitely a risk factor for development of caroticonis, independent of family history and other factors. But then really the idea of this presentation is to say, well, if a person has the disease and it's progressing, is there something else we can do? And the answer is yes, we can do a variety of things to try to stabilize the disease. Some of the more experienced people in the room, and I'm looking at this row right here with Dr. Hatch and colleagues, but sometimes fitting a hard contact on the eye with a really flat fit, you know, we know that some of these caroticonis patients would almost get like an ortho-carotology type, perhaps slowing of their progression. But that's not really predictable or reliable. Intracorneal rings like Intax and other rings, which are available internationally, definitely can provide some stabilization. Now, cornea collagen crosslinking is probably the best way to actually stabilize the cornea, and there's a lot of evidence and more than a 10-year track record really demonstrating and proving that it is effective. It's not 100% effective, but it's very effective. So I actually use the abbreviation, you'll see the abbreviation in this talk, KXL, just because CXL is too close to contact lens and in charting and stuff, it just gets kind of mixed up. So the German abbreviation was K for carotocornea crosslinking. The original work was done on this by Theo Seiler in Germany, and it's 20 years, if you can believe that, since crosslinking using riboflavin was invented. And we use UV light source, it's in the UVA spectrum, 365 to 370 nanometers UV light, and then just yellow solution, riboflavin, sounds really simple. It is really simple. And basically the riboflavin absorbs the UV light and it's not just the light energy itself, but perhaps other things are happening. And no one really knows exactly how it all works, biochemically or physically. But we do know, and it just is common sense to know that you want to deliver the energy or the effect at the site where it's going to do the most good and also prevent bad side effects or consequences. And so really the cornea is where carotocorus occurs. And so we want to make sure that the light is delivered to the corneal stroma. And obviously one needs to standardize the amount of energy delivered and kind of the process to get consistent results and minimize side effects. So that's done just by monitoring or modulating the time of exposure, the intensity of the light and the distance to the target, as well as trying to make sure that the eye is consistently saturated with riboflavin. So removing the epithelium is kind of the traditional way of doing this, where the epithelium is removed by a variety of different methods. It's scraping or many times mechanized brush, a brush called an amoyl's brush can be used or dilute alcohol solution can be used. But that, as one would think just by common sense, would allow better penetration of the riboflavin into the stroma. And obviously removing the epithelium is not without some consequences. And one is pain. The other is loss of your natural barrier function, which could increase the risk of infection from a surgical procedure. So there has been a lot of study in different methods of doing corneal collagen crosslinking. And certainly there's been a lot of work to try to make doing it with leaving the epithelium on more effective. But still most data and most practitioners believe that removing the epithelium really results in a better long-term result. The other thing that can be monitored is the intensity of the light and the duration of the treatment. And so the traditional approach to collagen crosslinking, which is called the Dresden protocol, is a 30 minute exposure to UV light, which is obviously a really long time. And the saturation time for the riboflavin is also 30 minutes. So this turns out to be like an hour and 15 minute procedure per eye. You can't do both eyes at the same time because the light is kind of, you know, it will work for one eye. But obviously if we could shorten that, that might be desirable for a surgeon and patient. We do know that the process works. We know that corneas are stiffened. You can see in this slide here that, let's see, where was the pointer. Do you have the pointer, Austin, or is this one? That's not this one, is it? I don't know. Anyway, it doesn't matter. I'm not sure where the pointer went, but you can kind of see in that OCT there. It's okay. I don't really have much to point out, but oh, there it is. You can see that the, this is just cross-section of a cornea that's been cross-linked. And you have this, we call it the demarcation line, where the more anterior part of the corneal collagen fibers have been compacted. And that's something that you would like to see demonstrating that there has been a fairly deep penetration into the cornea. And one of the very most reliable signs that this has actually worked is that you get predictable thinning of the cornea, which sounds weird, because keratoconus is a disease that causes thinning, but the thinning is actually a sign that the collagen cross-linking has worked. And if an OCT were done, you would want to see that line of demarcation. And it's just thought, the process of keratoconus, the basic defect, is uncertain, but probably does involve some destructive enzymatic processes. And so no one really knows exactly how this works, but stiffening and compacting and maybe killing off some fibroblasts, keratocytes, who knows. But anyway, the compaction does seem to stop the process fairly well. It doesn't seem to stop it if people keep rubbing their eyes. So it's important that this doesn't stop progression if people continue to rub their eyes. This is just kind of restating what I already said. But one of the reasons that the epithelium off longer 30-minute protocol seems to be more effective is that oxygen seems to enhance the process probably through some kind of free radical formation or other biochemical reaction. But no one really knows for sure exactly what's going on except that the cornea is compacted. So I like to think of it as cement drying or curing. We know that when we see concrete, it kind of condenses and hardens. And that's kind of what happens with the cornea. I believe that there is a direct injury or effect from the process and then probably some healing that occurs as well. It's unknown whether that healing or scarring, you know, they're kind of a parallel process, is how much that contributes. But it makes sense that that is so because the effect seems to increase for some time after crosslinking. Many patients don't achieve the full thinning or compaction or even as long as 18 months, patients may be actually getting better in terms of their changes in their corneal contour. There are some risks and fortunately they seem to be pretty low. I would say the main risk of the protocol that we do with epithelium off is potential for infection just because you're taking the epithelium off. You're putting a bandage contact lens on there. But if you didn't do the right thing with the light or if you were using a light that wasn't well controlled, you could probably damage the deeper structures in the eye including the endothelium and possibly even deeper structures. And then, you know, it is UV light. Possibly could be some long-term consequences such as ocular surface neoplasia or even squamous cell cancers. But that's unlikely as long as we concentrate our treatment on the non, you know, kind of stem cell type cells. And we try to avoid treating the limbus. I mean the light is a 9mm diameter light and so part of the process is not treating the limbus. There actually have been some randomized clinical trials which support the efficacy of this treatment to stabilize keratoconus with data going out 10 or more years in some studies. And there's many, many, many less good papers in the literature showing efficacy. And even with it being around for more than 10 years there's still not any real good long-term data because it's such a variable population that's getting this with real extremes in the degree of keratoconus that's being treated. Some people would just say, if I go to a meeting of cornea specialists some people would say, well, just cross-link them first because, you know, if you're going to do a transplant you might have all tried cross-linking and then other people would say, well, there's no progression and there's, you know, there's no evidence to do it. And so I just feel like there's not very consistent parameters for jumping in across our specialty. Hopefully we'll get better at that. The epithelia on and the shorter duration, higher intensity UV light techniques definitely work. We know that they work, whether they work as well as the more traditional way most people feel like the evidence does not support the same level of efficacy but that's still being worked on. We want to do this when we feel like a person has progressive keratoconus and that's not always easy to ascertain but sometimes it's very easy to ascertain and I'll show you some pictures of a 12-year-old that, you know, I mean literally it can change very fast over six months but most of us know how to, you know, map our patients and refract them and look at them and generally the topographic information is what you're going to use to determine whether or not a person is progressing but also progressive myopia certainly could be a sign of keratoconus certainly increase of astigmatism. We really want to catch it early in the process if it is progressing because it seems like the earlier you do it the better it works, especially in terms of improvement and uncorrected vision and avoidance of even the need for contact lenses and many patients. It's still a bit out there in terms of doing very young pediatric patients or other high-risk patients. Certainly what's approved in the U.S. with an hour-and-15-minute treatment is not and actually pretty low reimbursement. We got a referral, Matt Baugh was talking to me. He said, well, they want to send this mentally handicapped patient to the U to do cross-linking under general anesthesia on both eyes and I'm like, that's fine but, you know, it's going to be two-and-a-half hours and you can just imagine. So the accelerated protocols would be great for patients like that where you could really get the treatment done much more quickly and do both eyes at the same time. There are also a lot of interesting progress being made on combining cross-linking with vision correction, improving the shape of the eye with PRK generally, but also some with LASIK, either as a concurrent surgery or as a staged surgery. So this is a question for the residents and the fellows or anybody who takes call at Moran-Icena. Why is it important to avoid doing cornea transplants? Cornea transplants work great in keratoconus. The success rate is probably 98%. So who wants to answer that? Any resident who takes first call, why would you avoid doing a cornea transplant if you could? What's the number one reason? Ruptured globe, right? I mean, how many people in here have seen a ruptured PK and repaired it or seen it on call or whatever? I mean, almost all the trainees, you know, most of the faculty. I mean, that is what I tell my patients. That's what blinds people from cornea transplant. Now, you have glaucoma and complex things. But really that almost immediate blindness or really traumatic loss of vision is from trauma. And so we really... And deep anterior lamellar keratoplasties can rupture horribly too. And recently they're supposed to be stronger. But so that's the answer is... And just, I think, you know, some of our house staff have seen this patient. I had a patient who had very advanced keratoconus in both eyes. She's 23 years old. She basically debilitated contact lens, you know, relatively intolerant. I think 2080 best corrected in her worst eye. She had a transplant on her nine days after her PK. She got her eye ruptured by a friend who was a laundry basket. I don't know how that happened, but anyway. And she lost her lens. And, you know, fortunately she's doing okay. She was able to be repaired and she actually has pretty good vision. But needless to say, we did cross-linking on her less affected eye. That was still a candidate for cross-linking. We'll see how she does. So we have had a lot of experience dating back to 2013. We were in one of the... VEDRO is just the company who pushed through cross-linking in the U.S. through the FDA process. And so we were in one of their trials where we looked at the accelerated treatments with the shorter duration times, which were really nice. As short as two and a half minutes, up to eight minutes. We still had to put the riboflavin on. I think for that protocol, we were doing 20 minutes of riboflavin. And it actually worked really well. I think all of our patients at least stabilized or improved. We did have some post-lasic ectasia patients that didn't do as well. But even those patients in general stabilized and this group was biased toward more severe keratoconus because if your vision was too good, you were not eligible for the study. And then from about 2016 on, we've been doing this post-approval kind of either self-pay or insurance pay cross-linking. And we have... I bet we have a hundred eyes now, probably. And we've had really good results now. There are some people who really don't gain any additional function, but at least many of these patients who are... Most of these patients, one of the great things about practicing in Utah and Salt Lake is people tend to be... They tend to stick around so you have these longevity kind of follow-up in your patients. And they tend to stay insured and whatever. So I mean, I definitely have most of my patients from this trial are still seeing me and most of them are doing great. I don't think any of the keratoconus patients have gone on to transplant. And we're kind of seeing the same thing for our post-approval patients. I think they're in general doing really well. And I'm just gonna put a plug in for Dr. Meyer and Dr. Petty and our other contact lens fitters for keeping them from gene transplants. That's really the other arm of the treatment is scleral lenses in particular are just... I could say cross-linking and scleral lenses are on equal standing for really changing the paradigm for keratoconus because so many patients can stay in contact lenses longer, avoid transplant and be very happy. Just to be clear, Dr. Petty does contact lenses. Yeah. Dr. Jeff Petty is the good-looking one. So I already mentioned this a little bit, but you tend to get some flattening of the cornea. Interestingly, the topographic or the mapping results are often not coherent or consistent with the refractive changes. And part of that is because you're changing the relationship of the anterior and posterior curvature a little bit. So sometimes you don't see much decrease in the steepest cornea, but you'll see a few diopters decrease in the refraction. And so I'll kind of comment on that a little bit more in a minute. But certainly some patients who cannot previously tolerate special contacts are more tolerant of them. We have some patients that are actually able to get back into glasses, especially the younger population. It seems to have a little bit more of a reversal effect in early cases. Post-lasic ectasia, definitely in my experience is not nearly as effective in improving vision, but often does result in stabilization. Oh, just another comment about that. I really think part of that is because they're so broken when we find them. So please, if you see post-lasic ectasia patients, if you just feel like, hey, this something's going wrong with this lasic patient, send them for a pentacam, send them to us. And I feel like if we catch these patients earlier, we'll be able to help them a lot more. We really haven't had any significant complications from cross-linking. You are disrupting the ocular surface. Certainly there have been complications reported in the literature, and I'll go into that a little bit as well. But other than being kind of a PRK-like experience with a few days of pain and a bandage contact lens and all that, patients tended to do really well. We have had some of the post-lasic ectasia patients from that original FDA protocol go on to transplant. But again, I think the selection bias of doing worst cases, it probably didn't have a whole lot of hope of really getting better. So this is just a patient, and this was in the FDA trial. Just kind of gives you kind of a not exceptional, just fairly common outcome, where of course this patient has a lot of myopia and astigmatism, but actually had significant decrease in myopia two years. And this is a 21-year-old guy, so he's probably really going to progress without cross-linking. So he's my patient. He's doing great. He wears contacts most of the time, but the manifest refraction is in there to show, you know, really his myopia did decrease. If you look at the mapping, you're like, well, hmm, you know, I mean, he definitely, this is an exception because he went from 52 down to about 50, 51, but he has, you know, quite a bit less or more effect in terms of his reduction of myopia on his, comparing his keratometry to his refraction. This is just another fairly typical result with some improvement in best corrected visual acuity, and you can really even see these, this one here has a pretty significant difference in the anterior surface flattening after treatment, and that's a year out. So our post-approval experience has also been good, and I think even better because we're doing earlier cases in younger patients. You know, we kind of simplified our protocol a little bit. It's fairly user-friendly. Many patients are back in their contacts by a week or two. The payment part of this is really, in my opinion, a sad commentary on our system. When we started doing cross-linking, I mean, if you think about it, it's vitamin water, right, and it's a blacklight that some of these people had back in the 60s to light up their rock and roll posters in their room. So when we started this process, I had to go to the technology clinic at the Moran and say, okay, we've got this thing that we want to do, and it's not covered by insurance, but we want patients to pay $2,500 an eye, and this is how we're going to divide up the cost. The Riboflavin was about 600-something for the vials of Riboflavin, and so, but shortly post-approval, the company raised their price to about $2,700. Dan, what is it, something like that? I mean, this is like, it's just capitalism at its worst in medicine, in my opinion. So much so that the company will hire a third party to lobby your insurance companies and your payers and everybody to try to facilitate the process, and it's free to the surgeon in the hospital. We're jacking up our price, but we're going to provide the service where you can get this paid for, so I just think it's ridiculous, but anyway, it helps my patients, so I do it. This is just a post-approval patient. This is a 12-year-old, pretty typical young patient, and amazingly, these 12-year-olds can tolerate this without sedation. We just do it in the outpatient clinic, minor procedure room, but again, you can kind of see the topography. It really doesn't maybe look all that much better, maybe even worse, but there's significant change, and part of that is that you can't really see it, but the cornea is thinned, and then if we looked at these, people who know how tomography of the cornea works, you'll have this best fit reference space at B, F, T, E, F, best fit toric elliptical front, so that's going to give you a radius of curvature of the comparison surface that it's comparing to, and so that will actually change when you do crosslinking. The comparison surface will change generally flattening, and that's one of the reasons the maps are not as impressive, but overall the cornea is flattening, and that's why you get reduced myopia and better vision, and the astigmatic effect is definitely more variable, and probably less good, and that's one of the reasons why it's good to catch these patients early. This is a fellow eye of that other patient, and it just kind of shows, as we were waiting for the first eye to heal and kind of deciding whether the 12- or 13-year-old patient needed the second eye done, he had pretty significant progression, including notable steepening of the posterior cornea comparatively. So young people with keratoconus do tend to progress pretty fast. So probably there's a lot of people, there are a lot of people who won't benefit or maybe don't need it, or you're not sure if you're going to help them or not because the natural course of the disease is different as one gets older, but too old, too thin, too diabetic, or too much scarring, are going to be contact lens dependent and maybe need a transplant anyway, so I feel like there are patients where generally around 50, 50 or mid-50s is where I stop offering cross-linking to patients, but we all know those of us who take care of it, it's not the same for every person, and some people do progress in mid-life significantly, but certainly if they're progressing and if they're not too far gone, cross-linking makes sense. I think divining the goal is really important. Many of these patients may not understand that the goal is to stop progression and still be contact lens dependent, but as long as that's established, patients are very accepting and very appreciative. And I already talked a little bit about this. So cross-linking is kind of like a B-pen of ophthalmology, but I have issues with lots of other things in ophthalmology, like things like omidria, which is ketorolac and phenylapherin, which is, I don't know how much that costs, Dan, but, you know. 140 per bio. Yeah, and I don't think the drops cost that much, but anyway, so I'm not going to go into all that, but informed consent is really important. It gets a little tricky when you're operating on minor, so I'm really cautious to make sure I meet with the parents and the patient at least twice and go over everything. That's kind of obvious. Our procedure, this just describes it. I'll kind of cruise through this because we have other presenters, but it's done with topical anesthetic. 30 minutes of soaking it with riboflavin after the epithelium is removed. The surgeon actually removes the epithelium, kind of prepares the eye. Then we have a technician put the drops in. We take the lid speculum out when the drops are being put in, and then we have to put the lid speculum back in for 30 minutes during the UV exposure. Usually patients are out of a bandage contact lens by about a week. With the epithelium, sometimes we'll heal as quickly as a couple of days in these patients. You see whitening of the stroma early on, and then that's kind of a desirable endpoint. It looks a little bit like the frozen chicken that you put in the microwave, and the edges get a little bit thawed or get a little bit slightly blanched when you put it on the defrost setting. It's a little scary. The first few patients you look at it and you're like, oh my gosh. But even by the next day, they look pretty good. And then the thinning is really, I think the best indicator that it really works. Thinning on tomography. I already kind of addressed this a little bit, but people work at different ways to try to get the epithelium to penetrate if one is leaving the epithelium on, including trying to get the cell membrane to break down a little bit with somewhat toxic drops or substances using hypotonic solutions and even applying electrical current. I think the other part of the trying to make it more efficient makes sense if you just use brighter light in shorter time and deliver the same energy, maybe it's going to work the same. Sterile keratitis is kind of an interesting thing that we've never seen, but there was a big series of 700-some eyes in Middle East and Lebanon, I think, where they found some sterile keratitis, and I actually read that paper and I was like, or it was actually called a late onset PUK, but I don't know. I just haven't really heard about that in the U.S., so I'm not quite sure what that means. But certainly, infection is a possibility, and there have been a few infections reported in these patients. None in our center, fortunately. We have alternative treatments. We can't forget about those. Intax actually work pretty well, but I think they're less predictable, but we have some patients who have had real stabilization of their keratoconus with intrastromal corneal rings, and Intax is the most common brand used in the U.S. I'm going to just briefly, briefly touch on a couple other things here. I want to give our fellows plenty of time, but people wonder about other uses for cross-linking. This study came up where it was in Europe, I can't remember exactly where, but they just took these keratoconus suspect patients and just did PRK on them and they were older patients thinking that, well, probably they're pre-keratoconus is stable and they actually did very well. So that's maybe a testament to say, well, maybe we shouldn't be cross-linking older patients. I think the jury is still out on that. Infectious keratitis, it sounds like it would be a great use, but part of the problem is that the light doesn't really penetrate deep enough for many really severe corneal infections, but it has more efficacy in bacterial infections. It might make a lot of sense in a really kind of underserved setting where people may not come back and you just want to do what you can to try to debulk their infection, but one of the infections that we would love to use it for, if possible, would be a canthamoeba, but superficially, canthamoeba is actually pretty easy to cure with drugs and scraping and degrading and all the things. We try to identify that infection early. Once it's more deeply established, cross-linking really has not been shown to be very effective. And similarly with fungal infections, which also might be logically tried, it's a possibility to treat because they're so hard to cure sometimes, but it really is a lack of penetration. In our setting, it's just not practical. I mean, the drug's too expensive. We haven't used it for infectious keratitis. It doesn't work for radial keratotomy. I think that's pretty established. Some people say, well, it decreases the diurnal fluctuation a little bit, but there are some case reports, but also a lot of anecdotal evidence from practitioners. It really does not work to help radial keratotomy patients. I would like to try it on Terian's Marginal Degeneration. So if you have a person with active Terian, send them to us and we'll try to do cross-linking on them. I think it would work for that. I'm going to just go on here. So what about doing it in normalize, combining cross-linking with high myopia-lasic has actually been shown to be very effective. Combining it with PRK has been shown to be also effective, more effective if it's staged. There are a couple of papers out on this, meaning do the cross-linking first, wait six months, then do the PRK. That makes sense because I've already told you that things change a little bit after cross-linking. Interestingly, with the lasic patients, there was a big study, well, I'll just mention, usually they're not putting quite as much energy into these patients who get combined cross-linking with lasic or PRK. Three Joules as opposed to the 5.4. This lasic study by Kenalopoulos, who's a U.S. guy but did this study in Greece, they actually had really good results and so I think they're really, I mean it's not far-fetched to do a thin flap lasic on a keratoconus kind of suspect or at-risk patient if you cross-link. Definitely had very good results in this study. Most of us would do PRK. So it's effective, it's available. Please try to identify keratoconus early in your young patient. Send them to us. We want to see these people. We are getting insurance to pay for it reasonably well. We're not losing money, not really a money maker for Moran, but we're not losing money and we feel like it's really an important, almost public health kind of thing to try to prevent keratoconus from getting worse. You see that one young person that goes blind from their trauma after their PK and that's all you need to see. You're motivated to do cross-linking. The body of evidence supports the traditional Dresden protocol. I think along with a lot of other really hard questions for our new generation of doctors on how to pay for healthcare, this is just a good example of why you all need to get involved and try to apply some common sense to the medical-industrial complex if you can. And if you have any really brief questions, I'll take those. This is from my hike to Kings Peak two weeks ago. Yeah, Roger. Just to kind of laser scrape, you mean? Yeah, you know, that's a really interesting area and we're trying to put... I mean, combining trans-epithelial PRK and cross-linking makes a lot of sense because the epithelium acts like a, you know, a masking agent and we know in keratoconus if there's a cone and a bulge inferiorly, the epithelium is going to be thinner over that. So actually if you do a trans-epithelial PRK plus cross-linking, that makes a lot of sense. We've been trying to get the software for the laser scrape for our Allegretto for years and it's just not approved in the U.S. But people are starting to do that and I think we'll just start doing it. We'll just use... We'll double-card and figure out a way to do it. But that's a good point. That would be a good way to do it. Anything else?