 Our senior fellow Dr. Churgen is going to be going off to Phoenix at the end of this academic year. He's going to be talking about PVR, or proliferative vitroretinopathy. So the situation we deal with a lot in this academic setting. Thank you. All right. Thank you, everyone. I have about an 18 to 20-minute talk and I have 10 minutes. So if anybody needs to leave, it's okay, and I'll shorten things as best I can. I do have a surgical video, and what I'll do is I'll play it at the end instead of during the talk for those who need to leave. So I have maybe some upcoming financial disclosures, but none now. Typical history of a patient with PVR, although this can definitely vary. They come in with sometimes a long duration of a retinal detachment. We've seen people present a year after their detachment occurred. Maybe they'll have a first surgery that's a PPV or maybe they'll have a buckle of it, and then they just go through this cascade of redetaching, formation of scar tissue, redetachment, another surgery, another surgery put in gas, put in oil, and so they kind of circle the drain and tend to do much more poorly than other patients who have retinal detachments. This is just one of our patients who's had, I think, eight different surgeries, and you can see quite a bit of scar tissue here, this epiretinal proliferation. Some of this might be subretinal. Some of this looks tractional. It's actually deceiving here, optic nerve, old retinotomy with scar tissue around it. So this is a very common appearance of a fundus that has had multiple surgeries due to PVR. So what is PVR? It's basically cells that have migrated into an area, compartment of the eye, where they don't usually exist, and then they proliferate and they can form membranes and they can form contractile scar tissue. So how does it form? The most accepted theory is that you first have a retinal break that liberates RPE cells into the vitreous, where they don't normally live. And then there are vitreous growth factors like TGF beta and inflammatory cytokines that then cause these RPE cells to survive, proliferate, and undergo this process called epithelial mesenchymal transition, and then leads to another process of proliferation and invasion and then contraction. And what's interesting about PVR is that certain eyes will arrest at different parts of the cycle and other eyes will keep moving straight into that contraction phase. And you can see in this study here where they have the TGF beta showing this increase in the signaling and increase in the production of this molecule over time, which many attribute as one of the bigger triggers or molecules involved in the formation of PVR. So who's at risk for PVR? Well, practically speaking, I've seen PVR happen in eyes that I never thought would get PVR. But the classic risk factors are RD that's extensive, retinal tears that are large, especially giant retinal tears, preoperative PVR, meaning they're presenting with it at the time of diagnosis, vitreous hemorrhage with their retinal detachment, or you could also include in that intraocular hemorrhage during retinal surgery or after retinal surgery. Asthma is a huge risk for PVR and also intraocular inflammation or infection. And specifically, as our UVI to service knows all too well, our patients with CMV, R, and PR are very at risk for this. It occurs in 5% to 10% of all regmetogenous RDs, but 50% or more of ruptured globes. And there are no agents thus far that have been successful in treatment of PVR other than surgery. There's another imaging modality, OCT here, showing through a patient's very anatomically disruptive PVRs, almost no normal looking retinal architecture there because it's such an infiltrative process. Grading, I think I can skip this slide as mainly for the residents. Basically we grade it, but it doesn't necessarily change our management because if it's there, surgically we have to address it. So what's PVR made of? These are just some nice photos that show the different cell types that are involved. You have gliotissue and immune cells. All of these cell types are in the membranes and then the inter-retinal fibrosis has a little bit of a different milieu of cells. In terms of why PVR makes us so sad all the time is because it's responsible for 75% of our surgical failures. It's basically the rock in the shoe of every retinal surgeon. It can ruin a perfectly good outcome, perfectly good surgery and turn it into a count fingers LP2400 kind of case. It's a medical problem. It's not a surgical problem, but unfortunately the only way we know how to address it is with surgery. Questions about timing of surgery? This becomes a big question for us. This is something I've faced multiple times during just our fellowship here is you have a patient who had a good outcome and now they're starting to form PVR and it's early after their surgery. They were MAC on and now they have PVR and they're maculis starting to come off. Do you rush into this eye or do you wait? The literature and what we know about PVR says you should probably wait and we have absolutely sad on these eyes that used to be MAC on and now they're MAC off but if you go in and try and peel these membranes when they're immature they come off in little tiny pieces and what you want is for the PVR to come off in one beautiful sheet. This is where I was going to show a video. So what's been tried pretty much almost every anti-inflammatory agent is really amazing. So this is the list. You would think that if something anti-inflammatory was going to be the solution it would have been steroids because they knock out the entire inflammatory cascade but the sad answer to this was they actually did a randomized prospective trial. 140 patients did not improve the anatomic success rate with dexamethasone implant. So that was I think very disappointing to see. Methotrexate I think has been gaining some interest. There's been a few really good recent studies and this was done in 2016. They put 40 milligrams of methotrexate in their infusion bottles and they did have a very good attachment. They only used 29 eyes so it's hard to say that this is significantly powered at all. But 90% were attached and they included PVR, TRD with PVR and they also included inflammatory related detachments. And then this was a really nice study where Dean Elliott and crew of our mess engineer took they actually created a new in vitro model for PVR which I think is huge in the future for studying PVR where they took PVR membranes from six patients who had grade C or high grade PVR and actually cultured those membranes and grew them out in cell culture and then studied them and also studied the effect of methotrexate on those cultures. And what's great about this is most of the literature so far, most of the research that's been done on PVR has been like an RPE cell culture base as opposed to a human PVR membrane. So this was a really neat change for the field and I think opens a lot of doors for studying PVR. So in this study, up here you can see the cell density on control and this is six weeks later cell density hasn't changed much. This is actual human PVR membranes and then these are concentrations of methotrexate and you can see a very big difference in the cell density and also the activation of caspases which are associated with apoptosis. And then you can also see here just some nice data on the cells per high power field and the control versus methotrexate and the percent of positive cells for apoptosis. And this study I think has opened the door for more clinical studies about methotrexate and also another interesting finding in this study was that pretty much all six PVR membranes had different cellular compositions when they proliferated. So what we also learned from this study is that PVR is not a homogenous process. It is not something that the same treatment may work for all people because the kind of milieu of what's forming the PVR and that specific guy may be different. So there are questions about methotrexate. We certainly talked about it on our service a few times in these patients who have had recurrent attachments and really the jury has not decided yet on what is the best way to inject PVR if you're going to do it, how often it has a very short half-life, but also we do know certain other facts about methotrexate like it's safe to use in the eye, we use it in UVitis and it's safe to use in silicon oil as well which many of these patients would have. So and then this is another study I don't know if I'm out of time. I'm kind of am out of time. So basically I'll summarize this one really quickly. This was an RPE-based model and what they did was they basically took from the anterior segment literature that we use amniotic membrane, things like Procara. And now I know we're studying, we have an IRB here at the U to study I think more of a liquid drop form of amniotic membrane. And so are the effects, anti-inflammatory, anti-dysregulated wound healing effects of amniotic membrane or the molecules within, do they apply to PVR? And basically they were able to purify a derivative of the amniotic membrane into a specific molecule that has the anti-inflammatory properties and suppresses inflammatory and scarring responses. And then they did an in vitro study and this molecule dose dependently inhibited proliferation. It also inhibited migration and collagen delcontraction and it was non-toxic and this was in an in vitro study and they're going to be studying this in rabbits next. So I think this is also another exciting molecule. And then there's a lot of areas for research in PVR and these are some other new therapies that are being looked at and so it's an exciting time but it's an incredibly frustrating time to be caring for patients who have PVR. All right and for anyone who wants to stay, obviously only if you have time, I have like a two minute video of what one of these surgeries looks like because we often don't get to share surgical videos. So I'm putting in ports here. This is a surgery I did last year with Dr. Bernstein. I always go this fast. I'm just kidding. This surgery is at like 4x or 8x. So you can see over here. I'm doing an epiretinal membrane peel and these are actually sub-retinal bands. And so right here I'm making a retinotomy to access the sub-retinal space or maybe I haven't done it yet. So I've done the epiretinal peel. Of course that took like an hour but you'll see this is going to turn white and going to burn a hole through the retina. And now we're going with the max grip forceps. I'm going to go enter the sub-retinal space and try and grasp it at the middle of the membrane. But of course you don't want to grasp the core right because you can cause massive bleeding. And then you have to pay attention while you're peeling sub-retinal membranes. You have to pay attention to where your traction forces are. You can rip the retina straight off while you're doing this. You can I mean you almost always cause some sort of a tear. But this was just such a cool membrane because what you're going to see it's like this is like the last baby I gave birth to. You know it's like it's going to this is huge complex that comes out. Do you mean last baby you delivered? Delivered, yeah. Well I'm kind of giving birth to my first. So it's it's this like slow painful process of getting it out. You have to be so so so gentle. So you see now I've changed my tractional force to be going a different direction because you you know what pegs are still left and this is you know this is like 4x or 8x I know it feels slow and you just want it to come out. But believe me it's so you know it's amazing how much was actually underneath this retina. So you can't see it yet but there's a still huge complex is down here and down here and it's not over yet. And one of the things that's kind of challenging in retina surgery is once you drop something like that then it's floating in saline. It's actually a little bit harder to pick up because it tries to move away from you. So you'll see me struggle with that for a second of regrasping the membrane and you also need to regress close to the origin of where it is because you want to be pulling with control. So you'll see this last peg down here. You'll see it starts to slide out as I pull up. These are what we deal with with PVR membranes and they're incredibly challenging, fun cases, very diverse. If I think there was like two hours more of this surgery dealing with all this scar tissue there you go you can see it leaving the subredinal space there. That's the end of the video but so. Any questions? Yeah, we all hope for some type of medical means that we can stop that process. It's when you look at the rate limiting step of getting that final 10 to 15% of patient this is the collision point, this isn't the big one, this is far away. It'd be great, I tell patients all the time I wish I had something to inject or do to your eye to stop this process but we right now function in a very reactionary way with PVR. Probably because there's multiple different inflammatory processes that can result in this so probably not a single bullet that's going to work. Exactly, thank you.