Lecture: Laboratory Work Up of Uveitis Patients & Case Studies

During this live webinar, the evaluation and laboratory work up of a new patient with uveitis with be covered. The role of history and clinical examination, along with the importance of an associated targeted laboratory evaluation, will be discussed. Case examples will also be presented.

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


[Bob] Good morning, respected colleagues and friends. I am very honored that you would show up today in whatever time zone you are. It’s early, mid-morning here, about nine o’clock in Indianapolis, Indiana. And today I thought I would talk a little bit about the work-up of the uveitis patient, specifically looking for the cause of uveitis. My name is Ramana Moorthy, you can call me Bob, also. I’m a clinical professor of ophthalmology at the Indiana University School of Medicine and have been in practice for about 27 years here in Indianapolis as a uveitis and retina specialist. This particular topic is something that I’ve explored in trying to teach to many people. I’m hoping that we will have a chance to discuss this in detail.

How do we classify uveitis? The modern classification system is really one where we separate the etiologies into non-infectious and infectious uveitis. We used to call the non-infectious conditions so-called autoimmune, there may be underlying systemic immunologic abnormalities. But the idiopathic variety, where we cannot find a cause, account for the majority of cases of uveitis that we see. In fact the majority of cases are probably idiopathic or the work-up is completely negative from a review of systems as well as a clinical laboratory standpoint. And we cannot find any infectious causes which is the second variety of uveitis. In my mind, uveitis is either non-infectious or it’s infectious. The infectious group we can separate those into viral, of course, and bacterial causes. And under bacterial, of course, the major big two players that we worry about are tuberculosis, and many of you in some parts of the world where TB is endemic, it is a difficult diagnosis to make many times. Because many of those patients may have a positive test for, QuantiFERON test for TB or a positive PPD. But based on the clinical criteria that you use in the diagnosis of extrapulmonary or pulmonary TB, you have to use all of that information together to deduce whether or not the inflammation is caused by tuberculosis. Fungal, protozoa, and helminthic causes are also important things to keep in mind. Remember also that toxoplasmosis most often acquired these days, acquired infection from unfiltered drinking water sources, or potentially undercooked meats et cetera, undercooked produce, or contaminated produce. Those seem to be acquired diseases that are very common and accounting for more than half of the cases of toxoplasmosis which is still probably the most common infectious posterior uveitis.

Helminthic causes are also present. These are rarer in our area of the world but they may be more common in the tropical and subtropical regions of the world. And there is also another group of the so-called non-infectious conditions that are masquerade syndromes that can include neoplastic and non-neoplastic causes. By and large, anterior uveitis, another way to classify the uveitis is based on the anatomic location of the inflammation. By and large, anterior uveitis where the inflammation is in the interior chamber or you’re seeing cells and flare detected by the slit lamp using the highest illumination setting on the slit lamp, as well as a beam width of millimeter and a beam length of 2 millimeters. And a way to standardize the amount of cellularity and the amount of flare in the anterior chamber that describes where the information is. And that is by far the most common type of uveitis that we see in atomically.

Intermediate uveitis is actually very common and probably the most common form of uveitis in children is Intermediate uveitis. Where we see mainly inflammation in the anterior vitreous, sometimes going into the posterior vitreous, and sometimes associated with periphlebitis, and other changes, and secondary complications such as cystoid macular edema.

And of course, posterior uveitis where we see involvement of the retina and the choroid with inflammatory cells spilling over to the posterior vitreous. And panuveitis where we don’t have a specific area, that is, but all the uveal tract is involved. So it’s not predominantly one part of the uveal tract that’s involved and in those cases we call it panuveitis.

We can also classify uveitis based on the time course. Whether it’s acute, meaning it’s lasting less than three months old, if it’s chronic if it’s more than three months old, if it’s a recurrent if it has three months of disease-free activity off of therapy in between episodes. Versus chronic disease, which even if you have relapses they occur in less than three months of being off of therapy.

This is a beautiful picture from Emmett Cunningham of anterior uveitis at the slit lamp and you can see this is probably 3+ cells in the anterior chamber, there’s some irregularity of the margin of the pupil. And you’ll see the cells and flare. Let me just go back for a second here just so that we can do this. And you see, also, the little corneal edema. But this is how we measure this two by one millimeter beam, and count and hey, how many cells are there? So this is a 3-4+ inflammation according to the standardization of uveitis nomenclature that we use.

I’m going to start out with the first poll question, see if you were listening. What is the most common anatomic type of uveitis encountered in clinical practice? Intermediate uveitis, anterior uveitis, posterior uveitis, or panuveitis? The answer, of course, yeah. Everybody’s listening. That’s great. Anterior uveitis is definitely the most common clinical form of uveitis that we see anatomically in the clinic.

How do you determine what’s causing this inflammation? It seems to be a question that the patient is always frustrated about or the physician ends up being frustrated about. Especially when we do an extensive evaluation and we can’t find a cause. The key to determining the cause of uveitis, the key to understanding the disease itself, more than even determining the cause, because you want to be able to tell the patient what to expect, is to really obtain an accurate and thorough history. Know the history of the ocular disease, when did it start? How have you been treating it? How long has this been going on? And how many other? Has it been episodic? Has it been non-episodic and chronic? Was it associated with pain when it first started? Or was it just blurred vision and the eye was white or quiet indicating more chronic disease? And these are things about the actual disease process.

And then broaden your questioning about systemic health. Look at the history and physical form they fill out, if you use a form like that in the clinic, look at what medications they are on. That can tell you, a patient may not know that they have, believe it or not I have patients that don’t know they have diabetes. They insist they don’t have diabetes but they’re on Metformin for the last 10 years. Well, why are you on Metformin? People aren’t given it for some other reason. I think it’s important to look at the medicine list and then look at what diagnosis they put down for themselves in terms of what they’ve been treated for. Look at those things that can help you look into the history more closely and narrow down your questioning.

But when I perform a review of systems for the uveitis patient, I really do spend a lot of time specifically talking about the integumentary system so the skin. Have you had any skin rashes? Have you had any painful lumps or bumps underneath the skin or red spots underneath the skin? Have you had any skin lesions that look like little tumors or bumps that needed to be biopsied? Or have you had treatment before for a skin disorder? Have you had any fever blisters on your lip? Herpes labialis lesions history? Have you had history of shingles recently? These kinds of things are common questions that we ask about the skin. Then I also asked about oral mucosal lesions, like oral aphthous ulcers, if they have been present. Then I move onto the pulmonary system and ask about the presence of chronic non-productive cough, shortness of breath, a new onset of problems with shortness of breath, or difficulty with exercise tolerance. Getting winded very easily, unable to climb a set of stairs like they used to before. That can sometimes give you clues about pulmonary disease such as sarcoidosis, especially if it’s acutely active.

The next thing you can also do is potentially ask about the gastrointestinal system. By the way, the pulmonary system I ask about TB exposure and whether or not they’ve been treated for TB if they come from endemic areas of the world. Because of world travel before the pandemic, we had a lot of people going to places where there’s TB endemicity. And they come back and they may have acquired TB, et cetera, depending on what their exposure is. I asked about those kinds of things.

And then on the gastrointestinal side, I ask about abdominal pain, recurrent diarrhea, bloody diarrhea, history of previous diagnosis of inflammatory bowel disease, or hey, I’ve had a colectomy for ulcerative colitis. These kinds of things can be exceedingly helpful. Then I move on to the genitourinary system and ask about recurrent urinary tract infections that we might see in conditions like reactive arthritis, what used to be called Reiter’s syndrome. And I may ask about genital ulcers, which may be a difficult topic to cover in many patients in the clinic setting.

And then I move on and speak to the patients about specifically axial arthropathy and arthritis, as well as peripheral arthropathies and arthritis. Have you had any red, swollen joints in your hands or your feet, your wrists or your ankles? Have you had any specific problems with chronic hip and low back pain? Or early morning stiffness that improves with movement? Have you been treated, have you had back problems that you have seen a doctor for? These kinds of things can be very helpful in delineation of presence of seronegative spondyloarthropathies that are associated with uveitis.

And then I specifically talk about animal exposure. If they have cats at home, if they’ve had exposure to unfiltered water or drinking sources, those things that help me think about other sources of infection or inflammation. Infectious uveitis, for example, that may occur from exposure to toxoplasmosis or other things. And then I specifically ask about travel history of the patient. It’s a fairly detailed history, but you can go through it relatively rapidly in most patients.

But then after that I do an exam. And the exam is important. I know many of you, when I consult, often don’t give me the findings in the slit lamp exam and that may be because of the availability of instrumentation and so forth. But the slit lamp exam and microscopic examination for cells and flare in the anterior chamber, the presence of anterior segment complications of uveitis, such as presence of posterior synechiae, posterior subcapsular cataract. Interact intraocular pressure issues in glaucoma, angle closure, iris Bombay, those kinds of things you can really only see microscopically at the slit lamp. And a biomicroscopic slit lamp examination is very important to an analysis of the uveitis patient.

And then, of course, the evaluation of the vitreous, the presence of vitreous cells, and then the presence of the appearance of the optic disc, the vessels of the retina, the macula, the presence of edema, the presence of any retinal lesions, choroidal lesions. The evaluation of the peripheral retina, including scleral depression looking for pars plana exudates, if there’s vitreous, all those kinds of things are important facets of the ophthalmic examination.

A general physical examination may or may not be in your area of interest but if there are specific findings that the patient says that they have like a skin rash, look at it. Take a picture of it if you can, if the privacy laws allow. And I would recommend that you do that because that can often be very, very helpful. Once you’ve done that or once you’ve gotten an overall picture, then you begin the idea of laboratory testing or tissue biopsy, which may help confirm or narrow the spectrum of the etiology.

The lab testing isn’t a substitute for the history and physical. Many times I find that after I’m done with my history and physical, I order lab tests but it’s very, very limited testing that I do. Unless the patient specifically tells me that there have been systemic changes or problems or I note physical examination findings that push me in that direction. A shotgun approach to laboratory testing and ordering lots of tests is often not very meaningful.

And if an infection is suspected in a tissue in the eye, you’re going to need to do cultures or even Polymerase Chain Reaction evaluation, or PCR testing, for fluids or tissue. And if neoplasia is suspected, a tissue biopsy, of course, is going to be essential and these are going to be determined by your clinical examination and your history.

We already talked about all of this. A family history is sometimes important too, especially if there’s lupus in the family history. If I’m seeing someone who has retinal vascular inflammation, and vascular occlusions in a young patient, there may be a strong history of lupus, especially in African Americans in our part of the world. There may be history of sarcoidosis in the family too, there may be other things that run in the family, seronegative spondyloarthropathy, things like that.

A social history like smoking, travel, occupation, drug use is, of course, very important as well. Smoking is an important risk factor for chronic uveitis in persistence and stopping smoking can have a positive impact in the management of chronic inflammatory disease in the body. We talked about systemic illnesses. I also, though I didn’t touch on a lot of things that we’ll hit here again, in addition to the questions I’ve already asked. Asking about constitutional symptoms like fever, chills, and weight loss. Nutritional status: how do they look and how are they eating? Have they had weight loss? And then whether or not they’re immunocompromised. Are there, and this is going to be based on your history and what medications they are on. And if they have risk factors for HIV-associated disease. And then, of course, recent surgery to the eye or trauma to the eye can also be helpful.

And then we talked about best corrected vision, pupillary function, motility, confrontational fields, these are all part of the examination. More than any other sub area of ophthalmology, I do believe strongly that uveitis requires the broad knowledge of all aspects of ophthalmology. Because uveitis, unfortunately, is going to affect all of the tissues in the eye. Whether it’s complications related to the disease or direct structural changes occurring from the disease itself.

These are very important things that I cannot emphasize the importance of the slit lamp examination. When we look at the conjunctiva, it’s very important to flip the upper lid and look at the palpebral and bulbar conjunctiva, the upper lid as well as the lower lid, when you’re looking at somebody, for example, who has granulomatous inflammation. Because you may find that granuloma that you can biopsy and you have then a clinical diagnosis of sarcoidosis. And you’ve done everything, you know what the patient has, you know what the cause of the inflammation is. This is a directed biopsy of something that looks like granuloma. These are very, very important. I may have a picture of that to show you in a little bit.

Look at the cornea evaluation. The corneal changes can sometimes suggest herpetic disease. Look at the size of the KPs, that can tell you whether their large, granulomatous, and chronic or small and non-granulomatous, or even stellate in the case of Fuch’s heterochromic iridocyclitis or even CMV retinitis, for example. You can look at the appearance of the anterior chamber, or the structure of the iris, presence of transillumination defects, and iris atrophy, heterochromia, presence of synechiae. Nodules on the iris if they occur in the margin, those are called Busacca’s nodules, I’m sorry, Koeppe nodules and if they occur in the stroma, they’re called Busacca’s nodules. Presence of cataract. And then, of course, intraocular pressure and evaluation of the angle by gonioscopy. Especially if the patient has low intraocular pressures or high intraocular pressures. And, of course, we’ve talked about the evaluation of the fundus.

The laterality of the inflammation can be helpful. Unilateral cases with high intraocular pressure suggest herpetic disease or toxoplasmosis. Sectoral iris atrophy unilaterally may suggest the presence of herpetic disease, as does corneal scarring unilaterally. But it’s not always helpful because many seronegative spondyloarthropathies like HLAB27+ anterior uveitis are often unilateral in presentation. Scleritis may be unilateral at presentation as well.

Then look at the non-ocular clinical cues, they can be very very helpful. If you have a vesicular dermatomal rash involving the cranial nerve five, the division one distribution with nasociliary branch involvement with Hutchinson sign as you see in the top picture here. This patient has zoster-related inflammation. See, incidentally, also turned out to be HIV positive. This patient had very severe ocular disease.

And in the second picture if the patient has this desclemating exanthematous rash, I wouldn’t shake hands with that patient because they probably have active spirochetes that they’re going to share with you. This patient most likely has post primary syphilis. And the inflammation that you see in their uveitis is likely due to syphilis. And if they have this kind of a target lesion, this erythema chronicum migrans lesion from a tick bite, that may suggest underlying lyme borreliosis.

This is one of my patients who had severe intermediate uveitis and was HLAB27+. Not the typical presentation of intermediate uveitis but the patient has very severe psoriasis. So severe, in fact, that he was going to commit suicide because of his clinical appearance, this poor gentleman. He did very well once we started him on Humira therapy and psoriasis and the inflammation went away.

This is a patient that has systemic sarcoidosis with Heerfordt’s syndrome with parotitis and also dacryoadenitis, inflammation of the lacrimal gland. These can be very helpful, glandular inflammation like this with panuveitis is highly suggestive of sarcoid.

If somebody has a hypopyon, is it sterile? Is it infectious? Is it neoplastic? In the infectious cases, specifically of uveitis and we’re not talking about hypopien here, I’m sorry for the confusion of the slide. But there’s a purpose to that slide I’ll get to in a minute. But the infectious conditions, toxoplasmosis, you know the clinical appearance. The clinical appearance of many of these disease processes, the mental picture that you have of how that disease is going to look is going to help you delineate the etiology. In toxoplasmosis, we’ll typically see a unilateral focal choroiditis. I’m sorry for the misspelling, choroiditis in one eye. And often there may be anterior segment Inflammation in the patient and the intraocular pressure may be elevated in many cases of toxoplasmosis.

In herpetic disease with anterior uveitis, you may see corneal changes, iris sectoral, iris atrophy, the intraocular pressure will likely be elevated and increased. And there may be diffuse small KPs localized over the areas of corneal involvement or diffuse involvement. And some of them may be dendritic appearing keratic precipitates or smaller KPs, but not necessarily.

There may be, in late onset endophthalmitis, for example, there’s a history of pseudophakia, presence of characteristic capsular opacificaties that you see in propionibacterium acnes associated with endophthalmitis. In aspergillus endophthalmitis, there’s usually a necrotic granuloma in the posterior pole, very characteristic appearance. And CMV retinitis has very characteristic four patterns of appearance that you can fish out. Including the classic pizza pie appearance or granular or brush fire or frosted branch angiitis appearance. And toxocariasis has three manifestations, including the peripheral granuloma, focal macular granuloma, or diffuse endophthalmitic form. There are many different things, pictures, if you will, clinical pictures that help up with this pattern recognition. I really think this pattern recognition part is also really helpful and it comes from experience. So seeing a lot of patients who have inflammation, inflammatory disease and putting it together in your mind is very helpful coming up with a diagnosis.

On your top left, these are different kinds of hypopyon that we see. Let’s look at this first hypopyon on the top left. This is a patient who had exposure to Rifabutin because he was being treated for mycobacterium avian infection. He was an immunocompetent patient, interestingly, who had severe pulmonary disease, COPD, and he got a secondary infection. And this patient was being treated with a relatively high dose of Rifabutin and developed a hypopyon anterior uveitis. He was HLAB27-, he reduced the dose of the Rifabutin and he was able to tolerate the medication and the inflammation was treated with topical drops and it went away. This is drug-induced hypopyon.

And then you see the endophthalmitis. A patient who had cataract surgery five days earlier presented with severe pain and vision loss and hypopyon. You can see the steamy corneal appearance, and this hypopyon there was fibrin in the anterior chamber.
White keratin pain and vision loss after surgery, so this is a postoperative endophthalmitis.

And in the bottom left, you’ll see a patient who has a pseudohypopyon. It’s a white, quiet eye with a hypopyon. He had received an intravitreal injection of preservative-free Triesence and had developed some anterior migration of the medication around the intraocular lens and this ended up in the anterior chamber. So that’s a pseudohypopyon. And this would move around when you lay them flat and will lay around on the intraocular lens.

The last one, the bottom right, is the characteristic hypopyon of Behcet disease. It certainly could mean some mild injection of the conjunctiva, but this patient has an ephemeral hypopyon. If the patient were to sit up and shake their head, a hypopyon would disperse. Unlike the congealed hypopyon that we see with endophthalmitis or in some cases a very severe HLAB27-associated disease.

Vitritis. This is a picture of clinical appearance of dense vitreous haze in a patient that has posterior segment inflammation. Here is a typical appearance of toxoplasma retinochoroiditis. This is a patient who has a focal area of choroiditis. This is an 11-year-old boy that presented to us. You can see there are some retinal hemorrhages. But if you look very closely in this, this is a very characteristic finding of the patchy, vascular sheathing along the retinal vessels. And this can involve the arterials as well as the venules. This is the so-called Kyrieleis’ vasculitis. This is a very mild version of it, there are much more dramatic versions and pictures of this from toxoplasmosis. But this patient had elevated anti toxoplasma IgG and IgM titers and had an acquired disease.

One other thing in the differential to think about in a child who may present with focal choroiditis is bartonella-associated disease. They can look identical or very similar. Bartonella titers, bartonella quintana and bartonella henselae IGG and IGM titers against those two organisms, may also be helpful if your lab offers those tests.

Here is a patient who has tuberculosis panuveitis. This patient has anterior uveitis and had multiple of these small, yellowish focal spots, choroidal and outer retinal lesions, and large choroidal granuloma, and some significant inflammation of the retinal vasculature as well. Very characteristic findings of tuberculosis panuveitis.

Here is a patient that has, this is a famous photograph, it’s a little blurry image, I apologize. This is an image from Dr. Narsing Rao, my mentor, of a patient who has the so-called serpiginoid choroiditis associated with tuberculosis. This is a multi-focal inflammatory disease caused by TB, this is a very advanced disease. This patient has almost completely wiped out their macula. Anybody who presents with serpiginoid lesions and inflammation of the vitreous, you should do an evaluation for TB. This can be a manifestation of extrapulmonary TB.

This is a patient who has neuroretinitis associated with a macular star with ocular bartonellosis. Remember, however, although this Is a fairly characteristic presentation, the most common presentation of Bartonella infection in children, in particular, is focal choroidal inflammation. They can look, as I said, they can be small areas of choroiditis that occur in the posterior pole and they can be unifocal. And they will often have an elevated Bartonella henselae or quintana IgG and IgM titers.

This is a patient who has AIDS, who has cytomegalovirus retinitis. And this patient had very low CD4 counts, they were zero. And presented with hemorrhagic necrosis of the retina. The central portion between these two white areas is where the necrosis has subsided and once it subsided it leaves behind a very thin, atrophic retina that is prone to have holes. Sometimes you can see perivascular clearing in these herpetic retinitis, this is a patient who has zoster-related acute retinal necrosis syndrome or necrotizing herpetic retinitis. Here you can see these large, we call this a so-called thumb print necrosis appearance and you can actually, I’m sorry, you can also see perivascular clearing that is occurring as the disease is fading over time.

This is a patient where the systemic findings helped make the diagnosis. You can see the patient has oral aphthous ulcers, a hypopyon, and in the bottom right, evidence of retinal vascular inflammation. In the bottom right picture, you can sometimes confuse that with a viral retinitis because it can look identical. Behcet’s disease, Behcet-associated retinal vasculitis can often be associated with whitening of the retina and that whitening can be confused with necrotizing herpetic retinitis. That is in the differential diagnosis. I am telling you this because I have been burned by that many times. I’m thinking that the patient has acute retinal necrosis and placed them on antiviral therapy and it doesn’t work. Or I’ve done the opposite where I think, oh, they have occlusive vasculitis, this could be Behcet’s and they get worse or progress very rapidly. So you have to monitor these patients carefully if you don’t know. And today, fortunately, we have the ability to do an aqueous tap on these patients and send it for PCR evaluation in the laboratory, with a small amount of aqueous, looking for HSV1 and 2, varicella zoster virus, and cytomegalovirus. And that PCR is usually very helpful diagnostically when we’re dealing with patients who may have necrotizing herpetic retinitis. And differentiating from other causes of things that look like retinitis like Behcet’s vasculitis.

This is a patient who has very characteristic findings of Vogt-Koyanagi-Harada syndrome. This patient has bilateral panuveitis with multifocal choroidal inflammatory disease, exudative retinal detachments. The fluorescein angiogram shows the characteristic starry sky pattern of focal leakage with pooling of fluorescein in the late phases of the angiogram in the subretinal space. And in the later stages of the disease, has this sunset glow fundus that you see at the bottom middle and multifocal choroidal lesions inferely. I apologize for my slides, they keep shifting because of my mouse. I’m trying to move the mouse and I accidentally am moving the slides. My apologies.

And you can see also this patient has very characteristic poliosis, he’s only 20-years-old, has very white eyelashes and also has vitiligo on the lid skin. Very symmetric appearing, very interesting appearance to a classic Vogt-Koyanagi-Harada syndrome.

This is a patient, for example, who has HLAB27-associated fibrinous hypopyon uveitis. There’s a small, congealed hypopyon and a plasmoid aqueous that’s a lot. If you did the flare and cell rating you would see this would be a 4+ flare, because it’s a plasmoid aqueous, there’s nothing moving in there. You may see some cells in the aqueous component which may be very thin, but the entire anterior chamber is filled with this fibrinous material. And then the cells are all stuck in there or stuck in the bottom or in the aqueous phase of that. And this patient also had psoriasis. This is the patient who had HLAB27+ iridocyclitis. You can make this diagnosis just looking at that patient and listening to their history.

This is easy, right? This is a five-year-old patient that presents with severe vision loss. This is a patient who has had very severe juvenile idiopathic arthritis-associated uveitis. Chronic disease, the eye is white and quiet, there’s calcific band keratopathy, extensive synechiae. This patient also had high intraocular pressures and has a cataract. This patient, unfortunately, is somebody who had chronic long-standing juvenile idiopathic arthritis-associated with chronic iridocyclidis or chronic anterior uveitis.

Here’s my next question. Every patient who has a work-up for uveitis should be tested for which of these conditions? Rheumatoid arthritis, HSV, VZV, or CMV infection, toxoplasmosis, or sarcoidosis, syphilis, and TB? What are the lab test, work-up, which testing should you do? Which condition should you rule out in any case of uveitis? Where you would not be faulted for saying, by me, telling you that you ordered too many tests?

Let’s see what you all said and we’ll talk a little bit about it. Yeah, most of you got this right. Every patient who has uveitis should be tested for syphilis and tuberculosis, they’re identifiable causes of inflammation, and in our part of the world, at least, we like to rule out sarcoidosis. Sarcoid occurs everywhere in the planet, in every continent, and it is an identifiable and treatable and prognostically important cause of uveitis that should be looked at. It’s a very common cause of inflammatory ocular disease.

The other conditions, I test for toxoplasmosis when there is a lesion that looks like toxoplasmosis in the back of the eye. I test for HSV, VZV, and CMV if I see corneal or iris changes in ocular hypertension uveitis at presentation, that tells me. Or if I see necrotizing herpetic retinitis and I suspect there’s a virus involved then I would check for that by using PCR technology of the anterior chamber fluid. Rheumatoid arthritis and systemic lupus are interesting. I don’t always test for this. Now in juvenile idiopathic arthritis it is important to check for rheumatoid factor and antinuclear antibody. Why? Because the patients who are antinuclear antibody positive and rheumatoid factor negative and have polyarticular or oligoarticular disease, are more likely to develop chronic anterior uveitis. And those patients need to be screened carefully. And if they have uveitis, more than likely they will be ANA positive rheumatoid factor negative.

Short of that, in adults I don’t normally get an antinuclear antibody or anti double stranded DNA antibody, unless the patient, for example, if I suspect that they have systemic lupus based on adrenal renal disease, cutaneous disease, and ocular disease suggesting that the patient either has scleritis or has occlusive retinal vasculitis. And with the case of rheumatoid arthritis, I definitely will check rheumatoid arthritis or rheumatoid factor mainly in cases where a patient has scleritis. Because we know that the most common identifiable cause of scleritis, systemic cause of scleritis, in the non-infectious arena is rheumatoid arthritis. So in those cases I do check.

Very rarely there are severe cases of rheumatoid arthritis that can cause occlusive vasculitis in the retina, but that’s very rare and is associated with a condition called anti-CCP or citrullinated cyclic antibodies. This is a condition that is relatively uncommon and occurs in a very advanced rheumatoid arthritis.

It’s very rare that I checked those top three but I always check for sarcoid, syphilis, and TB: SST. That’s one thing that I want you to remember, if you take away anything from this talk, if you’re going to order lab tests those three should at least be on your list of tests that you check for. Every uveitis patient should be checked for those things.

Sarcoidosis, how do you check for that? You can check chest X-ray. You can check angiotensin-converting enzyme level. If they have significant symptoms or abnormalities on chest film you can also consider a chest CT with very thin cuts or spiral cuts looking for hilar adenopathy and interstitial lung disease.

With TB, typically in the United States we’ve been using interferon gamma release assays because we are non-endemic, necessarily. In endemic areas, I still think IGRAs or interferon gamma release assays are very helpful, QuantiFERON Gold, et cetera. But we also still do PPD skin testing. And a chest X-ray is, of course, very valuable to show if the patient has a Ghon’s complex or previous scarring related to tuberculosis pulmonary disease. Many patients in our country may not, may have extra pulmonary TB as well, so a thorough review of systems can be helpful in delineating this if they have a positive QuantiFERON and PPD and they still have ocular inflammatory disease.

Other tests are tailored based on the clinical appearance as I mentioned. One other test for somebody, an adult, who presents with hypopyon anterior uveitis we will usually check an HLAB27. I’ll come to that in a second. Syphilis, this is a dark field microscopy, this is somebody who has fluorescent crepanile antibody positively. This is what that looks like. And this is an explanation of how the QuantiFERON testing works. We don’t have to go through all of this, you guys probably all know. But we’re basically looking at the interferon gamma that’s released by inflammatory cells from the affected patient when exposed to the MTB protein. And the amount of the interferon produced is quantified in the quantification determines whether or not the level of quantification and the response to a mitagin versus the nil response tells us what is the likelihood that the patient has been exposed to TB.

Pulmonary sarcoid, this an example of the findings on a chest X-ray when you look at sarcoid. Patient may have stage one disease where there’s hilar adenopathy. But as you progress more into the end stages of the disease you’ll see much more interstitial lung markings. And eventually, emphysematous changes and restrictive lung disease developing in very advanced stages of sarcoid.

PCR testing, we mainly do for HSV, VZV, and CNV. Toxoplasmosis and this is from anterior chamber samples because they’re readily available in clinic. Vitreous biopsies and vitreous evaluation can be helpful when you’re looking for toxoplasmosis and other more esoteric things in the vitreous, in terms of infections etiologies. But polymerase chain reactions have been perfected to the point where we can use a small sample of .1cc of aqueous and that can test for at least four viruses based on that small sample. Viral PCR has become a standard thing that we often do in our office setting when we’re looking at patients we suspect have viral anterior uveitis.

You must always rule out sarcoid syphilis and TB. And then we look at, there’s various serologies based on your clinical appearance that you would also obtain on patients in terms of laboratory testing. So you really need to combine with a clinical appearance that the patient has and their clinical history, the other testing beyond sarcoid, syphilis, and TB.

These are just other things that we look for. I want to mention here, urinary beta-2 microglobulin is particularly important to check in cases of tubulointerstitial nephritis and uveitis syndrome. Many places around the world have apparently reported that there have been significant increases in TINU cases during the pandemic and after the institution of vaccinations for coronavirus. I have not specifically seen that in my practice, but it has occurred in multiple other practices around the world. Urinary beta-2 microglobulin is a marker for interstitial nephritis And this condition usually is a bilateral onset of anterior and or intermediate uveitis, usually in a patient in the first two to three decades of life. It’s a younger patient with bilateral acute onset disease with no other things in the review of systems that they may have. Presence of interstitial nephritis when you do the urinary beta-2 microglobulin levels are often elevated. The nephritis is self-limited but the uveitis can become chronic and very difficult and recalcitrant to treat.

There are some conditions where you rely only on the clinical appearance to make the diagnosis. Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia where there has been a history of penetrating injury in the patient in the fellow eye and the patient presents with bilateral ocular inflammation that is granulomatous with panuveitis. That’s sympathetic ophthalmia and that’s a diagnosis based on clinical history and clinical appearance. And Behcet’s disease is a disease the World Health Organization and the International Uveitis Study Group for Behcet’s has a diagnostic list of criteria for Behcet’s disease. Which includes the presence of oral aphthous ulcers being very prominent and required and it’s present in 90% of Behcet’s patients. Followed by genital ulcers, ocular lesions, and specific skin changes that may be associated with Behcet’s. Those are the criteria the WHO has proposed and that’s what we use.

There are certain cases of scleritis where I might check for systemic vascular entities such as GPA, granulomatosis, and polyangiitis syndrome, or lapsing polychondritis. And I have some pictures that I’ll share with you. And of course, with JIA we already covered this.

And we already talked about PCR. Today there are multiplex PCR available in some academic centers around the country. I know that in Singapore, for example, I know that those technologies are used excessively. Our colleagues in Singapore advanced the idea of aqueous paracentesis and PCR evaluation for viral uveitis. They’ve put that on the map. We’re thankful for their work in doing that. But PCR technology is now Advanced to the point where we can have even, for example, localized small units that can check Multiplex PCR for mycobacterium TB onsite and give us instantaneous readings. The WHO has made it a campaign to put these out in sub-Saharan African countries in order to be able to diagnose pulmonary TB very quickly based on sputum samples. So these kinds of technologies are available now that can do panfungal and bacterial or pan pathogen multiplex PCR looking for hundreds of pathogens simultaneously on small, tiny amounts of tissue samples or fluid samples from the eye et cetera.

Let me talk a little bit about therapeutics and I’ll come back. And there’s a reason for this. When you don’t know the cause, it’s very easy to jump to the conclusion that hey I’m going to hit this really hard with steroids. But let me ask you a question. If you suspect that somebody has infectious uveitis, corticosteroids should never be used alone in the treatment of infectious uveitis. Is that true or false statement? Corticosteroids should never be used alone in the treatment of infectious uveitis. That is correct.

If you suspect that somebody has infectious uveitis you should never give, other than maybe topical corticosteroids, you should never give, and I probably said systemic or regional or intraocular, you should never give corticosteroids aggressively either systemically, intraocularly, periocularly, alone, in the absence of antibiotic coverage. If you suspect somebody has infectious uveitis, put them on the appropriate antibiotic first and then be aggressive with corticosteroids treatment after they have had a chance to have loading doses of the antibiotic on board.

A follow-up question to that would be, excuse me. The next question: corticosteroids have no role in the treatment of infectious uveitis?. So corticosteroids have no role in treatment of infectious uveitis, is that true or false? So that is correct, that is false. I’m glad all of you got this right. Corticosteroids absolutely have a role in controlling the host response, the inflammatory response, after the patient has been placed on appropriate antibiotic therapy, then you can use corticosteroids aggressively. So this is a very important point that we need to think about when you’re treating a patient and you don’t know, necessarily, the etiology of the inflammation.So if you think it’s infectious, a specific antibiotic is essential.

If you don’t know if it’s infectious or not, put the patient on the worst thing that it can be that is infectious. In my case, for example, if there’s retinal lesions, et cetera, I’m thinking that it could be necrotizing herpetic retinitis. If I don’t know until the PCR results come back, I’m going to put the patient on antiviral therapy, and then start them on topical steroids, and then later, after a couple of days, after my results have come back negative or positive, determine whether or not I can use more aggressive corticosteroids such as with intravitreal or periocular. Never use corticosteroids like that, intravitreal or periocular corticosteroids or high-dose systemic corticosteroids when you suspect that the uveitis is infectious. Because you’re going to make that uveitis far worse and the visual prognosis far worse, particularly in conditions like aggressive or large toxoplasmosis lesions or more importantly, herpetic disease. But corticosteroids can safely be used once you know the etiology and you have the patient on the appropriate tailored antibiotic therapy and that’s been initiated for at least 24 to 48 hours before the initiation of corticosteroids.

If you’re suspecting masquerade syndromes though, this is based on history and clinical exam findings, but a tissue biopsy is essential. So you need histopathologic confirmation of this. And the most important masquerade syndrome that we don’t want to miss in our practice is intraocular lymphoma. When we do the primary intraocular lymphoma or primary CNS lymphoma in the eye, we need to do a vitreous biopsy. And sometimes will actually do a retinotomy and obtain a subretinal sample and send it to the pathologist for evaluation. And this can include specifically, not only just an evaluation by a cytopathologist onsite, but also immunohistochemical staining, staining specifically looking for markers and gene rearrangements such as the MYD88 gene anomaly that may be present, that can be very highly useful. And sometimes we also look for cytokine levels like interleukin 10, interleukin 6 ratios that can help us in making the diagnosis of intraocular lymphoma. But your laboratories have to be able to process these kinds of things or you need to send it to a place quickly where the cells and their cytokines can be rapidly evaluated. Because of the ephemeral nature of the samples they have to be handled very carefully.

This is a patient that you see with primary intraocular lymphoma with subretinal lesions here with vitritis. And this is one of the clump cells of the vitreous, you can see large nuclei, prominent nuclei with the scanty cytoplasm in the specimen that you see from the histologic histopathologic specimen that was obtained.

Here is a quick poll question, let’s see if you understand the treatment part of it. The patient has poor vision, severe anterior chamber inflammation, and a small pupil with very limited view of the fundus. The labs are pending. So what should you do for this patient with the severe anterior chamber inflammation? Should you start intraocular corticosteroids? Start periocular corticosteroids? Start high dose systemic steroids? Or start topical steroids at very frequent intervals? What’s the safest thing to do, what’s the most judicious thing to do when you don’t know the cause?

When you don’t know the cause and the patient has severe inflammation, until you’ve ruled out the infectious causes, the safest thing to do is to start the patient on topical prednisolone or difluprednate to get the inflammation controlled at least until you get the labs. Whether you do an aqueous paracentesis or whether you’re doing systemic testing including the other labs to make sure that you’ve ruled out syphilis and tuberculosis before you really go crazy on the steroids. You don’t want to make something if you’re not sure of the cause irretrievably worse. So you want to avoid regional or intraocular corticosteroids. And choose the most serious infectious or neoplastic condition and treat that first. Systemic antimicrobials never hurt anybody, intraocular antimicrobials, if you’re concerned so much that maybe a viral retinitis, for example, intravitreal ganciclovir can be safely given in even high doses.

And then frequent topical corticosteroids. And then look for the response. I would avoid oral corticosteroids early on as well, but if you feel comfortable and you feel confident, hey this doesn’t smell infectious to me, I think it is non-infectious, you can probably use corticosteroids but you need to monitor the patient carefully.

If the patient has a lack of response or worsening to corticosteroids, that suggests that it’s either an infectious or a masqueraded etiology. It’s not an immunologic entity, it’s not a non-infectious entity, that’s immunologic. Then you may need to do more diagnostic testing. You might need to even do histopathologic confirmation to more invasive testing.

I have a few minutes here that I am going to rapidly go through some cases. Some of these cases are really difficult, some of them are pretty easy. I have about eight cases. I’m running out of time, actually. I have to go see patients in a little while but I wanted to share a few cases with you and see if we can get an idea of how some of these difficult cases were figured out. The uveitis work-up is never a single one and done thing. Uveitis work-up for a patient, especially with chronic disease, is an ongoing, in my experience, something that we do over the course of time. We may do an initial work-up but how the patient responds to therapy, what their clinical courses will ultimately determine how that patient is going to do. And then what other systemic manifestations they may develop over time that will determine how we do the work-up. The work-up may not end after the first initial visit. But as time goes on, if they develop new skin lesions or if they have new pulmonary problems, that will help us in delineating the cause of the inflammation.

The first case, 27-year-old male presents with floaters in both eyes and shortness of breath. He’s had a 30 pound weight loss over six months and he lives with several cats in his trailer. He’s of modest background and not a highly educated person. His vision is about 20/50. He has granulomatous KPs in both eyes, there’s 3+ cells and 2+ flare in the anterior chamber of both eyes, and the vitreous has 3+ cells in both eyes, and the fundus examination shows cystoid macular edema in both eyes. And here is the clinical appearance.

So this vitritis, there may be small choroidal lesions that you can see temporal to the macula, or maybe down inferely, in each eye. You can see some of these little small, white spots. This panuveitis-type picture. And you can see the choroidal spots showing up on the fluorescein angiogram. This is clearly a multifocal choroidal process. This sounds serious systemically right? He’s had weight loss, he’s had difficulty breathing. So the top thing I think about is sarcoid. Sarcoid causes multifocal choroidal inflammatory disease and so let’s check for that. But he’s got all these funny things too, he’s got these little white spots in the periphery and I don’t know what these are. So I didn’t know what those were before.

We did a laboratory work-up. His ACE was high normal, lysozyme was normal, the QuantiFERON TB and PPD, those were all negative. FTA was negative, that’s the fluorescent treponemal antibody. And bartonella titers were negative, even though he has a lot of cats. His chest CT was positive for adenopathy and it was diagnosed that he had pulmonary hypertension. They did a right heart catheterization and his central venous pressures and his left ventricular and diastolic pressures were elevated. And this patient had this on the CT scan. This contrast CT shows large paratracheal lymph nodes, multiple other enlarged mediastinal and the retrocrural lymph nodes were present as well. We’re thinking, “Oh, this is probably, maybe this is sarcoid even though those tests were normal?” But he’s got a very dilated main pulmonary artery and significant enlargement of subcarinal lymph nodes too, indicating this goes along with pulmonary hypertension. It was very unusual looking.

And then he’s got a very enlarged liver. Well, that’s interesting. That could occur in sarcoid too, right? We’re thinking sarcoid. There’re also periaortic lymph nodes. This fella has something, we should go and maybe we should do a biopsy. So they did the biopsy of the lymph nodes. They didn’t find any TB, they found granulomatous inflammation and they thought this was sarcoid. So they started him on systemic steroids. The eye disease initially improved but then began to become significantly worse. And then he started developing fevers that he hadn’t had before. Hmm.

So here we are, we thought we have biopsy proven and we think it’s granulomatous, we think it’s sarcoid. We didn’t find tuberculosis, we didn’t find any other organisms necessarily here. But with steroids though, he’s getting worse. And he’s getting systemically worse. This is scary. So we’ve missed something. Maybe this is infectious? What should we do? Is this infectious or not? So what do we do? We have to biopsy something. The eye disease is worse, let’s do a vitrectomy. Let’s look at the vitreous sample and see.

We did a vitreous biopsy and I went after that pre retinal white material. We found that the mixed lymphocytes and large macrophages were present containing PAS positive material and we were able to get a qualitative PCR done and this was positive for Tropheryma whipplei. This is Whipple’s disease! This patient did not have neurologic manifestations, nor ophthalmic manifestations. But he presented with pulmonary hypertension and we did a duodenal biopsy. He has this beautiful, the substantial propia here. You can see these large intracellular PAS positive organisms,Tropheryma whipplei. And this was diagnosed Whipple’s disease and he was treated with Rifampin and Bactrim for six months and he’s been inflammation-free for five years.

What a difficult case. This is not a common case. Many of us uveitis specialists are lucky to maybe see one or two cases of uveitis in our career caused by Whipple’s. So this is very rare.

Case two, 79-year-old man with unilateral severe granulomatous anterior uveitis, vitritis, and hazy view of posterior pole. 20/40 vision in the left eye. And intraocular corticosteroids was given with rapid worsening of vision two weeks later. So he was given intravitreal steroids and now he’s light perception in the left eye and his right eye is still normal. He’s pseudophakic and on examination he has a lot of vitritis in the left eye. He has nothing going on in the right eye. Here’s his fundus exam in the right eye which is normal. He has a small tiny scar in the right eye, a little corneal retinal scar.

Here’s the left eye. Very hazy view of the optic disc. But this is what I saw, I’m telling you this is what it looked like, these large white areas of what look like retinitis. I didn’t know what this was. This patient originally had very good vision so rapid loss of vision, what is in the differential diagnosis with white lesions in the retina? I’m thinking that maybe this is necrotizing herpetic retinitis. That’s what this kind of looks like. So necrotizing retinitis. I’m thinking herpes viruses. So the two possibilities that are on the top of the list is that, herpetic retinitis. And maybe toxoplasmosis, there’s a scar in the other eye. Maybe this is really bad toxo? Because the patient did get intravitreal steroids and maybe he had an infectious cause that rapidly worsened. So both of these can rapidly worsen. So what are we going to do? We need biopsy. But in the meantime, what am I going to do?

I put the patient on aggressively, treated the patient initially with systemic antivirals as well as systemic triple antibiotic therapy, including sulfadiazine and pyrimethamine, along with high doses of oral valacyclovir. And then I took him to do a pars plana vitrectomy in short order within a day or two. And the PCR was positive for toxoplasmosis. The varicella zoster virus, HSV1 and 2, and CMV were both negative. But I didn’t know that at the time of the biopsy, so I injected intravitreal clindamycin as well as intravitreal ganciclovir.

The toxoplasma gondii PCR was positive. And the patient was treated with multiple injections of intravitreal clindamycin along with systemic pyrimethamine and sulfadiazine for a couple of months. And after six months, his vision was 20/100 in the left eye with chronic CME. He never really improved from there, for years I followed him. But this patient had a case of toxoplasmosis that was inappropriately managed by intravitreal corticosteroids and was made irretrievably worse. So this is something important to keep in mind in this situation. So don’t make things irretrievably worse. This is what he looked like after he healed, all those areas of retinitis that we saw resolved and was left with chronic CME. And fortunately, he didn’t have too much damage to the macular area.

The lessons that we learned here is never give intravitreal or periocular corticosteroids without antibiotic coverage if infection is even remotely suspected as a cause of uveitis. And tissue is always the issue for infectious uveitis. Tissue biopsy, tissue proof of infection.

Case three, a 69-year-old white female with painless subacute loss of vision over a couple weeks, or one week in both eyes. Metamorphopsia, a few floaters, no photopsias. And she had dyspnea, pleuritic pain, weight loss, and arthralgias. Vision is 20/60 in both eyes, white looking eyes, externally. A few cells in the anterior chamber but she has subtle disc hyperemia and exhibited retinal detachments in the posterior pole. But she had dyspnea, the dyspnea was new. She was having real trouble breathing while I was examining her. The exam is tough because the arrows are trying to point out an area of small serous detachment. I’m really sorry, this doesn’t project very well. This is an old film color photograph, this is from several years ago. And this patient also had a little macular serous detachment in the felt eye. The fluorescence angiogram looks like this. It looked like VKH! But she didn’t have tinnitus, she just had dyspnea. She had multifocal choroidal inflammation. There’s pooling in the late phases of the angiogram, in the subretinal space that you see inferely where that subretinal fluid was in that right eye. In the left eye, also, there’s a little pooling in the perimacular region and inferiorly as well, with this very starry skies pattern.

This is a multifocal choroidal inflammatory process. This dyspnea concerned me so we got a chest film. But she had no hearing loss, vitiligo, poliosis, headache, or meningismus. Chest X-ray was done for the dyspnea that revealed that she had bilateral pleural effusions. Severe. She had a liter of fluid that was removed from one side of the thoracic cavity alone. And about a half liter from the fellow. And we evaluated the fluid, when we evaluated her and that fluid was ANA positive. This patient had very high titers of antinuclear antibodies and double-stranded DNA.

So this is a case where I didn’t initially order antinuclear antibody. It was based on the findings of the chest X-ray that we went back and did serology and, of course, evaluated the pleural fluid. We suspected that this was some odd manifestation of lupus and indeed she had lupus choroiditis and she also had evidence of renal disease with mild proteinuria as well. She did very well on Imuran and corticosteroids and has maintained excellent central vision with durable remission off of all medications except for low dose plaquenil. Systemic lupus erythematosus associated with lupus choroiditis.

Next case is a 53-year-old woman who was diagnosed with granulomatosis with polyangiitis, this used to be called Wegener’s granulomatosis. This is a systemic disease process with pulmonary mass lesion. She had hematuria and elevated serum anti-proteinase 3 antibodies originally. She was treated with cyclophosphamide and prednisone but then developed painless vision loss in one eye after a month. This is after being treated for her GPA, she presented with this. Her vision was very poor in the left eye at count fingers and flipped, the right eye was 20/20 and unaffected. And we had fine KPs in the left eye, cells in the anterior chamber, and mild vitreous cells. This is her right eye and this is the left eye. This massive lesion.

This is a patient who’s immunocompromised, just have been treated with cyclophosphamide and prednisone. So this is a mass lesion, a necrotic granuloma in the posterior pole. I thought this patient had an infection. This is infection to me until proven otherwise. So we suspected this was aspergillosis in this patient. This is what it reminded me of. There was necrotizing retinal vascular involvement that you can see on the picture in the floracing angiogram here with a hypo fluorescent lesion underneath the choroid, and you can see retinal ischemia, retinal vascular ischemia present. And so I really thought this was a necrotizing granuloma. The differential diagnosis includes iatrogenically immunocompromised patients, subretinal abscess, aspergillus, TB, bacterial abscess, or could be maybe secondary lymphoma from the cyclophosphamide therapy.

We did serological testing which was all completely negative, including aspergillus serologies. So what’s the plan? We needed to start empiric antifungal therapy. We thought it was still aspergillosis. We held the cyclophosphamide therapy and continued oral prednisone and 10 days later the lesion was huge. It was much worse. The vision was much worse and you can see the expansion of the lesion. When this is happening, we are concerned about a fellow eye involvement so we will do now vitrectomy. The vitreous and subretinal biopsy, gas fluid exchange, intravitreal antibiotics, antifungal therapy. And the biopsy results unfortunately showed only macrophages, lymphocytes, and neutrophils; all cultures and stains were negative, PCR was negative, fungal and bacterial cultures didn’t show any growth and two months later the patient developed a retinal detachment.

This patient was thought to have an inflammatory lesion related to her GPA that affected her and caused a choroidal vasculitis and retinal vasculitis, resulting in a necrotizing granuloma of the retina. An unusual manifestation. This patient was treated, she had a massive scar, ultimately developed after we reinstituted her immunosuppressive therapy and got the inflammatory disease from her GPA better controlled in the eye.

This was not infectious. We thought it was infectious, but all the testing that we did proved it was not infectious. The abscess resolved, she received a total of 27 grams of cyclophosphamide and low dose oral prednisone and switched to azathioprine. She’s been disease-free. The fellow eye has been disease-free as well. And she has had remission of her systemic disease.

This is another case from my colleague Dr. Vitale of the same kind of thing with GPA with retinal vasculitis and choroiditis bilaterally in another patient. You can see a similar choroidal inflammatory disease. Less retinal vascular involvement in that case.

Case five, this is a 65-year-old cachectic white female presents with floaters and blurred vision for one month. And squamous cell carcinoma of the lung was treated with radiation chemotherapy controlled but was considered to be immunocompromised. She was a 70 pack year history of smoking, her vision was 20/60 in the right, 20/20 in the left, anterior chamber just showed a few cells in the anterior chamber of the right eye. The vitreous showed clumped cells in the right eye, left eye was normal. The retina in the left eye was normal but in the right eye, it looked like this. It looked like some sort of a retinal vascular inflammation with overlying vitritis. She had all this vitreous inflammatory material overlying the retina but there was retinal vascular inflammation you can see along the superonasal portion of the fundus. And she had some subretinal material and intraretinal material present as well. You can see a close-up of the vitreous here and the vitreous involvement. Didn’t know what was going on here.

Laboratory evaluation was performed on this patient and here’s the fluorescein angiogram. You can see that she has vascular, some peripheral ischemia. We thought maybe this is toxoplasmosis, it’s unilateral, maybe this is viral retinitis, we didn’t know. Maybe this is some sort of a paraneoplastic syndrome. Wasn’t likely because it was a non small cell lung cancer. Or could it be sarcoidosis or some other secondary thing? We did a laboratory work-up, everything was completely negative.

We thought it was still infectious. We started on oral acyclovir, she developed psychosis and had to discontinue medication after two days of oral valacyclovir. That is actually a rare complication of acyclovir, there are neurological complications of acyclovir and its derivatives. And the patient had no progression but she refused therapy. After six weeks there was very little change, but we decided that we probably should biopsy this because of its persistence. We did a vitreous biopsy, we did cultures, and we also did cytopathology, and evaluation of the pathologic specimens and preretinal membranes that were removed. All the gram stains and PCR were negative for infectious causes but papanicolaou stain in the OR revealed that the patient had unusual keratinized epithelial cells that were pleomorphic nuclei with irregularity and hyperchromasia. And this is highly suggestive and also this is the preretinal membranes that were removed. This was actually squamous cell carcinoma with invasion of the retina. And these were positive nuclear staining consistent with P63 immunoperoxidase stain, this was consistent with squamous cell carcinoma of the lung, metastatic to the retina.

This is a condition where we thought it was infectious and it ended up being a neoplastic cause, very rare, again, this is extremely rare. I’m not showing you to show off these cases but I’m showing you what we go through with the idea of how do we approach this patient? Because we’re not going to know what exactly the cause is right off the bat. This patient refused therapy, she presented a year later. I was trying to figure out, I had a picture of her presentation but unfortunately had a fungating tumorous mass coming out of her orbit because she refused systemic therapy all together, despite metastatic disease to the retina. Unfortunately she has succumbed to her illness. It took one year and she passed away. But it wasn’t infectious. But the diagnosis was achieved, but no harm was done in the process with achievement of that diagnosis in this case.

Another case, a 3- year-old white male with a two-week history of blurred vision in the left eye. His vision is 20/25 in the right, 20/400 in the left. There’s mild cell and flare in both eyes but no KPs in either eye. There’s no synechiae. There are rare vitreous cells in the right and there is mild vitreous cells in the left. This is the auto fluorescent imaging in this patient. This is the clinical photograph. I didn’t show you, this patient also had a desquamating hand rash, palm rash on both. And his partner was with him as well and this patient had been with the same partner for many years.

And this was the fluorescein angiogram of the ICG in the right eye. Here’s the left eye, you see this large placoid lesion in the posterior pole. Very characteristic finding and this is the OCT. You can see the OCT in the left eye, in particular, shows diffused disruption of the inner segment/outer segment or ellipsoid zone throughout. Very characteristic feature of what disease? You know historical details, monogamous, was HIV negative, was tested for HIV because he has a male partner. And we did testing of both these, all of these things looking for sarcoid, syphilis, and TB. And HIV because I was suspicious that this could be syphilis.

And the results, of course, revealed that he was FTA positive. and again, this is a treponemal specific test. When you test for syphilis, and don’t get an acute phase reactant test like RPR or VDRL, those are non-treponemal tests. And in the case of syphilitic uveitis, it’s a manifestation of post-primary disease. The primary markers for syphilis, such as VDRL and RPR are going to be negative. Because they’re only transiently positive. But the FTA will remain positive for many, many years even. But it was a very high titer and this patient was diagnosed with syphilis and was treated the remainder of the testing for QuantiFERON, TB, and sarcoid were all negative. And was treated with neurosyphilis protocol which is what these patients need. He actually required a 14 day course of high dose IV penicillin therapy and his vision recovered to 20/25.

And this was a simple case, I showed this previously. This is a 44-year-old Asian male that presented with pain, photophobia, and blurred vision. Had 20/100 vision. This is what he looks like. So your diagnosis would be? And I know you guys can’t comment but this is a patient who has, look at his skin, he’s got psoriasis. So I’m thinking this is HLAB27 associated disease. There are only two tests I would have obtained in this patient in a laboratory work-up. I would get an HLAB27 and I would check for syphilis. I check for syphilis in every case of uveitis. FTA or anti-treponemal IGG. Treponemal specific test for syphilis. And this patient was negative for the syphilis test but positive for HLAB27.

This is a case of a 56-year-old man, white male, who presented with blurred vision, floaters, and difficulty with night vision in both eyes. Both eyes looked similar to the right eye when you see this characteristic clinical picture. And this should be a no-brainer, the diagnosis is based on a clinical photograph. And this patient had evidence of perivascular staining on fluorescence and geography and had very mild cystoid macular edema, a common complication of this disease. So this is? Birdshot retinochoroiditis. That’s right, birdshot retinochoroiditis. This patient would be HLA-A29 positive. This patient will need long term immunosuppressive therapy to maintain control. We can slow down this disease, but we cannot treat it. 95% of patients with birdshot will be HLA-A29 positive. Will the HLA-A29 help you in the diagnosis? It only confirms. The clinical picture is the diagnosis. There’s hardly anything that looks like this that is bilateral on the clinical photographs.

When you’re looking for the etiology, Obtain an accurate history, review of systems, use non-ocular clues. Develop a system of pattern recognition, what does the disease look like? Obtain serology, especially if you think it’s infectious. Choose therapies that will improve but not harm the patient when you don’t know the cause initially. And treat the worst possible diagnosis it can be. And then obtain ocular tissue samples when your suspicions remain high that it’s infectious, despite a negative work-up serologically.
Or if they have no response to therapy or they become worse on the therapy that you have. Or if you have a fellow eye that becomes involved while you’re treating one eye, that also should tell you that you need to be more cautious.

I’m going to stop with the talk. I know I went over a little bit, looks like there’s some questions and answers.

The QuantiFERON test. Somebody said, when is false positive and when is false negative? I think your clinical impression is going to tell you. It is highly unlikely that you’re going to find somebody who has a false positive on QuantiFERON. But if you think it’s a false positive, I would definitely do a PPD skin test on that patient. We will see false positive if somebody has BCG vaccination. I think that’s what Dr. Alaja was asking here. If somebody has had BCG vaccination, in many of the endemic countries, it very well could be that you may have a mildly elevated IGRA titer, but you’ll also have a positive PPD skin test. And that can be very difficult to sort out in those cases. The clinical appearance, the presence of extrapulmonary tissue disease to suggest TB, so you have to go buy your own, your own Gestalt, your own clinical abilities and the help of your infectious disease colleagues into determining if this is TB or not.

To what degree can you depend, in the case of recurrent anterior uveitis, non granulomatous, positive IGRA and two labs, can you depend on it? One of the things about checking for TB is that you have to be careful. I know that we rule out TB in everybody, but what do you do with these tests where it looks like chronic anterior uveitis, there’s no manifestation to suggest that there’s choroidal lesions from TB, and the chest X-ray is negative, but you have this positive test. I think the decision and how you’re going to treat this chronic anterior uveitis and how it’s responding will tell you what you need to do. If the patient is responsive to topical steroids alone, I would just do that. I would send them to an infectious disease specialist to have this evaluated and the infectious disease specialist is going to ask you, “Do you think that this uveitis is characteristic of TB?” And chronic bilateral anterior uveitis isn’t characteristic to TB. That could be idiopathic, it could be sarcoid, it could be nothing. It could be no cause except idiopathic anterior uveitis.

But if you have somebody who has multiple choroidal lesions, a serpiginoid multifocal choroiditis and they have a positive IGRA test, that’s going to tell you it’s obvious. I think this would be highly characteristic of extrapulmonary TB. And that will tell your infectious disease colleague how they need to treat TB. So in endemic areas I think it’s a challenge, I don’t think there’s any right or wrong answer. You need to use the help of your infectious disease colleagues, and the help of your clinical history, and your appearance of the eye, and the ocular findings to make the diagnosis and decide on treatment.

If you need systemic immunosuppressive therapy and you have a positive QuantiFERON or IGRA test, in those situations you may need to have some prophylaxis or treatment of the positive QuantiFERON even if the patient has no other manifestations to TB before you put on put them on aggressive systemic immunosuppression. Because you don’t want to miss extrapulmonary TB and then have the patient have disseminated TB from the immunosuppression.

What do you refer when you mention Arlt’s triangle? Arlt’s triangle is the area of the lower 1/3 of the cornea where K inflammatory keratic precipitates deposit on the endothelium. That’s what Arlt’s triangle is.

What is your preferred treatment for recurrent ocular toxoplasmosis with immunocompetent patient? How long will you keep the prophylaxis treatment? If it’s recurrent and it’s a large lesion, the prophylaxis would continue long-term and I usually use Bactrim for prophylaxis. Sometimes I use oral azithromycin. But my preferred treatment for aggressive ocular toxoplasmosis nowadays is using a combination of pyrimethamine, if available, along with sulfadiazine. Pyrimethamine 25 to 50 milligrams BID and sulfadiazine 500 milligrams QID. And also will use intravitreal Clindamycin injections for the more aggressive lesions. 300 micrograms, we do 500 micrograms per 0.1cc of intravitreal clindamycin. Sometimes you can also add intravitreal dexamethasone, a short-acting steroid to help with the inflammation.

What is the most common cause of intermediate uveitis? Most common cause is probably idiopathic, intermediate uveitis which would be called pars planitis. Especially when there are pars plana exudates.

What is the difference between uveitis and floaters? Floaters that you would see are inflammatory cells and collections of inflammatory cells. There may be vitreous snowballs, but there may be individual inflammatory cells that you can see on the slit lamp. The slit lamp examination is very important in the evaluation of the intermediate uveitis patients. Normal vitreous degenerative floaters are going to be linear opacities and they will not look like small white dots which are inflammatory cells.

When will we treat intermediate uveitis? Intermediate uveitis can be very benign in older patients but in younger patients who are in their first decade of life can be very challenging and difficult to treat, can be associated with systemic significant complications. So if they have cystoid macular edema, if they have substantial vision problems due to inflammatory debris and floaters, I would treat those patients.

What is the alternative to oral steroids for TB uveitis? There isn’t a lot. Because if the TB is not adequately treated, aggressive treatment of tuberculosis I really think is very important. Once the Infectious condition has been deemed to be fully treated with initial two months of five drugs and four additional months of three drugs, so a total of six months the protocol and you’re done with systemic treatment. Then at that point, yes, you may use CellCept as an immunosuppressant treatment along with corticosteroids. But with the persistent inflammatory disease, that the host response that goes on to the original TB infection. The infection is gone but the post infectious inflammatory disease process continues to need to be treated.

What is the most common etiology of acute anterior uveitis in the USA? Acute anterior uveitis, most identifiable cause is HLAB27, otherwise the most common cause is still idiopathic in 60% of patients, you won’t find a specific cause.

Should everyone be tested for syphilis, TB, and sarcoid even if their first bout of non-granulomatous anterior uveitis? I used to say with the first bout you’re allowed a free pass. But what? I generally, because I’m a uveitis specialist, if the patient is coming to see me for the first time, yes I would. But if the patient has very mild disease they’ve had a recent viral produram or something and it’s just unilateral, it’s mild, goes away in a few weeks, I don’t know that I would necessarily work that up. But if they reoccur, I would definitely work that up. But I have tended to work-up patients depending on the severity of the disease at presentation, the laterality, the previous history of episodes et cetera. And definitely in a recurrent disease, initial presentation of hypopyon uveitis I definitely would work-up. I think in the vast majority of patients I will do a work-up of sarcoid, syphilis, and TB on practically every patient that I see. HIV testing I don’t do on every uveitis patient. I do it based on their clinical history.

Would you ask for a QuantiFERON Gold test for TB? Yes, this depends on the lab. There’s either a T-spot TB test, or QuantiFERON Gold, those are the two basic IGRA assays. There are a couple other newer ones that I’m not as familiar with but those are the two that are available in our laboratory.

What do you do when? Yeah, we talked about some of the stuff.

Is PCR for ocular good for ocular TB? Well it depends on what your lab and what primers are available at your laboratory. So I would check with your lab director. I generally don’t check for an HLAB51 and Behcet’s, even though 60% of patients with Behcet’s will be positive for this. Behcet’s, it’s a clinical diagnosis, as I mentioned.

What do you do when opaque media, well you can’t see the fundus. This is a very difficult situation when you have a small pupil. The use of ultrasound can be valuable but not definitive because you can’t assess the posterior segment. You can’t see the retina. And in those cases, if there’s a cataract et cetera, I think it’s very important to get the anterior chamber inflammation at least under control with aggressive topical medications, keep it quiet for at least three months, and then do things surgically to try to clear the interior segment media. But it’s very very difficult, that can be very challenging.

And I think the clinical course will tell you if the patient is still able to have light projection and can see fairly well, despite a small pupil, and synechiae, and a poor view of the fundus, that probably tells you is more anterior segment disease then posterior segment disease. But if the vision is very poor, they may have complications of the anterior segment disease like glaucoma and cystoid macular edema, or they may have posterior segment disease but you can’t really see. So you’re kind of stuck. That can be a very, very difficult scenario. And that may require surgical intervention after the interior segment disease has been well-controlled.

Can we treat TB patients sometimes with immunosuppressive therapy? Yes, again with completion of treatment of the TB, as I mentioned, that we can use some immunosuppressants under very, very careful guidance of the infectious disease specialist.

For acute uveitis states of VKH, what will your treatment regime be like? Well VKH is very severe, so I usually use fairly high doses of oral prednisone and gradually taper that prednisone over a three to six month period. And we’ll probably add immunosuppressive therapy based on the initial response very early in the game. I’m very careful about aggressive use of corticosteroids on those patients. I do believe that early and aggressive use of the first three to six months of oral corticosteroids reduces the risk of chronic recurrent disease developing. But immunosuppression is often added in the first couple of months after starting steroids by me. And so I use anti metabolite therapy immunosuppression initially and then we’ll switch or add Humira, et cetera, depending on how the patient responds.

Pending labs. What would be the correct dosage and active substance for topical corticosteroids? Anytime you treat anterior uveitis with topical corticosteroids, it’s very important to start very aggressively at high doses every hour, for example, if the patient has moderate to severe inflammation and gradually taper over the course of many weeks. Most cases of acute anterior uveitis for example for HLAB27 may last three to four months. So if you’re tapering that patient off in three or four weeks, they are going to reoccur, they’re going to become recalcitrant to therapy.

So I’d start every hour and very gradually every two weeks taper down by a notch. So I’d go every hour for two weeks, every two hours for two weeks, and then every three hours for two weeks, and then four times a day for two weeks, et cetera. That gradual kind of taper and close follow-up, at least every three or four weeks in the initial phases of the acute inflammatory disease.

It’s 14 days for syphilitic uveitis treatment, period. It’s 14 days. So that patient after 10 days for 20/25 he got 14 days of therapy, I don’t want to be confusing.

Does PPD remain positive for life? Yeah, as in latent TB. Yes, it can and even after treatment you’ll still probably be PPD positive. IGRA positivity can vary a little bit. After treatment it may fade but then it may still be slightly positive long-term in these cases because there is long-term immunity, long-term immune memory with the TB exposure. Latent TB in India, this treatment that I think I have to defer to the experts. Dr. Vaishali Gupta has done a lot of work on this and Dr. Morithai, I respect their opinions about this because I see so little TB in the US. We’re seeing more of it. But latent TB, if you suspect it’s tuberculosis uveitis you need to treat with the help of the infectious disease specialist based on what the criteria is in your country. It may be three to five drug treatment for a period of six months to nine months, depending on the severity of the disease process. And then concomitantly using corticosteroids to control the inflammatory disease in the eye and eventually treating, going to immunosuppression when the infectious disease specialist feels comfortable that you can do that.

Focal serous retinopathy. Somebody was asking about specific cases. I still think if it’s a PPD-cited positive treat it as extrapulmonary TB first.

Do you treat ocular syphilis IV penicillin which only manifests to anterior uveitis? If it’s syphilis, you have to treat it, yes. You have to treat it as if it’s neurosyphilis protocol. The eye is part of the central nervous system. If you get inflammation they should also have a lumbar puncture done to look for CFS, VDRL. The infectious disease specialist usually will help you with that.

How soon does starting antimicrobial infected uveitis would you start oral steroids? Usually if I suspect infectious uveitis, I’ll start steroids after about 48 hours of loading with antimicrobial systemically or intraocularly.

What is the sign of active vitreous inflammation? Active vitreous inflammation is you’ve got to look at the slit lamp and look for vitreous cells. I really think it’s important to look at the microscope.

How do you diagnose multi-drug resistant TB? Multidrug-resistant TB is based on a PCR evaluation and evaluation by microbiological specimen of sputum or extra pulmonary tissues. And this may require aggressive treatment. This is a very, very difficult area, it’s not my area of expertise. I can tell you there are numerous drugs for multidrug-resistant and also the XDTRB, the really highest threat that we have in some of these endemic areas, super resistant TB. These are very, very difficult to treat and far beyond my area of expertise.

Ocular TB without ethambutol? Ethambutol is associated with optic nerve toxicity. Some people avoid it. But I think as long as you’re monitoring the patient for optic nerve toxicity, I think it’s a useful drug still.

I can give a separate lecture on the treatment of uveitis, this is mainly for diagnostic purposes here. These are a lot of questions about Humira. I think we should probably have another lecture about treatment. I can go on for hours talking about treatment. But typically I use corticosteroids initially. If I’m thinking about systemic therapy, I then use antimetabolites for a three to six month period. And based on how they respond to that, I would then determine if they need the additional or substitution of the biologics such as Humira or Remicade.

And Humira is usually… Nope, I don’t usually do a loading dose. We just start every two week therapy. I used to do a loading dose of weekly first for the first dose, at day zero, week one, and then every two weeks thereafter.

Presumed Posner-Schlossman Syndrome. That has been linked to cytomegalovirus and anterior uveitis so I would do an anterior chamber tap and viral PCR looking for HSV-1 and 2, varicella-zoster virus, and cytomegalovirus. And if that’s positive, then that would tell me what the cause may be. We used to think this was idiopathic but many of these are turning out to be. And this is due to the work of Dr. Chi in Singapore.

Is topical steroid enough for severe uveitis, secondary to pulmonary TB for a patient who’s just starting anti-TB meds? Within a short period of time, systemic steroids may be necessary and I would discuss that timing with your infectious disease specialist.

How to differentiate worsening TB after treatment? Lot’s of TB questions. You guys must be seeing a lot of TB. And I think the immunologic component of the TB is treated with steroids, the infectious component with anti-tuberculosis medication. And it is very difficult, I think, to treat tuberculous inflammatory disease if it’s persistent after you finish the course of six to nine months of systemic immunotherapy. It requires persistence and very slow taper of corticosteroids. You can’t expect that in this disease process at the completion of the anti-tuberculosis therapy is going to solve the issue. It’s just the beginning, unfortunately, as far as the eye is concerned.

Ethambutol optic neuritis? Stop the ethambutol, that’s who you treat it.

Can we start steroids without diagnostic sampling? It does interfere with diagnostic sampling, particularly in the case with intraocular lymphoma. So if you start patients on systemic steroids and you’re looking for intraocular lymphoma, remember that steroids are lytic to lymphoma cells so your biopsy will be negative. And a false negative. And then the other reasons to avoid steroids before diagnostic sampling is that if you suppress the immune response you may or may not get a positive and clinically you may make an infectious condition much worse. I would worry about that. I would avoid systemic steroids if you can and do the diagnostic sampling as quickly as you can, particularly in case of lymphoma.

I’m going to end there. I appreciate your listening. You guys were fantastic. I hope that you all have a wonderful rest of your day and evening and I look forward to talking with you again. All right. Thank you.

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July 23, 2021

Last Updated: October 31, 2022

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