Understanding how the natural history of granulomatous vs non-granulomatous inflammatory disease differs is critical to understanding management. The goal of this webinar is to explain the underlying is critical to understanding management.The goal of this webinar to explain the underlying pathobiology of chronic non-granulomatous disease vs granulomatous disease, with a focus on explaining how granulomas cause the array of signs and symptoms of these diseases and how their distribution can account for related clinical laboratory findings.
Lecturer: Dr. Thomas Freddo, OD, PhD, MCP Health Sciences University, Worcester, MA
DR FREDDO: Hello, everyone. Welcome to you from Westport, Massachusetts, to wherever you are on the planet. When I was asked to give this talk, I was asked to talk really about the difference between granulomatous and non-granulomatous inflammatory diseases. So in the time we have together today, we’re not going to talk about the specific management of any particular disease. The idea behind this talk was to discuss more generally how these kinds of inflammation behave in a different manner, and how that should influence the way in which you think about the course of these diseases. Whether they are granulomatous or non-granulomatous. Certainly, as eye practitioners, one of the things that commonly clouds our thought regarding the difference between non-granulomatous and granulomatous disease is these things we call mutton fat KPs, which if a lot of what you know about granulomatous disease is defined by whether or not the patient has mutton fat KPs as part of their uveitis, then you’re probably in the right place today for us to discuss the topic at hand. But while we’re on the topic of KPs, just as a review, I would remind you that when we look at KPs, they look different, and their distribution can be different. And it’s important to remember the old teaching, regarding Arlt’s triangle, which you can see here on this cornea. Because we usually talk about KPs as being present either within Arlt’s triangle or not within Arlt’s triangle, with that difference being of diagnostic significance. There are several types of KPs. They include fine, diffuse KPs that can sometimes cover the entire inferior half of the cornea and produce edema. Often in these cases they’re so fine that you can’t distinguish them as individual white particulates. Then there are the classic distinct small punctate KPs, mostly in Arlt’s triangle, that are indicative of an active non-granulomatous uveitis. As a reminder, if you see pigmented KPs, this indicates that they are old KPs. Whether or not the patient can tell you if they’ve had a previous bout of this red eye, they’ve had a previous bout, because it is only pigmentation in KPs that occurs with time after a bout has resolved. Then there are these KPs called stellate. And what makes them unique, particularly, in a distribution outside of Arlt’s triangle, is that these are typical of Fuchs heterochromic uveitis. Here’s an example of those fine KPs on the inferior half of the cornea only. This case could give you a confusing presentation, and I realize we’re starting a bit off the topic, because this is non-granulomatous. But cases like this will show you a clear cornea on top, a hazy cornea on the bottom, and it can be a very confusing presentation, until you look through the clear cornea at top and notice the cells in flare. When you notice that, you’ll realize that the reason the cornea is hazy on the bottom is that the diffuse covering of KPs on the bottom of the cornea is interfering with the sodium-potassium ATPase pump sites on the endothelium, rendering the cornea edematous, where the KPs are present. These are pigmented KPs. Just an example to remind you what they look like, in a recurrent uveitis. This is what is meant by stellate KPs. Notice that they’re not star-shaped. Individually. Despite the name “stellate”. They simply look like stars in the sky. But particularly in Fuchs, the important distinction here is that as you can see they are not within Arlt’s triangle, in terms of their distribution. And finally, when we think of granulomatous, we think of mutton fat KPs. And so off we go to our discussion. What is it that really makes granulomatous inflammation different? Well, if we look first at non-granulomatous inflammation, non-granulomatous inflammation tends to be aggressive inflammation that is due to an antigen of high virulence, that the immune system believes it can eventually clear completely. And so it continues to mount an aggressive action to rid itself of this antigenic material. These usually produce all of the cardinal signs of inflammation. Rubor, calor, dolor, and tumor. That is, redness, heat, pain, and swelling. And the principal cell responders after the first responders have least the scene — meaning the polys and the eosinophils — tend to be lymphocytes, like the one to the right, the upper picture, histology picture, to the right, and plasma cells, the one in the lower right corner of the slide. Granulomatous reactions are a subset of chronic inflammation. That also manifest lymphocytes and plasma cells, so they have that in common with non-granulomatous inflammation, but importantly, these diseases are somewhat less apt to produce calor, rubor, and dolor, quite in the same way that non-granulomatous inflammation does. So it tends to produce diseases that don’t look red hot and aggressive. So there is often less redness, there is often less heat, and often less pain. Not no pain, but often less pain. Than there is with non-granulomatous disease. But in addition, what makes granulomatous reactions unique is the presence of a non-phagocytic macrophage called epithelioid cells. And in the lower right, in the central light colored area, are these epithelioid cells. These are unique macrophages. Although they are not by themselves generally phagocytic — unusually enough for a macrophage — they have a unique ability. That is, they have the ability to fuse together to form what are called giant cells, and these giant cells are phagocytic. In classical pathology we define three main types of multinucleated giant cells. On the left is the foreign body giant cell, in the middle is what’s called the Langhans type. Not Langerhans, but Langhans type, in which you see there a horseshoe-shaped distribution of nuclei that are very close to the cell membrane, as opposed to the foreign body type on the left, where the nuclei tend to be within the center of the cell. Finally, the last one on the far right is more rare to see. It tends to occur in granulomatous diseases that have a lipid component, somewhere in them. Like juvenile xanthogranuloma, for example, where you can get spontaneous hyphemas. In this case, you’ll notice that there’s usually a full ring of nuclei, but importantly, they’re withdrawn from the edge of the cytoplasm. So I’m not sure if you can see my cursor, but right now I’m circling the outside of the cell. So that you can see that this circle of nuclei is withdrawn from the edge of the cell, easily distinguishing it from the Langhans type in the center. In certain granulomatous diseases, these giant cells, when they form, can have particular inclusions. And we’ll mention them briefly later on. When we talk about inflammatory disease, we usually talk first in terms of the overall type of response that’s being mounted. And we usually divide them — although there are more subtypes being discovered — the classic initial division point is whether the response is overall what’s called the Th1 or Th2 response. And these can predominate, and one of them can inhibit the other. So this tends to being a situation in which either Th1 takes over or Th2. Th1 cells produce interferon gamma and interleukin IL-2. Th1 cells usually dominate in responses against intracellular pathogens such as bacteria and viruses. And granulomas produced in TB are therefore Th1-dominated. So the point we’re trying to make with this slide is to offer you the realization that one cannot sort Th1 and Th2 as a dividing point for granulomatous versus non-granulomatous. Th1 generally is the type of response, whether granulomatous or not, that is mounted against an intracellular pathogen. Th2 is what is usually mounted against an extracellular pathogen. So Th2 cells produce several interleukins. You can see here 4, 5, 6, 10, 13. And granulomas are produced in response to foreign materials — they are therefore Th2-dominated. And there’s a good review of these given in this URL, so you can go on and do additional reading, if this is of interest to you. The thing that characterizes granulomatous diseases probably the most, and not surprising given the name, is the formation of granulomas. Although we’re gonna see some granulomatous diseases, at least in terms of name, before we’re finished, that are not granulomas. So this is not as intuitively obvious as you might have initially surmised. Granuloma formation is an immune system strategy that has evolved to deal with those pathogens that have learned to evade the host system by various means. These include pathogens being able to resist dying, after phagocytosis, or by masquerading themselves to remain just below the radar for producing an all-out immunological assault, as we see in non-granulomatous disease. Epithelial macrophages, along with giant cells, coalesce to form granulomas, with the purpose of walling off these organisms or antigens to prevent their further growth or spread in the absence of the ability to totally eradicate this antigen or bug. It’s a strategy that resigns the system to the continued presence of the antigen, seeking containment rather than a continued effort at total eradication. I’m gonna give you a couple of examples. This one is TB. The tubercle bacillus can produce and secrete a protein that can mimic the C4-b fraction of the complement cascade that as you know plays a central role in inflammatory disease. Activating the complement pathway triggers the cascade and in the process the C2-a fraction is produced. Now, it turns out the C4-b mimic produced by the bug passes for C4-b well enough that it can actually combine with the C2-a fragment produced by the host. The complex that forms is a C3 convertase enzyme that then basically deposits C3 — which is an opsonin — onto the surface of the bacillus. So in a more light-hearted example, just to give you an idea of what this bug is up to, if we go back to that scene in the movie that you see depicted here, in which Tommy Lee Jones in the first Men In Black movie, is trying to get his gun back because this cockroach swallowed it up, actually stands in front of the cockroach and dares the cockroach to eat him. And if you recall in the movie, the cockroach quite happily does eat Tommy Lee Jones, who goes down into the bug’s gullet, finds his gun, and blows the bug up from the inside. But basically what’s happening with the bug — meaning the TB bug — is that by covering itself with C3, the TB bug is basically waving its hands in front of the macrophages and screaming “eat me!” And the result is that the bug gets gobbled up by macrophages and as you would expect, gets tucked away in a phagocytic vesicle where almost everything is digested away by the harsh enzymes and low pH. And since the general assumption on the part of the body is that once you’ve entered one of those vesicles you’re gone and we don’t really have to worry about you anymore, inside this vesicle, the bug is relatively below the radar system of the immune system. But the wall of the bug is resistant to these enzymes. And actually survives quite fine within these vesicles. The bug may then go quiescent for periods in which symptoms are less, or become activated, replicating and ultimately destroying the host’s cell, to then spread to other macrophages, destroying host tissue. Lung, lacrimal gland, the other tissues, or virtually any tissue that TB can affect. Or, and this is important for us in practice, it can be activated by the patient taking steroids that inhibit the macrophages, leading to rerelease of the TB bug. Even though these bugs are working under the radar, the system does know of their presence. And so it isn’t complete ignorance that occurs in the response that is mounted against such kinds of pathogens or antigens. And so what the system does, unable to completely purge this antigen or bug, is it builds a wall of epithelioid cells and giant cells around the bug or the antigen. And then, as you can see in each of these two cases, there is a second group of cells — mostly lymphocytes and plasma cells — that form an outer ring. And this collection of cells is referred to as a granuloma. Generally, we see them in two flavors. Particularly in TB, there tends to be necrosis within the center of the granule, and so we call that a caseating granuloma. And in others, as in the one on the right, there is no caseation in the center. It is a solid mass of granulomatous tissue, meaning epithelioid cells — and you can see one multinucleated giant cell there. And that’s the non-caseating granuloma. This caseated versus non-caseated we’ll come back to in a minute. Because it’s one of the classic things that distinguishes the granulomas of, for example, TB from the granulomas of, let’s say, sarcoid. Now, clinically, these all look like yellow spherical deposits of various sizes. So one of the important things to discuss is the real central role of the granuloma in the general course of these diseases. The signs and symptoms of granulomatous diseases are not entirely — but almost entirely — the result of where and how many of these focal yellow granulomas are produced, and the amount of destruction of normal tissue that their presence creates. Here’s a list of granulomatous diseases. Infectious on the left and presumed non-infectious — although the debate rages continuously as to whether sarcoid is due to some bug or to some antigen left behind by a bug. But today, we’ll leave it in the non-infectious category. What I would like to show you is a comparison of one from the infectious side and one from the non-infectious side. And we’ll use TB and sarcoid for those purposes. So how do the granulomas relate to the key diagnostic findings in sarcoid? You know that clinically a number of the laboratory findings that could arise would be that the patient might have elevated ACE levels. They also might have elevated serum calcium levels. They might exhibit hilar adenopathy on a chest film or chest CT and might exhibit a regional positive gallium scan. So let’s first look at ACE. You know ACE is produced normally by the pulmonary endothelium and catalyzes the conversion of angiotensin I to angiotensin II, which is of course a potent vasoconstrictor that will elevate BP. You also know that this process has been targeted by the development of drugs called ACE inhibitors, that are commonly used to decrease vasoconstriction as a means of treating systemic hypertension. It turns out ACE levels increase in sarcoidosis, because the cells of the granulomatous tissue also produce ACE. It’s important to remember, though, that ACE does not increase BP in sarcoid. Since there was not an unlimited source of substrate. Because, remember, this is an enzyme. In order for it to elevate BP, it has to have a large supply of its substrate. And there is not an infinite supply, thankfully, of angiotensin I around, and so even though you’ve got an abnormally large amount of ACE, it can’t produce elevated blood pressure, because you don’t have an equivalent and equally inexhaustible supply of angiotensin I. You just have an excess of ACE hanging around. Serum ACE activity, you’ll recall, is expressed in units per liter, in normal subjects usually around the range of 10 to 7. What about the elevated calcium levels? Well, granulomas can develop in bone, producing radiolucent defects that can lead to fractures. In the process, bone is being destroyed, and as it’s destroyed, the calcium is being released into the blood. This is a partial explanation for why patients have serum calcium levels that are elevated. It turns out there is also in sarcoid an uncontrolled synthesis of vitamin D3 by the macrophages. And this leads to an increased absorption of calcium in the intestine, in addition to the increased resorption of calcium in the bone. And so both will elevate serum calcium. Ultimately, both of them are related to the granulomatous disease. One more specifically related to the granulomas per se. This is of course hilar adenopathy. In this case, there are granulomas in the lymph nodes, present at the hilus of each lung, that enlarge them to the point that they become visible on a plain chest film or on a CT. So you can see around the cardiac profile there, and you can see the diffuse infiltration of the lung fields on the x-ray. On the other side, you can see a postmortem pair of lungs, and all of these large kind of black-blue areas for the middle of the lungs and at the hilus constitute these abnormally enlarged granulomas. Filling the lymph nodes at the hilus of the lung. And not in every case, but in some cases, a gallium scan is called for, in order to really make the diagnosis. Gallium 67, it turns out, partitions out with medium to large accumulations of granulomatous tissue. And so this is a classic panda sign, in which the parotids are involved, and you can see the gallium being taken up in the mediastinal region of the thorax, typical for the distribution in sarcoid. As a reminder, you can’t accumulate enough granulomatous disease within the eye, generally, for gallium scan to go positive. And so in this picture, in the area that appears to be the eyes, what you’re actually looking at is gallium accumulation in the granulomas that have infiltrated the lacrimal glands, leading to the symptoms of dry eye that can occur in sarcoid. You can of course get granulomas in the iris. We usually talk about two types. Koeppe and Bussaca. The Koeppe nodules are at the pupillary margin, and these are generally not held to be pathognomonic in granulomatous disease. You can see these in both granulomatous and non-granulomatous. The Bussaca nodules are held generally still to be pathognomonic for granulomatous disease. I would add a caveat to these, based on clinical experience, and that is that if there are multiples I would consider them pathognomonic for granulomatous uveitis. I have had one patient with a clearly non-granulomatous anterior uveitis who came in with no nodules, and about the second day after, which came back after a first follow-up visit on her steroids, she had a single iris nodule in the midperiphery of the iris. I would assume that this was that the inflammatory response was abating. Cells were beginning to migrate. And she happened to have a very dark brown iris. And so I’m assuming what happened was, in the presence of a very dense anterior border layer of the iris, these cells were being restricted somewhat from coming to the stroma to being circulating, and showing up as a small nodule. It did resolve, of course, but that was one case where I saw an iris nodule in what was otherwise clearly a non-granulomatous presentation. You can of course get granulomas of the lid and granulomas of the conjunctiva. In the upper left, you can see these lumps along the lid margin that are each representing granuloma along the lid margin, in a patient with sarcoid. If you flip the lid on the lower left, you can see several granulomas, subepithelial, within the stroma or the conjunctiva. And the equivalent appearance of those on the bulbar conjunctiva are shown on the other side where you’ve got something that almost looks a little bit — almost cystic. Yellow kind of translucent. And I think if you compare the appearance of the lesions on the lower left and subtract out the general redness of the lid tissue, you’ll notice that these two lesions look remarkably similar, but with the white sclera underneath one, and the red tissue of the lid underneath the other. Now, for comparison, let’s look at the signs and symptoms of granulomatous disease. Again, in TB, the symptoms of granulomatous disease are almost entirely the result of where and how many of these focal granulomas are produced and the amount of destruction of normal tissue that their presence creates. You know that in primary TB the classic initial finding — usually in kids — is what’s called the Ghon complex. This is the initial focus of infection, which includes a small subpleural granuloma, which you can see on the left near the cardiac profile, and can see on the far right on the postmortem specimen. And then there is usually a granulomatous focus somewhere in the lung, so one subpleural — so I may have confused you. I’m sorry. The subpleural one on the radiologic image is the one marked with the yellow arrow, in both the left and the right. And then a hilar node — again, depicted here by green on both the left and on the right. And together, these subpleural granulomas and granulomatous infiltration of the hilus of the lung together constitute what is referred to as the Gohn complex. In secondary TB, you can see there is much more massive infiltration of the lung, and it tends to occur primarily in the apical part of the lung. And you can see that radiologically on the left, and in the specimen on the right, where all of the yellow that you can see represents granulomas, and you’ll notice that they are largely confined to the apical part of the lung. Less so in the bases. Finally, and again, this is just a cursory overview and reminder, is miliary TB. When resistance to infection is particularly poor, a miliary pattern of spread can occur, in which we see myriad small millet-sized granulomas, either in the lung or in other organs. And taking care of eye patients, this one is a particularly important variant for us, because about a quarter or more of those with miliary TB will have choroidal involvement, as you can see here. So let’s look at the clinical course of granulomatous disease. Because these bugs and antigens are effective at staying just barely above the radar, most granulomatous diseases usually run a long, slow course of exacerbations and seeming remissions. Untreated, some can go away on their own. Like sarcoid. And untreated, some eventually lead to death, as can be the case with TB. Especially when it’s coupled with the immunocompromise of AIDS. As many of you know, if any of you were in South Africa, you know that down there, these two go together hand in hand. And unfortunately it’s often the case that AIDS weakens them, TB gets to them, and they ultimately die of TB. These are rarely raging inflammatory processes. Indeed, if you look at the list of signs and symptoms, of the most common presentation of sarcoid, on the left, you’ll notice that fever is not even on the list. So this clearly is not an inflammatory response. That is red hot, raging, and screaming. This is slow course, generally exacerbations and seeming remissions, that are very typical, and one of the things that is a hallmark of granulomatous disease. There are also some localized granulomatous conditions that I wanted to mention just for the sake of a complete presentation. And just a reminder that, for example, giant cell arteritis is a granulomatous disease. It represents a granulomatous response, we think, to the internal elastic lamina of medium and large sized arteries. So here you can see a section through a large vessel in giant cell arteritis. The arrows are pointing to giant cells. If we had an elastic stain, I could demonstrate to you that the inflammatory focus is in the tunica media, largely mounted against the elastic lamina, which will be partially shredded up, and the inflammation associated with this will swell the vessel wall, constrict the lumen, and give rise to the ischemic and potential infarcts that characterize this disease. This is also a good reminder that this disease tends to produce focal areas of granulomatous inflammation, along the vessel wall, and so when you’re sectioning a temporal artery biopsy in these diseases it’s important that the pathologist section the entire piece of tissue that you give to them, because there can be skip lesions that are missed if there is not adequate sampling of the specimen that has been taken. Also as a reminder, the corneal endotheliitis that can be seen accompanying herpetic disease represents a focal granulomatous response to Descemet’s membrane. If you look at the breaks that occur in Descemet’s membrane, as part of this condition, it is very common to find giant cells histologically located in those positions. I also wanted to mention to you — again, for the sake of completeness — something that we call a granuloma that is not in fact granulomatous. And that is the pyogenic granuloma, two examples of which you can see here. One on the left was due to incomplete closure of the surgical wound after taking the head of a pterygium off of the edge of the cornea, and you can see the scar on the edge of the cornea that is the legacy of that surgery. And another one on the right, where there was a small entrapped foreign body within the limbal region that gave rise to a pyogenic granuloma. Pyogenic granulomas are not granulomas. They’re in fact granulation tissue. As you know, when wounds are too large to suture closed, the wounds are often left to granulate in. That is, to allow the normal proliferative connective tissue healing response to replace the void in the tissue, and in doing so create a base for subsequent reepithelialization. The type of tissue that fills the void in these cases — in this case on a finger — is called granulation tissue. And years and years ago in the old pathology texts this tissue was also referred to as “proud flesh”. Granulation tissue, by contrast with granulomas, represents a tissue that contains new very thin-walled leaky blood vessels, in a collagenous matrix with lots of hyaluronate that will be capable of holding water and building tissue volume quickly, just as it does in the vitreous, and together with non-granulomatous inflammatory cells, this tissue will grow quickly, will proliferate, and will fill the void volume as quickly as can be done, providing a base for reepithelialization and subsequent remodeling of this connective tissue to give rise in most cases to a scar. There are no epithelioid or giant cells anywhere in these lesions. So this is an example of a pyogenic granuloma. If there is incomplete wound closure or one simply can’t close the wound, then this type of tissue, with new thin-walled vessels of very scant collagen matrix, continued presence of inflammatory cells, and lots of hyaluronate, which we have not stained for in this case, will fill that void volume and provide a foundation for reepithelialization. As a reminder, again, pyogenic granulomas are not granulomas. What you’re seeing here in this pyogenic granuloma is another way in which pyogenic granulomas can occur. In this case, it was due to the patient having had a chalazion, and that chalazion ruptured onto the inside surface of the lid. The patient was happy, because that big lump in their lid was gone, although their lids were stuck together, and because everything was gone, they thought everything was fine, and then a few weeks later, they pulled down their lid and there was this lump that brought them quickly back into the office. This tissue, importantly, represents connective tissue. Very thin walled vessel, new connective tissue, that is at the surface with no epithelium over it. So if you’ve ever had to work with these, you know that they are generally pretty easy to get them bleeding, and that’s what you can see here on this one. Indeed, as you probably know, patients with pyogenic granulomas often will report blood-stained tears, because some of these new thin-walled vessels have ruptured. So we’re just about at the end. As a take-home message, as a reminder, granulomatous diseases are caused by pathogens, antigens, that are usually detected, but are just above the radar system for what would normally trigger a more aggressive non-granulomatous inflammatory response. They are antigens that are hard for the immune system to effectively clear using its usual set of weapons. The general pattern of signs and symptoms differ in granulomatous versus non-granulomatous disease, with granulomatous diseases producing less of the classic signs of inflammation, less redness, less heat, less pain, but still some swelling. Or a nodule in the form of the granuloma. But they also tend to be more chronic, because the immune system cannot effectively eliminate them. So, to close, if you want to understand the difference between granulomatous and non-granulomatous inflammation, I think you can pretty well generalize from a comparison of what you know of the difference between a hordeolum versus a chalazion. Hordeolum of course is going to give a real red lesion, lots of heat and warmth, generally pretty painful, and a good amount of swelling. By contrast, when you look at a chalazion, there’s less redness, there’s usually almost no heat, the pain is certainly less than you would expect from a lesion of its size, but there is nonetheless swelling. And as a reminder to close, chalazion is the most common granulomatous disease seen in an eye practice. And here you can see the chalazion, classic lipid granuloma, with a pool of lipid on the upper left, the epithelioid cells and a few giant cells in the first ring of tissue, and then out beyond it, the lymphocytes and plasma cells that all collectively constitute the granuloma. And with that, let me stop and see if we have any questions. Thank you very much.
DR FREDDO: The question is: What are some cases seen in conjunctival granulomas? Well, there are a number of granulomatous diseases that can produce lesions in the conjunctiva. But you can also have focal granulomatous responses to things like… Say, if there was a piece of wood trapped underneath the conjunctiva. That’s the kind of foreign material that usually results in a granulomatous response, because it’s hard to get rid of. So you can see both granulomas that are a manifestation of systemic disease, as we saw in sarcoid, and you could also see it as a focal and local granulomatous response — in some cases, as we illustrated also in the talk. Let me know if that has given you an answer to the question you were asking.
DR FREDDO: Question. Can we differentiate tarsal conjunctival granulomatous reaction from classic follicles and papillae? I would say generally yes. Because the granulomas generally will have a slightly yellowish tinge to them that the classic follicles and papillae tend not to have. You also have to of course judge these in the context of what else is going on with the patient and whether there are other systemic manifestations that are moving you toward consideration of either a localized or systemic granulomatous disease. But that yellowish tinge — and in fact, at the lid margin, particularly in Black patients, it is not uncommon for the inflammation to actually erode the basal layer of the epithelium. And if you look carefully at those at the lid margin, it will erode the basal layer, and therefore there will be a little window in which you can see yellow instead of brown in that area that would not occur with a non-granulomatous inflammatory response like, for example, a hordeolum. Next question. Let’s see. What I’ve got now on top: How much granulomatous disease, specifically TB uveitis, do you come across in your practice, and what treatment would you give in the US? TB is pretty rare in the US. If you go to some academic centers, most of the patients that get seen with TB are patients who have just come to the US. From a TB area. Generally, if it’s an ophthalmic presentation, our job would be to get a basic workup, probably get a PPD, get a chest film, and if those are positive, then we usually move them off to the infectious disease people. To move on to regimens. That are typically used here in the US. I hope that helps. What defines sarcoid? That’s an interesting question. Because the debate rages as to whether sarcoid is maybe in fact infectious, rather than non-infectious. If you do some reading on berylliosis what you’ll see is that there seems to be remarkable amount of overlap and convergence between sarcoid and the signs and symptoms of berylliosis. So again, the epidemiologists have still not found a bug. They haven’t also been successful in finding a non-bug antigen. So technically, at the moment, the answer to your question, at least so far as I know, is that we don’t know what defines sarcoid, other than: It is a multisystem disease. That is caused by something that generates a granulomatous response. And the granulomas that are produced are of the non-caseating variety, by contrast with the type of granuloma produced in TB. I hope that helps. In cases of posterior uveitis due to granulomatous disease, are the clinical pictures different from those occurring in anterior uveitis, as in the KPs described earlier? Well, in posterior uveitis of course we’re gonna have both choroidal and ultimately it could be retinal involvement as well, secondarily. These patients can even have a panuveitis, in which they’ve got the whole uvea kind of upset. There can be vitreous haze, and so if the anterior chamber is clear, there are no KPs, then you can have granulomatous disease confined to the posterior uvea, but you have to be aware that you have to continually monitor the entire eye during a course of management. I hope that helps. From their causes, would their treatments differ considerably? The answer is yes. Because in the case of Th1-mediated granulomatous diseases, you have got a better chance that you might actually effect a cure or very close to a cure if you know exactly what the bug is and the treatments you offer are as effective as we always hope they are. So the answer clearly is yes. In terms of the non-infectious causes, the treatments generally would not… Well, they would differ less, because you’re trying to basically reduce the amount of tissue-destructive damage, and therefore loss of function in various organs, by suppressing the inflammatory response as best you can. Next. You said earlier that one of the examples of granulomatous disease in the eyes is herpetic endotheliitis. If you go through the spectrum of how herpes affects the cornea, a very small fraction of patients who have herpetic eye disease will go on to develop involvement of their corneal endothelium. And Descemet’s membrane. It appears to be only that subset when Descemet’s membrane gets affected that will give rise to a very local, very focal granulomatous response. But in general, in both the epithelial and stromal manifestations of the disease, we usually think of this as being non-granulomatous. It’s only when some antigen that is presumably within Descemet’s — although we don’t know for sure — gets released by involvement of the endothelium that a focal granulomatous response is mounted in that small number of cases. How can one differentiate between conjunctival concretions and granulomas? First off, by color. Concretions are usually kind of whitish. They have a granular appearance, and they usually occur within relatively clear little bags of fluid that are beneath the conjunctival surface. Some of these represent calcium. Because it turns out that calcium in the tear film is a relatively high concentration. And if you sequester a little bit of epithelium and capture an aliquot of tear film, if you change the pH or dehydrate it just a little bit, as can occur in these cases, it will lead to precipitation of the calcium into a little granule. Other concretions or deposits that are sometimes called concretions, if there are black particulates in there, I usually think about whether or not this might be some kind of eye makeup, usually if it’s a woman. But usually granulomas are subepithelial. They have a yellowish cast to them. They appear uniform across their breadth. And they usually don’t have a surrounding bag of clear fluid, like a conjunctival concretion would usually have. Next. Topical steroids in granulomatous uveitis… Generally, usually the same pattern is followed as treating any aggressive anterior uveitis. If need be, you go after it hourly. You’re generally waiting for a response. If you’ve got TB, you’ve also got the additional worry that the topical steroids could be sufficient to rerelease and redisseminate the TB. So you want to make sure you know what the patient’s TB status is. If that’s the kind of uveitis you believe you are treating. In terms of the taper regimen, generally I think most people taper based on signs and symptoms. Once you’re down to QID, the one that I generally use, that I learned from a well known cornea person years ago, that is easy for patients to remember, is that once you’re down to QID, we generally will tell the patient to do four drops a day for four days, three drops a day for three days, two drops a day for two days, one drop a day for one day, and then stop. And I’ve generally found that to be a pretty satisfactory regimen, and it tends to be one that patients can remember pretty easily. Next. In granulomatous uveitis, especially kids, what types of investigation are done? Child vision 20/20, they complain only difficult to visibility… I think this is the only thing I’ll say about it. Because I haven’t seen a lot of kids in my practice. Over the years. Is it’s important to appreciate that there’s a variant of pediatric sarcoid — and now, this is sarcoid, not granulomatous disease generally — that is actually non-granulomatous. And so it’s important to keep that in mind, in the context of managing these cases. If this was sarcoid, they had posterior synechiae with just a 1+ cell and flare… I guess I would need to know more about the case to know what it was specifically about the case that prompted you to believe it was granulomatous. The reason I say that is because, as you know, in juvenile idiopathic arthritis, or what used to be called juvenile rheumatoid arthritis, it is very common for kids to be largely asymptomatic, and come in with good vision, a relatively small amount of cells and flare, and already be syneched, with an eye that is relatively quiet. So not knowing more about the case, I would just remind you that in kids sarcoid, for example, can actually give a non-granulomatous presentation. And if it wasn’t granulomatous, given the description of the case you’re giving me, I would also worry about juvenile idiopathic arthritis, in a white and relatively quiet eye. What can be reasons for stellate-like diffuse precipitates in a child? He has scleroderma and CNS vasculitis. I can’t tell whether these… These are KPs… I don’t know if they’re within Arlt’s triangle or outside of Arlt’s triangle. You’ve got basically an autoimmune disease going on in the child, and virtually any of the autoimmune diseases can give rise to anterior uveitis. I probably would not — unless it’s outside of Arlt’s triangle, I probably wouldn’t give it an unusual — or consider it to be way out of consideration as being other than an anterior uveitis related to an underlying autoimmune disease, and I would probably manage it accordingly. I hope that helps. Next? What type of immune-related uveitis is seen in HIV patient? I think what you’re alluding to is what’s called rebound uveitis. In which, with the patient’s CD4 count below some critical level, they’re really not capable of mounting the kind of response that one sees in an immunocompetent individual who has uveitis. If effective HAART therapy is able to increase the CD4 count up to a level where the immune system can now respond, you can end up with what we call a rebound uveitis, in which all of a sudden now an eye that was white and quiet, because the patient couldn’t mount an immune response of any kind, now is capable of doing so, and has begun to do so. I hope that’s what you were alluding to. Next? Would you advise systemic steroids in granulomatous uveitis, knowing it will suppress macrophage activity? I think, as we mentioned earlier, you have to make a distinction between whether this is granulomatous disease that is of infectious origin or non-infectious origin. Is it a Th1 or Th2? The last thing you want to do is to allow a quiescent TB to be reactivated. And your risk of doing that is of course much greater. You can even do it with topical. Your risk of doing it with systemic steroids is even greater, and I think once you’re at this stage, unless it is absolutely essential I think what’s important is that, as an eye practitioner, that we be working very carefully hand in hand with the general physician, who is really doing the medical management of the underlying systemic disease. I hope that helps.