Lecture: Less Common Causes of Retinal Neovascularization

DR. SAMBHARA: Good morning, everybody. I want to thank everyone. It might not be morning where you’re at, but it’s right and early where I am. My name is Depepak Sambhara. I’m a retina specialist partner and the medical direct of research at the Eye Clinic of Wisconsin where I have been since about 2019. Where I am is the upper Midwest in the United States. And right now it is negative 2 degrees Fahrenheit, which is even worse in Celsius. It’s a cold winter day. I hope everyone is staying warm and cozy where you’re at. But I’m glad that we have such a nice turnout today because today we’re gonna talk about less common causes of retinal neovascularization. Really I think that might be a misnomer for my total because I want to talk about posterior segment neovascularization which encompasses a couple of different things. And so, let’s get rolling here. Here are my financial disclosures. I want to start with a quiz, I think to set the stage. Neovascularization can happen in the A, retina, B, choroid, or C, both A and B. So, I’ll give you guys a few seconds to start answering and you know we’ll see what the survey says in a couple of moments here. All right. And it looks like we have got a pretty solid core group of people that have chose an correct answer, which is both A and B be. So, again, posterior neglect neovascularization involves and encompasses both NV in the retina as well as the choroid. This is what I would call a softball of a question. I promise we’ll have a couple more quiz questions as we go along that will probably increase in difficulty a little bit. So, when I think about neovascularization conceptually, really thinking about where it is happening anatomically. Because the anatomic drive of where you are having those new blood vessels arise oftentimes gives you an idea as to the etiology and that can also help just mentally separate the different causes in your head. When I think about posterior segment neovascularization, I split it into two buckets. Retinal neovascularization, that happening in the retina and the Visucam tee async, and choroidal neovascularization, happening in the choroid. You can further sub-segment neovascularization into location in the posterior segment or in the retina as so whether it is in the macula or in the periphery. Now, there’s so many different ways you can categorize neovascularization and in some cases this might even be on a continuum. But this is at least conceptually a very easy way for me to think about what’s the driver and what’s the cause of these new blood vessels that are occurring? And so, when we think about it on a histopathological level, retinal neovascularization, that which is happening in the retina and potentially the vitreous cavity is caused by damage to the retinal vessels that causes vessel closure that leads to ischemia and vascular leakage. If we think about diabetic retinopathy, a common as of neovascularization across the world, we know one of the first things, actually the first histological thing you will the notice in diabetic retinopathy is loss on the endothelium, the loss of tight junctions in the basement membranes leads to a situation that will cause increased vascular permeability. When you have characterized of the endothelial cells, you have leakage, sometimes how you end up with macular edema. Way back into more conceptually applicable and well-studied versions of neovascularization, you know, at the lab bench, Arnall Patz, famous ophthalmologist in the 1950s helped to elucidate it as retinopathy with work in newborn baby kittens. And further elucidated with histological specimens in mouse models. The mouse model of oxygen-induced retinopathy is how we understand neovascularization and how we gathered a lot of insight into this process. We know that hypoxic conditions after you’re born increases VEGF, which is crucial for normal vascular development. If you are premature, a retinal vascular developing, and exposed to oxygen-dense and rich environment, you will reduce that VEGF load that’s for normal development, have regression of vessels. Back to room air or oxygen at 21%, for example, you’ll have hypoxia-induced overproduction of VEGF that stimulates retinal NV. You can see this happening on the pathologic stains on the slides on the right. You can see what a normal mouse retina looks like and what a hypoxic retina that’s exposed to hyper-oxygen concentrations then transitions back to room air looks like. And again, you see that on the slides on the bottom as well. So, this is a very well-understood conceptual model of retinal neovascularization that we still use today at the lab bench. What about choroidal neovascularization? It’s a little bit different, right? In choroidal neovascularization that drive for angiogenesis is actually happening at the level of the choroid due to some sort of pathology happening typically at the outer retina. So, VEGF over-production by the RPE leads to endothelial cell activation in the choroid. If you have a compromised membrane, you can get the formation of these nay isn’t a tubes that then invade and proliferate into the retina. And that causes choroidal neovascularization. The way I think about it is, you know, sometimes, you know, if you’re walking down the street and you have a sidewalk made of cement, sometimes you have blades of grass that poke through between the two slabs of concrete. That normally should never happen. And I think of those nascent blood vessels almost like the blades of grass between two slabs of concrete on the sidewalk as those new blood vessels that have broken through into the choroid. Conceptually, it’s a good analogy I use when talking to patients who have CMVs from any etiology. So, we talked about splitting up posterior neovascularization into either being from the retina or from the choroid. But you can also talk about it based on under lying etiology. This is by no means meant to be an exhaustive list of all causes of neovascularization. In fact, I can shout out some other ones that aren’t even on this list. But from a — just a broad approach, a broad way of thinking about how NV can be categorized in the posterior segment, you can put it into different buckets, but the reality is a lot of this is probably on a continuum. Meaning some of these conditions exist on a spectrum and probably fall into one or more of these buckets. So, I think about microvascular systemic ischemias being one bucket. Inherited diseases. Inflammatory and idiopathic. Iatrogenic, for example, is not listed on here. That would be induced by potentially by certain treatments. For example, parse lana vitrectomy, and choroidal vascularization. And radiation from tumors to the face or the eye, you know? Can cause retinal neovascularization. Trauma is also not here. You know, choroidal rupture can cause choroidal neovascularization membrane. There’s a lot of causes not on the slide. But conceptually to think about it, think about these as broad categories. We’re talking about less common causes, right? We’re not talking about the microvascular systemic diseases that we typically see in many of our clinics. I’m going to skip over vein occlusion and diabetes and talk about systemic or microvasculars I key ya by talking about ocular ischemic syndrome. OIS is the first topic I want to hit on. It is characterized by inadequate ocular perfusion due to underlying atherosclerotic carotid artery disease. We know the patients exist on a spectrum. The patients who end up having diabetic retinopathy are more common causes of retinal neovascularization may be at risk of OIS, but there are key differences here. The risk factor, the patient profile again, this is somebody who has the features of metabolic syndrome, pretty much the risk factors listed on the slide. As far as these go, these patients came in with asymmetric unilateral blurred vision, photopsias, or amaurosis, TIAs. These patients may have NVI, anterior neovascularization vas cue lair, Roth spots, hemorrhages, or pseudo-Roth spots, mid-peripheral hemorrhages. That’s typically a buzzword in the optometry, ophthalmology space, trying to clue you in on somebody with OIS. But obviously this is a talk about NV, obviously neovascularization is something you can see in OIS. But you as the treating physician or treating practitioner, what are you actually looking for? Now, if you’re like me, and you’re in a eye care facility, you may not have access to — access to a stethoscope at hand. But, you know, in my clinic, we probably have one and that’s to do HNPs preoperatively. but carotid bruits are textbook for atherosclerotic disease. If someone has a bruit, look for it. Especially if it’s asymmetric on one side. The things we do day in and day out in the clinic are fluorescein angiogram. It tells you there’s an issue with perfusion. And certainly a prolonged arm-to-retina time is indicative of some sort of occlusion happening upstream of retinal vasculature. Further more on OCT, may see signs of poor perfusion, in the form of a thin choroid, DRIL, disorganization of the internal retinal areas. You could see CME, it’s rare in OIS. But where I have seen CME in the syndrome, in the pathology, is actually re-perfusion injury. Somebody who is treated successfully for OIS. And the treatment for OIS, certainly if you see somebody who is a suspect, get imaging. Imaging, less invasive to more invasive. Ultrasound imaging to image the carotid artery. If you can’t get a carotid, think about if it’s a CTA or MRA. And get the patient in to see a vascular surgeon or intervascular neurosurgeon, interventional radiologist, whoever in the area performs these procedures. Specifically a carotid artery, or stenting. There is things that the treating surgeons are abiding by, the clinical trials like the NASCA trial that happened a couple decades ago. There are certain criterias for degrees of stenosis at which a surgeon might intervene. But the most important thing to do as an ophthalmologist or optometrist is to get that patient plugged in if and when this diagnosis is confirmed. Again, we want to rely on multi-modal imaging to cinch that diagnosis. Let’s transition to our next quiz question. Look at the picture on the left. That is somebody that looks like they probably have ectropion uveae, and the areas. In this patient with OIS, they’re more likely to have IOP that’s increased due to possible neovascularization of the angle? Increased due to being systemically hypertensive? Decreased due to poor ciliary body perfusion? Or decreased due to episcleral venous outflow? And we’ll give you guys, again, about another 15 to 207 seconds to answer. I promised these questions would increase in difficulty as we go along. And this question, honestly, may not have a true right or wrong answer. I think it really depends on when you’re seeing this patient. But I’ll give you my logic here.
So, we’re kind of split. A is the, you know, the front runner here. And I think that’s a reasonable answer. I think any time you see somebody with neovascularization, particularly if it’s this advanced or this severe, you’re gonna expect the angle to be zipped up, right? Specifically if on gonioscopy this person has neovascularization of the angle and peripheral anterior synechiae and they’re zipped up, you expect increased IOP. And catch people a little earlier than what the picture I’m showing here on the left is showing. You may actually see decreased IOP, or IOP not as increased as you would normally expect. Or not as high or proportionately lower than what you would expect for somebody who has this advanced NV. And that’s due to poor ciliary body perfusion. And so, remember, if blood ain’t getting to the retina, if you’re not getting blood to the retina or choroid, it’s also not getting to the anterior segment, all right? And so, the ciliary body is not being perfused. That is not happening. You are not making aqueous. You may have lower than expected IOPs. May see anterior segment inflammation as well in the population. This is an advanced angiogram of somebody with OIS. Pay attention to the periphlebitis and vessel wall staining. Truly arterial wall staining you see in OIS that separates it from other causes of neovascularization in the retina. The other thing would be capillary non-perfusion. So, if you see large areas where it’s just blacked out in your FA, understand that that is not normal. We want to see some level of perfusion. And when you’re not seeing it there, you’re seeing dead and ischemic tissue with a high VEGF load. And finally, those mid-peripheral venous hemorrhages also increasing your suspicion for this condition. What are some key angiographic findings that you want to pay attention to that are gonna separate this condition from others? Prolonged choroidal filling time. Arm-to-retina is taking a long time, but taking along for the blood to hit the choroid, the first thing to fill in an FA, understand that should tip you off to something that’s up-stand to retinal and choroidal vasculature that is compromised. I mentioned that arterial staining is happening at a greater level than venous staining. Should tip you off. And the FAZ enlargement, there is globals ischemia happening although the level of the retina that’s compromising visual acuity and ultimately contributing to the drill or the distortion of the retinal layers than you might see on OCT. Lean into multimodal imaging if you have the option. To help elucidate some of the nuanced features for a patient who may have OIS. So, let’s transition to the next category. And let’s talk about inherited forms of posterior segment neovascularization. Let’s start by talking about PXE or pseudoxanthoma elasticum. This is the progressive degeneration of elastic fibers leading to distinct skin and ocular manifestations. What are nose? The chicken skin appearance you see on the right. Yellow papules and plaques that exist inelastic replete areas, the neck, groin, and arm pits have this cobblestone appearance. 80% of the patients with PXEs have a mutation in the ABBC6 gene which is responsible for coding an ATP binding cassette transporter that is important for maintaining homeostasis of the extracellular components. It is inherited in an autosomal recessive. You want to ask about the family history and draw out the pedigrees. I know it’s a little bit of a nuisance to do. But when you see a patient with PXE, you’re really talking about their family history. Because you want to be able to prognosticate for their loved ones meaning children or grandchildren to give them a better idea of what their risks are of this condition. What are ocular manifestations of this disease? If you do a dilated fundus exam, see the characteristic modeling that typically happens in the periphery that’s referred to as peau d’orange, and that appearance is characteristic of the RP, outer retina and choroid. And classic in PXE are angio streaks. What are they? Break in Bruch’s member. Why? That’s where you see type 3 collagen. It’s a membrane that separates from the retina. It’s the reason the blades are grass aren’t growing into the slabs of concrete on the sidewalk. Why? There’s a barrier that exists, Bruch’s membrane, preventing it from forming. And that’s the fertile soil or the the areas for which choroidal neovascularization happens. Another characteristic thing that needs to be paid attention to when you see somebody with PXE is optic nerve head Drusen. These aren’t just pretty picks on fundus, but ONHD portends a greater risk of other conditions including ANION, or visual field defects. Pay attention if you see somebody with optic nerve head drusen. There are higher risks of certain ophthalmologic conditions that run with that finding. On exam I said that you would see that RP modeling, the Peau d’orange and angioid streaks. And on the OCT, you have the RPE atrophy from the lesions to the posterior pole. And on FA, you’ll see leakage that typically corresponds to a choroidal neovascular membrane. And it’s antiVEGF versus PDT. Back to the rubric of paying attention to where the posterior segment neovascularization is happening, mentally, it lets you separate where that pathology is, right? There is a reason people who have diabetic retinopathy don’t have ischemic drive that leads to CNVs. We don’t see CNVs in people who have PDR. Conversely, we typically don’t see retinal neovascularization in most people who have CNVs from like macular degeneration or myopathy degeneration. Why? Because where the pathology is happening. So, in somebody who has PXE, we know it’s happening from diseased collagen and we know that, you know, type 3 collagen is replete in those basement members in the choroid. And that’s why these patients with PXE tend to have CNVs and not RNV, and not retinal neovascularization. So, here on fundus photo we see pictures of angioid streaks. You see miniature breaks in Bruch’s membrane that give the characteristic appearance. This is somebody with poor visual potential. They have a CNV that was sub-optimally treated or are with left retinal fibrosis. These are the drusen clear on the fluorescence. Pay attention and get a visual field if you see a patient who has optic nerve head drusen. It’s a higher risk of visual field defects or ANION. And again, the hyper AF areas correspond to potential atrophy that are in the area’s fluorescein streaks. This is fluoro angiogram of the patient early and late, showing predominantly classic leakage from choroidal neovascularization associated with streaks center pseudoxanthoma elasticum. How do you leverage the image something when I showed the earlier diagnosis of OIS, try and get wide field imaging if you’re able to. And somebody with PXE, the pathology is happening in the macula typically. Don’t worry about ultra wide field imaging in this patient with PXE. You know this is happening at the level of the macula. Feel free to get a 35 degree or 55 degree photo without sweeps. Versus somebody with OIS, it’s in the periphery. If you’re able to get ultra wide imaging if you have access to it, make sure to try to get that photo. So, let’s transition to another disease where a lot of the pathology is happening at the periphery. And that’s sickle cell retinopathy. And many of you in the audience probably have many more — much more experience or many more patients in your clinic with SCR than I personally do in central Wisconsin. But I have seen a fair share of these patients myself and we know these patients tend to be a ticking time bomb. That the disease, only looking at the posterior pole, may be far more out of proportion and far more advanced than what a funduscopic exam of the posterior pole might indicate. This is characterized by occlusion of retinal vessels due to sicking of erythrocytes. More common in African ancestry. And the new guidelines typically is suggested at age 10. And that’s due to new findings that we’ve garnered from multimodal imaging. We know it’s from a single nucleotide mutation. From adenosine to a thiamine that’s basically changed the beta chain of hemoglobin from Valine to glutamic acid subpoena homozygosity leads to sickle cell disease, heterozygosity leads to sickle cell trait. The manifestations are on a spectrum. You have NPSR, non-proliferative sickle sell retinopathy. To proliferative sickle cell retinopathy. And then the presence of angiogenesis. When you see NPSR, there’s characteristic buzzwords and findings that we look for. Salmon patches, superficial retinal hemorrhages. And those retinal hemorrhages — those RBCs under go hemolysis. It leave a salmon-colored hemorrhage. They can have sun burst spots that are hyperpigmented areas in the retina, the posterior pole and mid-periphery, excuse me, that’s due to RPE migration. People with PR, or peripheral sickle sell retinopathy, more advanced disease due to angiogenesis that’s taking place. That happens at stage 3 whether you start to see florid neovascularization on fundus exam or FA. There’s a classic sea-fan that we talk about. That’s elucidated in this picture on the right in this ultra-wide field fluorescein where you see, you know, a functional zone of vascular — vascularized, vascularized tissue. There’s areas of nascent vessels that leak profusely on fluorescein. If they are left untouched, bleed and causing hemorrhage. The advanced stage is stage 5, TRD, retinal detachment. What do you look for in a patient that might have OIS? It’s typical retinal thinning on OCT. Again, this can be very subtle. Because a lot of the pathology is happening in the periphery to mid-periphery, not necessarily at the posterior pole. You might know see retinal thinning. This can be subtle. OCT-A with that being more predominant in the developing world and developed world, I should say, has led us to find decreased vessel density in some of these patients. And if you have access to fluorescein angiograms, we know that capillary non-perfusion is a great way to find early findings of people who might have PSR. These hairpin loops and sea-fan NV are very obvious on FA like you see on the picture on the right. The mainstay treatments are going to be a administration of either antiVEGF treat to decrease the vascular drive, scatter laser in areas of non-perfusion, photo retinal laser or parse play that vitrectomy in the cases of vitreous hemorrhage or retinal detachment. So, what do we see here on multimodal? On ultra wide field imaging? Number one, we see the sea-fan NV that we talked about that’s happening, excuse me, although these junctional zones. And number two, large swaths of capillary non-perfusion which is really the fertile breeding ground and the soil for the sea-fans are proliferating. And so, these are obvious areas that you might find if you do a dilated exam and look at the periphery. But again, if it’s somebody who has early NPSR, you might not see that. You might see something that looks more like this. Which is these characteristic salmon patches. Again, get that color due to hemolysis of red blood cells. This is what we’re trying to avoid, right? You want to find NPSR here or potentially earlier so you avoid a situation like this. This is stage 5, very advanced. It’s a combined tractional rhegmatogenous retinal detachment. Here is the retinal tear causing the area of the detachment. Next question. And I see Q&As coming in and I’ll try to stop after this to field through some of them. So, in these surgical sickle cell retinopathy patient, careful attention should be given to, A, the use of sympathomimetic agents? B, encircling scleral buckles? C, extra ocular muscle dis-insertion? D, are carbonic anhydrase inhibitors. E, both A and B. F, B and D. Or G, A, B, C, and D. Kind of like an all of the above answer. So, a longer question to give you some time to go there and then we’ll see what the survey says, what the audience has voted.
And most of you guys got this correct. It is basically that all of the above answer. Right? You want to worry about all of these things. Because the patient with sickle cell disease is going to be very different than the patient who has, you know, other neovascular disease. Particularly because this tends to be a younger patient. They may be a pediatric patient. Or they may be an early adult — early adulthood patient. The use of sympathomimetic can cause an issue, and encircling scleral buckle. If they have compromised blood flow, if you are squeezing on a compromised choroidal or retinal area, may be precipitating areas of infarction. When you dis-insert extra ocular muscles, in a normal or pediatric patient, don’t want to operate on multiple muscles at once because that can cause anterior segment ischemia if you dis-insert too many muscles at any one time. In a sickle patient, you want to be more careful about how you operate on these patients. And finally, CAIs, they’re diuretics. They dehydrate a patient. Dehydration in a patient with sickle cell does promote sickling. So, again, in the perioperative, post operative care of these patients, be careful. If this patient is a medically-managed patient who is coming in from trauma with a hyphema, for example, don’t use CAIs. Always be on the lookout. If it is a patient of African ancestry, has a hyphema, try and get a sickle cell panel if you can. Because your tolerability, and your risk tolerance of IOP is different and the meds using to tolerate IOP is going to be different. You want to avoid CAIs in those patients. Let me go through and field some of the Q&A right now and see what folks got to say.
So, there was an earlier question about CRVOs with macular edema. What is the first line treatment? In the United States at least, if you have access to antiVEGF therapy, that is going to be your mainstay treatment. Now, I always tell folks, you know, there is what I want to do, there’s what you want to do as the patient, and unfortunately in the United States, there’s what insurance tells us we’re going to do. And out of those three players, the ladder, unfortunately, for better or worse, is most important. It is what our insurance holders and insurance payers tell us to do. But the good news is, antiVEGF therapies are broadly approved by most insurance companies. If you see a patient with a CRVO, if they have macular edema, you want to treat with antiVEGF. If it’s a CRVO in the absence, and doesn’t show neovascularization, may monitor. Signs of NV, may give an antiVEGF as kind of a load to bridge them to PRP. And then I will PRP them within a week two weeks. Let’s take a look at another question. Can a patient who has neovascularization of the disk and neovascularization elsewhere have high IOP without NVI and NVA without a history of glaucoma? Can that happen? I think that that is less common to see a patient without anterior neglect neovascularization to present with extremely high pressures who have, you know, NVD and NVE. The usual circumstance is if they have anterior segment neovascularization, there is some sort of trabecular meshwork outflow obstruction that is leading to the high IOP that leads to this. You know, a — you know, a, you know, you’re talking about zebra conditions where you may see this without anterior segment neovascularization. And we’re talking about like ghost cell glaucoma or hemolytic glaucoma. You have RBCs from a vitreous hemorrhage. It’s posterior segment neovascularization driving RBCs to clog up that’s causing high IOPs. In the absence of anterior segment neovascularization. That, for example, is a condition where you may not have anterior segment neovascularization. It’s all posterior segment NV, but due to trabecular flow from obstruction from RBCs. The next question is about world level statistics of OIS. I can’t tell you that off the top. But I can tell you this is probably under-diagnosed in the United States. Because this is a very common — it’s very common to confuse this condition with retinal vein occlusion. You might say a patient with OIS has the same metabolic risk characteristics and risk factors as somebody who has a retinal vein occlusion. This might look like a CRVO if you’re not looking carefully. The keys are looking at what it looks like and paying attention to the subtle differences that you might see on multimodal images, arterial vein staining more than wall, carotid artery. And look at age range. Patients, unless they have a weird or whacky cause like hyperviscosity, they tend to be older and have other causes that tend to have a vein occlusion. Certainly OIS patients can be older. But identify seen OIS patients on the younger end who have bad artherosclerotic disease. Let’s look at the next question. How can retinal neovascularization in sickle cell be different than that in diabetic retinopathy using clinical evaluation? I think typically age of onset. If you are looking at multimodal imaging, younger population, areas of occlusion. Certainly that’s possible in a type 1 diabetic who might be in the pediatric age range. But you also know that a patient with type 1 diabetes is typically on insulin, right? So, use your historical, you know, and demographic kind of findings to help separate these patients out. Get an A1c, for example, to tell the difference. But again, the disease typically happens in the periphery early on. Again, unless you have access to OCTA or advanced multimodal imaging, we really don’t see loss of capillary density in the posterior pole with sickle cell patients just on fundus exam alone. Advanced imaging is gonna show that. I’m gonna just keep going and I’ll try and stop for the next round of questions. But let’s keep going here. And talk about another inherited condition. FEVR. familial exudative vitreoretinopathy. This is IRDs from a abnormal retinal angiogenesis that leads to incomplete vascularization of the peripheral retina. A spectrum of multiple mutations. So far to date, 11 mutations identified. And it’s typically autosomal dominant. That’s the most common variety documented in the literature. And the average age of diagnosis is much less — much younger than most causes of retinal neovascularization. You know, we’re talking about age 6. There are key findings that might differentiate a person with fever from a person with ROP. So, use history. For example, a person with ROP who may have peripheral retinal findings may be a young patient. May not have been exposed to — to supplemental oxygen after birth. They may also not have been a premature birth. Right? Use historical and contextual cues to help separate these patients. You know, signs that you’ll find if somebody has fever, you’re gonna see on ultra wide field imaging, and avascular peripheral retina. You may also see this in your peripheral fundus exam if you don’t have access to FA or ultra wide FA. The straightening of RetCam valley vessels or dragged macula. You can see that in FEVR as well as ROIAP. Falciform retinal folds, advanced finding of a patient who might have FEVR. The peripheral NV. Pay attention to the subtle differences because this is typically when it happens. You’ll see peripheral NV probably before you’ll see macular dragging or advanced changes in the posterior pole. Subretinal exudates and retinal attachment, looking for the findings. On FAs, they till have telangiectasias and disk leakage. And anomalous vascularity. And delayed AV transit and macular leakage. On OCT, there is a niched foveal contour that you might see in the patients. CME is — you know, your mileage may vary. It’s not necessarily a key finding in a patient with fever. But on OCT-A, you can see subtle changes in the avascular zone. The treatment for these patients typically is gonna ablative laser, photocoagulation, antiVEGF has been studied with varied success. And finally, presenting with any sort of retinal detachment, consider pars plana vitrectomy when indicated. This is a patient’s left and right eye with a FEVR. You can see the patients are more advanced in the patient’s left eye. The right eye, if you look at the fundus photo, there are subtle changes that you can miss. Right? This is a patient that you might skip over if both of the eyes looked like that right eye. But there are some vessel straightening that the OCT — that the FA makes more obvious than the color photo. That vessel straightening should be a tipping point to you that, hey, there might be some pathology going on in the periphery. And lo and behold, whether you look at the peripheral retinal temporally, there’s peripheral retina neovascularization. The falciform and retinal folds, TRDs, that’s something more advanced in the patient’s left eye. You can see they have poor visual potential because they have significant tractional bands, fibrosis, areas of staining, small areas of exudation as well. Let’s look at another condition here. I’m running a little short on time so I’m gonna try to speed it up so I have room or time to get to the Q&As. Inflammatory — I mean, let’s just think about it. Large gestalt kind of overarching umbrella term. It’s encompassing inflammation which can infectious. It can be autoimmune. It can be traumatic, technically. It can also be neoplastic. And that can also cause RNV from hyperviscosity, okay? So, when I think about inflammation, I’m typically thinking about uveitis or trauma. That’s what you should think about. Usually, if you’re having retinal or choroidal neovascularization in this context we’re typically thinking retinal vasculitis. Or choroidal neovascularization, think about compromised choroidal architecture or anatomy. Typically in VH. I’m going to touch on this, you may see this more often than me, depending where you are in the world. But Eales disease I have seen a few cases of particularly in training. It’s an idiopathic disease, characterized by occipital child abusive vasculitis and CMV. These are young males who end up having recurrent bouts of vitreous hemorrhage. The etiology, look at large cohort populations and datasets that have been published out of south Asia and out of the Middle East. And what we’ve found is that a possible hypersensitivity to tuberculoprotein is possible part of this. Patients with previous exposure to TB or hyperbacterium — mycobacterium TB, may have a reaction that ends up manifesting as a vasculitis. It’s periphlebitis. Why is it a vasculitis? Well, you have perivascular sheathing. That’s on fundus exam. That vascular sheathing associated with exudates and sclerosed vessels. And ERMs that can form. That’s indicative of the inflammation. Something that’s not on this that I think you should look for on OCT. If you use your heat map on OCT, thickness map, it typically highlights areas of thickening and what you can see in somebody with Eales disease is thickening that follows the retinal vessels. You will see that in a patient with retinal vasculitis. As they respond to treatment, you will see the hot spots that follow the thickness map on the OCT. They tend to get better and resolve over time as the patient has less periphlebitis or resolved periphlebitis. CME is rarely associated, and treat with antiVEGF or laser. And vitrectomy with the disease. This is a montage of ultra wide imaging on Eales disease. vitreous hemorrhaging that’s blocking. Areas of peripheral non-perfusion around the laser bed in the temporal periphery. And lo and behold, lighting up like a Christmas tree, neovascularization happening at the temporal periphery. Finally, we can talk about idiopathic causes. Again, there are far more causes than what’s listed here. Coats disease, Mac-tel, pachychoroid neovasculopathy. That’s what I’m going to focus on to end out the talk today and then answer the last few questions that have shown up in the chat. Pachychoroidal neovasculopathy is hallmarked by a thickened choroid with dilated choroidal vasculature. We are looking at this and many of you may see in the Middle East, Southeast Asia and South Asia, central serous chorioretinopathy, or polypoidal choroidal vasculopathy, PPE, think of that — the ocular manifestations usually are pigment epithelial detachments. Predominantly serous that could be associated with hemorrhage. Or loss of fundus tessellation if you have — but if PPE or CSR with CMV, these have rip roaring bilobed serous PPEs as you see here. And they’re hyperreflective material, as well as subretinal fluid. Possibly into retinal fluid. But look on the near infrared reflectance image. Massive subretinal hemorrhage. These are typically patients who present with very advanced exudative disease. When you look on multimodal imaging here on a angiography, you can see a polyp right near the fovea, blockage due to blood. And again, the characteristic bilobed that you see. These have type 1 CNVs on OCT or OCT-A because the pathology is existing at the subpar space. They respond well to PDT directly to the pupil or the feeder vessel. And dynamic OCG. Where you can see vessel fill early on in the choroid tends to give you a better view of what those feeder vessels look like. And certainly antiVEGF, a mainstay treating pack you choroidal neovasculopathy. This is a patient of mine. They have dry MD, but also pachychoroidal neovasculopathy. You can see thick choroid, a huge detachment. Subretinal fluid, emanating, from a CMV that’s next to the nerve. The macular cube kind of cuts it off. You can catch the edge of it. I’m gonna play the video again and show you again where that CNV is located or MNV. Here’s the subretinal fluid. Look where my cursor is, catches the edge of that type 1CNV. Massive exudation of subretinal fluid. This is a patient who you could relegate to monthly antiVEGF therapy if you wanted to. Or you could give them sub-threshold laser or photodynamic therapy. I elected to do the latter. Treat them with photodynamic therapy with verteporfin-guided PDT. This is them weeks later, four weeks. This is one session of PDT. No antiVEGF. I believe the patient went from 20/80, significant metamorphopsia to 20/25, and no reoccurrence since. So, CSR with CNV typically responds very well to monotherapy with PDT. People with pachychoroidal neovasculopathy for PCV, usually throwing the kitchen sink. You’re doing PDT to the polyp in combination with antiVEGF injections because they typically have a large, large exudative drive. So, in summary, neovascularization in the posterior segment is really a spectrum that can involve the retina, the choroid, or both. Broadly, these can be classified into microvascular ischemic, inherited, inflammatory, idiopathic, and iatrogenic. Though most of these diseases, or many of them, can exist on a continuum and fit many of these buckets. The principles of managing neovascularization involve suppressing angiogenic drive via pharmacotherapy with antiVEGF injections or steroid injections or ablation with photocoagulative laser while treating the underlying condition. Historical or contextual clues like the age, the demographics, the past medical history, can help rule in and also rule out certain diagnoses. In leveraging multimodal imaging, like ultra wide field angiography, OCT angiography can also highlight the extent of peripheral pathology and quite frankly get these patients diagnosed far earlier so you can get them plugged in to a far more regimented follow-up schedule. With that, I will end for some questions. I know Christmas, Hanukkah, Kwanzaa, we have many holidays coming up. Diwali, another holiday that just passed. I’m very thankful for you guys showing up and these are the two people that keep me thankful every day for doing what I’m able to do. These are my two kids and they are certainly looking forward to the holiday season. I really hope that you guys all have time to have fruitful time off with all of your loved ones as we enter the holiday season. And so, let’s end by addressing some of these questions that have shown up. So, what is your frank opinion on supplemental oxygen in the setting of NPSR? I think you have to be careful in using oxygen in these patients. Certainly for the reasons that I talked about earlier, you know? The drive of neovascularization that’s possible. But again, this is something if somebody is coming in, in an acute sickle crisis, for example, that is something you do. You put them on oxygen because that can help — you put them on oxygen and you also potentially give them fluids if they can handle it, you know, to try and treat sickling. It’s a little bit out of my wheel house. But certainly has a purpose. Let’s see. Another question. NCDs related to eye complaints? Academics? Whoever wrote that question, can you just further elucidate. Because I’m trying to figure out the acronyms here. And I’ll go back to that in a second. So, let’s skip and go to difference between Coats disease and FEVR? Think of Coats disease as being a unilateral disease, non-inherited, but predominantly exudative. Fever can certainly presence with exudation. But the sheer amount of exudation in Coats disease is more than someone with fever. That’s a telltale sign. These patients unfortunately with advanced Coats disease if they are, you know, on the younger end, may need combination therapy of cryo therapy, antiVEGF therapy, photocoagulative laser. You know, we’re really throwing the kitchen sink at these patients because they have such a vascular drive. Patients with FEVR can have the same findings, but I do think the peripheral pathology of peripheral junctional neovascularization is something you tend to see a little bit more. In Coats you can see more posterior pathology earlier on in that disease. Let’s see the next question. What are the treatment options in NVG patients with very high IOP and poor vision not responding to glaucoma therapy? So, you’re really in a tough situation. When you have somebody when NVG who has poor visual potential who has high IOPs. At that point, we’re really talking about salvage therapy. We’re talking about making sure that you as let’s say a retina specialist has all your bases covered by dealing with as much you can in the posterior segment that’s driving neovascularization. So, antiVEGF, if you catch them early enough to try to regress NVI or NVA that might be happening. But if they’ve already developed peripheral anterior synechiae and their angle is zipped up, it’s not going to regress in VA. You want to give antiVEGF. Try PRP, a full and total PRP so any neovascular drive is handled. And then if they have high IOP because they’re zipped up, that’s a surgical candidate. And then potentially doing a tube. So, surgical glaucoma procedures versus a diode laser or, you know, trans-scleral diode photocoagulative laser. Although that in an eye that might have poor visual potential with significant NV, that actually might be risk for ptysis. It is something that you might have to consider in that situation. You know, when pharmacotherapy is not cutting it and that’s not enough. So, somebody’s maxed out on max medical therapy. You’ve got your bases covered with antiVEGF as well as full PRP laser. Then you’re really talking about surgical intervention. And whether that is an Ahmed valve or with diode or CPC laser. So, let’s see if I can look at a couple of these others because I think we’re running short on time. I’ll go from the bottom up. What is your preferred treatment for CSR? For me, I’ll be quite frank, I see a lot of this in my clinic. My first line treatment is observation. Observation, most of these cases get better by themselves. If observation doesn’t do the trick, then we’re talking about intervention. And so, intervention for me is really reserved for a couple situations. One chronic CSR. Which is defined as C SR that is active longer than 90 days, okay? I give them three months to see if gets better by itself. Or if the patient is, you know, occupationally disabled and can’t go to work or perform their duties, then I will intervene sooner than later. I typically run a fluorescein and figure out where they may have a target for potentially sub-threshold laser or PDT. Before I will do PDT or sub-threshold laser, I will consider spironolactone. We know that these aldosterone-manipulating agents, these diuretics have a growing body of literature, they might be a better first line agent for active CSR. If the patient isn’t hypotensive, normal kalemic and their potassium is normal, I will talk to them and their PCP about starting spironolactone. But if they don’t want to mess around with spironolactone and they want a more definitive treatment, subthreshold laser has a place. So, does PDT. I typically have done PDT as long as there is a target. But if we are within a thousand microns, or rather 500 microns of the fovea, I’m doing half dose, half PDT or at that point, I’m thinking of subthreshold laser the closer I get to the fovea. Let’s look at the one above. What role does the OD — does an optometrist — play in the management of patients with retinal neovascularization from detection to management? It’s a great question. I mean, depending on where you are in the role — in the world, your role might be the first line. You might be the ophthalmologist truly depending on where you are in the world. And so, if you are in a medically-underserved area and you see somebody with neovascularization, your job is to try and number one, find out is that neovascular drive causing any sort of anterior segment manifestations that might cause immediate rises in IOP which you can treat? Right? Make sure they’re not at risk of developing MGV. If so, get them on lowering medicines. The next step is getting them to somebody that is able to treat. Meaning with antiVEGF therapy. To try and bridge them until they can get to a specialist for a fluorescein or for laser. If you as an O D have access to FA imaging, get it. If you don’t, get them to a specialist or a general ophthalmologist who can get a fluorescein to image the retina to look to see what the neurovascular drive is to drive the changes. Can you sit on NV? Truthfully, you can. Most NV is not going to lead to NVG, NVI overnight. That takes a long time. But if you’re seeing peripheral NV, it’s your cue to get that patient in sooner than later. And pay attention to the demographics, right? There’s a difference between a 60-year-old presenting with NV. When you’re thinking of all comers and possibilities. Than a 6-year-old child presenting with NV. So, look at the patient in front of you and certainly let the demographics play some role in the urgency to which you want to get somebody plugged in. Not saying that it’s not urgent for a 60-year-old to get in with NV. But when you look at the possible etiologies of why somebody that old might have NV, it could be diabetic retinopathy, it could be a vein occlusion. Certainly could be OIS. A significant risk for cardiovascular morbidity and mortality for stroke, right? Certainly that’s important and you want to get that patient in sooner than later. But if you have a 6-year-old, pediatric patient with NV, you really want to get them in earlier because there’s only a handful of things that are going to cause somebody that young to present with neovascularization. Let’s look at anything else? Are there any roles for non-steroidal anti-inflammatory eye drops like NSAIDs for CSR? Typically I don’t treat uses NSAIDs in CSR. I think part of the issue is number one, it’s hard for compliance. Number two, the drops burn. And number three, you know, if you are on NSAIDs long-term, it does confer a theoretical risk with corneal toxicity for corneal melt and neurotrophic users. I typically don’t do that. So, with that, I think I’m going to end the session. We’re just a few minutes over time. I want to thank you guys for coming here. I mean, there are a lot of people here today. I want to thank the folks at Orbis and Cybersight for the opportunity. If you have a chance, I am very much interested in medical education. So, I am on Instagram at Dr.Deepak. Give me a follow if you’re on Instagram. I try to post cases sporadically. I think that our job as ophthalmologists and optometrists as allied healthcare providers supercedes the bubble that we live in. The bubble that I live in is central Wisconsin. But the unique opportunity because of the Internet and because of collaboration is that we can bounce ideas off of each other and there are so many things that I learn from people from the audience today who manage some of these diseases at a frequency greater than I do. Where I think it promotes a great culture of collaboration. And so, you know, if we can be in touch afterwards, we can bounce cases off of each other, I would love that. If you guys come to conferences in the United States or in Europe or overseas, and I find myself there, please feel free to say hello. I think we have the greatest job in the world, taking care of people’s eyes. We are literally maintaining their independence. And that is a huge, huge thing. With that, I want to wish everybody a happy holiday season and thank you again for coming here. Please stay warm and stay safe. Thanks again, guys.