 And the sandbox was pretty cool for my kids. This is actually a mile outside of Riyadh. It looks remarkably like Utah. It's called, and we call the red sands. And then one day I said to my wife, we had this offer to go to Saudi Arabia and she kind of looks at me like, what are you out of your mind? From political conservatism to political conservatism, prohibitions on alcohol, social conservatism. And what's with this polygamy stuff? I said, no, seriously, it should be great. The desert blooms are much more beautiful. This is the view out my front door. Actually, when we first moved to Utah, you can see there are no houses there, but in the wintertime, by the wintertime, there have been many more. Backyard, lots of snow. Front yard, I mean backyard here in the springtime, just to let you know that everything changes, nothing's permanent, and that's just the way life is. Stuff we like to do in Utah, I ski. There used to be a day when I used to say, follow me guys, and there was no problem. We get a lot of deep pow. It's my son crossing eights up there. And one of my other sons getting buried below. But follow me dad is now the most dangerous, you know, a phrase on the slopes because I could never follow my boys these days because they don't keep their skis on the ground. If you're interested in entertaining video clip, check out When Rain Deer Attack on YouTube. One of my sons used to be a competitive longboarder and he had a collision with the deer going about 50 miles an hour. Both survived. My daughters are into competitive horse riding, like to get air. And in the summertime, my son and I like to go surfing particularly down in Baja, California. My wife actually picked me up on our first date on a motorcycle. I couldn't believe it, and in the middle picture is her on a dirt bike in Saudi Arabia with an Abaya on a no helmet. Don't recommend either of those things on a motorcycle. But our children have kind of grown and thrived. We have a large kind of extended family, as you can see. And you can see that in the bottom frames, there are ex-fellows and people that you may notice and our house is kind of open to all of you. And hopefully we'll have you guys visit us at some point in time. And become part of our family. So the people that are living at home now are my daughter, Sophia and the dogs. We're still crazy after all these years and doing okay. So here we, so you know a little bit about me. Now we'll get into a little bit of uveitis. Uveitis really defines intraocular inflammation. It is not one disease, but really about 30 separate disease entities with specific clinical features, courses, prognoses and disease specific indications for treatment. One can think of them broadly as infectious or non-infectious or mass grade syndromes. The non-infectious ones are thought to be auto-inflammatory or autoimmune. And there's no real etiologic diagnosis other than in infectious or Mendelian genetic diseases. It is a leading cause of visual morbidity in the world and about 10% of blindness in the United States plus by uveitis. Being fifth to sixth to visual loss after diabetes and age-related macular degeneration. The impact of which may be even more severe as the peak onset is between the ages of 30 and 40 during the peak economic productivity of patients with potential greater visual loss than age-related diseases. When we approach patients with the uveitis, it's unfortunately, I know you went into ophthalmology to get away from the continual rounding of medicine but it is more like internal medicine and that is that the history, the ophthalmic medical and review of systems is critically important in helping us guide our diagnosis and treatment. So as Sir William Osler said, listen to your patient he's telling you the diagnosis and I can't tell you how many times this has been true. So we begin with an ocular examination then a general medical examination to the extent that we can perform it in the clinic. Sometimes you're looking at the skin and then joints can be actually very informative. And then we form the differential diagnosis which is the keystone really to diagnosis in the uveitis. So the differential diagnosis is made by characterizing inflammation along several different dimensions. One is the anatomic location of the inflammation in the eye which we'll discuss. The presentation that is as acute a monophasic recurrent or chronic the course and its laterality. The lesion morphology location, the number of lesions and descriptors are important. What is located in the retina or is in the coroid. Then systemic and host factors are extremely important. Is this a part of a systemic non-infectious disease such as sarcoidosis or Bechette's disease or is this part of a systemic infectious condition like syphilis or herpes or toxoplasmosis? And then of course the immune competence of the patient is extremely important because characteristic morphology of lesions in the eye look completely different. And all bets are often terms of diagnosis by pattern recognition when a patient is immunocompromised either hydrogenically or by disease. Then of course the demographics where in the world the patient is from is important as certain diseases are more prevalent in certain populations. The associated signs such as when you can see in the panels to the right here of the targetoid rash of erythema migrants which itself would be diagnostic of Lyme disease or the woman up top with poliosis and vitiligo which is associated with BKH disease. A laboratory investigation is launched based on the history and the differential diagnosis and the importance of the laboratory as we will discuss in a couple of minutes is to exclude infection, identify entities that can impact the systemic health of the patient and provide prognostic information to the patient. And then one forms a treatment plan. Certainly you want to treat an infection with antimicrobial therapy and then treat inflammation or non-infectious uveitis with a step-by-step algorithm employing steroids and then immunomodulatory therapy in an ascending manner, assessing the treatment effect and monitoring the side effects and toxicity. The standardization of uveitis nomenclature or the sun working group agree to agree on what they're talking about in a workshop in classifying uveitis. And one of the classification systems that they agreed on was an anatomic basis and that is to divide uveitis as to where in the eye the predominance of the inflammation is. So anterior uveitis is predominantly in the anterior chamber. Intermediate uveitis is centered in the vitreous and characterized by pitritis. Posterior uveitis includes inflammation in the retina and the coroid. And pan-uveitis is an inflammation in which all three compartments are affected equally. So here we have some examples of anterior uveitis and hypopion uveitis. Intermediate uveitis, the slip beam showing active vitreous cell in the anterior vitreous. In the bottom left, a satellite lesion of retinocoriditis associated with toxoplasmosis. And then in the bottom, a serious retinal detachment associated with VKH disease. One classification system that I think is useful to think of that was not included in your reading and in the sun classification is kind of an expanded classification system which you might keep in your mind. And that is keratoyuveitis is herpetic until proven otherwise. As you can see in the slide up, it's the right with the sectoral artery. Sclero-uveitis, scleritis is frequently associated with intraocular inflammation and can be a hardware in about half the time of important systemic diseases. And then retinal vascularitis is a real mess in terms of classification in that the sun group did not come to a consensus on what they mean, but one can talk about retinal vascularitis as being either a primary idiopathic vascularitis or more commonly a secondary vascularitis either associated with a systemic disease or much less commonly with a intraocular infection rather or systemic disease or much less commonly with a systemic vascularitis. We can categorize vascularitis as to whether or not the arteries or the veins or both are involved as this has helpful differential diagnostic meaning and then the distribution of the vascularitis which is really the subject of the lecture. Then there's a lot of confusion as to what we mean when we talk about acute chronic or recurrent disease. When we talk about the onset of disease we talk about it as being either sudden or insidious. The duration being limited or persistent and three months being the arbitrary cutoff for that so that an acute vascularitis would be of sudden onset and limited duration whereas a recurrent vascularitis would be one that has episodes that are marked by recurrence of inflammation of three months inactive off of treatment whereas chronic disease has persistent inflammation which promptly relapses off treatment. One older classification system was whether or not it's granulomatous or non-granulomatous this is a purely clinical description not a pathologic description. Many diseases have non-granulomatous inflammation and it's not specifically helpful differentially whereas granulomatous disease is a little bit more helpful. You can see these mutton fat stuck on KP on the left and then a iris granuloma on the right. And the diseases that are more frequently associated with granulomous inflammation are included in the slide including sarcoidosis and lens-induced uveitis TB, MS and then of course herpes and syphilis which can do anything it likes. This is a very busy slide and I think the takeaway from this slide is on the left-hand column you have the anatomic location anterior to pan uveitis on the top infectious systemic and non-systemic diseases and highlighted in red and yellow and in whatever that other color is are syphilis lime tuberculosis and sarcoidosis and the point is that those entities can do anything they demo please so they can be in any anatomic location of the eye. So one always needs to think about those particular entities in the differential diagnosis. So here we have a list of the major differential diagnostic entities associated with anterior uveitis. So you have infectious diseases you can see here in a patient with classic sexual iris atrophy which can occur in both herpes type one and zoster. Here you have hypopion uveitis that can be associated with B-27 or Bacchett's disease. Here you have a white quiet eye that is associated frequently with JAA associated eryocyclitis and cataract probably from chronic steroid use. This is granulomatous KP with posterior sneakies you can see in a patient with sarcoidosis and this is a patient with Fuchs heterochromic eryocyclitis or Fuchs uveitis syndrome. These are the major differential entities in intermediate uveitis. This is a cartoon of intermediate uveitis showing on the bottom and inferior what we call a snow bank which is an accumulation of collagen and inflammatory debris which is gravitationally independent and then whitish accumulations of inflammatory debris on the surface of the retina. A frequent complication of intermediate uveitis you can see here is macular DMA represented by this petaloid leakage in the macula and what are termed snowballs which are actually inflammatory infiltrates that you can see here in a patient with intermediate uveitis. You will notice that these infiltrates are fuzzy, ill-defined and not well-circumstried denoting active inflammation whereas some eyes will have these types of snowballs that are well-defined, well-delineated and are not characteristic of active disease and we'll see that in the clinic and it's something that you will appreciate on clinical examination. And retinal vasculitis periaphylbitis is extremely common in patients with for example MS associated disease and one can appreciate the extent of vasculitis even more subtly and with more accuracy these days with wide field imaging. This particular patient had a fairly benign looking funnest exam with no sheeting as you might have seen on this examination in clinic. So this is a typical ferning type pattern which would be indicative of active disease and in a symptomatic patient and in a non-symptomatic patient needs to be treated. Post uveitis, it is important to understand and describe the primary level of inflammation whether or not the disease is primarily located in the retina such as in a top panel with toxoplasmic retinocoroditis or something that is multifocal as you see in the bottom which is a multifocal corditis associated with tuberculosis which is located in the chloride and the color, size and shape of the lesions are also helpful descriptors and help you in the diagnosis. So here for example, we have an amyboid or helicoid lesion emanating from the optic nerve which is characteristic of serpiginous corditis. This example are placoid lesions at the level of the pigment epithelium mostly occurring in the posterior pole which is a typical of the patient with ampy. These are yellow, orange, ovoid lesions predominantly seen in the posterior pole and nasal retina as one sees in their corotal lesions that are seen in burrachite retinocorodopathy. These are more punched out lesions associated with multifocal corditis and panneuritis. A very similar picture can also be seen in patients with histoplasmosis associated disease. This is a little bit more difficult to see but one can see these evanescent white dots surrounding the fovea and a granular looking macular in a patient with multiple evanescent white dots in the bone. Here is a list of the major infectious entities. The most common infectious posterior uveitis is toxoplasmic retinocoroditis which we'll discuss a little bit more in detail later but this is in an immunocompromised patient is characteristic of a patient with CMV retinitis. This is a non-infectious entity starcoidosis which has inflammation of vitreous in the retina, macorrhoid and the blood vessels and in this particular patient this is Brown as I remember the name in the anterior chamber. So this would be a panneuritis. And this was a most unusual patient with a kind of a cross between api and surpritidinous so-called relentless placoid multifocal corditis part of the spectrum of so-called white dots syndromes which again will be the subject of another lecture at some point in time. So these are the major entities and then there's panneuritis. So panneuritis affecting all three chambers. Always think about syphilis, BKH, Baychats, starcoidosis and of course sympathetic ophthalmia and this particular example is one of syphilitic corditis. This is an example of a patient that I saw in Saudi Arabia. You can see that they have stria in their retina and a very dull reflex and on flourishing angiography, pinpoint areas of leakage and pooling in the retina which is characteristic of exudative retinal detachment associated with BKH syndrome. And this is a patient with sympathetic ophthalmia with entities which is almost identical pathologically to BKH. So here we now have a language which we can kind of talk to one another about when we're discussing patients in the clinic or on the phone so that if you describe to me a patient with unilateral alternating relapsing anterior uveitis, the first thing that's gonna come to my mind is an HLA B27-associated disease. Whereas if you say I've got this patient with a unilateral focal retinitis and vitritus, the first thing I might think about is toxoplasmosis. An acute peripheral multifocal retinitis I'd be thinking about an infectious disease with an necrotizing retinitis. Whereas acute multifocal retinitis has a much larger differential diagnosis including the white dots and bones. So you can see that once we agree to agree on what we're talking about, we can actually communicate with each other in a much more effective fashion. So since we're in the business of vision in ophthalmology, we, the clinical assessment, of course involves visual acuity, intraocular pressure and then some type of system for grading inflammation. So again, the sunworking system didn't really come up with, but actually agreed to utilize the following system of grading anterior chamber cells for several different systems that were in use at the time. And that the actually number of cells in the anterior chamber on a one by one millimeter slit is counted from and is graded from zero to four plus. And there is actually pretty good inter-observer variability by one grade. Likewise, anterior chamber flare, which represents leakage of protein from compromised vessels is also graded on a scale of zero to four plus depending upon the degree to which the flare as you can, the analogy being this moisture in this effer rain in this forest obscures the landmarks, the anatomic landmarks in the anterior chamber. Vitrious haze is a little bit more complicated and there is no really good classification system yet that we have for vitrious haze, although many people are working on one that is based on OCT. This is what we currently use, which is the NEI grading system, which grades vitrious haze on a grading score of zero to trace to one to four plus depending upon the degree to which it obscures the major structures in the poachers segment. Obviously, media opacity will confound this grading system. And then another item in which the sun working system, working group could not reach consensus with sun vitrious cell scoring. Again, this may be addressed by OCT in the future, but it's kind of absurd to count 50 to 100 cells as two plus vitrious cell, but nevertheless, people do grade vitrious cell and to get an idea of vitrious cellular activity. I think that it requires a certain amount of experience and seeing a couple of patients with this, but one will see that if you have an active coreo-retinal lesion, particularly a retinal coreo-retinal lesion like tonsilloplasmosis, not only frequently, you will see vitrious cells over the inflamed area. Likewise, in patients with anterior uveitis, I'm sorry, very severe anterior uveitis or intermediate uveitis, one can see vitrious cells in the gel of the eye. Judging whether or not these cells are active or not requires a certain amount of finesse and experience. There are lacunae or clear spaces in the vitrious gel that frequently form in patients with uveitis and cellular activity within those lacunae would be more indicative of cellular activity because patients with chronic inflammation will have cells and pigment that are stuck onto the vitrious fibroids which do not necessarily denote activity. Likewise, snowballs or collections of inflammatory infiltrates that have fuzzy borders rather than well demarcated borders would be indicative of vitrious cellular activity. So we touched on this. The importance of the uveitis workup is really to exclude an infection. You don't want to treat an infection with a steroid. You want to identify systemic diseases impacting health such as B27-associated disease or sarcoidosis, guide appropriate treatment, and then provide prognosis information for the patient. So there's a difference, for example, between telling a patient they have a HLA-B27-associated anterior uveitis and a patient that has birdshed retinal cordopathy because the prognosis and the treatment for each of those is vastly different. One requiring just topical steroids which usually gets better at one attack per year. On average, it would be 27-associated disease whereas birdshed retinal cordopathy really needs to be treated if the patient is symptomatic and has disease that's active at the outset with steroids and immunomodulatory therapy with the commitment therapy for at least two years. So the workup should be selective based on the history and the working differential diagnosis. It should be staged proceeding from the more common to the rare. Always consider syphilis sarcoid and tuberculosis in your differential diagnosis that is considered but not necessarily always order tests for Lyme disease and non-demic area or TB. And then consider math grade syndromes in your differential diagnosis. Always have that in the back of your mind because you can be fooled sometimes. You may be dealing with actually in the plastic process that looks like it's inflammation in the eye. If there was one test that I had to order for UVIS it would be serological tests for syphilis which we can talk about a little bit more detail both an RPR and a VDRL but nowadays there is a reverse sequence algorithm employing enzyme immuno assays which are more sensitive followed by RPR for confirmation of the diagnosis. And then a TPP, a trepanemial Collidum Particle Glutination Test as a tiebreaker which confirms the diagnosis of syphilis. Lyme, I've never diagnosed a case of Lyme disease in Utah although my colleagues that in Indiana and in New York and New England do make this diagnosis, not a frequently. So where you are and the prevalence of the disease in the population is important. So we have, you know, PPD and quantiferon goals which are good screening tests for patients with for tuberculosis. Okay, so they have a reasonable sensitivity and specificity but the problem is that the incidence with the prevalence rather of the disease in the general population is low and so the positive predictive value of this test is poor. So that one would not routinely order a PPD on every single patient with uveitis but rather one might order a PPD in diseases in which you think that it might be more likely such as patients that present with choral tuberculomas seen here or ULS disease or prudence chorditis or patients that have significant exposure risks are those people in whom you are considering placing on immunomodulatory therapy or an anti-TNF therapy because that is mandatory to exclude that diagnosis as you could make a latent tuberculosis, whole minute. There are other tests that are reasonable to get in a targeted fashion based upon your examination. For example, a patient with a swollen optic nerve and a macular star, one once it would consider neuro-retinitis. The differential diagnosis for that is long but the most common cause is an infectious agent caused by Bartanelle Hensley or Quintana. In the fall, West Nile virus makes its appearance from New York to California and we have had several patients with West Nile disease. So if you see a patient with typical targetoid lesions of West Nile, particularly a patient with diabetes or a patient with any signs of an encephalitis, you may be the person to make that diagnosis. PCR of the aegis or vitreous is extremely helpful in the confirmatory diagnosis of necrotizing retinitis due to herpetic disease as you'll see. The routine screening of the serum is a really limited value. For example, for BZB and HSV or TOXO is they're so prevalent in the general population so it really doesn't give you any, a positive test doesn't really give you any useful information. A negative test, on the other hand, is useful actually in a patient with TOXOPosmosis. Again, as I was saying, 50% of the patients that present with acute non-grinulomus anterior ureitis will be HLAB 27 positive. So that is a useful screening test for that entity, especially since between 33 and 83% of those patients will have an undiagnosed, either axial or non-axial spondyloarthropathy. So you can be as an ophthalmologist, the person that identifies the systemic disease and I queer the patient as to their symptoms and if they have any symptoms, we send them off to rheumatology. ANA likewise is a very poor screening test for all uveitis patients. ANA positivity is useful in a patient in whom you suspect the diagnosis of systemic lupus or thymotomosis or in children that have anterior uveitis and joint disease as oligoarticular uveitis and ANA positivity confer high risk for disease. Beta urinary beta-2 microglobulin and serum creatinine are a good screening test for patients simultaneous bilateral anterior uveitis for the diagnosis of tubular interstitial nephritis and uveitis syndrome. And then ANCA and rheumatoid factor in CCP are useful tests and are imperative in patients with scleritis associated disease as one wants to rule out small vessel vasculitis which can be associated with severe necrotizing and metanitis and associated with increased mortality in those patients. Just a word about sarcoidosis. Sarcoidosis can do anything it wants. As you know, we see a fair amount of sarcoidosis here, not in the typical population that is defined in the United States which is an African-American population but more in the Scandinavian population so we see a lot more acute sarcoidosis. Asin lysis and IM are typically ordered for patients with this but they don't really have very specific predictive value in the diagnosis. If they are very high, they are helpful in the correct clinical diagnosis but they can be falsely elevated, for example, in children that have high aces or falsely low in patients that are on ACE inhibitors. The most useful screening test for sarcoidosis is a chest X-ray. So bilateral hyaluridinopathy is a very useful screening test for chest X-ray and it is a presumptive diagnostic tool. So that would be probable sarcoidosis. In patients that have clinical signs of sarcoidosis and a negative chest X-ray and you still have a suspicion of that, a chest X-ray is also very useful. In fact, it's suggested that patients over the age of 40 that have signs of idiopathic uveitis be screened and are suspected of sarcoidosis be screened with a CT scan as sarcoidosis can be diagnosed in a fairly high percentage of those patients. Again, sarcoidosis is a tissue diagnosis. You can obtain tissue from the lungs and lymph nodes but you can also look at the skin. One can take a biopsy from the skin or a conjunctile nodule and make the diagnosis. Likewise, the lacrimal gland. You may be asked to do a non-directed conjunctile biopsy over the diagnosis of sarcoidosis but this has limited value. Ancillary imaging are employed frequently including chest X-ray, sacroiliac films, GT, MR in patients with neurological disease or MS, particularly immunocompromised patients with toxo. B-scan including UBM are very useful modalities. You wouldn't want to have a surgical embedger in the B-scan in the eye below. And then UBM is useful in patients with arthritis associated with lens dislocation or malposition, cyclic membrane, celiac detachment. And in trying to discern the differential diagnosis of a wide patient's hypotenuse, which is a supervexing problem in uveitis. Utilize fulfilled and multi-pocal ERGs, visual fields, particularly in patients with bird shot and in patients with other more uncommon diseases such as azore or autoimmune associated uveitis. We frequently will in patients with posterior disease from intermediate uveitis to or those with diseases of the retinine chloride employ multimodal imaging. Fluorescene angiography is alive and well, I think in the uveitis world. It is a very highly sensitive modality for the detection of vasculitis and hence disease activity. It's very useful in delineating areas of non-profusion which may require laser treatment. ICG angiography is probably employed much more often in uveitis than it is in retina, particularly in patients with white dots syndromes as the chloride is frequently affected in these diseases. OCT, as you know, has revolutionized our ability to follow patients in time and provide quantitative information on macurodema but also to discern whether or not the edema is mechanical or inflammatory. And then OCT, I think will be much more helpful and in my practice has been useful in determining whether or not patients have vascularized lesions in the back of their eye associated with multifocal corditis or PICC, which we know are associated with a high prevalence of coronuvascularization. And then finally, when it's autofluorescence is a useful tool particularly in diseases involving the chloride and pigment epithelium such as the white dot syndromes, it is a way of noninvasively following patients to detect expansion of atrophy in areas where the autofluorescence is black or where there is hyperautofluorescence in which it is thought that this represents activity in areas in patients with multifocal corditis or inflammatory diseases affecting the pigment epithelium. In retina and in a UV-itis pattern recognition is important but as you can see here, things aren't always what they appear to be. Seeing things as they really are is a real trick in life if not in retina or in UV-itis. So when confronted with a patient like this, is this a non-infectious vitritus? Is it a necrotizing retinitis or are we dealing with a introncure neoplasm? So in cases like this, and particularly if the patient is immunocompromised, it is really difficult to tell just based on what you're seeing what you're dealing with. So in UV-itis of unknown etiology, particularly when the presentation is insufficient to make the diagnosis the present or it's atypical or you have treated the patient if it had a responsive therapy that is either inadequate or atypical when they get worse, one needs to rethink your diagnosis and suspect an intracurricular infection or malignancy. So biopsy really has the opportunity to change the management of your patient and affect their systemic health. And really the techniques that we employ as we will discuss later in other lectures including anterior chamber of paracentesis in eyes with necrotizing retinitis when that is really the only when the differential diagnosis is narrow, when the differential diagnosis is much broader in which you have to consider bacterial and fungal infections, a three-port, the tractomy is much more useful in that it allows larger volumes, dilute and undilute specimens and more control removal of the vitreous. One can also, I think it performs a therapeutic function in calming the eyes down in some eyes and allows one also to perform retocorto biopsy. So what is the key if it's infectious, non-infectious or neoplastic really? I think before you have stick a needle in anything in accurate and thorough history, complete examination and what is the appropriate clinical context and then employ a laboratory and invasive testing to confirm your diagnosis. So that I think is a really key philosophical approach to UVIS. So just on to treatment. I just wanna kind of review a therapeutic approach to patients with non-infectious UVIS and give you some data on where we're at with that, the appropriate use of local and systemic corticosteroids as initial and adjunctive therapy, the indications and complications and long-term benefits of immunomodulation used initially or as steward-sparing and then give you some idea of the new biological therapies and therapeutic delivery systems that we are currently using or that are going to be in the clinic shortly. So as we've said, the most important aspect of treatment is to establish a diagnosis, right? So you don't wanna treat infection with steroids. You wanna know what the anatomic location that will determine what you're going to be treating with, rule out infection and malignancy based on and then the pattern of the information. So we wanna treat an infection with antimicrobial therapy, employ aggressive but appropriately staged anti-inflammatory treatment in a step ladder fashion for non-infectious diseases. We want to employ immunomodulatory therapy at the outset for disease-specific treatments for those entities that require it and always be willing to take three or four steps back and reconsider your diagnosis if you have an eight typical response treatment or if new findings emerge. So every examination is an opportunity for a new diagnosis. So this step ladder algorithm consists of first corticosteroids by whatever means is necessary and depending upon the anatomic location of the inflammation from topical periocular to systemic steroids, then a low threshold for the employment of immunomodulatory therapy either as first line or as a steroid sparing therapy using conventional or biological agents. And I'm not gonna get into therapeutic photography but this may be a modality that is employed later. So basically we wanna eliminate inflammation, treat and reduce and prevent structural damage that limit vision, improve function and avoid and systemic and potential complications occur and systemic complications. So you wanna cake and eat it. And I think in a lot of cases we can do that. So the round choice of medications really determined by location, the laterality, the severity and the complications of the inflammation and the systemic health of the patients. So the topical steroids are usually sufficient for anti-UVIs except in children with JIA and then periocular individual systemic corticosteroids with or without immunomodulatory therapy can be employed for the rest of those diseases in the back of the eye. A word about topical steroids. There are a bunch of things that we can use, prednisone, durazole, the idea is to start off if you have inflammation that's one plus or greater with high frequency, QID to every two hours and then taper and keep them on a high dose of steroid, frequency of steroids until they turn the corner and then begin tapering them. Cycle pleads them to for pain management and to move the pupil. I prefer cycle pentallate to move the pupil rather than atropine which keeps the pupil in a fixed dilated position. I think maybe associated with more frequent association with postures sneakier. And you can stop cycle a feature once the inflammation has gone down to zero. Local steroids are very useful in acute remitting non-infectious intermediate posterior and panneveitis rather than chronic diseases. So we use them as primary treatment or as adjunctive therapy in patients that are on systemic treatment. It is frequently more often employed in patients with unilateral rather than bilateral disease to avoid bilateral injection and most often associated with uveatic macular edema. Contraindications of course would include any infectious uveitis. You can't take a depot out of the eye once it's in there. Scleritis is a relative contraindication. There are cases in which subcontractile steroids are very effective in non-necrotizing supporting steroids. And then one needs to be cognizant as to whether or not this patient is a steroid responder or not. Be willing to and be ready to treat it. So there are a couple of routes. We can perform a periocular steroid injection either as a subtenons injection or an orbital floor injection which has been shown to have good effect on the resolution of inflammation and macular edema. And there is little tachyphylaxis to that so there are repeated injections can be useful. We can inject it into the eye which also is effective in treating macular edema, improving vision and geriditis as well as no tachyphylaxis with repeated injection but a greater percentage of auger complications such as elevated intraocular pressure and cataract. We have the azure dex, dexamethasone delivery system which has shown improvement of visual acuity, vitreous haze and macular edema in both adults and in children. Is equally effective in vitrectomized and non-vitrectomized eyes it may be actually preferable in a vitrectomized eyes it's non-dispersive. And it is not as originally touted is associated actually with cataract formation and elevation intraocular pressure upon repeated exposure as one might expect. Just a word about UVic macular edema it is the most common effects also types of UVitis and it's the leading cause of visual impairment in patients for UVitis and about 40% of the time and in the must trial which I gave you guys to read 40% of patients still had persistent or unresolved macular edema at two years and about two thirds of them that were assigned to the systemic arm required at least one adjunct of corticosteroid injection. So there's this need to treat macular edema and usually it is treated with periocular injection. So the principles for treating macular edema are to control the underlying inflammation or infectious disease. And then persistent or recurrent edema is usually treated adjunctively either with regional or regional corticosteroids for unilateral disease or systemic corticosteroids sometimes in patients with bilateral disease and then modification of risk factors that we know are associated with this complications just smoking. So taking together it seems that intraocular injections intervitrial injections may be more effective than periocular injections and maybe associated with more elevated intraocular pressure and cataract. There is additional benefit with repeated injection and a lower relapse rate of macular edema in patients that are on concomitant systemic therapy. So this was actually studied in a trial that was published last year that we were a part of called the point trial. And this compared the best initial treatment whether it be periocular, intravitral or azure dex for patients with either active or inactive muviatic macular edema. And to make a long story short, it showed that all treatment groups did improve in terms of central macular thickness and best corrected visual acuity, but both intravitral approaches that is intravitral trampsilone and dexamethasone with the azure dex were superior to the periocular injection in terms of improving and resolving macular edema. There was a modest increase in intraocular pressure which was greater in the intravitral than periocular group. And the intravitral implant was not inferior to intravitral trampsilone. In fact, it may be, there was a signal that was not statistically significant to show that it may be actually a little bit better. So all in all, it seems that if you have a patient with severe central involving macular edema than an intravitral approach is probably the better way to go. There are exceptions. The problem with regional corticosteroids is that you have the cumulative risk of cataract, intraactive pressure, and then endoplaminase. They're relatively short acting and less effective for chronic inflammation. So an attempt has been made to come up with sustained delivery systems such as the Redicer, which is surgically implanted into the back of the eye. In the operating room, which delivers flucillinone into the eye for two and a half years and is associated as one would expect by marinating an eye and steroids for two and a half years, a high instance of cataract, elevated intraocular pressure and the need for incisional glaucoma surgery in 40% of patients. An alternative to this is an office-based flucillinone set nine insert, which has been approved by the FDA or UTIC. This has been shown in clinical trials to have significantly lower recurrence rates and improve visual acuity with less adjunctive systemic treatment by the higher risk of cataract surgery and elevation of intraocular pressure. This is 12 month data and there is now three-year data available, which I think I sent to you, at least the one-year data. In terms of macrodema, there is pretty good resolution of macrodema in some eyes who undergo UTIC versus sham. So I anticipate that the major use of this will be as adjunctive therapy in eyes with persistent macrodema, although that is not the label indication for that. An alternative delivery system, which I think will become available is a supercruital delivery of prime soma into the eye, which was studied in the peach tree trial in which supercruital trimesilone was delivered at day zero in week 12 versus oak sham. These patients, of course, were treated with steroids based on certain eligibility criteria, but the final endpoint in terms of improvement of best corrected visual acuity by three lines was obtained and 47 versus 16% of sham eyes. And there was really a robust decrease in central macular thickness after one injection, which was noted by four weeks in the CLSTA treated arm. Just so you know, intraocular methotrexate has been employed not only in the use of patients with intraocular lymphoma, but in patients with uveitis and in macrodema, showing decrease in uveitis and decrease in central macular thickness at three and six month time points and improvement of visual acuity, which corresponds with those points. Likewise, introvertual anti-veget therapy, both with rhinovizumem and bevizizumem have been used in small pilot studies, which have shown improvement of visual acuity and decrease in central macular thickness without any systemic side effects. There is currently an ongoing trial of which we are participating in our lead vanguard clinic called the Merit Trial, which is looking at the relative safety and efficacy of eyes with persistent or recurrent macrodema with controlled uveitis and comparing the odds you dex implant to nonsteroidal alternatives of anti-veget in the form of recentes and introvertual methotrexate. So stay tuned for that. Corticosteroids have a very bad reputation, but really are the centerpiece of treatment of severe disease. And when used, I think appropriately can be extremely useful in putting out a fire. You certainly wanna put out a fire with a fire hose rather than with a squirt gun. And I think that using prednisone in an appropriate fashion does that. Usually we start out with a dose of a milligram per kilogram per day, usually around 60 milligrams, which has been shown to not be associated with a dreaded complication of aseptic necrosis thermal head. And then therapy is then kept at that level and then tapered depending upon the clinical response. One can also pulse it with IV methylprednisone, as you know, from the optic nerve treatment trial. And one must always keep in mind that many side effects of steroids, including loss of calcium from the bones, particularly in post-menopausal women. So we keep patients honest by weighing them, looking at their serum glucose at baseline and fasting lipids annually and lung densitometry annually. You all read a paper on the guidelines for the use of immunosuppressive drugs. That includes failure of systemic corticosteroids on the acceptable side effects of steroids. Disease is known to be poorly responsive to steroids or a requirement of systemic steroids for greater than three months of more than 7.5 milligrams per day because it is thought that chronic steroids, and it is known that chronic corticosteroids at 10 milligrams per day are associated with at the long-term over 10 to 20 year period of cardiovascular side effects, whereas those doses at five milligrams are not. In that paper, there are certain disease entities in which immunomodulated dilation was thought to be, it was commenced at the onset of treatment, because the natural history of those diseases are known to be poorly responsive to corticosteroid monotherapy. They include Bechette's disease, severe autoimmune mucous membrane, pampagoid, serpigenous, necrotizing scleritis, sympathetic ophthalmia, and BKH. There are other diseases for which corticosteroids are the first-line treatment, but immunomodulation may be begun very soon after the onset of the disease. They include patients such as Birchot, multi-blogel cordycein, pan-uviatus, intermediate uviatus, and JAA-associated Zs. So I like to think about immunomodulation in two large categories. There are the conventional small molecule therapies, and then there is the biologics. So again, thinking in categories, the conventional treatments, we have anti-metabolites, including methotrexate, mycophenolate, and azithioprene, which inhibit DNA or RNA synthesis by inhibiting various purine metabolites. There are the T-cell transduction or chalcinary inhibitors, such as cyclosporin, tachylimus, and then the alkylating agents, such as chloramucilin from cyclophosphamine, which are used less frequently these days, given the side effects of these medications and the availability now of biological medications. So the treatment principles include acute care with steroids using large enough doses soon enough to put out the fire and then using steroids either systemically or as an injection as a bridge to allow conventional in-man modulation to take effect. You have to know the response time of these medications. So for the conventional small molecules, it takes two to three months for methotrexate and mycophenolate to become active. So as you were coming down on steroids, the conventional agents should kick in. We want to monitor the patients for potential toxicity depending upon the drug and have laboratory evaluations at baseline and regular intervals to monitor toxicity, including leukopenia and liver function tests and Bionic creatinine, depending upon the agent use. So for chalcinary inhibitors, tachylimus and cyclosporin, we would certainly check their Bionic creatinine. Just to give you an idea of the efficacy of single agent therapy, the site study, which was a very, which is an ongoing large, multi-centered retrospective, so five large uveitis practices in the United States showed that monotherapy with these medications is pretty good, okay, but not curative, okay? So about two thirds of the time, they are helpful, are steroid sparing and the remission rate is terrible with the exception of patients with cyclophosphamide. So we know that the alkylating agents can induce a remission in patients with severe disease. They are effective in certain disease and this has been shown by these studies here. I just put them up there to show you that particularly in JIA associated ureocyclitis, the single agent therapy can be associated with improvement in vision and decrease risk of visual loss and complications in this cohort. Similarly in patients with bird shot, multifocal, VKH and serpiginous, both conventional and cytotoxic agents have been shown to be useful for these agents. The MUST trial was a randomized controlled trial which the literature of which I gave you guys to look over, which studied the reticent implant versus a standard protocol using these conventional agents. And the outcome at two years, which was the designated outcome for the study showed that the visual outcome was similar from both groups but that inflammatory control was achieved at a slightly faster degree with the implant than with systemic therapy. It also showed contrary to the prevailing kind of bias that systemic therapy was actually very well tolerated and that patients did very well on that and that as one might expect, there were many obscure complications including cataract surgery and the need for incisional glaucoma surgery with a reticent. The MUST follow-up study at seven years also had a very interesting result and that by about five years, there seemed to be kind of a switch across over in these curves. So such that by seven years, there was a visual favor at the, visual acuity was better by a significant degree in eyes or on systemic therapy than the reticent implant. And that there was a mean loss of six letters in the implant group and this was thought to be due to reactivation of coriorentinal lesions. There was an incidence of, you know, visual loss down to 2,200 of 22% versus 13% in the implant arm versus systemic arm. We could debate this for a long time but we won't right now because I think there's a role for both systemic therapy and the implant in UVIs. These graphs just show that UVIs activity increases in the implant arm in the yellow arm by about five years and that macurodema on the right was initially statistically significant only at about six months in the implant arm and then that advantage was lost in about five years. So I think we also know just as in two years that there was a high incidence of acute complications in the implant versus systemic and that there were very few systemic adverse outcomes in the systemic group which is reassuring for people that treat patients with systemic disease so that the long-term outcome favored systemic versus implant therapy and that despite the fact that it had superior initial control of the implant there were greater than expected. There were expected on the ocular side effects but without systemic side effects. So what are the implications of that? The implications really depend upon the patient, okay? I think we might wanna start out with systemic therapy initially in patients but there are going to certainly be patients that either cannot tolerate systemic therapy cannot tolerate systemic corticosteroids that will do better with the implant. The principle I think and the lesson from this study more than anything is that continued sustained control of the inflammation is the key to good outcomes whether or not you have an implant in the eye or you're treating the patient with systemic therapy. Part of the problem with the implant therapy is that the implant there was no exchange of the implant that was mandated in the study past two years. So there may be a bias in these results but one has to be willing to take the implant out or put another one in. So biological response modifiers are the other classification of drugs. They are the kind of revolution in our treatment but not a panacea. This is just a small list of some of the biologic agents that are being used in UVIs today. I attended a lecture last year in which Jim Rosenbaum said that there were over 200 biologic agents that were being studied in various human diseases, which is mind boggling. But the ones that you will most likely encounter include the TNF inhibitors, including infliximab which is a chimeric monoclonal antibody to TNF. It is delivered by IV infusion. It's a chimera so that you can form antibodies to it and so methotrexate or some other immunomodulator usually administered with it. Adalimumab is a humanized monoclonal antibody against anti-TNF. It is delivered subcutaneously and has been approved by for intermediate panneuvidus and posterior vest in 2016. One can also form antibodies to Adalimumab. There was an expert panel on the recommendations for the use of infliximab and Adalimumab in which the overwhelming, sorry, majority was that the, that patients disease should be treated initially with an anti-TNF and that second line agent would be a failure of methotrexate or a small molecule for GIA and then a potential second line for agents that fail anti metabolite, calcineurine inhibitor or IMT failure for severe posturing panneuvidus. I distributed the visual one and visual two results. These were pivotal randomized controlled clinical trials for both active and inactive UVIS which led to the approval of Humira for the treatment of non-infectious posterior UVIS. One of the most important developments I think in the treatment of UVIS. So what are the concerns? Well, we know that TNF inhibitors can lead to an increase in infections such as TB and histoplasmosis so that all patients are screened with a PBD and quantifier and gold or an ELISA spot. There are reports of increased risk of lymphoma associated with these medications depending upon the literature that you read and increased risk of demyelination so that anybody that has a history of multiple sclerosis or parsplanitis which we know is associated with about 15% increase in the risk of demyelinating disease should have an MRI scan or if there are lesions on MRI scan and should not receive these medications. There is a variable response to anti-TNF therapy so there are non-responders, there are people who can develop antibodies and there are treatment related side effects. So what are our options? Well, there are a bunch of other anti-TNF agents. If a patient fails to humor, we might want to try infliximab because you have more flexibility in terms of the dosing of the medication so you can go as high as 20 milligrams per kilogram. There are other anti-TNF medications that may be effective, whereas Adelumab may not be. And then there are third-line agents which are currently being used such as Orencia or Bodicept, Rituximab, Anakinra, Sarlumab, and Tocilizumab. Rituximab, I just mentioned to you, is an anti-CD20 monoclonal antibody. Interesting that it works on B cells but actually is very effective in patients with refractory, scleritis, and auto-inflammatory disease and in patients with bucus membrane, Pemphagoi. And in some patients with refractory, uveitis due to JIA. Interferons have been interferon alpha-2a. And there's a wide experience with the use of this medication in the European experience for Bacchus disease, but not so much in the United States. And it has been effective in the treatment of recalcitrant macular edema. Interferon, intravenous immunoglobulin has been also employed in patients with autoimmune type of disease. Emerging data on newer agents such as ectema or Tocilizumab, which is directed against the cytokine anti-interleukin-6, shows that in case series that have been shown benefit in patients with refractory, uveitis due to JIA and Bacchus disease. And there have been two studies that have shown that it's been effective in patients with macular edema. So what about the risks, the systemic risk? This is kind of old data and it needs to be updated, but it's not been published yet. And that we pretty much know that the anti-metabolites and T-cell inhibitors, at least in the site database, are not associated with increased risk of mortality or cancer associated with the use of these medications. The TNF inhibitors at least in the site study did suggest that there's increase of mortality and cancer mortality associated with TNF inhibitors, but it was a very small number of patients and subsequent data suggested that this is not the case, at least for accurate inflammatory disease. You should be aware that there is also an Australian study that did show a significantly increased risk of malignancy in patients treated with IMT, but it lumped all IMT together, including cycloplasma and chlorine missile. And then we also know that there's a significantly increased risk for non-melanonics in cancer in patients that take medications such as mycophenolate and in every patient that lives in Australia. So that also may be a bias to that study. So to modify the prognosis, we have to have effective and sustained suppression of injoc inflammation for the early introduction of steroid spearing, immunomodulatory therapy, or sustained implantable local therapy if one wants to accept the doctor's side effects of that medication and indicate it for that patient. I think it's going to be key to identify and surrogate markers for complications of visual loss and then vigilant post-marketing surveillance of these new agents. And of course, randomized control trials are really useful to inform our treatment decisions as had been performed in studies such as the must the point merit and the peach tree trials. So I thought I would use the rest of the time to go over stuff that might be a little bit more interesting for you guys. I hope that provides a very broad overview and that the information that I provided for you supplements the material that I presented to you. In the past, I've split this into two lectures. It's an awful large amount of material, but it's a very broad brushstroke of the approach to the diagnosis and treatment of UVS that we will see on a case-by-case basis when we rotate in the clinic. Are there any specific questions about this that anybody would like to raise? Okay, so this is the audience participation time. So you can unmute yourselves if you like. So here we have a patient with anterior uveitis and macurodema. What is the anatomic location of this disease? Interim uvea to posterior pan uveitis? Anybody? Still just anterior? Yeah, anterior. And why is that? Because CME doesn't define posterior uveitis. You'd have to have retinal like vasculitic or croidal involvement. Excellent. That's very good, Cole. So structural complications, such as vasculitis, macrodema, or optic nerve involvement are, do note, posture involvement that define posterior uveitis. That's precisely correct. So here we have a patient with anterior uveitis, some, a little bit of anterior uveitis, patritis, macrodema, dis-smelling peripheral vascular sheathing, intermediate posterior pan uveitis. I think this is intermediate. Okay. But, well, I just don't see anterior, I see the vitritus, but then the CME and dis-smelling, and I think the vasculitis don't define it as posterior. Excellent. Very good. How about this patient with anterior uveitis, focal retinal croiditis, vitritus, and vasculitis? Posterior uveitis or pan uveitis? Sounds like pan uveitis. Yeah, I think so. That's exactly right. So toxoplasmosis usually can produce, is defined usually most often as a posterior uveitis, but it can produce a pan uveitis with granulomidus inflammation in the anterior chamber and a very specific type of vasculitis called cura-lesis arteriolitis, which have these very fine plaques on the arteries. Okay, so here's a 27-year-old white male presents to you on call, pain, redness, photophobia, ciliary flush. Recurrent episodes, this isn't the first time this has happened to him, got lower back pain. So what do you think in diagnosically and how would you wanna work this guy up? HLAB 27. Okay. So that would be the first thing, HLAB 27. So half the patients have HLAB 27 and they don't have arthritis. Do you think this patient may also need a referral to rheumatology or something? Do you get max or experts to guess? Okay, so the differential diagnosis of anterior uveitis, you're right, V27-associated disease in about 50%. Armpetic, lens-induced, base jets, drug-induced, TINU, trauma, idiopathic. You wanna ask the patient about back pain, oral and genital ulcers, right, and base jets disease, skin lesions, arthritis. There's a low percentage of patients with B27-associated disease that may have inflammatory bowel disease. So you might wanna ask them that and then of course, medication use. You definitely wanna get an HLAB 27 on this type of patient, sacroiliac as opposed to lumbar sacral films. And in a patient that might have bilateral simultaneous disease, 82 microglobulin is a good screening test for TINU. I always investigate patients for syphilis. So how are we gonna treat this guy? First episode, anterior uveitis. Most of the time, intensive topical steroids work. 90% of the time, about 11% of patients with B27-associated disease can become chronic. I think the importance of referring the patient to a rheumatologist, particularly if they are symptomatic, is that at least in more recent paper, 80, somewhat, 82% of patients at either axial or non-axial joint involvement that were with anterior uveitis. If they're HLAB 27 positive, there are chances of having ankylosing spondylitis or high and there is disease modifying traumatic treatment available to that patient so that you don't end up with kyphosis at the age of 50. Okay, so you're on call, okay? And you're confronted with this. What are we looking at? Anybody? So there's definitely a hypopion and then also just looks like, at least in the picture on the left, there's a little bit of maybe AC cell inflammation and a lot of injection as well. Okay, and what about on the right? Is there anything else in that hypopion? I'm not sure. Okay, to me, I think there's a little bit of blood in there too, very bottom of it. Gotcha. Okay, so what are you thinking about? I, you know, in terms of differential diagnosis of hypopion uveitis. Right, highest in the differential, probably be bishats. That would be high. Is that the first thing you think about? No. And I saw like city Utah. HLA B-27. Okay, HLA B-27. I think bishats certainly is in the differential diagnosis. No question about it. But you would need to ask questions that would be appropriate to bishats disease, right? What is their ethnicity, their drought, where in the world are they from oral, genital ulcers? That kind of thing. What else can... What else would you be concerned about? You're on call, you want to make sure, how are you going to... What other questions are you going to ask this question? Do they use IV drugs? Do they have any fever, sepsis, bacteria? And so why would you ask them that question? Ariana said endophthalmitis. I'm sorry, I didn't hear you yet. So endogenous endophthalmitis, right? So that would be endogenous endophthalmitis, right? IV drug abuse, have they had parenteral alimentation, right? Have they had a GI procedure recently? How else can you get this type of iridus if it's not endogenous? You can have exogenous endophthalmitis. You need to ask about like, how could the procedures that they've had any kind of surgery? Yeah, sure. So postoperative, right? Cataract surgery or the person on the left is pseudophagic, you know? So postoperative disease, what else can give you a high-propion? We don't see it here, but what piece of history would you ask the patient? Something leukemia could give you some kind of looks. Excellent. That's really, really good. So you can have a pseudo-hypropion, okay? Or a pink hypropion in patient with AML, for example. What else? Say this patient's a prisoner, you know? Or... A tuberculosis. Pugilist, you know? So trauma, right? I mean, trauma can give you a hypopia on uveitis, can't it? Just saying. And we don't see anything on the surface of the cornea, but can a cornea ulcer give you a hypopia on uveitis? Yes. Yeah. Or a karate uveitis. Okay, so this is just, again, another list of stuff, okay? You mentioned many of them. There are drugs that can give you a hypopia on uveitis such as rifabutin. One thing that we didn't mention was lens-associated disease, right? Intimesant lens, and then, of course, the uveitis, you know, syphilis, brucellosis, HSV infection. We've seen patients with ARN with hypopia on uveitis. And then, neoplastic disease. I think Rachel mentioned, you know, neoplastic disease. A blastoma in a child can give you a hypopia which you certainly don't want to put a needle on that eye, and then corneal disease. Okay? Here's a six-year-old female with chronic bilateral non-grinial almost anti-uveitis, a white eye, pushy subcoxer, cataract, and oligoarticular arthritis. What do you, what comes to your mind? J-I-A-A. J-I-A-A. Yeah, J-I-A-A is associated with urinocyclitis, exactly. So, typically, in a white eye, particularly if you see this, you already have a structural complication. Many times, these patients will also present with pushy or sneak-in, which, in and of itself, is a marker for the development of further complications. So, we would want to screen this patient with ANA, see what the age of onset of the disease is, whether it's their duration. Other entities in the differential are listed here. We would want to order up an ANA on this patient, possibly ACE and lysozyme and Lyme, depending upon their constitutional history, and a chest x-ray. So, children can get, they can get anterior uvitis associated with sarcoidosis at a young age. So, how would we treat this patient? So, if they have, this patient looks like they've already been treated with steroids, right? Or they have inflammation in the back of their eye, but more than likely, this PSC is a steroid-induced cataract. So, here, you have a very good case to work in conjunction with pediatric rheumatology to start this patient on immunomodulatory therapy to treat both their systemic disease and to spare their total exposure to steroids. Does that make sense to everybody? I'm resounding, yes? Yes. Okay. Here, we have a 20-year-old female with floaters, decreased vision, quiet AC, snowballs into a snow bank, epistotic parasthegias. We've got macchaedema, vascularitis. What broad category of disease are we thinking about? Intermediate uveitis. Good. Okay, so intermediate uveitis, the differential diagnosis of intermediate uveitis, you wanna think of certain systemic conditions, such as MS, sarcoid syphilis, or TB, or if you're in a Lyme endemic area, Lyme disease, that have very different treatment approaches and they can impact on the systemic health of the patient, right? Once you have excluded systemic or infectious entities, if then this becomes an idiopathic diagnosis. So parsplanitis is a subset of intermediate uveitis, which is idiopathic disease, okay? So they're not synonymous, all right? Are we clear on that? Yes. So intermediate uveitis is a anatomic designation, you know, designation, which can be due to idiopathic disease or associated systemic or infectious diseases, whereas parsplanitis usually has a parsplanis snowbank, but not always and is usually associated with intermediate uveitis. There are some uncommon causes as are listed here. So the workup, we wanna exclude syphilis, sarcoid, TB, Lyme, serology where appropriate and then consider a neurologic workup, particularly in a young woman, you would question the patient about, you know, signs of symptoms of MS, right? So tingling, parastasias, bladder, bowel and condoms or meats, sign. I personally do not order MRI scans on every single patient, every young woman with intermediate uveitis, but if there is any indication that they have any symptomatic disease, I would refer them to neurology and suggest that they scan the patient and I would avoid TNF inhibition in such a patient until I knew that they had nothing going on in their white matter. Wide field fluorescing angiography is extremely useful in kind of delineating the extent of disease. There are going to be patients that do have little areas of retinal vascular staining and sheathing and leakage in their periphery. If there are 20, 20 and no macrodemia, I would watch those patients, but the truth be told, we really don't know what the long-term history of that entity is. So the treatment options for a patient like this, if we're uniocular, would be periocular, intravitural, corticosteroids, right? Systemic steroids with or without immunomonditory therapy, an implant or an insert. And in some patients, maybe you're therapeutic, correct me? Okay, so here are some diagnoses we definitely don't wanna miss when you're on call, okay? So I'm just gonna kind of run through some of these things. I'm sure that many of you know about them and if you don't, that's okay. But I just, shout it out. You got this African male with, what do you see in there? Somebody. I see vitreous haze and also possibly, I can't tell, maybe a snowball. Sorry, the image is fuzzy for me. It looks like there is kind of like a coriorentinal lesion, some hypopigmentation, maybe some vitreous haze as well, almost like a headlight and fog, maybe lesion. Yeah, I would say so. So would you say that the lesion itself is well-defined or are the borders fuzzy? It looks like it could be well-defined but maybe just looks a little bit fuzzy because of the media. Yeah, I'd say it's a little fuzzy. What about the vessels around there? It's a little subtle, but you see a little vasculitis that says here with that. Okay, so I think your description is apt. I would call that a focal retinitis or focal retinocoriditis. So immediately, a diagnosis comes to your mind, right? It could be a number of things and these are the same diagnosis, okay? So in the upper right, you have a satellite lesion associated with a old coriorental scar of toxoplasmosis. In the right, you have disseminated toxoplasmosis in an immunocompromised patient and his autopsy showing a ring-enhancing lesion in his brain in an HIV patient. And then in the bottom left, you have a focal retinitis, retinocoriditis that turned out to be toxoplasmosis in a patient with acquired toxoplasmosis. So the differential, toxo, toxicoriasis, TB sarcoacyphalus, could be an advertising herpatic retinitis or focal bacterial fungal or endogenous endoplasm. These are kind of how you would start thinking about these things and work the patient up. So this particular patient had a very high IgG, which is certainly not diagnosed. Like if this patient had like no insurance and no money, I would call this, you know, probably a focal retinitis and make a diagnosis of toxoplasmosis. It's a clinical diagnosis, okay? A negative serology is useful in that it rules out the diagnosis. But, and a very high IgG might suggest it. But an intermediate level is not so helpful as many people are exposed to toxoplasmosis. And then of course, the presence of IgM or IgA are indicative of acquired disease in adult or congenital disease in infant. You can put in atypical cases, we particularly, we will perform PCR amplification of either the of the aqueous or vitreous, which can be useful in the differential diagnosis. In terms of treatment indications, you know, we're a uveitis service. So most of the time we treat these patients, but the natural history of it is to resolve in time. And that's a small act of peripheral lesions may be observed, only if you can observe them closely. In my experience, patients with toxoplasmosis are not exactly the most likely patients to return to their follow-up appointments sometimes. So I might treat them. But treatment is certainly recommended for lesions that are anatomically abutting visually threatening structures like the macular optic nerve that are producing visually significant pituitous and certainly in an immunocompromised host. The classic treatment regimen is pyramethamine sulfidiazine and folenic acid and corticosteroids in some cases at a reduced dose, usually at 0.5 milligrams per kilogram, after the institution of antimicrobial therapy, if there is significant pituitous associated with this. This is the classical regimen. As you know, pyramethamine is exorbitantly expensive and difficult to obtain these days. One can use clinomycin in addition to that therapy or alone, some people use it alone. More commonly, people will use Bactrum, particularly in a peripheral lesion that's not threatening the optic nerve or macula. Clinomycin can be added for lesions to push for your pull. What I have found that azithromycin and mepron or atopocone are very useful antibiotics with or without pyramethamine for treatment of... So azithromycin with or without pyramethamine, but can be used alone and atopocone, which I am told tastes terrible, although I've never tasted it myself. So there are cases in which I would perform an intervitural injection of clinomycin, particularly if you had a lesion that was very close to phobia and I wanted to get medication into the eyes as rapidly as possible and I was unsure the patient would be able to obtain a prescription for azithromycin and that can be delivered with or without dexamethasone. It's also useful in patients, say for example, for pregnant, in which many of these medications would be contraindicated. Here's another case presentation that you don't wanna miss and this was actually the eye of a patient I saw yesterday and I've known this guy for a very long period of time. He was a really nice guy that kind of a world traveler and it was actually me and Mar and it was referred to me with a branch vein inclusion because and in this picture, there isn't anything super remarkable other than I think a little bit of kind of round glass appearance in his temporal macular. But 24 hours later, what are you guys looking at here? Reduction and vision, what is the location of this disease? Can someone describe to me what they're seeing? Catherine? Yes, it looks like that there's definitely some more more haziness of the media, maybe some vitreous cell or sorry, vitreous haze and then there's also some punctate scattered choreoretinal whitening as well as some scattered kind of blot hemorrhages as well or just like punctate hemorrhages, the retinal whining and hemorrhages is what I'm seeing. So retinal whitening, right? Yes. There's vasculitis. All of the things that you're saying are true, okay? Medias hazier, there are these punctate areas, there's vasculitis in the top, if for temporal, you know, artery there. And then in the bottom frame, there's retinitis, right? Because it's obscuring the retinal vessels, making them stand out and relieve. So whenever you see retinitis like this in a otherwise immuno-competent or immunosuppress patients, what are you thinking about? Are you thinking about a non-infectious GVI as you can sit on for a while or is this more of an occur emergency? No, I think because of a Q onset and the fact that he said that he is not immunocompromised, I'd be worried about porn. Okay, well, you know, I don't know what porn is but I know it when I see it. But, you know, so porn actually is a specific diagnosis in patients with AIDS and they're very, very immunocompromised. I mean, Aaron, I'm sorry. Right, so an necrotizing retinitis. So I just wanna make sure that everybody on the call knows that if you see retinal whitening like this, think that that needs to go through your mind, okay? Because as you can see in 24 hours, this is progressed rapidly, okay? So at the time, he did have a actually broad differential diagnosis based on his travel history who's also on NREL. And so I performed a, the track to me on this patient, which was positive for varicella, confirming the diagnosis of a necrotizing or a pedigree to acute retinal macrosis is something you wanna think about when you see retinal whitening, okay? Initially described in 71, it presents just like this in the periphery with these areas unilaterally in about two thirds of the time with these areas of retinal whitening. This is an even better example of these multiple areas of retinal whitening and retinal hemorrhages that have been described as thumb prints in the retinal periphery. There is a occlusive vasculitis that is associated with this and vitritus is associated with this 100% of the time. So ARN is a clinical diagnosis, okay? You should suspect this diagnosis by your examination, okay? The natural history of this is to rapidly spread from the periphery to the posterior pole and leaving a wake of destruction in its path and a very high incidence of combined regmatitis and tractional retinal detachment. If one is sure that this is, if your differential is low and you think this is ARN and AC tap is very useful in confirming the diagnosis, but one does not wait until the result of the PCR to come back or the vitreous to come along. One institutes empiric therapy immediately, okay? Conventional therapy used to include IV acyclovir. However, and I would reserve IV acyclovir for patients that are immunocompromised or patients that have any type of neurologic signs or symptoms because that can kill people. But an alternative regimen that we use frequently is to use acyclovir or valetrexate two grams, three times a day, which achieves similar concentration of the blood as IV, plus intravitrile therapy with antiviral agents. Aspirin is also frequently prescribed because of the occlusive vasculitis and then following maybe 24 hours after or concomitant with antiviral therapy prednisone under antiviral cover because once you have the infection under control, what really kills the eyes, the inflammation associated with it. As I said, renal detachment is highly associated with it once there's a view. Personally, I think that there is a role for prophylactic battery or laser photo coagulation. And that's all I'll say about ARN, okay? So please have ARN in your mind when you are on call and you think about it. I'm gonna run through this pretty quickly. This is something that you may not see very often. This is a 40-year-old African female immigrant, okay? So right away, this patient is in a different category than your housewife from Provo that presents to your clinic, right? So no fever, weight loss, but she was BCG immunized as a child and a PPD of 15 millimeters with this multipocal coriditis. So you're thinking maybe this patient has TB. This is an example of a tuberculoma associated with tuberculosis uveitis. And I just want to show you that TB, hypersensitivity reaction, TB can be associated with a multipocal coriditis that you see here. So every patient with a multipocal coriditis gets tested for TB. There's a disease that you probably don't see very often that was initially described in young, healthy Indian men called Il's disease, which is also retinal vascularis, an occlusive retinal vascularis that's associated with tuberculin hypersensitivity disease. So in many cases, it's a presumptive diagnosis because 50% of the time you'll have no pulmonary disease. And quantifieron gold is useful in detecting latent disease, but not active disease. And sometimes the diagnosis is made basically on a clinical and exposure history and the chest x-ray in consultant consultation ID. Can be really tough, but I think that patients, for example, with that disease need to be on quadruple therapy. For some of this disease needs to be on quadruple therapy. A patient that is quantifieron gold positive, that has no other indications or evidence on chest x-ray would be regarded as kind of a converter. And if you're considering putting this patient on Adalimumab, for example, they would need to be treated with at least two agents. Okay, so here's another diagnosis you don't wanna miss. So Casanova, Idi Amin, Beethoven and Nietzsche, and at least in my clinic, the church lady all share something in common. Can someone tell me what that might be? It's that. Bichette's? I thought it's the SIF, yeah. It's the SIF, yeah, okay, syphilis, exactly. So syphilis can do anything at once. It seems kind of basic to go over this, but it's always presented at conferences and it always surprises people when it turns out that it's syphilis. But it shouldn't because every patient should be tested for it and should always suspect syphilis. Okay, as I said, it can do anything, but most of the time it presents as a posterior uveitis. And I just wanna kind of make you aware of two different presentations that are very characteristic of syphilis. One is acute syphilitic posterior placoid cordyretinitis that you can see here in this 42 year old guy with a high resexual activity, history of IVDA and previously HIV negative. You can see this placoid lesion in his left eye and the angiogram showing blockage in the area with late standing levels. And that is syphilis until proven otherwise, given his history. So this is taking the clinical history and the morphology together, that's placoid syphilis. The OCT is extremely helpful actually in placoid syphilis in showing these irregular nodular hyperreflectivities at the RPE and sometimes sub-rentinal fluid most of the ELM in some cases. And that goes away with treatment. The other presentation is a pan uveitis with superficial retinal precipitates of these small, creamy migratory lesions that don't leave big scars in the retinitis differentiating that from necrotizing retinitis. So here are two examples of both of an HIV positive and an HIV negative patient with this syphilitic superficial retinal infiltrates. And some of which, some of whom also, which I don't have a slide up, can have a multipropyl type of corditis. The history is important. Here's a 57 year old guy that was referred from neuro with blurred vision. And, you know, on his, when I took a history on him, sores on his hands and his mouth and his tongue, his RPR and FTA were positive. He had syphilis to involve in only his optic nerve. We did, we talked about some of the testing for syphilis. You know, these days we usually screen patients with an EIA and RPR to confirm it with the TPPA as a tiebreaker. The thing to remember about syphilis is that obviously it's a sexually transmitted diseases. Everybody who is alive is at risk for developing this disease and particularly HIV and syphilis kind of co-migrate. And so if the patient has syphilis, test them for HIV and vice versa. The CDC does recommend a CSF evaluation for patients at presentation for syphilis and then six months afterwards until the cell count is normal. The thing about the treatment of syphilis that is critical is that you don't give them, you know, a shot in the butt with benzothermopenicillin is considered neuro syphilitic disease and needs to be treated with intravenous IV penicillin at neurological doses. One more case and I'll let you guys go. This is a lady, a 57 year old woman with kind of a blunted affect who was referred to me with this progressive subrenal infiltration unresponsive to corticosteroids. And I really had no family history and had some weight loss. So right there, there are a couple of things that tip you off as to something atypical happening in this patient, right? He's got some something funny going on in her head, right? Progressive sub-retinal infiltration not responsive to your usual treatment. And this is what it looked like. These large areas of sub-retinal and sub-retinal pigment epithelial infiltration, bad vision in one eye, not so great vision in the other eye and vitritis, okay? Which was asymmetric and hey, so what kind of things are you thinking about? This patient was referred in within a diagnosis but endogenous endophthalminus that I was thinking of something a little bit different. Anybody? I think malignancy should be on the differential here. I'm sorry, I can't hear you. Like malignancy should be on our differential problem? For sure. What kind of malignancy would you be worried about? Some sort of maybe like a CNS lymphoma if we're thinking it's affecting the brain? Yeah, so it's precisely what was number one on our differential diagnosis, primary intraocular lymphoma or primary vitro-retinal lymphoma. And then of course, leukemic infiltration, meds and then other non-infectious or infectious diseases. And this patient actually had a vitreous biopsy in a sub-retinal aspiration. And her cytology indeed showed malignant cells, poorly differentiated malignant neoplasm and her molecular testing for IgEvG rearrangement was positive for a monoclonal B-cell population. So always think about you know, a neoplasmic masquerade in your differential diagnosis. I'm gonna stop there. I have test questions, but you'll get them in your OCAP review. I am open to any questions. I hope that the kind of broad brush stroke and the kind of illustrative cases were helpful and willing to answer any questions at any time.