Lecture: Update on White Spot Syndromes

During this webinar, we discuss the most common inflammatory chorioretinopathies of unknown etiology. Diagnostic testing modalities, differential diagnosis, clinical presentation, and therapy each condition will be discussed. We also discuss MEWDS, APMPPE, Birdshot retinochoroiditis, serpiginous choroiditis, and many others.

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


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DR MOORTHY: Good morning, everybody. This is Bob Moorthy, Ramana Moorthy, from Indianapolis, Indiana. I want to share with you what’s going on with white dot syndromes, and give you an update on that today. I like to call white dot or white spot syndromes inflammatory chorioretinopathies. The expert that I trained with, who I consider one of the foremost experts on white dot syndrome, taught me a lot many years ago, and continues to teach us a lot. And I hope with my training and experience over the years that I can impart some of his knowledge, which is vast, on the subject, and I humbly approach this topic to see if we can answer a few questions that you may have about these syndromes. I’ll start with a poll question. Let me get you onto the slide show here, and we’ll start with the first poll question. Which of the following viruses have been identified to cause APMPPE? Paramyxovirus, Epstein-Barr virus, herpes simplex virus 2, coxsackievirus A, or none of the above? So we have a mixed bag of ideas here. Although many viruses have been potentially implicated in the cause of APMPPE, and it is likely a viral illness, because patients have a viral prodrome, none has been determined to be the definitive etiology. We know that hand foot mouth virus, Coxsackie virus, and Paramyxovirus, have been associated with APMPPE. The etiology remains unknown. And there have been other associated systemic illnesses. The most serious of which, as ophthalmologists, that we need to keep in mind, is cerebral vasculitis. Because this can be fatal. Signs of meningitis that suggest that there may be active vasculitis going on in the central nervous system can be very important. If they have severe headaches, nausea, vomiting, meningismus, that suggests that they may have a serious disease process, and they need urgent neurological evaluation and should be admitted to the hospital. I see in my practice maybe two or three cases of APMPPE a year, between the four of us in our practice. The history is usually onset of bilateral disturbance in vision, usually central scotomas. There usually are not photopsias present. These may be asymmetric, and there may be a viral illness or viral prodrome prior to the onset of disease process in the eye, and there may be associated cerebral vasculitis, associated neurological symptoms. Usually, as you know, this disease is very characteristic — since it was originally described in 1986, there have been of course many numerous reports on APMPPE since then. Creamy yellow to grey white lesions that are flat, subretinal lesions at the posterior pole, the reaction in the vitreous may be very mild to none, and there are paracentral and central scotomas, as I mentioned. These lesions usually rapidly resolve. OCT imaging may reveal disruption in the inner or outer segment of the ellipsoid zone, and there’s usually quite a good return of vision in most cases, although pigmentary destruction may be present in the macula. Visual return may be a little bit less in other related diseases such as the so-called ampiginous version of this APMPPE. The subretinal fluid collections may be seen on OCT. Here is again a clinical picture of a patient who has bilateral disease with various stages of disease that are healing. You see on the left some of the whiter lesions are more acute, and the central areas of clearing that you see, and on the other side too, you may see some more peripheral lesions that may be getting more pigmented, suggesting that they’re in various stages of healing. Usually fundus photography and fluorescein angiography can be performed, and a classic description of inflammatory diseases arose from the original description of APMPPE in 1968. That is: Early blockage, early hypofluorescence on the fluorescein angiogram, followed by late staining of these inflammatory lesions. ICG angiography may be interesting, because this may show more pronounced hypocyanescence of these lesions, persisting throughout the angiogram. There may be increased reflectivity of the retinal pigment epithelium, and perhaps subretinal fluid. OCTA, which is a newer tool that not all of us have access to, may show a dramatic reversible ischemia of the choriocapillaris, which helps us understand why we see visual return in these patients. So here’s a photograph of that same picture, followed by the early phase fluorescein angiogram. You can see the very early laminar venous space here, and you can see after complete arterial filling that these lesions are hypofluorescent, centrally, the same lesions that you saw, and in the late phase, you see this staining. Typical of inflammatory lesions in the retina and the choroid. Here you can see the appearance of another case of APMPPE. Another bilateral case. Here’s the left eye, the right eye, on the fluorescein angiogram. Hypofluorescence early, late phases, staining. Here’s the corresponding ICG to that patient, and you can see — this is my friend Al Vitale’s case. And this again shows large areas, perhaps more hypocyanescence than you would see clinically. So you might see more white spread disease process involving the posterior pole. Here is the OCT angiogram. This is from another source. I don’t have OCTA in my practice, but we’re going to be getting one. And we can see in the early phases the hypofluorescence — or poor filling, if you will. I’m sorry. Fluorescence is not the right term. Poor filling in the early phases, and hyporeflectivity and these areas of ischemia in the choriocapillaris, and as the disease continues to fade, you can see the reversibility of the choriocapillaris. The lobular areas fill and become more normalized as the disease heals, indicating — well, this is why vision usually returns. The diagnosis includes other white spot syndromes, such as serpiginous or ampiginous chorioretinopathy. Multifocal choroiditis can also be in the differential, because the white spots, when they’re actively inflamed, can mimic those. Syphilis, sarcoid, and tuberculosis should be included in the differential, along with Bartonella, which is usually a focal choroiditis, which looks like toxoplasmosis. HIV positive patients can look very similar to some of the pictures of APMPPE I showed you earlier. Primary CNS lymphoma can also look very similar. Oral corticosteroids may speed resolution, but its efficacy has not been proven. High dose corticosteroid treatment is suggested if the patient of course has life threatening cerebral vasculitis. Life threatening complications can include choroidal neovascularization, and permanent reduction in vision can result from RPE scarring or choroidal neovascularization. You can see that APMPPE is a unique disease, but you’ll see some parallels to other diseases we’ll talk about. Here is another question. What is the most common cause of vision loss in birdshot uveitis? I’ll see what you folks thought on this. And a lot of people thought choroidal neovascularization, and some thought cystoid macular edema. Any of these can potentially cause vision loss in birdshot uveitis, but cystoid macular edema by far presents as early cases of vision loss and can result in longstanding vision loss in patients, so cystoid macular edema is by far the most common structural complication of the uveitis, and likely the most common cause of central vision loss in uveitis. Long-term vision loss of course can result from optic and chorioretinal atrophy, of the entire retina in some cases. The epidemiology is typically that it affects northern European patients more commonly. And as you know, HLA-A29 testing is often positive in these patients, when you see phenotypic evidence of birdshot. This test confirms the presence of birdshot. It doesn’t establish the diagnosis, however. Mean age of patients is usually presentation in the early 50s, although I have patients who are 30 years old, who have active and severe birdshot retinochoroiditis in my practice. There’s a slight female predominance, patients usually present with visual loss, floaters, photopsias, nyctalopia, and with more longstanding disease, severe vision loss can occur. Patients usually have subtle cream to pale orange lesions that radiate away from the optic disc along the choroidal vessels, extending into the periphery, and they’re often broadly distributed. Often as if somebody took a shotgun, birdshot-like pellets — that’s where the name came from — and shot the fundus with these little pellets. So you see these lesions throughout the periphery. Only late in the disease do you see these lesions become atrophic-looking. And I’m talking decades after the disease has been present. There’s usually little to no anterior segment inflammation, and variable amounts of vitreous inflammation, which can sometimes be very mild and sometimes nonexistent, even with substantial retinal disease. The fluorescein angiogram may show retinal disc leakage and cystoid macula edema, and early on you may not see it. ICG angiography may be much more beneficial. Cystoid macular edema may be present, and narrowed angles is not unusual. Here you can see a typical case. This is one of my patients who obviously has bilateral disease, but this patient has radiating — these creamy lesions. They’re subtle. They’re not thickened and elevated, usually. They’re very subtle and flat. But you’ll see these lesions following the choroidal vascular pattern, radiating away from the disc, and following the pattern of the choroidal rather than the retinal vessels. You’ll see subtle blurring of the disc margins here. Maybe even a subtle disc edema. And you can see in the fluorescein angiogram disc staining. Perivascular leakage, and in the late phases, you might see mild variable amounts of cystoid macular edema. OCT may show cystoid macular edema. Variable levels of outer retinal atrophy, there may be significant retinal thinning with longstanding disease. Enhanced depth imaging may show choroidal thinning with advanced disease, and may or may not show choroidal thickening, but choroidal thickening may be most apparent in peripapillary choroid, around the disc. The OCT may show subtle reduction of capillary plexus density, going along with the vascular changes we may see in this disease process, and it may explain why in some cases neovascularization elsewhere — meaning retinal neovascularization — can develop in birdshot uveitis. Very interesting disease in that way. And again, the fluorescein angiogram can be very useful to see the retinal vascular leakage and CME. Here’s the ICG angiogram, which can be useful as well. You can see the composite image here of a fluorescein angiogram on the left, and on the right side, you see the ICG angiogram. And spots are usually hypocyanescent in the posterior pole, and there may be more or larger spots than are visible clinically. I use this often to help me guide and see how the patient is doing, in terms of disease progression. Especially when you see the patient with this as an acute presentation pattern, you may often see with good treatment and resolution of many of these hypocyanescent lesions on the ICG angiogram. Testing is usually — this is a clinical diagnosis, based on the patient’s clinical history. And the clinical appearance, rather than any specific lab test. The HLA-29 testing, if it’s positive, provides us with strong evidence that this is birdshot, because there is a 95% correlation and concordance between HLA-A29 and the presence of birdshot. But it’s not a diagnostic test. Remember up to 8% of Caucasians can have that allele present, and 8% of the Caucasian population, at least where I live, does not have birdshot. It’s not that common. Randomly checking this on any uveitis patient is useless. I would check it specifically when you have the clinical pattern, so you can nail the diagnosis and call it birdshot. I have patients that are A-29 positive that have very typical phenotypic birdshot, and I have patients who are A-29 negative that have very typical phenotypic birdshot. The differential diagnosis is broad, and you have to consider other things. Sarcoid can cause vascular inflammation, CME can cause choroidal inflammation. The lesions look more juicy in the choroid, if you will, and there can be more punched out scars and atrophic scarring with disease progression, whereas you don’t see that that much with birdshot. Intraocular lymphoma is in the differential. An older patient that presents with choroiditis. Multifocal choroiditis in late stages of birdshot may look similar. Punctate choroiditis — this is really the same as multifocal choroiditis. Multiple evidence in white dot syndrome, especially when the patient has disc edema and staining. That can be seen in early stages. And TB is a differential in all uveitis cases as well. Medical therapy. I think it’s crucial to understand that birdshot is a disease that probably cannot be cured. We know from very good evidence with long-term studies shown at the Bascom Palmer Eye Institute and very good studies through the CITE study on birdshot that we know that short-term inflammatory flare control can be achieved with corticosteroids systemically, by even intravitreal periocular injections, but by the nature of this therapy, local therapy is not a viable long-term option. It may be useful for controlling cystoid macular edema. Long-term control of this disease requires immunomodulatory medications, in my opinion. This is needed in most patients. However, there are many patients who are minimally symptomatic or asymptomatic. Some uveitis specialists believe that these patients because of lack of symptoms can be followed. About 10% have very mild disease that may progress so infinitesimally slowly that you are not able to detect that the patient is losing vision over the course of years. Those patients potentially could be monitored, but the vast majority of these patients go on to lose vision without aggressive therapy with immunosuppression. Mycophenolate is commonly employed. Some doctors use a combination of mycophenolate and steroids. Long acting steroid implants can be used, but they need to be replaced after three years. Guaranteed they will develop cataract after the first year of implant placement, and remember about a third of these patients go on to have significant enough glaucoma that they may require glaucoma surgery. So that’s very important to remember, with fluocinolone implants, and that reimplantation will likely be required at the end of three years, and multiple implants may be required over the course of the lives of the patient. Monitoring these patients is very difficult. I think fluorescein angiography can be useful, if the disease is very active, but in chronic, treated disease, it can be very difficult to follow the patients, and see how they’re doing. OCT can be helpful to assess cystoid macular edema and presence of atrophy, Goldman visual fields can be utilized to determine retinal sensitivity and blind spots, and scotomas that are very common even in early phases of the disease, and long-term follow-up is very important. There is certainly a role for ICG angiography, as I mentioned, which could reveal more lesions and could be used to assess the response to therapy. In addition, electroretinography has been useful to study advanced disease and to evaluate how the disease is progressing on an annual basis. This is very useful when you have a laboratory that has standardized ERG protocols, and where this standardization will allow appropriate ability for repeatability and accuracy of this test. There is substantial variability in lab quality, in my experience, so if you’re lucky enough to have a good technician that can do good ERGs, this can be a very useful way to standardize and to follow patients. These patients may have some improvements in visual fields and ERG with treatment, especially immunomodulatory therapy, but this is a relentless, progressive disease, that we can slow down with therapy, but we cannot cure. It’s a lifelong disease. Disease-related complications — CME, epiretinal membranes. They’re quite common, in my clinical experience. It’s not uncommon to see patients have partial vitreous separations, and epiretinal proliferation on the surface of the macula, and this can result in perivascular sheathing and inflammation as well. Moderate to severe vision loss from retinal degeneration can occur over many years, optic atrophy, subretinal neovascularization, night blindness, reduced contrast sensitivity, color perception, with advanced disease, and progressive visual field loss with advanced disease. There is some apparent increased risk of normal tension glaucoma related to choroidal thinning with this disease, birdshot uveitis. The prognosis is guarded, because in some studies, 15% to 20% of patients with birdshot have a favorable prognosis, but the largest studies, with long-term follow-up, suggests that the prognosis is quite poor without treatment, and this is a function of disease duration and independent of systemic corticosteroid use. However, large cohorts showed that five-year cumulative incidence of visual loss of worse than 20/200 is about 20% with birdshot. Induction of long-term remission is possible in some patients. I believe that’s clearly possible. But it is not — that doesn’t occur in everyone. I would suspect that it’s around maybe 10% to 20% of patients that we can see this kind of effect. That may be that subset I was telling you about, that may have milder disease, that responds well. Poll question number three. Next disease process. Which of the following features of MEWDS is correct? Let’s see what you all… See if you guys got this correct. Looks like most of you got it. This disease — multiple evanescent white dot syndrome, which we’ll discuss next, it often follows viral prodrome, but it’s typically a unilateral disease, although there are bilateral cases. It may represent a spectrum of disease from acute idiopathic blind spot to multifocal choroiditis. Some people believe this is a phenotypic manifestation of the same disease, that’s variable, based on the immunogenetic makeup of the patient. That’s my teleologic understanding of this process. MEWDS is a benign process in general. It tends to occur most commonly in young, healthy women, and may follow a viral prodrome. There’s sudden onset of blurred vision in one eye, there may be photopsias, paracentral scotoma, shadow in the visual field with an enlarged blind spot, and often the blind spot may be shimmering, although this is not required with the diagnosis. My general impression is that patients with active disease will have the shimmering scintillations within that blind spot. The features are grey white, poorly demarcated, subtle grey lesions scattered around the posterior pole. These are 200 to 500 microns in size. The acute lesions may be hyperfluorescent and hyperautofluorescent too. On the autofluorescence imaging. This is one of the diseases where I really like to use autofluorescence, because I think it is highly useful in picking up some of these lesions, where you can’t see them clinically very well. There can be orange granular pigmentation of the fovea, which some people believe to be the sine qua non of the disease. Because the white spots may fade, and they’re very transient, within even 1 to 2 weeks. The granular pigmentation may persist a little bit longer. But it’s very common, very prevalent, in the early phases of disease. There’s usually minimal vitreal cellular reaction, if any, and there may be a prominent sectoral defect in the area most involved with the white spots. There may be apparent afferent pupillary defect. There may be clinical signs as well, in the absence of symptoms. That’s rare, but it can happen. Rapid resolution of lesions and usually a return to normal vision is very common. RPE scarring is very infrequent and very rarely results in permanent visual field loss. Here’s a patient with granular pigmentation of the fovea. You can see one of my old patients. And there’s granular pigmentation here. There may be a little blur at the disc margin here. But it’s hard to see the white spots very easily here in this eye. But here you can see — in Dr. Goldstein’s pictures, this beautiful picture of white spots. This looks like necrotizing retinitis, outer retinal necrosis. But this is a great case of multiple evanescent white dot syndrome. You can see confluence of some of these spots, and I’ll show you that on the autofluorescence imaging. Here’s another one of her beautiful pictures of a patient with granular pigmentation, the orange yellowish granular changes in the central macula, in active MEWDS. Fluorescein angiography may demonstrate the typical white-like collections of punctate hyperfluorescence at the site of the white lesion. I’ll show you what that means. ICG may show multiple hypocyanescent spots, clustered in the posterior pole. ICG angiography sometimes will reveal bilateral disease, even in an asymptomatic eye. I’ll show you a case of that in a moment. Visual field defects usually are revealed in a large blind spot, as I mentioned, and OCT may reveal subtle transient disruption of the ellipsoid zone and debris in the ellipsoid layer that protrudes into the outer layer and gradually goes away with the disease process as it heals. Autofluorescence is a very useful tool, and often overlooked with this disease process. I’ll begin with autofluorescence imaging here, with active disease in some of my patients. This is a beautiful picture. A patient who presented with acute disease, with numerous spots, surrounding the macula, and of course, around the optic nerve head. Very typical distribution of spots. These hyperautofluorescent spots. And follow-up… Look, the spots, some of them you can see they’ve spread. There are a few newer ones perhaps that you see, but many of the old ones have subsided and gone away. I apologize for the difference in the exposure time for the autofluorescence, but there’s improvement within two weeks of the central lesions, for the most part. Here is a patient’s — the same patient’s fluorescein angiogram and ICG. You can see the fluorescein angiogram showing the hyperfluorescence. This is in the late phases, throughout the nasal midperiphery, and you can see on the ICG angiogram a clearer representation of the spots that are active in the acute phase of the disease. This is another patient. But look at two things here. The wreath sign. This is a great example of what a wreath sign is. You can see this wreath of hyperfluorescence around the central — relatively hypofluorescent spots. This is one of the white spots, and that’s the wreath sign. Like a Christmas wreath, if you will. In the image on the right side, you can see that the patient has more confluence of this hypocyanescent spot. Same patient. Very interesting change. And again, look at the RPE changes in the central macula. Isn’t that interesting? You can see this even in the late phases of the ICG angiogram here. Here is a representation of some of the IS/OS disruption, and some of the excrescences get into the outer layer here. Very characteristic. And as this heals, you’ll see resolution of these changes over time. Another patient showing the fluorescein angiogram, the widespread nature of these lesions in the posterior pole. Typically these spots are not going to be visible in the far periphery. And there may be other wreath signs that you can see in this fluorescein angiogram, as I mentioned. Look at, also, the vascular staining. This is not an atypical feature in the late phases of the angiogram, of multiple evanescent white dot syndrome. Here’s a patient I was telling you about earlier that had bilateral disease. Symptoms were mainly in the left eye, but he actually had some active disease in the right eye as well. And these both revolve in two weeks. Again, it’s more common in young, healthy women. And the differential diagnosis includes acute idiopathic blind spot enlargement, which some people believe is the same disease, but without the white spots, where the white spots may not be visible. Acute zonal occult outer retinopathy. It can mimic some of the changes you see with MEWDS. And it’s in the same demographic group that’s affected with this syndrome as well. Typically young and women more than men. Multifocal choroiditis, syphilitic retinitis, and acute macular neuroretinopathy can be a subtle process — I’ll show you pictures later — that potentially could also be a condition in the differential diagnosis of MEWDS. Typically no therapies are recommended for MEWDS. Corticosteroids can be used if there’s significant optic nerve head edema, but usually are not necessary. The disease improves over 2 to 12 weeks. Disease-related complications such as permanent scotoma or large blind spot can occur. The development of a more permanent posterior uveitis has been associated with MEWDS. There are cases of multiple evanescent white dot syndromes that occur in conjunction with other syndromes so that’s why some people believe that these diseases may share a common pathogenesis but have different manifestations of the same underlying pathogenic process. We’re gonna move on and talk about another condition that can be difficult to treat. Multifocal choroiditis and panuveitis typically occur in patients who are younger, but can occur in all age groups. They’re typically older than the MEWDS age group, but occur more commonly in women than in men. Some authors believe that multifocal choroiditis with panuveitis, punctate inner choroiditis, and fibrosis/uveitis syndromes are different manifestations of the same disease. As far as multifocal choroiditis, pan uveitis, punctate inner choroiditis — a lot of people lump those together and call them idiopathic multifocal choroiditis. I think that’s a great point. My mentors feel that the commonalities of these diseases is far more important than the differentiation of these diseases. Historically, these patients will have visual disturbances, floaters, scintillating scotoma, and I rely on the scintillating scotoma and large blind spot to determine — even if the eye itself looks quiet — whether the patient has activity or subclinical activity in their disease, and I use that as a subjective way, in part, to measure how well the disease is controlled, and my choice of medications to treat this disease process. The choroidal lesions are often small early on, and the active lesions may appear creamy white and hazy with less distinct borders, and as they heal, they may be punched out. They may become confluent and quite large and there may be pericapillary scarring. There may be lesions in various stages of disease evolution that may be present, with several lesions being the same age, pigmented, and clumped, and others being more active. There may be variable level of vitreous and anterior chamber reaction, and vitritis is more common in this disease than with MEWDS or APMPPE. There may be sequential involvement of the eyes, but I have patients with distinctly unilateral disease for more than two decades and never develop it in the other eye. There may be fibrosis, and this usually results from the development of choroidal neovascularization, or from metaplastic changes of the pigment epithelium to result in subretinal fibrosis. This is a patient of mine, a nurse who presented originally — this is after ten years of disease — originally presented only with posterior pole involvement. And small lesions in the posterior pole and choroidal neovascularization. This was prior to the development of anti-VEGF treatment for the choroidal neovascularization. She underwent subfoveal surgery, and has good vision in this eye, but you can see with disease progression, multifocal lesions scattered throughout the periphery, many times hundreds of lesions of variable sizes, but most are about the size you see here in the periphery. About 200 to 500 microns in size, and variable amounts of pigmentation. Acute disease can be shown in fluorescein angiography. Early on, in the early arteriovenous phase here, you can see relative hyperfluorescence of these spots where the arrows are, and later on, you can see active spots here. This is an area of choroidal neovascularization she had adjacent to the fovea. Notice the disc staining as well. Not uncommon with multifocal choroiditis/panuveitis. This is a clinical diagnosis. But in the presence of this patient, even if it’s the right demographic, a workup should be done. You need to rule out the most common things. Sarcoid, syphilis, tuberculosis should be part of the armamentarium of testing any patient with uveitis. Sarcoid, syphilis, and TB should be ruled out. The imaging can be very helpful. Fluorescein angiogram, as I mentioned already. ICG angiogram may show midphase hypocyanescence, and OCT may show ellipsoid zone disruption and cystoid macular edema, which can complicate this condition, along with choroidal neovascularization. The differential diagnosis is very broad, as you might imagine. Sarcoid, Vogt-Koyanagi-Harada disease, serpiginous choroiditis, simply because macular involvement of serpiginous — the presence of choroidal neovascularization complicates serpiginous commonly. APMPPE in acute phase lesions may look similar to acute phase multifocal choroidal lesions, and we need to think about diffuse unilateral subacute neuroretinitis. Birdshot uveitis in late stages of the disease can look similar to multifocal choroiditis, but there’s usually less vitreous cell, and this disease process doesn’t involve the inner choroid. The differential diagnosis, again, continuing on, is very broad. One other thing — very important in the Midwestern United States to include in the differential diagnosis — is presumed ocular histoplasmosis syndrome. POHS — there’s essentially absolute absence of vitreous cells. The absence of vitreous cells generally, in the absence of any other symptoms, in an asymptomatic patient, that looks — with associated pericapillary chorioretinal scarring and neovascularization are the triumvirate that we look for. Punctate inner choroidopathy is similar. West Nile virus chorioretinitis can look similar, and syphilitic and tuberculous chorioretinitis as well. Dengue fever can also produce multifocal choroidal lesions. That’s in the differential diagnosis these days. The medical therapy is usually the use of systemic or periocular corticosteroids for acute disease and corticosteroid sparing immunomodulatory therapy for chronic disease, especially in patients who have the presence of other disease-related complications, and especially those with aggressive development of subretinal fibrosis. These patients have guarded prognosis and require aggressive immunosuppression. Anti-VEGF agents should be used for neovascularization, which is true in more than a third of these patients. And especially in punctate choroiditis. Surgical therapy can be used. Laser photocoagulation, and thermal laser surgery. Corticosteroid implants can be used for unilateral or asymmetric disease and patients who cannot tolerate systemic medications in the long term. Here is a patient who was treated, who had chronic cystoid macular edema from multifocal choroiditis. This patient had been on chronic low dose maintenance steroids for years on 5 milligrams daily, but had persistence of macular edema. We were able to reduce the presence of CME slightly, but you can tell on the fluorescein angiogram on the right, even after a year, there’s some disruption and leakage of the epithelium from the chronic macular CME. There are several complications — neovascularization in 23 to 33% of patients. Punctate inner choroiditis — the only difference that I see is that the choroidal lesions occur more clustered around the macula, they’re smaller, and there’s more prevalence of choroidal neovascularization. I’m not trying to separate these two. I think they’re phenotypic manifestations of similar disease processes. Cystoid macular edema can complicate this. Scotoma are not uncommon, visual impairment, not uncommon. Progressive subretinal fibrosis is the most severe complication, that can result in total blindness. Here’s a patient with a unilateral case of multifocal choroiditis. This patient was treated with an implant. She was intolerant of systemic corticosteroids for various reasons, so she received intravitreal fluocinolone. This is active disease at presentation. You can see multiple choroidal lesions, and here, three years after implantation, you can see the patient developed choroidal neovascularization, subretinal fibrosis. Here’s a subretinal fibrotic lesion that’s from inflammation. And you can see the number have increased and grown in number over the years, despite aggressive management. We’ll move on to the next disease. I’m trying to cover as many diseases as we can. I apologize if I ramble on, but these diseases are very interesting to me. Let’s see if everybody got this right. Especially those of you in countries with TB. Yeah. So M TB has to be considered in the differential diagnosis of serpiginous chorioretinopathy. This is not an uncommon manifestation of tuberculous uveitis in countries where TB is endemic. So this must be ruled out. This term, serpiginous choroiditis, is the preferred term to describe this. This term is quite different from serpiginous in the sense that it presents with much more vitritis, more multifocal lesions, and it’s more common in places where TB is common, though I have seen two cases in the Midwest. It’s different from serpiginous choroiditis, where the etiology of the disease is unknown, and there are less inflammatory changes in the vitreous. Typically no vitreous cells that are present, no anterior segment inflammation, and serpiginous tends to be… Men might be slightly more affected than women. Tends to be present in the fourth to fifth decade. It can be sequential involvement, may be asymmetric, but eventually it becomes bilateral. There’s usually no systemic disease. But it has been reported to occur with concomitant sarcoidosis, Crohn’s disease, vasculitic conditions, such as periarteritis nodosa. There has been observed disease in varicella zoster reactivation, although oral antivirals have not had any substantial effect in mitigating serpiginous choroiditis activity. Tuberculosis is a cause of serpiginous-like choroiditis, so we need to think about that in the differential diagnosis, and the workup of the patient. But again, this tends to be a clinical diagnosis. So the patients present with decreased vision, scotoma, and metamorphopsia. Two thirds of patients may present with scars in the fellow eye, indicating previous activity. And this is a relapsing and remitting disease. Intervals between activity can be variable, sometimes weeks to decades between activity. And that makes it much more difficult to treat. I think there are three distinct entities, the so-called classic peripapillary geographic choroiditis, the macular serpiginous choroiditis, which is very rare, and the ampiginous choroiditis, which is a very uncommon subset. It’s a mix between APMPPE and serpiginous. It almost looks like a multifocal choroiditis picture. There’s a large phenotypic variation of disease. Where they have been kind of lumped together, into these entities, although they may… The treatment is a little different for some of these entities. Classic peripapillary geographic choroiditis, the choroid may have grayish areas of active choroiditis that’s spread in a serpentine fashion, centrifugally from the optic disc. As the disease progresses, the disease approaches the macula. In the peripapillary phase, they may not have any symptoms of active disease. These lesions heal over 6 to 8 weeks and result in an atrophy of the choriocapillaris. You can have skip lesions, and sometimes you see it peripherally as well, with serpiginous choroidopathy. Each recurrence increases area of atrophy, and choroidal neovascularization is not uncommon, affecting more than a third of patients who have this. Usually the choroidal neovascularization is peripapillary or at the leading edge of the atrophy. Subretinal fibrosis can occur in up to 25% of patients. And the retina may look thickened or opacified, laying over the area of active choroiditis. Subretinal fluid may be present, and subretinal hemorrhage may also be present in active disease or choroidal neovascularization. More commonly with choroidal neovascularization. Macular serpiginous — usually the serpentine lesions are smaller in the perimacular region. The visual prognosis is poorer, for obvious reasons. Ampiginous choroiditis is a hybrid, as I mentioned. There are multifocal grey white lesions at the level of the RPE and choriocapillaris, new lesions may appear for up to two years, there may be anterior chamber involvement and vitreous cells, and this may involve the posterior pole and periphery, often randomly, and usually these patients respond to corticosteroids and immunosuppressive therapy, and their visual prognosis in general is better than the classic or macular serpiginous choroidopathy. This is a classic case, where we see bilateral disease. I’m sorry that I’ve had them switched here. Left eye on the left and right eye on the right. But you can see old lesions. And in the left eye here, you can see more recent active lesions here. That are in various stages of healing, affecting the fovea. Fortunately the fovea is still spared in the right eye, in this case. Here’s a patient of mine that had active disease. Adjacent to old scarring. She’s already lost central vision, and unfortunately still has new activity, and here she did not have choroidal neovascularization, but did have some subtle subretinal hemorrhage at the leading edge of the lesion. Here’s another patient where I have a composite here, that has perimacular involvement at the leading edge, with this whitish appearance to the outer retina, as well as the choroid, and you have two areas of active lesions. And you can see in the fluorescein angiogram it’s hypofluorescent in the early phases, and in the late phases, it stains. More typical of the acute inflammatory process of active lesions, as we saw, kind of like APMPPE. So that is why APMPPE and ampiginous are in the differential diagnosis. Here you can see a partially healing lesion where there was activity. This was that patient — another patient. And here’s the fellow eye. Where there’s more active disease, along the… And he’s already wiped out the central macula on the left here. And here you can see a composite image of the right eye of the patient that has evidence of choroidal neovascularization, that has occurred along with active disease, so you can see active disease with hypocyanescence in this portion of the fluorescein angiogram, with leakage in the mid to late arteriovenous phase from choroidal neovascularization. This was the same patient as you saw in the last image. Let me go back here. You can see this patient has CME here, activity, you can see some exudate and some fluid here, from the CME, but there’s an active lesion here, the active choroiditis, and here you can see the active choroiditis in the left eye. That’s the same patient I’m showing you in the composite images here. So on the left eye — the active lesion. Fluorescein shows staining of that lesion, not as intense as the choroidal neovascularization on the other eye. And you can see persistence of the hypocyanescent lesion in the late phases of the OCT angiogram. And you can see evident of subretinal fluid and choroid exudates that may be present, associated with choroidal neovascularization in the right eye of this patient. Here is another patient with choroidal neovascularization along the margin of the lesion. And you can see the fluorescein angiogram here, showing the leading age with subretinal hemorrhage, and in the late phases, there’s leakage along the area of choroidal neovascularization. Typically, this is a clinical diagnosis. Serpiginous choroidopathy. PPD testing, not so much RPR, but FTA and chest x-ray are all important, as part of the typical workup of any choroiditis patient that you’re evaluating, or any uveitis patient, for that matter. So the quantiferon TB is particularly important, because here we need to rule out the tuberculous serpiginoid choroiditis I mentioned earlier, because it can look identical to the classic serpiginous choroidopathy. Fluorescein angiography can be very useful in looking at lesions, and fundus can be very useful as well, because active disease may show subtle — it’s not gonna be as prominent as with MEWDS, but you’ll see in active disease there is hyperautofluorescence present. It will also be seen in regions of choroidal neovascularization. The spectral domain OCT may show in acute phases, and in chronic phases, retinal thinning, and in cases of choroidal neovascularization, you may see subretinal fluid and exudate. OCTA may show multiple small geographic areas of lesions that do improve with treatment, but they don’t improve to the extent that the APMPPE does. The differential diagnosis is broad. We’ve kind of covered it. The most important to keep in mind is the tuberculous serpiginoid choroiditis. All those things are in the differential diagnosis of this condition. Aggressive treatment is needed. With medical therapy in this condition. Immunosuppressive agents are often used for the control of this disease process. I have used Imuran, I have used cyclophosphamide as well. And if you look at some of the data, looking at long-term control of this disease, the longest period of remission with this disease process has occurred by using cyclophosphamide, or particularly cytotoxic immunosuppressives. These alkylating agents probably give us the greatest chance of long-term remission of this disease process, but they come at a price, obviously, because these agents are much more toxic from an immunologic standpoint. Corticosteroids either locally or systemically can be used for acute flares, with foveal threatening flares, I will often give intravitreal preservative-free triamcinolone. That can be very effective to get the acute disease process that is fovea-threatening under control. Obviously that runs the risk of glaucoma and cataract formation with repeated use, but long-term immunomodulatory therapy is very important with this disease process. The intravitreal fluocinolone implant can be very useful, but it may not prevent recurrences beyond three years, of course. Choroidal neovascularization is treated with anti-VEGF therapy, typically combined with corticosteroids or immunomodulatory therapy. Remember, choroidal neovascularization can’t be managed only with anti-VEGF therapy. You have to control inflammation, because the inflammation is releasing cytokines that are making VEGF — promoting the activity of VEGF. So you have to control the inflammatory cytokines on the one hand, and control the VEGF release on the other hand, that is causing these inflammatory choroidal neovascular membranes to develop. So as I said, choroidal neovascularization — 35% of patients can develop this with serpiginous choroidopathy. Chorioretinal atrophy is not uncommon as the lesions heal. Retinal vasculitis and retinal neovascularization, although they’ve been reported, are rare. Relentless placoid chorioretinitis — it’s rare. Bilateral, younger patients, men and women equally affected. Patients often present with photopsias, floaters, scotoma, reduced vision. There are various amounts of vitreal cells. Active lesions are creamy white, there may be numerous lesions throughout the periphery, and they can progressively increase in size. In some patients, these lesions can heal over the course of weeks and produce chorioretinal atrophy. But the prognosis for these patients is usually better, in my experience, and these can often be managed with corticosteroids alone, but the length and duration of corticosteroid therapy may be as much as one to two years. There can be 50 or more lesions throughout the fundus, and that’s a typical hallmark of the disease. Vision loss, metamorphopsia, scotoma, when the lesions involve the macula, can occur, and subretinal fluid may be associated with acute lesions, and the lesions heal with preservation of visual acuity. Here’s a patient with late stage, intermediate, partially healing phases of the relentless placoid chorioretinitis. You can see disc edema and numerous white lesions here. You can see when you look at a patient like this, what is it? Is it APMPPE? Multifocal choroiditis? Serpiginous choroiditis? Or tuberculous serpiginous choroiditis? All those things are in the differential. You need to think about the idea of a workup for this patient, including ruling out syphilis, sarcoid, TB. Once you’ve done at least those three, and have made sure any other endemic infectious diseases that you may be considering — before you embark on aggressive systemic corticosteroid therapy, or immunosuppressive therapy on these patients. So here’s the late phase — this same patient that I showed you earlier. This is later on, after the control of the disease process. You can see numerous lesions. He’s 20/15 in this right eye. The disc edema, the vitritis, has gone away. Vision is much clearer. Here’s the eye I showed you earlier. You can see the healed lesions, a lot of pigmentary disruption, but excellent central vision in this patient. Here’s another patient. Here’s another valuable tool. This fundus autofluorescence imaging. You can see old images that are hypoautofluorescent, and these acute lesions in the upper right that you see, that actually represent new lesions that this patient has had, and was symptomatic from. So this is a great way to follow the disease process. Here is this patient later, showing progression of this disease process. With newer lesions developing. She fortunately still maintains good central vision in each eye. And you can see the RPE level changes. The disruption of the IS/OS junction. Excrescences. These can look like the same kinds of changes that we saw with MEWDS, with multifocal choroiditis, and also even with… In some cases, the multiple evanescent white dot syndrome. These changes in the acute phase usually go away. You can usually see in these cases there will be — eventually develop an area of RPE atrophy, as these lesions heal, as you see in some of these older lesions on the picture here. The diagnostic testing using autofluorescence, RSFA, and ICG, are all useful. Spectral domain OCT I mentioned, retinal photoreceptor disruption, and surrounding areas of the ellipsoid, along with the choriocapillaris. The ischemia may improve with treatment but recur in adjacent and non-contiguous areas, and laboratory evaluation is done, but often not helpful. Because these patients — that’s how you come up with a diagnosis. It’s really diagnosis of exclusion. There isn’t any consistent systemic association. Treatment is usually oral corticosteroids and occasionally steroid-sparing immunosuppressive therapy. Persistent placoid maculopathy was described in the last decade. This is a disease that affects older patients. It’s bilateral and symmetric, etiology unknown. Patients present with decreased vision and central photopsias. They’re usually a well delineated jigsaw pattern, whitish plaque-like lesion involving the fovea and not contiguous with the disc. Satellite lesions may be seen. They can resemble macular serpiginous choroiditis. Vision may be good. These lesion persist in the macula for months and may be replaced by pigment mottling or atrophy, but invariably, patients will develop choroidal neovascularization. And that results in vision loss. I’ll show you a picture. Fluorescein angiography will show early hypofluorescence and late hyperfluorescence. There’s usually no leakage unless the choroidal neovascularization is present. There may be late filling, but it’s not gonna look like APMPPE. Not as hyperfluorescent. There is persistent hypocyanescence, the OCT will show hyporeflectivity of the outer retina and ellipsoid zone disruption, and we’ll see variable loss of outer retina in longstanding disease. Of course, choroidal neovascularization can be demonstrated in the late phases of the disease process. Hypoperfusion of the choriocapillaris that persists despite treatment is relatively characteristic, unlike APMPPE. You see stippled hyperautofluorescence early and hypoautofluorescence corresponding to damage in the late phase of the disease process. Here’s a patient with a jigsaw pattern, central hypofluorescent macular lesions, here in the midarterial venous phase in each eye, and you can see the characteristic changes with ellipsoid zone disruption, and RPE changes as well. In the central macula of both eyes, on the OCT. The treatment is usually corticosteroids in the acute phase, but that doesn’t seem to prevent development of choroidal neovascularization. Of course, anti-VEGF therapy for choroidal neovascularization. Many times in the late stages of the disease, the patient will look like just AMD, because they’re 70 years old so it’s important in patients who complain of symptoms such as photopsias to look at autofluorescence imaging, angiography, and OCT imaging to decide if there’s anything else going on besides AMD. So if patients have unusual images on these tests, you might be looking at persistent maculopathy. I have found many patients like that over the course of the last ten years. AZOOR is a disease that affects young women more commonly than men. It can be bilateral or unilateral, sequential in involvement, associated with systemic autoimmune diseases. Patients present with photopsias and development of scotoma with zonal visual field defects. They may have enlarged blind spots, initially, and these defects can go along the arcade vessels and can be sectoral in nature. Patients often have a normal fundus examination, and upon evaluation may see nothing. In two to three months, they may have vascular narrowing and zonal depigmentation and sharp demarcation between normal and abnormal retina. There can be annular variants. These are rarely seen. And I find that autofluorescence imaging, again, can be extremely helpful with this disease process. Fluorescein angiography may look normal in early phases, but with later disease, you can see pigment mottling and window defects, so it doesn’t really help that much. ICG angiography in the late stages can show the so-called trizonal pattern of normal-appearing retina outside the AZOOR line, minimal leakage in the subacute area, and similarly, there is a zonal change that occurs in the OCT, where you see disruption of the ellipsoid zone and the interdigitation zone, and you’ll see thickened outer plexiform layer, and in the late phases you may see RPE atrophy and persistent loss of the ellipsoid zone and ONL, and in subacute or chronic AZOOR lesions, you’ll see this trizonal pattern. Normal appearance outside the AZOOR line, drusen-like multifocal subretinal deposits, and then subretinal choroidal atrophy. Here’s a great picture of one of my patients, where you can see this normal-looking retina in the yellow line, the red line represents the area where you see the edge of the disease process, where you have disruption of the photoreceptors, and these granular changes of the photoreceptor level, and within the retina, and then as the disease becomes atrophic, you’ll see this atrophy developing of the choroid. The choroid becomes thinner, and you’ll actually see photoreceptor atrophy as well. Autofluorescence, again, is very, very useful, and shows a similar trizonal pattern with older lesions. Here’s an autofluorescence imaging of a patient who has had some progression of disease over a two-year period, a very subtle progression. You can see old disease down at the inferior section and newer disease in the superotemporal portion, with progression over a two-year period. Very subtle progression, but definite progression of disease. It’s hard to follow these patients, because many times they ignore the symptoms, and the symptoms can be very mild and subtle. Visual field testing can be useful to show progression of disease. ERG full field reduction can show some reduction in the a-wave amplitudes. Again, standardization of ERG can be useful in following these patients as well. There is no treatment that’s been proven effective, but I have in my patients shown some efficacy when we catch disease early, early onset, with oral corticosteroids. We may be able to slow down the disease process. Unfortunately, I don’t think there’s any way to specifically prevent the atrophic changes that occur, once the disease has started. Central vision is often spared, in most patients, however, with this disease process. So here’s another patient with very advanced AZOOR. They also have some drusen-like changes here. But you can see that this patient has pretty extensive kind of zonal involvement of the inferior half of the retina. The fovea is still spared. Here’s another patient with evolution of the lesion. So you can see the active zonal lesion that then ultimately kind of goes away. But there’s some subtle disruption of the pigment here, occurring in the area of the activity. Here is another example of the zonal changes that we see, that I showed you before. The atrophic changes in the inactive areas of old active disease. The marginal active — or the leading edges, where you see the photoreceptor RPE degeneration with the excrescences in the RPE photoreceptor,s and you see the knowledge. Acute macular neuroretinopathy — and we’re coming to the end of the talk here — occurs in the 2nd to 4th decades, unilateral or bilateral, it can be recurrent, there can be viral prodrome. Usually young healthy people present with this disease process. The cause is unknown. OCT angiography suggests that this may be a vascular insult to the deep retinal capillary plexus. Deep retinal involvement. This is interesting, isn’t it? This is not something we understood until OCTA. The symptoms usually are paracentral scotoma and decreased vision. The central vision is usually spared despite the paracentral scotoma. There may be one to several small circular oval or petaloid lesions, that are probably best seen in infrared imaging, in my experience, not so much autofluorescence imaging, with this disease process. They can appear dark red to brown, and they may be surrounded by the normal-appearing — compared to the normal-appearing macula. The diagnosis is based on the clinical appearance in the course and the age and demographics. Because the ICG tend to be normal. If you’re lucky enough to have OCTA, that can be helpful. Because of the flow deficits and deep abnormalities that you see. There can be hyperreflective band involving the OPL and ONL. And disruption of the ellipsoid and interdigitation zones, which will result in thinning of the outer nuclear layer, and there’s some restoration of the ellipsoid zone with healing of the lesions. Here’s a patient of ours that has acute AMN. You can see the infrared image, showing the characteristic paracentral lesions, good vision, and you can see the disruption of the outer nuclear layer, as well as the photoreceptor, in the ellipsoid zone here. And then as time goes on, there is some thinning of the outer nuclear layer that you clearly see, compared to the picture above, and you can see the partial restoration of the photoreceptor ellipsoid zone. So it’s a very nice picture of the OCT changes. The differential diagnosis can include vascular insults like paracentral acute middle maculopathy, which can look like large cotton wool spots, very different from the appearance that you see with acute macula neuroretinopathy. And the course of this disease — usually it’s central vision — usually is stabilized and good, and may improve. However, the scotoma may be persistent for long periods of time. Sometimes they never completely go away. The acute retinal lesions usually fade, but you may still be able to see them on infrared imaging. There’s usually no specific treatment that’s beneficial. So I’m gonna stop there. I appreciate you listening. I know I went over a little bit, but it’s a very long topic. I hope you enjoyed the presentation. I’m gonna see if you have any other questions related to this talk. It looks like there is a question here from Nepal about mycophenolate not being available. I have also used azathioprine as another agent. You can use methotrexate. But in birdshot, I find azathioprine is a good substitute. Patients are usually older. I like to use it in older patients. Any time you’re using immunomodulatory therapy like Cellcept or methotrexate, you have to make sure that younger patients are aware that this is associated with birth defects, et cetera. These agents should not be used if you intend to get pregnant or impregnate somebody else. So you have to have a long talk with patients on these agents of child bearing age. And tips about… Someone is asking: Can you give us tips about particular points that we should look for to make the differentiation among them? I hope that those were the tips I could give you. I think the key is to look at the clinical history of the patient. Younger patients with viral prodromes, with acute onset of changes, if they’re bilateral, it’s likely going to fall into that APMPPE spectrum, if it’s unilateral, it’s likely MEWDS. Examination and putting in your mind what the clinical pattern looks like, I think, is really important. So looking at good pictures of what these things look like, and then translating that to what you’re seeing, is really important. Now, some of these diseases, like AZOOR, acute macular neuroretinopathy, these are difficult even for doctors who see a lot of this kind of condition. So I would say pattern recognition is particularly important. So in your experience, are white dot syndromes linked to systemic inflammation? There are some, as I mentioned. As you know, systemic diseases — APMPPE can be associated with cerebral vasculitis and other viral prodromal illnesses. Evanescent white dot syndrome is preceded by a viral prodrome. Diseases like serpiginous have been associated with systemic vasculitides. Birdshot usually is not. Because of the clinical appearance, you have to rule out systemic associations before you come up with the idea that this is an idiopathic condition. So it’s a diagnosis of exclusion. And serpiginous choroiditis has been associated with some autoimmune disease processes and viral diseases. But again, the treatment is immunosuppression. The next question is: How do you remember all these diseases? You know, it’s like anything else in medicine. You have to see a lot of it. You have to keep seeing it every day. To remember it. And you have to think it. So I think it’s really, really hard to memorize all of these things. But for me, after 25 years of doing this, it’s easier, because I’ve seen every one of these things. But I will tell you: A couple of things to keep in mind. If you have access to fundus autofluorescence imaging, that is extremely helpful in white dot syndromes, like MEWDS and AZOOR. I do find that ICG angiography and fluorescein angiography, combined with autofluorescence, can be very useful. If you have spectral domain OCT, looking at subtle changes, look at those spectral domain OCTs very carefully, at the ellipsoid zone that correspond to lesions, this takes a little bit of time and effort, but that can be very, very helpful and can help you delineate what’s going on.

>> All right. Thank you, Dr. Moorthy. I think that’s a good place to stop.

DR MOORTHY: Thank you very much.

>> Have a good day, everyone.

DR MOORTHY: You too. Bye-bye.

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September 28, 2018

Last Updated: October 31, 2022

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