 I'm a bit of a low talker, can everybody hear me? Hopefully this will work. Thank you, Dan, for your introduction. It's been a great two years, two months short of two years. And at two months, I'll be moving to New York, where I'll have other residents to train. None is good, I'm sure. And buy shoes, all those things that attendings do. One of these three does not like to be photographed. This was a primary reason. It's been an interesting two years. I've learned a lot of retina, made some friends that grant with his beer fanny pack. And it's beautiful out here. There's so much to photograph. This was at Bryce last weekend. This was right behind the Moran, looking at the Ochre Mountains. And I learned how to ski. I thought I learned how to ski fairly well, but I was wrong. There's Dr. Vitaly. That's the face he makes when I'm doing a bit of a track to me. Kind of nervous. And here I go off in this letter, shame. My doctor says I'll be back. And Dr. Crandall says that if I, and I quote and pardon the rudeness, but he says if I present some retina crap, he'll let me come to his meeting and ski. I'll be talking about diagnostic issues in sarcoidosis. Some of you may know I have a background in ocular immunology in a life before retina. And this is a particularly challenging disease. And I find that making the diagnosis is difficult. And as ophthalmologists, we're often the first line in making the diagnosis. Sarcoidosis, the ophthalmic manifestations often come first. I'll start with a case that I saw back in residency in Virginia. Not much to do with retina, but a lot to do with sarcoidosis. This is a 37-year-old lady referred for a month of painless vision loss in the left eye. And her past medical and ocular history are unremarkable, as was her review of systems. Visual acuity, however, not so great in the left eye at 2,200. And she has a 1.5 log affron pupillary defect in that left eye. And you can see there is an abnormal left optic nerve and a lot of baller, an abnormal constriction of the visual field in the left eye. The right eye seems pretty normal. The wordry studies that were performed at the time by our neural ophthalmology service included ANA, ANCA, Bartonella, ESR, a lumbar puncture that was negative for cell count, protein, and cytology, a PCR that was negative for both HSV and VZV. Sorry for the omission. ACE and lysozyme specifically were normal. The high-relief solution chest CT was also normal. This is the MRI. You see this diffuse infiltration and enlargement of the left optic nerve extending into the pre-chiasmal left optic nerve, right optic nerve. It seems fairly normal. She was administered IV-soluble medrawl, started on a taper of oral prednisone. Her vision got better, and she was discharged with improving visual fields on prednisone 2100 with instructions to return in one week. She didn't. She came back in a year with worsening vision in both eyes, fluctuating vision in the left, no light perception in the left eye, 1.8 logaphrin pupil defect in 2020 in the right eye, visual fields completely dark in the left eye, and started to develop a superior and inferior arcuit scatoma in the right eye. Very worrying. So with little left to lose in the left eye, our neuro ophthalmologist, who does some orbital surgery too, elected to do an optic nerve biopsy. This is the MRI. You see enhancement of the left optic nerve, and now enhancement of both the left and the right pre-chiasmal optic nerves. Very engorge and large optic nerve with lots of vascularity. And a biopsy, I was lucky enough to get the slides from our pathologist. And you see these non-casiating granulomas. And this is a diagnosis of extra pulmonary sarcoidosis, sarcoid optic neuropathy. But what's interesting here and what highlights the difficulty in making this diagnosis is that the chest CT was normal. Lab testing was unremarkable. There were no other stigmata of systemic sarcoidosis. Sarcoidosis comes in many flavors. This is a patient in California with a granulomatous anterior uveitis, very fulminant. Patient here with coroidal nodules in both eyes turned out to be sarcoidosis. This patient was asymptomatic. Sarcoid can present with a surpigenous, a macular surpigenous-type appearance with these very scary-looking infiltrates in the macula. Subretinal fluid can mimic posterior scleritis with these RBE-level tiny little nodules. When you see this, it's almost always sarcoidosis. And this is a classic example of optic nerve granulomas. It can present as a vasculopathy. And although it's been reported to primarily present as a very venular vasculopathy, this is a patient who presented with a branch retinal artery occlusion in one eye, and then one year later with a branch retinal artery occlusion in the other eye proved to have sarcoidosis. This is an interesting patient from San Francisco who elected to get a Mayan eagle tattooed to her arm. And unfortunately, not quite the results she'd hoped for it enlarged. She has this big scar granuloma. And interestingly, every time she has this scar granuloma flare up, she develops this posterior uveitis, a choroidopathy, an inflammatory choroidopathy. And she could predict when her uveitis was about to flare by a span of one week when her tattoo would enlarge. And when I treated her with remicade, her tattoo never thickened again. Interesting. And scar granulomas have been described in sarcoidosis. So to summarize, sarcoidosis is a multi-system chronic inflammatory disorder of unknown etiology. Ophthalmic manifestations, I can't stress this enough, often comes first. It's often the tip of the iceberg. It's often the first thing that the patient is diagnosed with. And so it's important for us as ophthalmologists to make that diagnosis. Characterized by non-casiating granulomas, 30% to 60% of patients with sarcoidosis develop ophthalmic changes. Bilateral granulometous intraocular inflammation is frequent, although a large number of patients have non-granulometous uveitis as well. It may occur in the absence of apparent systemic involvement. That doesn't mean that systemic involvement will not occur. Only one third of patients with pulmonary sarcoidosis have symptoms, and two thirds of radiographic abnormalities, or bilateral, hyaluridinopathy, may resolve. And what's important to take on from this side is that pulmonary and extra pulmonary manifestations may be temporarily discreet. You may have uveitis one day, that may resolve, and then you develop pulmonary abnormalities. But what's more important is that when you see a patient with uveitis, you work him up with a chest x-ray, and you don't find bilateral hyaluridinopathy, it may have been there once, but disappeared. So the chest x-ray, although it's pretty good for finding adenopathy, may not pick it up at that particular time. So a group of very smart people led by Dr. Narsing Rao got together and came up with a series of clinical science laboratory investigations and biopsy results and provided us with four diagnostic criterias of sarcoid uveitis. And what was interesting about this consensus panel was that they came up with a list of clinical signs that they felt were suggestive of sarcoidosis and warranted further validation. These were granulometers, keratic precipitates, granulomas, or nodules, capinodules, on the iris rough, nodules on the face of the iris, trabecular meshwork nodules. More common than you would think. We never look for them. Tent-shaped BAS, when these resolve, perfluenteers in Ikea, snowballs or string of pearl vitruous opacities, macroaneurisms in the presence of vasculitis, bunched out PRP, like caroidal lesions, optic nerve granulomas, peri-vasculitis, specifically peri-venuritis, with candle wax dripping like infiltrates, with peri-vascular clustering of caroidal nodules thought to be particularly indicative. The laboratory tests that they suggested would be done include energy or assessing for energy. In this country, candle energy can be used, but in countries such as where I'm from, where you get a BCG, a negative PPD or Montoskin test in the presence of BCG inoculation. ACE and lysozyme, chest x-ray and CTs testing was thought to be useful. Abnormal liver enzyme test based on a report previously that said that almost all patients with sarcoidosis get small granulomas in the liver. And a lot of the panel thought that this was going to be useful. And as far as the diagnostic criteria categories are concerned, they came up with definite, presumed, probable, and possible sarcoidosis, where definite involves biopsy evidence and a compatible uveitis. And possible involves a negative biopsy for suggestive clinical signs and two positive lab tests. Presumed and probable involve radiographic evidence or suggestive clinical signs, but no biopsy attempted. In an attempt to validate some of these ocular findings, this group in Japan looked at 50, not a very large number, but 50 biopsy proven patients with sarcoidosis. And they found this, and they compared them with 320 inflamed control isopatients with bachettes and other vasculitis, et cetera. They found that more than half of the patients with biopsy positive sarcoidosis and associated uveitis had more than four positive clinical signs. So this is a test, a clinical examination as a test seems to be pretty good. Moreover, they looked at each of these signs individually for positivity within these 50 patients. And they found that bilaterality is almost the rule. So if you see a unilateral uveitis, it might not be worth your while to get Ace and Lysosine. Otherwise, the positivity of all of these signs is greater than the positivity in the control uveitis. Bear in mind, though, that there were 320 control uveitis cases and only 50 sarcoidosis cases. Similarly, when the lab values were looked at, almost 89% of these patients had, or 34, had a negative DB test. It's unclear which ones of these were BCG inoculated. And our Lysosine were elevated in 62%. Hyaluridinopathy was seen in 72. And just CT imaging proved abnormal in 86%. Liver tests proved to be, at least in this cohort, not a useful test. Earlier on, looking at an earlier iteration of the same workshop on sarcoidosis, this group in 2008 looked at 100 biopsy-proven patients with sarcoidosis. And they compared it with 147 non-sarcoid patients with various forms of non-infectious uveitis. And they looked at examination as a test for the disease. And they found that when two or more of these six criteria for diagnosis of ucalar sarcoidosis were positive on examination, then the sensitivity of examination as a test for sarcoidosis was 84%. The specificity was 83%. My problem with the study is that the validity of the sensitivity and specificity numbers cannot be discerned when you read the text. Because I really haven't talked about their specific numbers of people with each specific sign. What's interesting is retinal prairie phlebitis with prairie vascular nodules category 4 was actually fairly specific. So if you see that, go further in your testing. And we'll go through the various lab diagnostic tests that we use as ophthalmologists in sarcoidosis. I doubt any of us really use energy anymore. But ACE and lysozyme, it's useful to discuss these. ACE is elevated in 60% of patients with biopsy-proven sarcoidosis in some studies as high as 70. But do bear in mind that this test measures not the enzyme itself, not the presence or the quantum of the enzyme itself, but it measures its activity. It's an enzyme activity study. So if a patient is on ACE inhibitors, don't bother getting the test. If the patient is a child, don't bother getting the test either because almost universally in children, ACE will be high. Lysozyme, in some studies, elevated, perhaps, a little more frequently in biopsy-proven sarcoidosis than ACE. And in this study with biopsy-proven pulmonary sarcoidosis here, lysozyme levels were elevated to 80%, only 25 patients, though, more so than ACE levels. And lysozyme closely paralleled improvement in pulmonary function. Once again, a small study, and this is lysozyme levels in pulmonary sarcoidosis, a much larger structure than the eye. So in isolated ocular sarcoidosis, this may not hold true. Lysozyme, however, may be positive, such as ACE may be in TB, leprosy, osteoarthritis, and perinicious anemia. The first two hold true for ACE as well. So it should be ordered with caution. And a good medical history is important. Energy, as I said, negative responses to subcutaneous antigens. Useful in some studies as frequent as 90% of patients with ocular sarcoidosis exhibit some form of energy. And as far as imaging is concerned, the two most common ones are just CT imaging and just X-ray. Now, radionuclide techniques, I can count in the fingers of one hand the number of times I've used this in diagnosing sarcoidosis and looking at my UVIS patients. And I find that it has been useful in perhaps two cases where biopsy sites have been identified, one in the skin and one in the lacrimal gland. Just X-ray, bilateral hyaluradenopathy is what is seen in between 59% and 89% of patients. The just X-ray is abnormal, and that's speaking of atollectasis, interstitial pulmonary issues in between 85% and 95%. It is, however, a poor way of evaluating interstitial pulmonary disease. And as I'd mentioned before, abnormalities, radiographic abnormalities specifically, just extra abnormalities may be transient. And may not occur at the same time as your ocular abnormalities. Just CT is a better, though far, far more expensive way of evaluating the lungs for sarcoidosis complications. And lymphadenopathy is visible in 86% to 94%. It's also better than the just X-ray for evaluation of the lung per incoma. Most likely because it is a better way to assess the mediastinum and the axillary regions. Speaking to the pulmonologists, they recommend for evaluation volumetric scans, which are today's spiral scans with high resolution cuts at two different sequences. Look at the mediastinum and the lymph nodes and the pulmonary hyalum. And then also look at the interstitium, the lung per incoma. The American Thoracic Society suggests that CT be performed in these three instances when you're suspicious for sarcoidosis, atypical clinical or chest radiographic findings, detection of complications that are superimposed on infectious pulmonary issues or neoplastic pulmonary issues. A normal chest radiograph, when you have a normal chest X-ray, but have strong clinical suspicion for sarcoidosis, and based even on your ophthalmic findings, the chest CT is probably indicated. The older imaging technique involving radionuclides is probably be gallium citrate scanning. It's useful for localizing involvement. One must be cautious, however, just because you see increased uptake in the lacrimograms does not mean you have sarcoidosis. 25% of patients without sarcoidosis have increased uptake in their lacrimograms. I've used this test once, and that was only to look for lacrimogram involvement. And it's fairly useful. The pulmonologists use fluorideoxyglucose PET for assessing the activity of pulmonary fibrosis, because, as you know, that can be fairly static, but not very frequently used by us as ophthalmologists. Which takes me to biopsy. As ophthalmologists, we can contribute to patient care by finding sites to biopsy. And the lacrimal band is one structure that has been concentrated on for the last 20 years, when people have been looking for ophthalmoses. Conjunctival biopsy is a controversial topic. Vitrious TAP is something emerging. The first meaningful publication on that was the middle of last year in the journal Ophthalmology. Bronchoscopy, you refer to the pulmonologists when you think there is an issue. Sarcoidosis can affect the lacrimal band fairly frequently. This is the case in JAMA in 93, where there was gross involvement of the lacrimal band. And biopsy was performed making this diagnosis. Why the lacrimal band? Well, the incidence of caric conjunctivitis sicker is between 7% and 16% in sarcoidosis, so fairly higher than the general population. And gallium scanning demonstrates lacrimal band involvement or uptake in 83% of 61 patients in this study. And really, even in the absence of involvement, because in that same study, enlargement was only present in 10%. Now, as a test for sarcoidosis, that lacrimal band biopsy has a pretty poor record in this study and others. But when there is enlargement, 60% and 4 of 7 showed positive biopsy findings. So in conjunction with gallium scanning and in conjunction with orbital imaging, it might be a good way to make the diagnosis. The same group talks about 100 patients in whom they did a lacrimal band biopsy in the office by having the patient adduct and infra-duct and taking a piece of the apex. They report no complications. They did Schermer's tests on everybody afterwards. Conjunctival biopsy, as I said, is controversial. Whether or not it's a valid way of looking for sarcoidosis is up in the air. But in this paper in 77, with 100 conjunctival biopsies in patients with already histologically confirmed sarcoidosis, a positive biopsy was present in 33%. And these authors report that biopsy positivity was independent of the presence of nodules and follicles. This later study demonstrated biopsy positivity in 19 of 34. In this particular series of cases, they found that conjunctival biopsy was more likely to be positive in patients with ocular abnormalities consistent with sarcoidosis. And if the patient had follicles, they were more likely to have a positive biopsy 80%. In China, they looked at blind conjunctival biopsy, blind bilateral conjunctival biopsy in patients with ocular features, and they found positivity in 33% irrespective of the presence of follicles. And most recently, I believe it was July in 2012, this group in Japan looked at vitrectomy specimens where a number of eyes with 15 eyes with definite biopsy proven elsewhere, sarcoidosis, had their vitreous analyzed for CD4, CD8 ratios. And this ratio was 70, 70 to 1, so really high. And they compared it to patients with 27 patients with inflamed control eyes, a non-sarcoidosis inflamed eyes. And this ratio, the CD4 to CD8 ratio, was 2. So although this wasn't a very large study, there was a significant difference between the CD4 and CD8 ratios. And maybe vitrectomy, and perhaps even anterior chamber tap in an inflamed anterior chamber, may be a useful way to look for or to increase your suspicion for sarcoidosis. And lastly, don't be scared to send a patient to a pulmonary analysis. If you see by hyaluridinopathy and gestational pulmonary disease, these guys are pretty good at finding biopsy specimens. 46% yield in blind transbronchial needle aspiration biopsy. And what people tend to do more of now is ultrasound-guided endobronchial needle aspiration biopsy, 86% positivity in this very large study. So I guess the question begs to be answered. Why make the diagnosis? Why do we go through all these lengths to make this diagnosis of sarcoidosis? Well, first of all, as ophthalmologists, you may be the first person seeing the disease. You may be the first person to make the diagnosis. And this has ramifications on patients' systemic prognosis. If you have sarcoidosis affecting the eye, if the patient comes in with breathlessness, you're less likely to shrug it off and say it's just old age. It has prognostic implications in ocular inflammatory disease. Patients with sarcoidosis are more likely to have chronic disease, more likely to have chronic vascular insufficiency, ischemic retinopathy, and acistoid macular edema, and are more likely to require immunomodulatory therapy. Now, with the, there was a biologic declusema that is no longer available. But it was very specifically, it was very useful in patients with sarcoidosis, and when patients were diagnosed with that, the guys at my institute would often start them on declusema. Now, with the absence of that drug, it's no longer available. There will be other systemic immunomodulatory agents that are specifically targeting sarcoidosis. So once pathways are identified that can be targeted in this disease, this will be a useful, it will be very useful to make this diagnosis. And lastly, a real world medicine thing. If you have a patient with an ocular diagnosis, you're far less likely to get approved for systemic immunomodulatory treatment. You're far less likely to get insurance approval for a biologic, for instance. So for insurance purposes, it's important to make this diagnosis. Ocular features of sarcoidosis have been identified, but statistical validation of these features are not yet adequate. The way we like to practice is if ocular features are suggestive of sarcoidosis, and you have bilateral disease, then order the first-line test. Do not order the test if you have a unilateral recurrent alternating non-granulometous UVA just because your pre-test probability is awfully low. Biopsy easily accessible sites if possible. This helps make your diagnosis. Feel free to send the patient to the dermatologist or the pulmonologist to make further assessments. And consider further testing only if primary tests are negative and clinical suspicion still exists. Although the IWS criteria are not validated, it's useful if you see two or more clinical signs of ocular sarcoidosis to have a rather low threshold for obtaining at least a chest CT and possibly a pulmonology console. I'd like to thank Dr. Acharya in California, Dr. Vaidali for their help and the photography teams that were on UCSF and UVA. You guys should sign your work. Thanks. Happy to ask any questions. Yes, they didn't mention that. However, sarcoidosis is often bilateral on set, and it's often asymmetric. So the symptoms may be unilateral, but if you look hard enough, you may find signs or at least some cell or inflammatory stigma in the other eye as well. It is, that's a good point, but remember that I don't think we should have a knee jerk response. We should not immediately order ACE and Lysosine for every patient who comes in with UVA. Because if you do that, I mean, it's not a very good test. 62% means it neither rules in nor rules out the disease. And having a test that you can do little with or a test that makes you order very, very expensive follow-up tests, it may not be a good idea until you're sure it's necessary. We obviously look at it. It's important not to. And you have a review, does it, yeah, that's sarcoidosis. I would say it's fairly high. There was a very small study that showed a very large number of patients with or large proportion of patients with intermediate UVitis who had no symptoms at all. So they were referred by their pulmonologist for evaluation of their eyes. And sure enough, there was a cell in the anterior vitreous. And would you treat that? No, absolutely not. Absolutely not. Yeah, all right. Thank you. Thank you.