This lecture will review the global prevalence of tuberculous Uveitis and its various clinical manifestations. This will be compared and contrast did to the manifestations of sarcoid Uveitis. Diagnosis and management of these conditions will be discussed.

Lecturer: Dr. Ramana S. Moorthy, Indiana, USA

Transcript

DR MOORTHY: Good morning, everybody. My name is Ramana Moorthy. I’m speaking to you from Indianapolis, Indiana, in the United States. I’m going to give you two presentations today, on sarcoidosis — I hope you can see my screen here — and on tuberculous uveitis. I would like to begin with sarcoid, sarcoidosis, today. I’m going to switch over to my slide show here. So one of the caveats, as a uveitis specialist, I feel it is very important that when you see a patient with uveitis, that when we try to do a thorough history, physical examination, and then finally come to a conclusion as to the morphology of the uveitis, the phenotypic appearance of the uveitis, we then decide on what kind of laboratory evaluation we should do. The most important thing that we need to remember is that in every uveitis patient that we work up, with the laboratory testing, we need to make sure that we test for three things. Three things. And I want you to remember these three things. This is not in this lecture. But this is very important. If you learn anything from these two lectures, I want you to take this away. Sarcoidosis, syphilis, and tuberculosis are three things that we should always try to rule out in patients who have uveitis. Why is that important? Syphilis and tuberculosis are infectious causes of uveitis. Sarcoidosis is a non-infectious cause, but a very common cause of inflammatory eye disease. These things have significant prognostic significance for the patient’s total well-being. These conditions. And obviously at least one, for example, syphilis, can completely be cured with antibiotics. Tuberculosis has significant health implications for the patient and for society, and sarcoid has substantial health implications for the patient. I’m going to begin right away with a polling question. The first question: A workup for sarcoidosis should be considered in which of the following uveitis presentations? Unilateral acute anterior uveitis, bilateral chronic intermediate uveitis, multifocal choroiditis and panuveitis, or all of the above? Check your answers here. Okay. So half of you got what I think should be correct. So sarcoid can present in any of these phenotypic presentations. It can be acute anterior uveitis, it can be bilateral chronic anterior uveitis, bilateral chronic intermediate uveitis, multifocal choroiditis and panuveitis, it can be just choroiditis, it can be inflammation of the choroid and the optic nerve. So multiple different presentations. You know how we used to say that syphilis can look like anything in the eye? Sarcoid can almost look like anything in the eye. And I’ll show you pictures of this. Sarcoid is an extremely common cause of uveitis. In my part of the world, in the Midwestern United States, it is probably the most common cause of non-infectious uveitis that we see. It is particularly common in the United States among African Americans. About 10 to 20 times more common, depending on where in the United States you are. But it has been reported in all ethnic groups, in virtually every country in the world. So sarcoid is not race-exclusive. It can affect anyone. Many patients may present only with ocular involvement. So 25% of my patients clinically may present only with ocular involvement. That may necessitate the use of systemic medications. In which case, the systemic manifestation of the disease may be delayed or completely obliterated. So sometimes patients never develop the systemic manifestations, because of the concurrent systemic treatment that is given for the ocular disease. It represents up to 10% of uveitis cases worldwide, but I suspect in my practice, it may be substantially greater. Maybe about 25% or 30%. Its presentation is relatively uncommon in children, except for one condition, called Blau’s syndrome. Which is a specific familial systemic granulomatosis, which is akin to sarcoid, which is a close relative. Blau’s syndrome is an extremely difficult condition to treat. Very recalcitrant to therapy. And behaves quite a bit differently than the garden variety or typical sarcoidosis. Patients who have early onset of sarcoid uveitis, for example, typically will not get pulmonary disease and other problems. They’re more likely to have cutaneous or articular manifestations of the disease process. We don’t know what causes sarcoid. It is typically thought to be some sort of an immunologic reaction to some exogenous antigen. More than 100 years ago, Boeck suggested that exposure to pine pollen was the cause, because of the northern Europeans that typically got the sarcoid. It tended to occur in temperate climates. But we know that’s not necessarily true now. It can be immunogenetic in etiology, because many family members are described with sarcoid. I have a family with at least two generations of patients who have sarcoid uveitis. Other infectious causes have been proposed, including non-tuberculous mycobacteria. An infectious cause has been proposed, because there are clusters of phenotypic cases in the same geographic locale. In Indiana, in my state, for example, there is a building specifically in a small county in rural Indiana, in a small town. This particular building had multiple employees who came to see me with severe manifestations of sarcoid. Thorough clinical evaluation revealed no specific infectious cause in those patients. But multiple family members can be affected. Today there are investigative studies going on to use panpathogen multiplex PCR and deep genomic sequencing studies on fluids obtained in various tissues from sarcoid patients, to determine if there are underlying causes that we don’t know. Sarcoidosis is a multisystem disease, characterized by non-caseating granulomatous inflammation. Non-caseating, of course, refers to the histopathologic appearance of these granulomas. Or you may see epithelioid cells, multinucleated giant cells, Langerhans cells with nuclei at the periphery of the cells, and a thin rim of lymphocytes. Histopathologically, when you look at these patients who have this granulomatous inflammation, we need to make sure that the pathologist has performed acid fast stain to rule out the presence of acid fast bacilli. Because acid fast bacilli can certainly be seen in non-caseating granulomas and in early cases, non-necrotizing granulomas, with TB. You also need to rule out the presence of foreign body or fungi, which can also produce granulomatous inflammatory processes in tissues. So these types of specific histopathologic stains need to be done to rule out those infectious and foreign body causes. And once that is done, then you can firmly conclude that these non-caseating granulomas are indeed likely sarcoid. In effect, idiopathic in etiology. The ocular history of a patient with sarcoid uveitis really depends on where the inflammation is. Anterior chamber inflammation is going to result in patients having — especially if it’s acute, of course — patients having redness, pain, and photophobia. But the vast majority of patients that present to me typically have blurred or decreased vision and floaters, because they tend to have more chronic, insidious onset from disease. Most of them, as I said, may not have any pulmonary symptoms or extraocular manifestations of the disease. These extra ocular manifestations include pulmonary symptoms, such as a chronic cough of more than six months’ duration that is non-productive, lymphadenopathy, plaques, erythema nodosum, lupus pernio. As an aside, let me point out that most recently, tattoos have been associated with granulomatous inflammation of the tattoos and associated uveitis. This is felt to be very closely linked to sarcoid. It may be that patients who have a propensity toward sarcoidosis — the tattoo itself induces the inflammatory process. This is very fascinating, because there is some pathologic evidence that melanin may play a role in the pathogenesis of this inflammation. So tattoo associated uveitis is not on the slide, but it’s important for you to remember. In patients who have tattoo associated uveitis, that is like sarcoid, the tattoos inflame the same time that the eye does. So you may notice this very, very commonly. So I think that it’s very important for us to remember that cutaneous manifestations of sarcoid are not uncommon. Central nervous system disease with neurosarcoid can also occur. And arthralgias and arthritis can also be prominent. A mention should be made about the importance of cardiac disease. A recent article by Rosenbaum and colleagues in Portland has shown that patients who have sarcoid uveitis — 40% of these patients often have ongoing cardiac problems, ranging from arrhythmias to significant cardiomyopathy associated with sarcoidosis. So cardiac manifestations should be kept in mind, as many of our patients that we see with the uveitis may have substantial cardiac issues. Hepatic involvement with sarcoid can also occur, resulting in a very difficult to treat situation, because it makes it more difficult to use some of our immunomodulatory therapeutic agents. This is a picture of pulmonary sarcoid. Pulmonary sarcoid occurs in four stages. Stage one is associated with hilar adenopathy. And you see these large — the enlarged, widened mediastinum, associated with the chest x-ray, associated with nodes. Lymph nodes that are enlarged. In stage two, you have reticular changes in the lung fields, along with hilar adenopathy. In stage three, the hilar adenopathy is absent, and only diffuse reticular changes with widespread opacification of the lung fields, and in stage four, the reticular changes progress. Hilar adenopathy becomes a little bit more prominent, and we see volume loss in the lungs. Substantial restrictive lung disease occurs in the very late stages of pulmonary sarcoidosis. Lupus pernio is a very interesting manifestation of sarcoid. Granulomatous inflammation occurring at the level of the dermis. That you’ll see around the nose, you see this inflammation on the edge of the nose, on this patient. Excuse me. My slide is moving here. And then you’ll see these plaque-like elevations. These are typically non-painful, but the patients can be quite obviously — cosmetically bothered by these. These often do respond very nicely to corticosteroid therapy. Erythema nodosum in one of my patients you see here, who presented with severe panuveitis and other manifestations that I will show you — this is a non-specific finding that can certainly occur in sarcoid. Neurosarcoidosis often is associated with concurrent pulmonary disease. As you can see in this graph here. In this table. But cranial mononeuropathies, meningeal enhancement on MRI, psychiatric symptoms can all be significant manifestations. CSF analysis may reveal very non-specific findings, including elevated opening pressure, elevated total protein, and pleocytosis, and the cellular contents of the cerebrospinal fluid. There are many syndromes that are associated with uveitis that can occur, that we should be aware of in sarcoid. Lofgren syndrome is erythema nodosum. The patient that I showed you before had this. He had hilar adenopathy, febrile adenopathy, and acute iridocyclitis. Heerfordt syndrome has erythema nodosum — this is a picture of my patient’s massive enlargement of the parotid gland, bilateral panuveitis that flared severely, while she was on very high doses of corticosteroids and Cellcept. This is very, very difficult to manage case of sarcoid. This patient also had fever, hilar adenopathy, manifestations of both Heerfordt and the Lofgren syndrome. The ocular manifestations of sarcoid can show multiple things. And I mentioned many of these already to you. Acute or chronic uveitis in the anterior, intermediate, or posterior segments, or all of them. Orbital and lacrimal gland enlargement. Conjunctival granulomas. Nummular corneal infiltrates. Band keratopathy in advanced stages of chronic uveitis, mutton fat KPs, keratic precipitates, especially in the angle — Berlin’s nodules. That’s actually considered pathognomonic of sarcoid. Koeppe and Busacca iris nodules and large iris granulomata can also occur. Posterior synechiae, peripheral anterior synechiae, snowballs, vitritis, and of course choroidal and retinal manifestations as well, which I will show you in just a moment. This is a patient with sarcoid dacryoadenitis, the same patient with the parotid fever in the Lofgren syndrome that I showed you earlier. This is a presence of conjunctival granuloma. It’s very important, as one of my mentors, Dr. Ron Smith, once told me, that when you evaluate a uveitis patient, it is very, very important to look carefully at the conjunctiva of this patient. Because the conjunctiva may reveal very large conjunctival nodules, which represent a very wonderful way to biopsy and prove that someone has sarcoid. These nodules are very steroid sensitive. Once you place the patient on topical choroids, these nodules usually melt away very, very quickly. So it’s important when you see them to perhaps do a snip biopsy and send the biopsy to the pathologist for histologic evaluation. Because you will see these multinucleated giant cells with these peripheral nuclei, as you see here. The Langerhans giant cells, and you see the palisading peripheral lymphocytes on the margin of the granuloma, along with the non-caseation that you see. You can see perivascular lymphocytic infiltration, that you see here, in the picture on the right as well. So these are all common histopathologic findings. And again, when we do this, it’s very important to rule out with acid fast staining… We need to make sure that there are no acid fast bacilli, no foreign body, and no fungi. Because these can all present with granulomatous inflammation. So when we’ve ruled all those things out, we can definitively say, this is non-caseating granuloma from sarcoid. This is a mutton fat KP on the cornea. You can see these large greasy appearing KPs in Arlt’s triangle, which is the lower third of the cornea. And this distribution is quite common with chronic sarcoid uveitis. This patient also has posterior synechiae. Let me show you a better picture. This is my colleague, Dr. Debra Goldstein’s beautiful picture of multiple iris nodules. You can see the iris nodules on the border. These are called Koeppe nodules, and the stromal nodules are called Busacca nodules. On the stroma here, you can see the gelatinous nodules. Sometimes the Koeppe nodules on the iris margin can be very subtle. You have to look very carefully. They may not appear round. They may appear more ovoid and be associated with synechiae. This patient has KPs, more minor KPs, so KPs can sometimes be medium sized. This is a picture. I promised you that I would show you a Berlin’s nodule. This patient has biopsy proven pulmonary sarcoid and granulomatous anterior uveitis. And you can see on gonioscopy the presence of this nodule in the angle, suggestive certainly of sarcoid. This is by many considered to be pathognomonic of sarcoid uveitis. Posterior manifestation include perivenous sheathing, which is very common. I’ll show you some very good pictures of that. And retinal and choroidal granulomas. You can also have retinovascular disease that is occlusive, like branch retinal vein occlusions. Sometimes we may see, as retina specialists, a branch or central vein occlusion that may be associated with what looks like inflammatory sheathing, maybe vitreous cells that are significant, or maybe not. And there may be recalcitrance of this vein occlusion to anti-VEGF therapy. If you give anti-VEGF therapy to patients with vein occlusions from sarcoid, they may only improve to a certain point, and only after the institution of corticosteroid therapy, and immunosuppressive therapy, will their vascular occlusions start to really improve and make real gains. Anti-VEGF therapy alone will not be enough to control the macular edema or the ischemia or neovascular process in these patients who have sarcoid-related retinovascular disease. You may see chronic cystoid macular edema, optic nerve head edema, and even granulomatous invasion of the optic nerve head can occur, and can be quite striking in appearance. This is a patient of Dr. Goldstein’s. I promise I have some of my patients here too, but her pictures are usually quite convincing and beautiful. This is a picture of inflammatory vitreous snowballs in a patient with intermediate uveitis and sarcoid. This is one of my patients, with periphlebitis. You can see this focal — multifocal areas of periphlebitis. The classic manifestation is the candle wax drippings, and I will show you a better picture of that, but this is a forme fruste or beginning manifestations of these taches de bougie. This is a more prominent manifestation, almost like the candle wax is dripping off the margins of these vessels, very fluffy, sheathed inflammatory material that’s exuding out of the retinal venules. This is quite impressive, and you can see that there’s significant vitreous opacification as well. I apologize that my phone — I had silenced it, but it’s apparently not silenced completely. This is a patient who has panuveitis, but with multifocal choroidal involvement with large choroidal granulomas from sarcoidosis. And you can actually see inflammatory nodules extending into the retina from this. So this can be seen in other conditions as well. You can see the same kind of presentation in tuberculosis, and you can also see the same presentation in syphilis, in some patients. So that’s why sarcoid, syphilis, and TB are the most important things that we use to rule out the causes of uveitis. This is a patient that presented to me who is an African American, who had massive exudative retinal detachment in both eyes, and on clinical examination, looked very similar to Vogt-Koyanagi-Hirata syndrome. Exudative retinal detachment, and on the angiogram — showing the starry sky pattern that is very typical of Vogt-Koyanagi-Hirata disease. But this patient had an elevated angiotensin enzyme level, and pulmonary evidence of very advanced sarcoidosis. This patient responded very well to corticosteroids, but unfortunately developed significant glaucoma and other problems. Here are old chorioretinal scars from resolved inflammation. So there may have been granulomas here, but these are now atrophic scars in the periphery after healing. You may see this in patients with sarcoid. Here’s a patient who has a solitary granuloma of the posterior pole from sarcoid. A very large granuloma. Pretty impressive-looking. And this can be associated with exudative subretinal fluid in the macula, and sometimes choroidal neovascularization can develop as the star heals. This is the optic nerve granuloma that I was mentioning to you. You can see this massive infiltration of the optic nerve. Dr. Sen from the National Eye Institute was kind enough to provide us with this picture, a beautiful photograph of a sarcoid nodule. This melted away with corticosteroid therapy. But left behind some residual visual deficit. Well, let’s move on to seeing how we diagnose sarcoid. So I’ll ask a polling question. Which of the following tests suggest a definite diagnosis of sarcoid? Meaning what test will say: Hey, this is definitely sarcoid? A, an elevated angiotensin converting enzyme and serum calcium level, B, elevated ACE with chest radiograph showing hilar adenopathy, C, 18 fluorodeoxyglucose PET scan demonstrating increased metabolic uptake in the hilum, chest parenchyma, and lacrimal glands, or conjunctival biopsy demonstrating non-caseating granulomata with negative Giemsa and acid fast staining? I can’t see the last graph, but… Yes, you are correct. Most of you got that right. 66%. Biopsy showing histopathologic granuloma is definitive diagnosis for sarcoid. Everything else is possible or probable sarcoid. And I’ll show you the diagnostic criteria in a moment. So there are valuable tests that you can do for sarcoid evaluation, and there are less kind of valuable tests. But I think that together when tests are all positive they can be significantly useful. So, for example, a chest x-ray has relatively low sensitivity and specificity, but if a conjunctival biopsy is positive, you’re more likely to have chest x-ray that will confirm the finding of sarcoid. A chest CT specifically with spiral cuts through the chest, with contrast, which is a significant amount of radiation to the patient, can also be definitive. So if you see something on the chest film, and you really think this is sarcoid, based on what you’ve seen in the eye, then I think that more thorough evaluation with chest imaging is warranted in the patient. Especially if they have pulmonary symptoms. There are serologic evaluations for sarcoid. They’re less useful, but still part of the workup. I still use these tests. Because I use it with chest x-rays. So chest radiograph findings, along with serum angiotensin converting enzyme level, lysozyme level, even though they have low sensitivity by themselves, have improved sensitivity and specificity when they’re combined with chest CT or chest x-ray. I don’t use a gallium scan anymore, and some of our European colleagues that may be present on this call have access to PET scanning, using the fluorine 18 isotope, fluorodeoxyglucose PET scanning. If it’s labeled with isotope 18 of fluorine, you can see a significant amount of uptake, and this can be positive, even if the chest CT shows equivocal findings. It can be confirmatory for the presence of sarcoid. This is a much more expensive test, I believe. I do not have this… I do not use this test, excuse me, very much. Here is an example from a very important article on sarcoid imaging in nuclear medicine. So this is one of these fluidics, the PET scans. You can see massive lymphadenopathy, you can see hepatic involvement, you can see lymph node involvement throughout. And these are all part of presentation of sarcoid. So chest x-ray, chest CT, serum angiotensin converting enzyme level, serum lysozyme. Serum calcium can sometimes be helpful, and evidence of lymphopenia can be helpful. These are all more non-specific findings. Biopsy. So where do we biopsy? The most convenient place to biopsy for the ophthalmologist is likely the conjunctiva. There have been people who have suggested that vitreous biopsies — and there are a few papers from Japan, for example, that have shown that we can find granulomatous inflammation in the vitreous, that may suggest sarcoid — and of course, we need to rule out the presence in any of these biopsy of tuberculosis, non-tuberculous mycobacterium, fungi, foreign bodies, and if we can rule all these out, we know it might be sarcoid. Lacrimal gland biopsy might be an option, and lung or transbronchial lung biopsy might be an option, especially with transbronchial ultrasound, and lavage might be considered when biopsy is being performed. Skin biopsy might be helpful. If you biopsy the lupus pernio lesions, perhaps. Erythema nodosum is non-specific. There is something else called granuloma annulare, which can look like lupus pernio, but can occur all over the face. The nodules can be tender or inflamed, a little bit pruritic or itchy, and these can be biopsied by a dermatologist and confirmed to be granuloma annulare, because they have annular spread. These can be sarcoid. I have a patient with this. Nothing in the lungs. Elevated ACE, and granuloma annulare. So this can be an association. Ocular sarcoid has multiple diagnostic criteria. The sarcoid study group, international sarcoid study group, has come up with things that are helpful in the diagnosis. So we’ve talked about all of these already. Iris nodules, mutton fat KPs, trabecular meshwork nodules, peripheral anterior synechiae, candle wax description, optic disc nodules, and bilaterality of disease. Ocular sarcoid is more frequently bilateral. So one of the things I want to bring up here is the idea of unilateral uveitis. One of the most important things, as uveitis specialists, that we have to do before we start therapy, is to make sure that the patient is either infectious or non-infectious uveitis. Unilateral uveitis — and my lecture last week suggested this, and I reviewed this with you — but unilateral uveitis should raise the suspicion that there may be infectious etiology. For example, viral uveitis presence with ocular hypertension and most of the time is unilateral. That should give you the notion that perhaps infectious uveitis may be playing a role. It’s not always the case. Disseminated infectious disease can certainly present with bilateral disease. But unilateral disease — think about the possibility of other causes, and make sure you rule those things out. The international workshop on sarcoidosis deemed crucial laboratory testing — usually chest radiographs showing hilar adenopathy, elevated ACE, and serum calcium levels being elevated — all highly suggestive of sarcoid. The definite diagnosis is based on biopsy supported diagnosis of a compatible uveitis. Presumed sarcoid is when biopsy is not done but the chest x-ray shows bilateral hilar adenopathy, and granulomas that are compatible with sarcoid. Probable sarcoid is when you have no biopsies done, chest x-ray is normal, but there are three intraocular signs that I mentioned earlier, and two positive lab tests. And possible sarcoid is when you have lung biopsy done, it’s negative, but at least four of the ocular signs are present and two positive lab tests are present. So bottom line is to really know that definitive diagnosis… You have to have a biopsy. To support the diagnosis of definitive sarcoidosis. The differential of sarcoid includes the things we’ve talked about. Syphilis, TB, familial juvenile systemic granulomatosis, the Blau syndrome, associated with NOD2/CARD15, which can be evaluated and tested for. Vogt-Koyanagi-Harada disease, all of these are in the differential diagnosis of sarcoidosis. Multifocal choroiditis, panuveitis. JIA in children. Idiopathic pars planitis, in California, there’s coccidiomycosis, in upper portions of North America, it’s relatively endemic in these areas, and we have seen blastomycosis as well presenting like sarcoid. The management of sarcoid uveitis is corticosteroids. Corticosteroids are the mainstay, because sarcoid uveitis tends to be exquisitely sensitive to corticosteroids. But not all patients are going to respond only to steroids. But most will. Once you know that this is not infectious uveitis, topical corticosteroids, local injections of corticosteroids intravitreally, or periocularly, implantation of fluocinolone, Retisert, or now in smouldering cases, using the Yutiq injection. All of these are intravitreal therapies that are available. Of course, systemic corticosteroids. When there’s systemic involvement, lung involvement, cardiac involvement, hepatic involvement, brain involvement, we certainly think about the use of systemic medications to treat patients. Systemic steroids as a mainstay, followed by the use of immunomodulatory therapeutic agents, based on response. Cycloplegics are useful for chronic disease. This is of course local therapy. I’m showing you intraocular injection on the left, and in the upper right, you’ll see retroseptal injection with a 27 gauge needle and a 3 CC syringe of 20 to 40 grams of triamcinolone, and the bottom picture is the technique of the posterior sub-Tenon’s injection, using a 25 gauge 5/8 inch needle, a short needle, and injecting with 3 CC syringe in the superior temporal portion of the posterior sub-Tenon’s space. These can be effective ways of delivering corticosteroids locally. The Ozurdex and Yutiq and Retisert implants are all devices that can be utilized for the treatment of sarcoid uveitis. Of course, you need to consider the risks of corticosteroid therapy. Local injections are associated with significant increase in intraocular pressure, as we know. Very recent studies from the uveitis literature — very important study that have shown that periocular corticosteroid injections and intraocular injections all cause elevation of intraocular pressure. Intraocular methods cause more elevation of intraocular pressure, but better results in reduction of cystoid macular edema and control of inflammation. These local therapies are also associated with increased risk of cataract formation. Mycophenolate can be a good therapeutic immunomodulatory agent, especially in CNS and visceral sarcoid. Biologic response modifiers, however, are avoided, unless we have ruled out tuberculosis, prior to initiating therapy. So we have to make sure TB has been definitively ruled out. TB and sarcoid uveitis can look identical. I’ll show you some pictures of these things. Etanercept can also induce sarcoid uveitis, and I’ve seen it developing from the use of these TNF alpha inhibitors. Etanercept with Humira and infliximab, I’ve seen sarcoid-like inflammatory disease. So we can use antimetabolites or alkylating agents to treat the sarcoid uveitis. This is usually done in conjunction with a rheumatologist. Or pulmonologist. Someone who is an expert in the management of these medications. Or someone who is an ocular immunologist or uveitis specialist, trained in the use of these medications. You can also use T-cell signaling inhibitors in some cases. Most people nowadays are using tacrolimus. Rather than cyclosporine. Because of side effects. And of course, TNF alpha inhibitors, as I mentioned to you already. But there can be unusual side effects that can mimic sarcoid from these agents as well. There are many disease-related complications we already touched on. But cataracts, glaucoma, cystoid macular edema are very common to any chronic uveitis conditions. But they’re commonly seen with sarcoid. Neovascular disease in the retina and choroidal neovascularization can also be seen with sarcoid. And vascular occlusions, vitreous hemorrhage from neovascularization elsewhere in the retina can certainly develop. Cataract can develop in sarcoid. Cystoid macular edema, bilateral. This is a patient of mine, who has CME from sarcoid in both eyes. And here’s the angiographic picture. This patient has kind of an intermediate uveitis. You can see the hot optic nerve on fluorescein and the petaloid pattern. You can develop significant glaucoma. I’m sorry the picture is a little blurry, but this patient had cataract. So you can see the advanced optic nerve cupping, the pericapillary atrophy, large atrophic spots. This is the patient earlier who presented like VKH, after she had been treated for many years, she developed glaucoma. There is also this fibrosis. Much more extensive later in life. Here’s massive subretinal fibrosis in the macula, as the inflammation went away. You can see this kind of response with sarcoid. The prognosis is variable. With corticosteroid and with the use of immunomodulatory therapy, the prognosis has improved. But anterior uveitis is plagued by the — chronic anterior uveitis is plagued by the development of cataracts, glaucoma, and CME, which complicate the course. And of course, posterior and panuveitis can be associated with choroidal neovascularization as well as retinal neovascularization, and other complications, and has really the poorest prognosis. We already mentioned about the association of sarcoid, cardiac sarcoid. This is particularly important in patients who have posterior segment disease. And this is a very important observation made by Japanese researchers, as well as, as I mentioned, Dr. Rosenbaum’s group in Portland, Oregon, recently. That is the end of sarcoid. I’m actually going to move on to tuberculosis. And we’ll take questions as time goes on here, towards the end of the presentation. Many of you — and I hope you can see the screen — many of you are experts in TB. I’m not going to pretend to be. I see some TB. In Indianapolis. Because of global population dynamic changes. We see a lot of patients who have come from Sub-Saharan African countries to our part of the Midwest in America. We have a lot of people from Southeast Asia as well, who are immigrants, who have presented to us with TB uveitis. So this is a global problem. So the global tuberculosis disease burden is greatest at which part of the Globe? This is the first question in this part of the lecture. North America, South America, Sub-Saharan Africa, or Southeast Asia? We’re talking about numbers rather than percentages. Where is the burden the greatest? You all know, probably. Let’s see what you answer here. Yeah, so I thought this would happen. So C and D… I think that’s because we have a lot of people from these areas of the world, that are on the call, on the conference here. And I value your input. From a global perspective, from a pure population perspective, I believe that Southeast Asia has more cases, but from a disease burden perspective, in terms of association with other things like HIV disease, and the presence of multidrug resistant TB, et cetera, we’re seeing the prevalence of cases and the percentage of cases being more severe from Sub-Saharan Africa. But the number of cases is greatest in Southeast Asia. So the World Health Organization tuberculosis report in 2015 showed that there were 9.6 million new cases in 2014. And there have been one and a half million deaths worldwide from TB. And maybe 25% of those are actually — 20% of those are actually TB associated with HIV disease. So North America and South America — relatively low burden. Southeast Asia has the most number of cases. But a close second, certainly, is Sub-Saharan African countries, mainly, the Middle East has some cases. Of course, Europe has some cases. And the Western Pacific, interestingly, has a significant amount of disease burden as well. So we have a global epidemic of tuberculosis going on. And here is the WHO map, showing the prevalence of disease, and you can see Sub-Saharan African countries and of course Southeast Asia, where the disease processes are particularly important. You can see the total global distribution in terms of cases per year… Very high levels. Because of the largest, most populous countries are going to have very significant cases, even though the rates per population are a little lower in India and China, compared to places like South Africa, but the number of cases, the sheer number, is larger in Southeast Asia. Tuberculosis can manifest, of course, as latent TB infection. In places where TB is endemic, such as India, we may find that the presence of a Gohn complex, indicating latent tuberculosis, may be present in more than 25% of patients screened at random. With chest x-rays. So it’s quite prevalent in certain parts of the world. TB can manifest primarily as pulmonary disease, but extrapulmonary disease can certainly occur. Renal disease and uveitis — and uveitis is relatively uncommon. Its prevalence is about 0.7 to 10% of those cases. But it’s certainly not rare. The association with concomitant HIV infection increases the risk of developing TB disease, particularly multidrug resistant TB. And there’s a 7 to 10% risk if HIV positive of developing TB, compared to a 10% lifetime risk for those who just you have latent infection without HIV. And 25% of HIV deaths, as I mentioned earlier, are caused by tuberculosis disease. Here’s a distribution of TB and HIV. You can see intense concentration of HIV pandemic/epidemic going on in Sub-Saharan Africa, as early as just a few years ago, in the report from the WHO. Drug resistant TB has become more common. And resistance to rifampin and INH are certainly common. And there’s the extensively drug resistant TB, where we are really falling short of appropriate treatments. Treatments are very difficult to obtain, because they’re so resistant to all the available methods. The disease burden is really highest, unfortunately, in the poorest countries. And treatment failures occur because of lack of drug availability, and there are many organizations in the world, trying to change this, but it’s a very, very difficult battle. Patient non-compliance due to social, cultural barriers, that may exist for treatment, and increased prevalence of drug resistance all result in treatment failures. And of course, higher HIV rates in those patients — in the poorest countries — will actually result in much more treatment failures. Obviously the disease from a systemic standpoint presents with fevers, chills, night sweats, weight loss, it’s a subacute process of disease, progressing gradually, resulting in appetite loss and malaise. My aunt in India had tuberculosis, and it was shocking to me, when I saw her with the disease, because I had remembered her as a fairly well developed person when I saw her. After having the disease for nearly two years without appropriate diagnosis, mainly because she had not sought help, she had lost — gone from about a 70 kilogram weight to 35 kilograms. So this substantial amount of cachexia that we see with advanced disease can be very severe. Chronic cough. Sputum production. Hemoptysis, pleuritic pain with coughing, very common. And the renal disease, or even Potts disease, where we have spinal involvement, bony involvement, can occur with extrapulmonary TB symptoms. Tuberculous uveitis is actually a little bit of an enigma to me in part. We know the intraocular inflammation is resulting from TB infection, but it’s very difficult to isolate these organisms directly from ocular tissues. We can do it, but it’s difficult to do so. Tuberculous uveitis, in my opinion, for the most part, tends to be a paucibacillary disease. We know the bacilli are there, but in the absence of other manifestations elsewhere, with active ongoing TB infection in the lungs or disseminated TB elsewhere, it’s very difficult to say: This is the TB bacteria are there, and even TB therapy is making a difference in the treatment of the uveitis. But for practical purposes right now, in our talk, let’s say that the mycobacterium tuberculosis certainly is the cause. Transmittal for pulmonary infections by aerosolized droplets, but these organisms then disseminate from the lungs through the vasculature, into the choroid, retina, and into the uveal tissues. There’s a high affinity for highly oxygenated tissue for these organisms, so it seeks out places like the apex of the lung or the choroid. Remember, the choroid has a substantial amount of blood supply, and highest rate of amount of blood flow per volume for cubic millimeter of tissue, is in the choroid. The ocular manifestations of tuberculosis are due to two things: Active infection of the ocular tissue, where there’s primary inoculation from adjacent sites, which is actually relatively rare, but more commonly from hematogenous dissemination, as I mentioned, from the lung or other body sites. And of course, the second reason that you get inflammation is because it’s an immunologic reaction. And this is actually probably more common than the actual active infection. In places where we see less endemicity to the disease. I’ll show you what I mean by that in a moment. So the ocular symptoms can be like sarcoid. They can be a waxing and waning course, progressive increase in floaters, worsening of vision due to progressive intraocular inflammation, choroiditis, cystoid macular edema, posterior and anterior iriditis. Tuberculosis can cause which of the following? Scleritis, anterior uveitis, intermediate uveitis, panuveitis, or all of the above? I’m sorry I have so many choices here. But what do you think TB can do? So you guys obviously know more about this disease than probably most of us do in the United States. And I hope you will correct me if I made some errors in my talk. Regardless, I think all of these are manifestations of TB uveitis, because it can cause any and all of these things. Just like sarcoid and syphilis, TB can also be potentially considered a great mimicker. In scleritis, it can cause a nodular anterior scleritis, posterior scleritis with acute angle closure glaucoma. TB scleritis is extremely difficult to treat. I have a few pictures of it. Anterior uveitis — mutton fat KPs, iris nodules, posterior synechiae. Very rarely does it cause non-granulomatous inflammation. Retinitis can also occur with TB, just like sarcoid. And again, posterior uveitis manifestations can be just like sarcoid. Let me point out one specific thing that many of you from India know all about. This is the multifocal serpiginous choroiditis. This looks like the classic non-infectious serpiginous choroiditis, but it’s caused by TB. These result in multifocal disease in serpiginous-like choroiditis, and you see much more inflammation than you see in classic serpiginous choroiditis in this disease. That’s how I differentiate the serpiginous versus the serpiginoid disease. The presence of multifocal lesions is suggestive of tuberculosis serpiginoid choroiditis. As opposed to the non-infectious disease, which has usually very little intravitreal inflammation seen. You can see pan panophthalmitis, particularly in immunocompromised hosts. Definitive diagnosis requires demonstration of mycobacteria from body fluids or tissues. Very difficult to establish ocular TB. But when you do a chorioretinal biopsy, acid fast staining should be done every time you see uveitis. You may miss TB. So when you have, as a retina or uveitis specialist, you do a very advanced vitreous surgery and do ab interno or ab externo chorioretinal biopsy, one of the things you must do, no matter what you’re getting the biopsy for, is to rule out the presence of acid fast bacilli. In most cases, the diagnosis is presumptive. We have indirect evidence. A positive PPD or positive immune… The IGRA, or interferon gamma releasing assays. So these IGRA tests, the TB quantiferon TB test or the T spot TB test — these are useful tests that have come out recently. They’re more useful in places where TB is not necessarily endemic. But again, PPD skin testing is not particularly useful in places where TB is endemic. The therapeutic response to anti-TB agents is also indirect evidence that this is tuberculous uveitis. Positive PPD is indicative of prior exposure to TB but not necessarily active systemic infection. Most of these cases are latent tuberculous infection, and sometimes latent disease may not be seen in the chest. It may be latent somewhere else. It may be very difficult to detect in patients with positive PPD skin test. This is the intradermal injection, 0.1 CCs of purified protein derivative. Interpretation of the induration size depends on the person’s risk factors. So people who live in endemic areas, who have more than 15 millimeters, they’re considered positives. In people who are non-endemic areas, if you have 5 to 10 millimeters, that’s considered positive, like in the United States, for example. There can be a booster effect with PPD skin testing. Two step testing can help differentiate whether or not this is an actual TB or not. And IGRA testing, the interferon gamma release assays, can be utilized as a confirmatory test if PPD skin testing is equivocal. So if patients have indurations greater than 5 millimeters and HIV positive, or contact with TB recently and radiographs are consistent, those are considered positive and require intervention. If there’s more than 10 millimeter induration and it’s health care workers, recent immigrants, renal failure, et cetera, these are also considered positive. There can be false negative skin tests that occur, and these can be fairly high rates. Particularly the immunosuppressed patients or patients on corticosteroids where the immune response is decreased. Sarcoid patients if they have concurrent sarcoid with TB, that’s great, but that can potentially be false negative as well. False positives can occur in patients who have been immunized with BCG, like I have. If you grew up in the ’60s or ’70s in Southeast Asia. If you had intraluminal or intravesical BCG injections, treatments for bladder cancer, you may also be positive. Also positive PPD skin testing. Interferon gamma releasing assays cannot reliably differentiate latent TB from active TB disease, but they can be used in place of the tuberculin skin test and has been approved by CDC in our country. There are two methods. And basically the quantiferon TB — you measure the concentration of interferon gamma produced. And it’s produced against three different TB antigens that you’re looking at. And in T spot TB, you measure the number of interferon producing cells or spots, against two antigens.. So most people prefer the use of quantiferon TB, but these are both reasonably good tests to use for interferon gamma. Definitive diagnosis may require intraocular fluid analysis or tissue biopsy. There have been significant efforts in India or other places to develop multiplex PCR assays for TB. Getting samples of vitreous or aqueous fluid may in the future yield good response. We certainly — the World Health Organization’s efforts — the X-Pert MTB/RIF assay has been developed for rapid assessment of TB in the sputum. If it’s rifampin resistant, we can figure that out within two hours. Hopefully these assays will become more available for ocular fluid analysis as well, and biopsy of affected tissue can be considered as well. If you see conjunctiva, sclera, episclera involved, this may help us, in terms of confirming the diagnosis of TB. Culture and sensitivity testing is important for sputum. But mycobacteria are very slow growing, and an expert in mycobacteriology in the laboratory is really required for definitive diagnosis. I’m gonna move on to show you some manifestations. Many of you in India have probably seen these things, many of you in Southeast Asia and Sub-Saharan Africa may have better examples of these. For the most part, these are examples that I was shown from Professor Rathinam. I do have a few examples of my own patients that are not as dramatic as hers. This is iris granuloma. You notice the large white mass here that extends into the angle. The granulomatous KPs on the angle, the posterior synechiae that are present, and the granulomatous biopsy shows the acid fast bacilli on the lower right. This patient also had significant parotid gland and scrofulaceous adenopathy in her neck, associated with TB. This is a patient with granulomatous anterior uveitis, choroidal granuloma, and localized tuberculous abscess in the brain parenchyma that you see here. This patient, the granuloma improved with antituberculous therapy. And notice this patient had modest amount of intraocular inflammation. Not dense vitritis, but mild vitritis associated with this lesion in the choroid of the left eye. You see macular star formation in this large choroidal granuloma and the large exudative retinal detachment. This is a very famous picture that many of you have seen before, Dr. Rao’s. This is a patient with very advanced multifocal serpiginous choroiditis. You see evidence of subretinal fibrosis, and involvement in the central macula. This presence of subretinal fibrosis can also be seen in classic serpiginous. That’s why we think about this condition. Again, you’ll see more vitritis in active tuberculous serpiginous choroiditis than you would in classic serpiginous choroiditis. Just keep that in mind. This was another picture Dr. Goldstein was willing to share with me, with large tuberculous granuloma associated with tuberculous scleritis. Very difficult to treat. This is lipid keratopathy on the edge of the corneal lesion. Here is another patient that had a sclerokeratitis associated with TB, and osteomyelitis related to TB in her foot. Here’s another patient with TB scleritis, associated with choroiditis in the left eye, did respond to TB therapy and eventually scarred. Her vision did improve, even though there was foveal involvement. Here’s another patient with a massive choroidal granuloma in the posterior pole. This looks almost like the sarcoid picture that I showed you, and it can look like VKH, acute VKH. So notice the massive thickened choroid on the B scan ultrasound on the lower left. And then subsequently, with treatment, the granuloma has shrunk. It was just with antituberculous therapy alone. The inflammation improved, and you can see this resulting residual subretinal fibrosis from the residual granuloma scar. And so you can see here that the bacillary load was enough that it responded to antituberculous therapy. Many times, however, tuberculous multifocal choroiditis like this — this is a patient from South America, who presented to us in our clinic, who had multifocal choroidal inflammatory lesions. She had evidence of a panuveitis-like picture with granulomatous inflammation of the anterior chamber. This was after treatment with antituberculous therapy. This patient was treated with five drugs, initially, for two months, and three drugs for four months, for six months of systemic therapy. Directed, observed therapy is recommended in the United States. So they actually have to go to a state Department of Health official, and the official has to watch the patient every day take the medications. So this is very intensive therapy for public safety reasons. That’s done in the United States, directed, observed therapy. It’s usually done in most states, in most communities in the United States, as a rule. Here’s the patient that — from India, who presented to us in our clinic. Who was a young Indian woman who presented with TB vasculitis. Who had neovascularization elsewhere, and in the optic disc, and presented with mild vitreous hemorrhage. This patient was PPD positive, IGRA positive, and had very large induration. 15 millimeter induration. And had evidence of subtle pulmonary latent tuberculous disease. And this patient was again also treated in a similar fashion with five drug regimen for two months and three drugs for four months, and she was given corticosteroids as well. Gradually they were tapered and the neovascularization went away. Pediatric tuberculous anterior uveitis can look like chronic JIA. Here’s a patient with synechiae. And even calcium band keratopathy developing in this patient. This patient had a very intensely positive PPD skin test, that you see on the forearm, with some necrosis of the skin. This patient had significant pulmonary disease with severe hilar adenopathy. And some parenchymal disease as well, and responded to antituberculous therapy with resolution in the pulmonary nodules. Here’s a patient that had a massive tuberculous granuloma. I believe this patient was HIV positive, and this patient was treated — had immune reconstitution with HAART therapy and antituberculous therapy, and unfortunately… This patient was biopsied, shown to have evidence of granulomatous inflammation, acid fast bacilli in the lower right, and you can see this patient had significant inflammation in the anterior segment. This is the patient later. During treatment. And as he got immune reconstitution, unfortunately he developed necrotizing scleritis, massive inflammatory response. And in this patient, lost the eye. So this can be kind of a paradoxical immune response to a patient that, once their immune reconstitution has occurred, can result in a disastrous problem that’s very difficult to treat. The so-called MAC syndrome, or massive inflammatory response that occurs with immune reconstitution from HIV disease in the presence of TB or non-tuberculous mycobacterial infections. Differential diagnosis is very similar to sarcoid. Sarcoid, syphilis, in the differential diagnosis. VKH, sympathetic. All the other things that can cause panuveitis, and of course specifically pointing out serpiginous choroiditis as a differential diagnosis. Lepromatous uveitis, other diseases like fungal diseases are in the differential diagnosis as well. Therapy for latent TB — I’m not talking about in the presence of ocular disease, but latent TB is typically treated by itself with nine months of INH. Six months is considered acceptable. Nine months is definitive. An alternative is 12 dose, weekly doses, of INH and Rifapentine, or 4 months of rifampin if INH resistance is present. Prophylactic treatment with a single agent is possible, if you don’t have any other evidence of active TB disease. Or if the patient receives corticosteroids longer than two weeks, doses greater than 15 milligrams per day, in this case, prophylactic treatment of INH for six months to a year should be considered. If you have anti-TNF therapy being considered, INH prophylaxis should be considered three weeks prior to the first infusion. When you’re considering treatment with anti-TNF therapy for other immunologic diseases. These are the four agents that we typically have available. The isoniazid, rifampin, Pyrazinamide, ethambutol. We go to four to six months of just two or more drugs, depending on how concerned we are with multidrug resistance, based on where the patient came from or where they live. INH has hepatotoxicity, neurotoxicity. You’re all familiar with these. I’m not going to pure you with the concepts here. Pyrazinamide, hepatotoxicity. Rifampin, thrombocytopenia, nephritis, hepatotoxicity. Ethambutol can cause optic neuropathy that can improve with drug cessation. There are many factors in TB therapy, and patient non-compliance is one of them. Migrant or indigent populations, immunocompromised patients, and recent immigrants from countries where INH and rifampin are available over the counter, because they may be non-compliantly or inappropriately taking these medications, stopping or starting therapy, that can result in multidrug resistance. It’s ideal to have directed or observed therapy to make sure the patient is being treated. This is some information I put together from Dr. Rathinam, and this shows us what are the multidrug resistant or extensive drug resistant TB available antibiotics that are used. Everything from fourth generation fluoroquinolones to aminoglycosides have been used. With limited success. Clarithromycin, imipenem, et cetera. These are sometimes used for non-tuberculous mycobacteria as well. Corticosteroids should only be used with appropriate antituberculous coverage. The future directions really are going to be to develop a TB vaccine for prevention. And there are numerous other drugs that are under investigation, that we desperately need in the world. So my humble salutations to all of those of you who deal with TB. Much more commonly than I do. Because it is such a global problem. So I’m sure that you all have lots of clinical pearls beyond what I could share, and I appreciate your attention. That’s the end of the talk. I have a few minutes for questions. We’ve gone over a little bit. I hope I didn’t go too fast. I tend to talk a little fast, because I have a lot of material to cover, but I’m happy to share any other comments with you. I’m going to see if I can get the questions going. Let’s see. Maybe I can have Lawrence’s help with that. >> You can stop your screen share and if you open up the Q and A box, there are some questions. DR MOORTHY: We have 12 questions. How to differentiate conjunctival granuloma from papillary conjunctivitis? Papillae, as you know, will have a central vascular core, whereas granuloma usually have vessels on the edge of the granuloma. They can look like large follicles. But usually granulomas are pinker, a little bit more fleshy-looking, in my experience. It looks suspicious. Looks like a large kind of… Large-looking follicle, and it looks out of place, compared to the rest of the conjunctiva. I would biopsy that, when you see this. When do you decide on biopsying the conjunctiva if there are no associative features suggestive of sarcoid-like uveitis? Well, if you don’t see anything that looks like sarcoid, I don’t know that you necessarily need to do a blind conjunctival biopsy. Okay? So it’s very important… For us to consider biopsy, when you have the appropriate phenotypic appearance of the disease process. Excuse me. My speaker unplugged. Just one second. Let me replug my speaker. My apologies. So, you know, again, any time we consider doing something diagnostically for uveitis, it is based on our history and clinical findings. That’s really important. I want to drive that home. Many of us that rely on lab testing, and think… Well, we’ve done the lab testing. We’ve ruled everything out. No. I think it’s important that you ask the patient a history. What medications are they taking? What are the… If you see a patient with hypopyon uveitis, for example, you don’t need to check for TB, if the patient has been taking rifabutin for the treatment of non-tuberculous mycobacterial infection. Rifabutin causes hypopyon uveitis. I wouldn’t check HLA-B27 in that patient. That’s simply based on history. The historical evidence combined with the phenotypic appearance of the uveitis and the review of systems can really hone you in on where you need to go with the biopsy. If you have somebody with a hypopyon uveitis, I wouldn’t consider a conjunctival biopsy unless there was something else that told me that the patient had ongoing TB. So blind conjunctival biopsy I do not do. I always look and biopsy things that look suspicious. If I think it’s a granuloma, that I want to biopsy, I will do that. Okay? But blind biopsies have low yield. How different from lupus pernio… Both are manifestations in sarcoid… Yes. You know, I think that lupus pernio, those kinds of things, you can biopsy them. But again, I would refer to a dermatopathologist. I’m not a dermatopathologist. I think the response to corticosteroids can sometimes be very impressive with these cutaneous manifestations of sarcoid. Hypopyon is not a common feature of sarcoid. It’s much more common in HLA-B27 associated disease, and some forms of drug induced uveitis, like rifabutin. Have you had patients with sarcoid with ACE level at normal values? That can happen. For example, I will tell you that angiotensin converting enzyme values are useless in a patient who is on sarcoid and is on antihypertensive therapy with an ACE inhibitor. Remember, lisinopril, captopril, those kinds of medications are angiotensin converting enzyme inhibitors. So if those ACE inhibitors are present, your angiotensin converting enzyme levels are going to be zero. So they’re going to be useless for that. So that’s why you look at the history. You look what the medicines the patient is taking — to help you guide what tests are going to be useful for you. So in those cases, where patients are on that, I check a lysozyme level, I can check a serum calcium, but I would get a chest x-ray on that patient, especially if they have pulmonary symptoms. You consider granulomas at the base of the iris a risk factor for sarcoid? Well, that can certainly be a presentation for sarcoid. So look at the… Put a gonio lens on, and look at the angle. If you see sarcoid granulomatous… Because if you see other granulomas in the angle, those are Berlin’s nodules, you should check for serologic evidence and pulmonary evidence of sarcoid and look in the back of the eye too. Because there may be choroidal manifestations of the disease. In the case of Eales disease, how can the disease be attached to TB? That is a question that many, many brilliant people that are probably 100 million times smarter than I, have tried to figure out, for the last 50 years. And I don’t know the answer. Do we think that Eales disease is a retinal periphlebitis/vasculitis that occurs in association with TB? It’s so prevalent. I spent a year looking at long worm infections and their antigenic profile, and antibodies to those in serum from patients who have Eales disease. You know, we can’t find any specific correlation with TB. I will say this: That TB uveitis can be, as I mentioned in the lecture, kind of a presumptive diagnosis. So we use — and that goes to the next question. The role of PCR and AC TAP in TB diagnosis. That’s an excellent question. This is still a methodology that is in development. Fantastic world renowned specialists like Dr. Gupta — those people are working on a daily basis to try to see the value of these kinds of methods of diagnosis. So what they have used — vitreous samples, with PCR, for mycobacterium tuberculosis. They have appropriate primers to check for this. Those can be very useful tests in those situations. And the AC tap may be less — in my experience with these more — especially when you have posterior segment disease and more vitreous involvement, the AC tap may be less useful. And it may be less sensitive than the vitreous tap. For PCR studies. This is true, for example, in toxoplasmosis. Different disease process, but similar kind of principle. How do you differentiate TB multifocal choroiditis from white dot syndrome multifocal choroiditis? It’s a presumptive diagnosis. If you have a person who has a positive IGRA test, and they have evidence of latent tuberculosis infection in the lung, potentially, this makes you think of TB. So you have to treat that patient with at least treatment for latent tuberculosis infection. And then consider treatment of the multifocal choroiditis with corticosteroids. There are some interesting papers that have been presented in the last couple of years, that have been published, regarding TB therapy. There are a couple of papers from India, and a couple of papers from the group — the proctor group in San Francisco. Looking specifically at the value of antituberculous therapy in presumed tuberculous uveitis. Because this is a paucibacillary disease, many times only the additional of corticosteroids helped change the disease process and control the inflammation. So that makes you think… How much of this is us overreading the TB as a cause for the inflammation? But unfortunately, if we do miss those cases where TB is indeed the bacillary cause, the infectious cause, of uveitis, and treat those patients with aggressive corticosteroids and immunosuppression without appropriate antituberculous coverage, you run the risk of making a bad disease much, much worse, and losing an eye. And that’s something that I think we should keep in mind. Do you always ask for quantiferon TB for patients with serpiginous? Yes, absolutely, I always check that. No question about that. This is one thing that we should try to work out, rule out, especially if there’s vitritis associated with the serpiginous choroiditis. Could you tell us about a simplified chart that you follow generally classifying a uveitis case? So uveitis… I think of two broad categories. Okay? So uveitis can be differentiated into non-infectious and infectious. As a uveitis specialist, as an ophthalmologist, it is your duty to try to figure those two broad categories out. Because that differentiates how you then proceed with treatment. Then I use the morphology of the uveitis. Anterior uveitis, cells in the anterior chamber. Intermediate uveitis, the cells are mainly in the vitreous. Posterior uveitis, we have retinal and choroidal involvement. Panuveitis, no specific area, but all the areas are involved. Anterior chamber, vitreous, choroidal and retinal involvement. So morphologically, I will say… And then we look at unilaterality. Bilaterally. And then we go use the history. The history tells us a lot. Okay? So let’s say… And I have an 80-year-old woman who comes to my office, who presents with bilateral vision loss. She has a hypopyon in both eyes, she’s been having fevers of 103 and has been feeling very poorly, and her white blood cell count, her internist sent her over to me because of vision loss. She can’t see out of either eye, she has pain in both eyes, I know this patient has endogenous endophthalmitis and sepsis. I don’t even have to look at her. That’s how important the history is. You can do all the lab testing you want. In that patient with bilateral hypopyon, if you do HLA-B27, put her on oral steroids, she’s gonna die. You need to make sure you take a good history on this patient. So differentiation of non-infectious versus infectious, and then morphology, and then further honing down the differential, based on history, and then coming up with the laboratory evaluation. So that’s how I would do it as a flowchart for a general uveitis patient. Will I decide if I see the patient symptoms in anterior chamber he has tuberculosis or will I need other testing? Inflammation in the anterior chamber only… A lot of people will say… Well, why do I want to check for TB? I think TB doesn’t cause that. I always tell people that uveitis workups should include TB, sarcoid, and syphilis testing. Okay? So again, you look at — a clinical history should help you. If the patient doesn’t have any pulmonary symptoms, and they’ve been feeling fine, and they present just with a unilateral anterior uveitis, I’m not gonna check a PPD skin test on that patient. I have to have some reason to believe that. Oh, I went overseas. I spent 6 months in Laos, in a UN camp for refugees, and I came back, and I’m not feeling very well, and I got this uveitis. Well, I’ll be thinking about TB in that situation, certainly. And other infectious conditions as well. Next question. Can you have a primary sarcoidosis eye disease without systemic involvement? Absolutely. 25%, as I mentioned in the first slide in my lecture. 25% of sarcoid patients — uveitis patients with sarcoid — can present with only ocular disease, and that is the initial manifestation of the disease. Okay? 25%. A quarter. That’s a substantial group of patients. Minority of patients that have this condition. What are your tests you routinely request for uveitis patients for TB, sarcoid, and syphilis? Yes. So that’s an excellent question. Let’s start with syphilis. Syphilis. Do not get non-specific, non-treponemal tests. For example, a VDRL or rapid plasma reagent. Those two tests are non-specific tests, and they’re only useful when somebody has a chancre in their genitals, and you’re considering primary syphilis. Because uveitis occurs as a manifestation of post-primary syphilis. So only treponemal specific tests are useful for the evaluation of uveitis if you’re suspecting syphilis as a cause. So you should get an FTA, a fluorescent treponemal antibody, or an antitreponemal IgG. Most labs are doing antitreponemal IgG testing to evaluate for syphilis. Those are the tests you need to get. VDRL are useless. Those are transiently positive. The treponemal specific test will maintain lifetime you positivity. They will tell you whether or not there’s previous syphilis. They may not tell you whether or not the syphilis has been treated previously. So if the FTA is positive and you’re trying to rule out syphilis, in that case, history is gonna help you. Have you had syphilis before? This has to be a very up front conversation with the patient. So treponemal specific test for syphilis. The second test for TB I usually will get in my practice. An interferon gamma release assay, like quantiferon TB. In some cases, that’s not available, and I’ll use a purified protein derivative and administer it myself, intradermally. The third thing is sarcoid. For sarcoid, I typically will obtain a chest x-ray and an angiotensin converting enzyme level, lysozyme level, and serum calcium. Those are the things I typically do. A uveitis patient — should we always do which lab exam? I just mentioned that. So any uveitis patient, if you’re going to work up… The most important things are to rule out sarcoid, syphilis, tuberculosis. Those are the most important — that’s one of the — those things I want to have you take away from this talk. Okay? If you learn nothing else, remember those things. Now, that doesn’t mean you’re gonna find the cause in all these patients just by doing those three tests. You have to then add additional things to your tests or take away things from your testing, based on their history and clinical presentation. With that, I’m going to stop. I appreciate your involvement. And thank you so much for your attention. And I hope you all have a wonderful weekend.

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December 13, 2019

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