 So, today we are having an external guest, part of our Distinguished Speaker series. It's Dr. Lucia Sobrin. She is the Charles Edward Whitton Professor of Ophthalmology at Massachusetts Eye and Ear at Harvard Medical School. There, she also holds the position of Associate Director of the Retina Service. And she's also Associate Chief for Clinical Data Science at the Harvard Department of Ophthalmology. I also mentioned that she directs the Morse Laser Center and co-directs the Ocular Immunology and UV-Eitis Fellowship at Massachusetts Eye and Ear. Dr. Sobrin obtained her medical degree from the University of Miami and she completed a residency in Ophthalmology at the Bascom Palmer Eye Institute. She followed her residency with two fellowships, one in Retina at Mass Eye and Ear, and the other in Ocular Immunology and UV-Eitis at Massachusetts Eye Research and Surgery Institute. She also holds a master's degree in public health. Dr. Sobrin is internationally recognized as a clinical clinician scientist. She has made tremendous contribution to our understanding of diabetic retinopathy and UV-Eitis. Her work on UV-Eitis is directed towards improving diagnosis and treatment of this disease and identifying protective factors for non-infection UV-Eitis, among other things. When it comes to diabetic retinopathy, she has led several international studies, one of which includes multi-ethnic genome-wide association studies. These have greatly improved understanding, led to significant discoveries, actually, on the genetic architecture of diabetic retinopathy. And the strength of her work has come from her ability to leverage genetic methods to gain insight into ocular diseases with important implications from pharmacogenetic studies. Dr. Sobrin has received many awards and honors, including a senior achievement award from the American Academy of Ophthalmology and the Harvard Ophthalmology Excellence in Mentoring Award, which demonstrates her dedication to training junior faculties. She's an associate editor and executive editor for UV-Eitis for the American Genital Ophthalmology, and she's an editorial board member of Ophthalmology Science. Please join me in welcoming Dr. Sobrin here, and we very much look forward to her talk. Thank you very much for the introduction. I'll first just start saying that I have a cold and it is not COVID, and I will ask for your patience. If I have a coughing fit, I have cough mints, orange juice, tissues, and Purell up here to help me through the talk. And so I don't want to be that visiting lecturer that gave everyone a cold here in Utah, so thank you for your patience if that happens during this talk. So I will, the research seminar will focus a lot on my research, the genetics and pharmacogenetics of various eye diseases. But my Grand Rounds talk really is about one disease that I've been working on and struggling with in my academic career. And I wanted to share what I've learned with you. I have no financial interests or relationships to disclose. So autoimmune retinopathy, although it is a rare disease, I think it's important for everyone to know a little bit about it because it could present to anyone. These patients really have very vague symptoms and often very few findings on exam, and I even get referrals directly from general ophthalmologists who pick up on this and send them to me. So I think it's important for everyone to realize it because these patients tend to have a long delay in diagnosis because it's so hard to diagnose. I'm going to spend most of the talk talking about the challenges in diagnosis. And in particular, I'm going to emphasize the pitfalls of antiretinal antibody testing and the importance of ruling out other mimicking diseases. And I'll do this through a series of clinical vignettes about patients. And then I'll end on a shorter amount of time talking about the challenges in treatment. Most of you will not end up treating these. Some of you will, but most of you will not. But I'll talk to you about the struggles we've had deciding what to treat them with and then how to follow them to figure out if they're actually getting any better. So this disease was first recognized in 1976 in this paper. And the quote is that this is a blindness caused by photoreceptor degeneration as a remote effect of cancer. And indeed, the first diagnosis was in the setting of cancer. I took out this quote from the paper. Visual disturbances associated with cancer are ordinarily caused by METS, metastasis to the brain, meninges, optic nerve orbit, foridoretina. This report documents blindness caused by retinal degeneration of obscure pathogenesis in three patients with cancer. I think it summarizes it quite well. And although we've gotten to know the pathogenesis a little bit more, it makes me smile that back then it's obscure. And today it's still a little bit obscure for us as I'll show you. These are those three patients. So they all had advanced cancer. They all had ring-like scatomas. Their arterioles were narrow. Their optic discs more or less look normal, but their ERG, if they had one, was flat or they had extensive night blindness. And then on autopsy, when their eyes were removed, all of them had total degeneration of the retinal cells. Now it took about another 20 years in 1995 for there to be more insight into why this happens. This paper recognized one particular protein, recovering, which is a photoreceptor specific calcium binding protein, was expressed on the tumor of a patient who had cancer associated retinopathy. And in figure one, you see that patient, Sarah, binding to a human retina and lighting up the photoreceptor cells. So in their blood, these patients have antibodies to recovering. The reason they have antibody to recover is presumably because their body is trying to fight off their cancer and the cancer expresses recovering. But as a side effect, the antibodies also bind the recovering in the retina and lead to cell death. And then for further evidence in figure three, you'll see in lanes one, two and three, all these patients are patients who have car. So they have cancer and cancer associated retinopathy. And the 23 KD band that lights up is because is their tissue incubated with against the Sarah of the first patient who had antibodies. Maybe I'll show it on the screen. So. And then what they also proved is in lane eight, you don't see that band at the 23 marker on the Western block. That's a patient who has cancer, but doesn't have cancer associated retinopathy. So they're showing that it's present in multiple patients with cancer and cancer associated retinopathy and in patients without cancer who don't express this specific protein in their blood or on their tissue. They do not have a reaction. And then finally just showing a direct pathophysiology. If you inject anti-recoverant antibodies into a rat eye, it induces what looks like cancer associated retinopathy where the ERG goes to a very low amplitudes. So this is great in car. We kind of understand what causes a disease. There's molecular mimicry between tumor antigens and retinal proteins, but car is actually a really small part of autoimmune retinopathy. Autoimmune retinopathy, the two major categories are perineoplastic, which car is a part of. And then the other well defined subtype of that is Mar melanoma associated retinopathy. But there is a whole other type of air that is non-perineoplastic where we can't find an underlying cancer, but for all intents and purposes, the what we see in the eye is the same, which is widespread retinal degeneration. And that's the one we really don't understand. And that's the one we struggle with the most. So in non-perineoplastic air, this molecular mimicry might be against an unknown antigen, possibly an infection. Also possibly regress malignancy. We often worry that patients who present to us with air and we can't find a cancer in their body that they're actually, their immune system is doing so well at controlling the cancer. We can't find the cancer, but it's still having the side effect of causing the autoimmune retinopathy. And I have had patients who initially we don't find a cancer and eventually they do get diagnosed with a cancer over time. So this is a real concern also when it comes to treatment. And I'll talk a little bit about that. So why is it so difficult to diagnose these patients? Their complaints are very vague. Most commonly, it's going to be Phytopsia, Scutomas, or Nectalopia. And then the fundus really looks on a quick look, totally normal. You'll see sometimes some vascular attenuation, but really not much else. And it's easy to overlook it and call the exam normal. So really it has to you have to have a high clinical suspicion and patient who has vision loss, a normal exam, or only some mild vascular attenuation and visual field alterations. And the real way to start on the path to making the diagnosis is to next get an electro retinogram, which usually shows significant depression. To help us in this difficult task of diagnosing these patients, there was a consensus panel that came together and created these criteria. And we'll go through how these criteria play out. But they are electro retinogram abnormality, the presence of serum antiretinal antibodies. And I'll put an asterisk for that because some people this is quite controversial. Some uveitis and retina specialists don't even order antiretinal antibodies and we'll talk about why in a little bit. The absence of evidence of a retinal generation or dystrophy, other causes need to be ruled out as the reason for their visual function abnormality. And then the absence of overt inflammation, which would indicate a uveitis instead of autoimmune retinopathy. So we're going to spend a lot of time talking about the serum antiretinal antibodies. So here is a list of all the serum antiretinal antibodies that have been reportedly told to be associated with autoimmune retinopathy. I can tell you that the only one on this list that really has strong evidence that it's actually pathogenic is recovering, which we've already talked about. For melanoma associated retinopathy, there's also a protein called Trimp1, which is well characterized. And but apart from that, there's really more evidence that any of these other antibodies have any role in pathophysiology. Moreover, there are a lot of issues with the testing for antiretinal antibodies. In this paper, which was published in 2021 by John Chen and his collaborators, they actually found that 93% of patients whose blood they sent off for antiretinal antibody testing was positive for these antibodies. So 93% of people walking around totally fine, no eye problems have these detectable in their blood. So you can see it's a very poor marker for disease. We also did a study where we sent it to two different laboratories to see if we could get the same result from those two laboratories. And only 60% of the time did the two laboratories even agree that they were antibodies present or not, and only 36% of the time that they agree on the specific antibody. So there's a lot of variability in testing. The test has a high false positive rate. And so you can see why a lot of people feel like this is a somewhat useless test in autoimmune retinopathy. The other thing that's really important for the diagnosis is excluding other things. And this is where a lot of people, this is a trap that we can all fall into. And the thing to remember is that air is a diagnosis of exclusion. You really need to rule out many other things. And the things that are important to rule out are retinal toxicity. This is especially true in patients who present with CAR because some of the chemotherapy agents they're receiving are actually toxic to the retina. And sometimes this is really difficult. And the only clues you might have that it's the agent is that the timing with the start of that agent correlates well with the vision loss. But sometimes that's hard to distinguish. Vitamin A deficiency, especially in patients with bariatric surgery or liver disease can look a lot like autoimmune retinopathy. The big one we struggle with and we're fortunate with the state of genetic testing now that we're a little bit better off is inherited retinal degeneration which can look almost exactly like autoimmune retinopathy. And then occult posterior uveitis. And for this reason I get a fluorescent angiogram and an indecide angiography on every patient to rule these things out when I'm thinking autoimmune retinopathy. So we're gonna go through a couple of few cases to show you how these things play out. So my first patient is a 40 year old radiologist. And he says a few weeks, I've had a few weeks of peripheral vision loss in both eyes, my left eye is a little bit sore and both are sensitive to lights. And I noticed when I was playing soccer I just lost sight of the ball. So visual field loss. He has a family history of glaucoma retinal attachment because multiple people are nearsight in his family and lung cancer and some family members that smoked. And we were fortunate he had prior glaucoma suspect evaluation. So we had exam showing his exam was normal and actually his visual field was normal for several years. No other important history. And this is his eye exam. So if you looked at this eye quickly, it looks totally normal. There was a little bit of anterior vitria cell. His anterior segment exam was normal. His vision was 2020. His cup to disc is enlarged. That's why he's a glaucoma suspect. And then really the subtle finding is vascular attenuation, but it's pretty subtle. A lot of people would say he has a normal retina and not, and just say everything's fine and come back if you don't get better. But if you do the OCT, what you'll see is that there's loss of the outer retinal layers or indistinguishing of the outer retinal layers, especially temporally here. And this was the clue to his diagnosis. I told you I get diet testing to make sure they don't have retinal vasculitis. And you can see here that he had a pretty unremarkable fluorescein angiogram. It is normal in some patients to have a little bit of end vessel leakage. You can see that in the temporal far periphery of the left eye. And that doesn't mean they have retinal vasculitis. They can just have a little bit of leakiness from their blood vessels. And the same thing's true in inherited retinal degenerations. But this is his visual field. So a marked departure for what he had previously in both eyes and his ERGs were suppressed. So we did the workup. He had no signs of underlying causes of UVitis. He had normal vitamin A and chest X-ray was normal. He did have anti-retinal antibodies. So recovering the one that we hang our hat on was negative. And he had two other ones that were positive. I don't know if it would have changed my management very much that these were positive. If they were all negative, I may have still diagnosed him with autoimmune retinopathy eventually. Really the clinical picture was pointing in that direction. The most important thing was to rule out a genetic cause of his disease and that was negative. So he has a autoimmune retinopathy at this point based on the criteria we went through. And then the next step is obviously to rule out cancer, especially with this history of lung cancer in his family. And what I typically do is a brain MRI and a PET CT. I usually do skull base to pelvis, but this gentleman was a radiologist at Mass General Hospital and he changed his order to scalp to toes. I think he wanted to be extra sure he didn't have cancer anywhere. It was also the fastest PET CT I ever got, got the next day after ordering it. So it's helpful to have a radiologist as a patient. So he meets everything. He's got ERG abnormalities. He's got some anti-retinal antibodies. We can't find any cause for retinal degeneration or distra-free minimal inflammation. He's the closest thing that I can show you to non-perinatal plastic autoimmune retinopathy. Now the asterisks is that the genetic panels that we have, they're pretty good. They cover about 60% of the IRDs that we know about. There are mutations out there we don't know about. He could have one, but the rapid onset of his disease, the good documentation we had previously that he had normal visual fields for years, I think this is about as good of a diagnosis, strong of a diagnosis as I can make for this patient. So now I'm gonna show you a couple of other patients who might've gone down this autoimmune retinopathy diagnosis path but ended up having something else. So the first one is a 66 year old man and he needs a flashlight to walk around his house. So in March of 2021, he had foggy vision and they attributed that to his cataracts and he had cataract surgery. And this is a very common path in autoimmune retinopathy patients because you don't see anything on exam. They do have some cataracts. So they get cataract surgery and things don't get better. Actually, his vision worsened after cataract surgery. So he sees a retina specialist who looks at him and diagnosis him with dry AMD. But it's a little bit of funny picture and so they send the patient to see our inherited retinal degeneration specialist. His ERG is depressed. His visual field shows central scatomas. They have a plan to send a genetic testing panel. He's 66, so a little bit unusual to be presenting with this at this time, but they're gonna do it for completion. And then they send him to me to consider autoimmune retinopathy as well. So the most notable thing about his history is that he has longstanding severe Crohn's disease. No family history of retinal degeneration. And he's feeling totally fine. Here's his fundus. Again, if you looked at it quickly, maybe some Druzen yellow deposits in the periphery, but not much going on there. Central vision is mildly decreased, but no signs of inflammation. And on his OCT, I think you can appreciate there is just some mild indistinction of the outer retinal bands here similar to the first patient, the radiologist. He gets a fluorescein and ICG that are normal and he gets antiretinal antibodies and they're staining on immunohistochemistry. His serum causes a reaction with photoreceptors in a human retina. So he meets the ERG, he has the antibodies. We've tried to rule out retinal degeneration and he doesn't have any inflammation. So does he have a non-perineoplastic autoimmune retinopathy potentially? So the other thing we did was a vitamin A level and it was less than five. And so I've had several patients come to me to rule out autoimmune retinopathy and the reason that they actually had the depression and changes on OCT was just a vitamin A level. So I just bring this case up, just the importance of getting a vitamin A in every patient that comes with a concern or a possibility of autoimmune retinopathy because that's an easy fix and it's a lot better than getting immunosuppressed. So this guy ended up having vitamin A deficiency, got repleted and was just fine. And the Crohn's disease was a little bit of the clue because he probably has malabsorption and that's why he had vitamin A deficiency. So I tell my residents and my fellows that you need to prove to me it's not something else when you tell me a patient has autoimmune retinopathy. This is the list of everything I absolutely get on patients who come to me to rule out this diagnosis. So I get genetic testing on every single one. And this is the problem, the one disease, the inherited retinal degenerations that we often still have issues with because as I mentioned, the genetic testing is really helpful if it's positive. You've confirmed the diagnosis, they don't need to get any immunosuppression and they might eventually be eligible for gene therapy studies. But if it's negative, it's really not as helpful because the patient can still have an IRD of an as yet unknown genetic mutation. We do look at some clinical clues as delineated in the table there. ARS tends to be more sudden onset. Typically they don't have any family history of retinal generation. It's a little more asymmetric and they typically don't get bone pigment deposition like bone spectacles in the periphery and inherited retinal generation is the flip side of that. But none of these distinguishing factors really are 100%. And so that's why the genetic testing really helps us, especially if it ends up being positive. And I'm gonna show you a case to illustrate the point about genetic testing. So this is a 40 year old woman. So nine years before she came to see me, she noticed a dark circle, what we think is the scatoma in her left upper visual field. She was examined, everything looked fine. She was sent off. Four years she came back. Now she has these scatomas in both eyes. She's 2020 that exam is reported as completely normal. And she's diagnosed with an ocular migraine. She goes a couple more years, come along. She still has these symptoms. And now they're able to document temporal visual field defects and on a formal visual field testing. And she's diagnosed with ABC. So acute idiopathic blind spot enlargement. But she continues to complain bitterly and she's referred for possible autoimmune retinopathy. She has no family history of retinal degeneration and she's, as I said, 40. Visions great centrally anterior segment exam, totally normal. Here is her normal fundus exam. And on a quick look, yeah, looks pretty normal. If you look closely, there may be some RPE changes, but I think on a quick exam, many of us would call this normal. Here, she has some RPE changes probably around the arcades that are somewhat subtle and could easily be overlooked. The auto fluorescence, however, really shows it nicely. And auto fluorescence is another test that I mentioned in the list that is very useful. So you see this hyper auto fluorescent ring around the bovia. You see these stippled hypo auto fluorescent lesions in the temporal macula and nasal to the nerve. And in the left eye, they're even more prominent. Here, she has outer retinal loss and really only the fovea has preservation of the outer retinal layers on both sides of the fovea. She's lost the outer retina and that's highlighted here. She has peri central scatomas in both eyes. They correlate somewhat nicely with the auto fluorescence findings. And her ERGs are down there. It's not terribly down. You can see the normal range on the right. So she's mildly depressed in some parameters. It's actually normal. So she has ERG abnormalities. Did I, sorry, I skipped too much. So she had antiretinal antibodies. Her vitamin A was normal. We've ruled that out. And she had immunohistochemical staining of the photoreceptors. So she had an ERG abnormality. She has antiretinal antibodies. No other cause so far for visual function abnormality, not evidence of inflammation. So is this autoimmune retinopathy? Well, she wanted to have autoimmune retinopathy because the alternative was she had a genetic problem. So we sent the genetic testing and she in fact had two heterozygous variants for H2A. And this was what our inherited retinal degeneration specialist was the mildest case of H2A they'd ever seen. Remember, she's 40 years old, no family history. Her ERG, some of the parameters are still normal. And yet she has bona fide inherited retinal degeneration. And she didn't wanna have this because she knows there's no treatment for this. Whereas for autoimmune retinopathy, even though our treatments are not always great, at least we can offer them something. So she was very disappointed to find this out. But here is where genetic testing really makes a difference. And you might say, this 40 year old with mild ERG, how can she have an inherited retinal degeneration? And the genetic testing really is key for this. So she had a pericentral-like pattern of RP. So I hope that's sort of been a clear way to think about these patients and how to approach them and all the things that you really need to rule out before you give them that diagnosis. And once you make the diagnosis, the important thing to remember is that you have to rule out the occult malignancy. Half of the patients who have car will have their visual symptoms prior to getting their malignancy diagnosed. So we've been the ones to send them and have their CAT scan of the chest and where they first find out that they have a mass in their lung. Car has also been documented up to 10 years after diagnosis of cancer, so it can go either way. Small cell lung cancer is the most common one, although many other cancers have been reported to be associated with car. And if there's no known cancer in the patient, it's very important to talk to the primary care. And as I mentioned, what I do is I get a PET CT skull-based Tepelvis. I send them to their dermatologist to get a full evaluation, make sure there's no melanoma anywhere, and make sure all their other cancer screenings are up to date, mammogram, colonoscopy, PSA, applicable, and then go from there. So those are the challenges in diagnosis and how to approach these patients. And then I'm gonna end up by talking a little bit about the challenges in treatment. One challenge is to find out, figure out how we can tell if the patient's treatment is actually working for them. Because a lot of these patients will present with advanced photoreceptor loss, and it's hard to know if we're doing anything with the treatments that we're doing. Their retinal cells are dead, they're not gonna come back most of the time we know that, and are we really affecting any change by treating them? Another question, when I was in fellowship and residency, my mentors would tell me they would follow antiretinal antibody titers. I've already told you that some people don't even bother to check them for diagnosis, but some people were following them serially over time as a marker of treatment effects. So if the antiretinal antibody titers went down or the number of antiretinal antibodies decreased, that would indicate to them that there was some positive response. So I'll talk a little bit about that. And then the issue that I alluded to, which is if we impair a patient who has non-pure neoplastic air with immunosuppressive therapy, and they have an underlying malignancy that their immune system is controlling, are we gonna impair their immune system from controlling their cancer and potentially unmask their cancer? And so we'll talk about these things. So here's a list of all the immunosuppressants local and systemic that have been tried with some reports in the literature of success with treatment. I will focus on rituximab and intravenous immunoglobulin because those are the ones that we've found to be the most effective. But all of these have some potential role in the treatment of these patients. I'll say that plasma phoresis acutely can help in some patients, but in my experience, it hasn't been very effective because the damage is already done. And if you remove the antibodies, the body's just recreating them immediately. And so I have never found that to be particularly helpful in my patients. So rituximab is typically the drug that I use first line. There's a rationale. Rituximab is an anti-CD20. So it knocks out B cells. This is thought to be at least in some cases antibody mediated. And so there's good rationale. So we reviewed the results of our patients treated with rituximab. Seven of them had cancer associated retinopathy, nine were non-perineoplastic and we had followed them for about 17 months. 13 of them had had some prior immunosuppression and three were treatment naive. And we tried to be very selective in calling something success. So for their visual acuity to be better, they had to improve two SNEL in lines and for their ERG to be better, they had to improve 40%, which is a high bar. So what we found, and what I used to counsel my patients when I'm talking about this treatment to them is that 14% of eyes had improvement in vision. And 63% of eyes had stable vision. So I tell my patients, the most likely thing is that we're just gonna be able to stabilize you. There's a small chance we'll make you better. And then in a quarter of the time, we're not gonna, you're actually gonna get worse despite our treatment. And ERG outcomes really didn't show much improvement with the rituximab. 25% of eyes had extinguished ERGs at baseline. So we had nowhere to go and we excluded them. But the remainder of eyes really had stable ERG parameters over the period of treatment. And this probably is just a reflection of the fact that globally, there are retinal photoreceptors in the periphery are damaged and most of those are dead and they're not gonna come back even if we stop the ongoing immune process. Similarly, the OCTs did not get better when we looked at total macular volume or subfield macular thickness, they stayed the same. But I thought I'd highlight a couple of patients who improved because these are the patients who give me hope that sometimes we're doing something with what we suggest as a treatment to these patients. So this is a 69-year-old woman. She has non-perinatal plastic air. We gave her steroids and she really didn't improve very much with steroids. And then we gave her a rituximab weekly over four weeks. And you can see that her vision improved dramatically. She used to not be able to drive to my visits. She used to have to have someone drive her and she went from 2200 to 2025 in the right eye and to 2040 in the left eye. You can see her ERGs didn't change very much. They weren't severely suppressed. They were only moderately suppressed but they didn't change very much. But it made a big difference for her central visual acuity. And I'll show you another patient that also had that kind of result with a different treatment. This is my second patient with rituximab that improved. She was a young 23-year-old woman and we had treated her with milder things first. So mycophenolate. And you can see this graph of her vision at presentation. She's getting worse. We start her on cell sept and she continues to get worse. And then we start rituximab and then her visual acuity improves. So these are the minority of patients. I don't emphasize this with my patients. These are the exception but these are the patients that give me some hope that we're doing something. The other treatment we've been using quite a bit is intravenous immunoglobulin. So this is when we infuse pooled immunoglobulin into patients. It's used for many different autoimmune diseases. But we've reviewed our patients with this. This is a rare disease. So we had nine patients treated with IVIG with long-term outcomes. And what we tried to do in this study is actually compared them to natural history because some people, there's not a lot about natural history about autoimmune retinopathy. And sometimes you don't know if they were gonna stabilize anyway. That's the natural history of disease. They get worse initially and then they just stabilize. Or if your stabilization is actually due to the treatment that you're giving them. And so we took patients that either refused treatment or were followed. The neurofemologists at our institution used to follow these patients many years ago and they didn't used to treat them. So we took their data and compared them to the patients we treated with IVIG. So if you looked at the IVIG patients, a good percentage had visual improvement and the rest were stable. But if you looked at the natural history cohort, none of them had vision improvement. A third had stability, but two thirds had significant vision decline. And when we looked at ERG parameters over the long-term, the IVIG patients were less likely to decline compared to the natural history controls. And so typically now what we do is we start rituximab and we repeat rituximab on an every six month basis typically and in between we give intravenous immunoglobulin to this patient. So that's typically our first line treatment now. Almost always in conjunction, I can think of, if I think hard, probably I can think of a patient who didn't want to get rituximab for whatever reason and we've done IVIG alone. Or we only gave them maybe one dose of rituximab and they didn't tolerate it and then we just continued with IVIG. But typically I'd like to give the rituximab. So back to our radiologist. So we gave him IV steroids, prednisone taper, rituximab and then monthly IVIG. And seven months post diagnosis, his symptoms had improved, his vision was stable at 2020. Remember, this is a radiologist, 40 year old radiologist. So this is career ending for him if we can't preserve his visual acuity. And you can see that the area of the outer retinal disorganization is still there but it hasn't progressed towards the center of his vision and his symptoms are stable and he's able to work. And so that is the outcome for him which we're quite pleased with. So the other thing I alluded to was monitoring response to treatment is sometimes tough. We typically follow visual acuity, visual field, OCT and ERG. I showed this patient, I had a patient with cancer associated retinopathy who I treated with intervitral triumcinolone. And he would come, you can see that his vision would drop to hand motions and we would lose the outer retinal bands completely. And then I would give him an intervitral triumcinolone and I know those outer retinal bands don't look great but they show up after the intervitral triumcinolone at least in some degree and his vision would improve to 32. So intervitral or local steroids are also an option in these patients and avoid some of the issues with systemic immunosuppression that you might be worried about in patients with cancer. But this is an example of why OCT can be a good way to follow patients. But I'll say that antiretinal antibodies do not appear to be a good marker of disease and I don't follow them. I still get them at baseline. I think it's a force of habit. They rarely change what I do but I don't repeat them over time. And we looked back at our patients with air. There was five with car, one with mar and the rest non-perineoplastic. And we tried to correlate the number of bands of antiretinal antibodies to their visual acuity, their OCT and their ERG and there was no correlation. And so I don't really think the antiretinal antibodies are great for diagnosis and I think they're not useful for following patients either. So the take home points are that air is the diagnosis of exclusion. You have to prove it's not something else first. And in particularly you need to avoid over reliance on antiretinal antibodies when making the diagnosis. Just cause antibodies are positive doesn't mean they have the disease. You have to go through the exercise of ruling out everything else. We have, I've seen non-retinal specialists order antiretinal antibodies and send patients to me and they haven't gone through the, they haven't gone in an FA, they haven't ruled out vitamin A deficiency. So really antiretinal antibodies are a problematic test. And you shouldn't hang your hat on them. Always investigate alternative causes and in particular now with genetic testing being so available, always get genetic testing. Sometimes you'll be surprised in someone who you didn't think there's any chance they have an inherited retinal generation. They actually do have one. The malignancy workup always has to happen if you make this diagnosis and treatment can require trialing several agents, local or systemic steroids. And then in most, for us at least we're using Rituximab and IVIG most consistently cause they have the most efficacy in our experience. So I wanna acknowledge all my research fellows. Also our IRD service and the Arcalyr Genomics Institute which shares a lot. They both share patients with me and help me get genetic testing and help me rule out inherited retinal generations. And I'm happy to take any questions you might have. Is a very, oh, that for a residence is a very, very sensitive sign. I would say it's 80 to 90% of my patients that ever come in and say they have to have a flashlight around their house. Actually I have vitamin A deficiency. So that's the first thing you should think of. Then in terms of the question you showed for your inherited retina disease patient of the one with us to A, the auto fluorescence. Do you routinely get auto fluorescence? Is that helpful at least in diagnosing either excluding or in diagnosing autoimmune? I get auto fluorescence on everyone but it is not that helpful. So the perifovial hyper auto fluorescence ring you can see that in both diseases very commonly. It's actually the most common auto fluorescence finding in autoimmune retinopathy. And the stippling auto fluorescence changes also are not that helpful. If they're very symmetric that's the only time where I think maybe it pushes you a little bit. But even then honestly I've seen air patients look very symmetric as well on auto fluorescence. Thanks. Great. So welcome to Snowy Salt Lake. All I understand you've had some snow back in Boston here. We're familiar with snow, yes. Yeah. So if you think about the fact that these retinal antibodies are really quite common and that cancer is quite common and yet air is very uncommon. Has anybody looked to see what may be different about these patients that they're susceptible to when obviously the conditions that create it aren't that uncommon and yet actually having the condition is very uncommon. Yeah, I'm not aware of anybody who's been able to look at that. I think it would be interesting. It's rare the patient that presents and we can't find the cancer and later we find the cancer and it would be interesting to look more carefully at those patients and see if there were any clues early on about that. But I have to say, I mean I've have several patients with non-perineoplastic autoimmune retinopathy I followed for seven to 10 years now maybe even a little longer and they haven't developed cancer yet. So even those patients are rare and the ones that later develop cancer. I have more patients. Melanoma is a terrible disease as you all know and I have patients who develop more and sometimes I think that when they have immune reactions not just the more but also sometimes rental vasculitis or UVitis they actually have a better prognosis. Their immune systems revved up so much it's causing problems in their eyes but it's keeping their melanoma away and I've seen patients when I first met them where I was like, oh gosh, this is terrible this person's not gonna last and now I'm eight years later I'm still seeing them and they're doing great their eyes we controlled the eye inflammation somewhat but they're still controlling their cancer and it's really remarkable to me. The immune system interplay with cancer is mysterious. So I still do a retoxin and IVIG and most of them you would think you I always talk to the oncologist of course the oncologists are always like, sure why not? Because some of these agents are high doses used to treat cancer retoxin map obviously IVIG has no implications if a patient's really worried for whatever reason like they have a family history of cancer they really are worried. I tell them IVIG is not an immunosuppressant and it's safe for you to try and those are the patients that might avoid retoxin map the oncologists have never pushed back on me. I've seen a couple of these patients and what I tell my when I counsel my patients I have a similar discussion to those who have immunotherapy adverse events that we've seen anecdotally that patients who do have this robust immune reaction actually have a great response to their cancer. I have seen one patient who had a occult car with just very early symptoms that was accelerated by initiation of immunotherapy and it was such a robust and profound response over three days that we did plasma phoracis with very heavy immunosuppression with great success and found that they had durability of their just two infusions. So I like to use that as an example to kind of reassure other oncologists and the patients that they might still be having some effect on their cancers even if we're immunosuppressing them. Yeah, that's great. I mean, that's a great example of where plasma phoracis helps for us it's so hard to get plasma phoracis. And so by the time we arrange everything it's been weeks to months but there where you have a patient where you have the whole team on board and you can get things going quickly. I think that's a great scenario to try plasma phoracis on. Yes, yes. So how do you ask about Nectalopia? I've seen a few of our elderly VA patients who complain of a harder time seeing at night who have had ERGs for possible car. These patients can still get around in dim lighting and but have a harder time driving and reading. I mean, I don't have anything special about the typical question for IRDs is of course, can you see the stars at night? I don't necessarily think the Nectalopia is always so dense in these patients to ask for that. It's not a perfect symptom. Like I said, the symptoms in air are sometimes vague. So I just ask, do you have difficulty seeing at night but I'm not sure. As you said in some elderly patients, there are many reasons why they would have decreased night vision and it may not be that specific of a symptom. Did your radiologist have any other autoimmune conditions? None at all. Even though the antiretinal antibody testing may not be useful for diagnosis, they can be useful in convincing reticent insurance carriers they should pay for expensive treatments. Definitely possibly. I have, I can't remember anyone who has denied something because I didn't get, I mean, I always get antiretinal antibodies. So I guess I've never had this scenario but I often find that the reviewers for insurance companies have no idea about the diseases that we treat. They can't pronounce the word UVitis, for example, when I talk to them for the peer-to-peer review. So, but it's, but I'm sure that I think it could definitely happen that it is an important part for insurance coverage. Do you think there's still any relevance to the old term autoimmune related retinopathy and optic neuropathy? Specifically, do these patients have both an optic neuropathy and a retinopathy, I think? Do you think there's still a spectrum of disease involving both sites? Yes, I rarely have seen, Aeron is the acronym for this disease. I definitely have seen patients that have both retinal degeneration and pale optic nerves that are probably not just a secondary effect from retinal degeneration. They're pretty rare and often it's really hard to distinguish, to convince yourself that the optic neuropathy is there. Sometimes the MRI will show that their optic nerves are attenuated and then you have the ERG showing the retinopathy so then you feel like they have both things. So I think it's possible, but most of my patients with AR, their optic nerves and all their optic nerve function is fine. Yep. Yeah. Yeah, I, you know, I not always in my experience, I also had a patient who had MAR directly after their first checkpoint inhibitor infusion. So the next day, total night blindness. In my experience, the thing they noticed the most is just sudden night blindness and just peripheral vision feel loss. So for me, the symptoms, I don't really make, you know, I don't, I hear the vague symptoms, but I don't hang my head on any particular symptom. So I've redone it and I can think of a couple of patients when like six or seven years have passed and I know the panel has gotten significantly better and the patient I'm thinking of, it didn't show anything else. Six to seven years later. But yes, but I mean, within a couple of years, the panel is not gonna be that much better. So it's probably not worth it. So I do, so I do the induction infusions, usually two weeks apart and then six months later and then another one, six months after that. And then I try to extend out nine months and then a year. And if everything's really stable, I think about stopping it. And then after that, I stopped the IVIG. Yes. Yeah. So those patients who that's, so that dosing is typically for lymphoma. So the dosing of two weeks, two infusions, two weeks apart is the typical dose for autoimmune diseases like ankylvesculitis, et cetera. I, those, I had talked to a couple of people about that dosing and around that time that I was treating those patients. And so that I gave them more intensive treatment. I don't know if that's what made the big difference for them. I mean, the truth is after one retoxin infusion, your B cells are gone. I'm not really sure, four made a big difference and it's hard to get insurance, insurance companies to pay for four infusions. So going forward, I've only done two. So it was really, cause I think at that point I was like, what is the most I can give these patients to see if this really works. And I haven't really done, besides those two patients, I haven't really done many other patients with that dosing regimen. Yeah. Sure. I don't, only if they have new symptoms. I mean, they continue their normal age related, cancer screenings, but only if they have new symptoms. And I mean, I have a very clear discussion with them. You could have a, this could be a side that your body is controlling a cancer and you have any new symptoms, let us know. Thank you, thank you for your questions.