Lecture: Viral Uveitis

DR MOORTHY: Good morning, everybody. I wanted to — my name is Ramana Moorthy. I’m talking to you from Indianapolis, Indiana. I’ve given a few of these Orbis lectures before, and today we wanted to talk a little bit about viral uveitis. I’m gonna see if I can share my desktop with you here. I hope you can see that. We’ll go to full screen here. We’ll actually start with the first question. And the first polling question here is: Viral anterior uveitis can be caused by which of the following? A, cytomegalovirus, B, herpes simplex virus 1, C, varicella zoster virus, D, all of the above. I’ll give you about half a minute to respond. So that’s right. Most of you got this right. Excellent. So viral anterior uveitis can be caused by any of those herpes viridae. These viruses are part of the herpes virus family. HSV is missing in that list, and that could potentially do it swell, and Epstein-Barr virus has so far not been isolated from the anterior chamber, although there are some hints that it could be involved. I wanted to break up the talk about viral uveitis into the anterior and the posterior uveitides. But in the middle of the talk, I want to change gears, because many of you are probably calling in from part of the world where you’re probably greater experts in some of the syndromes I’m talking about with viral uveitis, because you’re seeing it firsthand. And I’ll talk about that in a moment. Let’s talk about the common things we’ll see. Herpetic anterior uveitis is one of the common uveitides that are often missed. There are examples of the syndrome, such as Posner Schlossman syndrome, associated with elevations in intraocular pressure, where patients present with pain, it quiets with steroids, and the ocular hypertension associated with this syndrome also quiets with steroids. That’s thought to be caused by herpetic viral diseases, specifically cytomegalovirus in this case. Fuchs heterochromic iridocyclitis, more of a chronic syndrome, has been associated with isolation of DNA from the — excuse me, RNA from the anterior chamber, through reverse transcriptase mechanisms of detection. Of the rubella virus. So rubella virus has been associated with many cases of Fuchs. It’s also been shown to be associated with antibody levels for rubella virus in the anterior chamber in comparison to the serum. And also deep genomic sequencing has been shown in cases of Fuchs to actually sequence it to when the actual rubella infection occurs. So many of these conditions have these viral etiologies that we used to think were idiopathic or unknown. The diagnosis of herpetic anterior uveitis like this is kind of a mixed bag, sometimes, that can be difficult. But there are some common features. There can be overlap of various features with non-infectious uveitis, but there are some clues that it might be viral, because viral anterior uveitis, herpetic anterior uveitis, often is unilateral. Mild inflammation is often present. There is rarely if ever a hypopyon, for example. So you’re not going to see that. But you may see KPs. But often there is hypertensive uveitis. In other words, at presentation the patients may have significant elevation of intraocular pressures. And the iris may show changes, depending on how long the uveitis has been present, because there is often atrophy of the iris stroma, resulting in fairly significant damage to the iris sphincter, as well as transillumination iris defects, which I will show you a picture of. So clinically, for example, Posner-Schlossman syndrome and Fuchs heterochromic iridocyclitis — these two conditions can be similar to anterior viral uveitis, and their management can also be similar as well. So there are other non-ocular features of herpetic anterior uveitis that may aid in the diagnosis. For example, the presence of cutaneous manifestations, such as the classic vesicular rash of herpetic disease, whether a dermatomal rash from zoster, or whether it’s a localized area of vesicular cutaneous eruption, adjacent to the lid or on the face, from HSV, that is seen in children, for example. Corneal changes may be helpful. Keratic precipitates, whether fine KPs that are diffusely present or fine star-shaped KPs present on the cornea, can be very helpful in diagnosis. And of course, the iris changes, as I mentioned, and response to corticosteroids or lack of response in some cases can also be helpful in diagnosis. The cutaneous manifestations — usually there’s a prior history of intense unilateral pain involving the dermatome supplied by the ophthalmic division of the trigeminal nerve in the cases of varicella zoster virus, and you’ll see the breakout of the rash, with Hutchinson’s sign, where the tip of the nose is involved in the rash, meaning that the nasociliary branch of the first division of the trigeminal nerve is involved, and that involves corneal sensation, and that’s where this neurotrophic varicella zoster virus hangs out, and that virus goes down the nasociliary nerve onto the cornea and can cause inflammation. But sometimes there are variations of these cutaneous manifestations. You can see the pain is less intense or nonexistent, the skin lesions may be limited to a very few vesicles, making the diagnosis very difficult. Sometimes they can even be absent, and that’s called zoster herpeticum. It can occur, though it’s rare. And the lid vesicles in children can be small or few and might be misdiagnosed as something else, such as staphylococcal or streptococcal disease. A frank dendrite is obvious. There can be significant stromal edema with KPs underlying the stromal edema. When it’s inactive, the KPs can be very, very mild, mild superficial haze, that can cause significant alterations in corneal topography. And irregular astigmatism and loss of vision, based on corneal changes. There can be supportive evidence, of course, when you have, in addition to the corneal changes, the presence or history of concomitant cutaneous lesions as well. Sometimes you can have oriental endotheliitis present, where the cells become dysfunction due to infection from HSV or cytomegalovirus — I say CMV here, but certainly any of the herpetic viruses can potentially cause that, and the stromal edema can have a linear or ring-like distribution of fine KPs, could be coin lesions as well, and it’s very striking, because you’ll see a round area where there’s inflammation where that corneal edema is present. And I’ll show you a picture of that. Sometimes it can be very diffuse and it can be confused for corneal decompensation. And that is a very difficult diagnosis, then, to make. But often the presence of KPs and inflammation in the anterior chamber can help. Here’s the classic epithelial dendrite in HSV. Often it can sometimes be associated with anterior chamber inflammation. Here’s a more kind of geographic epithelial ulceration. With probably some significant stromal scarring, and obviously this is more chronic and recurrent, because of the pannus formation that you see here inferiorly. And then here’s a patient who’s got stromal keratitis. A little blurry image. My apologies for that. And here’s a patient that’s got necrotizing keratitis. So there can be a gamut of manifestations of corneal changes associated with these herpetic viridae. Here’s a classic example of endotheliitis. You can see the corneal epithelium is all kind of in the inferior half of the cornea. The superior half, you can see the iris more clearly. So this significant edema is kind of localized. That kind of gives you a clue that it could be herpetic. Here is the varicella zoster virus associated with dendrites. These dendrites tend to be multiple and a little bit more irregular. They can be smaller as well. So-called microdendrites. And they can be sometimes confluent, like they are here. There can be nummular keratitis, which is more common with varicella zoster virus. So these may be present. And then of course you can have necrotizing infectious-looking keratitis, stromal keratitis, in varicella zoster virus disease as well. Keratic precipitates can be very helpful. These can be a mixture of sizes varying from fine to medium sized mutton fat KPs, and they can be localized to areas of keratitis if there’s edema or corneal inflammation. The CMV form of uveitis is a little different. I’ve alluded to it already. Much of this work has been done in Singapore by Professor Chi, and she is an expert at this and has isolated through anterior chamber PCR evaluation, two forms of cytomegalovirus anterior uveitis. One is the acute recurrent form that mimics the Posner Schlossman syndrome. So these patients can have KPs, elevated intraocular pressure, and this can be recurrent. The chronic anterior uveitis form can look more like Fuchs. There can be numerous KPs, diffusely distributed, with fine stellate KPs, medium sized, they can have a surrounding halo, and this can be similar to the kind of changes that you would see in the rubella associated Fuchs heterochromic iridocyclitis. Even though we’re talking about cytomegalovirus, remember, we’re generally talking about immunocompetent hosts, not people who have AIDS or who are immunocompromised. These herpes viruses are ubiquitous, so it’s not uncommon to see these infections. Here’s an example of diffuse KPs in a patient who has a herpetic anterior uveitis. And you can see some of them are very tiny. If you look microscopically at some of these, they can have a stellate kind of appearance, dendritic appearance. Incidentally, if you see a patient who has CMV retinitis in AIDS, for example, these patients often will have these stellate KPs on their cornea in the anterior chamber and may have a mild anterior chamber inflammation depending on their CD4 count. If their CD4 count is a little higher, around 50, for example, as opposed to 0, when they present with CMV retinitis and AIDS, they may have a mild anterior chamber reaction that doesn’t cause any symptoms, but often with this kind of appearance — these were clues that from the AIDS epidemic in the United States 25 years ago, where we often saw this very commonly. Herpetic anterior uveitis has been recognized, but we haven’t put it all together into this format until these more immunocompetent patients have been diagnosed with this, and we looked more carefully at these cases. Here’s an example of the larger KPs, kind of scattered around. Even though they’re inferior, they’re spread out. They’re not all localized to Earl’s triangle, but kind of inferior. Here’s another example of more diffuse, and the dendritic KPs, if you look carefully here in the smaller KPs, and magnify them, some of them have a little star-shaped configuration. So these are very helpful, diagnostically. In getting back to the iris manifestations, other clues — the iris may be atrophic, with iridoplegia and mydriasis, because of the damage to the dilator muscle, and you’ll see large transillumination defects and sectoral iris atrophy, which can occur in any of the herpetic anterior uveitic syndromes. You can’t tell looking at that that the patient had zoster, HSV1 or 2, or CMV. The only way you can make the diagnosis as to the causative agent, really, is to do additional testing, which I’ll talk about in a moment. In cytomegalovirus, anterior uveitis, whether it’s chronic or acute, and in rubella, you may see a moth eaten appearance to the iris. You probably will not see the large sectoral atrophy associated transillumination defects that you see in this picture. There in the iris you’re gonna see kind of a more moth eaten appearance. In patients who are more deeply pigmented, for example, who have darker skin and more dark iris color, in those patients you may see iris nodules, in Fuchs uveitis syndrome and the rubella chronic uveitis, and the iris can have a funny, fluffy appearance, even though they’ll have this nodular appearance to the iris, they’ll actually have flattening of the iris crypts and folds, so you’ll still see kind of a flattening of the iris appearance. So the diagnosis can be made most of the time — in my experience — clinically. So you’re looking at a unilateral uveitis with increased IOP at presentation, so it’s a hypertensive acute anterior uveitis, with maybe associated mild corneal changes. Presence of iris atrophy. Previous history of cutaneous skin rash. All of these things can help you nail the diagnosis, as this being herpetic. In the absence of clinical findings, how do you make the diagnosis? I have patients sent to me where blood tests have been done, looking for… Looking at the serologic evidence of herpetic disease. Unfortunately, those are not very valuable, because most of us, by the time that we’re in our third or fourth decades of life, have probably been exposed to these viridae or have been vaccinated against them already, and as a result, our antibody titers may already be positive, and they’re false positives, or they’re unreliable. If these viral titers are negative, it helps you rule out, when you get systemic, for example, HSV1 and 2, anti-HSV1 and 2 IgG/IgM levels, those can be helpful in kind of telling you if it’s negative, that hey, this is not a viral anterior uveitis, likely. But the best way to make the diagnosis of viral etiology is actually to perform aqueous paracentesis and to perform polymerase chain reaction at your laboratory. Most laboratory can perform PCR for varicella zoster virus, HSV1 and 2, and CMV, the most important things to rule out. If you’re concerned about toxoplasmosis, aqueous PCR is not as useful. The true positive rate is quite a bit lower than it is for the viral etiologies, the herpetic viral etiologies of this. In these samples. And that has to do with the primers and the availability of that toxoplasmic DNA in the anterior chamber. So how do you treat these patients? We talked a lot about diagnosis. So if the patient has active epithelial defect with uveitis, you need to first cure the anterior epithelial disease of the cornea before you put the patients on topical steroids. So remember that. Because they have active viral replication going on in the cornea. If you put the patient on steroids, and whether you use topical antivirals or not, if steroids are started before the epithelium is completely healed, you risk making the disease much worse and turning it into a necrotizing keratitis-type picture or a secondary infectious keratitis, on top of the viral disease. And that can be very disastrous and difficult to manage. So I would avoid using corticosteroids until the epithelium is completely healed. And in fact, treating with oral and/or topical antivirals — and I really like oral antivirals, because if you have uveitis going on from herpetic disease and you have a corneal epithelial defect, I think that the oral antivirals, such as valacyclovir, 1 gram, 3 times daily, pretty high dose, can be very helpful. You don’t have to use that high a dose. But you could potentially get away with 500 milligrams three times a day of valacyclovir. That’s very useful. If valacyclovir, the ester of acyclovir, is not available for you, you can use acyclovir at 800 milligrams five times a day for a couple of weeks, and then taper down to twice daily maintenance for several weeks, until the uveitis improves. As far as the eye disease is concerned, I tend to use the oral antivirals a lot longer than dermatologists or internists may use for the treatment of the cutaneous disease associated with zoster, for example. I would avoid, in cases of herpetic anterior uveitis, avoid oral or regional periocular corticosteroids, and you never should use corticosteroids alone, in the treatment of some of these viral uveitides, because you may take an anterior uveitis, thinking it’s non-infectious, put them on oral prednisone or give them a shot of steroid around the eye, and they end up with a necrotizing process in the retina or cornea. But many of these disease processes do respond well to corticosteroids, once the antivirals are started. Let’s talk a little bit about some of these. The steroids — the amount of steroids that you need is very mild. Even if the inflammation is quite severe, very rarely do you need to use drops every hour to control the inflammation in the eye, once the cornea is healed. Often you can use drops as infrequently as four or five times a day, and gradually taper these medications. In acute recurrent CMV anterior uveitis, for example, the Posner-Schlossman syndrome, there’s mild cell. If you keep using steroids, it may alter the immune status, allowing more severe manifestations of the virus. So in this case you have to do paracentesis, verifying that it’s CMV causing the anterior uveitis, and put the patient on appropriate makes. Now, in cytomegalovirus anterior uveitis, it’s very difficult to treat these patients, because what are you going to use? Valacyclovir and acyclovir are not effective against cytomegalovirus. They’re effective against varicella zoster and HSV1 and 2, ten times more effective and sensitive to valacyclovir than varicella zoster virus, but it’s not effective for cytomegalovirus, because of the viral DNA polymerase being resistant to acyclovir. So for that reason, ganciclovir was developed originally. And this particular antiviral is very expensive. And can be very toxic. Ganciclovir can cause profound pancytopenia and myelosuppression, so if you use it systemically, you have to use it very carefully. Zirgan, a topical version of ganciclovir, is also available as a gel-like drop, and Zirgan gel can be useful in the treatment of cytomegalovirus associated anterior uveitis. This may help you, in terms of reducing recurrences. And controlling the disease process, relatively quickly, and if you treat with these antivirals, along with some topical steroids. In the case of the Fuchs uveitis syndrome associated anterior uveitis, from rubella, for example, we don’t see… There’s not much value in using antivirals, because there are no specific antivirals that can treat at this point RNA viruses like the rubella virus. All of these anterior uveitides caused by herpes and cytomegalovirus often require concomitant antiviral therapy, but rubella doesn’t have any antivirals that we can use. Let’s move on to rarer things. I’ll ask the next polling question. Arboviridae are usually transmitted by which of the following routes? Birds, human respiratory droplets, ingestion of contaminated food, or mosquitoes? Arboviridae. This is gonna take you back to medical school. So Arboviridae are usually transmitted by mosquitoes. It’s true that birds can be primary hosts for the viruses, but usually they’re transmitted by mosquitoes or ticks. There’s one exception that I’ll show you in a moment. Let’s talk a little bit about some diseases that are making a comeback in different parts of the world. And I’m ashamed to admit they’ve even made a comeback in developed parts of the world like the United States because of the avoidance of vaccination by certain population subgroups. Here’s an example. Measles, or the rubeola virus, part of the paramyxovirus family. Causes fever, respiratory syndromes, and this diffuse maculopapular rash, and the Koplik spots that you see in the soft palate, the roof of the mouth, here, in this young boy that has this infection. It used to be a real scourge, until we developed vaccination. The mumps, measles, rubella vaccine, or the MMR vaccine, is often given during childhood and often given at multiple times up through adolescence, and this particular vaccine is quite effective in preventing measles. But we are seeing patients develop measles associated diseases now. And recently we’ve had an outbreak of 1200 cases in the United States. Patients may present in early cases of measles with dry eyes or mild keratitis, and this can be associated with corneal ulcer formation in the most severe cases. But in later stages of the disease, if it goes untreated, even if the rash goes away and respiratory symptoms get better, the patient can harbor the virus longer in the central nervous system, perhaps, and can have evidence of late stage — including macular necrotizing retinitis, and evidence of subacute sclerosing inflammation. These are late stage disease manifestations. So the ocular manifestations of this disease can be devastating. It can cause blindness and other more serious problems. Even death. So this is a very, very serious problem. Avoidance is really the best therapy, because once you get this infection, and get this virus, we don’t have antiviral therapy at this point, for rubeola. So measles is an important one, an old disease that we shouldn’t forget about, because of the problem with vaccinations. Even in developed countries. Rubella virus — we already talked about it a little bit. It’s been implicated in Fuchs heterochromic iridocyclitis, as I mentioned. Reverse transcriptase PCR analysis, antibody analysis of the aqueous, have all revealed the presence of rubella virus, and deep genomic sequencing has actually shown cases where, when the actual infection with rubella virus occurred — which is fascinating. But this is a Togavirus, a single stranded RNA virus, not transmitted by mosquitoes or arthropods. Usually respiratory droplets. This is called German measles, and patients can have rash, fever, and lymphadenopathy. And if it’s contracted in pregnancy, it can cause congenital rubella syndrome. But Fuchs heterochromic iridocyclitis is one of the manifestations. Here’s a presentation that many of you pediatric ophthalmologists may know. The triad of cataract, cardiac abnormalities, and deafness is the classic presentation, but you can also see microcephaly, mental retardation, morbilliform rash, hepatosplenomegaly, and meningoencephalitis. I have patients with this syndrome that I see even now today. Any of these patients — when we first recognize the syndrome, and since then, obviously reach adulthood and continue to show these kinds of retinal changes that we continue to see in adult patients. Viral posterior uveitis can be caused by numerous different viruses. The rarer things that I want to talk about a little bit today are based on the world stage of things that we have seen, that have had global implications. And many of you are experts in these diseases. And I’m not going to pretend to be an expert. I’ve only seen a rare case of these, where many of you have seen probably many, many of these cases. The Arboviridae typically are going to be insect — delivered to the humans through insects. The main obligate host, however, typically, for these viridae, may end up being a bird population. For example, in West Nile virus. But they can have different obligate hosts. But mosquitoes can transfer blood from the host to humans, through mosquito bites or tick bites. So the Togaviridae and Flaviviridae are two of the subfamilies of the Arboviridae family. So Chikungunya took Southeast Asia by storm, and has spread as far as the Caribbean and South Florida, and is probably going to spread into North America as time goes on and global travel increases. West Nile virus, similarly, started in central Middle Eastern portions of Africa, and has spread from the Nile Valley up into Europe and across the Atlantic ocean, through bird migrations, bird populations, and travel, and ended up in the United States as well, and we see it not uncommonly with numerous infections reported even in Indiana, every late summer season. And the Zika virus has recently — another mosquito-borne illness. It’s not a true uveitis, even though there are uveitic manifestations that occur in this virus. In the newborn and the fetus — this virus has been a problem in South America, Central America, and now extending into the southern portion of the United States. In Florida. And of course, yellow fever. There has been a longstanding problem in many parts of the subtropical and tropical portions of the world. Another mosquito-borne illness. Most of these mosquitoes are the Aedes species, either Aegypti or albopictus, with stripes on the body, feeding behavior at dawn and dusk. Symptoms include febrile illness, with varied ocular manifestations. You can have variable anterior chamber and vitritis. In most cases, it’s self-limited, but it can result in significant problems. This fatigue syndrome can last a year. I had relatives who had it, who were in bed, not able to do anything for months with this, in India. Here’s an example from India, Dr. Mahendradas’s case of Chikungunya associated virus. You can see retinovascular involvement on the fluorescein angiogram, thickening on the OCT, and gradual improvement of retinitis and resolution of the symptoms as the immunocompetent host heals from this process. Zika virus is transmitted by the albopictus mosquito, resulting in manifestations of microcephaly and these chorioretinal scars, indicative of chorioretinitis. This was famously reported in the — about three to four years ago, at the outbreak of zika in Brazil, South America, and other countries in South America, expanding into southern United States. And most people get it, get infection from zika, and get an illness that they often recover from, but these mosquitoes can transmit it from people to people in the community, but if a pregnant woman gets zika, it can be disastrous because of the severity of the birth defects that are associated with this condition. West Nile virus can cause a significant amount of uveitis, and we’ve seen it even in Indiana. And this is usually transmitted by aedes aegypti. You can see the distribution starting in kind of the Eastern — Northeastern and Southeastern portions of Africa, extending into Southeast Asia, into Europe, and across the Atlantic, as I mentioned. And even in Australia, we’ve seen it. This condition is again the mosquito to bird. Bird is the… The obligate host. But the incidental hosts are usually animals, other mammals, like humans, through mosquito bites. Usually this causes a febrile illness, aseptic meningitis, but in the eye, you can see a very characteristic multifocal choroiditis, vitritis, and even vasculitis. Here’s a patient of mine. This is the optic nerve, this is the left eye, and you can see these lesions that kind of follow the retinal vessels, and even the choroidal vessels. With these punched out pigmented chorioretinal lesions in various stages of healing. There’s snowball vitreous opacities inferiorly, and subtle vascular sheathing. Here’s the fluorescein angiogram of the patient. He was in the healing phases of the disease when we saw him, as these scars were already healing. This patient had a moderate vitritis, and he improved with corticosteroid therapy. He presented many weeks after the actual infection. This was misdiagnosed as the flu and we actually did West Nile virus titers, which were positive, indicating that he indeed had exposure to West Nile virus. The treatment is usually supportive, oral prednisone can be tapered over three to four month. Very rarely, areas of choroiditis can be associated with choroidal neovascularization as occurs in the macula, and it can be treated with intravitreal therapy. Central vision is preserved, and patients usually do fairly well. It’s usually bilateral when it occurs. Yellow fever is another single stranded RNA virus, transmitted by Aedes or Haemagogus species, and presents with influenza-like illness but can cause hemorrhagic fever and circulatory shock. Yellow fever vaccination has been associated with uveitis as a side effect, just for your FYI, so sometimes you may see patients who got a vaccine for yellow fever and has subsequently developed an anterior uveitis. Sometimes they can even develop unusual multifocal choroidal lesions as well with the vaccine. That’s an unusual kind of side story to this. Dengue fever, another hemorrhagic viral illness, can produce numerous manifestations, as can the dengue fever vaccine. So interestingly, these patients can develop vitritis, retinal hemorrhages, vascular occlusions, as you can see in this picture from a patient in India. This is a ischemic vein occlusion that this patient had. Remarkable. They can develop choroidal effusions, disc edema, optic neuritis, they can get ocular third nerve palsies, panophthalmitis. And it’s usually the young patients who have the exuberant cytokine response to these diseases that develop the more severe forms of disease. They can present with abdominal pain, bleeding gums, and of course the hemorrhagic complications of the disease. The filoviridae have most recently been brought to our attention because of the ebola epidemics that have occurred. Some of you are probably calling from areas potentially that have been affected by this. The ebola virus — most of us know that the African fruit bat is the reservoir, and animals may be exposed from these infected bats. A human eats these infected animals. It’s probably spread, again, ultimately from human to human through exposure to body fluids of the infected. And ebola virus disease is a hemorrhagic fever, it’s deadly, and the ebola virus can persist in the eye, even in cases where the patient has recovered from the hemorrhagic fever. And the viral persistence can result in anterior chamber severe inflammation, often nine or more weeks after the viremia has cleared, with hypopyon formation, it can look like HLA B27 associated cyclitis, and usually these patients are treated with systemic corticosteroids and regional corticosteroids with improvement, but they need aggressive management of the disease with steroids. You can also see small choroidal lesions from patients who have healed from the ebola virus infection. So you see these small punched out choroidal scars. You can see subtle corneal manifestations, and of course this is a patient who had severe vitritis on the lower right here, associated with post-ebola virus persistence following the hemorrhagic fever recovery. The marburg virus is another filoviridae, and the Lassa virus. These are things I have very little experience with, but they can present with hemorrhagic fevers, Lassa fever can as well, they can be associated with uveitis and high IOPs, as can marburg. These have been recovered from intraocular fluid and tissue. So these are things to keep in mind as we evolve into a global society, that things that affect many places of the remote portions of the world where there are large populations and now global travel — we can see these diseases expand to other parts of the world. Now that I’ve talked kind of about the exotic diseases, and talked about anterior uveitis first, and now posterior uveitis, I’m gonna switch over to the posterior uveitis that I see more commonly as a retina and uveitis specialist here in the US. So the polling question next is: A 40-year-old patient presents with vision of hand motions in the right eye, with granulomatous KPs, IOP of 43, and a vitritis and hazy view of the posterior pole with areas of whitening of the peripheral retina in the right eye. The left eye is completely normal. What is the next most helpful step in the diagnosis and management of this patient? A, obtain a thorough medical history on the patient, B, aqueous paracentesis with PCR for VZV, HSV, CMV, C, B scan ultrasound, or D, serum IgG and IgM antibody titers to HSV1, CMV, and VZV? It’s a longwinded question. This guy has really bad vision, vitritis, hazy view of the posterior pole with areas of whitening of the peripheral retina. Most of the people got it. I guess we still have some non-believers. Serum IgG and IgM antibody titers — if they’re negative, they’re helpful, but if they’re positive, they don’t tell you anything. Tissue is the issue. You go in and get a little bit of aqueous fluid, because you’re suspecting a viral retinitis. I hope you all thought that. The IOP is high, they have retinal whitening. The worst thing this can be is a necrotizing herpetic retinitis. Right? And so that’s what you want to go — in terms of treatment, you want to not miss that diagnosis. Because if you miss that, you put this patient on steroids, give them a steroid shot, they’re blind forever. They’re never gonna see again. So you want to make that diagnosis quickly. So aqueous paracentesis, very helpful. So a necrotizing herpetic retinitis is usually caused by zoster. The most common agent. But can also be caused by HSV1 and 2 and can also be caused by cytomegalovirus in the immunocompetent host. That’s quite rare. Usually we see cytomegalovirus causing cytomegalovirus retinitis of course in the setting of AIDS or the severely immunocompromised host. So HSV1 and 2 — HSV1 in particular — is the most common etiologic virus in young patients that causes herpetic retinitis, but in older patients, patients over the age of 25, varicella zoster virus is still the most common agent. Usually… I break up the necrotizing herpetic retinitises into two groups. The group where this occurs in the immunocompetent patient, where this immunocompetent patient gets it, it’s called acute retinal necrosis syndrome, or ARN. You know we’ve used this term previously. This implies very prominent intraocular inflammation, because the host is immunocompetent. They have normal lymphocyte and neutrophil function. They’re going to generate a lot of inflammation to the virus and the eye. Whereas in a patient who has AIDS and very low CD4 counts, there will be a massive viral load exposure, and these patients develop very bad retinitis, but very little inflammation in the eye, because they can’t generate the inflammation, and that’s a different kind of necrotizing herpetic retinitis in the immunosuppressed patient, and we call that progressive outer retinal necrosis, or PORN. We’ve kind of gotten away from using those terms. ARN and PORN. We always call it herpetic necrotizing retinitis, either in the immunocompetent or the immunosuppressed patient, because that tells us more about how we need to treat these patients and what the outcomes may be. Patients often present with decreased vision and floaters, there may be pain with patients who have acute retinal necrosis syndrome, because of the inflammation. The features of acute retinal necrosis or necrotizing herpetic retinitis in the immunocompetent patient is that there are peripheral areas of retinal necrosis with discrete borders of the periphery with rapid progression, circumferentially, and centrifugally, towards the center of the macula. There’s occlusive vasculopathy, often, highly attenuated and white vessels, that can precede the retinal whitening. There may be some optic nerve head inflammation as well. Some people have scleritis and pain associated with it. So this is an example of that occlusive arteriolitis that we see in necrotizing herpetic retinitis. See the hazy view. This is in an immunocompetent patient. So these are the arteries that are white and very necrotic. It’s hard to see the necrotizing retinitis, but it’s there. It’s subtle. But out in the periphery here, where it’s more white, that’s actually the retinitis. Here’s a more classic example. You can see the occlusive arteriolitis in the — posteriorly, there are a few retinal hemorrhages here, and you can see in the periphery this diffuse retinal whitening with retinal hemorrhages. It’s a very ominous kind of appearance. It tells us this is necrotizing retinitis. Sometimes the necrotizing retinitis will have posterior extension, with the smaller satellite spots of infection, of the virus. And these can extend all over. That tells us — even though there’s uninvolved… Apparently uninvolved-looking retina, all of this retina ultimately has been involved. The posteriormost extent of these white lesions tells you how much retinal necrosis there is. And here’s what we call the thumbprint pattern of necrosis. We’ll see these areas of retinal whitening. There’s actually some perivascular clearing, as these lesions become intumescent and heal. And you can see this healing process. Here’s the cracked mud appearance, where there’s perivascular clearing of some of the inflammatory cells in the necrotic retina. As the healing process continues in necrotizing herpetic retinitis. Progressive outer retinal necrosis, which is the necrotizing herpetic retinitis in the immunocompromised host, is usually — the vitreous is pretty clear. And you’ll see outer retinal involvement or full thickness necrosis in the peripheral retina with or without macular involvement. Sometimes you’ll see macular lesions alone, the so-called white cherry red spot lesions in the macula of both eyes, and peripheral areas of retinitis as well. And that’s kind of characteristic of presentation, of progressive outer retinal necrosis in patients who are HIV positive, with AIDS and very low CD4 counts. Diagnosis of necrotizing herpetic retinitis is a clinical one in general. Confirmation with PCR of aqueous or vitreous fluids can be extremely helpful in diagnosis of which virus is causing the retinitis, to help manage the therapy. Here’s a patient with necrotizing herpetic retinitis with AIDS, and you can see that there’s very little vitreous inflammation here. And you can see these punctate lesions posteriorly, and they become confluent in the periphery, as this disease process is spreading towards the macula. These confluent areas of necrosis in the periphery are not associated with a lot of inflammation. The retina looks kind of… Very diffusely white and damaged. Here’s another example of a patient with AIDS, CD4 count of 0, who presented with this very severe necrotizing herpetic retinitis. Progressive outer retinal necrosis syndrome. The risk factors for necrotizing herpetic retinitis in the immunocompetent patient may be difficult to ascertain. There may be a history of prior herpetic infection, patients may have a history of herpes labialis lesions or herpes zoster ophthalmicus, they may have had some… A small time period of immunosuppression that has gone away, or the patient may be immunosuppressed from AIDS or cancer chemotherapy, bone marrow transplantation, et cetera, or organ transplant recipient, who is on chronic immunosuppression, and those patients are also going to be at risk, but they will present more likely with the more aggressive form of the necrotizing herpetic retinitis or progressive outer retinal necrosis in the immunocompromised host. The differential diagnosis can include many things. Because of that white clinical appearance. Let me go back a slide. So this appearance can be seen with syphilis, it can be seen with toxoplasmosis, it can be seen as primary central nervous system lymphoma, occurring in the subretinal space. It can look like this too. So many things can look like this. But the clinical course of this type of necrotizing herpetic retinitis is very rapid in comparison to some of those other disease processes, and PCR evaluation of the fluids for viruses can help you nail the diagnosis and get on treatment right away. One other important thing in the differential that I want to point out is Behcet’s disease. And many of you who are in the Mediterranean and the Asian portions of the world, far East, et cetera, may see a lot of Behcet’s disease. And Behcet’s can be associated with occlusive retinal vasculitis that can mimic necrotizing herpetic retinitis. I have been fooled many times, when I thought that the patient had necrotizing herpetic retinitis, when in fact they actually had Behcet’s disease. Primary CNS lymphoma is a disease that you don’t want to miss the diagnosis of. But you have to keep that in the back of your mind. It’s a much more rare condition than even necrotizing herpetic retina. Systemic leukemias and lymphomas can also look like this, but again, very rare diagnosis. Here is one of my old patients with Behcet’s disease, who has retinal vasculitis. I thought he had acute retinal necrosis. Look at all this area of retinal arteriolar attenuation and involvement and vasculitis. And then you can see retinal hemorrhage and this retinal whitening. This is gonna easily be — you can easily confuse this with necrotizing herpetic retinitis. But this patient had oral aphthous ulcers, presented with hypopyon in the other eye, and initially we didn’t know — in those days — this was many years ago. We didn’t have PCR available. So we ultimately made the diagnosis of Behcet’s disease, and the patient recovered, thankfully. The medical therapy for necrotizing herpetic retinitis is to begin intravenous acyclovir, followed by oral acyclovir. For the most severe diseases. However, these days, even in very severe necrotizing herpetic retinitis, we have been able to use oral valacyclovir at 1 to 2 grams, three times daily. 2 grams, three times daily, is a very high dose, and you can actually cause crystallization of the drug in the renal islands, so be very careful. Make sure the patients are adequately hydrated when you do that. This high dose should be used anywhere from 4 to 6 weeks. So I really believe in aggressive therapy. 2 grams, three times daily, probably for two weeks, and 1 gram three times daily for the next 4 to 6 weeks, and gradually taper down to a maintenance dose once the active retinitis has healed. You may supplement this — the systemic therapy — with intravitreal therapy that I’ll show in just a moment. You can also use famciclovir, another kind of variant, another form of acyclovir, that can be useful. If you don’t have valacyclovir available. IV acyclovir is usually given at 1.5 grams per square meter of body surface area, divided into three equal IV doses per day. This can be managed through your infectious disease specialist. Again, the IV is given for about two weeks, and then oral agents are then started for many weeks thereafter. I tend to keep patients on maintenance antiviral therapy with this disease for many months, depending on the severity of the process. So maintenance therapy is important. Even in the immunocompromised patients. But I would say that at least three or four months, maybe longer, if both eyes are involved. I will say this: That in the immunocompetent patient, there is a role for corticosteroids, but corticosteroids should never be used alone in the treatment of this disease. If you put a patient on prednisone without antiviral therapy with necrotizing herpetic retinitis, they will become blind. They will never recover. So you can start oral prednisone to control inflammation in the immunocompetent host, once you’ve started antiviral therapy, and you have started to have good control of the retinitis. The earliest I usually start oral prednisone is within the first week after the initiation of antiviral therapy. So progressive outer retinal necrosis is much more difficult to manage. So often we have to use, in these patients who are severely immunocompromised, aggressive antiviral therapy, often combining intravenous therapy, with multiple agents, like acyclovir or ganciclovir, with foscarnet, and this has shown some improved efficacy, but these patients rapidly progress to blindness, and so we will be very aggressive with intravitreal therapy in these patients as well. There has been some value, we think, in the use of low dose aspirin to protect from vascular occlusions, but this is conjecture. It’s really not based on a lot of very hard evidence. Many of these patients — one of the complications of necrotizing herpetic retinitis is that it can result in retinal detachment. So many patients can go on to retinal detachments, and the frequency of retinal detachment, I think, is really related to the amount of retina involved. If there’s only some mild patchy peripheral retinal involvement, you catch it early and treat it, it’s unlikely that patient will develop retinal detachment. But when the patient has much more diffuse retinitis and more than half of the retina is involved, you’re probably going to get significant vitreous opacification, condensation, contraction, and development of tears in the very severely damaged necrotic retina that’s very, very thin, and then you can get retinal detachment. Usually this is treated with vitrectomy, silicon oil placement, sometimes we use scleral buckle as well, in the severe cases, where there’s a lot of inflammatory debris and changes in the vitreous. So retinal detachment is a very important disease-related complication associated with necrotizing herpetic retinitis. As an aside, I will mention that patients who are immunocompromised, who get this progressive retinal necrosis type of necrotizing herpetic retinitis, can have a very high risk of developing retinal detachment. Close to 100%, probably 90%, will develop retinal detachment, and they can lose vision as a result of that. Optic nerve involvement from the retinitis can be primary or secondary. It can result in significant optic nerve atrophy. And this can also be associated with postencephalitis appearance. So this is a patient who had acute retinal necrosis, which has been managed and controlled, who presented several weeks after the initial presentation with a retinal detachment. The macula is detached. Her vision was hand motion. And these patients — this patient underwent vitrectomy, scleral buckling, and silicon oil placement. There can be other complications, such as retinal ischemia, cataracts, hypotony, all of these are potential complications. I’m gonna move now and talk about the last topic, which is related to the immunocompromised patient. CMV retinitis is the most likely cause of necrotizing retinitis in which of the following patients? A, HIV positive patient with CD4 count of 500 cells per cubic millimeter? B, patient with rheumatoid arthritis treated with hydroxychloroquine for 20 years, C, a cadaveric renal transplant recipient on azathioprine and tacrolimus, or D, a patient with chronic non-infectious intermediate uveitis treated with maintenance of oral prednisone of 5 milligrams daily for 3 years. Which of those is more likely to develop CMV retinitis? Let’s see what you guys did. See if you got the question right. So let’s talk about this. So the right answer is C. Cadaveric renal transplant recipient. So HIV positive patients — CD4 counts usually have to be less than 50 for them to have CMV retinitis. People who have CD4 counts that are relatively high, 500 cells, they’re not the most at risk for developing CMV retinitis. Could it happen? Yes, but unlikely. But the patient who has been treated with renal transplant who is on azathioprine and tacrolimus, they’re profoundly immunosuppressed. They can indeed develop CMV retinitis and I’ve seen many patients in the past 25 years who presented exactly that way. Bone marrow transplant patients also. Similar group. The other thing… Choice B — rheumatoid arthritis and hydroxychloroquine — those patients are not immunocompromised enough to develop a CMV retinitis. 25 years of Plaquenil therapy can result in macular damage and macular toxicity, so you should be checking for that anyway in those patients. A cumulative dose of more than a milligram and a half of hydroxychloroquine increases substantially the risk of developing maculopathy from hydroxychloroquine. So that’s an unrelated topic, but important for you to know about. G, non-infectious uveitis treated with oral prednisone — those patients are not immunocompromised enough to develop CMV retinitis. Highly unlikely. CMV is part of the herpes virus family, as you know. We can see it as a congenital infection, where it’s vertical transmission from the mother, during pregnancy, and that can cause various syndromes in the newborn. You can see it as an acquired infection, usually from sexual contact with other body fluids, or it can be transmitted from infected blood or transplantation from an organ of a CMV positive donor to a CMV negative recipient. These are all possibilities. And I’ve seen the latter — all of these manifestations of CMV infection. And all of these modes of transmission I have seen. So there’s a latency in these viruses. These are DNA viruses, so they can establish latency in various cell types, everything from alveolar cells to neurons. The recurrence from latency occurs when the immune system has been impaired. In other words, most of us are exposed to this ubiquitous virus in the environment. It is only later that many of us can develop infection as a result of changes in immunity. Congenital infections can have devastating neurologic and ocular effects, including blindness, but acquired infection in children and adults can cause symptoms similar to infectious mononucleosis syndrome in immunocompetent patients. Recurrent infections depend on immune status. In HIV/AIDS, it manifests as retinitis and a clinically important disease associated with CMV, and retinal involvement occasionally occurs in other patients, such as transplant patients. And there may be other organs involved. The GI tract or central nervous system as well. In an HIV/AIDS patient, it’s a more diffuse, systemic disease process, because of their diffuse immune system compromise. There are certain populations that are more likely to have CMV infection or prior infection with CMV. Health care workers, hemophiliacs, men who have sex with men, persons from developing countries may be more likely to have these serologically positive for previous infection. CMV retinitis from recurrent disease usually occurs in patients who are immunocompromised, as I mentioned, and it’s one of the major opportunistic infections in patients with AIDS. Approximately 30% of AIDS patients develop CMV retinitis in the pre-HAART era in Western countries, but the number of new cases in developed countries reduced by 80% initially, with the advent of HAART, and stabilized at this level, has not gone away. But in developing countries, particularly resource poor settings, CMV retinitis remains a real clinical challenge and many of you know that. I don’t want to act like I’m an expert in this area. I trained in one of the areas where the AIDS epidemic was rampant in the United States, so I have a lot of experience of CMV retinitis and AIDS, but you may have much more experience now than I do because of where you live and what you’ve seen. In AIDS CMV retinitis usually occurs in patients where CD4 counts are low. And patients usually have blurred vision or vitreous floaters. This is one of the most common symptoms. Patients may occasionally present with a detachment, with advanced disease, but it’s rare. It’s one of the first manifestations of AIDS very rarely in Western countries. I don’t know how that is in more undeveloped countries, but it could certainly be a presentation as a first manifestation of AIDS, but it’s uncommon. Diagnosis usually occurs in the presence of active viral shedding in the HIV positive patient in the blood or urine. Other body tissues may be involved symptomatically. And in an organ transplant patient, you may want to inquire — the CMV status of the donor. Often that’s available through the organ bank. That can be very helpful in the management of the patient, determining whether or not long-term maintenance of anti-CMV therapy will be required. In patients who are at high risk for CMV, they should be screened, especially when their CD4 counts are below 50, until there’s reconstitution of their immune system with highly active antiretroviral therapy. Here is a patient who was an organ transplant recipient, CMV positive donor and CMV negative recipient, who developed CMV retinitis after an intravitreal injection of triamcinolone, preservative-free triamcinolone, that I had given her for the treatment of diabetic macular edema. This was prior to the availability of anti-VEGF therapy and this patient was on chronic Imuran or azathioprine, and chronic Prograf, antirejection medication. She was profoundly immunocompromised, but she was harboring CMV from her donor organ. And here’s what happened. This patient was given the steroid injection, and unfortunately she presented with severe vision loss and had peripheral retinitis. We did an aqueous paracentesis and PCR confirmed the presence of CMV, and this patient was treated with antiviral therapy. Stabilized, but the vision did not improve. Because she has diffuse involvement, even though the retinitis is only peripheral here. The nerve is pale. There is significant arteriolar occlusion from the virus, so she lost a lot of vision in this eye. CMV causes a necrotizing retinitis and has the basic characteristics of dense retinal whitening with scattered areas of intraretinal hemorrhages. It can be a pizza pie or wedge shaped area, but it can have centrifugal spread with central clearing, and there may be vesicles. There are four manifestations of CMV that you should know. One is the thick and fluffy cottage cheese and tomato ketchup fundus, or the pizza pie retinitis, where thick and fluffy retinal necroses are present along vascular arcades, there can be dry granular appearing retinal whitening of the peripheral retina, there can be isolated involvement of the optic nerve, which is rare, and this can be usually spread from adjacent retinitis, but you can have isolated optic nerve involvement. And of course, the fourth form is the frosted branch angiitis. In addition to the retinal whitening, there’s a subset called brush fire appearance. I may have a picture of that. Here’s the classic appearance of the tomato ketchup/cottage cheese appearance. Ophthalmologists like to refer to food when we look at the retina. We can think of this as pizza pie. Ketchup and cheese on a slice of pizza. Typical kind of fluffy retinitis appearance for CMV. This is classic. Here is another patient with optic nerve involvement, macular involvement, at presentation. This was the initial presentation of a patient who did not know he was HIV positive. Rare kind of presentation of AIDS. This is a patient that lost a lot of vision in the eye. Here’s kind of the granular appearance. You can see the grainy appearance, rather than the fluffy necrosis. There’s retinal hemorrhages here as well. Here’s another granular appearance, a pearlescent area of healing that you’re seeing, with central clearing. Here’s the brush fire appearance. Sneaky granular retinitis that’s rapidly progressing. You have to be very careful and watch for advancement posteriorly of the leading edge of the retinitis. This is the leading edge. This is the peripheral — this is the posterior portion of the retina. Here’s another granular appearance to the retinitis. Here’s more kind of a mixed appearance. Here’s the frosted branch angiitis appearance, a very classic beautiful picture from Dr. Vitali of this frosted branch angiitis. The disease process, the retinitis, can be unilateral, most commonly. But a significant minority can be bilateral. Most eyes contain only one focus of retinitis, but you can have multifocal involvement, especially in severely immunocompromised patients. And inflammation is often low grade, because these patients are immune compromised. With the recovery, you can see significant immune recovery uveitis associated with CMV that can lead to complications such as cystoid macular edema, epiretinal membrane formation, and that can cause significant vision loss. It is a clinical diagnosis to make, based on the history of patients’ risk of getting the disease, and the clinical appearance. HIV antibody status and CD4 counts are crucial in patients where you suspect HIV disease. And PCR of ocular fluids can nail the diagnosis. So it can allow you to determine if it’s cytomegalovirus. Why is that important? Imagine that you have a patient who presents to you with a necrotizing retinitis who has had previous bone marrow transplant. And I have seen this multiple times. The patient presents with necrotizing retinitis, you think it is herpetic, but you’re not sure what is the etiologic agent, and you put the patient on acyclovir at high doses, and they continue to have progression of disease, and vision loss over the next couple of weeks. When there’s no response, people often forget that… Hey, this could be cytomegalovirus, and they’re not going to respond to acyclovir. Why? Because the cytomegalovirus viral DNA polymerase is not sensitive to acyclovir. Remember, these antivirals actually block the activity of the viral DNA polymerase by interfering with the DNA synthesis. So as they — ganciclovir, which is a different methylated form of acyclovir, if you will, that is the agent that you want to use. Or foscarnet. You want to use that to treat cytomegalovirus retinitis. So I already talked about risk factors. And the differential diagnosis is broad. It includes other causes of necrotizing herpetic retinitis like HSV and VZV. Toxoplasmosis and syphilis can look identical to this in the HIV positive or immunocompromised patients. They need to be ruled out. You can do aqueous or vitreous samples for PCR and you can do serology. It’s still helpful, but in the HIV positive patient, it may not be as helpful. Syphilitic serologies may be important to get. Remember that all of these diseases travel together. Just because somebody has one disease doesn’t mean that they can’t have syphilis. It’s very important to check for that. And intraocular lymphoma can also be common in patients who are immunocompromised. That can only be determined by vitreous biopsy and cytopathologic evaluation. Bacterial and fungal infections of the retina can also mimic this. One of the important benign things that can mimic CMV retinitis is HIV retinopathy, retinal hemorrhages, and cotton wool spots. Sometimes that can be confused with retinitis when you have large cotton wool spots, but these usually are not associated with significant vision loss, there’s usually no significant anterior chamber or vitreous inflammation that you’ll see in these patients, and these patients often have CD4 counts that are quite high, in the greater than 200 range. Those are all clues as to the diagnosis of HIV retinopathy. Probably the most common manifestation of HIV disease in the retina. So medical therapy for cytomegalovirus retinitis in the immunocompromised patient usually involves induction of antiviral therapy. Now we have oral valganciclovir, which can be given at 900 milligrams twice daily, for two to three weeks, for induction, minimum, and then dropped to 900 milligrams daily maintenance, to control retinitis, and oral valganciclovir is almost as effective as intravenous ganciclovir. Sometimes the cytomegalovirus may be resistant to ganciclovir, and viral evaluation and PCR evaluation may help you in determining the resistant strains. And you may be required to use foscarnet. We may supplement with intravitreal therapy as well, and I’ll get to that in a moment, but these immunocompromised patients will require maintenance therapy. Maintenance therapy involves lower doses of the agents, and these are often kept up until the patient has immune reconstitution. Once CD4 counts are greater than 100 for at least four months, you can consider discontinuation of anti-CMV specific therapy, when they’re on HAART therapy. Intravitreal injections of ganciclovir and foscarnet are off-label, but can be used for induction. For induction you have to give injections device weekly in the involved eye or eyes, and then once weekly maintenance therapy. Laser may be of some benefit, but not always. There are complications of therapy. Neutropenia, anemia, thrombocytopenia can occur with ganciclovir, anemia can occur with foscarnet, but foscarnet is more likely to cause renal toxicity because of the phosphate moiety of the drug that can cause direct toxicity. Cidofovir is an uncommonly used antiviral because of ocular side effects, including uveitis hypotony, which can cause irreversible retinal damage, but often requires the use of concomitant oral probenecid to protect the kidney from the drug, and hydration is very important for the drug, to prevent renal toxicity from Cidofovir. Retinal detachment is probably the most important immediate potential risk for CMV retinitis. Greater than 25% of retinal surface area involvement increases the risk of retinal detachment. And once immune recovery occurs, that can be a complication as well, because these patients often develop vitritis once their CD4 counts become high, and can develop cataract, and local or systemic therapy may need to be used. CMV strains resistant to antiviral therapies exist. So we can use other drugs such as Cidofovir or Leflunomide. You can have death from coincident extraocular CMV disease in patients who are severely immunocompromised. That ends my talk. I’m gonna take some questions. I’m sorry I ran over, but I thought this was important to cover. I hope you found this information useful. Let me see if I can get the question and answers going. Let me start with the first question. Would you talk about intermediate uveitis? That’s a little bit of a different topic. Let me get back to that at the end. Let me see if I have any other questions that are related to this. Intermediate uveitis — I think you’re referring to as non-infectious uveitis? And that’s really kind of a topic… I usually use a stepladder approach for treatment of intermediate uveitis. The laboratory workup should include ruling out sarcoidosis, syphilis, and tuberculosis, and if you’ve ruled those things out, generally I use oral corticosteroid therapy, bilateral or local corticosteroid therapy, non-infectious and unilateral… And even topical Durezol with milder cases can be very effective. But long-term management may require in the most severe cases the use of immunosuppression with antimetabolites such as methotrexate. This is for non-infectious uveitis. Second question includes a 38-year-old female patient treated somewhere for uveitis of the left eye, improved, no more complaint. Now has panuveitis of the right eye, anterior uveitis, vitritis, macular edema. Treated with topical steroid, antibiotic drops, no improvement. Improved on periocular corticosteroid. If you’re thinking it’s viral uveitis and you’re not sure, obviously periocular corticosteroids with viral uveitis probably would have made it much worse. So it probably isn’t that clinically, but if you’re not sure, I would recommend doing an aqueous paracentesis through clear cornea in a sterile fashion. Sending 0.1CC of fluid to your laboratory to perform PCR evaluation for HSV1 and 2, cytomegalovirus, and varicella zoster virus. That will nail down whether or not this patient has a viral uveitis or not. Next question. Even in developing countries, we rarely see CMV retinitis now because most patients get antiretrovirals. Thank you, Dr. Mathenge. I appreciate that. I think the work of many of you at the level in global ophthalmology — and please don’t take any of my comments in a condescending way. I have tremendous respect for all of you. You have seen many, many more diseases and lots of various diseases than I have in our little neck of the woods. I think it’s very important to point out that even in developing countries, there has been a tremendous push by many of you to get access for your patients to appropriate antiretroviral therapy, to treat HIV. And my hat is off to you. This is wonderful. So it’s great to know that CMV retinitis is even now rare. I think there’s another question. This looks like a consultation day today. 34-year-old woman presents complaint of sudden vision loss, photophobia, redness, pain in the right eye. Examination, poor vision, hyperemia, anterior chamber fibrin in the lens, posterior synechiae, no red reflex, fundus cannot be seen, signs of previous attack in the left eye, visual acuity is better in the left eye, noticed that such conditions happen after flu, problems or pain in teeth, rheumatologist says nothing abnormal with her. Shows vitritis. What is the best workup? Any uveitis like this, a panuveitic presentation, acute panuveitis, think about the possibility of infectious first. Rule out infectious causes. Presence of fibrin or hypopyon with vitritis — I think about the possibility of infection. Is the patient immunocompromised? Have they been ill, had fevers? Find out medications they might be taking. If there’s a risk that they’re septic or have a bacteremia that potentially could have caused this, maybe the bacteria is the cause, and putting them on steroids without appropriate antibiotic coverage would be a mistake. So in this case, tissue is the issue. Sometimes you may have to do — if you’re not sure — vitreous biopsy, or anterior chamber paracentesis. But that may be risky in a hot eye with non-infectious uveitis. So one thing you can do immediately is to start the patient on topical corticosteroid therapy intensively, such as difluprednate or prednisolone, while you do the laboratory workup, to rule out the most common infectious causes, such as tuberculosis and syphilis. And other more endemic causes of infectious uveitis that you may have locally in your area. Everything from listeriosis potentially to… You need to think about all of the other potential causes of infectious uveitis in your area. And once that’s been ruled out, then I think that you can start more aggressively, using oral corticosteroids. If she had a similar episode and recovered in the other eye, and go back and find out what was done to treat her, that will also help you. Sometimes these are — diagnosis and management of uveitis patients is often a work in progress. The most important thing in these cases is to make sure you rule out for sure whether the patient has an infectious uveitis or non-infectious uveitis. And once you’ve done that, then you can be safe about… You can feel safe about how you treat these patients. Do not make an infectious uveitis much worse by sticking a needle in the eye and putting steroids in the eye if it’s infectious. You will blind them forever. So that’s why you have to be more ginger. Use topical agents aggressively to clear some of the uveitis, see how it responds. If it doesn’t, follow the patient very carefully, maybe every couple of days, until you see what’s happening. If they get worse, then go after the tissues. Get a biopsy. Inject intravitreal antibiotics if you need to, and treat as an infection and then start treatment with appropriate steroid therapy, if you need to. That would be my approach in these tougher cases. What is your treatment options? Next question. I’m gonna move on here. What are the treatment options for nummular keratitis, and the given treatment period? If it’s intact, topical corticosteroids can be used at low doses. If the nummules are active, you’ll see stromal edema, activity in the underlying epithelium, and if there is viral etiology, there’s previous history of viral HSV or VZV infection that’s causing the nummular keratitis, I would add antiviral therapy when they’re active, and maybe maintain them on antiviral therapy at low doses. I would put them on acyclovir, for example, 800 milligrams five times a day, for a couple of weeks, and down to twice daily maintenance, 800 milligrams twice daily or 400 milligrams twice daily maintenance for a long period of time, if they had multiple recurrences. If we cannot do PCR of the AC, what about blood serology? As I mentioned, blood serology is only useful if the patient has negative serologic evidence, to rule out the virus. So viral serologies — especially in older patients — if they’re over the age of 25, they’ve already been exposed to many of these viruses. Not particularly that useful. Unfortunately then you have to go by your clinical and your historical evidence to determine how you treat these patients. So this is really important. How well can you tell drusen appearance and cotton wool spots from an early case of necrotizing herpetic retinitis? Drusen… So I want to make sure that I understand. Drusen are deposits under the retina that are benign and associated with age related macular degeneration, if they’re soft drusen. Now, that’s very different than… These are subretinal. Versus cotton wool spots, which are into superficial retina. If you’re not sure where the location of the lesion is, get an OCT. If you’ve got access to OCT imaging, the cotton wool spot will actually show up as thickened area of the inner retina. So the inner retina will be thickened and opacified on the OCT. In necrotizing herpetic retinitis, as I said, you’ll see full thickness retinal involvement. If you do an OCT, the entire retina will be opacified. Generally there will be not much going on in the subretinal space. All the photoreceptors will be thickened or even destroyed in the cases of necrotizing herpetic retinitis, on the OCT image. But your clinical image should show diffuse whitening. There may be vitritis, and that’s gonna tell you — if you’re not sure, and it’s a small area, it’s not immediately sight threatening, follow the patient carefully and see what happens within a few days. If there’s progression and enlargement and the patient is losing vision, you know it’s probably necrotizing herpetic retinitis. You definitely don’t want to miss that. If you’re not sure, you can always put them on antiviral therapy. You’re not gonna lose anything by putting them on antiviral therapy. If you made a mistake, you would rather be mistaken towards the most serious disease that it could be, and treat that. Because you won’t lose anything by doing that. I do not have access to intravitreal injections for treatment of CMV retinitis. Oral ganciclovir is available. Is it okay to use this? And how long should I use it? Yes, it’s okay to use it. 900 milligrams twice daily as induction therapy for two or three or four weeks and 450 milligrams… I’m sorry. 900 once daily or 450 milligrams twice daily for maintenance therapy seems to be as effective as intravenous ganciclovir. And so this is useful. If you don’t have access to intravitreal injections, that is concerning. You might want to talk to local pharmacies. If they have IV ganciclovir available, they may be able to formulate something for you, for injection. So intravitreal injections — you can use fairly high doses of ganciclovir. The traditional teaching is 2 milligrams, a 10th of a CC, but I’ve used as high as 20 milligrams, a 10th of a CC, of ganciclovir, and injected it sterilely in an intravitreal fashion. Patient, 40-year-old, ALL, maintenance phase, developed granular type retinitis and vitritis, unilateral, only test positive CMV DNA… How about aqueous tap for PCR? In this situation, the patient probably has CMV. They’re immunocompromised, on maintenance phase, but if they’ve had a bone marrow transplant especially, they’re high risk. So those patients should be treated with oral valganciclovir, 900 milligrams, twice daily. You should manage this with the oncologist. The ALL in an adult has a much poorer prognosis than in a child. So acute lymphoblastic leukemia is actually a relatively rare diagnosis. It’s not as badass acute lymphoblastic, but it should be managed carefully with your oncologist. What antiviral can be used for intravitreal injections? Is it the same as intravenous? Yes. They’re interchangeable. You don’t have to do anything differently. There are crystallizations that can occur when you combine foscarnet with the ganciclovir, but it doesn’t seem to be toxic to the retina. But foscarnet is more toxic to the retina than ganciclovir. As I mentioned, ganciclovir intravenous — you can use 2 to 20 milligrams for 0.1CC. It’s a safe dose. You can go up higher if necessary. But that’s very easy to get from the intravenous preparation. Foscarnet is available typically — I use 1900 micrograms in 0.1CC. I’m sorry. 1800. That’s the typical IV formulation. So you can draw it up directly from the IV formulation. Talk to your pharmacist in your hospital to get that makes, if you have one. So I’m going to end. I appreciate your information. And I appreciate your involvement. Looks like we have a last question. Somebody else… Let me take this, before I leave. I have to get back to work. 36-year-old female, patient complains red eye, dull achey pain, three weeks, Pred Forte, antiglaucoma medications. History of bilateral keratoplasty, cornea, keratitis, some pigment at lens and pupil margin. I have given topical antibiotics, after five days follow-up, right dendritic ulcer on keratoplasty. So the question is… Do you stop the Pred Forte? I would recommend that you do, until the topical dendritic ulcer heals. Because right now the main problem sounds like there’s herpetic keratitis. Not a transplant rejection. So I would recommend that you put the patient on oral antivirals. Which will result in more rapid healing, probably, in this patient. So that you can reinstitute your topical steroids once the epithelium is healed. I would use valacyclovir or oral acyclovir. 3 milligrams, five times daily. Can you write the formulation? I’m assuming you’re talking about the intravitreal therapy. 2 milligrams, a 10th of a CC. Tell that to your pharmacist. 2 milligrams per 0.1cc for ganciclovir, foscarnet is 1.8 milligrams in 0.8CC. Thank you very much! Have a great weekend and rest of the day. Thank you for your attention.