00:00 Good morning everybody. Thank you very much for the program chairs for inviting me to come from California to my home state of New York.

00:07 I grew up in Rochester. I went to medical school here at Cornell. So it's awesome being back. Today I wanna talk about barrio and ask a provocative question. Is this really the most neglected emergency? Here's my financial disclosures. Nothing is relevant to this talk.

00:27 Different.

00:33 So, All right, here's a visual field. You guys can probably diagnosis as bad glaucoma. Optic nerve and, inferior arc, nasal step, all connecting to probably advanced moderate advanced glaucoma. Right. And we spend a lot of time and energy on glaucoma. Next door, there's probably a whole session. There's a whole subspecialty on glaucoma. Spend about $3 billion to try to prevent this disease or treat it or diagnosis surgeries it or drop it.

01:08 And that's the same as the GDP of many small countries. Right. And we do it on glaucoma. And I'd argue that most of that money is spent very early before the patient even has glaucoma. Okay, here's another visual field. This one's not from glaucoma. It's from this beautiful barrio with a horn, horse plaque, distal retinal whitening and inner retinal hyper reflectivity and thickening on the Oct.

01:34 We don't spend $2.8 billion on pre okay. But yet it's a similar deficit. So the question is why is there such a big difference in the investment. And it could be just because there's no treatment right. Historically. Or whether it's ocular massage IOP lowering you can try hyperbaric oxygen. You can try the YAG laser or even go in and do vitrectomy and try to pull out the MLS.

01:59 I think we all know none of that stuff works really well, so maybe if you can't treat it, you don't think about it. Or maybe it's more insidious than that. And it's this paper, really the only big paper on bio in the literature from the late, great doctor Ray. And he found this to be kind of a benign disease, with 89% of patients getting a better than 2040.

02:20 He even found that people who started with good vision, ended up with bad vision, end up with good vision. And this is kind of a killer statement. It's like, well, if the natural history is so good, how are you going to ever prove that a treatment works? Right? And this may have really kind of hindered the thing. And I'm not sure these really fit with modern clinical practice.

02:38 And let me show you this patient case. You know, it's an 82 year old, white female that she had over her left eye. She's a vascular path. And sure enough, she has a really a vision ruining, destroying bio. And another beautiful Highland horse plaques. Right. This patient was 2400 and never got her vision back. And also and we'll get into this as well.

02:58 When we went to the emergency room, she has another thing that's not great. And that's two strokes going on the exact same time. So we really want to study our patient population, figure out how often all of this is happening. So we try to find the true north on this. We looked at all of our patients who have been coded for a barrio that's about thousands of patients.

03:19 And with our medical students, our residents and our attendings, we really carve that out to really 760 patients with a definite multimodality imaging confirmed diagnosis of barrio. Okay, these patients all had symptoms within 30 days of the diagnosis. These aren't patients with all diagnosis. These aren't patients with misdiagnosis. These aren't patients with just like a cotton wool spot or whatever.

03:40 These are the true thing. And we have about 450 these patients who we had follow up for. As you can imagine, we saw a lot of beautiful Highland horse plaques. It's kind of a just a gorgeous retina is gorgeous. And this is a gorgeous study to do. And you can see all the plaques here, here. The results, on baseline is a sick patient population.

04:00 As you can imagine. All of them are vascular past lots of smoking. And this is Northern California where there's not a lot of smoking. But these patients seem to be doing that. You can see from their past medical history the fair amount of mis pass strokes. And honestly, a lot of them are already on medications that you would use to kind of prevent this disease but still develop the disease nonetheless.

04:26 This thing is interesting. Okay. First conclusion it's not a benign disease. If you take the whole patient population, a third of these patients end up 20, 50 or worse. Okay. So a third of the patients are going to lose their driving ability or driving vision in that one eye, depending on your state. If we just look at the patients who were before the event, we had an optometry visit or another ophthalmology visit, and we knew they had good vision.

04:48 You know, they were 20, 40 or above. A quarter of those patients go on to be worse than 2040. Okay. So I think point number one, I think we've shown this is not like a disease that you want. We did find the opposite of doctor here, that the presenting vision strongly impacts the final vision, which I think that makes intuitive sense.

05:07 Like if you present worse than 2050, there's about a two thirds chance you're going to remain that way. This stuff's more interesting, the kind of presentation, you know, we've done a big study on scenario and in general, those patients, because they lose all the vision in one eye, they will make their way to the emergency room at some point, urgently.

05:26 But for perio, it's almost like they feel like they can sleep it off. Their glasses are blur or need to be changed, or their contact lens isn't quite right, so maybe half of them are waiting for an appointment with their optometrist or ophthalmologist, or they're just calling the call center and asking for device. And our call center. Although they know acute monocular total loss is an emergency, I'm not sure they've been trained to think that maybe partial losses as well.

05:48 So because of that, they're not coming to emergency services very quickly. Maybe I'll call them within a day, some of them waiting more than a week. And if we're ever going to treat this thing, it's going to have to be done acutely. As you probably all know, this is probably the most important thing of this entire talk. The risk of stroke or MI again, because this is a patient, a pure patient population.

06:08 I think this is probably one of the best estimates of risk of stroke in this patient population. And I'll tell you, if you see these patients in their chair, they're really in danger. They're in grave danger. There's about a six times risk for below ten times risk or maybe 12 times risk for creo that they're going to have that they're either having a stroke at that time.

06:31 They either are silent stroke or they're going to have one either that day or within 30 days. So these patients really need to be referred, to a stroke center. Pretty pretty quickly. Fortunately, we did not see the same thing for myocardial infarction, which is also different than in past published studies. I think this makes sense because the pathophysiology for the conditions are different, with stroke being more of an embolic phenomenon like ratio.

06:56 And am I being more of an outcome of cirrhotic local phenomenon. So in summary, patients with perio often present in a delayed fashion. It's not a benign disease. It can really lead to irreversible vision loss. And I think anyone in this audience is looking for something to really tackle next in terms of treatment. If you're tired of thinking about geographic atrophy, maybe our occlusion is a way to go.

07:18 And perhaps the most important point, it's it's a harbinger of cerebral stroke. You have to evaluate both Vo and co equal importance. And the patient may have just a small field cut and not want to go to the emergency room, not realize that this is a big deal, but you have to tell them it is a big deal because that small field cut there become a big field cut, or it could become hemi for paresis or some other neurologic thing.

07:43 So evaluate them, get them to a stroke center where they can mitigate the risks, and you guys can save your patients from really severe downstream complications. Thank you.

07:59 I think we have a comment coming up right here, Jim. Hold on. There's that. We have a question. Robin. Oh.

08:09 I don't know if that's working. That's that's a great presentation. Thank you. And I agree. And it was really a disservice to patients that the read that. So the big problem is that in the chair they may be 2050. But if it's a superior branch artery occlusion their inferior field is gone. So it's a nonfunctional eye. So we do TPA in these patients would do intra arterial TPA if they get in within 12 hours.

08:38 And we've had some successes. But I have to twist the arm of the interventional radiology because well, you know, in the literature it says this. So I'm hoping that you publish this because that's going to really be helpful because I if I sit down with him and I can explain it, I usually have to do this over the phone or a chat line that basically you're going to lose the functionality, even though they may only be maybe 2060.

09:03 It's key. And certainly your point about the risk for stroke is huge. So I appreciate that. Yeah, I wish we had more fields in our database. So that we could really help quantify a lot of that. But yeah, your point is very well taken. Okay. Thank you. I have a follow up question for you, Richard. There is a recent awesome article, a case report in ophthalmology that showed an intra arterial TPA of somebody had a central retinal artery occlusion, and they improved vision after, doing surgery within 20 hours.

09:33 Should we start doing this much more frequently? Should we try to do this? And, Richard, would you would you be taking all your arterial occlusion patients to the o.R. To intra arterial TPA? Them? So we do. You know, the Eagle trial, which also sort of tied our hands. So was done within 24 hours. So we've been able to convince, our team within 12 hours because it's safe if you're doing intra arterial, and we use Oct because it's much easier and more available then than getting a fluorescein in these patients.

10:11 So we treat anybody that comes in and then at time we may we offer that to them. Yeah. I mean, I have to applaud the centers in New York would have come together to really lead the world in getting these patients taking care of in a timely fashion with intra arterial. It's amazing. It's it's it's a challenge.

10:27 So even, you know, they come in day late and it's, you know, late. So yeah, at CP you were doing intravenous for patients with within 4.5 hours. We don't stretch that out as far an inter arterial. It just it's, it's more of a logistical burden because not all of our hospitals will do that. Or is intravenous.

10:45 All of our emergency rooms are prepped and our needle, our door to needle time is very short, and we can get patients treated within 45 minutes. With all the testing done before. Well, the stroke centers have done a great job because they they basically do it within, you know, they treated within 4.5 hours or less. But I think that there's not good education that, we can do the same thing in the eye, that the eye is a stroke.

11:12 So. All right. Thank you. So our next speaker is Doctor David Asian Palm. And he's going to be presenting the potential of tyrosine kinase inhibition a new mechanism of action.

11:27 Thank you for the heat Jasmin I appreciate it. It's always very hard to follow Robin for two reasons. Number one, he's an incredible presenter and number two, he's talking about saving lives. And I'm talking about reducing potentially the frequency of individual injections. I'm David Brown from Retina Vitreous Associates of Florida. I'm going to talk about the potential of tyrosine kinase inhibition.

11:48 I'm a highly conflicted individual. I and I do have a financial interest in both eye point and ocular therapeutics highlighted here. So we know that there is a durability need in the treatment of common retinal disease. We know that macular degeneration has poor long term outcomes with frequent injections a lot of dropout. We see a direct relationship in both macular degeneration and diabetic macular edema to injection frequency and improvement in visual acuity.

12:15 And we see the newer agents incrementally extending the intervals on the left side. You see, for Issa Mab, compared to mostly first generation agents gaining about 1 to 2 weeks in this publication of 190 patients. On the right side, you see a small study looking at most patients with a flipper 7 to 8mg, getting about 8 to 10 weeks between injections.

12:35 So we have a ways to go with durability. We also know retinal fluid fluctuations are a predictor of poor outcomes. And the bottom right of this slide, you see patients who have more fluctuation in their retinal thickness and macular degeneration developing worse visual acuity. So we want fewer and is less fluctuations. And that's where tyrosine kinase inhibition potentially comes in.

12:55 The MOA is unique. This is a drug that works intracellular leave to decrease the downstream effects of multiple transmembrane receptors that are tyrosine kinase driven, including vegetable receptors tied to receptor placental growth factor receptors. So it hits a lot of receptors. There are multiple tkis and development. We're going to focus on the two on the left side of the slide here.

13:16 UIP one I don't want to otcs TKI, both of which are in phase three development. We'll start with UIP one 901. This is of role IB anti vitriol insert. It's a polymer injected through a 22 gauge needle. It has some new mechanistic technology that was first revealed around Academy. This is implying that this particular drug may inhibit the transmembrane receptor for IL six reducing intraocular inflammation and a nonsteroidal anti-inflammatory type of pathway.

13:49 And we have data on this drug going through phase one. And phase two will focus on the phase two studies. This is the two trial of treatment experience, where AMD patients exposed to either a low or a high dose of UIP one, nine and one on the top versus weak of liver support on the bottom within a fluid receptor running.

14:06 And what we see here in this phase two trial is that the primary endpoint was met, and there was non-inferiority and visual acuity between a single dose of UIP 101 and low end high dose range versus a flavors of eight milligrams. And there was also strong anatomic control. The top two lines you'll see the blue and the purple line kind of flat after the UIP one 901 injection, you see a little uptake in average retinal thickness, but a stability of that following administration of the UIP one.

14:33 On the one you see the familiar of libre, cep, sawtooth and gray. Here we see the swim lanes for UIP one 901 dots. To the left are injections before running and treatment dots to the right of the vertical lines are injections after, with an 80 to 90% reduction and injection frequency after administration in phase two. This is a Verona phase two DME, also with UCP 1901.

14:54 Low and high dose single doses versus a single dose of a flipper also met the primary endpoint, showing a reduction in supplementation. When the UIP 101 TKI was given versus the single dose we see here in the top visual acuity and diabetic macular edema, with an improvement in acuity in patients with type one nine, and one superior to that with a flipper up on the bottom.

15:17 We see a greater dive in the CST with the TKI than with the Libre set, so it's promising. Here's an interesting slide. This shows UIP one 901 compared to the burden of study, which was recently presented on behalf of Genentech. This shows patients with DME who are given random Mab monotherapy monthly. Here is the Cardenas result. Ran a busy Mab plus anti il6 antibody improvement in visual acuity.

15:43 Here's the overlaid tracing from Verona looking at the single dose of the TKI, implying that the TKI does indeed have potentially anti-VEGF and anti il6 properties. Again, cross trial comparison. Take it with a grain of salt. We've got to bear this out which we're going to try to do safety with. UIP 1901 has been very good with no evidence of intraocular inflammation related to retinal vasculitis or occlusive disease.

16:08 In DME or AMD, we have a fully enrolled phase three wet AMD trial. Looking at Lugano and Lucia, parallel trials for registration and AMD, we are going to start enrolling in Q1, a pivotal phase three DME trial looking at repeat dosing of a high dose of UIP one 901 versus a flavor step. Q8 weeks. Very exciting times.

16:29 Let's look at the other drug. This is exiting IB. This is the other tyrosine kinase inhibitor in late phase phase three clinical trial. This is exiting IB. It's a highly selective Pan inhibitor. The basic science data on it is it is a very potent, tyrosine kinase inhibitor with a more potent formulation than the others.

16:51 In clinical study, we see that it is delivered as a hydrogel through a 25 gauge needle, similar to hydrogels used in other therapeutic conditions. This is a different development program, a little different approach. So comparing these is going to be interesting when we have all the compendium of data in the next 12 months, this one from phase one on the left straight to two.

17:10 Phase three registration will trials, a superiority trial and a Non-Inferiority trial. This is the superiority trial for exiting IB, which is looking at a single dose of the exit and IB versus a single dose of a Libre seven. The primary endpoint is looking at the proportion of patients who maintain vision, looking at basically how quickly patients lost 15 letters by the primary endpoint at week 36.

17:33 Interesting design. Here's a more traditional design. The sole our design. This is a repeat dosing trial of the otcs TKI on the top versus a flip eight weeks in the middle versus of libre. Sept 8Q6 months on the bottom. This is looking at a non-inferiority and repeat dosing a more traditional design. We're going to look at those two in compendium as potentially a registration package.

17:55 Both of those are going into an extension trial. So X these patients are all going to roll into Q six months on TKI. New program from TKI is the diabetic retinopathy trial. This again one from phase one on the left to propose phase three trials on the right side. Here the phase one study looking at 22 patients, 14 of which were exposed to Otcs TKI versus sham, showed that there was a general reduction in diabetic retinopathy severity in the blue columns on the top when exposed to a single dose.

18:25 In the phase one study of oat TKI, and on the bottom, there were zero vision threatening complications in the SS 47 and 53 patients who were exposed to the OT TKI. So it has positive early data, early phase data. Few patients look at the retinal volume, even though these were not DME patients. They all had retinal fluid because they are severe.

18:46 Dr.. Patients in that retinal volume decreased when the patients were exposed to otcs TKI. The planned Helios phase three design is a single dose of otcs TKI versus a single dose of random busy Mab primary endpoint of week 32. The second plan design is looking at a repeat dose of otcs TKI versus a single dose versus sham looking for a regression of dress.

19:09 In conclusion, few. It's a lot. Tyrosine kinase inhibition may improve the potency and durability of treatments available in AMD and DME. There are multiple studies with various designs. It's going to be difficult to compare these results to each other. We're going to have to do it thoughtfully. Tkis will probably be used with existing therapies. All of these studies in AMD have a run in with the Libre Sept.

19:32 All of them have a flavor Sep supplementation. This is going to be an ad therapy, not an order. And lastly, finally, we are entering the era of multiple modes and lines of therapy. Like all the other complex diseases in medicine, it's about time we're doing this and it's a fun time to be in drug development and retina. Thank you.

19:53 That was excellent. And it's probably going to stimulate a number of questions and comments. However, we're going to actually hold those until the end of the session.

20:02 All right I'm going to go ahead and introduce my co moderator, Doctor Jasmine Francis, who's going to present overlapping inflammation and malignancy case studies and clues. Good morning everyone. I have no financial interests or commercial relationships.

20:19 We're going to go through a series of cases. I'm going to show you, two eyes. And I'd like you to mentally make note of whether you think this is a benign or a malignant diagnosis. So here is the first two cases. And the answer is as I've shown you here. And then I'm going to explain to you why these are the malignant or benign diagnosis.

20:43 That they are. So this one as you can see here, these AML or Notic lesions along the superior arcade are actually for teller form in appearance. They are hyper auto fluorescent. There is a large amount of detritus in the eye. And on CT this is really what gives it away. You can see that there is this sub RPE material, which is pretty characteristic once you put this all together of a vitreous retinal lymphoma.

21:09 This I was treated with intra vitreous methotrexate and retouch some up and on follow up did very well and responds nicely. Conversely, that other eye that has this, a male anoxic lesion along the superior arcade, you can appreciate that it has sort of ill defined fluffy borders to it. The auto fluorescence, just like it does it is for virale can be very helpful at finding these other areas of abnormalities.

21:37 And then on the Oct what's characteristic here is you have involvement of the choroid, the retina and the vitreous. And that is all diagnostic of an inflammatory condition. What about these two large elevated melanocytes lesions. Yes. One of them is inflammatory.

21:58 And it is that granuloma that's on the right side. So let's figure this out together. What I'm showing you here is characteristic for a UVA all melanoma. You can see the pattern on the auto fluorescence. There's an extensive sub retinal fluid, an orange pigment and the auto fluorescence helps with that. The Oct demonstrates that this is in the choroid.

22:18 There is significant sub retinal fluid. This, ultrasound couldn't be more, characteristic of a UVA or melanoma. It's dome shaped. It's got low reflectivity. It's got acoustic hollowing. All signs that these are probably epithelial cells that are neatly, uniformly lined up together. When it is peripheral like this, we like to do a PubMed to determine whether the ciliary body is involved.

22:45 That's important for, treatment planning on the for which I do not routinely do. It's really good for lectures. It is not needed for diagnostics. But this shows you that there is a double circulation sign. And all of that is, characteristic of a UVA or melanoma. By contrast, here is this sclera, choroid or granuloma. You can see in the auto fluorescence it's really rather bland.

23:10 On the Oct there is some undulation of the choroid, the ciliary body is involved. And then on this ultrasound you can see that it's well defined. And it almost looks as though it's either within the choroid or it's actually within the sclera. And you may also appreciate that there is some inflammation of the orbit posterior to this on the far.

23:31 This is poorly vascularized. You do not see the double circulation sign. And then this is what really gives it away. So you've got this diffuse injection on the overlying apsara and conjunctiva. You're not really seeing the single sentinel vessel that you would see with a UVA on melanoma. What about these two lesions here? MLA notic a little less obvious on that left handed image.

23:56 Although do take note of the optic nerve there. And this is the answer. So you've got a granuloma and a metastasis. So this granuloma it's got kind of indistinct borders. You can't really make out where it starts and where it ends. This patient complained of pain which you can get with metastasis. But it's a bit more common with a granuloma.

24:16 There are cells in the vitreous which is less common with a metastasis. You can see that there's some retinal fluid there. This is clearly a charoite lesion. And then on the ultrasound you see that there is mixed reflectivity. And this is what tells you that this is not a cradle hemangioma, which would typically have a high reflectivity and a smooth shape.

24:37 And then the ICG is very helpful here because it will show these hypo fluorescent punked out spots, which is can be found in these inflammatory conditions. This patient ended up having sarcoid and was treated with steroids. And you can see did very well. Here is another example of a granuloma. This is actually a top. So granuloma. And just to emphasize on the Oct that you have involvement of many layers.

25:01 So the Cari the retina and the vitreous there. And the ultrasound is helpful in showing that there is inflammation of the sclera and the core. Right. And of course that diffuse epi scleral injection as well. Conversely, metastasis, really, truly does have extensive sub retinal fluid typically, very often they are multifocal in a way that a coral granuloma is not always and it's a bilateral.

25:29 The Oct has this undulating feature which you can see with colloidal Mets, but also lymphomas. And then there is this mixed reflectivity here on the ultrasound. What about these two.

25:44 So on the left you have a coral lymphoma on the right. This is it's really a good idea to remember this image because, this nothing else really looks like this. This is a focal scleral nodule. So for the choroid lymphoma, these creamy, deep, multiple areas, very often they're in only one eye. Commonly they can be in both eyes, though.

26:08 You can see the auto fluorescence there. It is. Results in expansion of the choroid, undulations of the choroid. And on the ultrasound is actually quite important to get an ultrasound because it will show you involvement of the, of the orbit. So very often these choroid lymphomas will have concurrent involvement of the orbit. And that's helpful because often that is the site that you can biopsy.

26:38 And then this is the focal scleral nodule which is considered benign. These often once you find them are going to be stagnant. They often do not change over time. They are characteristic, as you can see on the Oct is by far the most important image to get, is you can see that it's really in this glare and pushing up into the choroid.

26:59 What about these two? So these actually look very similar, but one of them is a matte and the other one is the immune checkpoint inhibitor colitis that we saw earlier. So on the cradle Mets extensive sub retinal fluid it's typically bilateral multifocal multi lobed mixed reflectivity. In the ultrasound. And you can see undulations here on the Oct.

27:19 Whereas with choroid ISIS again it is also bilateral. But you don't see these well-defined elevations in the choroid. You just kind of see this chunky infiltrated choroid. Often it's around the optic nerve and it's very often much of the coral that is involved. What about these two here? So I'll tell you that the vision is down in both eyes.

27:45 It's about 2070 equally in both eyes. So on the left there you have vitreous and lymphoma. And on the right you have, syphilis. So these can both give Alta retinal disturbance or Alta retinal loss. And disturbance of the retinal pigment epithelium, with vitro retinal lymphoma. What's helpful is attack the ACC and to find a mid 88, mutation and, follow up here, patients do very well.

28:11 And then, with a syphilitic version of this where you've got loss of your outer retina, obviously it can be useful to do, serologic testing. And obviously you need to look at the brain as well, because this is often concomitant with neuro syphilis. And then just some highlights here. If you have a refractory uveitis or stellarator, it's important to think of the obscure histo, say ptosis.

28:36 And then if you have a refractory uveitis vitreous retinitis, it's important to think for sure retinal lymphoma these can have intra retinal infiltrates and also these outer retinal infiltrates. If you've got a hypo pen that has a high FEMA or a high FEMA with a hippo pian, think leukemia, this responds nicely. And then if you have these tan white clumps, remember the tan is what's crucial here.

29:01 I actually think that this could be metastatic cutaneous melanoma. You can also have involvement in the posterior segment as well. Again showing these you these white tan pigmented clumps. Thank you.

29:22 Our next speaker is going to be Vlad de connaitre. And he's going to be speaking about updates on drug toxicities.

29:34 Thank you for the invitation. Always love to come here. Not too far. Is a rough day for a Jays fan, but I can finally understand what the Mets fan talk about. So, nothing to disclose. So we're gonna talk a little bit about a few things, but really about drug toxicity. I'm going to use a case to highlight, importance of this.

29:57 And then maybe have a discussion about technology that we can use in the future. So to make a little bit simpler, a systemic drug associated ocular toxicity or drug toxicity, as any systemic medical therapy can, that can cause unintended deleterious effects on the ocular tissue. We've seen it already. But from the front to the back to the optic nerve.

30:21 And then screening is a different thing, really. It's about a systematic, clinically based approach to monitor those patients in the asymptomatic phase, hopefully to catch it early and, change course for them. And that's where the challenge lies. So, you know, we have lots of things right now that are being used that we're monitoring. There's things that we don't want to see in our clinic, but sometimes, they have high risk of toxicity as well.

30:48 There's new ocular therapies. We talked about some of them already. And then there's new therapies that we don't even know how they're going to affect the ocular tissues. And we're going to talk a little bit about that. So here's a case this is a SBP 101. This is a patient in a clinical trial for metastatic pancreatic ductal adenocarcinoma.

31:10 Both these cases from Columbia in the last couple of years. This is the screening visit. Part of the protocol is visual, screening and ocular imaging and being seen by a specialist. Everything looks okay. Still looks okay. Great. Two months later, after starting the treatment. Very different story patients. Not doing well. And you can see the RPE changes, on that, image and the images to the right.

31:37 They're, quite severe. Unfortunately. Patient passed away three weeks later. And that was the end of, or follow up about seven months later, case two shows up to our clinic, part of the same trial. Everything's great, but after starting the therapy, you can start seeing the changes. And they keep growing and growing and growing patients. Not really bothered here.

32:03 September 2024. And you can see the RPE changes around the nerve and around the vessels. Particularly a superior arcade. And you can kind of see really nicely here if you, take that cross section of that area, RPE changes and I'm going to show you over time. So September tober discontinue the drug. There's a little bit of growth after, but it does kind of stop growing.

32:28 So, important to know, but there is a little bit of growth right after the discontinuation of the drug. It's quite impressive. Again, patient passed away. So we took these and we obviously let everybody know. Said, hey, you know, be on the lookout. A couple of papers are out. So why is this reaction occurring? Well, maybe it's toxicity to the RPE.

32:47 There's RPE cell death and inhibitor renewal. So people, you know, discuss this before. But the questions really we have to discuss now is a community is, you know, how do we really approach these, especially in a clinical trial and novel drug therapies and if they're asymptomatic, would you continue the drug? And if the drug is expected to actually improve life expectancy, does that change your perspective?

33:08 And I think that's the important thing here. Because these patients in this particular trial really showed that, you can increase, you know, the life expectancy by a couple months doesn't sound like a lot. But remember, a metastatic, pancreatic cancer, it's quite severe. So in this particular setting, it might mean a lot to these patients.

33:26 So what is the real problem we actually have to solve. Back to that. Well, a lot of these drug toxicities, we want to be catching patients at the asymptomatic phase where they have some retinal changes, often retinal, but could be other things. And there's lots of novel treatments right now in trials that we're going to be involved in, and some which don't have ocular screening as part of the protocol, which may show up in your clinic.

33:46 So important to answer those questions. And our resources are limited. I mean, we are stretched thin. Let's not even talk about the other issues that we're dealing with. So this is just an added thing that we have to do now. And it's really important for our patients. So how can we tackle this. Some examples I'll talk a little bit about I just sprinkle there's an eye coming later.

34:05 But really a lot of these biomarkers should be done automatically or with assistance. And looking at the RPE and the ellipsoid we can do that. So this is work that was published previously, but you can definitely look at the ellipsoid zone and use CNN prediction to map it out. We presented this at several, with russa koff Oakley, in slack there.

34:28 And we did show that you can, you know, really accurately, segment the ellipsoid automatically so you don't have to do it manually, which is nice. Others have also done this before. If you look at this particular image, which I showed you already, if you segmented appropriately, you can really see that easy RPE thickness heatmap, which is a much better, predictor on how patients are going to do and visual acuity and all the other things that we actually care about.

34:49 Instead of the final sort of fluorescence, which is our gold standard right now, we can look at the easy in the optical fashion. That easy at risk zone can be something that we can, investigate a little bit further. So here's an example of that same image that I showed you before, but classifying the, total loss of the easy versus easy that's at risk can help us track changes over time.

35:09 And you can see from time point October 20th, 24 to March 2025, the changes in the in the, easy loss and easy at risk areas and finally, auto fluorescence. You know, there is a problem with quantification. I mean, everybody here in the audience would love to quantify our fluorescence. And these are beautiful pictures. And my colleagues at Columbia have spearheaded a lot of this work.

35:29 But there are issues with this. One of them is standardization, acquisition time and difficulty in our clinic. And that really doesn't allow us to scale because of that. And then, of course, there's lack of normative databases as well as, pathology for ground truth. So one thing you could do is, you know, take those images and actually analyze them, in an, in an automated fashion, pixel to pixel comparison between, you know, the time point here and see if I can show you so from here, if you use, some sort of, baseline darkness value, which here is the nerve, you can really analyze the whole lesion and start comparing those fluorophores from one time point to another in terms of, some characteristics. So here, you know, DF, which is a standard in the literature in 90 degrees, of this darkness. But you can actually look at other measures as well to make a little bit more easy to track these changes over time. And these fluorophores can really help us clinically.

36:24 To track these, these are patients. And really what's important is even if I wanted to do this, I couldn't. And that's I think the power of some of these tools is they allow us to do things that a specialist could never do, even if I devoted myself to it. Because it's a pixel to pixel comparison.

36:42 So some conclusions, and hopefully we have some nice discussions around this. Systematic therapies continue to, you know, require our community's involvement, and it's only going to increase over time. We are really more important than ever with all the new drug therapies coming out. This is a particular novel treatment which requires ongoing retinal screening. So if you see patients in this trial and if, this gets approved by the FDA, you'll see them in the clinic.

37:08 And we really have to have a discussion around these systemic therapies and how we, are going to approach it, because if we can improve mortality but sacrifice vision, a lot of these issues are going to fall on us to discuss with our colleagues. I don't relish the discussion of having to tell somebody, you will go blind, but we're okay with it.

37:28 Because you're going to live six months or a year longer. But that is coming. And finally, we can try to use deep learning models to help us because I don't think we have the capacity to start screening all these patients in our clinic. I think thank you for everybody, Columbia, for, their support and also for our collaborators.

37:46 Thank you.

37:51 Thank you. Glenn. Next up is doctor Mark Briseno. He's going to speak to us on what all retina specialists should know about diagnosing, testing and managing inherited retinal disease patients. Thank you to the organizers for allowing me to speak today. And the invitation I'm coming from the University of Rochester, the other part of New York. These are my disclosures.

38:14 This is an outline of what we'll be discussing. It'll be a little challenging to cover everything in here to run diseases in eight minutes. But this is a synopsis of what we'll be discussing. And really wanted to focus on retinitis pigmentosa. This one envelops quite a number of our patients, and really hones in on the point of the challenge with managing these patients.

38:33 So basically, we want to make sure the history, the symptoms, the pedigrees of family history is absolutely critical. And then of course, medications, as we've heard from excellent talks earlier, we want to exclude other causes that can look like genetic disease, infection and vaccination status and other aspects are quite helpful. And then distinguishing is this a syndromic disease or are there other manifestations outside the eye that we need to be concerned about?

38:59 Or is this non syndromic. And so most importantly as we found in recent years is the molecular confirmation is absolutely critical for these patients for the diagnosis. As you can see with the Venn diagram retinitis pigmentosa alone, there's so much overlap and heterogeneity between genotypic and phenotypic variations in these diseases. We're going to focus on one in particular KL and three also known as Batten disease which is right in the middle of our P.

39:26 But as you know, with a large cohort of patients, we actually find that there's quite a bit of phenotypic variability. So not only is there not in just an isolated retinitis pigmentosa type of phenotype, but you can actually get an isolated macular dystrophy in addition to syndromic versus non syndromic. Associated retinitis pigmentosa as well. And so this is actually spans across the CLN genotypes not just KL and three but the other variants as well with different numbers on associated with them.

39:57 And this really just hones in on the importance of the genetic confirmation. And multimodal imaging has been particularly crucial with us. On the flip side of that, retinitis pigmentosa, almost a third of cases still have an unknown cause, despite so many different genotypes associated with that particular phenotype. And one particular example, we were a patient with a stickler syndrome genotype, a call to a one mutation that, in addition to having clinical features consistent with that diagnosis, including intraocular lens, this location also had a retinitis pigmentosa phenotype, and this was confirmed.

40:33 With or with IRG as well, and whole exome sequencing, which did not reveal any other consistent mutations to warrant that retinitis pigmentosa phenotype. So it's still an emerging field, and hopefully we'll be learning more in that gray area for the 30% will continue to shrink over time. So Urg is can be quite helpful along with other functional testing including Goldman visual field.

40:58 Classically, however, the feasibility and availability of these often is compromised out in many retina practices and isolated to just, some academic centers. You know, sometimes there's actually a joke that it's easier to get genetic testing often than it is to get in the RG. And so fortunately, multimodal imaging has really exploded in recent years. And so this is particularly crucial in monitoring, managing and diagnosing these patients as well.

41:27 So the auto fluorescence in which we've seen a lot of today is absolutely critical for for that monitoring. Now when it comes to the genetic testing we've been quite lucky to have free to patient, panel testing available. Thanks to a lot of, foundation support. However, there's been quite a bit of turnover with the with the viability and availability of of these this testing for patients.

41:53 Some genes have been excluded. However, the ones that are available over years, they have added back into these panels or that were not previously available. Single gene mutation can be quite helpful if you already have, an established pedigree or patient and family history consistent with a prior mutation. But this can also be supplemented with whole exome sequencing, which notably is only 1 to 2% of the genome.

42:16 This is the coding aspect of the gene. That's fairly critical for, really characterizing the the coding part of that genome and then whole genome sequencing. And of course the introns or the non-coding parts are also helpful as well. Unfortunately, the cost of this has gone down from thousands to fewer thousands of dollars. But hopefully in the near future this will continue to fall and be more available for patients in the near future, and would be remiss to not talk about classic findings of typical everyday disease and not be thinking about it here.

42:50 Renal diseases. So obviously we see a lot of patients diabetic retinopathy, macular degeneration. And this is just an example. This was a patient just referred for routine usually macular degeneration. You saw in clinic. And given the advanced changes both non-executive as well as Exadata features and new vascularization sera and SRF sub retinal fluid. You can see clearly on Oct in a fairly young patient.

43:16 She was in her early 50s with symptoms that had started already by her 40s. This kind of prompted, getting a panel testing, which ended up revealing a timp three mutation autosomal dominant with sores B macular dystrophy. And so this is particularly helpful to make sure we're not missing things. And obviously a very busy clinic that, we may commonly be coming across that an otherwise unexpected managing these patients, you know, fortunately for many inherited retinal diseases, if, secondary choroid only a vascularization were to develop.

43:47 We do know from the literature that their response is quite favorable in these cases of C and V. But we also don't want to forget the rest of the picture. You know, a lot of times cataracts can be associated with these, dystrophy. And so referring them to a proper hearing to your segment colleague to manage this visual rehabilitation and low vision.

44:06 We don't want to forget about either. And recent technology has really helped these patients out, even if this is something as simple as an iPad. And then, of course, the genetic counseling with these results for genetics and the system in macular edema can be a little bit more challenging. Of course, carbonic anhydrase inhibition is quite popular, although it does have more mixed results.

44:25 So one also touched upon the first and only FDA approved gene therapy for blindness were other gene, which is specific for that by allelic RPE 65 dystrophy. Our center has been, lucky to be a part of this. This experience of about 500 or so is estimated across the country. And this is our surgical team of from our institute.

44:44 And it's going to show this an example case. So it has quite a bit of phenotypic variability. Like many inherited retinal diseases, the pseudo color fundus photographs here kind of shows an unimpressive picture relative to what you then see on the auto fluorescence. Profound global hypo auto fluorescence. And this is a patient who had hand motions to very close counting fingers vision in her eye, 27 years old.

45:09 Not all of them are myopic, but myopia has been associated with this particular disease, which can vary from leaders congenitally morose with profound vision loss to, several years into life of I mean to compromise the vision. And so this is an example surgical video here for the trial we perform localized per for the sclerotic mes themselves, rather than just classic, trans conjunctival suture or less vitrectomy.

45:34 And one of the sclerotic means, notably, is an unveiled trocar cannula. And that's for the eventual delivery of the sub retinal gene therapy. So we're performing core vitrectomy here and then of catalog. Excuse me. Trying sinaloan to stain for, the posterior halo and visualization of that. Obviously for delivering the sub retinal gene therapy, we want to make sure that post here is elevated.

45:58 And in this particular case, you can see that the halo is actually quite firmly attached. It doesn't have that sort of elevated structure otherwise may. And in this case we use a soft tip cannula to help release that from the posterior pole. And then going back to the vitreous cutter to help isolate that poster high up in the periphery and extend the vitrectomy school to press examination looking for atrophic areas prophylactically to run any retinal detachment here with a and a laser.

46:30 Here we have a 41 gauge sub retinal cannula. And we get the right pressure there. And then we localize it to the superior arcade. In this particular case, oftentimes we've been doing some research with non-human primate eyes. There can be anterior propagation of the sub retinal bleb. So to make sure we have adequate treatment we then also perform small build, along the inferior arcade.

46:53 And notably it's not right in the full view about just adjacent to it. And there have been reported cases afterwards of macular atrophy in areas that were treated with the bleb itself. Perform a full air exchange and close the these that were then created. And so basically it's an exciting time. X-linked retinitis pigmentosa again is impossible. So all the trials going on in here mental diseases, but wanted to focus and highlight on this one as well, which is another hot area.

47:21 There has been several, ongoing trials, two phase three studies that did not, unfortunately, make their primary endpoints. However, secondary endpoints were met and another one with positive interim results in the phase two trial right now. And so we're definitely in an exciting time. And I'm like, thank you again for your attention.

47:46 Thank you Mark. We're now going to move on to the luminary Richard Speight, who is going to talk about new findings in Arctic Pat McKillop. He.

48:01 Thank you. Jasmine. You know, optic pits are really hard to understand. They they look simple, but they're complicated, mostly because we can't see what's going on. But I, I developed the I guess this is a better way to get this to move forward. My slides are stuck. Can you move the flights?

48:24 So we have to go backwards like five slides now. So these are my disclosures. So I did develop a way, new kind of workflow of image processing to get to manipulate images from dream CT, which is a kind of a new Switzer. So CTE, which has tremendous ability to image both in terms of the breadth of its imaging and the depth as well.

48:46 And then we can look at scans and also do volume rendering to look at in 3D. So I defined an object pit complex as a defect in the laminate composer. And a subsidence or cavitation that displaces the nerve tissue posteriorly. And there's a potential communication between the vitreous, the increased neural cavities which I'll show you in the subarachnoid space.

49:09 So fluid can enter into the retina. And it seems to push its way into there. So they can define these as either congenital. Those are ones that are present from birth or they can be acquired. That's like you see in sometimes in patients with glaucoma. So this is a patient and there's a kind of a neuro sensory detachment here or certainly fluid there.

49:30 And you would say, oh this looks like no pit retinal squeezes. But if we actually look at the optic nerve, you can easily see with this extended ability to image deeply with, the Swift source device that there is a pit there. It's just that you can't see it because there's a kind of a loose connective tissue in front of the pit.

49:49 And you can follow this down so it fits that, that like the definition I gave for not the pit complex, it just that you don't exactly see the pit itself. There's an inner opening to this, and you can follow this all the way down through the loose connective tissue, down into this deep cavitation that's present below or behind where that lamina or would be.

50:09 So that really fits the thing is the definition of the pit complex for me. So I did a inner retinal fenestration for this patient and flatten down here. She has seven years later, 2020. This patient was referred to me because he had a macular hole, which seems like kind of strange why a 31 year old would have make a hole.

50:26 But following a surgery, not only did in the macular hole closed, but he had a retinal detachment and it's not so obvious that he had a pit. But if you actually look at this, you can follow that he does have loose connective tissue. Again, on top of this thing that would fit the definition optic pit. And you can see that there's a cavitation that goes all the way down about 1800 micrometers below Brooks membrane opening.

50:47 So this is really far posteriorly. And he has other cavitation again deep to the nerve head. I wrote a paper long time ago where I showed different ways that fluid can come into the retina through an optic nerve pit. And I just want to highlight one of those just to use this idea later. There's can be normal patients, but some patients can get fluid that just goes straight under the eye.

51:11 This is a kind of a rare thing, but here this is a daughter of a, ophthalmologist. And she had, elevation of her. I ilm just related to a pit. Now that that I elim elevation is pulling up on the retina, but you can tell that has to be a pretty good head of pressure going into there to lift the ILM to lift the retina.

51:29 So, it's not just some fluid just accidentally finding its way. There's coming under the head of pressure. Now, she went on, I followed her, she didn't really know exactly where she's coming back. But this thing over time, just ruptured itself. I didn't have to do any surgery at all. And eventually the detachment did flatten out on its own.

51:49 She didn't realize she had the attachment, didn't realize when it ruptured. Lot of the fluid can come in through the inner layers or the ganglion cell layers. And here's some examples of that. This patient is an optic pit, and you can see that there's a defect in the lamina rebozo with the fluid that inch retinal fluid sub retinal fluid.

52:08 But look at that gigantic cavitation below. That were the lambda Kaposi's. We didn't have ability to see this. What previous ways of looking at optic nerve pits? Some fluid can go directly sub retinal. Judy, Kim and I described cases. They're usually younger kids who have this. Here's a patient who does have some retinal fluid. We can also look at what's inside the the cup itself.

52:32 And there's no material that you can really see inside this. And there's really you can't even see a connection necessarily between where these cavity patients are deep to the lamina or in the area of where that limb the defect is. And the fluid underneath the retina.

52:48 But you can kind of follow it up. If you look there's often these like kind of, hypo reflective tissue that's present that you can follow up to where the fluid is. Some of the patients in their optic nerve cup appear to have vitreous. Now this wasn't vitreous sucked down into the cup. That's what Mark Johnston said. Because you do operations so you can't pull it.

53:06 Vitreous out. I don't know if you ever tried this, but it is really anchored in there. And you could follow this vitreous all the way down, and you can see how deep this cavity goes down to the below the nerve. And this also extends a couple millimeters below brooks membranes opening. And we can slice into this in different directions.

53:22 And you can see the vitreous is firmly attached here. And ordinarily secondary vitreous and supposed to be found in the optic nerve. So to get there it had to migrate the cells that made the vitreous. Probably Mueller cells had to migrate down into that. And that's probably due to a lack of the boundaries that are found in patients who don't have, have an optic nerve pit.

53:40 Some of the tissue look like trabecular. And you say, well, how can you get your inside of an optic nerve pit or inside that at least a cup of the optic nerve? And, here's another example of these trabecular, a long time ago, Kyoko Matsui and I described how you can look in the through pathologic myob's and look down through into their nerve.

54:00 And you could looks like you're looking into the sub arachnoid space and you could see trabecular there. I think what happens in these cases is that the trabecular cells or what the white cells migrate up into the area of the cup because there's a lack of normal barriers, not a laminate or both. Present. How does the fluid get into the retina?

54:20 This is the only patient out of this whole series where you can actually see a connection from like a deeper kind of area up into the optic nerve. And if you follow this through slices, you can see there's an area here that the fluid, by the way, it's not coming from the pit. You can see that there's a kind of a hole that in this sort of cavitation, and that leads in a pathway up into the retina.

54:41 And you can see here again that the area is a little complicated, but the area of the fluid coming up is not in any way touching the pit. So the pit is there. But the fluid comes because there's an optic nerve complex. This patient had a stock of vitreous. You can see that trabecular stuff in the the cup.

55:00 But if we look at this this is kind of an interesting thing. The fluid seemed to come up into the retina around the blood vessels in a perivascular space. And we know the system is prominent in the brain, and that's a way of fluid being transported into in the peripheral tissue of the brain around blood vessels. People have supposed that there's a system in the optic nerve, but this looks like a way that it looks like the lymphatic system present.

55:26 That's probably present. You have the nerve gets co-opted by the fluid pressure driving this up, and it comes around the blood vessels up into the retina. Finally, some patients I couldn't really figure out how the fluid got there. In this case, I, segmented the picture and converted all the black space and the purple and the we volume render that.

55:46 You can see there's a collection of these distorted spaces of the retina, but you can't follow how the fluid gets sent up into the retina. And to me, this kind of implies either the fluid percolates or that it comes through, intermittent ways. But in any case, for fluid to get up into the retina, there has to be kind of a pressure driving it up there.

56:04 And I just harken back to this thing where the limb was ruptured. So, the fluid eventually gets pumped out, but it doesn't seem to go the way it came. So how does the fluid get into the retina? Some people say, well, that's CSF, but if you look at the cerebral spinal fluid, pressure is about five millimeters lower than the interac of the pressure.

56:25 So it seems hard to believe that how could the CSF get driven into the retina? And some people say, well, it's vitreous fluid. But there again, the fluid pressure in the retina is the same as in the eye. So there's no driving pressure for that. So I think there's a different explanation for that. If you look at the optic nerve when it's eye moves it's particularly in adduction.

56:47 The optic nerve gets really bent. And people have done finite element analysis of this kind of pressure or stress put on the nerve at the border between the nerve in the eye. And it's under really a lot of compressive strength or stress. So you can imagine, we're having a problem with the forward thing again. If you have this kind of blob of fluid and you move your eye, that bulb is going to get compressed just like a bulb and an eye dropper.

57:15 What's going to happen? That pressure is going to go up. It's got to go someplace. And it could easily get driven up into the eye. So, this kind of gave me the idea about this inner retinal fenestration, which we've now done on many dozens of cases. It's just make a small hole in the retina near where the pit is.

57:30 And the fluid goes from the pit area up into the vitreous cavity. That retina flattens out, and it's a very high success rate. So I showed you, this some new concepts, the idea of an optic complex, be wary of a no retina squeezes. They really do have pits. There's cavitation in the nerve almost uniformly. There's a lack of normal barriers, and, the fluid can come up through melt the.

57:54 So migrating up into the retina. And I think the repair is fairly easy. Thank you. Very. Thank you, doctor speed. So next up we have, Doctor Jasmine Francis, and she will be presenting a macular edema in ocular and he malignancies. Thanks, everyone. I'm just advancing here. There we go. I have no financial interest or commercial relationships.

58:28 I'm going to discuss these elements. And we're going to start with intraocular tumors, both benign or malignant and CME. So almost never do you see CME with retinoblastoma or UVA or melanoma. That is naive with vitro retinal lymphoma for the most part one does not CME if the eye is naive, although if there is a T-cell response.

58:51 So an inflammatory response to the B-cell vitreous lymphoma, which occurs in about 15% of cases, then one might see CME. So here's an example of a patient who has biopsy proven vel has uveitis. Anterior segment. Suggesting that there may be a T-cell response has this CME which improves a little bit post-treatment. It is possible with malignant intraocular tumors, particularly metastatic tumors, to have wide macular edema, along with the abundance of sub retinal fluid, which we talked about earlier.

59:27 And then with pari neoplastic phenomenon also possible to get CME. And here's a case of B dump in which this progressed to, basilar detachment for benign intraocular tumors. Obviously hemangioma customers angio mas can give CME and exudates and vaso proliferative tumors. There was a nice case earlier. These often will have CME due to traction.

59:55 Here is a case that had a fractional macular hole, was treated with a membrane heal and steroids and had a nice response following that corridor. Hemangioma, particularly those that are diffuse rather than solitary, can have steroid macular edema, as do combined hematomas of the retinal pigment epithelium and retina, because obviously they have a defunct interface between the vitreous and the retina.

01:00:25 Colloidal granulomas, as one would expect, can have CME. What about this unique type of CME? Does anybody here know the diagnosis? Go ahead and shout it out. This is a cavernous hemangioma so it's not a true CME. The way to approach this is to treat the intraocular tumor itself. Have listed out some ways that we do that. And then one can also treat the CME with the, tools that many of you in the room already use.

01:00:56 Moving on to heme cancers and the possibility of cyst or in macular edema. So lymphomas rarely will give a CME unless there's a hyper viscosity syndrome. Leukemias can give CME. This is largely due to venous venous stasis, hyper viscosity. One can get infiltration of the optic nerve, the vitreous, the choroid, and when it infiltrates for choroid, one can get RPE dysfunction.

01:01:22 Breakdown of the RPE and influx of fluid. And then of course the hyper can caballo goblet anemia can also give CME with expansion. If immunoglobulins through a number of different mechanisms which I have listed but I'm not going to go through, one gets an increased osmotic pressure gradient, which results in fluid retention in the outer nuclear layer and then CME.

01:01:48 And then as you get this increased, leakage, you can get traction of the mula and photoreceptor cells, retinal discontinuities, the ILM breaks. And then you can have fluid into the sub retinal space as showing you here. Characteristically for him, cancer related CME, there is no leakage on the F.A. and there is a lack of peripheral non perfusion that you might see with other diagnoses.

01:02:16 And of course you're going to look for other signs of hyper viscosity, as I've shown you here. So the intra retinal hemorrhages, the venous dilation, the optic nerve edema. And due to this disturbance of the photoreceptors, these patients can have EEG changes. The main treatment here is to treat the underlying cause, which is the heme cancer. And these tend to be less responsive than one would hope to methods such as intravenous steroids and anti-VEGF.

01:02:44 Here's a patient with Walden's dry macular globule anemia. You can see the CME here. And after all of these treatments, this is how she looked. So these can be refractory, very difficult to treat. Moving on now to cancer therapies and how this may result in macular edema. The most obvious here is radiation retinopathy. The mechanism is vascular so microvascular at the level of the endothelial cells.

01:03:12 This is dose dependent. Higher the dose of radiation the higher the risk of radiation retinopathy. Typically the threshold of the optic nerve and the retina is the same. It's about 40 gray of radiation, and this can be worse in patients who have diabetes or hypertension. I think we all know how this appears in the eye. So, hemorrhage, cotton wall spots, perivascular sheathing and nervous radiation, optic nerve edema, of course, the CME as well.

01:03:39 We could argue about ways that we treat this. The, bottom line is there's no excellent treatment. There is a small proportion of patients who will temporarily do well with anti-VEGF and steroids probably have a role as well. Here is a patient who did in fact respond temporarily to anti-VEGF treatment. And then these are all the cancer drugs that have been associated with CME.

01:04:01 We'll go through these briefly. So the vaccines this is the paclitaxel docetaxel used to treat breast lung and ovarian cancer. This disrupts regular cell transport and therefore results in fluid accumulation. Here is a patient who has CME. There is no leakage of fluid on the FDA. Typically this can be reversed with drug cessation or drug reduction.

01:04:30 And then this I've sort of mislabeled this. The bottom is the post. But you can see that there is this doesn't respond as well as one would want to. When the drug is stopped. It responds a little bit. There are case reports out there of this responding to anti-VEGF, the calcineurin inhibitors. These are used for immunosuppression after a stem cell transplant.

01:04:53 These results in endothelial injury and then that results in fluid that is an entity called thrombotic microalgae apathy which one can get related to these drugs. I've listed here all of the signs that patients, may accumulate when they have this problem. And it's a combination of this that can then result in this, hyper viscosity retinopathy with CME.

01:05:21 Here is how this patient looked. And once this patient's thrombotic microalgae or puffy was, treated with supportive measures and the drug was stopped, the CME went back to normal. Imatinib is a tyrosine kinase inhibitor. It's used to treat different types of lymphomas and leukemia. It blocks the Pdgf receptors, which eventually results in fluid accumulation and CME.

01:05:48 This is a very rare side effect of this drug. So on the order of about 1% of patients, what is more common is these patients will develop Perry ocular edema, as you can see here with the upper eyelids. And they can also have sub conjunctival hemorrhages. And this typically does not leak on the Effie. A brut nib is used to treat, febrile.

01:06:13 So primary CNS lymphoma. And one can rarely get CME. There was a case earlier that was described by the panel, that can sometimes be a leakage. And this can respond to NSAIDs and steroids and cessation of drug. And then finally the Map kinase inhibitors listing here what the Map kinase pathway inhibitors are. And then just to demonstrate that not only do you get these sub retinal fluid foci, but you can get intra retinal fluid as well with drug reduction or drug cessation or even keeping the patient on the drug.

01:06:47 This can improve over time. And the lower down in the pathway that you block with a drug, the more likely you are to have the macular edema, immune checkpoint inhibitors. These potentiate the T lymphocyte lymphocyte response which kills the cancer. But also you can get off target to normal tissue. And obviously as a result of that you can get macular edema.

01:07:11 And these respond well to systemic steroids. And that's it.

01:07:22 Our next speaker is going to be Sophie Bakri. And she's going to speak about an update on McTell trials and treatment.

01:07:34 All right. Well good afternoon everyone. These are my financial disclosures. And, I'd like to start with defining what McTell is, and that's macula two. Logic. Tasia type two. It's a bilateral progressive retinal neurodegeneration that leads to central vision loss and functional impairment. And it leads to progressive loss of the, ellipsoid. Zone. And it's associated with abnormalities in the mula glia, the RPE, the photoreceptors and the ganglion cells.

01:08:10 And what you can see is that there are corresponding hypo reflective cavities on Oct McTell, type two is underdiagnosed, with an estimated prevalence of 0.1% in the United States, and the incidence is 2700 new cases per year. So, there's been a lot of research recently done on McTell, and a lot of that was made possible by the Laue Medical Foundation.

01:08:43 So there was a family in Australia, with McTell, and they visited the NIH in December 2003. And, with their support and funding, the Macular Taseer project has grown to involve many global, sites. There are study participants, investigators, sponsors, and of course, the Lowy Medical Research Institute and Lowy Family who should be really, thanked for this.

01:09:12 And there are selected proceedings in one of the, retina editions in McTell. Best corrected visual acuity does not always reflect the disease. Burden. So we know that there's an on face area of easy loss and also those corresponding hypo reflective, areas. And it may correspond to, visual acuity only really when the fovea is surrounded, or involved.

01:09:41 So, two thirds, sorry, three quarters, of McTell, patients develop an easy loss. Five years after diagnosis, and 45% progressed from non-central to central. Easy loss five years after diagnosis. And that easy area loss can result in significant visual loss. Fundus photo fluorescence is used to detect the earliest stages, of McTell. As you can see here in these, photographs.

01:10:13 So what about treatment? So, mula, glial cells we know, have an important role in supporting the viability and the function of the photoreceptors in the retina. And they secrete neurotrophic factors and growth factors such as ciliary neurotrophic factor, known as CNT f. And it's the mula glial cell dysfunction in McTell that leads to retinal neurodegeneration. CNT protein is well-established as a neuroprotective factor for photoreceptors, and CNTs binds to the CNT f receptors on the Mula glial cells, and it prompts the the mula glial cells to produce the neuroprotective factors and In preclinical models of retinal degeneration, photoreceptor loss was slowed with intra vitriol injection of CNT f, and that has supported the rationale for development of CNTs as a potential treatment for retinal degenerative diseases, including McTell. The problem is that Cncf has a short half life, which presents a challenge. And, so one of the goals was to develop, Cncf to produce, sustained, levels.

01:11:31 And that's been done by encapsulated cell therapy ICT that enables continual delivery of CNTs, to the retina. So genetically modified cells are encapsulated, with a membrane. And they are designed to secrete the therapeutic substances such as growth factors, or proteins, rather congeners. Rather in terrorist cell is a first in class encapsulated cell therapy that houses the allergenic RPE cells and it's surgically implanted into the vitreous cavity and attached to the sclera for stability.

01:12:13 And it releases CNTs for long term durations. And revoking a gene was approved by the FDA for treatment of adults, with McTell in March 2025. It's an outpatient surgical procedure. It's a three millimeter, pars planar scleral, incision and, the implant is fixated, to the eye, as you can see from the picture on the right, it does lie outside the, visual.

01:12:42 Axis. An analysis of 49 Rivkin energy and implants up to 14.5 years demonstrated consistent release of, CNT f and, there was no visible discoloration or tissue adherence or material breakdown in macroscopic examinations of these plants. Up to 14.5 years, rather was studied in two identical phase three clinical trials involving more than 200 participants. And that was rather a gene, versus sham.

01:13:19 The primary area was the rate of change in Easi area loss from baseline through month 24 and secondary endpoints were changes in retinal sensitivity and reading speed. The baseline characteristics were well balanced across treatment arms. Within each study, and at two years the Rev Akin A gene led to reductions in loss of easy area retinal sensitivity and reading speed compared with sham.

01:13:48 So now we're going to look at the effect of baseline ellipsoid zone area loss on these parameters. And there was a difference in treatment responders in treatment response between trial A and trial B. And so participants were divided into high responders. If they have a 50% or greater reduction in disease progression based on easy area loss.

01:14:11 And there were nine variables assessed using a univariate approach, and two were found to be associated with a response. And they were easy. Area loss and a history of diabetes. Both smaller baseline easy area loss and diabetes were associated with higher odds of treatment response. There was a difference in the distribution of baseline lesion sizes between trial A and trial B, with trial A having more patients with smaller lesion sizes.

01:14:47 And when you take out the patients with the smaller baseline lesions across both studies, it is found that the magnitude of reductions in easy area loss and retinal sensitivity were now similar between studies. As a secondary endpoint, the proportions of participants with a 15 led to or greater decrease in vision. Was looked at, and as you can see, there were more participants with a 15 letter, or less, decrease, in the treatment arms.

01:15:22 So why did vision decrease in some patients? Well, it was primarily due to cataract progression or vitreous macular traction. And you can see this, here again, Victoria Macular Traction. So overall the ocular treatment adverse events were mild and transient. And the most of the serious events were related to surgery. And they were transient and they were expected.

01:15:46 And here you see the mild to moderate non ocular adverse events. So the take home point saw that River Kennedy terrorist cell led to significant reductions in the rate of easy area loss in participants with McTell met the primary endpoint and is now FDA approved and available for patients in clinical practice. Thank you. Thank you.

01:16:14 Thank you.

01:16:22 All right. Final speaker of this session is Scott Walter, who will speak about AI assisted virtual scribing in retina practice. Thanks, Jasmine. And, Vijay here for the invitation to speak and to the meeting organizers for the invitation to speak today. I'm going to be talking about my experience over the past, ten months now using, let's see, artificial intelligence based scribing in retina in the, in the clinic.

01:16:50 So these are my disclosures, none of which are relevant to this presentation. Documentation is of extreme, importance, in terms of communicating with other providers, communicating with ourselves from one visit to the next, justification for billing, and coding, as well as legal protection in the event of, a lawsuit. Obviously, provider preferences in terms of documentation, a very substantially, I remember, you know, one of my mentors at, Bascom Palmer had very simple notes with, one word impression, one word plan on most patients.

01:17:23 But nowadays, most of us are documenting more comprehensively. Here's an example of a level five and and visit with a detailed comprehensive eye exam, interpretation of office based imaging and then a impression and plan with multiple problems being, documented, uniquely on the date of service. So what is the clinical workflow that allows us to document to this level of detail in a busy retina clinic?

01:17:48 Seeing 50 to 60 patients a day, I see ocular oncology and complex retina in addition to bread and butter, retina. So we need a workflow that allows us to be efficient and yet to capture the complexity of all these patients that we're seeing. So we have in room assistants who are responsible for rooming the patients, setting up the procedures, logging drugs, and actually kind of driving the EMR.

01:18:08 When I'm, in the room with the patient so that I can see what I want to see in the EMR, but they're not actually doing the documentation in real time. They do organize the problem lists so they'll identify the problems that were actively discussed during the encounter so that we can build for the encounter on the date of service.

01:18:24 But that's all that they do with the EMR. Then we have an asynchronous virtual scribe whose responsibility is then to document all of the subjective and objective information that was captured during the visit recording and formulate that into an assessment and plan. We use EMR, known as Next Tech, which is popular in retina practices. We initially started doing this just with an asynchronous virtual scribe.

01:18:49 And so we're using go to meeting to create a audio transcript of the encounter. And what we've layered on in the last ten months is an ambient AI documentation tool called freed, which basically listens to the encounter and comes up with, formulates the, diagnosis impression and plan in, verbiage that's, appropriate for EMR documentation.

01:19:14 So then the virtual scribes workflow, they basically open the patient encounter in next week. And in freed they'll read the visit summary and freed, which is a 2 or 3 line summary of what happened during the visit. Get some oriented to the big picture of what happened. They'll listen to the audio recording, but they can speed it up so they're not going to sit there for ten minutes.

01:19:33 If I'm in the room for ten minutes, they're going to sit there for, you know, 4 or 5 minutes, speed through the recording. And they'll, simultaneously edit, any of the inaccuracies that they find in the freed summarization of the office visit and then they don't have to type it all out. All they have to do is spot any inaccuracies, correct any mistakes, copy and paste this into our EMR.

01:19:55 And what you can also do is you can teach free. So if it made a mistake, you tell it that you know, you correct the note and you you teach it. And basically it gets better and better at, producing documentation that accurately reflects your, encounters and style. So, there are different documentation styles that, that we use.

01:20:14 Active documentation is kind of when I'm, presenting structured data that I want the scribe to, to put in verbatim. So examples. Well, we'll get to examples of this. And then ambient documentation is when I'm just having a natural conversation with the patient, and I want the scribe or the AI scribe to into intuitively formulate the documentation based on that.

01:20:35 So most encounters are a bit of a mix of both active and ambient documentation. So, when the, you know, we start the conversation, I'm just having a natural, conversation with the patient and, the AI is able to document their subjective complaints with, with great detail in ways that I think humans have a hard time, recalling all the details that the patients are giving us an in terms of the history of person illness and then, active documentation.

01:21:01 So then after I've had a little initial conversation with the patient, I'm going to go through, my imaging interpretation and my exam in a very systematic way. And I like to be very detailed in terms of how I capture that information. So that's kind of a phase of active documentation. And then we go back into the patient counseling, which is more of an ambient documentation style, where if we're discussing a common, a common problem, I expect that the scribe or the AI system will be able to complete the documentation using general knowledge of retina, where some pre-specified templates that we have in our EMR.

01:21:34 If I have a patient with a more complex problem, then I may actively document the impression and plan. This is exactly what I wanted to say, but I think what we're realizing is that the AI is so good at ambient documentation that a lot of this active documentation I was doing is completely unnecessary. So here's an example of a patient I saw, this week on Wednesday, I think, with a new diagnosis of colloidal melanoma, you can see this was a lengthy end of the day visit totaling 55 minutes.

01:22:02 And there's the, full transcript of everything that was said between me and the patient. Obviously, we're not going to read through all of that, but I'll just kind of give you a little snapshot of how accurately the ambient AI is. So this is just the raw transcript. Okay. This is not the, the summarization. So were you having routine eye exams?

01:22:20 Well, I missed one one year. The year before. They told me I it freckle, but not to worry. And then I didn't go last year because I was too busy. Well, I wish I'd seen you a little sooner, but here's where we are now. Clearly this is a melanoma at this point. It's not benign. Benign more wouldn't do this in terms of detaching the retina and growing to this size.

01:22:37 So clearly it means cancer. And it definitely needs treatment. Treatment plan is breaking therapy a couple of procedures to implant the radioactive device. So this is what I'm actually saying to the patient. And then this is how it summarizes that. So this is a 50 year old female who presents with vision changes after missing a year of routine eye exams.

01:22:55 Evaluation revealed a coral melanoma with associated positive retinal detachment. Patient has family history of renal cell carcinoma, raising concern for about one cancer predisposition syndrome. Here's our treatment plan. We're going to do plaque brachytherapy, genetic testing CT scans and potentially enroll this patient in a clinical trial. And here's the surgery scheduled. So that's just the summarization. The first shot.

01:23:17 You know, everything else that, the AI produces could be copied and pasted directly into the medical record, pretty much as is with minimal editing. So here's an example of an HPI, here's, the Oct and fundus photo findings and all of our multimodal imaging, documented with extreme detail. And no one had to type any of this.

01:23:37 This is just automatically happening as I'm, seeing the patient. So, here's the problem list it comes up with, which I think is sufficient to build a level five ENM. Office visit on this patient. You have detailed discussion. It's highly specific to the patient. And, hits kind of all the, the key bullet points in terms of multiple testing modalities, being ordered and, high risk, disease.

01:24:04 So and of course, it also, sorts the problem list according to different problems. A patient actually had a single episode, during the office visit. So it's even able to capture captured that and it even comes up with the ICD ten coding for us, which I think sometimes or, you know, office scribes have a hard time selecting the right code.

01:24:23 So pretty impressive that it was able to not only, you know, do the work in terms of documentation, but also, give us some tips on coding. I don't actually use this, but it produces a patient, handout that you could hand to the patient, which summarizes, you know, post visit instructions and follow up for the patient.

01:24:43 And so I think the current advantages is that it's really improved our precision and accuracy, particularly in terms of capturing those subjective, complaints from the patients in a way that our techs were never doing, very accurately. And as certainly as allowed me to document detailed, objective findings on exam and, imaging, with precision.

01:25:03 And it really simplifies the transcription process. My virtual scribe set out on the first day of using this, like her wrists were thanking me because it saves so much, typing effort on her part. The AI summarization consolidates information across different time points in the encounter, so sometimes the conversation starts at the beginning. We pick up in the middle and then we say something at the end.

01:25:23 And rather than having to kind of call through the transcript or the audio recording to find that the AI just consolidates all that information across different time points into a summarization, it filters out all the small talk that we don't want incorporated into the EMR. So it really saves time, particularly for longer encounters. These large language models are very powerful in terms of processing complex conversations, with patients and with, you know, verbiage that, you know, is specific to our specialty, but it produces well worded EMR appropriate verbiage, and we can teach it so it learns over time.

01:25:58 To, to do a better job. Some limitations. There's often right and left I confusion if I'm not specifying exactly which I am speaking about. Imaging versus exam confusion occurs at time. So the auto recording still remains essential to confirm, the findings. And, it only knows what it here. So sometimes, you know, patient knows they're getting a nightly injection.

01:26:19 I know they're getting an eyelid injection, but I may not say the word Eylea. So, you know, it has a hard time because it's not integrated into the EMR. So occasionally there are hallucinations. But, it gets to know the patient over sequential encounters. So everything that occurred before, it knows when that patient comes in again.

01:26:37 And it helps to make the notes better over time. So it doesn't yet integrate with our EMR. So the findings still have to be manually transferred. And I do think that a human in the loop remains critical to ensure the integrity of the data that we're putting into our EMR. So if you have further questions, happy to discuss by email or phone, here's my contact info.

01:27:00 All right. Well thank you Scott. Unfortunately we have run out on time. So we are just going to stop the Q&A and go into the medical retina cases next.

01:27:18 Sunday.

01:27:34 How, can there are two questions, polling questions that are going to go up. If you can please scan the code and then go ahead and answer them. Thank you.

01:28:17 Never forget. Nice. I wonder what to do about how to make me crazy. Remember how I, I don't understand what happened to love. To get you back. All right. Hello. Thank you. So much to the meeting organizers for having me. I'm the session chair for this medical retina case conference. My name is Arthur Venkat. I'm a medical retina and uveitis specialist at the University of Virginia.

01:28:50 I'd like to introduce our panelists. We have Doctor Gaetano Barilla from Manhattan. Pioneer. We have Doctor Who teach Mehta from NYU, and we have Doctor Lucy Copps from NYU as well. So I'll go ahead and invite our first, speaker. We have doctor Sandy Wu to present our first case.

01:29:18 Good afternoon. And everyone, I'm Sandy Wu, I'm one of the PGA tour resident at Columbia, and I'm very happy to be back at Olson. Right now again. And thank you very much for having me. So today I will be presenting a short but sweet case, title A Hazy Battle. In the past. We don't. Know, I think there's something wrong with the slides, but.

01:29:43 I think the slide is not moving. It'll keep. There you go. Okay, so I think some of the slides somehow were missing from this version. I'm just going to quickly go through it verbally. So this is a 29 year old male. He is presenting with, symptoms, right eye vision dimming, photophobia and pressure pain for five days.

01:30:05 His past medical history was notable for HIV on heart. His last viral load testing was four months ago, which was pretty undetectable. And the CD4 count was 685. He also had a history of progressive sin skin, hypo Mila gnosis, and he received a skin biopsy five years ago, which only showed chronic inflammation. He had a history of chlamydia and a positive talk.

01:30:27 So Cara IgG can I. History wise, he has myopia in both eyes and a recent infection that he couldn't really characterize more but result after antibiotic ointment.

01:30:42 Okay. When we ask about further symptoms, he mentioned that he's also having a new right side headache since the vision change started and he's currently sexually active and practicing unprotected sex with multiple different partners. He is of African-American or Hispanic race, and he has a family history of a mom with poor vision, reportedly due to diabetes. On initial exam, his visual acuity in the right eye was scout finger and the left eye was 2030 minus two.

01:31:12 His anterior segment exam otherwise was notable for a trace injection in both eyes and cells in the anterior chamber in both eyes, but was worse than the right eye. Posteriorly, we can see a slightly hazy vitreous in the right eye, and a possibly minimally hazy vitreous in the left eye. So this was his fundus Aptos photo on the first encounter.

01:31:33 Although he came in with only complaint about the right eye vision, we actually noticed this multifocal, part lace up brand of fluid in both eyes. And as you can tell, the vitreous in the right eye is a little bit hazier as compared to the left side. And the patient actually has a pretty hyper remet right optic disc with some border blurriness.

01:31:55 And on the macula OCD skin, we can actually appreciate again the multifocal bolus. There is no detachment in both eyes. And in the right he has this pretty visually significant boundary layer detachment. That's really right on the phobia origin. There are actually some vitreous cells in the media. On the NFL he does have some disc edema in both eyes.

01:32:19 So just to quickly summarize, 29 year old Mel, he came in here with right eye vision change. And he's having uveitis and serious retinal detachment in both eyes, as well as a partial detachment in the right eye.

01:32:36 So I would like to ask our panelist, what is your differential diagnosis for this young man? Do you have any more questions for him, and what would you do as the next step? Looks like? It's a good presentation for Herodias disease. He's got a lot of systemic symptoms that sorry detachments typically seen in an inflammatory disease like Herod's disease.

01:32:57 Yeah. Basilar detachment is pretty near and dear to my heart. And with, the VRM group, we had reported the first presentation of this several years ago in a patient that had acute toxoplasmosis. And so there's that pressure from the caudal inflammation, which then disrupts the RPE. And we think there's some sort of split in the photoreceptor layer to create that, a sense that in the years, you know, basilar detachments and seen in numerous conditions.

01:33:25 Right. So the list just gets on and on and on. But clearly you have a young person here with a pan uveitis with basilar. You can localize this to inner choroid RPE. So Herodias or Vcjd does come up pretty high. But you also want to also think infectious, you know, TB syphilis should be on your workup as well.

01:33:46 You know, honestly, anything can be up there. So look for sarcoid. And that's. Yeah. And an HIV as well. So that's kind of where I would initially be thinking that, I would double check. Did you have any, like, neurologic symptoms ringing in his ears, prodromal symptoms. Consider neuroimaging, I guess, to rule out any. Yeah.

01:34:08 One other thing to add to the differential. If he's like an ITP or a ITP like syndrome, which can happen actually, very infectious. So, you know, something to think about as well. You can get isolated detachments with that as well. Thank you very much. These comments are all very spot on. So if you just Google differential diagnosis for basilar layer detachment, you're pretty much get like a super long list of all the different ecologies that I kind of summarize over here.

01:34:37 However, a lot of these don't actually fit, our patients presentation and medical history. Exactly. So what we did is we also look up the differential diagnosis for pan uveitis. So now we have a much shorter list infectious ways. Syphilis TB toxoplasmosis, inflammatory disease like sarcoidosis, age for shared sympathetic ophthalmic and other things that are maybe probably the most notable.

01:35:02 One is a neoplastic process. And based on our patient's condition, we can kind of convince ourselves we can't really rule out anything infectious because of his, HIV status. And he's being on hard for a long time. Although the retina, appearance doesn't look exactly like the typical toxoplasmosis inflammatory ways, sarcoidosis and BCC are pretty possible candidate.

01:35:26 The patient personally denies ever having any ulcers in the mouth or the genital area. So but shares is maybe a little bit lower on the list, and he has not had any trauma or surgery to any of the eye. So Tamiya is probably the lowest on this list. So we did a pretty extensive work of trying to capture all the possible, itchy allergies.

01:35:47 We also tested him for the HIV, though in the lymphocyte subsets just to better understand his immune status, we pay specific attention to syphilis, and we also did a Texas ray and urinalysis. As the panelist mentioned in addition, HLA typing, which is in hope to capture some other autoimmune disease. In this geologies, we also recommended lumbar puncture with CSF study and with a special focus to the syphilis test.

01:36:13 We immediately started him on topical proneness alone and cycle and the plane. It's basically if the RPI returns positive, we're going to start I.V. antibiotic and treat him and work him off as new syphilis because he was mentioning about having the headache. If the RPI was negative, we're going to treat him as a presumed vka and start I.V. methylprednisolone.

01:36:35 So the workup returned with a negative RPI. He is positive with a IgG Toxoplasma. We also did the CSF study, which actually only showed a cell count of three. So it wasn't really exactly a plea or psychosis picture. Thankfully, his viral load and CD4 counts were pretty robust, so now the impression was a probable. Vcjd syndrome. We immediately started him on I.V. methyl pred one gram for three days, and the patient said, I'm having a lot of improvement in my vision, my IPA, and my headaches are basically gone.

01:37:08 His right eye visual acuity improved to 2050 at this point, and we are seeing some clearing of the anterior chamber and vitreous cells. He was done started on a penicillin dosage of one mg pre K two weeks after the initial presentation. The visual acuity and body has already improved to 2025, and he now has a really clear and quiet and to chamber and vitreous media.

01:37:29 The run up appearance has much improved, which I'm going to show in the next slide and the air to a typing return only with a genetic barrier. In the DRP three LDL, his DRP one and Dr. four were with normal limit. So these are the fundus photos. Two weeks after the initial presentation, the multifocal supplemental fluid has actually kind of resolve is hard to tell based on the photo.

01:37:54 He still has some trace retinal full like appearance over the macula and nearby the object is that right up to disk now no longer looks hyper rhythmic.

01:38:03 And on the Oct here we can appreciate this much resolved spinal fluid in both eyes. And the prior posterior detachment is now non observable in the right eye. The left eye though there is still some supplemental fluid that's hovering over the phobia region. So we just last saw this patient for his two months follow up. His visual acuity has maintained at 2020 and one month after we saw him.

01:38:28 And there is no recurrence of inflammation on the exam. Now in both of his eyes, we're mainly seeing some eases on granulation, but otherwise there is no residual SOP, right? No fluid.

01:38:40 Thank you so much. I'm so sorry we're out of time, but, that was great presentation. And I'm going to introduce one more panelist we have up here. Doctor Catherine Talcott from Cleveland Clinical Institute. Thank you for joining us. Thank you everyone. Yeah. One last thing I would add is just I would have probably covered with Ibi penicillin.

01:38:55 You guys were very lucky. You can always unearth a little bit of syphilis in the process of treating something inflammatory. So thank you so much. Thank you.

01:39:07 And I'll invite Doctor Aaron Brown for our next case presentation.

01:39:16 Good afternoon. Thank you. To the, organizers and our panelists. The title of my presentation is Off the Rip. I'll be presenting two cases. Great. So our first case is a 78 year old female referred for a cradle lesion in the left eye. Patient had some blurry vision and extensive medical history. On the call, her widefield image.

01:39:37 Here we can see a some ovule pigment, epithelial detachment, with sort of asymmetric appearance. A few, drew the deposits and the nasal side of the phobia. On the far, we can see that there are two focal areas of leakage. Super temporarily. And then this sort of, ring of hyper fluorescence in this late phase image on the Oct, we can, note a sort of corrugated appearance of the RPE.

01:40:04 There is hyper reflective material, just under the RPE, you can see some caudal expansion, some choroid vessels, pre cradle cleft and then small amount of, sub retinal fluid. So, before we go to the management, I'd like that. How does this patient again 7870 and shows the other eye. I don't have the other eye.

01:40:28 I would like to see the the other as the other eye is basically normal. We'll say the other is normal. No, No deposits. If you, it looks like you're thinking about an anti-VEGF injection. Anti-VEGF injections? Yes. That's exactly what we did. The patient is given an injection of bevacizumab two weeks later, presented with a sudden onset visual worsening.

01:40:48 We can see extensive sub retinal hemorrhage here, some guttering of hemorrhage, inferiorly. And then just sort of a, modeling appearance in that area of the macula that we can't see. Two, a lot of blockage on the FDA. Yeah. So, I mean, it's pretty unfortunate situation here. Obviously, you have a large, fiber vascular pad. It's the right choice to proceed with therapy.

01:41:12 And unfortunately, it looks like it resulted in a hemorrhagic RPE rep. Yes. No. The question is, could you have done something different going back different anti-VEGF choice? Or is it PTT? You know what it where obviously there is some new vascular component here, but what is that coming from? What's the ideology of this? Is this idiopathic and V?

01:41:30 Are we missing or are we looking at something like pollock oil instead? Exactly. I was going to add about what I was going to bring up. So did you have an ECG for this? Yes. I don't have the ICU in this presentation, but the ECG was consistent with pollock oil for this patient. Once we're able to see, you know, through the heme, we got an ICG which showed some, you know, a bunch of grapes appear in some, polyps.

01:41:51 Yeah. Maybe there's two focal spots that were like your biggest lesions that you showed up on that say yes. Yeah. What are the things that's really helpful to do for these patients is to just cancel them, like, before the injection as well? Because the suspicion, you know, like, you can cause rips. And unfortunately, the repair also was caught was, accompanied by a fair amount of blood that's there.

01:42:10 And you did Avastin for your injection. Does some people will actually say, you know, maybe you should use something, more like Avastin versus something like for some AB for these large peds, which, you know, can really improve that sub space. But you use in some ways the most conservative but still had a rep. But they can happen.

01:42:28 They can happen, I think with any medicine. And yeah, you know, you I, I worry about the most at the beginning of starting treatment. But it can happen. You know, it's delayed in the process too. Yeah. And then there may be some data suggests that it that might be better in like a PCV type patient. But I'm not sure you would have changed management there.

01:42:43 I guess the question is what do you do now. Would anybody put like, a bubble in or try to move the blood around? Just you want to see where the blood is right now, some of it might been some retinal or migrated to some retinal space. So hopefully. And it is a lot of it is spread.

01:43:00 Yes. So it could be potentially display Sibo. Yeah. And that you could consider injecting like TPA like separately. It looks like there's probably some contiguous like sub retinal space because the hemorrhage is pull down pretty inferiorly beyond the arcade in your fundus photo. You just want to make sure it's not a lot of it sets up our P.

01:43:17 I also tell patients once you've had a rip, you know, it does tend to stabilize the disease a little bit more after that, because I think a lot of people, worried that their vision is just going to continue to get worse. But once I feel like there's they're usually more stable. How do you decide if you want to do intramural or sub retinal?

01:43:33 Really good question. Challenging I think really depends. For me it depends on like what the follow eye looks like. I want to see that it's mostly some retinal blood and lots of RPE blood. That's there. You know, I think about like, the patient status because it's going to the or I think about if they're going to be on sort of blood thinners like long term because, you know, you can you can take some much of the or do TPA just place the blood and then they can just have another bleed because the risk factors are there again.

01:43:59 So I feel like it's a nuanced, discussion for sure. I just took care of someone who I, I had a, I did TPA on and I actually saw them the day that it happened. I let them think about it for a week. The next week they looked about the same and they were pretty motivated. They were like monocular.

01:44:14 And so, I displaced it. And Vision's measuring better, but unfortunately with the, you know, their vision is usually permanently impacted by having that. So this patient was offered surgery and declined. So, we continued anti-VEGF injections for them. And, you know, the vision hasn't really improved. But, I want to, move ahead. Thank you, Doctor Talbot, for bringing up, for some, because the second patient has a history of wet AMD in the right eye.

01:44:38 Intermediate dry in the left had been getting injections in the right or c nvm. But then presented with decreased vision in the left. Here's a photo of that I, focal area of leakage on the RFA. And then two focal peds. So we initiated for the Mab in this eye as well. At CU, six weeks after the first injection, those two PD sort of coalesced into a, a single, hyper reflective deposit.

01:45:04 And then, two weeks after the second injection, presented with a new stoma. And then here on the wide field, you can see, some, sort of spooling of the RPE, staining there on the Afe and then, a really nice RPE rep, there with the associated, sub random fluids studies with the patient patients that have these serous peds.

01:45:28 I very, very specifically counseled, that RPE rep is a huge risk. Yeah. The other thing is with those right ankle peds, obviously, you told me this is an AMD patient. I still get an ECG just to make sure we're not dealing with something else. Again, like a poly portal type of process. But I would have very heavily comes, counseled this patient about repeat risk.

01:45:48 So it's really you mentioned PDT. I've seen a decent data on half Fluence PD combined with anti-VEGF have is do you ever have consider implying that in these patients I mean, in those cases they're clearly at risk here. I've done half the ones PD t plus anti-VEGF in unresponsive AMD patients. Like if they're really recalcitrant to every agent.

01:46:09 Yeah, but not at the other start none of the start. Now, I do think just this is great. You're talking about RPE rep. So you're going to talk about it more here. But it's just very hard to predict this. We've tried to come up with identifying risk factors. A colleague of mine, Doctor Saraf, has been thinking about this since his training days.

01:46:26 I'm not sure he's come up with the mathematical formula yet to, to, to, to be able to tell those predictors, but they should outline that. Yeah. So I'll kind of okay. And zoom ahead here I know I've taken some time. So Doctor Gass presented a pretty cogent theory of why this happens. You have the CVM growing up, you know, this sort of fibrous deposits into the RPE, which provide some traction once you, you know, inject this patient or PDT and the doctor gas, that then you get this sort of pulling.

01:46:53 Doctor Spade pointed out that these, these areas are not empty spaces that you get this, fiber vascular material growing under the RPE. And so when you inject, you get that, that tension hole, and then, you know, something's got to give. And that's sort of a theory behind why you can see all these fibrous deposits under the RPE.

01:47:11 Doctor Saraf in this paper, pointed out two important sort of diagnostic findings in terms of predicting which are, a ring sign of, of hyper reflectivity in the Afe and then these sort of, micro defects, micro tares that you can pick up on. Okay. So here's a ring sign. This is from that doctor Scraps paper.

01:47:30 And our first patient had something very similar around that that ped. And in terms of these micro tears, I mean, if you have patients, it's really interesting to go back and look because a lot of them will have this. And, you know, you can see here and maybe it's shadowing, but you know, there is some sub retinal fluid in that area.

01:47:46 So, you know, kind of picking out where that if you see that micro tear, so you see a ring sign, then looking at the from micro tear, you may be able to pick it up. And obviously all these patients should be counseled other okt findings. So the PD heit a PD high of 400 to 550 micrometers is likely predictive.

01:48:07 Stress lines on the on Fos. So I didn't point this out when we looked at our patient. But oftentimes in those areas of sort of the corrugations of the the B scan, you'll see these stress lines on the, on Fos, which, you know, indicate some, tension, some pulling, and then, again, the micro rips and then these, you know, peripheral sub retinal clefts also sort of, portend a poor, prognosis which goes locations, It's great. Thank you so much. I think we're out of time, but, yeah, it's a great discussion. Thank you. And then finally, I'll invite Doctor Kevin Allen to present our third case.

01:48:55 All right. Thanks, the organizers, for giving me the chance to present. As mentioned, my name is Kevin. I'm a PG three resident at the Cooley Institute at Cleveland Clinic today. I'm excited to talk about my case. A Ballad of Perseverance with faculty, discussing Doctor Talcott.

01:49:13 I have no financial disclosures. All right, so this is a case of a 43 year old, incredibly kind female who presents Ed with two days of worsening blurry vision in the right eye.

01:49:26 Her past medical and ocular history is otherwise unremarkable, but attention is drawn to her strong family history of malignancy and her review systems was notable for headache, generalized fatigue, and also recent worsening, nosebleeds. Her visual acuity was down to 2025, and the right eye with full color normal pressure. The eyes themselves are white and quiet with no AC reaction.

01:49:53 Here are the dilated fundus exams in both eyes. Attention drawn to the right eye. We can make out with this arrow sign a few, er, areas of hypo pigmented yellow patches that correlate to areas of hyper auto fluorescence on far. Otherwise, the left eye actually looks pretty normal. We do an Oct mark through these lesions. You can see that there is pockets of cell brightness, fluid.

01:50:21 There's also splitting of the photoreceptor layer concerning for a basilar detachment and maybe some thickening of the choroid in both eyes.

01:50:33 Well I kind of gave it away, but I was gonna ask the panel for their differential. But in this 43 year old female with a single, eye with a base layer detachment, at this point, we were thinking most likely it could be serious. You could have inflammatory etiologies like vka. So, you could have infiltrate over lesions into the core, leading to damage and ischemia.

01:50:53 And then, of course, you could have infectious etiologies. And in rare instances, shearing forces from trauma. And this was completely unilateral. This was completely, you know, okay. And so subsequent workup in the Ed demonstrated that she had a pronounced leukocyte ptosis with a white count of 47, thrombocytopenia with platelets of 28, and then for a full smear showing 75% blast.

01:51:17 Subsequent peripheral and bone marrow flow cytometry demonstrated this was in the B-cell lineage, with, next generation sequencing showing BCR able confirming B-cell lymphoma plastic leukemia. She was subsequently admitted for induction of chemotherapy. So at this point, we actually thought that this was most likely due to an infiltrate of process in the choroid from her acute leukemia. And so we elected to observe her closely during treatment to see if this would resolve.

01:51:44 So ocular manifestations of leukemia actually quite common. More than 90% of patients will have an ocular sign or symptom during their course. And actually 50% will have an ocular symptom at, initial presentation, largely from leukemic retinopathy due to hematologic perturbations. But you can also have a direct infiltration into the optic nerve and other ocular tissues like the choroid.

01:52:09 But often these signs and symptoms will resolve, with treatment of the underlying leukemia. And in this, an uncommon finding can actually be a serious retinal detachment. And so here's a case series demonstrating it's frequently bilateral. But also more often seen in the lymphoblastic cases. And this is thought to be due to infiltration of the choroid by these leukemic cells driving ischemia, inflammation and dysfunction, causing the RPE to do a poor job pumping out fluid, leading to sub retinal fluid accumulation.

01:52:40 And as shown in this case series, frequently this responds nicely to treatment of the underlying leukemia. So in our case we did have valid. So thanks to the previous speaker who introduced this already. But it's when you have detachment or splitting of the photoreceptor layer at a weak point in the retina or the outer retina, which is directly posterior to the elm.

01:53:01 And in a retrospective case, series, we demonstrated 164 patients, actually most commonly from VQA, as we just heard or so or MP. But you can also see it in CSR and oxidative pathologies like AMD. And so in our case, similar to the serious retinal detachment, we thought that this was because of choroid dysfunction being driven by leukemia, that maybe we caught this very early, leading to sort of that dramatic shift in fluid dynamics causing the splitting of the layer because she was only 20, 25.

01:53:32 So it's pretty remarkable that she noticed. So here we show at her initial visit a month after induction, we see resolution of that vascular detachment quicker than the sub retinal fluid. As we typically see. And then after two months, we see that it's now completely restored with restoration vision back to 2020.

01:53:51 And so big takeaways is that leukemia frequently has ocular manifestations, and is a time when we, as ophthalmologists, can actually lead to diagnosis of some pretty serious underlying disease. We showed for the first time at least, that I could find that vacillated attachment can be a presenting symptom of acute leukemia without other signs of leukemic retinopathy. She did develop some later in her course, but not at presentation and at.

01:54:15 The pathogenesis is still under investigation. But we believe this is most likely due to an ischemia or inflammatory damage to the choroid. With that, I'd like to thank all the providers who helped care for this patient. Great case. In case. Comments from the panel. Did you, again, if you go back to the, I showed at the beginning where they seemed like the quote was symmetrically, yeah, increase.

01:54:43 But then you only had manifestations on one side. So it was the thought that she may ultimately develop the same thing in the other eye without treatment. Yeah. I mean, it's very possible. I agree with you. When I saw that the carotid seemed thicker, I also thought there was maybe a little bit more granularity in both. Okay. But yeah, we we would have expected if she didn't get treatment.

01:55:03 It probably would have happened the other day. And you do see like a slight decrease in the choroid over time. And so yeah, I think it looks like it gets much better over time, which is surprising. The risk we have in the other I think. So, yeah. The risk of sounding like the poster child for IgG. You might have seen something on IgG.

01:55:20 Yeah. Another eye as well. When the choroid is that thick, I find it. I'm suspecting infiltrate of processes. ICG will show some early signs. So I asked about bilateral versus unilateral. For that reason you might have seen early signs in the follow up on ICG. Absolutely. And I think for the Chinese to Larry, I mean, it's easy to look at this and be like, oh, it's probably just a CSR, right?

01:55:42 But that's why there would be a little bit less common. And then the second thing to really scroll through the OCD to look for some kind of serious BD somewhere. And if it's not there present, and it makes me think of like other not less common etiologies, that's usually not CSR, right? It could be some scary cases where you can think it's CSR.

01:56:01 It ends up being a malignancy. Right on. Foma. And do you think this was like an early mild form of a multifocal Bess. Almost like I almost looks like that. I think, you know, I think to your point, you have to think about if you see a basilar like, like detachment, like the differential is very specific for that, but really keeping things broad.

01:56:19 But it looked like that, too. The other thing that we found was surprising that like, I was surprised that the vision was still 20, 25. With the way that it looks there. It's kind of impressive if you think about just the mechanics of it. Why the. Yeah, it's surprising. Some of these patients. I had a ITP patient with lots of basilar detachment.

01:56:34 So she was 2020. It's kind of really shocking. How did you, have this patient, be evaluated in the Ed. Like what triggered that initially? So she initially actually presented to the Ed just for the blurry vision I see. And so sort of simultaneous to us seeing her, you know, they always get the reflex CBC and BMP.

01:56:53 So the leukocyte ptosis was pretty much found simultaneous to our exam. That's lucky. Yeah. Yeah yeah yeah. Thank you very much. Was great British.

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