 Good morning, guys. My name is Alvi Talley. I am a UVitis and retina person here. And today we're going to kind of give you an overview of the general principles and epidemiology classification diagnostic approach. And treatment of UVitis is a lot in this lecture. I don't expect you to absorb it all. But it will give you actually a pretty good overview of the topic and approach. So some of you know me. Many of you don't. So I thought I would just give you a little introduction of where I'm coming from. So in a previous life, I spent about seven years in Saudi Arabia doing very much what I do here in UVitis and in vitro retinal disease. But in actual fact, I'm a wild animal trainer, along with my wife, four kind of monkeys that are pictured here. These are my kids. And these are triplets. And this was taken at Kennedy Airport the day that we left for Saudi Arabia. And my son seems to be looking at me like, are you sure you know what we're getting into here? And he said, yeah, yeah, it's really cool. I mean, we've got ultra-modern living facilities. It's really, really great. You're going to really enjoy them. They have the gigantic sandbox out there. This is actually about a mile outside of Riyadh, Saudi Arabia. It's very reminiscent of southern Utah, I think. But these large sand deserts, we used to go out there with our kids and hopefully not get them lost, which was easy to do, actually. We used to go camping in the desert a lot. And this is my wife. And we got an opportunity to come out to Utah and to interview here. And I said, yeah, we got this chance to go out to Utah. She's kind of looking at me like, what is with you? OK, OK, from one state where it's dry to another to desert to desert to kind of fundamentalism and religious conservatism and polygamy. I mean, is there something going on here? So no, but really the desert bloom here is much more beautiful than it is in Saudi Arabia. This is actually a shot outside my front door. When we first moved there, you will see that in the winter time, it looks similar, but there are a few more houses. And any of you who were up at my house last weekend knows that there are a lot more houses in our neighborhood now. So we enjoy the four seasons that Utah has to offer. There was a time when I used to go skiing with my kids. And I used to say, well, follow me, guys. And this is my son crossing some 8s. But now the most dangerous words on the hill are follow me, dad, which I would never do. And my kids like to get a lot of air and get upside down. They seem to like dangerous sports. Notice the protective shoes here. Anyway, and this is my son, Ryan, who does competitive longboarding, which is kind of like downhill skiing on cement. And if you really want an entertaining video on a warm up run, check this video out on YouTube when reindeer attack collision at about 45 miles an hour with a deer as he's coming down this road. My girls are into more expensive hobbies, like horse riding and competitive horse jumping and stuff like that. My son and I like to go surfing. We're headed there actually tomorrow down to Mexico. These are my kids growing up now, 20 and 21, or 21 and 1 half. Our house is, at least for the moment, empty nest, which is actually very nice. And my boys are now two dogs. And my wife and I are still doing OK crazy after all these years or being driven crazy after all these years by these four guys. Anyhow, so let's back to the topic here, UVitis. So UVitis is Latin for grape. In fact, I used to play in a band called UVial Blues, but that's another story. So UVitis is not actually one disease. It's a really collection of 30 separate entities with distinct clinical features, course, and prognosis, and disease-specific indications for treatment. You can broadly think of them as falling into either infectious or non-infectious categories. They are frequently auto-inflammatory or auto-immune in etiology or a neoplastic, masquerade syndromes. And really, an etiologic diagnosis is often not very fruitful, because really, etiology can be proven only, I think, for infectious diseases and certain diseases with medallion genetics. It is prevalent. About 10% to 15% of the blindness in the United States is due to UVitis. It's the fifth to sixth cause of visual loss after diabetes and macular degeneration. The thing is that the peak onset is in the most productive years of life. So really, the personal economic impact of this disease may be even greater than that for age-related diseases. Visual loss is not insignificant. So both impairment and blindness occur with fairly high frequencies and occur more often in more severe diseases. As you can see here, it's less more prevalent in patients with posterior and palliativeitis. So the back of the eye has more blinding disease. So how do we approach a patient with UVitis? As Sir William Osler said, listen to your patient. He's telling you the diagnosis. So history is actually quite important, as opposed to the approach, maybe, in other areas of ophthalmology, where it's quick look and gone. So the history includes an ophthalmic history, a medical history, and a review of systems that you can elicit while you're talking to the patient or by means of a questionnaire that we frequently will ask the patient to fill out. Then the accurate examination in which the anatomic location, grade, severity, the inflammation are assessed, this assessment of structural complications. A general medical exam, to the extent that you can perform this in the clinic, so you can look at the skin. You can look at joints. You can look at deformities. It gives you an idea of what's going on with the patient. And then the key is the formulation of differential diagnosis before you have ordered any laboratory tests. So based on your exam and your history and your review of systems, the formulation of a differential. So how do you form a differential? By really characterizing inflammation along several dimensions. So where is it located? Where is the anatomic location of the inflammation? Anterior intermediate posterior panneuviasis. We'll go over that. What is the presentation, course, and laterality? Is it acute? Is it chronic, monophasic, unilateral, bilateral? What is the morphology, location, and number of the lesions? And what are the descriptors that are associated with lesions as important? Is it a retinitis, a choroditis? Are there a few lesions or a lot of lesions? Is it in the posterior pole? Is it in the periphery? Is it grinding lomates or non-grinding lomates? Then there are host factors that are important. Is it associated with systemic condition that's non-infectious, like sarcoidosis, multiple sclerosis, bechettes, VKH, or a systemic infectious disease, like syphilis? And what is the health of the patient? What is the immune status of the patient? Because the appearance of diseases will look very different if the patient is immunosuppressed. And that includes not the obvious immunosuppression of a patient without a diagnosis of AIDS, but patients who are relatively immunosuppressed, such as people that are on chemotherapy or elderly patients that are winding down their immune system. Then where's the patient from? The world's shrinking, right? So there are certain diseases that are more common in certain parts of the world. So we see them here. It's a large refugee population in Utah. What are the associated symptoms and the associated signs? Then based on the differential diagnosis, a directed laboratory investigation is launched to, and the purpose of this is really to exclude infection and to identify systemic diseases that may impact the health of the patient and to provide prognostic information for the patient, which we'll talk about. And then a treatment plan is formulated with appropriate antimicrobial therapy in the case of a patient with infectious disease. And then a step-latter algorithm, depending upon how severe the disease is, using anti-inflammatory medications and the early implementation of immunomodulatory therapy, which is either first-line in certain indications or steroid sparing, to avoid prolonged exposure to chronic corticosteroids. And then, of course, you need to assess your treatment and monitor the side effects and toxicity thereof. So how do we categorize disease anatomically? There was a group that met about 10 years ago the standardization of uveitis nomenclature working group, which I was a part of. And publication was generated from this, which I think I encourage you all to read. And basically, you've got a bunch of uveitis eggheads in the room in order to kind of agree to agree on what you're talking about. So it's important for communication purposes, research purposes, and then how do you talk about your patients? So we agreed that we would classify inflammation anatomically. There are other ways to classify it. But where is the predominance of the inflammation? Is it in the anterior chamber, so-called anterior uveitis? Is it intermediate uveitis? That is, is inflammation concentrated more in the vitreous than the peripheral retina? Is it a posterior retinitis, by definition, involving the retina or choroid? Or is the inflammation not distributed in one anatomic department, but all three, so-called pan-uveitis? So here are some examples of a hypopia on uveitis in a patient with anterior uveitis, intermediate uveitis in which you see cells in the vitreous. A posterior uveitis in a patient with toxoplasmosis, where there is a definitive scar on the retina and a satellite lesion of active retinitis. And pan-uveitis in a patient with exuded retinal attachment in a patient with VKH syndrome. This classification system is OK, but I think that it does not include certain very important categories of inflammation. So keratou uveitis, inflammation of the cornea, and the anterior chamber, is important category of disease. It is herpetic until proven otherwise. Likewise, sclero-uveitis doesn't have a home in the sun nomenclature, but is obviously important, because scleritis is important with some type of systemic association, about 50% of the time. Then retinal vasculitis. There was no home for retinal vasculitis either, but retinal vasculitis is a very common accompaniment of intermediate posterior pan-uveitis. And it's a very large topic, but in essence, it can be primary. You can just have retinal vasculitis, or it can be associated with other inflammatory diseases. And it can particularly affect the arteries of the veins, or both. And that's important, because certain diseases more commonly will affect the arteries, such as acute retinal croses, or the veins, such as sarphagosis. So it helps you in your differential diagnosis. And then, rarely, but in very important cases, vasculitis can be associated with systemic vascolytic conditions, only in about 1% of patients. But that's important to identify. Then, this may seem simple, or even insulting your intelligence, but it's not. Because when people classify uveitis, they use terms that really don't make sense. So it's important to know what you're talking about when you say, what's an acute uveitis, and what is a chronic uveitis? A chronic recurrent uveitis doesn't make sense to me. An acute recurrent uveitis does make sense. So the onset of disease is either described as being sudden or insidious, and the duration is either limited or persistent. And arbitrarily, a cut-off of three months is designated for the duration, so that an acute uveitis would be something with sudden onset and limited duration. So it has a start and finish, as opposed to recurrent uveitis, which is marked by episodes of inflammation in between three months. And then, chronic is persistent, which relapses promptly off of therapy. So it's important to have that kind of down. One can also classify uveitis as to whether or not it's granulomus or not granulomus. I think it's a good descriptor, but it isn't very specific, especially for non-granulomus inflammation. But non-granulomus inflammation is pictured here with these small KP on the corneal surface here that are nondescript, really, and may occur in many forms of uveitis. Granulomus inflammation, on the other hand, has a different appearance. It looks like these stuck-on, kind of mutton-fat type of precipitates. And it is also characterized by nodules on the iris. So it is important because the differential of patients with granulomus uveitis is a little more limited. And it would include entities such as sarcoid, sympathetic, lens-induced disease, and an intraocular form, body, VK, HTB. And note that herpes and syphilis can do anything. Likewise, this is a busy table, but the reason I put it up there is just to kind of classify the major uveitis along the anatomic axis. And whether or not it's infectious systemic or there is no systemic disease, it's just an ocular disorder. And I just want you to point out that syphilis can pretty much do anything. Sarcoidosis can pretty much do anything, okay? Lyme disease, again, is spirochetal disease, which and TB are important things to consider that have multiple presentations. The major diseases that the differential of anterior uveitis are listed here. Infectious diseases such as herpes, seen here with transillumination defects and atrophy of the iris. Systemic diseases such as HLAB-27 associated disease here is a hypopia on uveitis associated with that. This is an eye with JIA associated uveitis, a quiet eye with a cataract. This is a patient with sarcoidosis, fat type of KP. And this is a patient with Fuchs uveitis as serone with iris hetochromia. There was no systemic disease associated with this. The major differential of intermediate uveitis would include infectious disease such as syphilis and Lyme. Systemic diseases would include multiple sclerosis, this is an important consideration in sarcoidosis. And then an idiopathic variety in which there is no associated systemic disease called parsplanitis. So when we talk about intermediate uveitis, we talk about intermediate uveitis associated with, you know, whatever systemic condition. If there is no systemic condition, it is in terms of parsplanitis. So intermediate uveitis and parsplanitis are not necessarily the same disease, right? You may have similar manifestations of the disease, but in terms of your nomenclature, you would say intermediate uveitis associated with MS if there is no systemic association, parsplanitis. So the character's findings of parsplanitis would include macrodema, which is a major cause of visual loss, and these precipitates or snowballs in the vitreous inflammatory exudates and retinal vascularitis. As you see clinically and on angiographic wide field and regular angiography, okay? With leakage and staining. Posterior uveitis, I think it's very important to specify and think about what it where is, what is the primary level of the inflammation? Is it primarily in the retina? Such as in toxoplasmic coriobritonitis? Is it primarily in the coriite? Like a patient with TB, okay? Then the location, the number, and the descriptors of the lesion are important in helping you think about the differential diagnosis. So are there many of them? Are there few of them? Is it in the posterior pole, in the periphery, or both? What is the color, the size, and the shape? So just to illustrate this, this is a patient with an amoeboid or geographic area of coriorettinitis, characteristic of surpigeonous corditis. This is a patient with ampy, with placoate type of lesions, okay? Different than the previous one. These are yellow, orange, ovoid lesions in the deep retina and the pigment epithelium characterized, characteristic of birch-head retina cordopathy. In contrast, here are punched out coriorettin lesions that one sees with multiple corditis and panacea, or even patients with many others, such as PIC, or histoplasmosis. And then, if you can see them, there are these tiny, evanescent, tiny little white dots here in the patient with mutants, multiple evanescent white dots in there. So the descriptors are completely different, right? But the descriptors are important in describing what it is that's right here. The major differential in patients with posterior uveitis include infectious diseases such as this patient with CMV retinitis and these other diseases listed here. Systemic diseases such as sarcoidosis with this pan-uveatic picture with retinal vasculitis, metritis, coroidal, and retinal lesions. And then, those with no systemic diseases is a patient with a kind of a variant of ampy and surpision is called relentless placoid coriorettin opathy. Then, panuveitis, okay? So, always think about syphilis, okay, in your differential diagnosis, all right? Syphilis can, this is a patient with syphilis with characteristic pre-retinal exudates. This is actually a Saturday Arabian woman with an exudative retinal detachment, okay, and leakage on their fluorescent angiogram with pooling characteristic of VKH syndrome. And this is a patient with multiple coriolesions. It's very similar to VKH syndrome, except this is a patient that had these lesions in the context of trauma. So, this is a diagnosis of syphilis ophthalmia. So, where does that get us? It allows us to talk to each other, okay? So, if I am going to say, yeah, I got this patient with unilateral alternating recurrent anterior uveitis, I'm thinking, you know, likely that this may be an HLA-B27-associated spondyloartheropathy-associated disease or HLA-B27-associated disease. In contrast, a unilateral recurrent focal retinitis, like the picture we saw, unilateral focal retinitis, I'm thinking about hoxoplasmosis, okay? But if you tell me, I got this AIDS patient with, you know, chronic focal retinitis, I'm thinking, well, maybe not, maybe it's probably, it could be toxoplasmosis, but it's more likely CMB retinitis. A bilateral multifocal acortitis with cream colored, with, you know, orange, ovoid lesions would be more characteristic for a shot. So, what do we do when we assess the patient? Obviously, we're in the business of vision, right? So, best corrective visual acuity, I think is important in the clinic, intraocular pressure, and then standardized method for grading inflammation. This was another task of the Sun Working Group and in the paper that I encourage you guys to read. So, we agreed to agree on a classification system in which the anterior chamber cells would be graded on an ordinal scale from zero to four plus, depending upon the number of cells that you can actually count, okay, in a one by one millimeter slit, okay? This is a pretty good example of what you see, you know, when you're actually looking at the patient here. Flare, okay, is a proteinaceous material that is extravasated through incompetent blood vessels in the anterior chamber, much like, you know, you might see if you went to a movie theater and someone was smoking a cigarette, of course, and you might see particulate matter and projected from the projection booth. And that is graded, again, on a scale of zero to four plus, depending upon the degree to which the flare obscures these structures in the anterior chamber. Note that in this classification system, hypopion is not included in this, so that's graded separately, okay? So, four plus flare is a lot of flare with fibrin in the anterior chamber that you might see, for example, in a patient with a postoperative endothelitis, okay? You might also see a hypopion, so you would grade them separately. A little more tricky and a little less satisfying is the grading of vitreous haze, in which a system has been adopted that had been in place for a while using an NEI grading system basing flare on the visibility of structures based on indirect ophthalmoscopy from zero to trace to four plus. So, zero, everything is crystal clear, four plus, there are no structures visible. There are obvious problems with this grading system because the vitreous is not the only thing that produces media opacity, so it lends the cornea that can produce this kind of problem, but it's the best we have so far. People are working on this. Equally as problematic, and a grading system for which there was no consensus was a vitreous cell. However, I think grading vitreous cell to some degree is important, okay? One of the reasons why there was no consensus is because in this grading system, which people kind of use roughly, how are you really gonna count 250 vitreous cells? No, but you are gonna get an idea how much vitreous inflammation is in the eye. The other problem is that eyes that have had previous inflammation, eyes with PVD, sometimes can have debris in their vitreous, they can have cells in their vitreous that are there constantly, that no amount of steroid is going to make go away. So particularly cells that are stuck onto vitreous fireballs are more representative of inactive inflammation as opposed to cells that may be swirling around in the lacuna or the clear spaces in the vitreous that are kind of swirling around in Brownian motion. Another index of activity would be kind of so-called snowballs or precipitates, exudates in the vitreous cavity, such as you see here. The margins of these snowballs are, this one in particular is not very crisp, okay? So fluffy type of snowballs would be indicative of activity as opposed to well-certified snowballs. So there are kids with intermediate aviages that have these very well-certified snowballs that are just hanging out in the inferior vitreous. 20-20 vision, no macrodima, they're not active, okay? They've had that for a long time. However, there are people with fluffy snowballs that would be indicative of activity or people, for example, with an endogenous fungal endophthalminus that have these fluff balls in their vitreous. That's the sign of activity. And the other thing is that when you have an inflammatory lesion in the retinol or chloride, frequently there are cells over the inflammatory lesion. So I think it's possible and important to actually look at that. So for example, in a patient with toxoplasmosis with biomechroscopic examination, you can actually look at the lesion and you can tell that if you look in the anterior vitreous and then posteriorly, there will be a collection of cells over the inflammatory lesion. So I think in that sense, vitreous cells are important to grade. The sun grading system, just I point this out to you here because there are a couple of important concepts. Inactive means no inflammation, okay? Grade of zero. However, normal eyes will have a grade of less than one cell and 0.5 or less are generally acceptable level of cellular inflammation in the eye. And it depends on the context, but that's a more nuanced decision that we can talk about in clinic. But the goal is no inflammation, okay? Improved or worsened for research purposes, you know, a two step increase or decrease. Obviously there's a ceiling and floor effect, right? You start out with one plus, and you go to zero, you're improved. Remission. This is a problematic definition in my opinion. Inactive off of treatment for greater than three months, there are diseases in which this just doesn't apply, okay? There are certain chronic diseases, like JIA, associated irdocyclase or birch-eyed random choropathy, in which this definition of remission just doesn't apply. That's a subject for another discussion, but this is what we've got. And then the idea of corticospirid sparing is a very important concept. So we will see that, you know, the goal is to have patients steroid free or unacceptable dose of steroids. And that dose, at least in this publication, was less than 10 milligrams per day. That has gone down since then to probably more like five, okay? And the reason for that dose is that at that dose of chronic steroids, the chances of developing serious steroids associated side effects are very small, okay? So you want to do whatever it takes in order to get the patient off steroids, systemic steroids, for greater than three months, or get them on an acceptably low dose of steroids. And there are a variety of medications that are immunomodulatory medications or biological medications that we can use that are steroid sparing, that are also anti-inflammatory to achieve that goal. Is that clear? That's an important concept. Okay, and then, you know, particularly at this time of year, you know, when we're kind of all looking at patients together, oh my God, they're two plus cells. Well, maybe not, you know, maybe it's one plus. Okay, so I'm not super stickler about that because I know that there's variation, okay? And that as long as you're internally consistent with your grading system, that's okay. And that was actually studied and show that there's agreement within one grade of a very high percentage. So that, I think, is reassuring. So people aren't all over the map, right? But you get a feel for what level of inflammation is significant. Okay, we talked about this. Why do you work up the patient at all? You know, univitis is complicated, but it's not. Okay, I think that on the one hand, you just, you want to try to keep it simple if you can and you will try, you will at least I am always thinking, is this an infection? I really don't want to get burned by not treating an infection because if you treat a patient that has an infection with steroids, they will get worse and there can be disastrous consequences of that. And there are all sorts of publications of literature about people that have injected eyes with individual time sin alone, you know, with acute renal necrosis and then toasts the eye, okay? So we don't want to do that. So we want to make sure that there's not infection. So UVI's work is important to exclude infection, to identify systemic disease impacting the health of the patient, that's really very important, okay? And then to guide appropriate treatment, right? So you treat an infection different than a non-infectious treatment and then certain diseases require immunomodulation at the outset and then to provide prognostic information for the patient. Okay, so if you diagnose a patient with an HLA B27 associated spondyloarthropele or HLA, if a guy comes in, you know, with acute anti-UVitis and you die and you get a HLA typing on him and he's B27 positive, that's important information, okay? Doesn't really modify your treatment so much, okay? You're going to treat him with topical steroids but you can tell the patient, you know what? You're going to, you're a chance of having another recurrence of this is about one per year, okay? We can probably treat this 90% of the time with topical steroids and we want to make sure, you know, based on your history, you're telling me you have back pain, okay? That bothers you in the morning. I'm concerned that maybe you have an inflammatory disease of your spine, I want you to get to see a rheumatologist. You can actually, you know, save that guy from becoming kyphotic, you know, at the age of 50 or, you know, so it's important information. How do you go about, it's based, the work of the laboratory investigation in general are based upon your history and review of systems and your degree of suspicion for certain entities start from, you know, basic stuff to the more exotic and then always consider a syphilis sarcoid or tuberculosis in the diagnosis opposed to your uveitis, okay? Always consider it, don't always have to test for it but think about it, okay? Always test for syphilis, all right, retract that but think about sarcoidosis or TB. And then in the back of your mind, think, could this be a masquerade syndrome, okay? Maybe it's not uveitis, you know? Maybe it's not, maybe it's a malignancy, okay? That's important to think about. At least have it in your head. So just to worry about certain types of diseases, okay? Syphilis, if I had to order one test in the work of a uveitis, it would be an FTA, okay? Because you can cure a patient with, you know, penicillin with a syphilitic associated uveitis, okay? There are basic, ophthalmology has a long-standing tradition of ordering both specific and non-specific tests. So FTA plus an RPR or VDRL test are important to order together. If you had to do one test, it would be an FTA. But the reason why you order them together is because the RPR and the VDRL are non-specific, okay? They can vary with treatment, so they become negative with treatment, whereas the FTA remains positive for life, okay? And if it is not, if the patient is not treated, it can become negative, okay? So a patient can be untreated, still have, you know, develop tertiary syphilis and have an RPR that is negative, but if the FTA is positive, then it needs to be chased down. Lyme disease, I think, is exceedingly uncommon here, but, you know, it does occur. I think we had no cases, we looked at this actually, maybe one case of Lyme disease in 10 years here. We may have another, but that's another story. And so, but in endemic areas or patients that are traveling from endemic areas, it's important diagnosis to consider. So my colleagues on the East Coast frequently order Lyme serology on their patients. You will also see that there are certain, there are physicians out in the community that order Lyme serology on patients for remunerative reasons, you know, for patients that are having chronic fatigue syndrome and all this kind of stuff. So it's important to sort that out and know about the test, okay? Infectious diseases, you know, testing for tuberculosis is important in certain settings. Routinely screening every UV-itis patient for PBD is probably not useful. It's particularly in this kind of population where the incidence of the disease is low, right? Okay, so the positive predictive, although the tests for PBD and for quantifier and gold are sensitive and specific, the incidence of the disease in the population is low. So the positive predictive value of the test is not gonna be very good. You have a lot of, you know, false results, okay? However, there are certain clinical clues in terms of granulomus inflammation. If the patient has nodules that are characteristic of a corotal tuberculoma, patients with retinal vascularitis that would be suggested. Illus disease, patients with surpigenus-like lesions should be tested for TB for sure. Certain patients with multifocal corditis and immunocompromised patients. And then there are patient factors. So immigrants, the highest incidence of TB is associated with the elderly and with the immigrant population, HIV population, patient with significant exposure risk. And then prior to instituting systemic immunomodulatory therapy. So it's important in patients, you know, particularly if you're gonna put them on systemic corticosteroids or TNF inhibition. There are also entities in which I think it makes sense for targeted testing, such as patients with neural retinitis. Bartonella species are the most common cause of neural retinitis. West Nile virus will be seeing some of that come September. You know, patients with multifocal corditis with specific lesion characteristics, such as this targetoid kind of lesion that you see on the fluorescent angiogram in the correct clinical context, particularly in a patient that had a history of encephalitis. PCR of the aqueous in vitreous are also extremely important in sorting out viral retinities, such as acute retinal lacrosis syndrome. They are, there is limited value for the routine screening serologically for herpes and for varicella and toxoplasmosis, particularly for viral, because, you know, everybody's exposed to these agents. And there's a high prevalence in the general population. Intoxo, you know, 25% of the population is seropositive. A negative test for a patient that you suspect of having toxoplasmosis is helpful, it excludes the diagnosis. As I mentioned to you, HLA-B27 in a patient with unilateral alternating recurrent anti-UVS. So the person comes in with a unilateral alternating recurrent anti-UVS, I would get an HLA-B27 test on that patient, okay? They have chronic UVS, I might not, right? Because 50% of these patients are positive and about a quarter of these patients or a third of them will have an undiagnosed spondyloarthropathy, okay? ANA is a test, we'll see a lot of patients that come in and have been referred from the outside everybody has an ANA test, okay? And it's just not the, again, the positive predictive value of that test is very, very low for screening patients with UVS. In fact, patients with lupus frequently don't develop UVS per se. They'll develop retinal vasculopathy. But it is important in children that have anti-UVS to screen them for oligoticular GA associated disease. So in that context, it's important, or in a patient that has findings that are associated with lupus. The patient comes in with a malarash, they have psiricitis, arthritis, that would be a patient with a vein occlusion or an arterial occlusion, I might actually work them up for that. Beta-2 microglobulin is actually a good screening test for a disease known as tubular interstitial nephritis and uveitis. You see this in children and young women with bilateral chronic anti-UVS. And then ANCA rheumatoid factor and CCP are very important, particularly in patients with scleritis, to exclude Wegener's, rhinolomaceous, sort of lapsing polychondritis, as the systemic disease associated 50% of patients with scleritis and those vascular conditions are extremely important to diagnose because they're associated with high mortality. Sarcoidosis, just one word about sarcoid, it can produce any type of uveitis, as I mentioned before. The organs affected are predominantly the lungs, the skin, the reticular endothelial system and the eye. A lot is made up about ACE and lysozyme. They are not specific tests. They are not useful screening tests in general for diagnostic purposes. However, they can be help you, put you in the ballpark of a patient, for example, that comes in with rhinolomaceous inflammation that is characteristic of sarcoidosis. I would order those tests. There are people that don't order those tests. But high ACE and lysozyme are indicative of that disease and they become lower when you treat the patients. There was one study that showed that high ACE and gallium scan was very highly predictive for the diagnosis of sarcoidosis. But those are, gallium scan is not a test that we perform very often. So the other thing about the angiotensin-converting enzymes that can be physiologically elevated in children and depress some patients on ACE inhibitors. So there are a lot of confounding factors. Laboratory tests that are a little bit more useful would be patients with sarcoidosis that have hepatic involvement, which is not uncommon. So a complete metabolic profile and a patient with elevated liver function test is angriolomaceous uveitis, might suggest that diagnosis. Probably the most useful screening test for sarcoidosis is a chest X-ray. So 90% of patients with sarcoidosis will have some type of findings, particularly bilateral hyaluridinopathy in those with active diseases. In patients that have a clinical scenario that is very suggestive of sarcoidosis or have granulose inflammation and their chest X-ray is negative, but you still think that they might have that. A chest CT may be a valuable test to obtain because it's more sensitive in detecting adenopathy in patients with a negative chest X-ray. You know, the tissue is the issue. Necessarily the definitive diagnosis of sarcoidosis, that being said, it can be other stuff, okay? A granuloma, non-causing granuloma is not specific for sarcoidosis, okay? But it puts you in that category. So when you think about that diagnostic procedure, you're always thinking, well, let's do a transpironial biopsy, but there are other places that you can actually make the biopsy and spare the patient that kind of invasiveness. So look under their eyelids for a nodule, okay? Look on their conjunctiva for a nodule. Look on their skin, okay? So patients with sarcoidosis will have skin findings that can be biopsy. And the lacrimal gland is also a place. Just a word you may get consulted, you know? We'd like you to do a non-directed conjunctival biopsy in this patient that we think has sarcoidosis. There's just no value in doing that, okay? If the patient has a nodule on their iris, you know, then I would think about doing that. There was a international workshop on ocular sarcoidosis that kind of categorized disease into categories of definite presumed, probable, or possible, depending upon whether or not you had a compatible UV-itis, whether or not there was biopsy-proven disease. So definite, obviously biopsy-proven disease, presumed with bilateral hyaluridinopathy, but no biopsy probable, with a compatible UV-itis with three signs and two laboratory investigations. So those have about a 60% chance of having disease, okay? And I just wanted to point out some of the signs that you might see in a patient with sarcoidosis. So you have, on Gonioscopy, these tent-like PAS that are very characteristic. So these are characteristic clinical signs. You can have these granulomas of the optic nerve. You can have periflebitis. Collections of inflammatory exudates in the inferior retina, and not infrequently characteristic white kind of cortirental spots. So these are all signs that you see in patients with sarcoid. Moving away from sarcoid, but in general, in terms of your work of the patient, as I mentioned to you, chest x-ray is important, not only for sarcoid, but for TB, and for other diseases such as wagoners in which you may have cafeteria lesions in the lung. Again, CT and MRI scan for TB, lymphoma, toxoplasmosis, and MS. B-scan, you wouldn't want to have a surgical misadventurer in this eye, always a good idea to B-scan patients with medial capacity to see what's going on in the back of their eye. And then UBM is actually very useful in detecting maybe causes of hypotony. So hypotony is a really bad complication of long-term inflammation in the eye, very, very difficult to treat, but in some cases, you can't treat it. Particularly if you can identify a cyclitic membrane that is pulling on the ciliary body, detachment of the ciliary body. And then you can also kind of say, well, ciliary body's shot, if the ciliary processes are atrophic, you can identify that on UBM. And your approach would be different. You wouldn't be treating patient surgically or with inflammation. Then multimodal imaging is really key in assessing inflammation in the posterior segment of patients with uveitis. Fluorescine angiography, you will hear a lot about fluorescine angiography and OCT angiography, which is coming and will be a very important tool, but I will tell you that fluorescine angiography is here to stay in the assessment of patients with inflammatory disease. And I think will still be very useful in patients with neovascular AMD in certain cases, but certainly in patients with inflammatory disease because it gives you an idea of what's happening physiologically in the patient. So the assessment CME may be better served by OCT, but certainly retinal and coronal neovascularization, vascularitis, non-profusion, all these things are complications in patients with inflammatory disease and require fluorescine angiography and wide-field fluorescine angiography is becoming particularly useful and confounding, I think, in how we approach and make management decisions. Again, ICG angiography, not a lot of application for ICG angiography. These days, I think in retinal disease, there are a couple of retinal entities for which it's really important, like PCB or even some RAP lesions in the retina, but for many core retinal lesions, ICG angiography is important, okay? It can help you diagnostically. For example, in patients with certain types of white dots and roms and patients with birdshot retinal cordopathy. You know, OCT is extremely useful, particularly in differentiating inflammatory versus, you know, tractional macrodema, but also gives us a lot of information about what's going on in the outer retina these days, particularly important in patients with visual loss associated with white dots and roms and seeing, you know, what's happening in the outer retina and seeing what's reversible and what's not reversible. And then the assessment of the core rate is becoming increasingly important and useful in monitoring disease activity and response to treatment. So for example, patients with VKH will have very thickened core rates, okay? And then when you treat them, the core rates become thinner. And then likewise, auto fluorescence is, I think, useful, particularly in patients that have inflammatory conditions that affect the outer retina and the pigment epithelium. We don't exactly know what the significance a lot of these findings can be sometimes, but hyper-auto fluorescence is frequently indicative of disease activity. And what is interesting about that is that the hyperfluorescence can occur remotely from the area of active inflammation and it will be modulated with treatment. I just wanna, okay, so I still have a lot of stuff to talk about in terms of treatment. So that's basically the approach to diagnosis, okay? I can give you kind of a, we've got about 10 minutes and I'll keep going here about treatment because I think it's the treatment goal. It's not the specifics of the agents and things like that, that's important, but it's really the approach that I'd like to give you kind of a handle for. So what's the goal of treatment? It's basically to have your cake and eat it, okay? That is eliminate inflammation to prevent complications, okay, and to avoid toxicity. And I think it's achievable in a lot of cases. So what's the important thing? It sounds fundamentally simplistic, but you have to have a diagnosis, right? So you wanna know if you're treating infection or a non-infection, and then you wanna have a diagnosis because there are certain disease-specific indications for treatment, okay? So a patient with Bechette's disease with vasculitis needs, immunomodulation at the outset, okay? A patient with B-27 associated disease, these topical steroids, okay? So it's important to have that, okay? Step-ladder algorithm just in general. Treat the idea is to put the fire out, okay, with a fire hose, all right? Not, you know, a water pistol. And that is to use whatever it takes to get the inflammation under control, okay? So if you're dealing with a non-infectious agent, non-infectious uveitis, use steroids by whatever means necessary, and by whatever route is necessary to get inflammation under control for a limited period of time, okay? So for anterior segment inflammation, topical steroids, periocular steroids for patients with an acupuncture or intermediate uveitis, and then brief systemic corticosteroids. I put this oral non-steroidal anti-inflammatory medication there only because it is useful sometimes in patients that have a indication for the use of these medications. So for example, patients that have a spondyloarthopathy that are on a systemic non-steroidal, okay? Then to have a low threshold to introduce steroids bearing immunomodulation, okay? So a patient is not responding to steroids, rethink your diagnosis, number one. But if you cannot taper them down to an acceptable dose, then have a low threshold for employing these agents. Then there is local therapy that is extremely effective, such as flucinolone implants, okay? But comes at a price of significant complications, okay? Coenin cataract and incisional glaucoma surgery. So the route and choice of medication is determined by the location anatomically and the laterality of the inflammation and the systemic health of the patient, right? So here are our options, right? Topical steroids can be used pretty much, are used for anterior uveitis, but they can be used for anterior uveitis associated with any of these entities, right? Periocular steroids are frequently used in patients with intermediate uveitis particularly because topical steroids will not penetrate to the back of the eye. Periocular steroids are useful for intermediate uveitis and in patients with macular edema, particularly unilateral disease, okay? But they are also very useful as adjunctive therapy in patients with posterior and pan-uveitis and in patients that are on systemic therapy with immunomodulation that may have recurrences of inflammation, that you may wanna just treat that blip, okay? And then you have implantable steroids, systemic steroids and immunomodulation. So those are the options. Topical therapy, I'm not gonna say a lot about it, you know, it's just treat with high doses, don't start out with DID, right? Start out with a high dose of steroids for inflammation and then get the inflammation under control and then taper, okay? There is limited delivery to the posterior segment, with the exception, possibly, in patients that have vitrectomized eyes in which potent steroids may be actually useful, for example, in the treatment of macular edema. So diphenylpredonate may have better penetration. As I said to you, start out high and then taper. Use cycloplegia in patients that have significant anterior and second inflammation. There's controversy as to what agent to use. The reason for using cycloplegia is one for pain to decrease ciliary spasm in patients with severe anterior segment inflammation and also to prevent post-esneakia formation. So I prefer to use an agent that moves the pupil. So atropine will keep the patient in a dilated state for two weeks. So a patient has significant inflammation, I would be more inclined to treat them with homotropine or cyclopentally to move the pupil. We know that, you know, this is associated with cataract and elevated intraocular pressure and that more potent steroids are more apt to give that, to put the patient at risk for that. And there are steroid preparations that are at lower risk, such as Ramex loan. Systemic steroids also have a lower risk of cataract and elevated intraocular pressure. Periocular steroids are very useful for acute remitting non-infectious intermediate posterior pan-UVIs as I mentioned to you before, as primary therapy or adjunctive therapy. And it's particularly in patients with UVatic macrodema. There are a number of ways you can deliver it. You can deliver it as a posterior subtenance injection on orbital floor injections you can see here. The approaches are equivalent in terms of their efficacy. In general, you can obtain resolution and inflammation about 60 to 65% of the time. It lasts for about three months. There's visual improvement in about half of the patients and there's additional benefit for a second injection. At least the literature suggests that 85% of patients will improve with a second injection. This of course depends on the individual patient, right? So you're not gonna say, well, you know, every patient I have is going to give them a second injection. It really depends on how they respond. Again, cataract and intraocular pressure elevation are always problems associated with local steroid injections. Periocular and retro bulbar hemorrhage. There are certain specific side effects associated with delivery modes. So patients with subtenance injection will be more apt to develop ptosis and lidretraction, whereas patients with the orbital floor injection will have orbital herniation more frequently. I think orbital herniation is probably better side effect to have than ptosis. But, you know, and it's also easier to deliver in the clinic. But they're both not great. We can inject steroids into the eye intervitrally. As you know, the complications include endoplaminus is the worst complication of cataract and ocular hypertension, which can occur in about 25% of patients after one injection. Cataract usually ensues after about four injections of intravitral steroids. We now have a, you know, a rotable co-polymer, you know, the Ozuridex injection, which is dexamethasone implant that's been approved for the treatment of inflammation intermediate and posterior UBI. It's been also for macrodema associated with diabetes and vein inclusions. The post-marketing surveillance suggests that it is not quite as effective as, you know, the label indications. That is that it's labeled as a six-month kind of treatment, but really the clinical experience suggests that it's more like a three-month efficacy that, yes, cataract does occur, okay, in about 10 to 15% of patients. And yeah, intraocular pressure does occur, but maybe a less frequency than patients with intravitral corticosteroids. So the durability is still about three months, requires multiple injections. It's particularly useful in eyes that are retractomized, okay, because it doesn't have the dispersive effect that, say, try and synolone would in a retractomized eye. A word of caution you want to make sure that it would be contraindicated, relatively, well, contraindicated in eye with, that's a faking, or in, and you need to be kind of circumspecting eyes that have open posterior capsules. Sometimes these implants can migrate into the anterior segment and produce significant corneal edema. If it does happen, they need to be removed. They just can't watch it. The problem with regional corticosteroids is that they're relatively, relatively short-acting, okay? So just to make sure that we're on the same page, this is, there is no one-size-fits-all for every patient, right, okay? So there are patients that you can give a periactor steroid to that have intermediate UV-itis once a year that do fine, okay? That's pretty much how I'd manage that patient. But there are patients that don't, okay? There are patients that require multiple injections. So it's relatively short-acting. It's less effective for patients with chronic inflammation. So the problem with chronic inflammation with a corticosteroid injection is that you have this kind of intermittent pulse, right? So you're treating it for a while, they get worse. Treating it for a while, they get worse. And you can have this with each kind of recurrence of inflammation, the sawtooth kind of decline in a rental function. So you don't want to treat patients that way in my judgment. Plus you have the cumulative effect of cataractin and glaucoma. You can use, there's an implantable device, a registered device that has been approved, for patients with uveitis, and was quite effective in reducing recurrence as compared to the fellow eye, reduction of adjunctive therapy, and frequent adverse effects. So cataracts, in fake guys, 100% of patients get cataracts, 70% of patients have ocular hypertension, 40% of patients require incisional surgery. So it may not be the best first option, okay? For a young person with intermediate uveitis, it's fake that has reasonable vision, because you need to tell that patient, yep, you're gonna get at least two surgeries, maybe three. But on the other hand, if you have a patient that has terrible disease that just will not take immunomodulation or it cannot tolerate corticosteroids, it's a very good option. Or in patients that you can't get approved for medication, or this is a $20,000 device, by the way. Or patients that just are not doing as well on systemic corticosteroids therapy. So again, it needs to be individualized to the patient. The flucinolone-acetanide intravenous insert has been approved for diabetic macrodema. It's coming for uveitis, okay? So there's another option for intravenous injection. This is a biorerotable polymer, so you still have this polyamide cylinder that's hanging out in the vitreous, lasts for about two and a half years, and has similar side effect profile, but not as bad as the redisert insert because the concentration of drug is less. Just intervitral methotrexate has actually been studied in inflammation. There is only one really good center that has been looking at it, and we're actually trying to look at this now, okay? It has been useful in the control of inflammation and in the reduction of macrodema, and has placed certain patients into extended remission. I personally have not had that experience, but I'm open to this as an agent in patients that don't respond well. So we're conducting a clinical trial for macrodema in which one of the arms is intravitral methotrexate. Systemic corticosteroids, you know have multiple side effects, okay? Drive you and the patient crazy, but I think that corticosteroids are actually manageable, okay? Most of the time, if you know what you're doing with the patient, if you define the period of time that you're going to treat the patient with, and you manage the side effects appropriately. So every patient that is on corticosteroids for more than six weeks requires adjunctive treatment with vitamin D calcium, okay? You need to weigh the patient to keep them honest, okay? So because weight gain is a major side effect, but it's not compulsory. So you can counsel the patient to not eat high caloric food. You need to check their lipids and bone densitometry annually. Just guidelines about the use of immunosuppressive drugs. So you've tried, you know, steroids and they're just not working, okay? So patients that fail steroids, patients that have unacceptable side effects of steroids, or diseases we know are poorly responsive to corticosteroids, so we'll review in a second, or a requirement for corticosteroids that's greater than 7.5 milligrams per day require immunomodulation, okay? Those diseases for which immunomodulation is commenced at the onset of therapy include Bay-Shet's disease with retinal vasculitis, oculosychiatrician, mucous membrane, Pemphagoid, Serpigenous Cordocacy, Necrotizing Scleritis, Cepathetic Ophthalmia. There are a whole bunch of other diseases in which the early implementation of these diseases, implementation of these medications is important for the long-term treatment of these patients as they have very long-term type of inflammation. Those include patients with bird shot, multifocal cordias, VKH, some patients with intermediate EVIs and JIA-associated erosiculitis. Just to kind of give you broad categories, it will stop. There's, I think it's important to think about immunomodulation in two large kind of categories. There's conventional treatment and then there's biological treatment, okay? Conventional treatment consists of the group of medication, the anti-metabolites, which include methotrexate, which is kind of first-line treatment, microfenylate or cell sept and azathioprene. There are T cell transduction inhibitors, such as cyclosporine and tagrolimus, which can be used as add-on therapy because their mechanism is different. And then the alkylating agents, which are much more potent medications that are used a lot less frequently, such as chloramucilin cyclophosphamine, that carry the risk of significant side effects and actually increase malignancy and mortality. The flip side of that is that those are the medications that can induce permanent remissions more often. I will go over this stuff in more detail the next time we meet, okay? But I just wanted to show you that there's a large study that looked at the, it's a retrospective study at these agents and the anti-metabolites, azathioprene, methotrexate and microfenylate, all work pretty much the same in terms of their efficacy, their steroid sparing capability and their toxicity. Their remission rate is very, very low, as opposed to cytotoxic medication, in which they are more effective, but the trade-off is that the toxicity is quite high. We'll get into this stuff later. I hope this provides, oh, the, then there are the biological agents, okay? So non-conventional therapy, there's a whole host of new medications in the pipeline, some of which we use routinely now, biological response modifiers that are therapeutic proteins that are bio-engineered as antagonists to immunoactive molecules, okay? These are usually recombinant antibodies that can block cytokines, cytokine receptors, cell surface proteins or other bioactive proteins. The idea is to provide a more targeted and more specific therapy and decrease side effects. That's the hope of that, okay? And there are pretty much two of them that are used frequently in our clinic, infliximab and adelumab that are TNF inhibitors. They're different in that infliximab is a chimeric molecule, a mouse, human monoclonal antibodies delivered by IV infusion as opposed to adelumab, which is a humanized molecule that can be delivered subcutaneously. There are advantages to, and disadvantages to both of these medications, this can be more titratable, there's more leeway in terms of dosing frequency in the dose, whereas this is more of a fixed dose. And just to let you know that this was recently, I mean, like a couple of weeks ago approved by the FDA for use in IVitis. There are a whole lot of other biological comments that we'll talk about later that we're kind of borrowing from our colleagues in rheumatology and hematology that have been tested actually in limited fashions that some of which show promise, some of which have had really disastrous kind of results or have not met any kind of primary endpoint. So the bottom line is that biological agents and new therapies are out there. They're being developed, people are really looking at them. As with new modalities that come in every, there's a lot of enthusiasm initially, but I think that one needs to maintain a critical eye. It is not a panacea. These are non-remitive agents, that is they're not curing disease, okay? And frequently they will have, their efficacy will wane in time. So there's still a lot of room for study in UVIs therapeutically, certainly mechanistically, and it remains challenging. So this is kind of an overview of stuff and we'll get into specifics in the following lectures. I would be happy to go over this in more detail with you in our next lecture, okay? Thanks a lot.