Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole, and we have a panel for you today with three Northwestern Medicine physicians highlighting the 2025 AAO Conference, a thought leader recap. Joining me is Dr. Robert Feder, he's a Professor of Ophthalmology, the Vice Chair of Education, and the Director of Cornea Services in the Department of Ophthalmology; Dr. Liza Cohen, she's an Assistant Professor of Ophthalmology; and Dr. Timothy Janetos, he's an Assistant Professor of Ophthalmology as well. Thank you all for being here so very much. So as we get into this conference, Dr. Feder, I'd like to start with you. How was the event overall in your opinion? Do you have some initial highlights you'd like to point out?

Robert Feder, MD: I do, Melanie. But first, I'd like to just tell you and the audience how pleased I am to share this podcast with Liza Cohen and Tim Janetos, my colleagues who are outstanding clinicians and real experts in their subspecialties. So, I found this academy, and I've been going to the academy for many, many years, but this was really exciting in terms of the breadth and the depth of surgical cornea and infectious disease. So, I'd like to touch on a few of the things that I found particularly interesting.

First was cornea surgeons know that patients with glaucoma who have cornea transplant surgery, those transplants don't seem to last as long, but it's never really been codified. And there was an excellent presentation on endothelial keratoplasty and glaucoma where they looked at 1,146 cases of endothelial keratoplasty. And what they found was that the five-year survival, if the patient had had a trabeculectomy, was only 49%. And if the patient had a tube shunt, down to 33%. So when patients are having glaucoma surgery and they may need cornea surgery later on, it's certainly something worth thinking about of how you approach the glaucoma surgery in order to impact positively on the cornea transplant longevity.

I was talking with Tim Janetos earlier about a graft rejection study where they took samples of the aqueous from the anterior chamber. And if they found what are called corneal inflammasomes or cytokines in the anterior chamber, those patients were much more likely to have rejection problems.

There was a really interesting study on a procedure called DMAK, and now we know about DSEK and we know about DMEK, but this is DMAK and that's Descemet’s membrane anterior keratoplasty. So, this was, I thought, very cool. They used Descemet’s membrane on the surface of the eye in cases where there's a chronic epithelial defect. So, the advantage, instead of using amniotic tissue, which might be currently used, by using Descemet’s membrane, it has a number of positive impacts on the cornea. It promotes limbal stem cell healing, inhibits neovascularization, it'll heal a non-healing epithelial defect, and it protects against collagenase. It's better against collagenase, an enzyme that dissolves the cornea than amniotic tissue. And it's clearer than amniotic tissue, so the patient is able to see through it. And this can be done with cross-linking, if necessary. So, they found that 86% healed and 89% for limbal stem cell deficiency, 74% for persistent epithelial defects and neurotrophic keratitis at 80%. So, there was very high improvement in this new technique. And the Descemet’s membrane is dried on the cornea. It sticks by drying to the cornea, rather than putting sutures through it.

Another highly anticipated study was the DEKS Study, the diabetic endothelial keratoplasty study. We've known for a long time that diabetic donor tissue is more difficult to prepare for DMEK surgery. The Descemet’s membrane can rip and be difficult to prepare. But what we didn't know is if donors from diabetic patients would do better or worse than donors from non-diabetic patients. So, this was a large study, very well-conducted, 1,421. Two-thirds were non-diabetic, one-third were diabetic. And the bottom line was the diabetic donors didn't do any worse than the non-diabetic donors. So, it's more difficult to prepare for DMEK. But in the end, the patients did just as well if they had a diabetic donor or a non-diabetic donor. That was a highly anticipated study. It was very well conducted and gives us confidence when the donor happened to be diabetic.

We're all very interested in cultured endothelial injections. So in contrast to cornea replacement surgery, either full thickness or partial thickness cornea transplant surgery, hot off the press is this idea of injecting endothelial cells into the anterior chamber. Now, there's a great Japanese ophthalmologist, Shigeru Kinoshita, who's been doing this for over 10 years, and he's got 10-year data that shows very stable corneal endothelium and improvement in corneal edema with this.

But in the United States, we've got two companies that are sort of competing with each other, both in phase III studies. One company is Aurion, which uses gravity after injection. So, they inject the cells, they have the patient go face down, and those cells settle down onto the cornea. And somehow these endothelial cells know what to do once they get there. They use ripasudil, which is a ROCK inhibitor, which improves the endothelial function. The other company, MSL, uses-- now check this out-- they use nanoparticles among the cells, and then they use a magnet on the front of the eye. And these cells just are drawn by the nanoparticles to the back of the cornea to the right place. I mean, it was fantastic. They showed a slide, and it was like a video. And you saw the cells were colored red and they had the magnet over here, and you could just see, in over like three minutes, those cells were just going over to where the magnet was. I mean, this is like futuristic stuff, but it was really fantastic.

Now, you might say, "Well, what do you do? Do you strip the endothelium like you would for DMEK or DSEK and then inject the cells? They don't. They just go ahead and inject the cells. So then, the question is, "Well, what happens to the guttata that are there and the Fuchs dystrophy?" Well, there was a clinician who did a very nice study, basically polishing the Descemet’s, polishing the guttata to see if that would make a difference. And it turns out that the cells somehow know how to go in between the guttata, these little bumps on the back of the cornea. And if you used a concentration of 10,000 cells per square millimeter, the cells would actually cover the guttata. So, it hasn't been worked out exactly how many cells should be injected. And the bottom line is how well do the patients see, and this might be a cautionary point. It seems like the DMEK patients tend to see a little better than the cells that have had cultured endothelium injected. So depending on the patient's needs, a clinician might decide to give injections or not give injections.

The one amazing thing is that one donor-- these are cultured endothelial cells-- one donor could provide cells for a thousand patients. So if this really takes off and we really, you know, perfect the proper concentration and whether you use magnets or whether you use ripasudil or what you use for the endothelium, we really need to see how well do those patients see and do they see as well as conventional surgery?

There's a whole other line in terms of treatment for keratoconus. Intacs are polymethyl methacrylate arcuate inserts that can be placed within the body of the cornea in keratoconus patients. You could think of it like wearing suspenders to sort of shore up the place where the cornea is a little weak. And now, there are two ways of using tissue to shore up rather than using plastic. So, there are two ways of doing this. There's one called CTAK, C-T-A-K, corneal tissue addition for keratoconus or for keratoplasty and CAIRS, C-A-I-R-S, corneal allogenic intrastromal ring segments. So in both of these, you're using tissue instead of plastic. Advantages there, the plastic could tend to erode either anteriorly or posteriorly. The tissue won't do that. One of the groups uses gamma radiation to sort of kill off the cell so rejection does not occur. And it's clear, and it just becomes part of the patient's eye. So, it's very cool and there's no risk of rejection.

Ed Holland, who is renowned nationally and internationally as a ocular surface specialist, especially for surgery for the ocular surface. He made a very impassioned plea, and that was in patients with limbal stem cell deficiency, and I mean 360 degrees, don't do penetrating keratoplasty on these patients. It increases the risk of glaucoma. They're more prone to cystoid macular edema, graft failure, the graft will fail if you put a penetrating keratoplasty in a patient with limbal stem cell failure, and there's just increased inflammation. So, you want to do a keratolimbal autograft. You want to improve the surface in some way before you do the keratoplasty. But if you just do keratoplasty on these patients, they just don't do well. And the patients are much better served by having the surface improved before any keratoplasty is done.

I think the last thing I'll mention is fungal keratitis. And many cornea transplant surgeons, particularly doing partial thickness, either DMEK or DSEK have experienced fungal keratitis. And we're looking for ways of reducing that risk. And so, there was an assay that could be done that identifies live candida in the corneal storage media. So, this is a 20 to 30-minute test that can be done on the storage media before you use the tissue. And what it did was it reduced the risk of candida from 11 cases in 25,000 to one case in 25,000. So, is it worth doing this to prevent, you know, 10 cases of candida after keratoplasty? I think most surgeons would say, "Boy, that's certainly something to think about."

Melanie Cole, MS: Dr. Feder, this is absolutely fascinating and you have so much information to impart to us. So, I'd like you to keep going here, and I'd like you to speak about what you feel as you've been telling us all that you've learned, how you'll be leveraging a lot of this exciting stuff-- and what an exciting time in cornea. So, tell us how you're going to be leveraging some of this in your practice.

Robert Feder, MD: Well, you know, Melanie, obviously, it's our goal to bring the things we learned from the academy and make that part of our clinical practice. Many of the things that I saw that were the most exciting we're probably not quite ready for prime time. Here's an example. How about AI machine learning that can be used to identify the source of infectious keratitis? So, this study, they took 1200 images of different kinds of infectious keratitis. And AI was beginning to learn how to say that this is a mold, or this is pseudomonas, or this is what the organism was. I mean, if this is the future of cornea external disease, are we in trouble? I mean, is this going to take our jobs away? I don't think so. It's certainly not ready for prime time, but really cool, is it not?

We're interested in the SCOT2 study. The SCOT2 study was looking at the use of steroids, and whether when and where you could use steroids for infectious keratitis. And one of the questions that has been asked for a long time is whether collagen crosslinking or cornea crosslinking should be used in infectious keratitis. And what the SCOT2 studies showed was that you ended up with larger scars and more pain if you did crosslinking. So, this study said to me-- and if I'm going to, you know, bring what I've learned into my clinical practice-- if I had a recalcitrant infection, would I go ahead and do cross-linking? Based on this, I probably would not, because the patient seems like they're not going to do as well.

One of the other things, the minimum inhibitory concentration. So when we're looking at sensitivities, we want to know how sensitive is the bug to actual antibiotics or antimicrobials that we're using. And it showed that the MIC is predictive of a worse vision and scar size. So if the antibiotics were relatively resistant, those were corneas that weren't going to do well in the long run. I found that interesting.

Topical insulin is now being used, and this is something I would integrate into my clinical practice, is the use of topical insulin, one to two units per milliliter for persistent epithelial defects. So, insulin not only treats your diabetes, but insulin can help heal a chronic epithelial defect.

I was talking with Dr. Janetos before we began filming about antibody drug conjugates. These are antibodies that target cancer cells, and these are becoming used more and more frequently in the treatment of difficult cancers. And this was a very important statement that was made or study that was made, and I am definitely going to integrate this into my practice, is that some of these medications are associated with external disease problems like conjunctivitis or keratitis or white plaques on the cornea, pseudo-microcysts, little bubbly microcysts on the surface of the cornea. And when we see these changes, our inclination is to go to the oncologist and say, "Look, this patient is having eye problems. You probably should stop the medication." And the proper thing to do is not to stop the drug because when patients had these changes, they lived longer. It almost means that these drugs were working, because they're targeting the antigen not only in the cancer, but some similar antigens in the cornea. So, it's almost like a canary in the coal mine that tells you that this drug is working. If you stop the drug, the patients don't live as long now. Now, if it's a severe complication, like a corneal melting, that's really significantly dropping the vision and sight-threatening, that's a different situation. But for these minor problems, if you can use artificial tears or serum tears or vitamin A or other ways of getting the patient through it, they're actually going to live longer because you've not stopped that medication. That's a really important one, easy to integrate into anybody's clinical practice.

Melanie Cole, MS: Wow. As great an educator as you are, Dr. Feder, and as much as you've learned from other presenters, what about your presentation? Because, obviously, you are so good at this. Why don't you tell us some of the highlights from what you presented?

Robert Feder, MD: All right. So, I gave three talks at the academy, and I really enjoy delivering two of these. One of them was the first time I'd done it. But let me tell you about those first two. One is tips and tricks for impending corneal perforation. So, nothing is scarier than a comprehensive ophthalmologist, looking at a patient who looks like they're thinning to the point of near perforation. Some clinicians want to get that patient to a cornea specialist as soon as possible.

There are some warning signs. And I think if you see these warning signs, then you know there's a problem brewing. And maybe you can get the patient to the cornea specialist a little sooner. One is radial folds. You see these radial folds in the cornea to an area that's a little suspicious. That's warning sign number one. Another warning sign is clearing centrally. So, you're treating the patient with a cloudy cornea and you're using these medications that are strong antibiotics, and you begin to see the cornea clearing in the center, to the novice trainee, they look and say, "Wow, we're really making progress here. Look how much the cornea has cleared." And the patient might even say, "You know, Doc, I think I'm seeing a little better." But that's a real warning sign, because the cornea is thinning in that area. There's just not as much cornea there to make it cloudy.

Another great use of technology in these cases, sometimes there's a cloudy cornea and there's a hypopyon, which is a layered pus in the eye. And they're so cloudy, you can't tell where the cornea stops and where the hypopyon begins. If you use anterior segment OCT, we are like really into this technology of borrowing from our retina colleagues and making this useful in the anterior segment. But anterior segment OCT will show you where the cornea is and where the anterior chamber is, and you can judge how thin the cornea actually is. And maybe that's a warning sign that you need to get that patient to the cornea specialist.

And also, the use of amniotic tissue. Amniotic tissue can be used in thin areas that aren't healing well. You can layer this, and then actually put mattress sutures over the amniotic tissue to sort of hold it in place.

The second talk that I wanted to talk about a little bit was a corneal dystrophy update. Years ago, I chaired the Basic Clinical and Science Curriculum. This was the committee that puts together these 14 volumes of ophthalmic knowledge. And ours was Section Eight on Cornea and External Disease. And for the last probably 10 to 12 years, we've been doing an update on the BCSC for cornea and external disease. So, my charge was to spend nine minutes talking about an update on corneal dystrophies.

And so, the things I'd like to share in this podcast is I'd like to share the IC3D, which is the International Committee for the Classification of Corneal Dystrophies. We consider this the bible of corneal dystrophies, and it's available free. You can put IC3D in your favorite browser or maybe put that with cornea, and you'll get this free download. A beautiful colored pictures of all the dystrophies, a deep dive in the corneal dystrophies. So definitely, you want to have that in your ophthalmic library.

And then, I talk a lot about technology and how technology enables us to differentiate certain corneal dystrophies. A technology of major importance is using tomography in cases of Fuchs dystrophy. So, Fuchs dystrophy over time can cause swelling of the cornea. And by using corneal tomography or if you have a topography to device, if we look at the isopachs, those are the rings around the thinnest cornea, if they're irregular and if the thinnest cornea is decentered nasally and if there's posterior depression, those are findings that are consistent with the beginnings of corneal decompensation or corneal edema. So, looking for those signs, when you have confluent guttata and you're wondering if I'm going to do cataract surgery, is this patient likely to go on to corneal decompensation? You can look at these findings on corneal tomography. And it gives you insight as to how stable that cornea is going to be.

And the other thing to keep in mind is that many genotypes exist for the same phenotype. So, you can look at five different patients, they might all look the same, but the genetic abnormality is different in all those. And the same is true. You might have the same genotype, but there are many different phenotypes that come from that same gene. So, it's important to understand the complexity and the need for genetic testing. You might have a corneal dystrophy that you say, "Oh, this is brand new. There's never been one like this." But if you do genetic testing, you find out it's just a variant of a dystrophy that's already known.

So, these were the highlights of my talk on corneal dystrophies. And I encourage you to get that IC3D paper that was published in Cornea Journal. It's really terrific.

Melanie Cole, MS: As much as you have discussed here today-- and it sounds downright sci-fi, some of it-- it is very exciting. I'd like you to summarize what you feel that colleagues who may not have been able to attend would really have liked to know. It's kind of in your opinion, is there anything else, important information, learnings, that you would like to make sure that we hear? Because, boy, there's so much.

Robert Feder, MD: Right. I would say the two big takeaways that I would like clinicians out in the cyber world to take away one would be Dr. Holland's plea not to do penetrating keratoplasty when the surface is completely disrupted. Those patients will not succeed. They will end up with more complications, and it'll be a dismal failure. You want to improve the before you do any kind of keratoplasty.

And the second thing was these targeted antibodies in cancer treatment, you will encounter these are being used more and more, and I feel that my colleagues are going to encounter conjunctivitis and different kinds of punctate keratopathies and maybe even white plaques on the cornea. Don't stop the drug. Don't make your oncologist feel these are terrible eye problems, you need to stop the drug. Use artificial tears, Vital Tears, like serum tears, vitamin A, ways of enriching the surface. Try to get the patient through. Support the patient so that they can continue to use those drugs, which are life-saving. The study showed it added a year of life, even if they had eye problems, in fact, especially if they had eye problems, because that means that the antigen in the cornea, similar to the antigen in the cancer, it's working. So, you want to support those patients and keep them going. Those would be my two most important takeaways.

Melanie Cole, MS: Thank you for all that information, Dr. Feder. That was absolutely riveting. And now, Dr. Janetos, onto you. I'd like you to speak about the uveitis and cataract highlights that stood out for you.

Timothy Janetos, MD: Well, thank you very much for having me. And I first have to commend Dr. Feder for the whirlwind cornea highlights at the AAO. Clearly, there was a lot going on at AAO. And you went through I'm guessing pretty much everything in cornea world there at AAO, so that was wonderful. Some things I would like to highlight that I think is one of the main takeaways for me when it comes to uveitis care is just how many new novel therapeutic agents are on the horizon. And by on the horizon, I mean, in the next two to three years even, we may see some of these agents coming out. And some more data and trials that really help us know how to treat uveitis patients.

So for instance, you know, currently there is only one systemic FDA-approved medication for uveitis, which is adalimumab. And we use a lot of different medications off-label, some of which are highly supported by data, some of which we really don't have much data to support their use. Now, adalimumab works very well for uveitis, but it still fails in about 40% of our patients. So, there's a number of patients that are resistant to this medication. It's also a biologic medication. So, it is difficult to produce. It is expensive and it is not available in, you know, limited resources settings.

There are other medications that are used in rheumatologic conditions that we use off-label. One of these are JAK inhibitors that are approved for a variety of rheumatologic conditions, such as rheumatoid arthritis. And they are small molecule inhibitors, JAK inhibitors. They're not biologics. They're easy to produce, and they're oral medications, unlike biologics, which are injectable. And we've used them in uveitis before, but we really have no data to support that use or no good data. And they're not used on-label, so it's hard to get insurance approval for them.

There are now two phase III trials, JAK inhibitors in uveitis. One of them, the HUMBOLDT trial that was recently published, showed a very high success rate of JAK inhibitor, especially for anterior uveitis. So, this is something that I think will have FDA approval in the near future. I mean, I really do think in five years. And it'll provide a lot more ability to treat our patients.

Another trial when we think about therapy for uveitis is there's systemic therapy, but then there's also local therapy. And we currently really only have systemic or topical corticosteroids, periocular corticosteroids, intravitreal corticosteroids, which typically work great for the non-infectious uveitis, but they cause cataract. They cause glaucoma. So, they have a lot of side effects. We are now developing more targeted local inhibitors. So, interleukin-6, which is implicated highly in non-infectious uveitis and has been shown to be in high levels in the vitreous and aqueous humor in uveitis patients. And we actually use systemic interleukin-6 inhibitors for uveitis patients. There are now phase III trials that were reported at the AAO of intravitreal IL-6 inhibitor that had two phase III trials that were recently published. And it showed a very good success rate in treating cystoid macular edema, not only treating it well, but comparable to corticosteroids and an improvement in the patient's vision.

So, this would be, you know, I don't want to say anything is a silver bullet, but it could be a silver bullet in the sense that we would finally have a non-steroid option to treat uveitis locally that wouldn't come with those side effects of cataract development or glaucoma development.

So, I think that the main highlights for me at the AAO is really just how many therapies are on the horizon. I mean, these are phase III trials that I'm talking about that have already completed. So, the next step is just FDA approval, and I do think they'll be part of our armamentarium to treat uveitis going forward.

Melanie Cole, MS: So on the very near horizon, and that's very exciting. What will you be leveraging in your practice as you're talking about these? Tell us how you're going to be using them yourself.

Timothy Janetos, MD: Well, I think if we do, and I know we will soon, have an IL-6 inhibitor that is local for local treatment, that will really be a game-changer. And I think we will stop using a lot of the local corticosteroid agents or not use them nearly as frequently. And we'll be able to avoid giving patients glaucoma and giving patients cataracts. You know, a lot of the agents, for instance, the JAK inhibitors that I mentioned, we do already use off-label for our uveitis patients that have failed adalimumab, the FDA-approved medication, but it's very hard to get those agents. So, insurance won't approve them. It's difficult. And to be honest, we don't have good data to support their use. We have a lot of observational retrospective data. We're almost at sometimes throwing things at the wall and seeing what sticks in some of these patients. So, having data to support their use and having FDA approval would be a game-changer in order to get insurance companies to cover these agents, to have other options for patients who, you know, fail other therapies.

In terms of, you know, changing my practice from things that I saw at the AAO, and again, this is along the same route of therapeutics, but in a different way is, you know, we know some things that work in uveitis care, but we don't know when to stop the medication. So, JIA patients with juvenile idiopathic arthritis who also have uveitis, we treat them with these agents and we keep their eyes quiet, but we never really know when to stop therapy. And now, there's a large trial that was presented. An NEI-funded trial that looked just at those patients, those who are younger, who have chronic uveitis and who are controlled on adalimumab. Do we stop the medication or do we continue it?

And so, it enrolled patients who were quiet for on average two and a half years on the medications. And then, it switched them to placebo. So basically, stopping the medication or continuing adalimumab. And there was a very high failure rate in those who stopped adalimumab therapy after about two and a half years on average. And that is something that really will change practice, I think, for a lot of uveitis specialists. Because right now, the general guidelines from rheumatologic organizations is for chronic uveitis control, we keep patients quiet for two years, and then we try to taper therapy or stop therapy. And a lot of times, we fail. And what we saw in this trial is there is a very high failure rate, especially for pediatric uveitis. So, you know, I think it's still worth for patients trying to take them off of medications. But I'm going to be a little bit more hesitant, for sure, especially for my younger patients on perhaps keeping them on these medications a little bit longer before trying to stop them.

Melanie Cole, MS: Dr. Janetos, you had a presentation as well. Tell us what you talked about.

Timothy Janetos, MD: So, I had two presentations this year, and one of them was a sort of general presentation on if a patient walks in with anterior uveitis, what do you do? You know, my main points of that presentation is, even though we're ophthalmologists and we like to look at the eye and we like to use fun technology, we still have to remember that we're all physicians and history is very important in patients. So if somebody walks in to your clinic and they have new hypopyon uveitis, it's very important to know, well, did they have cataract surgery last week, or do they have lower back pain, right? Those are two very different scenarios. One is HLA‑B27 uveitis, and one is endophthalmitis. And you treat those two very differently. So, we have to remember that history is important for these patients.

The other thing is doing a dilated eye exam for every new anterior uveitis patient. Even if it's somebody that is your routine patient, if they come in with a new episode of anterior uveitis, you can't diagnose that unless you look at the fundus and rule out issues with the retina. You know, I've only been practicing independently-- now I'm in my third year, but I have gotten referrals that have been for anterior uveitis with no dilated eye exam. And 99% of the time, it's fine. But 1% of the time, there's, you know, acute retinal necrosis in the back of the eye. So, it's very important to do a dilated exam for all patients.

The second presentation that I gave was with a group on cataract surgery in uveitis patients. And I think the biggest takeaway that I would want to give for that is that the cataract surgery is not the important step. That is the number 10th on the list of important steps. It's really about the preoperative management and the postoperative management of these patients.

So in uveitis patients, it's very high risk to perform surgery, and we want at least three months of eye disease quiescence. And we want a lot of perioperative treatment and frequent followup afterwards. And counseling the patient is very important, because these are higher risk surgeries and there is likely already structural damage from the patient's uveitis. And so, it's important to let the patient know that this is not a routine cataract surgery that you're going to be following with me frequently afterwards.

The last thing is everyone always asks about, "Well, what is the, you know, uveitis treatment around the time of surgery?" And there's no one-size-fits-all. It depends on the etiology of the uveitis. It depends on how long it's been controlled for, how hard it was to control. And we use everything in our toolbox. We use oral prednisone, we use periocular steroids at the time of surgery. We use intravitreal injections of steroid implants. All of these things, we can use to try to keep the patient quiet at the time of surgery. And it really all depends on, you know, that individual patient and what their uveitis is.

Melanie Cole, MS: Dr. Janetos, it sounds like there was so many important learnings from this year's conference for you to discuss, including your presentation. So, what else? If you were to give your key takeaways from the conference and even notable presentations from other Northwestern medicine physicians, what would you like other providers to know that may not have been able to attend?

Timothy Janetos, MD: Well, I think the biggest thing is that in five years from now, treatment's going to be very different for uveitis patients. Just like 20 years ago, all we had for our patients was oral prednisone and methotrexate. And a lot of times, we failed with treating them. And now, we have a whole host of options. And I think in five years from now, we're going to have many, many more, and that means better control of our uveitis patients, preventing those complications such as cataract and glaucoma. And I think we'll have more data to support use of agents that are already on the market that just need approval for uveitis. So, I think give it five years, and we'll be in a totally different spot.

Robert Feder, MD: I actually had a couple questions for Dr. Janeto, if that's okay. So, one is how do you know if the uveitis is due to interleukin-6? I mean, are you doing a tap and doing an assay? How do you know that?

Timothy Janetos, MD: Well, no, it's interesting because I know we chatted very briefly about this. But there are researchers out there who are trying to develop a profile of a uveitis patient. So, that is taking fluid from the vitreous or from the aqueous in various diseases and phenotypes that we know of. So, HLA‑B27 uveitis, and then seeing, "Okay, what are the specific cytokines and inflammatory markers that are unique to that type of disease or that phenotype?" So, why does adalimumab only work in for 60% of patients and not the other 40%? And maybe it's because adalimumab is targeting TNF-alpha, but there are certain phenotypes or diseases that TNF-alpha is not the driver.

So, that is maybe the 20-year goal where we know that each disease is really driven by this specific set of cytokines, or maybe it is more personalized. And when someone walks into the room and they have uveitis, you take a sample and you run the cytokine panel and it says, "Okay, these are the top ones, and these are the agents that are going to be most effective." We're definitely not there yet, but maybe 20 years from now.

Robert Feder, MD: My other question was with regard to cost. Whenever these fantastic new drugs come on the market, they're so astronomically expensive that it's very difficult to use them, your patients can't afford it. Do you have any sense of whether there would be compassionate use, I mean, especially if you have children with severe uveitis?

Timothy Janetos, MD: Yeah, I mean that's always a difficult question, and there's no good answer. You know, I think that some of the medications that I think will be on the market are already medications that have been around for five, ten years. They're just now being approved for indications of uveitis. You know, some of the companies that make these drugs will have compassionate use programs or they'll have copay assistant programs that will allow patients to be on the medication.

The last thing I would say is there are generics now, and they're not so much generics, they're called biosimilars. Because a biologic agent like adalimumab, you can't make a generic version just inherently. But there's a lot of biosimilars on the market, which are slightly different drugs, but the costs are slightly lower. And so, they do make them more available to certain patients. But we don't know how effective they are for uveitis. So, there are different avenues for sure to get patients what they need. Good news.

Melanie Cole, MS: Well, thank you so much for that. And Dr. Cohen, we did not forget about you. Tell us what stood out for you in the Highlights for Orbital and Oculoplastic at the convention this year.

Liza Cohen, MD: Yeah. And thank you so much for having me for this podcast. It's such an honor to be amongst my colleagues here. So, in terms of orbit and oculoplastics, the American Academy of Ophthalmology meeting is usually proceeded by the American Society of Ophthalmic Plastic and Reconstructive Surgery or ASOPRS fall meeting. And so, you know, myself and I know a lot of my colleagues usually attend both meetings, because they're at the same location. So, I'll share some insights from both of those meetings. There's certainly some overlap in terms of, you know, new things I learned, what was presented.

But, you know, kind of the key things that were new this year at both ASOPRS and the Academy. It's actually kind of similar to what, you know, Dr. Janeto shared about uveitis treatment. There's a lot of new innovation in terms of medical management for thyroid eye disease, which has come about in recent years. You know, this historically has been a condition that's difficult to manage, has a great effect on our patient's lives and, you know, really no great medical treatments for managing it. You know, historically we used steroids and then did surgery on these patients. But it's really a medical disease. And so, recently, with the advent of teprotumumab, which is an IGF-1 receptor blocker, there's been a lot of hype about using medications to treat thyroid eye disease. And so, you know, there's multiple medications and clinical trials currently that, you know, similar to what Dr. Janetos was saying, I think it's going to change a lot of our management of thyroid eye disease and, you know, shift things potentially more medically in the future. So, some of these medications that are currently being investigated in trials are biosimilars like other IGF-1 receptor blockers, both IV and subcutaneous, which, you know, would allow for patients to inject themselves with these medicines and not need to go to an infusion center, which would be good and more convenient for them.

There's also other medications that target other pathways involved in the inflammatory cascade and thyroid eye disease, including neonatal receptor or FcRn blocker medications, which are subcutaneous as well as IL-6 inhibitors. And so, you know, I think this is a very new and exciting time. And, you know, I think in the next several years, there's going to be a lot more options in terms of medications that can treat patients with thyroid eye disease.

Other things that, you know, we're interesting and are always presented at the ASOPRS and Academy meetings in terms of oculoplastics are new surgical techniques. You know, there's lots of different talks, but some of my favorite ones that were presented that I think I might myself are using both anterior and posterior lamellar grafts, like a graft-on-graft technique for a full-thickness eyelid reconstruction. Historically, you know, the mindset has always been, "Oh, well, you shouldn't put a graft on another graft because then where's the blood supply going to come from to support this new tissue? So typically, we use flaps in addition to grafts in those cases. And since the anterior lamella and the posterior lamella and the eyelid oftentimes need to be reconstructed differently, that's typically what, you know, most people will do is a graft and a flap. However, there was one, you know, interesting study presented at the ASOPRS meeting where a full thickness skin graft was used with a free tarsoconjunctival graft. And, you know, the outcomes were excellent in terms of reconstructive results, both functionally and aesthetically. So, that's something that, you know, I might incorporate into my practice as well.

Some other interesting surgical techniques which were presented were the use of tarsal–conjunctival onlay flap or a TAO flap by Jeremiah Tao, basically for patients with exposure keratopathy or severe lower eyelid ectropion or retraction. So typically, these patients are treated with, you know, standard ectropion repair or retraction repair or like a permanent lateral tarsorrhaphy, which limits the patient's visual field, and it's not the most aesthetically pleasing. So, this technique involves doing like a mini-Hughes tarso-conjunctival flap, laterally from the upper eyelid. So, maybe like a few millimeters long. And denuding the lower eyelid margin, suturing the tarsus from the upper eyelid to the lower eyelid. And that basically provides some support for the lateral lower eyelid to be elevated and diminishes the ectropion or retraction and, you know, provides a very aesthetically pleasing result that patients tend to be happy with.

There were also lots of interesting talks about various brow recontouring or lifting techniques. You know, everyone kind of has their own preferences in terms of what they like to do for cosmetic forehead or brow recontouring. You know, one technique that Guy Massry has kind of pioneered is like the endoscopic style lateral brow lift, basically, which involves, you know, elevating the majority of the forehead through multiple incisions posterior to the hairline, but not using an endoscope. You know, knowing the patient's anatomy and the anatomy of the facial nerve and of the supraorbital and supratrochlear or neurovascular bundles. You know, you can safely do this procedure without the use of an endoscope, which obviously saves time and, you know, is safer in terms of anesthesia for the patient. So, I thought that was, you know, another technique that I'll probably incorporate into my practice as well.

Robert Feder, MD: Liza, you and I share patients who have ocular cicatricial pemphigoid, and these are patients where due to inflammation, the surface of the eye just sort of shrinks up. And maybe Tim Janeto can pipe in as well for ways of arresting the inflammation. And then, Liza, maybe you could comment on the kind of reconstruction you can do when there are symblepharon, the lid is attached to the globe. And can some of these new surgical techniques that you were learning about at the academy, can they be useful in that setting? So, maybe, Tim, you want to go first and talk about the kind of anti-inflammatories that we could or should be using for ocular  cicatricial pemphigoid?

Timothy Janetos, MD: You know, that's a great question. To be honest, I tend to let my cornea colleagues manage OCP. I don't manage it myself. But, you know, I do know that at least some of the people that I know that who do manage that typically use something like CellCept or an antimetabolite to hopefully prevent some of that scarring.

Robert Feder, MD: We have a dermatologist at Northwestern, Rachel Lipman, who does a fabulous job of helping us with these patients, and she has a special interest in these patients. Liza, what do you think about reconstructing these really tough cases?

Liza Cohen, MD: Yes. These cases are always very difficult. You know, because of the degree of inflammation and scarring of the conjunctiva, oftentimes they have significant symblepharon and entropian of sometimes all four of the eyelids with, you know, eyelashes rubbing on the eye. And it's extremely uncomfortable for these patients. You know, it's difficult to treat. But I think, you know, if you're willing to put in the time with the patient, there are multiple options for reconstruction.

You know, another thing I took away from the meeting, there was a presentation regarding ultra-thick umbilical cord amniotic membrane, which is basically a thicker version of kind of like the like see-through, you know, very, very thin amniotic membrane. And the nice thing about that is that, you know, it can provide more stability for eyelid support. You know, using that to reconstruct the tarsal conjunctiva, I think, you know, would potentially be more beneficial than the thinner amniotic membrane, but less thick than, you know, the other option, which is taking a mucus membrane graft from, you know, either the buccal mucosa or the nasal mucosa. And those procedures also have the downside of having donor site morbidity when you're taking a graft from somewhere else on the patient. So, that's, you know, something I'm looking into incorporating into my practice as well. But yeah, I mean, these cases are always difficult. And, you know, thankfully, we're able to work together on these sorts of things.

Robert Feder, MD: Yeah, that's always helpful.

Melanie Cole, MS: Dr. Cohen, what did you speak about?

Liza Cohen, MD: Yeah. So, I gave two presentations at the AAO meeting this year. The first was part of an instructional session about oncology pearls for the non-oncologist, basically geared toward like comprehensive ophthalmologists. And it was a fantastic session with interesting talks on anterior segment, on eyelid, on orbit, and on, you know, various biologics and their ocular side effects. So, my presentation was regarding the management of eyelid lesions in terms of, you know, key features to diagnose benign versus malignant eyelid lesions and how, you know, we can better distinguish from these things in terms of the patient's history and clinical exam. And then, also, you know, going over the most common benign and malignant eyelid lesions of the eyelid so that we can better recognize these lesions.

And then, I also talked a little bit about pearls for doing eyelid lesion biopsies, especially for comprehensive ophthalmologists. So, namely, you know, first off, knowing when to biopsy if something looks suspicious. If there's eyelash loss, if there's loss of the meibomian glands, distortion of the normal tissue architecture, if there's rapid growth, those are all concerning signs for possible malignancy. If the patient's immunosuppressed, if they're a smoker, if they have significant sun exposure, those are also risk factors. And then in terms of actually doing a biopsy, you know, important things are documenting first with photographs, communicating your suspicion to the pathologist, making sure to obtain a nice representative specimen. And so, that was one of my talks at the meeting.

And then, the other talk was part of an orbital radiology session that was put on by the NASAOS or North American Society of Academic Orbital Surgeons Group, which I'm a part of. And, you know, that session focused on various conditions within orbital pathology and their radiologic features and kind of new things in terms of in radiologic diagnosis. And so, my talk was regarding imaging in patients with thyroid eye disease. So, I reviewed the most common imaging techniques that we use in these patients, namely, computed tomography or CT imaging, magnetic resonance or MRI imaging, and ultrasonography. And I reviewed, you know, the various reasons why you would obtain one type of scan over the other, and then what those different scans can tell you. And just in a nutshell, I think CT imaging is most useful when planning for surgery, particularly orbital decompression surgery, which often involves removing the bone of the orbit to expand the orbital cavity. And the bony anatomy is highly variable in patients. So, it's important to have good preoperative imaging. And CT imaging really provides superior imaging of the bony anatomy compared to MRI.

MRI imaging, I think, is useful, particularly when the diagnosis is uncertain. You know, maybe something looks like it could be thyroid eye disease, but there's some atypical features, you know, that could make you think, "Oh, is there something else going on?" Like a different type of orbital inflammation or lymphoma, or a carotid cavernous fistula. There's lots of different conditions that can present with proptosis or bulging of the eyes, like thyroid eye disease does. And so, MRI provides better soft tissue detail in terms of imaging as well as better characterization of contrast enhancement. And so, for those reasons, you know, I think, it's better when the diagnosis is uncertain.

Also for malignancies, there's various imaging sequences on MRIs such as diffusion-weighted imaging and apparent diffusion coefficient or ADC imaging sequences, which can provide additional information if there's a mass in the orbit that you think might be benign or inflammatory versus malignant. So, I think for those reasons, MRI is preferred when the diagnosis is uncertain. And in addition, if there's concern for compressive optic neuropathy, I think oftentimes it's useful to have both CT and MRI in thyroid eye disease patients because CT will provide useful information for potential bony decompression, which a lot of those patients end up needing.

But MRI is useful in terms of determining if there's enhancement of the optic nerve, exactly how large the muscles are, how much inflammation is in the orbit. And then, ultrasound as an imaging modality can be useful in terms of monitoring patients in the clinic. It's much less invasive; however, it's limited by the depth of evaluation. So, those were my two talks at the academy meeting.

Melanie Cole, MS: Is there anything else, Dr. Cohen, that you would like to mention? Any key takeaways for your colleagues that may not have been able to attend?

Liza Cohen, MD: Yeah. So, you know, the ASOPRS and the AAO meetings are always very useful for oculoplastics in orbit. You know, I think the main takeaways from this year's meeting were, like I mentioned before, that treatment of patients with thyroid eye disease is really going through a revolution currently with all these new medical therapy options that are in the pipeline. And so, I think, you know, being aware of these options and, you know, perhaps enrolling patients in these trials and knowing that these things are going to come to fruition and be approved by the FDA in the very near future is really exciting.

And then, you know, some of the surgical techniques I mentioned are always, you know, fun things to try and there's oftentimes videos. And, you know, for these meetings, you can also-- if you didn't have the opportunity to attend-- you can register for the meeting virtually and oftentimes watch a lot of these videos and see how these types of surgeries are done.

Melanie Cole, MS: What an exciting conversation. I want you all to give one last final thought, and I'm going to start with you, Dr. Janetos, what you are looking forward to as follow up to this year's event? What's on the horizon? What's exciting to you, Dr. Janetos, and what are key takeaways from this really interesting conversation we're having here today?

Timothy Janetos, MD: Well, the followup is whether anything that I mentioned here actually ends up happening. So, I can think of numerous examples, you know, a few years ago where there's always something exciting on the pipeline. And it's just there and it's right at the end, and then it never comes to fruition, whether that has to do with that last study that it didn't end up working as well as it seemed to be presented to or, honestly, for business reasons. You know, uveitis is a rare disease. It's an orphan disease. So, it's sometimes hard to get these therapeutics through the door. So, that's really going to be the next two to three to five years, whether these therapeutics come to market. And I hope they do. I have a lot of hope and a lot of them show a lot of promise, and they really are at the end of the pipeline. But it's yet to be determined.

Melanie Cole, MS: Dr. Cohen, you're up next. What are you looking forward to as a follow-up for orbital and oculoplastics?

Liza Cohen, MD: Yeah. So, you know, similar to what Dr. Janetos had to say, I think hopefully seeing these new medications to treat thyroid eye disease go through trials, hopefully become approved and actually be able to use them and in clinical practice, you know, is something I'm certainly looking forward to for patients with this disfiguring condition. And then, also, like trying out some of these surgical techniques for myself and talking to colleagues about it and, you know, hopefully seeing some follow-up presented at our next ASOPRS meeting in the spring.

Melanie Cole, MS: Such an exciting time in all of your fields. And Dr. Feder, you know, I was going to give you the last word here. What would you like the key takeaways to be from this discussion today and really the most important aspects, what you see on the horizon, what you're most excited about?

Robert Feder, MD: Well, to be honest, I think the thing I'm most excited about is the level of enthusiasm in innovation. You know, you may think that the world is an unsettled place. But in ophthalmology research, clinical and lab research, there's a tremendous amount of enthusiasm and cooperation. When we think of Dr. Shigeru Kinoshita work in Japan with injecting cult-cultured endothelial cells, I mean, these are in phase III trials. If this takes off and you can have one donor provide enough tissue for a thousand patients, I mean, what could be more transformative than that? So, you know, that's just one story and there are many stories like that.

Your biggest takeaway is that we're in a tremendous field and there's great enthusiasm and great cooperation between clinicians in different countries and clinicians within our own country.

Melanie Cole, MS: Well, certainly the enthusiasm and the collaboration is so exciting. And I thank you all, because this was really such a great discussion and there were so many things that you learned at this year's convention. So, thank you for imparting that wisdom to us today. And thank you again for joining us. And to refer your patient or for more information, you can visit our website at breakthroughsforphysicians.nm.org/ophthalmology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole. Thanks so very much for joining us today.