 Okay, good morning, everyone. I'd like to welcome you to UVitis Grand Rounds. The topic today will be on the update on the treatment of UVatic macular DMA. I'd like to welcome everybody here, including the resident applicants that are joining us by Zoom. I'm going to give you an overview of what's new on the treatment of macular DMA and UVitis. This will be followed by presentations by Akbar Shakur, Marissa Larshall, and Marcus Altman on surgical and local and systemic treatment. So UVatic macular DMA is a major problem affecting all anatomic subtypes of UVitis. It's a leading cause of visual impairment. The MUST study showed us that 40% of patients do not have resolved macular DMA. That is it's persistent at two years and that 40% of patients relapse their macular DMA and that fully two thirds of those patients require adjunctive therapy that are on systemic treatment. So the underlying principle in the treatment of UVatic macular DMA is to control the information by whatever means necessary using a topical systemic periocular or with or without immunomodulatory therapy, depending upon the anatomic location, the laterality, the severity and the diagnosis of UVitis. Persistence in recurrent macular DMA is usually treated adjunctively with a topical regional or systemic steroids, again, depending upon laterality with an assessment of the vitria macular interface abnormalities and the modification of risk factors such as smoking, which are known to contribute to this complication. Our choices, the basic choices are regional corticosteroids, periocular corticosteroids, intravitral corticosteroids. There's the clinical impression that intravitral corticosteroids are more effective, albeit associated with greater increase in intraocular pressure and cataract. Indeed, five injections of intravitral prime serum will give you a cataract. Then, of course, there's the dexamethasone implant that has been approved, which shows efficacy in terms of inflammation and also in macular DMA, but is also associated with cataract formation and elevation of intraocular pressure greater than the study that led to its approval. So the point study was a randomized control trial that actually went ahead and compared these three treatment modalities with a primary outcome of the proportion change of the central subfield thickness at eight weeks and secondary outcomes of improvement and resolution of macular DMA. This is the bottom line result and that showed that while all three subgroups had a reduction in macular DMA represented by a number less than one, here the periocular had less of a reduction and only about 23% as opposed to 39% for intravitral trimestinalone and 46% with dexamethasone. I think this is more easily seen in this graphic representation of the improvement with the intravitral lines up here, intravitral injections up here as opposed to periocular injections which were clearly significantly and clinically superior as well as in terms of resolution macular DMA with the intravitral arms being superior to periocular. As expected, intraocular pressure rise was greater in patients with intravitral treatment than periocular. So the conclusions of the point trial is that while all treatment groups improved central subfield thickness and best corrected visual acuity, intravitral trimestinalone and dexamethasone implant were superior, both in terms of reduction of improvement and resolution of macular DMA with the expected modest increase in intraocular pressure. And so based on this, the conclusion is that for most patients, an intravitral approach may be the best initial treatment for patients with center-involving macular DMA. So there's a problem with regional corticosteroids in that they are relatively short-acting and hence less effective for chronic inflammation because it's associated with kind of subtle structural change each time you have a recurrence of inflammation and of course the cumulative risk of steroid exposure with cataract intraocular pressure elevation and optimized with each procedure. So a sister study which was recently concluded and recently reported at the American Academy of Ophthalmology a few weeks ago, the Meritz trial looked at non-steroidal alternatives for the treatment of macular DMA and compared it to intravitral dexamethasone implant. So there is evidence in retrospective studies that anti-begev and methotrexate are effective in the treatment of macular DMA. So all these patients had exposure to an intravitral corticosteroid. So this was a randomized three-arm parallel design study of comparative effectiveness. The three treatment arms of a repeat dexamethasone injection versus methotrexate or round-of-bizmab patients were stratified to either being on treatment with immunomodulatory therapy or not. And the fall at the primary outcome was at 12 weeks and then a monthly fall of until 24-week anniversary closeout. The primary endpoint was the percent change in central subfield thickness from baseline measured on OCT with similar secondary outcomes of a proportion of eyes with improvement or resolution of macular DMA, the change in best corrective visual acuity and safety outcomes chiefly related to intraocular pressure and decreased in vision. So I just want to show you what the treatment schedule is. It mimics what we do in clinical practice. All patients received one of their assigned injections up front. Patients in the dexamethasone were required to have an injection at eight weeks if they met re-treatment criteria, which virtually none of them did. And then methotrexate, again, was required if they met re-treatment criteria at weeks four and eight. And round-of-bizmab was given three injections up front as it is similarly in clinical practice. So the bottom line results here show that the dexamethasone implant was superior in reducing the thickness and statistically significant at all time points and at 12 weeks between methotrexate and round-of-bizmab. So it was a 35% reduction for dex, virtually nothing for methotrexate at 12% and 21% for round-of-bizmab. I think this is also more easily appreciated in terms of improvement and resolution of the dexamethasone implant being on top, showing that it was clearly superior to the other two with methotrexate really not performing very well. And the peak efficacy was at about eight weeks but still at 12 weeks, there was superiority shown in the dexamethasone implant. Oops, changes in visual acuity. Again, for the dexamethasone implant was the only arm that showed an improvement in visual acuity at all time points at about a line of visual acuity, five letters. A methotrexate showed no improvement and there was no statistical improvement in visual acuity in round-of-bizmab, only about one letter. As expected, intraocular pressure events were greater for the dex implant with IOP elevation greater than 24 and of course, associated use of intraocular pressure lowering medications. Intraocular pressures greater than 30 were seen infrequently in all three groups, less than 10%, and a visual decrease of greater than three lines was seen mostly in the dexamethasone, in the sorry, methotrexate group. So the summary of the results of the merit trial was that dexamethasone is superior clinically and statistically to methotrexate and round-of-bizmab at 12 weeks, both with respect to the reduction in central subfield thickness, improvement and resolution of macular edema and that only the dexamethasone implant showed a significant improvement in best corrected visual acuity at 12 weeks with about an improvement of one line. Dexamethasone had a higher occurrence of IOP elevation as expected and the methotrexate had a higher outcome or lots of free lines of vision, but this was due to mostly due to macular edema and most of those patients actually recovered when they were crossed over to intravitural steroids. So what do you do when you have recalcitrant macular edema that just persists? So there are some alternatives. We know that we have a reticent implant, we have glucinolone setonide insert, we have newly developed and newly approved supercoital delivery of primicinolone. We discussed the merit trial. I would also just briefly discuss some of the conventional and biological immunomodulators which do show a salutary effect on treatment of macular edema and there is more controversy associated with the use of actual retraction is a primary modus of treatment of macular edema in uveitis. So the flucinolone implant or the resistor implant is effective in treating intraocular inflammation with decreased inflammation and recurrence rate in the fallow eye, stabilization of visual acuity, but at a pretty high cost of cataract in 100% of fake guys and a very high percentage up to 70% of patients needing medical therapy or IOP and a pretty high rate of incisional cataract surgery. In the must follow up study at seven years, you can see that there was a tendency for in the line in arms which represents patients that were implanted to have an improvement in their macular edema but this was statistically significant really only in the first six months and this advantage was lost at about six years. Newly approved sustained released flucinolone setonide insert or UTIC has been developed specifically for uveitis which shows excellent anti-inflammatory efficacy and it is an office-based procedure which delivers an implant same steroid flucinolone but at about a third of the dose of the reticent. The thing that is interesting about this study is that at least in the first year of the study 71% of the patient had resolution of their macular edema as opposed to 48% of patients with sham. So that this is a office-based procedure which may be actually useful for patients with very chronic macular edema that require repeat intravitural injections. A kind of a novel concept is the supercruital delivery of medications specifically of trimicinolone developed by ClearSide Biomedical and now distributed as I peer by Bausch and Lohm. The concept here is that supercruital delivery would deliver a higher amount of steroid where it needs to be under the chloride RP and retina with less exposure to the anterior segment and hence maybe less exposure to glaucoma and cataracted side effects. This was trialed in the peach tree trial which was a phase three randomized controlled study in which supercruital injection was delivered at day zero and at week 12 and as compared to a sham, it wasn't really a sham. They didn't receive an injection initially but then they were able to be rescued at four weeks with mostly periocrine and intravitural steroid. It reached its primary out point at endpoint of greater than three lines of visual acuity gain in about 47% of patients but impressively since this was a study that was designed for the treatment of macrodina it showed a robust decrease in central macular thickness as early as four weeks represented on this blue line here and which sustained throughout 24 weeks in the study. There is really, there were very few cataract events in both arms and very few problems associated with elevation intraocular pressure. There is no comparative data with the fluosicinolone set and I insert or supercruital delivery yet but we will see because it's in the works. So I just like to mention that as you know, Humira and infliximab anti-TNF agents are used in the treatment and Humira is approved for their treatment of uveitis and that these agents themselves do have a salutary effect on macular Dema when treated. And a recent publication showed efficacy of TNF inhibition as opposed to patients treated with conventional DMARDS such as methotrexate and cell sept with a significant reduction of central rental thickness and associated improvement in visual acuity at one in four years and a reduction in the requirement for systemic steroids. I think that it's also important to note that in this study, rescue treatment was required and well over a third of the patients so that this need for adjunctive therapy is a very real thing. The other thing that is not mentioned in this study but I thought I would mention to you is that patients that are on immunomodulatory therapy have about a 75% reduction in the need for adjunctive therapy than patients that are not on that. So many of our patients are on immunomodulatory therapy. What about other immunomodulators? So we know IL-6 blockade is a new modality that is available to us in the form of tosylizumab or actemera, which has been approved for use in patients with severe refractory RA and polyarticular JIA and as the neuro people know in GCA. And case series suggests that it may be very helpful and beneficial in patients with uveidic macronutrient. In fact, recent publications showed that tosylizumab improved a complete response of uveidic macronutrient versus anti-TNF medications. So it's nice to be able to get this medication but it's extremely difficult to get approved for this indication or for uveitis. We're working on it. Interferon alpha 2A administered systemically shows great promise and is quite effective in reducing macrodema in patients with really chronic macrodema. It requires prolonged exposure to this medication. So they need to be on it for years. And the problem with this is that the medication is difficult to administer. It is associated with side effects that most patients experience through to maybe treatment limiting. Finally, I'd like to mention that paris pentatricum probably does have a role in the management of uveidic macrodema, certainly in the presence of obvious vitreous macular interface abnormalities as you see here but also in patients with recalcitrant macrodema that are refractory to medical care. There is obviously a wealth. There are a lot of papers on there that show an improvement. But I would say that the overwhelming majority in my read of the literature is that there's a partial complete regression of macrodema in 33 to 59% of patients. And this is mostly seen in patients with intermediate type of uveitis. So in summary, uveitis, uveic macrodema is a major cause of decreased vision. The treatment principle is really treat the underlying inflammation first and then adjunctively or persistent recurrent macrogene with intravitral corticosteroids. We've learned that intravitral triamcinolone and dexamethasone implant are superior to subtenance canal log injection and that the intravitral dexamethasone implant is superior to methotrexate and randavizum from the Merrick trial. We have at our disposal corticosteroid implants and inserts that may provide extended treatment such as at the UT and is IPR, but also the registered implant. Systemic and immunomodulatory and biological therapy themselves are salutary in the treatment of macrodema and will reduce the requirement for adjunctive therapy. And part of the treatment likely has a role in the management of macrodema, although this really will require all design perspective comparative treatment. So I'd like to turn it over to Akbar who will be discussing the surgical management of a intractable macrodema. Thank you. Can I do the presenter mode? It doesn't matter, don't worry about it. All right. Thank you all. Thanks Al for a great introductory talk. I'm going to be discussing one of the aspects of UVitis management that Dr. Vaitali discussed and specifically we're going to be talking about surgical management with implantation of deposteroids. And this is a illustrative case where we used a deposteroids implanted surgically as an adjunctive treatment to immunomodulatory therapy. So this was a 17 year old Asian girl who was referred for arthritis and that is often the case when they referred for arthritis, it wasn't arthritis. And she had floaters and lots of vision in both eyes. She had a three year history of this and was recent, was currently actually admitted for suicidal ideation to uni. She has a history of depression, anorexia. She complains of anodonia suicidal ideation and auditory hallucinations. And she has a diagnosis of MDD with psychotic features. At presentation, her best corrected visual acuity was 2400, 2300. Her intraocular pressure was 1719 and she had some cell in the anterior chamber. Cell in the vitreous, two plus in both eyes with haze and systoid macular edema in both eyes as well as periflebitis and this is her OCT. And a hallmark of severe systoid macular edema is the presence of this sub-retinal fluid in addition to the systoid changes, the spaces in that are intra-retinal. And geography showed significant vascular leakage with this very arterial or clearing this fern-like pattern you see in intermediate UVitis as well as papillitis seen in both eyes. So we thought this was most likely intermediate UVitis, could be inflammatory infectious. Of course, you have to entertain retinal vasculitis. So lab workup was done, which I won't belabor, but infectious and non-infectious etiologies were investigated, all of which were negative. So the final diagnosis was intermediate UVitis, likely of the parisplanitis variety with significant systoid macular edema, vascular leakage, ultimately near vascularization of the snowbank was found as well as vitreous hemorrhage, which was noted later. The slow taper of oral prednisone in consultation with the patient psychiatrist was started with concurrent initiation of steroid sparing immunomodulation, we use mycophenolate one gram twice a day. As one would almost expect, her symptoms improved, but her psychiatric symptoms worsened. She had aggression towards peers and family with psychosis and suicidal ideation. So we very quickly decreased her prednisone to 20 milligrams daily and administered intervitral steroids, specifically the Azidex implant in both eyes. And there was complete resolution of CME. There's no steroid associate ocular hypertension and her dose of mycophenolate was increased to the maximum, which is 1,500 milligrams twice a day, so three grams a day. Despite being on cell sept, her visual acuity remained at 2,200, her macular edema was still there, but improved. This time, an angiogram showed not only diffuse leakage and papillitis, but also these little areas of hyperfluorescence denoting neovascularization, which is a feature of inflammatory disease in some cases can be a feature of peripheral non-perfusion, but can also be just a feature of inflammation seen here in the later frames. This dark area of blocking here is vitreous hemorrhage. So laser was performed to the areas of retinal non-perfusion and fearly, and we started Adelimumab or Humira, and there was some improvement of CME, but not complete. Three months after starting Adelimumab, she seemed to be doing pretty well. Her vision was 2,100, limited by some macular atrophy. Her neovascularization remained, vitreous hemorrhage had resolved. But unfortunately, three months later, she developed dense vitreous hemorrhage on the right more than the left, and the vision decreased to 2,400 in the left and count fingers in the right. And you can see here, not only is there significant media opacity, but there's also, it's the right eye and the left eye, but there's also significant macular edema. So we finally decided, okay, this is a patient on significant immunosuppression on Humira and mycophanolate maxed out, not doing well, still bleeding, still has CME, so we bit the bullet and decided to do not only a vitrectomy, but also adjunctively a reticent implant in both eyes. And a similar vision then stabilized to 2060 with resolution of the CME still some. And some macular atrophy in both eyes. So just to talk about the Redisert, Dr. Bhaitali talked to you guys about the data, but as far as implantation is concerned, I had a really fast fellow, but three millimeters posterior to the limbus and incision is performed as full thickness, you have to make sure you break through the septi and the coroid, the wound is gaped, the Redisert is implanted using full thickness strut sutures. This is then dyed in a 311 fashion, making sure it's quite tight. And then the trailing sutures are buried interest clearly so as to avoid pointy things. The wound is then closed with interrupted prolineinino suture. The conjunctiva is closed, and the tenons are closed over the Redisert. And then lastly, the adjunctiva is closed the trailing prolinein sutures are pulled and allowed to fall flush with the spirit. It's amazing what you can do in one minute and eight seconds. So in summary, this is an 18 year old girl with now 18 year old in this particular time with significant bilateral intermediate uveitis complicated by massive CME vitreous hemorrhage and macular atrophy. She was unable to tolerate steroid due to suicidal ideation and surgery was indicated for failure of immunomodulatory therapy, vitreous hemorrhage and intractable systoid macular edema. So intermediate uveitis can present with varying degrees of severity. Manifestations may include vitreous cell and haze which can be vision limiting, retinal vasculitis, systoid macular edema in a good portion of patients and it's probably the most common cause of irreversible vision loss if there's a macular atrophy. Uveated glaucoma and cataract do occur at a fairly frequent rate and optic nerve edema. Retinal non-perfusion with new vasculation in the retinal periphery and optic nerve head with vitreous hemorrhage can be present in between six and 28% as well as other structural manifestations such as every retinal membrane. Late findings in untreated disease include cyclotic membranes, tractional or regmatosinous retinal detachments which are very hard to treat. Hypotony, which is a terrible complication and tysis. Deposteroid implants can be used as both a primary and adjunctive treatment for uveatic macular edema. To go beyond the reticert itself, one teaching point from this particular case is that not everybody can be treated with systemic steroids. Psychiatric adverse effects of corticosteroids are quite common in a meta-analysis of 935 stimulative patients. The average incidence of psychiatric side effects was 27.6% and 5.7% of those were severe. And that includes when there is a risk of harm to oneself or others. So do bear that in mind when you treat people with systemic steroids. There's no particular age predilection or dose dependence despite conventional wisdom. And there's a significant association with pre-existing mental illness to do talk to patients, psychiatrists. And there's a minimal, with a significant increase in risk in women. And I'll turn it over to Dr. Lorschel. I'll answer any questions if you're having. You've already mentioned that that is the knowledge of 5-month-long-term rate of an in-bed patient with 3-week-long-term rate. You know, even six years later, she recurred. So we needed all of them. With macular edema in the right eye, 32-year-old, she had a previous lab workup that was unremarkable. And her first episode of UVitis was in January, just in the right eye. Later that year, she received a subtenance kennelog injection for vitritus and macular edema. And then she went two years without another episode until 2019. And she presented with some anterior chamber inflammation and macular edema. Again, she was administered a subtenance kennelog injection, but the macular edema actually got worse. And so at this point, as per Dr. Vitaly mentioned, the intravitural steroids have been proven to be more effective than subtenance kennelog. And so an ozardex was performed, intravitural dexamethasone. And we can see the OCTs of these. This was when she presented with macular edema, was given a subtenance kennelog a few weeks later and it actually had no effect or even a little bit worse. And then after the ozardex, it flattened out. So now it's November. It's only four months after the last ozardex. And she presents again to the triage clinic with recurrence of anterior chamber inflammation and recurrence of macular edema. At that point, she was started on Durazol and received another ozardex. But at this point, it's a young patient. She's fake it. It is unilateral disease, but if she's requiring ozardex every four months, we have to think of other ways to treat this. And so we discussed several more long-term options as such as immunosuppression. She was a little hesitant to do that because it was unilateral disease. The UVIs itself was fairly mild and controlled with drops. It was really just the macular edema that was giving us grief. And so she opted for local treatment at this time. More of her medical history included gastric sleeve surgery. So we were really trying to avoid oral prednisone in her case. And so she'd had previous mild intraocular pressure rise with intravitural steroids, but a pressure of 25 not on glaucoma drops to me is not a complete contraindication to keep using intravitural steroids. Whereas a patient with a fragile nerve, glaucoma, if they're already on max drops and the pressure goes to 25, that's a completely different story. And so a pressure of 25 without glaucoma drops, we think we could just potentially treat prophylactically or there'd be a good response from intraocular pressure lowering drops. And so this was after the Ozurdex, of course the macular edema flattened out. And we decided to use the UTIC, which is the Long Acting Fluidine-Alone Intravitural Implant that can be administered in clinic. The UTIC was placed just one month after the Ozurdex. So I didn't wait for the macular edema to recur again. I didn't wait those four months for the Ozurdex to wear off. We just went ahead and implanted the UTIC soon after the Ozurdex. And this is, I think a popular technique because UTIC doesn't have that sledge hammer effect that Ozurdex does. It's not a big bolus of intravitural steroids upfront to get rid of the macular edema. It's sort of low and slow and this little maintenance of steroids in the eye can help prevent recurrence of macular edema. But we find it's not quite as effective as that initial bolus of using the Ozurdex. We can see the pressure increased mildly to 22 after the Ozurdex injection and then up to 27 after the UTIC. But that was without glaucoma drops. So COSOFT was added and the pressure normalized. So after a few months, the pressure was normal but of course her cataract was worsening and so she underwent cataract surgery. And to date, this patient has not had a recurrence of her uveatic macular edema. She's had mild episodes of anterior chamber inflammation treated with drops but the UTIC seems to be holding strong as far as her macular edema. Caveat to this, I looked back at my data and I have implanted 18 UTIC over the last few years. I think this is my only case that was like a slam dunk that after she had the UTIC that she had absolutely no macular edema in the following three years. So it's not that this is absolutely representative of the strength of UTIC. I think we find that more often in patients that are requiring Ozurdex maybe every three months consistently for macular edema, if you put a UTIC in the eye, maybe you can stretch those Ozurdex out to five months. And so over the course of several years it really reduces the number of intraocular steroid injections they require. But I think less commonly it's like one UTIC and they never have CME again. This is a different case, a 51 year old man that's otherwise healthy. We use NGAU to abbreviate non-gramulomatous anterior uveitis and he was presenting with painless blurred vision in the right eye. He had previous episodes of uveitis about one per year that had responded to topical steroids alone. The history of Lasik and his laboratory workup was unremarkable including HLA B27. So on his exam, his vision previously 2020 uncorrected in the right eye had dropped to 2070. And this time his anterior chamber was quiet but it was noted in triage to have inflammatory cells in the vitreous as well as macular edema. So it seems like his disease has now morphed into more of an intermediate uveitis. This is his macular edema at the triage visit. He was started on prednisolone acetate six times a day and I saw him a week or two later and his vitreous information had actually subsided. It was mild to begin with, some topical steroids can help with that but his macular edema didn't budge. And so at this point we have an otherwise quiet eye but with persistent macular edema. And so what can we do for this patient? This is really the art of medicine. Oftentimes there's no one right answer of how to treat uveitis. Of course there's some wrong answers like putting intravitural steroids in an eye with an infection but with inflammatory CME we have several different good options. And so you have to just take it case by case for a certain patients. Sometimes you get some information from the patient that may sway you one way or another such as a phobia of needles or perhaps they were on oral steroids in the past for something else and they just remember the side effects being intolerable. Of course there's some more absolute contraindications for certain treatments such as putting an ozardix in a unicameral eye or patients with really fragile glaucoma, advanced optic neuropathy and a history of steroid response. We'd wanna avoid periocular steroid injections and probably dursal, no dursal can be really hypertensive. And then Dr. Shakur mentioned the psychiatric side effects and of course for oral steroids we have to consider patients with uncontrolled diabetes and the effects on glucose. So I have a discussion with a patient. A lot of times I lay out the options if there's not an absolute contraindication and then oftentimes they can decide. And so this gentleman, he was young, fit, healthy. He said, let's try the oral steroids. I don't love the idea of a needle around my eye. And so we did a six week course of oral prednisone that tapered off the topical steroids and he had 2020 vision a month later with resolution of the macular edema. But unfortunately soon after about a month after stopping the oral steroids, he presented again now with some mild intraocular inflammation in the anterior segment, but no macular edema. And so at this point, recurring soon after prednisone taper we have to start thinking about other ways to treat this more long-term such as potential systemic immunosuppression which is beyond the scope of this talk. And so lastly is macular edema, the best part of my job or the vein of my existence. I think it cuts both ways. You can see a patient that's 2070 and you give them one injection or a few weeks of prednisone and they come back and you've cured them. They're the happiest patients. They're 2020, but on the flip side of it, you have a patient that presents with chronic macular edema. They don't know how long it's been there. Sometimes you put an Osoridex in or use some other treatment form. And a month later, their OCT looks perfect and their vision has not changed. And that's because there can be chronic ellipsoid zone dysfunction and loss of the photoreceptors from chronic macular edema. And so the picture looks better and the patient notices no difference. And so that's one of the challenges with treating macular edema. And of course, the recurrent nature of it, especially in patients that are on systemic immunosuppression and their uveitis is otherwise quiet, but they have to keep coming every three to four months for injections. They're like, hey doc, what's going on? I mean, you've fixed uveitis and why do I still have to see you every three months for injections? And so a little bit of both, I think is the answer to that question. And that's all I have. Okay, so hi. I'm gonna talk about sort of additional local treatment options for uveatic macular edema. Particularly, I'd like to focus on two cases that hopefully highlight and kind of emphasize some of the concepts that Dr. Vitale had gone over with respect to some of the trials for local steroids. And hopefully highlight how that kind of played out in clinical practice for two patients. So the first patient is a 54-year-old gentleman with sarcoid-associated intermediate uveitis that was biopsy proven at least in his lung. It was diagnosed in 2010. He made his way to uveitis clinic in February of 2016. I'm in the setting of having chronic floaters in both eyes with redness, pain, light sensitivity, his vision was 2030 in both eyes and he had normal intraocular pressure. This is just his optosphoto. It's a little bit hard to appreciate, but just on exam, really the only thing that was notable was that he had mild vitreous cell with some vitreous haves and the same thing in his left eye. So mild active intermediate uveitis in both eyes. This was his fluorescent angiogram, just showing that there is peripheral retinobascular leakage in both eyes. There's hyper fluorescence of the optic nerve in both eyes indicative of papillitis. And then kind of more subtle is that you can appreciate there's this small amount of petaloid leakage in the center of the macular in both eyes indicative of angiographic CME, but on OCT, this was not clinically apparent. So there was no clinical CME related to the active uveitis. And so the assessment for this patient is that he has symptomatic active intermediate uveitis with widespread angiographic leakage without macular edema. And so just getting to the slide that Dr. Vitale showed, this patient isn't sort of in the spectrum yet of clinical macular edema. And so really we're gonna focus on just treating his inflammation. So for him, we focused or started with systemic corticosteroid with oral prednisone. Understanding that something like topical steroid probably would not be sufficient for an intermediate uveitis with sort of significant involvement of the retinal vasculature. Local steroid, such as periocular intravitural steroid probably wouldn't be the best choice with a bilateral process. And immunomodulatory therapy might be a little bit too aggressive kind of for a first time episode. And so this patient was treated with systemic corticosteroid oral prednisone starting at 60 milligrams and tapering over several months. He ended up coming back four months later after finishing the prednisone taper now with decreased vision, his right eye, which I'm gonna focus on. So he is now 2060 in the right eye at this time, still normal intracular pressure, albeit increased vitreous cell and a bit more vitreous haze. And what you can see on the angiogram is now there's increased sort of the central petaloid leakage in the right eye. Sort of this angiographic macular edema, now corresponding to clinically apparent central macular edema in his right eye related to active uveitis. And so this patient was actually enrolled in the point trial. I remember that this was the trial comparing periocular corticosteroid, so subtenons can along two intravitural steroid, either ozardix or triumcinolone. And so this patient was randomized to receive periocular steroid with STK. And I'm just gonna kind of go through kind of his OCT. So he received his first STK at the time of enrollment. And you can see that a month later, he had complete resolution of his macular edema, as well as good treatment and resolution of his active intermediate uveitis with the vitreous haze. And then all of his subsequent visits for the trial for the full six months, he had sort of resolution or no recurrence of the macular edema and his visual acuity remained in good range. And so even after that for the subsequent three years, he was just observed, he remained quiet, no intraocular inflammation and no macular edema. And then in January of 2019, he had a subtle recurrence, just a slight amount of sort of juxtaphovial intratenal fluid with symptomatic blurring of his vision. And because he did so well with STK the first time, he was treated again in the same way with an STK, which resolved the intratenal fluid. And then another three years later, he came in now with symptomatic blurring of vision, his left eye. So this is OCT of the other eye. He did not have any active intraocular inflammation, but he did have increased macular edema in the left eye. And so again, because this patient responded so well previously to STKs, he was given an STK in the left eye, but in this case, it did not show any improvement. He actually got worse with the macular edema. And so at that point, he was switched over to receive, oh, sorry, and so this was the angiogram showing that in the left eye at that time had sort of again, that active petaloid leakage with papillitis in the left eye. And so he was given an ozardix and at that point had really good resolution of the macular edema with improvement in vision. And so just to highlight and to go over again, the results of the point trial showing that in general, the intravitreal corticosteroids were significantly better than periocular steroid at improving macular edema, as well as improving visual acuity related to macular edema, which ended up playing out for this patient's second eye, the left eye that it happened in, but sort of in the real world, so this is sort of a recommendation. So this patient was one of those patients who had a good response initially to periocular steroid, which is why it was used and was effective, at least for the first several recurrences of the macular edema. So the second case is a 73-year-old woman who has HLAB-27 associated anterior uveitis. She has ankylosing spondylitis. She's had prior vitrectomies and epiretinal membrane peel, cataract surgery, and she had an Ahmed valve placed in the left eye for uveidic glaucoma. She was previously on systemic immunosuppression with oral methotrexate, but that was stopped due to adverse events and side effects. And as far as her ocular presentation, her sort of active ocular issue was not really any inflammation in the left eye, but it was recurrent macular edema related to prior inflammation for which she was receiving serial ozardx injections with good response. And so for this patient, we're sort of focused on not active uveitis, but recurrent or persistent macular edema. And so this patient with a unilateral disease was receiving regional corticosteroid with ozardx that was working with good effect. So just as an example for the left eye, this was back in August of 2016. The patient presented with central CME in the left eye, received an ozardx with good improvement. And then again in 2017 had recurrence of central uveidic macular edema and received an ozardx again with a good central improvement, at least by four months later. Again, had recurrence the subsequent year in April and at this point was actually enrolled in the Merit trial, which again, just to summarize, compared patients with the three different types of intravitural treatments. So either ozardx, methotrexate, or anti-vegif with ranivizumab. And this patient was actually randomized to receive methotrexate. And so I just go through kind of, she had ended up having four serial monthly injections of methotrexate and what she can appreciate is that there really isn't much change at all in her macular edema over time. And so at that point, the patient was crossed over to receive ozardx and again, had a really good response as she had previously with essentially resolution of her macular edema. And so even after the trial, the patient continued to receive intermittent ozardx with really, which had good efficacy for her macular edema. Unfortunately, at the end of 2019, developed endoplamitis from exposure of her Ahmed valve and the Ahmed was implanted. And so then when she subsequently recurred with her macular edema several months later, the question was, is how to treat this? The goal or the worry in this case was that doing another ozardx might induce a significant intraocular pressure response. Now that she did not have a tube in place. And so the patient was decided to try maybe kind of the third arm of the merit trial, which was to do an anti-vegette treatment. And so she received a vast in the left eye and actually got quite a bit worse. And so subsequent to that was then given an ozardx which she had a good response to previously. Unfortunately, developed a quite significant sterile endoplamitis which was treated. It was not found to be infectious in nature. It happened just a couple of days after her injection. So ultimately then given sort of the numerous issues with the ozardx inducing sterile inflammation, the patient then underwent a couple of months later a reticent implant with an Ahmed valve placed at the same time. She required several perioperative or she required perioperative steroid as well as a couple of adjunctive periocular steroids to help control her CME. And then at this point now, two years after that she remains quiet without any CME. But as you can see just with the recurrences she has distortion and damage to the central retina from these recurrent episodes of macular edema. And so I just want to highlight this is the last slide that Dr. Vitale had to summarize. So really the first key for treatment is for you get a macular edema is to treat the underlying inflammation. And then after that there are these adjunctive treatments. So the first being with our first patient kind of highlighting the results of the point trial which is that in general, intravitriocortico steroid with ozardx or Trampson alone is more efficacious than periocular steroid for uveic macular edema. Although again that is just a recommendation and so some patients can have a good response and do show significant improvement as our patient initially did. And then there's the results from the Merit trial which as our second patient showed that intravitriol steroid tends to do significantly better than either methotrexater or anti-vegF. And then depending on the comorbidities and other factors and if additional treatment is needed that there's these options for corticosteroid implants such as the Reticert which our second patient finished with and has been doing really well with. So that's all I have. Hopefully highlighting those principles that the other three have gone over so far.