Pseudoexfoliation Glaucoma

Hello. Welcome to I3Ears, your off-mology OCAS Board of View podcast. We're your host, Ben Young, and Andrew Pau. Just a reminder that these episodes are meant for medical education only, not for diagnosing anything on your eye. Each week we take a high-yield topic and talk about the why and the how. And Andrew, this week, I think I saw something that was high yield, so I wanted to ask you what the heck I was seeing. There was this patient I saw on the clinic. When I was looking at their anterior segment, I saw there was this weird, fine, whitish, flaky stuff on their pupil margin. And after I dilated them, there was this bullseye pattern on their anterior fake egg luns capsule. Is this something that you recognize, Andrew? What was that? Well, the features that you've described so far do remind me a lot of what we call pseudo-exfoliation. And I know that you're sort of just playing along and pretending not to know what it has been, but it's a pretty common problem for people to have, especially, well, let's ask you what the demographics of your maybe pretend patient was, how old was this person? Maybe I was just paid more attention because I knew we were recording this week and I had to brush out for my glaucoma stuff. But she was an 80-year-old woman. And another thing is she kept talking about her Viking family lineage. She was quite proud of that Scandinavian background. Is that relevant at all? It is. It raises our pre-test probability that this is, in fact, pseudo-exfoliation. And the things that you've described on your exam, this sort of pupillary margin flaky crap is very often seen in it. And the stuff that you're describing on the anterior lens capsule is also really, really a big tip off that this is probably pseudo-ex. And as a glaucoma doc, I worry a lot about this condition. But let's, you know, we haven't actually talked about whether this woman has glaucoma or not. We just are talking about this probable pseudo-exfoliate of condition. What are some other exam findings that we can talk about for pseudo-ex? Oh, I have no idea. What are they? Well, let me ask you, in this retina clinic of yours where you astutely picked this up, how long did it take her eye to dilate? No, it took freaking forever. Is that relevant? It is. For whatever reason, folks, and we'll probably talk about some reasons why that's probably happening to this person, it takes a pseudo-exfoliate of syndrome patients longer for their irises to dilate even with, you know, your tropic amide or phenoliferid drops. The iris can also do some other weird things. You can see it be, as some people call it, jiggly, than usual. And that's the erododinesis aspect of it. But it's not the only thing that can jiggle around, too. Did you try like knocking on the table when she was on the slit lamp? Yeah, you know, I routinely do that, so. It's one of my favorite things to do. I'll pound on the table. Yeah, I'll pound in the table, and while I'm doing so, I'll kind of chuckle and tell the patient, this is a legitimate medical maneuver. And what are you looking for when you do that answer? I'm trying to see if, as I pound the table, the lens or iris jiggles. And when the iris does, we said that's called erododinesis. And when the natural lens does, that's called feco-denises. And it's also responsible for a lot of the other associated pathologies you can have with this. But okay, maybe you saw it, maybe you didn't. What else might you see on examination, Ben? Yeah, I mean, you know, now that I think back to some patients I saw in residency, they're not, I sometimes wouldn't see that kind of whitish flaky stuff in the people margin. But instead, I might, it might be more obvious that they have transolumination defects at their iris margin. Sort of. Yeah, although transolumination defects are very typical of different kind of glaucoma syndrome we'll talk about in another episode. But you're right. This one has them too, just more at the margin than the other kind of characteristic finding of the other problem. Yeah. So what you're looking for in this is, does their iris transoluminate and where does it transoluminate? Does it do so in the peripheral iris or more at the margin? In pseudo exfoliation, it'll happen more at the margin. Did you? I know I'm going to get laughed at for this. Did you happen to do a gonioscopy of this patient? I do it on every patient, Andrew. In weeks leading up to our recordings. But would I find if I had gonio at this patient? You might find some relative pigmentation of their trabecular mesh work less so than in other diseases or syndromes where that's really the thing that's going to tip off everything. But it might be more pigmented than you'd expect to see, even to the point of having what we call a sample EC line, just anterior to Schwalbe's line, which looks a lot, a lot of people call this a brown sugar speckled appearance. That's another way to describe sample ECs line. Yeah. That's not the pigmentation of the trabecular mesh work itself, right? It's a pigmentation where would it be relative to the trabecular mesh work? Terrier to it. And another thing that's anterior to the trabecular mesh work is Schwalbe's line. And it sample ECs line is anterior to that. Well, this is a bizarre collection of things that can happen to someone's eye. Why would that happen? Why would all these things happen? So let's just solidify it for people. This is pseudo-exfoliation. We're talking about and you're right. It's just a random grab bag of stuff on exam. It all relates back to the underlying pathophysiology, which is a bunch of junky cellular debris, extra cellular matrix that's people kind of Lucy Goosey called fibrillar ECM, just sort of junk that gets deposited throughout the, throughout the anterior segment of the eye. It's in and on a lot of stuff, including lens epithelium, the lens capsule, the iris itself, even the zonules that connect the ciliary processes to the lens. You can see it in the angle sometimes. It's another gonoscopic finding if you see like, hmm, you know, it have to be pretty severe for you to see that flaky stuff in the TM, but sometimes people can see it. It's even deep in the iris, like in the iris stroma in the iris pigment epithelium, even in the blood vessels. In fact, it's even more perfidious, I'll say, pervasive, throughout the entire body. This is something that we've only kind of more gradually come to understand, but all of this extra cellular fibrillary junk. If you go looking for it on a biopsy of some completely random non-ocular thing, you can find it in blood vessels everywhere in a person's body. It'll be in their skin, their lungs, their heart, their liver, the clinical significance of those non-ocular pseudo-exfoliative build-up crap is really kind of unknown. It seems to really just affect the eye, thankfully, for the rest of the body. What is this stuff exactly? Is this something that we have to memorize? Thankfully, not even the BCSC just kind of throws air quotes in there, says, calls it fibrillary extracellular matrix. But even though you don't have to remember exactly what it is, I think telling you a little bit deeper will help you remember why some of the exam findings pop up. So consider this. It's a thought to be a dysfunction of elastin formation. And if you don't have enough elastin in places where it should be, go figure maybe these structures are going to be a little less elastic than they ought to be, and therefore more susceptible to deformation or less able to clear themselves out with their natural self-cleaning processes. So think of an optic nerve. You kind of want your optic nerve to be a little elastic, right? To kind of bend but not break with things like pressure forces. So maybe this is why people are more prone to glaucoma who have pseudo-exfoliation because they don't have enough elastic material embedded in things that should be elastic. So not only is their pressure can go, because their pressure can get higher as well, right? It's not that they're just that their optic nerve is, you know, possibly kind of more susceptible to injury. Yeah, I think what you're getting at is this junky stuff, this excess extracellular debris, can also deposit and obstruct the trebecular mesh work, which can therefore create ocular hypertension and make you more prone to glaucoma, right? But it's not just that in and of itself, it's also kind of like a two-hit thing. The trebecular mesh work might be more easily obstructed and also the optic nerve is more susceptible or might be more susceptible to deformation injury. Now one last thing about to synthesis to kind of bring that all together, if you don't have enough elastic and if it's not properly getting incorporated into tissues, it should be what's happening to it. It is floating around as a precipitate and that is what that whitish flaky stuff is, just elastin fibers that might not be totally properly formed along with a couple other groupies, molecular groupies hanging out too. Like, uh, stuff like laminin, alpha-alastin, hyaluronic acid. Just junk that it sort of accumulates around it, but you can imagine that this is truly a problem with elastic things. And that means maybe things are less elastic, maybe things are more elastic than they should be in some cases. Coming back to my legitimate medical maneuver of hitting the table and trying to see the iris or lens jiggle around, that excess jiggling can actually be from the zonules being way too loose. And if those zonules aren't taught tethering the lens to where it should be, then the lens could move around more than it should, jiggle more and even potentially dislocate. And if you have a lens dislocate, that's harkens back to another one of our older episodes, Ectopia Lentus, people with pseudo-exfoliation can be prone to Ectopia Lentus. - Yeah, either before or after cataract surgery, right? - Right, and so cataract surgery is much more hazardous for people who have this condition. 'Cause your lens, your natural cataract may not stay where it should. It might move around more than you should. Not great when you have a feco needle right there. - And they have the worst iris dilation to you, right? So it makes it even tougher to get things out of that capsule. Are there any genetics we need to know? Like, are these all, are they all skin and avian? And are they all developed the same gene mutation? If it exists. - The classic teaching is that this is more prevalent in patients of Caucasian descent from particularly the Scandinavian area. That is coming more into question with recent epidemiologic research. Actually, a lot more people than just, you know, elderly Caucasian people have this. But the textbook thing to know is, if you hear the buzzword Scandinavian Caucasian, think pseudoxfoliation right away. As far as the genetics of this go, you know, okay, Caucasian people, is it hereditary? Maybe it's localized to them. Maybe it's something about their genetics. You'd be correct. And in, you know, glaucoma topics, a lot of the time, unfortunately, you have to remember a random gene. This is the one you got to remember for pseudox. It's called Laxel 1, L-O-X-L-1. That stands for Lysoloxidase-like protein. I don't think you really need to remember. Laxel, just, I don't know. Something about how it rolls off the tongue always made me think of something that could be a little movable jiggly kind of loose. - Yeah, it's got like an accident, like pseudox2, you know, it's kind of got that. - Yeah. And, you know, if you dive deep into the literature, it seems like this gene is responsible for cross-linking things together. That should be incorporated or cross-linked together, more structural integrity. And if you don't have that functioning, maybe that's why the elastic fibers or elastic component doesn't get incorporated. That's really all you need to know, though. Just the name, Laxel 1, associated with pseudoxfoliation, and that's as much as you need. One thing to think about in the epidemiology, though, is just having a mutation in Laxel 1 does not, of course, mean you will get this kind of glaucoma in the future. It just increases your risk. - Got it. - But it's a huge risk, 'cause like 50% of people who have Laxel 1 end up having pseudoxfoliative glaucoma. - So can you tell me more about the natural history of pseudoxfoliation? You know, in the patient that I saw, I thought I only, the stuff that I was seeing was only obvious in one eye, is that typical for pseudoxfoliation or what's going on there? - Yeah, so because it's a, as we've said, a systemic condition, this crap built up everywhere, you might see it more than one eye than the other, but it's still probably in the eye that is less obvious. Some people call that form-fruist pseudoxfoliation or just like some clinicals barely there, pseudoxfoliation. But you can be sure if one eye demonstrates exam findings of it, the other eye definitely has it. It just might be too subtle to notice, which will change over time, possibly. - Well, with my patient, if I, let's pretend I did a careful examination of their optic nerve and did not think they had a glaucoma and their visual field was okay, is I mean that they're set that they're one of the 50% or whatnot of these people that don't get glaucoma? Can I let them go? - It's certainly nice to know that they don't have any glaucoma-dus optic nerve findings just yet, in which case I'd say this is pseudoxfoliation syndrome. It's not yet glaucoma. But when it starts showing signs of optic nerve damage that really looks characteristic of glaucoma, right? Like superior inferior rim thinning, ocular hypertension and all that stuff, that's when we start stop calling it pseudoxfoliation syndrome and start calling it pseudoxfoliation glaucoma. More are in a little bit about, when should we be calling this pseudoxfoliation? But we care a lot about it. And I think your description of, okay, pseudoxfoliation syndrome only, they're good to go, no glaucoma, not quite, unfortunately, because the other distinguishing part, the reason why we glaucoma specialists care so much about this of all the secondary open-angle glaucomas is that it is the most aggressive, and unpredictable glaucoma. We're talking about a natural history right now. This is the extreme. - Of open-angle glaucomas, right? - Yeah, you can have a patient who looks totally fine, and they're doing great for like five years, and then you see them in a routine follow-up and bam, out of the blue, their pressure's 40, and they've gotten a lot worse with their visual field defects. It is the most aggressive secondary open-angle glaucoma, unfortunately. Here's a quick evidence-based medicine plug, and you don't need to memorize these numbers, but just to demonstrate how different they are. When you look at a visual field, that one of the summary statistics you can look at is the mean deviation. And usually, if they have a completely normal visual field, you'll see they have a mean deviation of, let's say, zero decibels. If the field is totally black, it'll, the worst you can be, is like minus 35 decibels or so. So there's studies out there that kind of have looked at rate of change. How aggressive is this, right? And let's just say that the early manifest glaucoma trial, this is our evidence-based medicine plug, showed that for primary open-angle glaucoma, people lost about one and a half decibels per year. That same trial also showed that pseudo-exfoliative glaucoma patients, however, were much more aggressive. They lost like almost a whole three decibels every year. And that doesn't sound like a big number, but think of it this way. You only have 35 decibels on this scale to go before the field is totally blacked out. - It's almost like 10%, right, yeah. And even if you did, like you don't actually care so much about the entire field being wiped out, you care if that field is starting to approach the center. If the defects are starting to approach the center, so that can be a bit misleading. Anyway, I'm starting to ramble too much. - It's good, that's where you're for, you're to ramble about, you're enabling me too much. It is a catastrophic level of aggression. That is that word, literally, is in the literature, like anything that this rate of progression is catastrophic. - What's like a normal age for them to present at? You know, the patient, though, I saw was 80, but is this common, uncommon? - It's really uncommon if you're younger than age 50. But it is sort of an older person's disease. 80 years old is prototypical. Usually you'll find these folks after the age of 70, where it starts affecting them, or starts becoming really obvious on their exam. - Is there any gender predilection? - Good question. No, but there are other glaucomas where there are gender predilections, so later we'll kind of do a comparing contrast. - And we talked about Scandinavia. Is there more you want to talk about Scandinavia? I don't know, it's not that you really need to know this, but some studies have suggested there's actually an association with the further north you are, or the further south, let's rephrase that the further you are away from the equator where you live, the more likely you are to have this. So nobody really knows why that is. Some people have postulated it's got something to do with side exposure even, but nobody knows, it's just a weird epidemiologic court. - Listen, Earth, you're a job now to figure that out, so we can know I'm like dying to know that's very interesting. Okay, well, now we've properly identified this patient as pseudo-expolation, and let's say that they get glaucoma, I mean, I guess something that I wonder, is does it really matter if we know if it's pseudo-expolation or opening a glaucoma, except our prognosis? Does it change anything with our management? - Good question. So yeah, you said it right. The first thing we care about is that this is a more aggressive and potentially more devastating disease. But yeah, there are things to it that you have to be a bit careful of as far as your management. Everybody knows if you're their ocular hypertensive, even if they're not just get their pressure down if you can. In trying to do so, though, you might reach for, say, SLT, or maybe some of your attendings still have an argon laser around ALT, both of those, you know, they're versions of laser trebecular plastic. great ways of delivering some gentle laser energy to try to get the outflow process working a bit better. That can work for sudo x, but if it does it's usually going to work a little less well, or at least maybe it's going to stop working sooner than it would have if you did it for somebody else. We talked already also about how cataract surgery is a little more fraught and hazardous because of those loose zonules, so you're going to be very cautious about it and maybe even one day when you're doing cataract surgery, you may want to even put it into your little surgical checklist. Does this person have sudo exfoliation and make sure you know that about everybody you're doing cataract surgery? Because it is pretty common, like it is, you know, if you're like operating in a VA, I mean, I feel like a pretty good number of the patients, it's not like a rare thing, you know, that like like microsphere or fakie or something like that, you know, you'll see this on a typical OAR day. Yeah. One last thing to know about it is, you know, there are some forms of glaucoma where removing the lens might help a bit, particularly the ankle closure glaucoma is really removing the lens could help, but it doesn't help at all in sudo exfoliation. So just take the lens out if you have to, don't think that it's going to help their glaucoma that much. And that was actually like really interesting for me, just like as a side note, because before I had thought that the mechanism of sudo exfoliative glaucoma, like before this recording, I thought the mechanism, the IOP spike problems and sudo exfoliation was from the iris rubbing against the lens. I mean, that's supposedly the motivation for why they get that bull's eye is from where the iris is rubbing against the lens kind of dilating or in constricting back and forth and leaving that mark on the lens. But Andrew has educated me and I did not and this makes it all make sense that while that is like a finding and a feature of sudo exfoliation that there may be some like shaping and such, that's not actually the cause. Like when you remove all that stuff and, you know, remove the majority of the anterior lens caps when doing cataracts or a jury doesn't actually fix the problem. It's more of this inbuilt pathophysiology with then Andrew mentioned before. You're giving me too much credit, my friend. But let's deepen one more thing. Why the hell is it called sudo exfoliation to begin with? I think Ben you and I had, yeah, mutual training and common, of course, when we were taught by some of the same people in residency. And sometimes we get an earful about, you know, calling it pseudo exfoliation. And the often refrain that you hear from a lot of people of that opinion is there's nothing pseudo about it. It's a real disease. Yeah, it's true. So then what the heck was true exfoliation. There is a distinct entity from this. That's kind of totally different in pathophysiology. That's supposedly called true exfoliation syndrome. The reason that our pseudo exfoliation was named sort of after it was because the exam findings were very similar, particularly the anterior lens capsule appearance, that sort of bull's eye appearance of the whitish flaky stuff on the surface and pseudo exfoliation looked kind of similar to in true exfoliation. How the lens capsule, the anterior lens capsule would actually split apart, delaminate itself. Now, appreciate all the leading questions Ben, but I know you know more about it than you let on. Can you tell the audience what true exfoliation was really from? The thought is it's from intense infrared energy. So the classic example historically was glass blowers that when industrial glass blowers would be exposed to stuff for long enough and they wanted to find a look a lot like what we talked about pseudo exfoliation. Yeah, just really intense heat. And I don't know if any of you have taken like a glass blowing class like you got a group on for you or something, it's surprising. I've done it once. So it is really hot hotter than anything else I've experienced than to do that every day all day long is definitely an occupational hazard. So it's not just glass blows, of course, heavy industry, heavy industrial workers exposed to this amount of infrared heat and energy. It happened to them more often. It is pretty rare these days though, thanks to I assume OSHA safety precautions. Yeah, I like I've never actually seen you know, glass blowers, exfoliation or true exfoliation. Have you ever seen it? No, thankfully. Yeah, so I can't I can't even imagine what a capsule of rexis would be like to do on a person with that. Yeah, you can't pretty scary, but I think what I'm trying to say is if you've got that group on for glass blowing, go ahead and use it. Just make sure you wear your safety protection. One other thing that we should mention about the nomenclature of this, you know, if you whether you call this pseudo-exfoliation, the disease we're talking about, the, you know, Viking high pressure glaucoma thing, whether or not you call it pseudo-ex or exfoliative just to keep your attendings happy, you have to make sure that you distinguish pseudo-exfoliation syndrome from pseudo-exfoliative glaucoma. And again, if you have all these exam features of pseudo-exfoliative, but no actual optic nerve damage yet, then it's just pseudo-exfoliative syndrome. So both eyes could have pseudo-exfoliation syndrome, but only one eye of between the two might have glaucoma. So Andrew has some review points to help tie everything together now. Sure. So as we go through a lot of these different types of glaucoma, the important part for you as a student and trainee will be knowing which characteristic matches with the correct disease process, right? So a few things we're going to ask you what, when you hear of pseudo-exfoliation, what should you think of? And the main thing really is higher risk cataract surgery and more aggressive glaucoma, more unpredictable glaucoma. To kind of comment it the other way around, say you don't know that it's pseudo-exfoliative yet, but you see other concerning things, you should think of pseudo-exfoliation amongst your differential diagnosis. And this, you know, we're talking about this as a secondary open-angle variety, but actually when you see narrow angles, angle closure, you have to think of pseudo-exfoliation too. It's sort of the weird mimic, because if those leucisonules are allowing the lens to displace forward, that can narrow your angle. Doesn't all the time, it does not do that all the time, that's why we usually categorize this as an open-angle glaucoma, but sometimes it can be in the differential for why your angle is narrow as well. Same for ectopialentis, ectopialentis among the differential for it, you should also think of pseudo-exfoliation. And as we'll see, in the next episode, it actually shares a lot of exam-finding sort of in common with another kind of open-angle glaucoma, a pigmentary glaucoma. There's some buzzwords too that this, that should make you think of immediate association with pseudo-exfoliation. You want to rattle some of those off-pen? Don't forget terms like lock cell one, that's hygiene. Fibular material is what's deposited, and we think this is all due to an elastened arrangement. They can get ectopialentis, so we talked about cataract surgery or before cataract surgery, and it's the most aggressive, like we said, of the secondary open-angle glaucomas. Their patients tend to be Scandinavian, older, and they can have a sample EC line, but there's other things in difference for a sample EC line. Which is a goniascopic finding one more time. So that's all we have for this week. 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