Lecture: Update on the Spectrum of Orbital Inflammatory Disorder

This webinar will review the diagnosis and management of infection and non-infection orbital inflammatory disorder, including IgG4 disease, granulomatosis with polyangiitis (Wegner’s), histiocytosis X, and idiopathic orbital inflammation. We will discuss the use of immunomoduators and typical regimen for each of the above disorders. The surgical approach and challenges for these diseases will also be addressed.

Lecturer: Dr. Vivian Yin, University of British Columbia, Vancouver, Canada


DR YIN: Good morning, everyone. And thank you for joining us for another Cybersight lecture. My name is Vivian Yin. I am an oculoplastic and orbital oncology surgeon. At the University of British Columbia. So today, I thought we would address the issues of orbital inflammatory disorder. As most of you know, this is a spectrum of disease, where I’m not gonna be able to cover everything that constitutes an orbital inflammatory disorder, but I thought we would go over some of the most common and some of the stuff you don’t want to miss, because of the potential morbidity or mortality to the patient. So feel free to put into the Q and A dialogue box any questions you have, as we go. If it’s appropriate for me to answer at the time, because there’s a clarification of something I’ve said, I will do so at that time. If it’s a general question that requires a little bit more explanation, then I’ll talk about them at the very end. Okay. Let’s get started. For today, because, as I mentioned, this is a wide spectrum of disease, and we’re not gonna be able to cover details of every specific disorder, I want us to have at least at a bare minimum an approach to how to diagnose these diseases, specifically for those of you who have been to my lectures in the past. You’ll know that I’m a huge fan of ophthalmologists having at least a basic understanding of how to read CT scans. I think that is within everyone’s wheelhouse. And what you’re trying to look for on the CT scan is signs or clues that will allow you to think about things that are dangerous, things that you don’t want to miss, things that you want to dig a little deeper. And then I do want us to look at a couple of differentiating pathology features. Not because we’re gonna be reading these slides, necessarily, but sometimes when you get a report from the pathologist, they will use certain words that are supposed to indicate to you whether they are low or high risk, things you should be worrying about, and then lastly, avoiding some of the treatment pitfalls. Everything we do, as surgeons or doctors, have side effects or complications. And I think it’s very important to know how to deal with those. And that’s what makes you not just a good physician, but an excellent one. So this topic can be rather dry, at times. So the best way for me to help you remember these cases or these diseases is by showing you real life cases of mine. So this first one is a 12-year-old boy who presented with some swelling on the left upper lid, and was actually previously treated and diagnosed as having dacryoadenitis. Now, this was the outside scan. On presentation, on your left, and then three days later, and usually patients get rescanned, because they’re not responding to therapy. Because he was treated as a presumed infectious dacryoadenitis, he was put on broad spectrum antibiotics. And we’ll talk about choice of antibiotic a little bit later. But looking at this, what would be some of the things that may give you a clue as to what is actually going on here? So this is gonna get our brain juices going nice and early. What are the signs on this scan that I showed you earlier, that is now on the bottom right of your screen? That you think will help you with your diagnosis? Is it the indentation of the globe that you see slightly there? Is it sinus findings? The temporal swelling of soft tissue? Or is it none of the above? Is it only diagnosable by tissue biopsy? So I’ll give it a few more seconds. These are not meant to trick you. These are meant to highlight some of the points that I want you to get. Most of you thought it was temporal soft tissue swelling. And some thought it was indentation of the globe. Sorry, I don’t speak Spanish, but I will get Lawrence from Cybersight to help with any questions you have later on, if you have some questions that you want to ask in Spanish. So the most important feature on the CT scan is actually the sinus finding. So you’ll see, as I’m trying to outline with my pointer here, that there is sinus opacity. This is an atypical presentation of orbital cellulitis. Now, swelling is something that is very easy for us to hone in on. And I’m just gonna go back to the previous slide. To try to show you that even early on, you can sort of see that there’s hypodensity, within this mass that has a slightly hyperdensity around it. And then you see that the sinus opacity involves mostly the ethmoidal, but you’re starting to see some maxillary opacity as well. On the second scan, you definitely see complete filling of that mathematics sinus. Now, of course, I’m trying to show you this scan, because I wanted you to comment on the pronounced temporal swelling, and I wanted you to comment on the indentation of the globe, but trying to tell you that those two findings are usually non-specific. So the temporal swelling can happen if there’s a bad enough orbital inflammation. Because of spillover, and it can be actually an indication of either infectious causes, inflammatory causes, or even malignant causes. As we know, malignancy can cause a secondary inflammatory response, as the body responds to the tumor. So the thing you want to look for is: Is there sinus opacity? And then go from there. So moving on, in terms of orbital cellulitis, most of this talk is gonna be about non-infectious organisms, but we can’t look at non-infectious causes, unless we know what to look for on an infectious cause. So this is really just to highlight to you that: Look for the common things being common first. So infectious orbital cellulitis is still the number one cause. And I told you that this was a 12-year-old child. So in children, this is by far the number one thing you’re gonna see in the orbit that is gonna cause a red hot eye. And for children, most of them are your usual kind of upper respiratory tract infection. Organisms — your common strep, both strep A and non-hemolytic strep. Staph aureus. Now, MRSA infection is actually becoming more common in children. Depending on where you are in the world. So I put it in brackets, because it’s still less common to have pediatric population already having MRSA, but it’s becoming something that you should at least think about. And then H flu, and then now there’s more and more children with polymicrobial infection as well. Most recent review in 2018 found that now it’s as high as a third, which is much higher than what textbooks used to talk about, in terms of pediatric cellulitis. The old school teaching that 30% will respond to antibiotic still holds. And of course, if they’re less than 9, it’s more likely that they will respond to antibiotic alone. The case I’ve shown you is one which did not. And those are the cases where you want to think about surgical draining of those abscesses. For those who are less than 5, the number one initial recommendation is actually to cover with cephalosporin. I’m talking a little bit about antibiotic, because I want to make sure that people don’t just always think that as first line for cellulitis you should use broad spectrum. In children, you can actually use single agent as a starting point, because they do tend to be monoorganism involving, rather than polymicrobial. So you use broad spectrum antibiotic if you think this is a polymicrobial infection. So if it’s an older kid, maybe it’s not a bad thing to start with broad spectrum, but if it’s a younger child, it’s okay to start with a single agent, and watch them carefully. There’s more and more literature now about starting steroid earlier. They have a better course and a shorter duration in hospital. There’s some debate — there’s a study that came out, written by a colleague of mine, that talked about starting steroid immediately. So they offer parents the option to start IV steroid concurrently with antibiotic. Instead of starting steroid afterwards. I would say I still err on the side of being cautious. So it makes me a little bit uncomfortable to start concurrently. So I tend to let at least one or two doses of antibiotic in, before I start IV steroid. The dosages is typically not as high dose as we use for other inflammatory disorders, which I’ll talk about later, so you can use a 0.3 milligram per kilogram dosage. If this was an adult — you can ask me what’s the cutoff. And I’m gonna say: There really isn’t one. 18 is not the magic number. In my case, a 12-year-old — you start to think of them as little adults. But when I say adult, in this case, thinking about necrotizing fasciitis, we’re really talking about middle aged adults. So if you’re dealing with a 60-year-old or older, even sometimes 55-year-old, you start to think more about necrotizing fasciitis and fungus, and make sure that those are always on your differential, especially if they’re not responding. In terms of orbital inflammation or infection in COVID 19 patients, I personally have not, only because BC, where I am, in Vancouver, has not had a lot of COVID patients. We have seen conjunctivitis patients. We have one patient where we were suspicious of COVID-19 with an orbital inflammation, but the patient ended up being swab negative. Colleagues of mine from the US have shared a lot of patients with orbital inflammation secondary to COVID. That will not be within this talk, but I can briefly touch upon that at the very end. So kind of telling you what orbital cellulitis looks like, and I want to contrast it with this, so this is another patient who was sent in actually with the diagnosis of presumed orbital cellulitis with an abscess, and the referral actually requested for me to drain the abscess. The photo on your right there is not very clear, because this is actually a photo I took from her electronic medical record profile. But this was the date that she came to see me, and you can see some fullness of her right upper lid, maybe a slight proptosis, but other than that, her eye is not that hot, and the imaging finding, the two views of the CT, are shown to you on the left there. Now, looking at this scan, though, what would you say are your signs that support this being an orbital cellulitis? The subperiosteal abscess you see there, which was the reason for referral? Is it the lid swelling and fullness I mentioned earlier? Is it her age? I mentioned to you that one of the presenting reasons why she got the scan was that she was having headache. Or is it none of the above? So I’m glad everyone is paying attention to subperiosteal abscess, classic what I told you — of slightly hypersignaling at the edges, and then hypodense in the middle, so by all means, this looks and smells like a subperiosteal abscess. The one thing I’m trying to highlight with this is: When things don’t look typical — and what I mean by typical is that the kid, you saw the subperiosteal abscess involving the orbital side of things. But one of the things about this particular patient that made me think it was unusual was the fact that the abscess carried into the brain. So you’ll see that there’s an intracranial component of it. And you can see it on the sagittal, most prominently. But even on the coronal, you can see it. The other sign to look for is bone. See how there’s a breach of bone here? So if this was a simple orbital cellulitis, the things that are missing is the eye is not red and hot. So any time there’s an inflammatory or infectious cause, like the kid you saw with the profound temporal swelling, this lady’s eye, besides a little bit of swelling, is pretty quiet. So for someone who has an intracranial extension of an infection that started in the orbit, the picture doesn’t fit. And the other thing is — previously I told you to look for sinuses. That was the indicating factor that this was an orbital cellulitis. And you see on her scan, her sinuses are pristine. You can seen see the start of the sphenoid sinus here on this side, and there’s nothing there. So the picture is not fitting. She’s missing the red and hot eye. She’s missing sinus opacity, which is almost a requirement for the diagnosis of a subperiosteal abscess. So this lady actually had diffuse large B cell lymphoma. I did go in and try to find out what was going on here, for the combined purpose of — one, if it is an abscess, I would drain it, but really what I was trying to get at was a biopsy, to figure out what was going on. Either this was something incredibly unusual, like I was thinking atypical organism, like parasitic infection — like — this is probably not an infection. So orbital cellulitis might be a topic you think is boring, and you know how to deal with it. But it’s important to know that when the pictures don’t fit perfectly, think about the potential for alternative diagnosis. In terms of imaging choices, I personally prefer CT. And the reason is because MRI will not tell you things like bone breaches. And as you can tell from this case, how important bone is. So I think CT is something that is quick and a good first starting point. MRI is superior for really trying to delineate crystal clear soft tissue delineation. Such as if after the biopsy you want to know whether this is invading, meaning infiltrating the brain or not, MRI will be much better than CT on that. Before I would say 95% of the things we do, we actually don’t need an MRI. Okay. So if there’s no more question about orbital cellulitis or those two cases, I’m gonna move on. B-cell lymphoma from intracranial invading the orbit, versus orbit to the intracranial. So the honest truth is, Andreas, we don’t know. A lot of these cases, as you know, B-cell lymphomas, or lymphomas in general, are blood diseases. So the assumption is that it is circulating in the patient’s entire system. That particular case was interesting, because the foci almost looked like it’s coming from bone. Of course, we know it’s not, just logically knowing what diffuse large B-cell lymphoma is doing. More likely, that probably could have started from either the intracranial or the orbit, and then one invaded the other. By the shape of it, it’s probably more likely that case started intraorbital and then went intracranial, and that’s probably why she was having headache and that’s why she got scanned. I think we do have a lecture — I think one of my previous lectures about orbital syndromes, I did cover the topic of diffuse large B-cell lymphoma of the orbit. So if you look up on the archive, I believe you can find the lecture there. Bone erosion and lymphoma — it’s actually not as rare as you think. So with diffuse large B-cell lymphoma, I find bone involvement is much earlier. If it’s MALT lymphoma, then you’re right. Bone involvement is not that common. So diffuse — I just had a case, actually, recently. It’s not involved in this talk. Who also had pretty significant bony involvement. So I would say if you have bone involvement, you think higher grade. NK T-cell lymphoma or diffuse large B-cell lymphoma. Sorry about that. So the first kid is kind of our starting point. And he was referred in as dacryoadenitis. So I wanted to show you what a dacryoadenitis should look like. You need to know what the most typical presentation looks like, in order to know when things are atypical. So this is what the most typical dacryoadenitis looks like. If this is the scan I got sent, I’m pretty comfortable that I don’t even need to examine or talk to the patient. I can pretty much treat on spec. And some of the features on this scan is the fact that — while it’s clearly lacrimal gland, so you can see that it involves the gland morphology, whereas on the other side, you see the thin and slender profile of the globe, and then on the axial, you can see that there’s not really any posterior extension. So if this was a lacrimal gland dacryoadenitis that is of non-infectious or non-inflammatory origin, and it’s actually a malignancy, you’re gonna see posterior extension. So the glands tend to enlarge circumferentially. They should not just be anterior, but it should actually extend posteriorly as well. And this kind of heterogeneity is very typical of an infectious dacryoadenitis. So if you see heterogeneity within the lacrimal gland mass, that is less likely or highly unlikely to be a malignancy. In that you don’t have to worry about missing something. And you can actually treat as an infectious cause first. I’ll come back to orbital cellulitis in adults, because I want to just finish the component about dacryoadenitis. So dacryoadenitis is a Latin word that just means inflammation of the lacrimal gland. It actually is not — the word itself does not tell you what the underlying cause is. So you can think of them — that they could be infectious. Or they could be inflammatory, or as I mentioned, they could be masquerades. So slapping the patient with a diagnosis of dacryoadenitis actually doesn’t tell me what you think is actually going on. Of the infectious causes, like all infectious causes, whether it’s orbital cellulitis or dacryoadenitis, it could be bacterial or viral, or atypical. Atypical infection of the lacrimal gland is actually quite rare. I’ll highlight some of them, which I’m calling them — inflammatory here. But the one that comes to mind is I just had a patient with potential syphilis of the lacrimal gland. So those are quite atypical, and you probably won’t see them very often in your practice. And usually those, in terms of diagnosis, you’re really looking for other systemic signs, in order to help you with the diagnosis. So we’ll cover some of these infectious causes, and we’ll cover some of the inflammatory causes for sure. That will probably be the two most difficult things to figure out, whether it’s inflammatory or infectious. We’ll skip the masquerade, because there’s a whole lecture on lacrimal gland malignancy on Cybersight. I’ve given a few months ago as well. So there are quite a few questions about steroid use in orbital cellulitis in adults. So I do not check CRP before starting IV steroid. We can talk about that at the end again. In terms of why — I would be curious to know why you would be using CRP as an indicator. Is it that you were thinking of using it as a disease marker? In terms of starting steroids in adults, yes. I follow the same rule as well. That I usually want a couple of doses on, and it depends on how hot and how the patient presented. If I’m more worried about potential non-infectious causes, then I tend to start the steroid a little bit earlier, almost as a trial, to see if the steroid really helped or not. If I’m more worried about atypical infection, or one of the infections that are harder to get ahold of, so I’m thinking about necrotizing fasciitis, or a fungal infection, then I tend not to start steroid at all. So it is driven a little bit by what organism I’m thinking about. And I do use steroid routinely for the garden variety orbital cellulitis. It helps the patient recover a lot faster, and you’ll get the patient kind of out of the hospital faster, as well as the patient would just kind of go back to work sooner. So that’s why I do use it, even in adults. In terms of how long do I use it for, I find you don’t need it as long as for inflammatory causes. So typically, I will give three doses, and that’s more than enough. Or sometimes I can even get away with just one high dose IV steroid — would be sufficient. We don’t have enough evidence to show how should we really use steroid in cellulitis, to tell you the truth. Because for a very long time, people shied away from using it, thinking about — that you’ll make the infections worse, you’ll fight against the antibiotic. So I have to say that it’s relatively new, meaning only in about the past five years or so, that people have become more comfortable with using steroid. Okay. So in terms of causative agents for infectious dacryoadenitis, which of these would you say is not a possible organism? So I’ve kind of given away a little bit about this, because I mentioned syphilis earlier as one of my patients. And herpes simplex — can it be an organism? Staph aureus? Acanthamoeba, and Lyme? Which of these is not a possibility? Perfect. So the reason I’m throwing this in there is we’ll see acanthamoeba later, but there’s no role for acanthamoeba in dacryoadenitis. You will be surprised that sometimes residents tell me atypical infection of the lacrimal gland is acanthamoeba, but to our delight, that is not a possibility. The ones I don’t want you to forget is herpes and Lyme. So these are what I would consider less common dacryoadenitis causes. But they should be always on your differential, and yes, herpes should be on your differential for almost anything under the sun. So not common, but definitely herpes is so pervasive now in our society that it can cause almost any orbital cranial syndrome, any cranial neuropathy, any infectious or inflammatory causes. So here is a list for you of all the possible infectious dacryoadenitis. We’re not gonna go over each of these, but I kind of categorized them in terms of frequency and color coded them for you. So for bacterial, you’re still dealing with the same organism of orbital cellulitis. So staph, strep, and H flu are still your most common. In dacryoadenitis, which is more common in adults than in children, you also want to think about Moraxella, as well as pseudomonas. Moraxella, because it’s part of the upper respiratory tract infections that we think about, and pseudomonas, what I would consider to be more of the quote-unquote spectrum of atypical. TB and syphilis you’ll see once in a blue moon, but they’re both on the rise in terms of prevalence in our society and across the world. Because of that, you will see increased incidence of dacryoadenitis, because of these organisms as well. So for the sake of time, I’m gonna go a little bit faster. Just to contrast an atypical presentation of dacryoadenitis, so this was a young lady, 25-year-old, who presented with bilateral upper lid swelling, and as you can see from the scan, she has bilateral lacrimal gland enlargement. She was given prednisone with presumed inflammatory causes of dacryoadenitis, for five days, relatively high dose, so 50 milligrams, that’s probably — in a young individual, close to 1 milligram per mil, and there was no response. So at this point, you’re probably thinking: You want to, one, make sure that this is not a malignancy masquerading. But bilateral lacrimal gland cancer is incredibly rare. I think I’ve seen one in my career. And it was a squamous cell. But this is probably — when it’s bilateral, more likely still to be infectious. Especially in this age group. So she actually was tested for mono, because of some other vague symptoms. And this was actually a case of bilateral lacrimal gland involvement from mono. So rare things do happen, and sometimes tissue biopsies do help you make these diagnoses, or doing a good history, and then a good inflammatory workup, based off of your history. Switching gears a little bit to the non-infectious causes, so this was now an older individual. So a 71-year-old lady, who actually was presenting for chronic inflammation of her lower lid. And the reason for the referral is actually this little spot right here. I mention that I do a lot of oncology, as well as orbit. So this lady was sent in to me, to say: Question mark… Is this a cancer on her eyelid right here? Is this something that was a chronic inflammation, that was actually a malignancy that was missed for many years? And on the CT scan, you notice that there’s this homogeneous mass in the medial orbit. You can see that it tracks to probably the posterior two thirds of the orbit. Her vision was normal. She’s just kind of hot and inflamed. As you can see, caruncle, edema, injection throughout. So this was a lady that actually had Wegener’s. Now, what were the clues on CT scan that makes me start to think down this path? It’s that if you look very carefully, this is why I favored CT, because bone helps me a lot in my diagnosis. You’ll notice that the bone is missing on this side. Right? So if you compare to the other side, even though orbital bone is quite thin, you can still see a faint line here. And you can see also the contours. I always say: Look for symmetry. We’re a mirror image of our two sides for a reason. You can see there’s bone destruction here. There’s no bone in this section, and even some hyperostosis reaction, which goes along with inflammatory causes, and the other thing is to make sure that all the scans look the same, so you know this is not an artifact, so if you look on the axial, similarly, I can’t see the shape of the faint line that I see on the other side. So Wegener’s, or granulomatous polyangiitis, the preferred term now, is an autoimmune inflammatory disorder. On pathology, it’s important to distinguish this from the next entity we’re gonna talk about. It’s important to know that, yes, you get a mixed reaction. So you’re gonna get all of your inflammatory cells, including lymphocyte, eosinophils, plasma cells, and epithelioid. So what do they look like? This is an epithelioid. So it looks different than your typical lymphocyte, which are these really blue cells. So you can see if you are uncomfortable reading pathology slides, the one thing you should take away from this is: Are there a lot of blue cells? If there are a lot of blue cells, you think two things. One is inflammatory, or one you think lymphoma. So then the next question you ask yourself is: The blue cells all look exactly the same, with nothing else but blue cell. If the answer to that is no, then you’re most likely dealing with an inflammatory cause, like this one. This is not just a sheet of literally blue Skittles with nothing else. And the other thing you look for is: Is there any giant cell? Multinucleated giant cells, which is this guy. These big blobs with kind of a couple of different blue circles. You can see it here in high mag, but you can also see it on low mag. This is a multinucleated giant cell. There’s one here, there, and lots of them throughout. This is a sign that you’re dealing with a typical Wegener’s or granulomatous polyangiitis. What is nuclear dust? It’s a word used in pathology to describe vasculitis. This is nuclear dust. This is a blood vessel you can see in red. And you can see that there is kind of breakdown, around those microvasculature, and that’s telling you that this is a vasculitis. So these are small vessel vasculitis, and that’s kind of the hallmark of GPA for you. Like I mentioned, they’re autoimmune. It is not common, quote-unquote, when you compare to diabetes, or when you compare to hypertension, but for orbital conditions, this is actually quite a high incidence. So it’s 3 in 100,000. For most of our orbital conditions, we’re looking at 1 out of 100,000. So this is actually something you will see in your practice. And in your lifetime. The serological diagnosis is based on a marker called ANCA, and ANCA is separated into cANCA and pANCA. For a lot of time, there was a lot of debate in terms of which of these two is diagnostically more common. So historically, in the literature, we know that cANCA is more common in Wegener’s than pANCA, by far. But more and more, there’s literature to show that maybe actually there are patients with just pANCA elevation who actually do have Wegener’s. So don’t dismiss those cases. There are 10% of patients who have pANCA elevation only. Orbital involvement is very, very common. 50% of your Wegener’s patients are gonna have orbital involvement. And the ocular involvement, which is the cicatricial conjunctivitis, scleritis, PUK is less common than the orbit. So as orbital specialists, we’re gonna see this even more than our other ophthalmic colleagues. The one worrisome thing with Wegener is CSF leak. The bone erosion can involve the cribriform plate, and I’ll show you a case of that in an image later on. And these patients do have mortality. You don’t want to miss a patient with orbital Wegener’s, because they require multidisciplinary systemic investigation. Patients with Wegener’s have a higher and an earlier mortality. And the key kind of high incidence leading to mortality is hospitalization for infection. So in-hospital death, which is 2.5% of these patients, is most likely due to inflammatory or sepsis. Renal failure occurs in about 28% of these patients. And by renal failure, I don’t mean a little bit of kidney dysfunction or decreased kidney function. I mean end stage kidney disease, needing dialysis or transplant. And unfortunately, most of these patients are low on the transplant list, because if they get a transplant, they’re gonna fail again if the Wegener’s is not under control, so they tend to be slightly lower on the totem pole for a kidney transplant as well, which is unfortunate. So early intervention and preventing them from getting to the stage of kidney failure is really important. The one thing that gets overlooked is that these patients also have a lot of cardiac abnormalities. So five-year cardiac event, meaning heart attack, cardiac failure, CHF, is actually as high as 11% of these patients. They can even have pneumothorax, because infection — if they have a nodular involvement of their lungs, those nodular involvement — they can eat through bones of the orbit. They can actually eat through structures of the lungs, and cause a pneumothorax. So definitely don’t take these lightly. They need aggressive immunosuppression, lifelong, in order to prevent them from running into some of these mortality issues. In terms of treatment for GPA, it is, as I mentioned, aggressive immunosuppressions. The specific number one or number two agent will change a little bit, depending on where you are. So even within North America, there’s an East Coast, West Coast divide. On the East Coast, methotrexate tends to be the first agent people go to. On the West Coast, people like cyclophosphamide a little bit more. Why is there such a difference? I don’t know. I think it’s just habit. It depends on where you’re trained, and you tend to stay and practice where you’re trained. And because of that, I think there’s a slight divide between the first two there. Rituximab is becoming more and more of a favorite, as a first line, because of its better tolerability, compared to methotrexate and cyclophosphamide, in terms of side effect profile. However, it’s way more expensive than cyclophosphamide and methotrexate. So by and large, you’re gonna see those two agents as first line drugs, and then followed by rituximab, as the third one that you’re gonna see. IVIG, mycophenolate, and azathioprine has more to do with — especially azathioprine is more for maintenance dose, because of how well tolerated it is. IVIG and mycophenolate tend to be for refractory cases if they break through methotrexate or cyclophosphamide. Relapse rate is really high. These patients sometimes get a dosage drop or drug holiday, but when they do that, they do tend to relapse, and in five years, half of these patients tend to relapse, even if you get some form of drug holiday or control in the beginning. So don’t let these patients discharge from your practice. They really do need at least at a bare minimum a one yearly touch base. So looking at another case that I kind of promised you, about how bad Wegener’s can get, so this is another lady, 69-year-old, who came in actually — unfortunately not well controlled. She was lost to follow-up. She lived in the northern part of BC, which is a really, really rural community, and hard to get to, with few specialists, so she actually presented to us with CSF leak. And after the CSF leak, as you can see, the missing cribriform plate here. After that was stabilized, she was discharged for hospitalization, she was asked for some help from myself and the plastic team, for dealing with the progressive corneal thinning she has. Now, you can see that she has no orbital bone on either side. But it’s the left side that was more severe, and you can see that she has almost no soft tissue covering the globe, so you can understand why she has corneal thinning. She has non-wetting of her ocular surface. This is a clinical photo of her. On the surface, she doesn’t look so bad. This is postreconstruction. We tried to close the hole on the left side and reconstruct some sort of globe protection, and really, you’re not trying to make her look pretty. We’re actually trying to close it with the least invasive approach possible. Recognizing that she will probably break through until her Wegener’s is under control. So we’re saving a free flap for a rainy day. But you can see, even with a strong glabellar flap, this is paramedian, so it follows the blood vessels. This is a vascular flap that we rotated in. You can see she’s already starting to fistulize up here. You can see by the arrow, and she’s starting to fistulize down here already. And on her other side, she has a small hole that was starting to fistulize. So these are cases where you’re gonna be chasing your tail as a surgeon, unless medically, they really immunosuppress her well and she stabilizes. You can also see the classic telltale sign of her nose changing shape, because of the bony changes from Wegener’s as well. Okay. So we are about halfway through. We’re gonna talk a little bit about another inflammatory spectrum of disease. So switching gears to another disease, this is a 71-year-old lady, who also presents with actually droopy eyelid for a year, and came in requesting for a ptosis repair. And you can see on the scan here that she has this fullness in her right orbit. Centered around the lacrimal gland, and you can see that this lacrimal gland looks very different than the previous one I’ve shown you. So this is homogeneous. There’s no heterogeneity to this enlargement. And unlike the dacryoadenitis that I showed you earlier, which was predominantly just an enlargement with just involving the front, without this tail, this lady looked very different. So this was actually a lady with sarcoid. So this would be categorized under kind of atypical enlargement of your lacrimal gland. Sarcoid contrasts from Wegener’s in that, on pathology, even though both of them are inflammation, this one is non-necrotizing. So Wegener’s also has a lot of fibrosis shown. This one does not have any fibrosis. You’re seeing these kind of lobules. This is because this is a lacrimal gland specimen. This is not these kind of — this pink line in between is not because of necrosis. This is because these are the natural septations that occur within the lacrimal gland. You see a lot of blue dots, but it’s not a sheet of blue. It’s not lymphoma. If this was lymphoma of the lacrimal gland, you would see uniform blue throughout. So this is what sarcoid looks like, with the lymphocytes you can see, you see the ductal architecture that is still preserved, showing you that this is a lacrimal gland. So this is a sarcoid, which is a rare cause of lacrimal gland inflammation. Non-caseating is another term for non-necrotizing granulomas. And they do have a high propensity for lung involvement. However, 50% of these cases have no lung involvement. But they have a very high propensity for eye involvement, in about 40%. They are more common in African Americans, in the North American literature. Almost by about threefold, or higher. And steroid is still the first line for these patients, so unlike Wegener’s, which you pretty much get them almost immediately on both steroid and immunosuppression, in sarcoid cases, you can try to see if you can get away with getting a remission with steroid alone. And if that doesn’t quite happen, as well as you want to, then you can start immunosuppression with methotrexate. There’s more and more literature on trying to use TNF alpha blockers, and there’s quite a number of clinical trials ongoing in the world, multicenter trials, about this. Once again, these newer drugs are being investigated, because they’re better tolerated, they have less side effects, however, they also come at a price, so all of these agents are much more expensive, by magnitudes of five to tenfold, compared to methotrexate. These patients are much easier to get remissions. So about two thirds, you’re gonna get them — remission meaning off drugs with no disease involvement present. In about two thirds of the cases, in contrast to Wegener’s, which is really, really hard to get them into complete remission. Even then, they relapse quite commonly. There’s a lot of controversy about ACE level, about ten years ago, in terms of how useful are they in terms of diagnosis for sarcoid. Sarcoid is a very difficult disease to actually diagnose. Tissue is king in terms of helping you with this diagnosis. However, ACE level was something that is taught to us, as the marker for diagnosis, so I thought we should touch on this. ACE is not very sensitive for sarcoid diagnosis at all. That’s the bottom line. And I included the ocular diagnosis symptoms there for you. More and more, the diagnostic criteria in recent years, from 2019-2020, are based on consensus statements of experts who treat sarcoid, and more and more, it’s actually like how we diagnose, let’s say, multiple sclerosis, that it’s on a spectrum of clinical findings and radiographic findings, and you have a scoring sheet about whether this is a probable case of sarcoid, or definitive or likely. So that kind of tells you that — look these up, if you have a case that you really think smells like sarcoid, but you’re not getting the serum markers that you want for definitive diagnosis. Now, if you do have an elevation of ACE, and you have the classic clinical symptoms, then that is a definitive case of sarcoid. Sarcoid can look also much more inflammatory. This is an example of an inflammatory case of sarcoid. So you see the kind of conjunctivitis, inflammatory conjunctivitis, and potentially a little bit of early PUK on this patient. Much more swelling than my case. And much more kind of prominent of an orbital finding. So sarcoid can present with more inflammatory look, or more of a quiet look, which was my case. Without much swelling. And just kind of a ptosis and some fullness in the upper lid. Now, moving on to another inflammatory syndrome, and these are the three that I really want you to take home, because some people might not have seen them in their career, so this was a younger patient now, instead of the 70-year-olds which I showed you in the two previous cases, this was a 13-year-old female. Comes in, also complains about lid swelling. Most of these patients will come in saying they have a fullness on their upper lid, their lid is droopy, and they want you to fix the lid. And when you scan the child, you notice that there is significant bony destruction. And on the MRI scan, on the sagittal, you’ll notice that it’s not infiltrative. So the brain is being pushed rather than being eaten into. So this sign is important, because whenever we see bony destruction, we’re thinking cancer. But then this kind of reassures you that it’s not an infiltrative mass. So this was actually a classic imaging finding of Langerhans cell histiocytosis. So for the sake of time, I’m not gonna do this poll, and I’m just gonna move on, so that we have enough time to talk about some of these questions you’re having, which are all great questions. So Langerhans cell histiocytosis is actually very common in the frontal bone, and in the orbit, which commonly presents to an orbital surgeon, rather than a neurosurgeon. It has a broad systemic involvement, so it has all these categorizations, because it’s a spectrum of disease, so it can be unisystem, meaning it involves just the organ. If it’s more than that, it’s multisystem. It can also be unifocal or multifocal, meaning involving both orbits or both kidneys. So that would be multifocal. That’s what I mean by system versus category. It’s an eosinophilic granuloma. They’re very different from lymphocytes. The lymphocytes are much denser. Most of us don’t do microscopy. So this is really for academic purposes. But on your exam, they might still want to test you on this. Which is — on EM, you’ll see these classic granules. So these are diagnostic of Langerhans cell histiocytosis. And it constitutes about 1% to 3% of pediatric orbit tumors. And as I mentioned, orbital involvement is actually very common. So the good news with this is you may have a horrible imaging finding and it gets you really, really worried initially, but these are easily treated. So for the orbital disease, they respond beautifully to curettage, meaning you do an incision. You don’t have to try to, quote-unquote, cut it out neatly, like the way we do with other orbital masses. You can actually take a small curette, and just kind of shell it out like an ice cream, and they do come out in little fragments. So they’re not encapsulated, usually. And if you have any residual that you’re worried about, you can actually inject a little bit of steroid, and it melts away beautifully with no residual whatsoever. So these are quite easily treated, surgically. There are a couple of spectrum — or I would say multisystem involvement of Langerhans cell that has gotten names to them. That’s all it is. Hand-Schuller-Christian is the one that has DI. Diabetes insipidus. They tend to be older individuals and tend to be multifocal as well. And then the Abt-Letterer-Siwe is the one we really worry about, because these are highly fatal, and they’re the ones that have multiorgan involvement and multiorgan system failure, and are typically young. And they come in quite sick. These are the two that also exams like to ask you about, because you want to make sure that you remember that some of these kids can be quite sick, and you really have to involve a pediatrician and a pediatric rheumatologist. With these spectrum diseases, these ones that are named, survival is quite poor. So two-year survival is less than 87%. Once again, just make sure that you check these children, if they present to your clinic as a first presentation, that they don’t have other systemic involvement. If it’s just orbital involvement, those kids do very, very well. One last case, and we’ll highlight one last disease. And then I’ll get to some of your questions. This is now an older individual. 78-year-old. Also coming with swelling. There’s always the story of falls. So I never trust a story of falls, because I feel like everyone older than 60 or 65 is gonna tell you that they had a fall history. So they had a fall three years ago, and progressively had gotten more and more swelling of her right eye. Another lacrimal gland mass that you see here, or centered around a lacrimal gland, some indentation of the globe, which just tells you that the mass is firm, and as I mentioned, always look for bone changes. This is a classic bone change that is actually bone erosion, or bone molding around the tumor. So why do I use that word? Or why do I highlight that? Unlike the kid, which I showed you earlier, which I’m gonna go back to, and just make sure that you get that differentiating factor — so see how sharp this edge is? It’s like a square. And how it’s like a square — it’s almost like I took a saw and just cut that off. And how there’s this kind of moth eaten appearance. These are bones that I consider eaten away by whatever process is going on. And in contrast to that, if you look at this case, it’s smooth. It doesn’t have like — it has a point to it. So it’s not me taking a saw and cutting off an edge, and it doesn’t have — it’s very smooth-appearing. So these are telling you that this process has been chronic, and it’s just slowly eaten through, rather than — slowly kind of molded through, rather than eaten away by whatever process is going on. This tells me it’s more likely to be a benign and chronic condition, rather than an acute and malignant, versus one of these lytic, meaning bone eating diseases. So even though it looks very prominent, and it’s kind of molding away some of these bones, I was leaning towards probably this is most likely an inflammatory disorder. And this was a patient with an IgG4 disease. I want to highlight this, because there’s more and more literature talking about this now. It is an immune mediated — and it’s fibroinflammatory. So unlike the non-caseating lacrimal gland case of sarcoid I showed you earlier, in contrast, this one has a lot of necrosis. It is an older individual, and unlike the previous cases, which we saw that most of my patients were female, this one has a male predominance. And lacrimal gland involvement in this spectrum of disease is about 20%. So also not low. In terms of involvement of — within the orbit, what is the most common, lacrimal gland is the most common, and then soft tissue or muscle can be involved as well. IgG4 is also like sarcoid very difficult to diagnose. So most recently, they come up with a system to try to categorize them into definitive, possible, or probable. So like most of the difficult to diagnose, you’re gonna define them into three categories like this. And this is all coming out of the rheumatology and arthritis literature. And it’s based on a combination of clinical, histopathological, and serum findings. Now, once again, we’re lucky in orbit that it’s not that hard for us to get tissue, so tissue diagnosis is still the easiest one to find much more of a definitive diagnosis of things. Here is a spectrum of all the different systemic involvement that it could get. Besides the neck, besides lacrimal gland, salivary gland is actually quite common, and it’s common to be bilateral. And here are the lists of the other organ systems, pretty much lung, pancreas, anything you can think of, the renal wall, as well as retroperitoneal fibrosis can occur. Management — like some of the other inflammatory syndromes, first line is still steroid, and you’ll see a recurrent theme, that a lot of these agents overlap. So like what we talked about earlier with sarcoid and Wegener’s, how methotrexate and rituximab becomes your first and second line treatment, same with IgG4. If you can get them on steroid and get them into remission with just steroid alone, great. If you cannot, you start to fall back on the second line, which is predominantly rituximab and methotrexate, and third line being the mycophenolate and azathioprine. These patients tend to go into relapse as well, but steroid remission alone is pretty high. 60% you can get them onto steroid with taper and they do pretty well. I know there’s a question of steroid and dosage of steroid. We’re gonna come back to that. But by and large, generally speaking, with steroid for inflammatory disorder, you’re looking at 1 milligram to 1.5 milligrams per kilogram. Depending on how high and high refractory these diseases have been, you’re gonna see different — either 1 or 1.5. In contrast to this case, which is our last case of the day, and then we’ll come back to some of these questions, this is a 54-year-old female who also has swelling for about three months. A little bit more acute, and I know there has been some question about pseudotumor. I agree that we don’t really use the word “pseudotumor” anymore. Because it’s kind of a misnomer. It’s not really tumor. Now most people use the word idiopathic orbital inflammation. So this was a lady with idiopathic inflammation. So which of these tests would you think you have to perform in someone in whom you’re suspicious of idiopathic orbital inflammation, but you’re not sure? So I’ll give you a second. This is the question that will help you put everything together. I hope you’ll recognize some of these diagnoses are not so easy. Exactly. Yay. I’m glad you guys got the point of the story. Which is that really idiopathic orbital inflammation is a diagnosis of exclusion. It’s something that you call it idiopathic orbital inflammation only after you cannot find one of the above causes that we have talked about. And there is more and more effort at trying to better define it, and there is a nice consensus statement, published in 2017, in JAMA Ophthalmology, with a panel of experts, international experts, trying to kind of categorize some of the more common findings in IOI. Now, you’ll see that a lot of these overlap with some of the other syndromes. Maybe with the exception of bone being intact. IOI, unlike IgG4, doesn’t tend to involve bone, whereas you saw in the case of IgG4, there’s some bone molding. They can be subacute setting, like in my case. The misconception is that oh, IOI has to be like orbital cellulitis in its acute presentation. That’s not necessarily the case. I would say more and more, I’m seeing IOI that are subacute in presentation than acute. They have to have no other systemic disorder. So let’s say you have a patient that looks exactly like the one that I showed you, with kind of fluffy orbital fat stranding, but they have no systemic sarcoid. Then I would say you really have to make sure this is not sarcoid, before you label it as IOI. Now, there’s some pathological findings that are listed on the right there for you, in terms of: There has to be no necrosis. Because IOI does not necrose, like some of our IgG4 disease. And there is, you’ll notice, some positivity of IgG4, even with idiopathic orbital inflammation. So sometimes distinguishing between IOI and IgG4 is difficult. And because there’s a cutoff for what is tolerable IgG4, because IgG4 is a marker of inflammation, so it’s not a marker on its own. So you do tolerate some positivity of IgG4, even with IOI. So in terms of IOI management, steroid is by far probably your number one. And some of the dosage questions earlier — so I do tend to start off with 1 milligram per kilogram. For steroid. And yes, when you think about that, that is very high dose. So that means I’m putting some patients on 70, 80, sometimes 90 milligrams of prednisone a day. With taper. If you’re having a hard time tapering them completely off steroid, then you start adding some of these second agents, such as methotrexate is usually our go-to. There’s been some new literature, talking about using rituximab as the go-to, rather than steroid, to try to decrease some of the side effects we know high dose and long-term use of steroid can cause. And the literature looked at every two week rituximab dosing, and most of the patients in that Korean study actually ended up needing four infusions of rituximab. Once again, rituximab for me, in my practice in Canada, is very hard to justify, because of the cost. When I can easily give them steroid, which costs about 15 cents per pill. Recurrences actually do recur with IOI as well. Just because it’s not one of these exciting syndromes that I talked about earlier, IOI patients — you do have to warn about recurrences. I don’t follow these patients long-term. Instead, once I’m able to get them off steroid and quiet, what I tell them is: You have a chance in your lifetime of recurrence, up to 30%. If it happens again, you know what it feels like. It does mean that you have to be reinvestigated. And just because they had IOI once doesn’t mean they can’t get orbital cellulitis the next time. So you still have to rework everything up and make sure you’re not missing something, before you can relabel them as IOI. So I hope that we covered some of these major approaches to this spectrum of disease. By and large. I didn’t cover everything, because we didn’t have time to do that. We’ll be here for days if that’s the case. But I want you to at least have a diagnostic approach to avoid any overtreatment or undertreatment, and to do that, you have to know: What are the most typical signs of each of the inflammatory syndromes? What are the CT features? What are the pathological features? And then most importantly, to avoid any treatment pitfalls. What do I mean by that? There are patients that have complications from systemic disease. There are patients that have complications from surgical management. So you have to know where the danger zones are, and which patients are gonna recur, in order to know how not to get into trouble, so to speak. So that is a whirlwind of orbital inflammatory disorders. I will try to get into some of the questions now, if people have time to stay on. If not, what I will try to do is work with Cybersight to try to maybe answer some of these questions with some other formats. Recalcitrant IOIs do happen. And those are the patients that you start on a steroid-sparing agent. And cyclosporine or azathioprine are both reasonable choices. I’m finding that rheumatology tends to favor methotrexate as their first agent. But I think azathioprine is fine as a first choice as well. It tends to bring things into remission in the literature a little bit less than methotrexate. Periocular steroid injections are controversial. I get a lot of referrals for periocular steroid injections for IOI, as well as thyroid eye disease, which is another topic I didn’t cover in inflammatory orbital syndromes, and part of the reason is because there’s a beautiful lecture in the Cybersight library, specifically about thyroid already, so I wasn’t gonna duplicate topics. I would have to say that I do not find orbital steroid to be all that useful for general IOI or general thyroid. The one condition that I do find useful for steroid is trochleitis. So those are a very specific disease entity. If I fail steroid, my first choice is methotrexate. Just because I see the best response with methotrexate. About fungal orbital infection in diabetes… Yes. So absolutely. So if patients are immunosuppressed, and diabetes falls into that spectrum of immunosuppression, you have to think about fungal and you have to think about necrotizing fasciitis earlier. Than a patient who is non-immunocompromised. So there’s a lot of questions about refractory steroid. As I scroll through this… So those have — it’s a duplicate and I answered them already. There is an interesting question about: How do you manage postinflammatory fibrosis? Mohammed, that’s a great question. I find that it is — the honest truth is it’s difficult. However, I will say that is probably one population I do intralesional steroid injection. The other agent to think about is 5FU. So I’m finding that I’m using 5FU more and more. So I used to use 5FU a lot for most of my cosmetic cases, for scarring control, and I’m finding that I’m using 5FU and mitomycin a lot more in orbit. So in orbital fibrosis, especially if there’s intraocular muscle involvement, I’m using a combination of mitomycin, 5FU, and steroid to try to control some of those fibroses. Now, I’m not talking about injecting it directly into the muscle. I’m talking about injecting it around the muscle, to try to free up some of those strands of fibrosis that happen. And yeah, sometimes that may require me to do a surgical scar release, and then inject medication around that area of fibrosis. Orbital fibrosis triggered by sinus surgery? It’s possible, especially with some of the Wegener’s patients, when they do reconstructions. If you’re talking about sinus surgery, from sinusitis, and that triggering orbital fibrosis, that is highly unlikely. And the reason is because they are supposed to keep — they do keep bone intact, so there should not be any transmission to the orbit from sinusitis surgery. If you are seeing that, then I would say you have to dig a little deeper, and just make sure that there is nothing else going on. So intralesional injections for Langerhans cell histiocytosis — what dose do you use? There’s actually no particular dosage per se. So usually it depends on how large of an area. I like using 40 milligrams per mil for my injection, just because then the volume is smaller. So I usually draw up the volume that I think the lesion will take, quote-unquote, so to speak. And typically that ends up being 5 milligrams or less. So for the sake of time, and I know everyone has to go, yeah, thank you, everyone, for attending. And I’m sorry that I couldn’t get to everyone’s question. But I’m so happy to see that there is such great engagement, and that people have lots of questions about this spectrum of disease. So thank you, everyone, and I hope to see you guys another time, on another Cybersight lecture.

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July 17, 2020

Last Updated: October 31, 2022

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