 So now we'll have Tara Hahn present. She's going to be talking about posterior uveitis with some of the newer immunologic treatments. It's actually Tara Hahn. Thanks, Rhys. I'm going to be presenting a neurophthalmology case of this. So that's at Southern. You know, there's that Southern case, but I'm all for it. I think it's intentional. So this is a 52-year-old male who presents to the neurophthalmology clinic complaining of a gray cloud off-center in his right eye. He's noticed this for the past three weeks, and he's not had any symptoms in his left eye. On review of systems, he endorses a swimming feeling in his head and says that he feels off balance. He's also noticed that food tastes different, and he's lost about 25 pounds in the past month. He has a mild headache in the morning, which is new. He's not had that in the past. And he denies any tinnitus or pulsing tinnitus. Pastocular history is just remarkable for a remote history of a corneal foreign body in his left eye. And his past neurologic history is unremarkable. He has no history of migraines. Interestingly, he was diagnosed with metastatic melanoma about nine months ago and developed hypothyroidism from his immunotherapy, and was started on levothyroxine about four weeks ago. His medications. In the past, he was on a combination of nivolumab and epilebumab for 12 weeks, and now he's on nivolumab only. And that was for the treatment of his melanoma. And he's also on amyloidipine, rosuvastatin, trasadone, and levothyroxine. His social history is unremarkable. On exam, his vision in the right eye was 2030. His pressure was normal. He had a 0.3 loguna APD on the right. His color vision testing was normal, but he did have a mild amount of red desaturation on the right. His critical flicker fusion was asymmetrically decreased on the right. His extracular motility was full, but he fell off target with left head thrust and had psychotic eye movements with head rotation to the left. And his anterior chamber slitlamp exam was within normal limits besides some corneal irregularity on the left. These were his fields. You can see on both eyes, he has enlarged blind spots. On the right, he has a superior and inferior arcuate. And on the left, he has an inferior arcuate. On dilated exam, he had 3 plus optic nerve edema on the right side. He had half plus cell, no haze, and a blunted foveal light reflex. He had some venous tortuosity and a normal periphery. In the left eye, he had one plus optic nerve edema, no cell and no flare. His macular was normal. His vessels on the side were also tortuous, and his periphery was normal. On OCT, the top is the right, and the bottom is the left. He had some subretinal fluid underneath the fovea, and his left was normal. And then on FA, he had diffuse leakage of the optic nerves late in both eyes. This is the right and the left. So his differential that we considered. First, CNS metastatic disease. He has been treated for metastatic melanoma, has these new headaches, and CNS symptoms. We also considered BKH, increased intracranial pressure, CNS lymphoma, CSCR, neuro-retinitis, syphilis, sarcoid, and drug induced GBI. So upon further questioning, he also endorsed a history of some hearing loss, which was recent, and then also said that he had had some whitening of his eyebrows, which was new, whoops, I kinda see it here. And then he also endorsed some hypopigmented areas along his jaw line, which were also new. His workup included RPR, FTA, quantifier on gold, ACE, slice design, B12, and folate, and those were all within normal limits. He had a lumbar puncture, which was remarkable for a pleocytosis, but was otherwise normal, including cytology, which didn't show any malignant cells. He had MRI brain, which was normal, didn't show any evidence of metastasis. And prior to presentation, he had already been started on a course of oral prednisone by the referring provider, so that was continued. We considered treating him with an orthodexin, his right eye for the sub-retinal fluid, but that resolved within two weeks, so he didn't end up needing that. So his presentation was consistent with a VKH syndrome, which is a bilateral granulomatous pan-uvidus and serous retinal detachments. The criteria for diagnosis include that there can't be any history of ocular trauma or surgery because histopathologically, this is identical to sympathetic ophthalmia. And then three of the following four have to be met, bilateral chronic urodocyclitis, posterior uvidus, with any of the following multifocal exudative retinal or RPE detachments, dyscyperinia or edema, sunset glow fundus, which is a yellow-orange appearance of the fundus due to depigmentation of the coroid or the RPE, and neurologic signs such as tinnitus, meningesimus, vertigo, hearing loss, cranial nerve symptoms, or CSF pleocytosis, and any cutaneous findings such as alopecia, poliosis, or vitiligo. So then the other question is, is this in any way related to his cancer? There have been several reports of VKH like syndromes and patients treated with these immune checkpoint inhibitors like he was on. There's one case in the dermatology literature of a 55-year-old on nebola MAP was found to be actually HLA-DR4 positive and treated with topical steroids with resolution. And another case of a 54-year-old with melanoma on ebola MAP who was observed and their symptoms resolved. In these cases, the onset of UVitis can be a media or delayed. And in the phase three clinical trial data of ebola MAP ophthalmic inflammatory conditions such as UVitis, episcleritis, and scleritis occurred in less than 1% of patients. So to contrast the first case, this is another case that presented to the UVitis Clinic. This was a, and she also had a VKH like picture after starting an immune checkpoint inhibitor. She was a 78-year-old female with metastatic melanoma who developed hearing loss, rash, vision loss within two weeks of starting pimbrolizumab. She had ciliary body detachment and choroidal effusions and panuveitis. The hearing loss and the rash resolved with systemic steroids, but her vision loss continued to deteriorate. And she developed bilateral retinal detachment despite repeat subtenon's canal log injections. Jandar went a complex retinal detachment repair with reticent placement and her final vision was count fingers in the right eye and 2050 in the left eye. So what exactly are these immune checkpoint inhibitors and how can they cause UVitis? As you remember from immunology, T-cell activation requires a co-stimulatory signal which comes from the CD80, CD86 ligand interacting with the CD28 on the T-cell. So here's the first signal and then this is the co-stimulatory signal. CTLA4 is a CD28 homolog expressed on T-cells that also interacts with CD80 and CD86 to cause an inhibitory signal of the T-cell. Similarly, PD1 is expressed on T-cells and it results in energy of the T-cell when it interacts with PDL1. Tumors can hijack these inhibitory pathways by expressing PDL1 on their surface and allowing for tumor growth. In 2014, Novolemab was the first immune checkpoint inhibitor to be approved for the treatment of cancer and it's now approved for metastatic melanoma, non-small cell uncancel, renal cell carcinoma, bladder cancer, head and neck squamous cell carcinoma and classical Hodgkin's lymphoma. In fact, these drugs have been so successful that there's now five PD1-axis immune checkpoint inhibitors that are approved for the treatment of cancer and there's over 100 ongoing clinical trials for immune checkpoint inhibitors, so we'll most likely be seeing these drugs more often. So as you can imagine, with any drug that interacts in the immune system this way, there are some autoimmune consequences. The most common of these are rash, colitis, hepatitis, endocrinopathy and pneumonitis. And because these are so common, they've developed consensus guidelines for the treatment of these. They're generally graded on a scale of one to four based on the severity of symptoms. For grade one to two, generally treated with supportive care, may involve holding the drug. Grade three to four involves holding the drug, treating with systemic steroids and it may involve hospitalization. The majority of these events are reversible with a short course of steroids and rarely other immunosuppressant agents such as influximab are necessary. And PD1 inhibitors, which are nivolumab and pimbrolizumab have a lower incidence of these events than the anti-CTLA-4 drug, epilomab. And then in our patient's case, he was treated with a combination therapy of nivolumab and epilomab, which was approved for the treatment of metastatic melanoma because it showed improved survival compared to monotherapy. But as you can imagine, the immune-related adverse events of this combination therapy are more severe and they often have a shorter time to onset. The ophthalmic manifestations of these drugs are less well characterized and there aren't any consensus guidelines. There's been kind of a variety of presentations described in the literature, so I'll go through some of them. There's a case report of youth thyroid ophthalmopathy induced by epilomab from melanoma and that was successfully treated with IV steroids. There's another case report also with epilomab of bilateral uveitis and neuroretinitis with optic dyscadema and macular edema, which was also successfully treated with steroids. And then there's been a case of an 81-year-old male. He actually had a history of macular degeneration that was dry and developed concurrent bilateral peripapillary CNBM and a unilateral sub-vovial CNBM that was thought to be related to his epilomab treatment and he was treated with anti-vegeth in the cessation of the drug. And there's been one retrospective review where they looked at patients treated with epilomab who developed orbital inflammation and found that four of these were orbital inflammation, two were uveitis, one was peripheral ulcerative keratitis and all were treated with systemic steroids. And this is a chart from that review article which just kind of goes over some of the cases that I've talked about and their treatments and whether they resolved. So as you can see, most were treated with systemic corticosteroids, some got topical corticosteroids, most had resolution and all but one, the drug had to be held. So then the question is, if we're holding the drug and giving these patients steroids, are we impacting their overall survival and decreasing the chance that their cancer is gonna be treated? So there's been two studies in the oncology literature that have addressed this question. One was a study on patients with epilomab that found that one third of these patients did require systemic corticosteroids for some type of immune-related adverse event but the immune adverse event or the need for steroids didn't impact their overall survival. And then there was a similar review of nivolumab which showed that 24% received systemic immune-modulating agents and again, that did not impact their overall response rate. So in summary, immune checkpoint inhibitors are becoming more prevalent, ocular-related adverse events are rare but they can include uveitis, orbital inflammation, CNBM, thyroid ophthalmopathy and neuroretinitis. The majority of these manifestations resolve with steroids and steroids do not impact overall survival. Any questions? So I submit that the steroid survival question is still not totally answered. You start talking about subgroups and then subgroups and you talk about them about it not being statistically different as what we say that it did impact survival. And my understanding is that in general it looked like it wasn't as good but it wasn't statistically different so it made me a power issue as much of anything else because you're getting out of relatively small groups and these things are amazing. I mean people who routinely, it was a death sentence they're surviving and it looks like it's long-term survival so absolutely and the holy grail when you talk to oncology is this whole immunotherapy concept and idea so we're just barely getting started on what's gonna happen. So I think that we have enough that you do comfortable doing that but I don't think you definitively know what the steroid's doing impacts your survival. And of course, the other thing to remember is the whole concept now is not we're there now it's gonna be more and more and more. So the more we do, the more we're gonna expect other type of immunological results and I thought that peripheral ulcerative curatitis but that's a very bad disease as well. I can see that starting to flare up and so I think we as ophthalmologists are gonna start seeing a lot more of this and we need to be prepared. I think we'll need to figure out better ways to start doing local therapy and such things as steroid implants and the like stuff like that because we get a better handle on exactly what's happening. So actually they found that certain immune related adverse events so for example with melanoma if you develop vitiligo it's actually a positive prognostic sign because it means that the drug is working. That means it's going after anything associated. So in these studies they actually found a trend towards actually people who were treated for their immune related adverse events it trended towards a better prognosis. That could possibly be because they were having a better response because of the steroid. Exactly. So let's remember the more the immune system seems to be revved up and going out of whack. Jon Zone used to always love before we had going with this to talk about he would have patients with in-stage metastatic melanoma in which they just said, I'm sorry there's nothing we can do. And then all of a sudden they would go through a violent, spontaneous immunological reaction and these people were just awful and miserable and the melanomere just disappeared. It's like two percent of patients. Spontaneous complete resolution. So he used to go on for a long time. He said we figure out how to do this and turn that immune system in. But I mean I can still remember it was a brandy. It's just awful. I mean they just, they don't know what's going on. And all of a sudden, oh, every single melanoma, the thing in the body and they're cured. So we need to understand that the reason why they could be doing better is really the fact that their immune system has really been revved up. Not necessarily that that means that the steroid treatment was making you any better. So I just know that some people are looking at really don't know exactly, but if you want the immune system to just go crazy that maybe steroids are still not a good idea in spite of what we have because we don't understand all the causal issues. I think this is an under-reported issue with the subject of, you know, Chris and I find that what's striking in this case I think there should be a rule. The important thing is to have a long conversation with people. Sometimes it's often a huge air response by a quality and sometimes it goes, are really improving survival then, local therapy can. As far as the steroid question has been, is there any steroids or, you know, since then, only the patients who've had some sort of dramatic immune... And, you know, for a lot of the more common side effects, they do have a grading system. And so like, for example, for rash, just any patient who gets a rash, they don't have the drug held and they're not given systemic steroids. They're given something topical. So I think, you know, an ophthalmic manifestation could be similar. If it's mild and not vision-threatening, but as in the case of the second patient, if it's, you know, they're gonna be curative melanoma but be blind potentially, then it's kind of a different conversation. But at least with everything else, they've developed kind of a grading system. And in some cases, you know, the pneumonitis and hepatitis can people die from that. So that's another thing to think about. Yeah, you'll have complications that you just simply have to treat with time. With that bar, I think that to the extent we can treat it locally and not have that systemic impact on what we're doing, that's probably gonna turn our time to be smarter. We've got this issue. If you really have bad complications, that means that you really are doing what you need to to try to get rid of the tumor, too. So they're responding better just because you're getting what you need. It's gonna take time to feral all that out. But this is just to start, and this is the hot topic in oncology is a rep in our immune system to get rid of the cancer. So we're gonna see a lot of this. Dr. Wang. Yeah, they're a resource for finding out about these kinds of problems. Of course, there's published literature, but after a couple of case reports have been reported that people will stop reporting single cases, but the FDA has a very robust database of adverse events for these medications and you can find a lot of medications there. And they're just anybody who'd like a copy at the most recent neurology site meeting in April, there was a teaching session on adverse effects of some of the newer cancer codes and these and all of their other friends were highlighted because there are a lot of off-family and neuro-off-family side effects of not just the checkpoint doctors, but some of the other anti-managing new medications which you've never heard of and patients may not know the name of and may not even be on their medication list because it's an infusion they're getting monthly so it's not on their list of medications they're taking every day. So it is a reason for actually asking somebody's medical history just to throw that out there. Thank you.