 I'm Chris, I think I know most of you in this room. We're gonna kind of change course a little bit. I'm gonna talk about a topic that we hear a lot about in grand rounds, mainly for an M&M series, but I think we should maybe at least talk about kind of the outcomes of some of those cases of endothelmitis that we've been discussing. And so why do we care about endothelmitis? Well, so if we look at Medicare rates from 2010 to 2014, there was reported 1.2 to 1.33 cases per 1,000 cataract surgeries. That resulted in an 83% rise in medical care costs associated with that single surgery. In 40% of those cataract cases and greater than 90% of TRAB surgeries, visual acuity outcomes will be worse than 2,200. And then with the TRAB itself, you have a yearly risk of 1.3% of developing endothelmitis. We're talking a significant vision altering disease process. We have basically one major randomized control trial that was actually performed in the early 90s and was published in 1995 with subsequent kind of iterations of post hoc analyses. And that was the endothelmitis of the TREC to me study, which we're all familiar with and I'll talk more about as we go through this presentation in case you are not familiar with it. And to base our treatment in the clinic at least off of a randomized control trial, like I said, the EVS is one of the only, if not the only randomized control trial and it's specifically looked at acute endothelmitis following cataract surgery. So the endothelmitis had to be within six weeks of surgery, had to be cataract surgery, visual acuity, had to be somewhere between 2050 and light perception. You had to be able to visualize the iris. The cornea had to be clear enough to perform a detractomy. And then there had to be a hypopian or sufficient enough inflammation to at least obscure the second quarter arterioles of the retina. However, that doesn't leave a very broad group of patients to fit into this actual study. And I think it was a great study but doesn't really help us in a lot of other cases. So I'm not even gonna mention all of these because I'm gonna mention them in the next slide. But what do we do? Well, I guess the next slide after this, sorry. So the EDS basically concluded and like I said, there's been subsequent iterations but probably the most that we get tested on multiple board exams that we all talk about is basically performing detractomies for light perception or worse visual acuties at presentation. It also showed that ID antibiotics or of no benefits or no additional benefit. I think you kind of cast a little bit of doubt on that if you actually look at this study because I think it actually reduces some of the complications but wasn't statistically significant. And then there was a subgroup analysis of diabetic patients that seemed to do better with a lower threshold for a vitrectomy than you're just one of the male patients with endophthalmitis. However, this is the slide I was alluding to what do we do in cases of post-injection endophthalmitis, glaucoma endophthalmitis, glaucoma associated endophthalmitis, retinal surgeries, corneal procedures, chronic endophthalmitis, severe cases of endophthalmitis, post-traumatic endophthalmitis, endogenous or exogenous endophthalmitis. That leaves a lot of patients, quite frankly, that we have really not a lot of guidance on. I mean, there have been some non-randomized control trials and some kind of post or basically analyses of those to give us a little bit of guidance but like I said, not a randomized control trial. In these cases here, this is a case that Dr. Shakur actually just operated on for the second time last week. This is a fungal endophthalmitis. This would not have qualified for the EVS. And then here's a no-cardia case which also would not have qualified in the EVS due to the significant inflammation. So these presumably are the ones that have the worst outcomes, right, that don't fit into the EVS. We'll talk about that more as I kind of go through this. I mean, then also the other side of that is there's been some kind of changes in management of diseases since 1995. We've had presumably more patients exposed to the risk of endophthalmitis that's most likely related to intraditory injections. I don't have specific data on that but I think you could easily make that conclusion. You use smaller report sizes for most of the tractanies with the idea of being that there's less risk of a complication related to the smaller report size. And then the EVS, you actually look at the actual IV medications that they gave. They have very little intraocular penetrance. The fluoroquinolones were not even invented in 1995. So now we have better intraocular penetrating medications. And then we also have, like I alluded to earlier, some retrospective data and there's multiple reports. This is just one of them that I'll suggest here that in severely inflamed eyes that you do a tap and inject initially if their vision is better than light perception, see them within 24 hours if they're not improved. These patients seem to do better if they had to retract me within that first initial presentation within 24 hours. There's multiple iterations of this kind of thought process out in the literature. I'm not gonna dwell on it. Still wanna show some data. However, with all that said, we still have poor outcomes with endophthalitis. And are there things that we can do to help improve clinical outcomes? Specifically, non-surgical, even surgical. That's kind of what I'll talk about here coming up. So we basically, and this started with Reese Feist. You all remember him. We started a retrospective data collection where we looked at every post-procedure endophthalitis case treated here at the Moran. So that may be a referral from an outside provider or that may be a case that was actually caused by a surgery or an intravisional injection from in this facility. That included basically charts from 2009 all the way to 2018, some nine years of cases. We collected a bunch of data, most specifically visual acuity and sighting procedures, the long-term outcomes and the treatment administered. And I'll talk through that as we go. And so then this is kind of the demographics of the overall presentation. And I'll get to our main question that I'm not gonna present yet because I just wanna show you the demographics of these nine years of endophthalitis cases. Average age, 72 years. There was a total of 83 cases. Like I said, these are all post-procedure. So all the endogenous or exogenous cases are excluded. And then I don't think, I remember seeing a post-traumatic case, but those have also not been included as well. 88% of them received an initial tap and inject basically off of EDS criteria. 33% of them, so a third of them actually needed retreatment of some types who either have attracted me or a repeat tap and inject, mainly inject. And then what I'll talk about here in a little bit, about 19.3 or 19.3% of them received oral steroids as part of their treatment algorithm. The follow-up time varied anywhere from one to 2,938 days with an average of 471 days. So pretty significant follow-up. A few of these one-day follow-ups were outside referrals and then I think returned back to their referring provider shortly after the tap and inject we performed. So that's pretty common for tertiary referral center. So then what features of these endothemitis cases can we kind of clean? So inciting procedures as you can kind of guess this matches with the kind of amount of procedures that we do here at the Moran. So leading kind of the I guess charge for amount of total endothemitis cases cataract surgery, secondary IOL placement was the leading kind of cause or inciting procedure followed by intravitural injections here. Retina procedures kind of followed that afterwards. The surgical complications. So we looked through all of the surgery, op notes on these procedures that we had available to us and only about 12.2% had actual documented intraoperative complications. And specifically for cataract complications because we always talk about cataract complications and the risk, well-developed and well-documented risk breaking the posterior capsule. I think most of these can be attributed to breaking the posterior capsule except there was a small cohort of cases with just an anterior capsule tear with the developed endothemitis. But most of those related to either dropped lenses or amdor just a posterior capsule tear. Was your previous slide cataract specific? This one? Or the one this one? So this was actually overall. Okay. But yes, so most of those were actually cataract specific. Hard to say exactly from kind of some of the documentation of other specific complications. But yeah, that included everything. Intravitural injections and I think this just states or shows us what we most commonly use in the clinic. So we have Avastin and Iliya kind of leading the charge. And I've talked to the rutina fellows, specifically Dr. Calvo quite a bit about this, but we don't have a lot of cases of Ozzardex or post-Ozzardex endothemitis, which is interesting. And if you look in the literature, you actually don't find a lot of documentation of that. You would think that that would be more common as just steroid, but don't really have an answer for that. Then kind of consistent with what we find in the literature and it's kind of changing how we basically manage endothemitis, but basically a third of cases are coagulase negative staff. Then a third of cases are unidentified species. So something looks like endothemitis, but we can't actually identify an organism. And I'll talk about that a little bit more here in a second. Visual outcomes and sorry, this slide's really, really busy. So I'm gonna break it down into basically two categories. So, well, three baseline presentation and final and then two kind of overall categories. So baseline visual acudes presentation. So at time of endothemitis or diagnosed endothemitis, as you can see very poor visual acudes at that time. And then by the time that their last follow-up that we have documented, kind of a broad spread. And so if we make that easy, I like thinking easy, breaking things down so they're simple. So if we kind of consider anything 2070, 2080 issues, okay, vision, and then everything kind of worse than that is bad visual outcomes. We can see that we kind of have a spread, obviously a presentation poor visual outcomes. We'll talk more about that as we go, but that's just kind of the overall kind of follow-up of these patients. What happens with these endothemitis patients after they've developed endothemitis? Unfortunately, they're not out of the woods, as we all know that they all have high risk of developing complications. Most notably, non-clearing vitreous debris, pretty significant. Some of them actually had to have the tractomies to remove the debris to increase visual acudes. Retinal detachments, macular edema, epiretinal membranes, and then tisis, and or a nucleation or evisceration. And I'll talk more on that here in a second, but we're talking some pretty significant complications. So then what kind of led us to actually looking at this? Yeah, looking at endothemitis outcomes is, I guess, interesting. It's not the most gratifying thing because a lot of them don't do well. But our main underlying question, do steroids help? And there's been some literary kind of question circulating for quite some time on this exact topic. And so let me give you kind of the case for steroids. So in inflammatory, infectious uveotides, like acute retinal necrosis, syphilis toxo, after we've started treating the infection with significant posterior inflammation, we will actually start patients on oral steroids, okay? Specifically for toxo, we may even give intravisual dexamethasone, okay? So that's almost a, I hate to say standard of care, but because it's not truly a standard of care, but that's what's done out in the uveitis world. Then from multiple studies, there have been multiple small randomized control trials. There's been a larger, more recent randomized control trial of patients basically receiving intravisual dexamethasone at the time of diagnosis of endophthalmitis. So they get vancomycin, septasidine, and dexamethasone intraviturally. Data has been unfortunately inconclusive with visual acuties basically unchanged from the control group. The kind of question that we posed was well, intravisual dexamethasone has a half life of five and a half hours. The only thing that we can kind of follow or at least from animal data and then a clinic follow-up appointments, animal data says that hemokine level spike within 12 hours of inoculating the vitreous cavity. However, they say significantly elevated for seven days. We can kind of see that in clinic as well. And then we also know from animal data that the inflammation alone is leading to irreversible retinal damage. So presumably if we impact or reduce the amount of inflammation, do we preserve some retinal function? But with a drug that only lasts five and a half hours, is that truly enough? So we hypothesized similar to like I suggested in acute retinal necrosis, toxoplasmosis, these other significant inflammatory infections that an oral prednisone taper may significantly impact intraocular inflammation resulting in better long-term outcomes. So that was kind of the underlying hypothesis. So just to emphasize after our UGITIS grand rounds two weeks ago, all these patients received a TAP and inject and dexamethasone introvitrally at the time of diagnosis were almost all of them. We did not start oral steroids until 24 or 48 hours after that initial TAP and inject. So they are covered from an antibiotic standpoint prior to the initiation of an oral steroid taper. And that was started with a very high dose one milligram per kilogram typical to what you would see in our UGITIS clinics. So the demographics, unfortunately, this is a pretty small study but I just wanna show you the data to kind of give you some food for a thought. So if we look at the non-steroid group versus the oral steroid group, they were about the same age, 72 versus 69. There were more males for whatever reason than the steroid receiving group. And then diabetics, about the same, maybe a few, a slightly higher percentage of diabetics. And then average follow-up was pretty close to the same. The visual acudes or at least presenting visual acudes seemed to be worse in the group that received oral steroids. So 93.8% of them had count fingers or worse visual acudes at time of presentation compared to 77.6% that did not receive oral steroids. The organisms isolated maybe were suggestive of more aggressive organisms. So you have a stronger or I guess more organisms that are strep species in the group receiving oral steroids than you would otherwise see in the rest of the groups. But like I said, this is pretty small. 16 total cases that received oral steroids. And so you could I guess make the argument and then looking at this that glaucoma procedures were more likely to receive oral steroids than not. And then cataract surgery was kind of the inverse of that where they were unlikely to receive oral steroids in their follow-up for whatever reason. So there seems at least from that data, like I said, very small to be a bias, a bias from us of giving oral steroids to the worst cases, okay, which kind of makes this data that I'm about to show a little bit even more interesting. So the other side of do oral steroids make things better is do oral steroids make things worse? So that's the concern of anyone, right? Anytime we give oral steroids, do we make things worse? When we look at visual acudes, like I said, oral steroids patients seem to have worse initial presentations. However, by their final outcomes, there seems to be no difference. So it didn't seem to lead to worse or better long-term visual acudes. And an interesting thing, and I didn't show this with the entire overall cohort, but by one month you can predict almost 70% of patients' final visual acudes by one month, which isn't that surprising because the inflammation has gone away. But I guess from the standpoint of being a tertiary referral center, it's kind of important because long-term follow-up or at least referral from outside providers, we don't know underlying pathologies, we don't know what their baseline visual acudes were. In most cases, we're literally doing tap and injects to treat the inflammation and infection and then following them thereafter. So we can have discussions potentially with patients at one month stating your visual acudes can be somewhere around what we're seeing right now in most patients. Sorry, can you go back to that slide? Where's the no steroid? So the no steroid is the... It's the paint. Yeah, it's this light gray line on each of these, this here. Can you see that with the laser that I just pointed out? Sorry, that doesn't project very well. I can show you the screen up here if you'd rather see that. But sorry, it's basically trust me on this, I guess, since you can't see it very well. But there is no difference, despite me wanting there to be a difference. Actually, I didn't really care, but there is no difference between them of any meaningful kind of magnitude. However, the one thing that steroids seems to change, and this is probably important from an oculoplasty standpoint. So I started digging through the oculoplastics literature, looking at what happens when a patient actually loses an eye. So there is a huge psychosocial component to evisceration, tycis, and patients have higher levels of depression, anxiety, issues with their overall kind of appearance when they do not have a normal appearing eye, even if it isn't functioning. So we see about the same amount of rates. Can you see that gray? You may not be able to see the gray here. You can, okay. So you see kind of rates of everything with oral steroids, so retinal detachments, non-clearing vitreous degree, macular edema, epiretinal membrane. You do not see any patient receiving a nucleation or evisceration for a blind painful eye. You do not see any cases of tycis develop in the patients that receive oral steroids. So are oral steroids salvaging the globe? I don't know. Like I said, this is a pretty small data set. If you do the math, we should at least see one case of either tycis or a nucleation of evisceration from a blind painful eye. Like I said, we've followed them on average for over 450 days, so this isn't like we're just not seeing long-term outcomes. So concluding thoughts, like I said, you can't take too terribly much, except maybe raising questions to pursue larger studies, but probably the thing that is already well known in the literature is that isolation of organisms is fairly aggravating. We saw about a third of patients did not have an identified organism. That was due to low yields, the way that we send specimens or have previously, and then even mishandled specimens with our lab here at the university. So that is kind of pushing us in a lot of these very atypical cases where we're going in for vitrectomies for diagnostic standpoint of basically using pan-organism PCR. I'm not gonna show you the data, but we seem to be having much more, we're isolating much more organisms, many more organisms than we previously have, and some of them are very atypical that we would have never have found on kind of culturing mechanisms used here at the university. Then one-month visual acuties, like I said, the larger cohort, and then also the visual acuties once you separate the two between oral steroids and non-oral steroids groups, seems to be fairly predicting that one month to their final visual acuity. What that really means in the grand scheme of things, it just helps us kind of talk to the patient as we're developing this new relationship, presumably, or maybe a relationship in a different clinic, a retina clinic instead of a cataract clinic or a glaucoma clinic. Then steroids don't seem to make things worse. In fact, you could say that maybe they actually reduce the risk of losing the global together, so maybe they actually help some. Overall visual acuity, they don't seem to do anything for, but like I said, small study, you'd have to make a much larger study multi-centered to actually answer that question truly. And then I've kind of hounded this from the very beginning, because I've been kind of a proponent of this for quite some time, but I think there actually needs to be an updated version of the EVS, so the endothemitis retract me study. We have enough retrospective data at this point that I think people are, even at this point, if you read some of the retina groups around the country, they are not even basing their treatment algorithms off of the EVS. That's how archaic they feel that it is. I don't know that it's truly that archaic, I think it actually gives us a good framework for treatment. And then probably the overall arch, overall kind of thought and endothemitis, preventing it and then early detection of it is paramount, right? So we're talking minutes to, well, maybe not minutes, but hours for treatment of this, but if we could avoid it all together, that would be ideal. And so I think unfortunately, or fortunately most of the thoughts or at least literature looking into this has been dedicated to prevention and I'm not saying that that's wrong. I think that's actually very good because if we could prevent it all together, then we don't have to worry about actually treating it. But that's kind of been at the expense of looking at treatments or changes in treatments. So with that said, there's been a bunch of people that have helped on this and I guess with that, any questions, concerns, thoughts, I'd be happy to answer those. Dr. Petty. So you don't need to go back to the slide, but at the beginning you showed the baseline visual acuties and with so many of these patients being AMD injection patients, and it seemed like visual acuity was an outcome. They can't possibly have a good output. Can't get that right. So that, how are you accounting for that? And what are your... So I didn't show it, yeah, I didn't show it in this data. And I probably should have because I agree with that 100%. You can't have a patient that has a normal baseline vision of 2100 and expect them to recover to 2040. And so I think, and that's why I emphasize the one month visual acuties. So there's too much inflammation to know a baseline visual acuity. If we've never seen the patient, we have been told maybe there's macular degeneration in this patient, but we don't know what their baseline visual acuity was. By the time you get to one month when inflammation has subsided or most of it has, of course, the case of non-claring vitreous debris, you still have significant visual altering things. But basically what we started to adjust for was actually looking at their preoperative if we had that or pre-endophthalmitus visual acuities, and then comparing that to long-term visual acuities, which then of course weighs in what was their actual baseline visual acuity, rather than, okay, they have count fingers vision due to endophthalmitus plus or minus something else. So the presenting visual acuity is a little bit deceiving compared to what was their visual acuity prior to the presentation. So in a count fingers patient at the beginning, how, let's say 2400, how do you account for... So their return back to their baseline, so if their count fingers before endophthalmitus, you would presume they're gonna return to count fingers. Thank you for telling me. Thanks Chris, it represents a lot of work. And I just wanna point out a couple of things. One is, you know, there are two visual acuity outcome in endophthalmitus and reducing inflammation are two almost separate outcomes in a study like this. And I think it's very complicated to measure inflammation in a study like this because, I mean, we do have the stunt criteria and everything, but I don't think that, you know, I mean, your inflammation in a systematized fashion is just like terrible eye filled with pus or whatnot. And so the rationale for, as you point out, is to, you know, reduce inflammation and then, you know, get an instant bystander damage from inflammation, presumably, right? So a couple of questions are that we know that the organism that is defending organisms in large part determines outcome at every outset. So it's almost as you point out in your slide, you know, at one month you can predict outcome. So in those eyes that are going to do well, okay, maybe using oral steroids is useful in reducing inflammation, you know, and obtaining a view and hastening that recovery, the inflammation. And also another important component is that some of these eyes are painful and aren't maybe headed to ticis and that maybe steroids will reduce some of those symptoms. So it'd be interesting to look at, you know, in those eyes that did well, you know, did inflammation yourself more quickly, you know, or in those eyes that did poorly, you know, what was the effect of oral steroids in that sense. So, and I think that an important finding is that, you know, people did not do worse with steroids because there are papers that suggest that maybe individual steroids, the outcomes, were worse. And it's a mixed bag as you point out in your internet. Oral steroids tend to be used in the more severe cases. Patients that present with ingredients have managed a lot of end-of-the-mind. I seem to find that patients that are less severe tend to do a lot better. It's an anecdotal sort of, right. And it also allows you, I mean, you clear your views so you can see what's happening in the back of the eye, the way that just letting the eye kind of smolder along. Not as slow as Tepromonic, 60 for five days. Yeah. 40 for five days, 20 for five days, stop. So, you know, I mean, there is, as you pointed out in your introduction, there are infectious entities that are not end-of-the-mind cases in which we use oral steroids and the reason for it is to reduce inflammation. It's associated with the infection itself. And it may or may not actually lead to a better outcome. Overall, when you look at a large series of patients, right, I mean, so with acute retinal necrosis, for example, if you have a very large area of retinal necrosis and you can't see anything and you treat them, you know, with any viral medications and with steroids, you may actually hasten the view. But if they have a lot of retina effect, that they may end up having retinal detachment. But the exception is important, right? Don't you think? I mean, the individual patient is also important. So, I mean, there are the individual patients for whom you treat with oral steroids actually do well, you know, so doesn't do any harm is helpful because you might be more apt to treat inflammation in the hopes that that particular patient may do well if there's no, you know, overriding reason that it does harm. Right. Is there a discussion that's so reminiscent of corneal ulcers and some studies showing that there were some showing they do better and in the end with the organism being so deterministic about getting to the point where specific organisms we know respond better to steroid or not and either corneal or overriding. I don't think we have needed. Yeah, from an endothelmite standpoint, no. Organisms that are much more inflammatory but I don't know that we've shown anyone a show that producing that information improves things. Dr. Calvo. One other thing about controlling inflammation which I think makes sense for the steroids is besides, you know, the point of trying to improve the view into the eye, decreasing the media pacification from botrytis and ipokialin, but, you know, it's been shown by, I think a research I was done here at Marin that in ophthalmitus early, you see vasculitis. That's one reason why a lot of these retinobasculitis, that's one reason why a lot of these patients, after the views cleared, their vision remains poor, their retinas thinned. It's because they had a lot of vasculitis during the infection and so that would suggest if you get steroids in early, you're going to theoretically decrease the amount of vasculitis they have and therefore preserve retinal perfusion which would hope to keep their vision. So aside from, you know, improving our view of media pacification, I think that it could have an important, like, vascular benefit as well. That paper by Andrade Imsousis actually showed that the few patients seems to be part of the initial insult in acute retinal necrosis as well in which we have a lot of experience with steroids, so the circuit does make sense. And I think from speaking to my previous life in the research lab, so I haven't looked specifically at the retina but I've looked at both the CNS and in the cornea and I can tell you in tissues that don't regenerate very well or even the cornea, for example, there seems to be an inflammatory kind of response to the infection, it seems to be critical to clear the infection, but there also seems to be some kind of additional inflammation that you can actually reduce or basically ablate and it has no effect on long-term outcome that actually makes things better because it seems to be a pathological immune response rather than a beneficial response. So I think that's kind of the overall thought process and a tissue, brain, retina, wherever you wanna go, tissue that doesn't regenerate very well, if at all, that you can't have inflammation, it's leading to apoptosis, cell death, or just pathological changes. I have a quick name question, like why don't, why do antibiotics not work with staphylococcus right now? Why do antibiotics not? They do. Systemic, that's probably the question you got. Oh, so intraocular penetration of medications isn't great, even with inflamed retinal blood barriers, they still don't seem to get into the tissue very well, so you're not getting high enough concentrations. And I presume nobody's really looked at this, at least that I'm aware of, but if you waited long enough, then maybe it would work, but unfortunately you're talking about a tissue that any damage to it is long-term and can't be recovered. So it's not like a systemic blood infection where you have some time because you're not seeing permanent pathological changes, at least that a patient can describe to you. In the retina, for example, where you need to control things relatively quickly, you don't have time to wait for intravitural concentrations to build, but most of those drugs, like I said, and I didn't even show this, but 10 of the 60-some isolated organisms that we found were actually resistant to levofloxacin, which is one of the highest intraocular penetrating drugs that we have. So that's crazy, thinking, okay, we could use systemic antibiotics, but are they all resistant to the one drug or a class of drugs that we have that actually? I think the drug that has permeability is enough to be good. Yeah, and with a compromised retinal blood barrier, you'd think that the concentrations would be higher, but you just don't have time to wait. So, it's crazy.