ICE Syndrome

Hello, welcome to IZ for Ears. I'm Osmo GeoCass, part of your podcast. We're your host Ben Young. And Andrew Powell, just a reminder that these podcasts are for medical education purposes only, not to diagnose things on anybody's eyes. Each week, we take a high-yield topic and talk about the why and the how. This week, we're talking about the ice syndromes. Okay, ice, ice, baby. What is ice syndrome? Well, I figured for these syndromic things, 'cause we're gonna have future episodes soon on the other anterior segment discgencies that ice syndrome is part of, like other stuff like Axonfeld-Rieger syndrome and Peter's anomaly. I figured we'll just follow a usual format about these with starting with their epidemiology and going to their pathophys and then their clinical presentations. Yeah, what does ice stand for? Let's just start simple. It's irritable, corneal, endothelial syndrome. And is that correct? I actually took that totally for granted. I did too. No, that's true, that's true. Freaking nailed it. Freaking nailed it. Okay. So yeah, tell me about the epidemiology. How old are people when they get it and is there any gender predilection? Yeah, so the first thing, even though we call this a syndrome and my own bias is to always think of these syndromic conditions as something that is passed down through families with syndromes. And while that's true for some of the other anterior segment dysgenesis, that's not true for the ice syndromes. So before we talk about whether it's more so in women or men, I just want you to know straight away. There's no familial inheritance pattern for the ice syndromes. They're actually sporadic. And then to that end too, it's the second thing I think of is, oh, well, they're all inherited. Therefore, a lot of these are congenital. Ice syndromes actually not congenital. It usually starts, it presents around between the ages of 20 to 50, which again is distinct from some of the other anterior segment dysgenesis like Axonfeld readers. Oh my God. I'm between 20 to 50. Oh my God, Ben. But you have one thing going for you in that you are male, 'cause ice syndromes does present more often in women. Mm-hmm, I see. But you do look a little funny, Ben, and that actually also is in your favor for the ice syndromes, because there are no associations with any systemic findings. Okay, I look at Ben. (laughing) I am not a syndromic face. (laughing) I expected you to jump in a lot sooner, I was like, he's not, do you know what I'm saying? I do look special, but not syndromic. That's the epidemiology, just in a nutshell. Ben, tell us a little bit about why it happens, what's the pathophysiology as best people might understand the ice syndromes. Yeah, so it's basically the corneal endothelium growing where it's not supposed to grow. So it's supposed to be just in the back of the cornea, but there's some speculation. For example, the cornea BCSC says that the endothelial cell may, for some reason, behave more like an epithelial cell. So just like, you know, we'll probably do this another episode, but epithelial downgrowth is a really, really bad thing for the eye because if epithelial cells somehow get into the eye, they'll keep growing and pulling on things and covering things up. Ice syndrome is sort of like that in a sense, except instead of an epithelial cell getting inside the eye and wreaking havoc, it's endothelial cell that's just behaving like an epithelial cell. And there's another thing that's strange about that endothelial behavior in ice syndromes. There's, you know, always collagenous and fibrillar elements in all endothelial endothelial cells. And it's normal for that collagenous and fibrillar stuff to be there. But what's abnormal about them in the ice syndromes is that they have these creepy, crawly little filipodial processes and cytoplasmic actin filaments. So those might be the very reason then why the cells kind of migrate further down into the eye than they ought to. And we'll talk about again where the limits are, that they should be, where they should stop kind of in the angle, but they don't, they just keep going. And it could be these kind of like finger-like contractile elements that are helping to migrate them further down. And also when they contract, they cause PAS, which causes a lot of the intracular pressure problems of the ice syndromes. And we'll talk about that in a second. - Yeah, great. So what does this actually look like? How does this present in a person? - Right. So it's always unilateral. And that's a very key distinguishing feature about how it keeps it distinct in your mind from the other things like axon-filled reekers, which is bilateral. The way I remember that easily is axon-filled reekers has two names in it, two eyes, ice syndrome, ice is nice, small, compact, I-C-E, so one eye. - And then another place that this comes up is a contract that's something called P-P-M-D, which I think we covered in another episode in the Cornell-Destrophies episode. - Yeah, I think you and Amanda talked about it. - That's right, yeah. It was covered, but to remind you, it's basically almost like a bilateral ice, but this is an actual dystrophy. So we review Cornell-Destrophies if you want to hear more about it. - Mm-hmm. So the other thing you may already know about the ice syndromes is that there's three of them. There's actually three clinical variants all having some mixture of IOP problems due to angle abnormalities and some proportion of iris abnormalities and corneal abnormalities, too. But before we talk about those three kind of distinct clinical entities, let's just talk about the areas of abnormalities and then we'll talk about which ones are more predominant in which of those clinical entities. Why don't we start with the corneal endothelium again then just to talk a bit about how it presents clinically. We've already talked about the pathophysiology of why it's abnormal, but what does that present like in a nice patient? - Yeah, I mean, so again, it's an endothelial assault problem. So the endothelium supposedly looks different like a "beaten bronze" appearance because of that extra kind of membrane growing across the endothelium. And one place that this can be tested is on a specular microscopy. Basically, the endothelium, you know, normally it's all these little hexagonal cells that, you know, that line the back of the cornea. Because of this membrane, on spectrum across, it looks pretty different. So remind you normally on specular, the endothelial cells look white and they have basically a kind of a dark border, a dark hexagonal border around them. That's just, you know, the space between the cells. On an isendrome that is reversed. So the outline is white and the actual cells look dark. So if you get a picture respect and there's things just look off for different, then maybe the colors are flipped. That's called light dark reversal. That's almost pathonomotic for isendrome. - Yeah. - Yeah. And because there's an endothelial problem, they can even have microscopic edema, even without high IOP, because there's an endothelial problem. And this is most prominent in the most corneal version of isendrome channlers, but we'll talk about that more in a bit. - Yep. All right. The other things that go wrong in the isendroms are problems of the angle and the iris. And at the angle, you'll get peripheral anterior senike develop, which the characteristic thing for isendrome is that they're very high or tall, which means they go past where they should, they go past Schwalbe's line. And I'm gonna skip ahead a little bit, Ben, do you actually remember what Schwalbe's line is even supposed to be? - I know this. It is where the corneal endothelium ends. So it's a line where the, the stroma joins. It's the line where the corneal endothelium ends. It's like a sharp demarcating line on Gonioscopium. - Right, so it's of all the different Gonioscopic structures. You know, if you even if you're really familiar in experience with doing Gonioscopia as a resident, you know, in the end, it all boils down to do you see scleral spur or not? Or do you see at least tribicular meshwork or not? And a lot of us might forget to look for Schwalbe's line because honestly, it's harder to see anyway and it doesn't really clinically matter all as much. In this, it does because Schwalbe's line is where corneal endothelium is supposed to halt. Like anything posterior to that, there shouldn't be any corneal endothelium anymore. But in the ice syndrome, that corneal endothelium does not respect that border and it just keeps on going down past it. So the endothelium membrane, it's kind of migrates down further to cover over the tribicular meshwork a lot of the time, even down onto the iris surface, the far peripheral iris surface sometimes. And again, that endothelium has these abnormally contractile and filipodial elements to it that when they contract can actually start initiating PAS, the peripheral anterior sineake. And because you basically have this little highway from anterior to Schwalbe's to posterior to Schwalbe's that you shouldn't have, the PAS in ice syndrome is high or tall. It goes up a lot higher onto the corneal endothelium than you usually see for other things. You don't actually have to have the PAS to have high intracular pressure. You can just have the endothelial membrane that covering the TM. And that covering might be enough to inhibit the outflow. If it's still kind of early in the syndrome and before that endothelial overhang has really developed into a PAS, you might have high IOP without obvious PAS, but it's still the same problem. - How about the iris been moving a little down further along that? - So the iris can have lots of atrophy, including things like translimination defects or just even frank holes. Is that clear how this relates exactly to the endothelial membranes, but that's what we can see. - The endothelial membrane, though, can definitely pull the whole pupil into an eccentric position. What is that called again when the pupil is pulled over? - That is coractopia. - That is correct. - Opia. - Thank you for writing in the joke. - This is correct. - I felt pressured to take him where I get on. - I felt pressured to say it. - And you see how stupid it sounds when somebody else writes it. - Hmm, don't compare the quality of your joke ever. Okay, so to go along with that as well, we can get ectropia and UVA, which is where the iris pigment epithelium, which is normally posterior on the iris, gets pulled around so that you can see it anteriorly. So we'll see like kind of the darker stuff on the people where you margin the people being pulled across. There's a bunch of things I can cause this. Basically anything that can kind of pull on the iris such as regressed new vascularization. The iris can cause this, but isis definitely one of them. - Yeah, maybe someday we'll have like a differential episode just for different physical signs and that could be one of them. - That'd be a great one. - Like, yeah, the board review thing we wanna do anyway. - All right, so what are the like eyes for mouths, like an eyes oral board or nose? - So, all right, so we've dragged you through all the three different clinical areas in which eye manifestations of eye syndrome can manifest. So what are the three different clinical entities, the different combinations these can present in, the three main variants are, number one, essential iris atrophy, number two, Chandler syndrome, and number three, Kogan Reese syndrome. Ben, you wanna start us off with a brief walkthrough of essential iris atrophy, like between the iris, the angle and the corneal problems, which is it more of, I guess, the name essential iris atrophy would kind of give it away, right? - Yeah, I think thanks for the softball. Yes, this one is predominantly corneal. I'm not joking, it's an iris atrophy, yeah. - So, all of these can have some manifestations of all the things we just talked about, but this one's mainly iris. So, you know, they can have the corytopia, the fringoles, translimination defects, it can cause the coloration to be lightened so they can have heterochromia, and remember, ice is unilateral, so it's only the one eye is gonna be affected to the other eye over remain normal. - Which is why they end up looking like they have heterochromia. - Right, right. - What about Chandler syndrome, what that? - Chandler syndrome. You cannot believe how much I tried to relate this in a meme's format somehow to friends, but couldn't come up with anything helpful. Chandler syndrome is the most common variant of the ice syndrome, it's like up to 50% of the ice syndromes, and maybe you might figure Chandler see for cornea, it's actually just mostly cornea, with an arguable amount of angle problems, the iris, though, is mostly fine. Think of it primarily as just the corneal problems that the microscopic edema, the beaten bronze appearance, the need to treat with hypertonic saline stuff, maybe not as much pressure or iris problems, and then I'll just go on to wrap it up with Cogan-recentrum. There is one thing we haven't mentioned, and I figured we'd save it for talking about Cogan-recentrum, because that's the only place it gets talked about. You can also get little tan-pedunculated iris nodules on the surface of the iris. Sometimes they're not very frankly-pedunculated, sometimes they're just diffuse-pigmented lesions on the surface of the iris. All of these are thought to be, again, caused by endothelial contraction, endothelium that's made it onto the surface of the iris, contracting it up into a little mound of nodule. I remember this, because this is very typically just seen in Cogan-recentrum. That's the only place it's really mentioned, not ever in Chandler's, not ever in essential iris atrophy on the textbooks, but so I remember thinking of it as Reese's Pieces are on the iris surface, and we do have a substantial international community that's, among our audience, that's just a candy. I don't know how far, what is that? - I think that I would bet that the tentacles of Reese extend across the globe. So if you haven't heard of Reese's Pieces, you can tweet us, and we'd be interested to see kind of what the extent of their marketing arm is. - But I wouldn't bet. - Yeah, I mean, I was a little, I wanted to make a joke about American multinational conglomerates, but I didn't want to give any advertising. - Oh, yeah, no free pub. - No free pub. - Right, right, right, so we have not sold out to big chocolate. - So Arnomonic is generic chocolate peanut butter candy Pieces, or Cogan Reese's Room, which helps you get away with sea for chandlers being sea for cornia, even though Cogan Reese is also sea. - Exactly, no free pub, no free pub here. Arnomonic is generic chocolate peanut butter candy. Pieces. - Oh my gosh. - All right. - How do you treat this? It's the usual stuff with problems with corneal swelling, and the usual problems with corneal swelling and IOP reduction. You just treat it with drops, the IOP lowering drops, the hypertonic saline drops, and surgery if you have to. - Some subtleties of both, well, mainly the glaucoma treatment, though, for the corneal stuff, yeah, you can do penetrating care to plastic, you can do just decimating stripping care to plastic, per the corneal book, those are totally legit. The glaucoma surgical interventions are a little trickier because, number one, you might wonder if anything like laser trebecular plastic is useful. It's not, again, remember that works more in pigmented presentations, and there's not really any pigment to this endothelial overreach of the angle. And you also, the other thing that's mentioned in the books is that you can do a trab, a trebeculectomy, but they do have a tendency to fail earlier than usual because the endothelium just plasteres itself right back over the fistula that you make. That doesn't mean you have to do a tube shunt, though, because you can actually blast that thin endothelium membrane away with a yag laser, then then restore your trab again. So, you know, if they don't have great conjunctiva to do the tube width, then you can't, don't have to completely rely on a trebeculectomy. I figured to wrap up the episode. We'll, again, talk about Axonfeld-Rieger at a later episode, but because there's so much confusion often between these two entities, ice syndromes and the Axonfeld-Rieger stuff, I figured we could pepper in these quick, factoid distinctions between these in both episodes. What do you think then? - Yeah, hit it. - All right, so maybe four things. Number one, ice is sporadic, whereas Axonfeld-Rieger is autosomal dominant and real quick. We, again, will repeat these in both episodes. Axonfeld-Rieger, autosomal dominant with mutations in the Pidex-2 and Fox-C1 genes. Again, we'll talk about that stuff later. You know, new number two, Ben, I've been talking for a while, sorry. - No, fine, no, fine, fine, I'll do number two. In ice, the corn on the thelium goes past, Schwabby's line, so it continues beyond it. In Axonfeld-Rieger's, the Schwabby's is actually interiorly displaced. So instead of the endothelium moving posteriorly, in Axonfeld-Rieger's, the line stops more anteriorly, which is called a posterior embryo toxin, a little confusingly. - So I think of this, sorry, I should have mentioned it earlier. The cornilindothelium is kind of moving from anterior to posterior in ice syndrome, almost like an icicle hanging down from the ceiling. Whereas in Axonfeld-Rieger's, it's common like the Schwabby's line is way up higher, further anterior than it should be. So it's like coming from the ground up instead. Number three, this is more easy. Ice is unilateral, like we said, and Axonfeld-Rieger is bilateral. - Yeah, just to keep you empty. - Yep, yep, yep, yep. - And number four, very helpful, Axonfeld-Rieger does have other systemic problems, whereas ice syndrome is just the eye, the one eye. - The one eye? - Yeah. - Cool. I have a little bitty on differential for coagin' Reese nodules. I don't know, I can just say it, and then we just keep it or not. So there's a bit of a differential though, for little bumps on the iris, and there's actually not many things that cause that. So here's a little bit of a difference, So what I've got, one is iris mammalations. So these are like little bumps. They're usually a little bit finer looking than Cogan-reced nodules. But critically, they're the same color as the underlying iris. Unlike Cogan-reced, which tend to be more tan. And iris mammalations are seen in ocular germamellinocytosis with nevis of odus. So that's a different thing. So you should look for nevis of odus to help differentiate unilateral nodules in the iris. The other thing are lish nodules, which you'll remember are the little nodules that can show up in neurofibromatosis type 1. Usually between starting between the ages of 5 to 10. But the one key difference is this is a systemic problem, so they should be bilateral. And they occur in children younger than people who get ice, and it should be bilateral. The last thing are brush field spots, which are just little-- they're typically hypopigmented or blue spots on the iris. But in that's associated either with just being normal, like, you know, it doesn't have to be with anything or with down syndrome. They tend to have more brush field spots. There's something-- there's a long name for what we call a pseudo-brush field spot, which is just in people with really blue irises. But that shouldn't be tested on. So in summary, the differential for iris nodules are Cogan-reced nodules, which she just talked about are, you can remember, as generic chocolate peanut butter pieces. There are iris mamellations with ocular dermal-- ocular dermal melanocytosis, which are not tan in color. They're the same color as the underlying iris. And list nodules, which should be bilateral, and appear younger. Sounds good. OK. Thanks, Andrew, for that great review of ice syndromes. If you liked what you heard, you can follow us on Twitter at eyes4earys with number 4. And we also have our website, www.eyes4earys.com. It's been a while since I updated it. Sorry, Ben, it's updated now. Oh, yeah, no worries. And if you'd like sport podcasts, really helps us leave a rating review on Twitter as we approach OCAP season coming up. And next week, we'll hit you back with Accentfold Reeger Syndrome. And as associates, bye. OK, dope. That's good.