 I'm going to get started. And I want to leave enough time to go over the quiz at the end. But it was just the quiz is just based on the reading. And I'm not going to cover the reading. So just to be able to help you. All right, so I think most of you know me. So I'm Emmy Hartnett. And I'm going to talk on pediatric retina. A lot of these slides, it's hard for me because I know the residents and the students. And then the number of people actually show up, varies, and I don't know who's coming and who's not. So some of this you may have had before. I don't know in pediatric retina. Pediatric ophthalmology, I don't know if they talk on RLP. So some of it I'll flop over, go over quickly. And then I want to be able to get to the other retina cases. Because some of them are very important for you to know as you're taking care of the patients that you might be referred by a pediatric ophthalmology. So we're going to start with retinopathy prematurity, which is a leading cause of childhood blindness. And on your right, there is the worst stage called stage 5 ROP. It looks like there's a cataract. There's no cataract. There's a quiz right there. It's actually a scar that's behind a crystal clear lens. And behind that scar is a total retinal attachment. So it's, even with successful surgery, the vision is poor. But we still try, because a little bit of vision in the child can, they can use it very effectively. And we also try, because there's a lot of research to restore or improve visual ability. So what we know now may be totally different in coming years. So we're running into all the chance we can. But we think of vision loss at ROP from abnormal angiogenesis or blood vessel growth. And that's what causes a stage 5 ROP, where you get the tractional detachment, that scarring that pulls the retinal off. And there have been several multi-center clinical trials that have shown we can reduce the risk of vision loss from stage 5 ROP by either cryotherapy, 50% risk. We really don't use that anymore. We don't use cryotherapy. Or even if we go in earlier and use a laser at a less severe stage, type 1 ROP, we can reduce the risk from 50% to about 9%. And it was significant. So that's what we usually do. And we'll go over those later. But there are also other causes of vision loss in ROP. And it's not always related to this aberrant angiogenesis. There can be abnormal profusion on neurons, these neurovascular effects, where either you don't get enough oxygen nutrition to neurons, or maybe other types of signaling mechanisms. And how we know this is that 25% of the treated infants who did well in the early treatment ROP study, these were successfully treated infants, still only had 20, 60 vision or worse. So there's something else going on. And potentially it could be from the laser too. Is this threshold ROP associated like correlated with the stage of ROP? We're going to go over that a little bit later. But this was actually for type 1 ROP, the 20, 60 vision. And then there also can be vision loss from extreme prematurity. So extremely low gestational age infants who never developed ROP at all. So these would be 23-weekers. They have reduced vision and ERG responses even at age 6. So there clearly are other things going on in premature birth and potentially in ROP or the stresses surrounding ROP. And when you think about it, we only think about the retina circulation when we talk about ROP. We think of the fact that the retinal vessels are fully developed in the human at term birth. So when a baby is born premature, they don't have fully developed retinal vessels. And then they have all these stresses on top of that that lead to retinal prematurity. So we only think of the retinal vessels because we can see them. But there is a lot going on with the regression of the hyeloid and also the coroid, which we really don't see in the premature infant, and the effects of the oxygen and metabolic demands on the neural retina. So the neural retina needs the oxygen. The photoreceptors use a lot of oxygen, right? And they may continue in their development. But if they have insufficient or damaged vasculature in the coroid or the retinal circulation, they may not develop appropriately. They may not have the right signaling molecules. So there's a lot to learn yet. So just to remember that. Did I get your question completely or do you need to see what threshold ROP is? It's a level of severity of the blood vessels and of something called plus disease. And I'll show you some of that. The other thing that makes it difficult when we look at, we tend to look in the literature when we're looking at different ways of treatment because now there's a lot of interest in anti-angiogenic agents, like anti-veget agents. And ROP, and so we look in the literature and studies mostly case series are presented but ROP is very different in the United States, other areas of the country. There are areas like Mexico and also India where they still have oxygen induced retinopathy. One of the things that we learned in the United States like in the 1950s was that high oxygen at birth, unregulated oxygen, 100% oxygen, which was what the incubators were able to provide that that caused ROP, Retro-Lental Vibroplasia, it was then called. And so there were a lot of efforts to improve the regulation of oxygen, to be able to monitor it. We have resources, like we have enough nurses, respiratory therapists to make sure that the ventilators, ventilator support is working. And a lot of these countries just don't have it. Even if they're able to blend the oxygen or monitor the oxygen, they may only have nurses that are doing everything. So there is still oxygen induced retinopathy. So where the blood vessels develop, they're bigger babies, they're older babies, their vessels, their retinal vessels develop, but they actually get oxygen damaged to the retinal vessels. And they have broad areas of avascular. That's different than the ROP we see in the United States. There can be differences in maternal fetal risk as well, like preeclampsia. Preeclampsia is a very interesting condition that affects obviously the mother who's pregnant. And the interesting thing about preeclampsia, Julia Shulman, who was a fellow with us and is now practicing in New York, she reviewed data from a large group of patients out of Utah. And we looked at the effects. The question was, does preeclampsia increase the risk of ROP? The problem is that preeclampsia is so linked to premature birth and is a risk for premature birth. And premature birth is so linked to ROP that you get into this collider bias. So when we looked at mothers with preeclampsia, mothers without kids with ROP, kids without preeclampsia actually was a risk factor for ROP. But when we only restricted our subgroup to infants with ROP and looked at whether or not mothers had preeclampsia or not, it looked protective. So we are interpreting that that either preeclampsia may provide some kind of, we have some experimental evidence that it may provide a preconditioning effect that makes the infant less susceptible to ROP. But it also could be that there are more severe risks associated from premature birth on ROP than preeclampsia. So it's a complicated issue. But resources, as I mentioned, also other things that cause premature birth, poor nutrition infection, maternal infection, and then also diagnostic ability. So there have been several studies out that looked at how physicians would diagnose severe ROP or threshold ROP or type 1 ROP. And they didn't have agreement. So if you're saying that you're waiting till a patient has an infant has more severe ROP like threshold disease, which is more severe, and you're enrolling them in a trial, the outcome might be much worse than if you enroll a type 1 ROP. So there are a lot of things that make it worse. So what we do know is that ROP is associated with high oxygen at birth when kids in the US were first, when it was first recognized that there was this thing called retro-lental fibroplasia. They did a bunch of different studies. And they exposed animals, healthy animals, full term, not premature. And they exposed them to conditions that were present in those incubators at the time. And so they didn't know for the temperature, they didn't know what it was. And so one of the things that came up was high constant oxygen caused this damage to the blood vessel followed by blood vessel growth into the vitreous. Clinical trials then were found. Arnold Patz was one who really showed that high oxygen increased ROP. And then reduced oxygen levels in the US virtually caused ROP to disappear for a while. But as more extremely premature infants, either low gestational age or birth weight, were able to be survived, we start to see it in older infants. So we recognize there are other risks besides high oxygen at birth. And the risks include fluctuations in oxygen. And so people have studied oxygen. They looked at low oxygen. They looked at supplemental oxygen. And the studies have shown that it may depend on when during the prenatal course you get the high oxygen, that it may actually reduce ROP. Low oxygen at birth reduce ROP, but it increased mortality in several big clinical trials, the support study, the BOOST study. So these were international multi-center clinical trials. So we know what we're starting to think is maybe low oxygen at birth. And then at some point when you start to see the vascular vascularly active form, so tortuosity and dilation of retinal vessels, blood vessels growing into the vitreous. That's what makes up type one, our threshold ROP, that that may be the time to increase the oxygen levels. Oxidative stress has often been touted for ROP. I believe it is a risk factor, but it's more complex than being able to give, like, vitamin E to infants. Those studies have not been shown to reduce ROP safely. And so there's no really strong evidence of the benefit of antioxidants in preventing ROP so far. What about nutrition and body weight effects? So there was a lot of experimental evidence that showed that poor growth after birth was associated with less normal retinal vascularization and more severe ROP. And this was also associated with low insulin like growth factor one. So clinical trial actually infused insulin like growth factor one into babies that they figured out it was about the same level as what it would be if they were in utero. And they found no effect. But they also had a lot of trouble with the study. They didn't quite get the levels and the babies to be the levels that they wanted. It was right around the time when the oxygen studies came out, so neonatologists were worried about mortality. So they increased the oxygen levels. So we still don't know about that. And then genetics. And so this is where there's no one gene that's associated with ROP. But when you look at the studies throughout the world, they're mixing apples and oranges. They have extreme, when we did extremely low birth weight infants, those born under 1,000 grams, we found that variance in brain derived neurotrophic factor were associated with severe ROP. Whereas if you look at other studies, they include infants that are not quite as premature. And so they found other aspects. So there's been no generalizable replication of findings. So just to go over it, high oxygen birth is definitely a risk factor. Other oxygen stresses may be associated with ROP, like fluctuation in oxygen, oxidative stress, nutritional effects, genetics. So when we, so some of this, I'm assuming you read the assignment you had for this talk. So that's part why I'm not going over the really basic stuff about how the retina vessels grow and all that. But one of the things that can be, I think, very confusing is the idea of the phases of ROP or OIR, oxygen-induced retinopathy. And those are usually based on experimental models. That's phase one used to be basal obliteration. Phase two used to be basal proliferation. That compared to the stages. So the phases were developed in the 1940s or 50s by Ashton. The stages didn't happen until the 1990s. But we can align them. And the phase one probably is a little bit different, or is different now, because we no longer have big babies who have high oxygen that causes damage. In the United States, we have babies that may get some oxygen damage. But they also have a delay in the vascularization out toward the Earth's Serato. So there are two things that go on, and that's increased with fluctuations in oxygen. So the phase one, we see the compromised physiologic vascularity, or basal obliteration, and delayed physiologic retinal vascular development. And phase two is the basal proliferation, or the growth of blood vessels in the eye. And in the human, you might say there's a phase three, because none of the animal models develop stage five ROP, or retinal attachment well. So these are, this would be the stage that occurs with stages four and five, OK? So that's like a brief. This is kind of another way to look at it. This is ROP, so in the human, you see the optic nerve down at the left, the retinal blood vessels grow, and there's a very faint line. I don't know if there's a pointer here, but I think you can see that. I don't know if it's as well. If you want to use your own. Yeah, there is one in there. Also. This looks like a mystery. Yeah. I don't think that's going to work. Yeah, because I want to make sure. And you can use that. Sure. It's all over there. Joe, please stop me if you have a question. Or if it doesn't make sense. Just let me know. Because there we go. OK, so here's the line, OK? And then stage two is a ridge that has a three-dimensional kind of volume. And this may both be in phase one. And you don't have to worry about phase one and two. It's just when you read it and people confuse it. And I'm just trying to make sense out of it. And then stage three is when you have blood vessels grow into the vitreous. It's phase two. And then this is stage four ROP. So you can see all this is retinal detachment and scar tissue. And it's blooded. If we have time, I'll show you how we treat this with a lens very protracted. I have a brief video. This would be considered phase three. So how do we classify? So maybe I should have started this earlier. But we talk about where normal vessels grow. So if you've got a really extremely premature infant, the blood vessels, like 22 weeks, the blood vessels are only in the posterior pole. 22 weeks is vasculogenesis. Those are where you have angioblasser, these endothelial precursor cells that actually migrate from the outer neuroplastic level layers, so embryology. And they grow up from the outer retina to the inner retina. And they do that because they're migrating toward a chemotactic gradient of stromal derived factor, so not VEGF, so other factors. That's probably what we get in zone one. And then in zone two, we have a, so zone one is twice the distance to the macular circle that radius is equal to twice the distance to the phobia. Now that's hard, because premature baby doesn't have a phobia, so you're estimating. So how do we figure out zone one? We take a 28-diapter lens, and you're looking with an indirect ophthalmoscope, and you're holding the lens so that the optic nerve is right in the center, and then you see what vessels fall into that image. And if you have even some vessels that don't make it all the way to the edge of that field of view, that's considered zone one. So you can see that they're all different kinds of zone on eyes. You could have the whole 12 o'clock hours not making it, and that would be very bad zone one, but you might only have one, and that may not be so bad. And then zone two probably occurs through angiogenesis, where the blood vessels, so you have existing blood vessels where you get budding angiogenesis, so the endothelial cells proliferate and migrate. And they usually go out toward a gradient of vascular endothelial growth factor, which is produced by astrocytes. So that's or angioblasts. And I'm sorry it's so confusing, but it's partly because of the difficulty in studying human eyes. So we use rodent models, and they don't necessarily align as a cell type or even sometimes the growth factors. So zone two is a circle centered on the optic nerve. The radius is the distance from the optic nerve to the nasal or a serata. And the reason this isn't drawn all the way is that you're given a disc diameter. Like when you're trying to figure out is this zone three, you look in nasally. And if the vessels, there's no ROP, and the vessels fall within a disc diameter of the or serata from the two nasal clock hours. That's considered zone three. So you can see that zone, or zone, yeah, that's considered zone three. So you can see how you could have a zone three eye that where the zone two over here, temporally, might be pretty posterior. So there are differences. And then zone three is the temporal crescent. So in other words, as long as the vessels in reach the two clock hours nasally without ROP, any avascular retina is just considered zone three. Does that make sense? And then when we look at the vascular activity, so this is what makes up plus disease, or this is what makes up threshold or type one ROP. And so we have vascular tortuosity and dilation, and we talk about quadrants of involvement. And that's an example of plus disease. So type one ROP, this is what was the 15% risk in the early treatment ROP study, was zone one, any stage of ROP with plus disease. Zone one, stage three ROP without plus disease, or zone two, stage two or three with plus disease. And plus disease was defined in two quadrants. And I will say like cryo-ROP, I can tell you what it was, the threshold disease. But we don't, it falls into type one severe. So threshold disease was, it was zone one or two, stage three, and it could be their five continuous clock hours or eight total clock hours of stage three. And what we found was cryotherapy reduced the risk of retinal bad outcome like stage five ROP. The problem was in zone one eyes. The zone one eyes, there was an 87% risk of developing stage five ROP. And so we knew that we needed to relook at what stage three, you know, and what those zone one eyes are. And we also knew that we needed to go in a little bit earlier. So that's why we don't wait till threshold disease if at all possible. The, because of the differences in ROP throughout the world, you screened for ROP based on the risk profile of the infant. So in the U.S., it's usually less than 1500 grams birth weight or less than 30 weeks gestational age. But it also depends on the NICU. And then at 31 weeks post gestational age or four to six chronologic age, whichever is older. And this is being a little bit adapted. So let me define post gestational age. That's the gestational age plus the chronologic age in weeks. So if you have a 23 or let's say something easier, 24 week gestational age baby who's 16 weeks chronologic age, right? That baby would be 40 weeks. That baby would be considered sort of term post gestational age. And the reason it becomes important is that some of the risks that we are some of the risk of type one ROP usually peaks at around 35 weeks post gestational age, regardless of the gestational age or birth weight of the infant, which is interesting. And that's where I think we're seeing the importance of the development. Because the photoreceptors and other neurons within the retina may continue to develop on their developmental, their clock that isn't affected by premature birth, whereas the vessels are. So think about that when you think about the mismatch between neurons and vessels. So how do we screen? You can use indirect ophthalmoscopy where you can actually define this is severe ROP, top one ROP that needs treatment or should be considered for treatment. You can also make the call is the retinal vascularization to the aurisurata. So we can, you know, basically if it's in zone three without ROP and they've never had a vast and, I mean that's a big bugaboo but I mean that makes us have to examine them till they're fully vascularized. You can discontinue retinal vessels or you can look in and say, well we need to examine again in one to two weeks or half a week depending on the severity of the ROP. But we can also use imaging. And this is different. The imaging is very helpful but it doesn't let us know whether or not a baby needs treatment. It lets us know whether or not a baby needs an examination to be considered for treatment. And that's called referral warranted ROP. So it's a console for indirect ophthalmoscopy or examination. And that can be stage three ROP shown up here. It's zone one or plus disease. So any of those can be considered referral warranted ROP. So these are the treatment warranted ROP. So as I mentioned, the type one ROP tends to be at 35 to 37 weeks post menstrual or post gestational age. The risk of blindness is 15%. It was reduced to 9%. And it includes threshold ROP where there was a 50% risk of blindness reduced by 50%. When we looked at whether they were in zone one or two. And this is what, we already went over this. This is what type one ROP is. And the important thing is plus disease in two quadrants. Cryo-Rop was plus disease in four. So here are some examples of type one ROP. We think of this peripheral severe ROP where you have dilation and tortuosity and you have neovascularization. This is something called aggressive posterior ROP. And this is different. This occurs usually in babies that are born 30 or not born, but they're often very young post gestational age, 32 to 33 weeks. They have severe plus and flat neovascularization in zone one or two. So you don't see the typical stage one, stage two progression. You just see this neovascularization. And we call it flat neovascularization because it doesn't, it's just like you just see the fuzzy kind of appearance of the neovascularization at the edge. Basically, if you see a really posterior vascularized retina and there's plus disease, that's a concern. I also wanna mention, this is considered like a blonde fundus. We're able to see the deeper coroid vessels. When you're looking in ROP, you have to start at the optic nerve and follow the vessels out to the periphery because you can be fooled. You see those vessels in the periphery and they're actually coroidal vessels but they're not the same as retinal vessels. So it can be an extremely immature eye with poor vascularization of the retina. And it may, you know, don't be fooled by the coroid. So here's treatment. So treatment can be laser to the peripheral vascular retina. We tend to put the laser spots not too white and they tend to be about a half a spot to a spot apart. This is an example of reactivation of stage three after laser and what happens is in aggressive poster ROP, we tend to treat up to that flat neovascularization because we don't know if that's real vessel or physiologic vessels or abnormal vessels but also because there's an increased risk of bleeding if you treat that. And then after the regression occurs, you're left with a new area, what we call skip area and that needs to be retreated. So aggressive poster ROP almost always requires additional laser treatment maybe two or three weeks later. But that's in aggressive poster ROP and zone one disease, we're finding that treatment with anti-vegaf may be a better way to go, at least at the present time. However, there are risks and we don't know the right dose or the right compound. So I'm kind of, I'm gonna go over this a little bit. So why even think about VEGF in ROP? Well, first of all, VEGF is really important in normal vascular development. So that's worrisome, right? We don't want to inhibit it. But it becomes increased in diseases like that are associated with blood vessel growth into the vitreous. So diabetic retinopathy, neovascular AMD, renal vein inclusion, it's increased in hypoxia and that's because hypoxia inducible factors which are the transcription factors that lead to transcription of VEGF are stabilized in hypoxia and they're degraded in normal oxygen levels. And ROP is affected by low and high oxygen and so it seemed kind of logical that VEGF would be involved in ROP. But as I said, it's, and it is important in pathologic and abnormal vascularization ROP but it's also important for normal retinopascular development. And our lab looked at VEGF and what we interestingly found was that, and PE-DEF didn't really play a role here. We were looking at that as a angiogenic inhibitor. But we found that experimentally, VEGF is increased early and if you have increased signaling through the receptor too, that that causes the endothelial cells to have these abnormal cleavage planes and their mitosis are abnormal and they grow on top of each other. When you regulate VEGF, you can actually extend normal vascular development. So this was counterintuitive because at a certain level you could actually inhibit the abnormal blood vessels and extend the normal vessels. But when we did more, and this was also found in clinical trials, the first clinical trial was called the beat-robs study where they used 0.625 milligrams of Bethesda and Ababaston in a quarter of a microgram. I mean, you know, think about the areas of error, right? I mean, these are being diluted. There are adult doses. We're using different needles. You're trying to do 0.025 mLs and inject into the vitreous. And they found that the Bethesda enzyme reduced recurrence of ROP at 54 weeks post-gestational age compared to laser. But the other criticism about the study is that the laser, that's a huge amount. I mean, usually laser works at 91% of patients. So there's been a lot of concern about that. And it permitted normal vascularization, reduced severe myopia, so nearsightedness, which also occurs in these babies, and reduced recurrence of their ROP. But the Bethesda system gets into the bloodstream and it reduces systemic VEGF for over two months. And VEGF is also important for the kidneys, the liver, the brain. So there are concerns about the safety. And then what about in the retina? So if you inhibit the way that Bethesda's MAB works, is that it regulates, it inhibits the binding of VEGF to receptors one and two. And receptor two is the antigenic receptor. That's what we want. But VEGF receptors are also on retinal neurons and glia, and so it can have abnormal effects by hurting the retina and neurons. And we found that in our experimental study. So there's an ongoing clinical trial now called ROP-1, and we've used de-escalating doses of Bethesda's MAB. And so far, we have gone down to one-twentieth, the dose of beet rot. And that is effective, but we still have Bethesda's MAB in the bloodstream, and it still reduces the systemic VEGF. So what about Ranibis MAB or Lucentus? So it's a different agent. It's a fab fragment of the humanized anti-vegia. It has less systemic absorption, and it's a shorter half-life. But CERES report recurrences of ROP-1, it's been used. So how do we compare these two? So there was a study called CAROB, which only has 19 infants, and they used two doses of Ranibis MAB. So ROP-1 was for type one ROP. But CAROB was for this more severe zone one stage three, zone one NERP with plus disease, or poster zone two stage three with plus disease and aggressive poster ROP. So it had a more severe phenotype to be able to be enrolled, and the successful outcomes were different. So this was looking at reduced type one ROP at three to five days. This allowed two retreatments for up to 28 days, and that an unsuccessful outcome was, I mean two retreatments after 28 days, and an unsuccessful outcome was needing treatment before that. So it's really hard to compare these studies. This is, we've gone over, we've gone over that, but look at this too, the number. So in ROP-1, we had many more zone one, ROP or CAROB, very few zone one, and zone one tends to be more severe. The ROP-1 study had so 23% that required either had early failure or labor currents, an 18% avascular retina persistent, and CAROB had avascular retina in 45%. And then in the higher dose had 84% avascular retina. So what about this avascular retina I'm talking about? That can be like a time bomb, and you can get recurrent ROP even up to a year after a single dose of anti-vegetable net high. So most of us, or many of us are considering lasering those eyes. So that does become important. Oh, right here, what I wanna say too, is that people keep talking about CAROB, or Ranibizumab as well, it doesn't reduce the systemic VEGF for two months, but it does for two weeks. And if you require additional treatments, then you're still affecting systemic VEGF. So we don't know what that means yet. The rainbow study, this was similar to the CAROB study. It used two doses and compared to lasers. So here we actually have a comparison. And it was zone one plus zone two stage three plus, or APROP. And the primary outcomes showed that there was success at, I mean, success was in about 80% patients, and there was 62% with laser, but there was recurrent ROP founded 31% with the anti-vegetable. So I'm gonna go through this quickly because I wanna make sure we have time, so I wanna leave five minutes for the quiz. This just says that we found that even with the ideal dose, worked out a way to have an ideal anti-vegetable dose by knocking down VEGF in the other cells so that the amount that was released into the vitreous was the same as what it would be in a full-term animal that wasn't in oxygen fluctuations. And even with that, we had sending out the outer nuclear layer. So a number of questions persistently vascular retina, we went over it's different if the baby never had anti-vegetable, if they're into zone three, we monitor it, we may not treat it. If the baby had anti-vegetable, we either have to make a decision to continue to monitor that baby, or treat with laser. And as they get bigger, they're harder to examine. Okay, let me see here. So these are the guidelines. Now, lasers still considered the standard for many type one ROP, but we based on the beat-rope and other studies for zone one stage three plus for hemorrhage, the recommendations are to offer bevacizumab, and we can actually, it's been published at a lower dose, so I often use 0.25 milligram now, or we could use renovizumab based on the rainbow study, which has not been published, but the clinical trial is out on clinicaltrial.gov. Okay. So serous retinal attachment can also occur, it tends to, and that can be after laser or cryotherapy, usually not after anti-vegetable. It can resolve spontaneously, and sometimes we treat it with subtenants or systemic steroids. Progressive stage four ROP tends to occur after treatment, where we start, instead of having a vascularized component, we actually get a scar tissue that forms at the junction of the vascular and avascular retina, and it can lead to a retinal attachment. This shows on cross-section and a diagram, the retina being pulled up, and this is what it might look like on a reticam image. And for that we do, we have to think about the wrists, but we do a lens sparing detractomy or sclerobuccal. Remember that there may be anesthesia wrists, that's sort of an area that's still be, we're not sure about, we're getting, you need to talk to anesthesiologist, but remember the difference in the infant versus the adult. So in the adult we have four to six millimeters to enter the retina without tearing the retina. That's a safe zone, right? Right through the pars plana. The infant does not have a pars plana. They haven't developed ones. They have a pars placata, and basically you have 0.87 millimeters and a full term infant to be able to enter the vitreous cavity without hitting the retina. And you also wanna not hit the lens. So we don't just operate on any baby, you know, we consider this. And what are goals with the lens sparing detractomy? Our goals are to try to release this area, sort of the connections between the retina and the enter part of the eye, and also the circumferential retina and the enter posterior. We tend to start peripherally like this, if we can, because otherwise, if you release this part of the traction, the retina gets pulled out and it's too hard to get to. So if you can do that, we do. We're not always able to, I don't know if we have time. Oops. What happened there? That was interesting. I don't know what I did. So I can show you a little bit of a lens sparing detractomy. Let's see. We put in about 0.5 millimeters posterior to the limbis. And this just shows we're not, all this stuff here, which is vitreous in retina, we can't tell. You know, we removed, and this has been sped up too. We removed the connections between the ridge and the enter part of the aurasurata and also the enter posterior ridge connections. You can actually see in some of these where the retina gets, starts to move, but we're not, I'm not even here. You can see how you pull on the vitreous, but I'm not removing that because I don't know if that's retina incorporated and you don't want to get a break in the retina because they don't work and you have an inoperable retinal attachment. It's very different than adult surgery. And just to, oops, sorry about that. So this is how it started out. And then this is how it looks. I mean, we don't have much macula, but it's all subtle back. So even though I did not release any of this, I mean, I didn't go after it. It just settles back over time. The RPE pumps out that sub-retinal fluid and allows the retina to reattach. So all infants are followed for visual rehabilitation and maximize visual development. And there's a high risk of myopia and strabismus, later risk of retinal attachment in high school. So I asked these parents to get them involved in early intervention. I've worked very closely with pediatric ophthalmology. That is absolutely critical to improve the visual because that's our goal. Our goal is to have these kids have vision. This is just going over some of our, fine. Okay, so that's ROP. Now I have four minutes. And I do have some, what I can do, I'm gonna give another talk on AMD and I can do some of the different cases that I have for different pediatric retina conditions, maybe then, tell me what you'd like. Cause I wanna have time to go over the quiz. Just get like a handout for like explanations for the quiz or just what the answers are about the cases in person. Oh, is that help? Okay, so this is a four year, is that okay with everyone? Do we have a consultant? Four year old boy with reduced vision in the right eye. You can see the visual cutie, the hyperopic. This is how the, the fluorescent angiogram looks. So you see there's, how would you describe that, SHROB? So there's blockage in the inferior macular along the inferior arcade and there's an area that looks like, I mean, over time it may have been leaking, like, you know, scarization. Great, and there's, it might be hard to tell, but there's actually a vascular retina here, so it looks like there's non-perfused retina. This is the OCT of the macula. So this is subphobia, what would you describe that? So there's a lot of edema there, thickening of the macula, like cystic edema. Good. And then this is the full field ERG. Does anyone want to say what they see here? It sort of sounds depressed. Right, electronegative. So in another way to think about, I think about it as the B to A wave is reduced so that the B wave is less, we still have an A wave. So there are a few things that cause that in kids. Can you think of some of the things? Congenital stationary night blindness, right? You can get it in severe diabetes, that's probably more adult, right? Anything that infects the inner retina? Or how about excellent retina scises? So that's a common ERG that's, in fact, many times we use an ERG to be able to make this diagnosis, but it's not like that all the time. So I think my, that pre-slides at 60%, so in a study done, now where we have genetic testing that was only 60%. So the excellent retina scises is caused by a mutation in the RS1 gene, which encodes retina scises. And what we see are non-leaking foveal cysts. It's in a male, almost always, although it has been reported in females. It's associated with vitreous bails, vitreous hemorrhage, peripheral scises, and it's passed on the maternal side. So if you have some of the Turner's syndrome, for example, they might have excellent scises, but that's unusual. It's not very common. We really don't know what retina scisen does. It can be produced by cells and important adhesion. Some people feel maybe it's important in the sodium, potassium, and ATPS pump. There is a mouse that develops retinal degeneration as well. It's been clinically to have four types. And this child had laser within the schisisk because of the vascular retina. I thought, oh, what a neat thing that's gonna get rid of the neovascularization. And it did to a certain degree, but some of it's still persistent. So that neovascularization, I think, is probably also from just pulling on the retina and chronic traction. So there may be other reasons why that's present. All right, any question? That was quick, but this gives you, this is a lot quicker than earlier. Okay, so five-year-old boy who has poor vision in the left eye, no family history, no history of trauma, right eye is totally normal. Okay, so what do you see here, Rachel? So at the macula there looks like there's, it looks flat, it kind of looks like scar tissue. Then there's some clumps. Okay. Let's see the periphery too. Yeah, good, we will do that. So just describe what you see by color. It looks yellowish like a trophic. Good, and you can see the vessels kind of go over it, right? So it's in the rut and that's not on top of the rut. It's a little hard to see that. So as you said, look in the periphery. So what are you looking for there? Maybe massive agitation, right? And centrally and telangentasia. Okay, that's the key. Anyone have any clues what this is? Perfect, okay. So if we do an angiogram, the thing that we used to treat, before angiograms, we would treat codes disease based on seeing where the telangentadic vessels are. What we've learned is that the retina actually can have pretty extensive non-perfused retina. And if we treat that, it improves the outcome of the codes disease. So what about the prognosis of visual acuity here when we look at the OCT? I'm gonna tell you, unless somebody has a nose. So the agedates are under the retina. So they're between the photoreceptors and the RPE. And that's usually associated with poor visual outcome. And this just tells us it's in young males 80% of the time. But that means girls can get it 20% of the time. So don't forget when you get a girl that has something like that, that it can be codes disease, it can. It has this light bulb type of aneurysms, telangentasia in the periphery can cause macular agedates. And it can be bilateral, but that's, so it can actually be bilateral as far as non-perfused retina is 60% of the time. And it can even have some vascular abnormalities. But when you have truly bilateral codes disease with agedates and severe, you should think of conditions like facial scapular, humor muscular dystrophy. And usually there might be other conditions associated systemically that you get that. Wide-angle fluorescein, anti-vegetous controversial, neighbor-dose vision for coriorentinal nestemoses. But the primary treatment is laser. And if you have severe codes disease where there's retinal detachment and that can occur, then again, you don't wanna put a hole in the retina and treat it as you would, like an adult retinal detachment, you have to drain externally. Do a detractive and a laser and sometimes silicone oil. So here are the stages of codes disease that have been determined where we get telangentasia only telangentasia ex-phovial or extra-phovial. Retinal detachment can be subtotal or total. That's stage three. If you have a total RD and glaucoma, that's stage four. And advanced end-stage disease is often painful and they require a nucleation. So even with stage three, which would be here, and I'll show you an example of that. Or maybe I won't show you an example of that. But that may not be associated with good vision, but it's worth treating it to preserve the eye and to save some visual acuity and potential in the future. So I'm gonna, this is the patient after. He developed 2060 vision, so not terribly bad. He had some embliopia that had to be treated. He's not really good now about wearing his glasses, so his vision's dropped. So the embliopia treatment is essential. Yes? Which areas are you aiming to laser in these cases? So, good question. Okay, so what you do is you treat the telangiectatic areas here with, so what I use is very low power, continuous. So I put it on continuous settings and I paint the vessels and then I do scatter treatment in the abascular retina. Okay, this is a 10-year-old with reduced vision, best corrected visual acuity. Lured vision thought due to Coates disease in the macula. So here's his OCT and this is through the superior macular region. But look at his fovea, beautiful, right? So his prognosis for vision should be excellent. 13 months after laser, he looks good, but he still has 2070 vision. So Sophia, what do you think? What would you, I'll just show you. That's his refraction. So he was treated for embliopia and his vision improved to 2025. So remember to treat the embliopia, always work with your pediatric ophthalmologist, it's critical. So Coates wide-angle fluorescing valuable to assure full treatment, OCT and discerning cause of vision, whether it's from exudates or whether there might be something like embliopia and value of anti-veget is not clear. So we're gonna be working on that. So three month old female referred for persistent fetal vasculature. This was the other eye. So not, that's okay, I'm so sorry, I need to go over. These are great, I wish I could stay. Thanks. So late frames of the angiogram. So no, this is a girl. We think about a number of things, right? When we have a vascular retina and the periphery, what do we think of? So. More like you can go ROP again. ROP, right, not premature though, but that's a great thought. What about familial, I should say vitro retinopathy? Incontinentia pigmenti, okay? So incontinentia pigmenti occurs in girls, okay? But it's almost 100% of the time associated with rash. So no rashes, no family history. You might not get family history of it because it could be a sporadic mutation. No hair or tooth or, this is all with incontinentia pigmenti. Anyway, so this was fever. And she had laser treatment and periphery. She had an LRP5 dominant mutation. This has only been reported once. Mother has also the same mutation and she is entirely normal. This condition is so, it's amazing. So it can be very variable and it can be very variable between the eyes, right? So there can be a peripheral avascular retina and a child or infant who is not born premature. It can be exudative or fibro vascular. Treatment can be laser to the peripheral vascular retina and they're tracked to me for retinal detachment. And anti-vegeta is still exploratory. So we don't, even though the, and I'm gonna give you all the actually genes here, there can be genes in the wind signaling pathway, which are NDP, Frizzle 4, LRP5 and T-Span 12. This is not ZNF408 and there's also other CTNN1, which is I think through beta-catenin. But even though we have all these genes, 50% of the time we don't find a genetic variant. So, and KIPF11 is also another mutation. LRP5 mutations can be associated with osteoporosis and osteopenia. And for those children, you need to consult with endocrinology because they can have bone density issues. And my patient did and she actually had a break in her femur. So, this you can see anywhere. It can be variable. This patient also had fever from Frizzle 4 and she developed a tractional macular detachment from an epiretinal membrane. Her sister had a regmetogetist detachment. So totally different. And then just fetal vasculature can be a number of things. Do you get copies of the talk? It's a lane that she can send it out to us. Persistent theater vasculature can have anterior findings or clear lens. Surgery to release trait. This is non-axonal trauma. I wanna go over this briefly. So, it's from probably shaking one trauma. It can cause schesis cavities in all layers of the retina with bleeding. But it can have subhylone or sub-ILM bleeding. And sometimes you can, you have to get imaging, right? But sometimes you can have the baby, if it's right in the phobia, they'll end up with amblyopia or they can get anisometropia. They can get very minorsighted by having blockage of light to the retina. We can do surgery to release that, to reduce the risk of amblyopia and blindness. But sometimes what you can do initially is just have them sit in a car seat when they're awake and then gravity settles out of the vision and visual axis. So, I don't know if that, they can still get weird staphylomas, but that at least preserves their foveal instruction. So, it's something to consider in those cases. But many times people will say the brain is so damaged, it's not worth it. But I think we should try because sometimes the kids who have severe brain involvement from the shaking can still later have visual potential. Now comes, I'm sorry, we're leaving. Okay, that's it.