 Welcome to Grand Rounds, everybody. Today, we get the pleasure of listening to Dr. Ronald Hobbs. Fun facts about Dr. Hobbs, he said that in fourth grade, he took second in his 100 meter dash. And third grade took second in the Whipple Ball toss. Those are his exact words. And then I don't know if you can correct me if I'm wrong, but I heard that he was the second choice for the Retina Fellow as well. First one could have come, something like that. So Ron's just kind of a second place guy. But so this is Ron's last Grand Rounds here with us. He's been an awesome Retina Fellow, been great to work with, and has taught us all a lot. So we really appreciate what he's brought to our program. And he's going to teach us a little bit about crystalline retinopathy. Thanks, Trent. You forgot to mention, I was also my wife's second choice for a husband, but I just want to quickly give credit to Jim Gilman for this picture here. I love this picture. He shared it with me last year. I remember when I came and interviewed here, and you get that view out there of the Salt Lake Valley, I just thought it wasn't even really fair to have a building like this and a view like this. And for other places where you go interview and you're just stuck, you don't get a view at all. So I love that photo. First off, financial disclosures. I have none really. I don't get money from any outside sources. This is where all my money goes right here. We'll get started. Patient one, this patient presented to the Retina Clinic here with the complaint of, my vision seems a little worse. A 56-year-old male complained of gradual worsening of vision bilaterally for about one year's time. He had been seen by his local doctor in a small town in Utah and was noted to have some retinal changes and so was referred to us. He really denies any other symptoms other than the blurriness associated with his vision. His past medical history, pretty vanilla, you know, a history of hypertension. He did have a history of a knee replacement surgery a couple years prior. There was some concern over an infection in his knee that was cultured, but that had all long since settled down. No significant family history. He has mild myopia, mild astigmatism. And other than that, he's just on metoprolol for his blood pressure. Vision, 2040 plus in each eye. There's no APD. And the rest of the external exam is normal. And then the anterior segment exam, he has no inflammation. He has traits to 1-plus nuclear sclerotic cataract bilaterally. And the remainder of the anterior segment exam is normal. He does have asteroid hiolosis in his left eye. And the rest, I'll show you for your enjoyment here, here's the pictures. So picture the right eye here. You can see these glistening golden crystals kind of surrounding the periphobeal area a little greater nasally. You can't see it real well on there. You can see a vessel running here, retinal vessel. And crystals definitely are superficial to that vessel there. And again, same thing here, vessel running right here with crystals sitting superficial to it. And here's his left eye. These aren't real pigmentary changes at the retina here. This is because of his asteroid. There's areas that are out of focus in the left eye. This right here is real pigmentary change in the retina. But again, crystals surrounding the periphobeal region there. Here's infrared, a picture of both eyes again. And you can see that slight pigmentary change there in the retina and these crystals throughout. Not quite as noticeable on infrared imaging as on color. Here's his OCT, some pertinent findings. You can see he has these small cystoid spaces here in his outer nuclear layer and his inner nuclear layer throughout the retina. Additionally, you can see these little hyperlucine spots. These correlate with the crystals right in the nerve fiber layer there. Every time if you go through and look at the cuts, you can see the line, the raster line going through. And you are catching little crystals in the nerve fiber layer there. Additionally, you can see he has lost his photoreceptor segments there. His junction, his ISOS junction there, is washed out centrally in his right eye. And here's his left eye, a similar picture. Again, you have some little cystoid spaces. This one a little more superficial, some here in the outer plexiform layer and some more superficial ones here as well. Again, these little crystals noted right along the edge of the nerve fiber layer. And he's got some photoreceptor drop out again. Not quite as significant as it is in the right eye. Here's his forcing angiogram. So early here at 14 seconds, one minute, three minutes, and six minutes. But early you can see he's got some little telangiectatic vessels that seem to fill here around the central fovea. At a minute, you're starting to see leakage temporally. At three minutes, it starts to surround the entire fovea. And you have this petaloid pattern at six minutes in the right eye and in the left eye, very similar pattern again. You have this early hyper fluorescent spot, but you'll notice as you go through all the photos there, that doesn't expand at all, it stays the same. But again, you have these telangiectatic vessels temporally and you can watch those expand, that leakage expand throughout. Here's his fundosodal fluorescent. And notice you don't see any crystals on this. You do see some slight pigmentary changes in the macula in both eyes. And confocal blue light reflectance here really demonstrates these crystals more impressively than the other photos. But here's the crystals in the right eye and in the left eye. So differential diagnosis. I put up here just the differential diagnosis for retinal crystals. And that's what we're gonna talk about a little bit today. We'll talk about what this patient has. You know, I think this is a pretty good list to have in your mind when you see someone with crystals in the retina. So number one, canthazanthin, not canthazanthine, canthazanthin, we're in the United States here. And that's usually associated with normal vision. Tulk, often very good vision as well. Primary hyperoxyleria. Usually that'll have just a very mild visual impairment associated with it, methoxy fluorine as well, usually mild, although that can be significant. Tamoxifen also can be milder, it can be quite significant, depending on the level of changes seen in the retina. And then some that have, can have pretty significant vision changes associated with them would be pietis, crystalline dystrophy, cystinosis, bilateral acquired parapherovial telangitase. I know that name for this has probably changed five times during some of your career. Right now we're calling it macular telangictasia, mactail, idiopathic macular telangictasia. So I'll refer to it as that throughout the remainder of the discussion today, but mactail. Nitroferantoin, another drug that when used chronically can't cause crystals in the retina. And then some genetic diseases such as, other genetic diseases I should say, such as chokrin-larsen, which usually associated with significant vision loss and gyrate atrophy. For those of you like to see it lumped into different categories, here's your genetic diseases, your pietis, gyrate, cystinosis, chokrin-larsen, primary hereditary hyperoxylary. And then vascular, mactail and talc, idiopathic being chronic retinal detachment, white dot fovea, toxic, you have your canthazanthin, spelled wrong here, but tamoxifenitroferantoin, your secondary hyperoxylary due to medications such as methoxy fluorine and ethylene glycol, and then your metabolic disorders that can cause a secondary hyperoxylary as well. Associated with sarcoid or liver disease, bowel resection, renal failure. Our own Mike Teske here has a paper, an American journal of ophthalmology on crystals associated with, we presume, excessive rhubarb ingestion. This was published in 1991, but a woman who would eat about six cups of rhubarb a day, really liked. I have a photograph. You have a photograph? I was looking at it last night. They were black and white, but anyway, pretty impressive. It's gonna be fun to see her now and see what she looks like. Spinach. She ate a lot of rhubarb, so I don't have follow up on, I wish she was here to tell us what she looked like when she backed off on the rhubarb, but. Yeah, I didn't get pictures for that. But for those of you who like rhubarb, try to keep it to one pie a day. So we'll go through the differential here and talk just briefly about each of these and the main manifestation. So first, tamoxifen, you know this, it's anti-astrician drug, used mostly for breast cancer, but recently it's been used as well for brain cancer with some efficacy. In the past it was used at pretty high doses, about 100 to 200 milligrams a day. Now we've decreased that quite a bit to more around 20 to 40 milligrams a day and we've seen that the toxicity has decreased as well with that. But most people who are on this, they're asymptomatic or they have decreased central vision, color vision. A recent study on long-term, not recent, but in 98 I should say on long-term tamoxifen, you showed about 12% of the women who were on 20 milligrams a day developed the retinal toxicity. What you see is you see these golden inter-retinal crystalline deposits. They're in the peripheral region again and they can be associated with macular edema and with pigmentary changes. The OCT demonstrates crystals in the nerve fiber layer and in the interplexiform layer. In addition, with tamoxifen, you can see whirl-like changes in the cornea. It's a similar drug to amiodarone that can give you that and also to chloroquine and hydroxychloroquine, which we also know are associated with retinal toxicity in that they bind to lipid and it's thought that you get deposition of drug lipid that deposits in the retina. So treatment for this, it's recommended that anyone who's on tamoxifen be followed yearly with the retinal exam and that if they do start to develop crystals, that we have an important discussion with the oncologist on the benefit of keeping them on the tamoxifen because at that point they can start to develop cystoid macular edema and they can start to lose vision. So you need to have a serious discussion on whether or not to keep them on that. On fluorescein angiography, when they have edema, you'll see kind of a petaloid pattern of leakage and the OCT can be very helpful for following these patients. You'll see CME and you can follow the progression, improvement or worsening with stopping tamoxifen with OCT. Next is canthazanthin. Canthazanthin is a carotenoid derivative. It's used as an oral tanning agent. So most of the first papers associated with toxicity for this were coming out of Canada. Probably because they don't get any sun, exactly, exactly. So a lot of people there were using it, touting it and then we started to notice these changes where you see retinal crystals developing associated with its use. These crystals in canthazanthin are usually greatest nasally, but again, you can get a ring of them in the perifovial area, but more commonly you see a nasal between the fovea and the optic nerve head. Just about everyone with canthazanthin crystals is asymptomatic. They hardly ever, they don't seem to pick up on it at all. ERG can pick up some very subtle changes, but most patients don't notice it or complain of it. What you'll see is you'll see multiple inner retinal crystalline deposits around the macula and again, greatest between the fovea and the optic nerve head. This is an older OCT, but you can see these crystalline deposits is superficially here in the retina. And when they've actually done histopathology on this, it looks like it is true deposition of canthazanthin in the retina. We're pulling out the canthazanthin molecule, lipoprotein complex out of the retina. And over time you can see some loss of Mueller cells and that's why we postulate that the ERG probably can be slightly decreased as well. But like I said, the FA, color vision, patient symptom wise, usually it's all normal. So the recommendation, of course if you see crystals, probably stop the canthazanthin. There are some people who have photosensitivity disorders that really benefit from canthazanthin and the increased pigment. And so when they need to be on it, they should be followed every six months and you can work on lowering the intake and work again with their primary care doctor on finding a balance if they need to be on it. But, and the deposits may regress or may not regress with stoppage of the canthazanthin. The next is methoxyfluorine. We don't tend to see this very often but it is, it has been noted in the literature. This was an inhalational anesthetic agent. It's quite old agent and pretty rare today. The main reason it's rare today is because when it's used on long surgeries, it tends to deposit these oxalate crystals that develop deposit in the kidneys and the first symptom you get is they start to, patients during the surgery will start to develop kidney failure. And then shortly after that, you'll start to notice you can get deposition of these crystals in the retina. They'll deposit often within the arterials themselves or just outside of the arterials in the retinal tissue. Usually they require surgery of over four hours to get to the point where these deposit. And in the past medical history, of those who develop them usually demonstrates renal insufficiency of some sort in the past. Again, this is a generalized crystalline retinopathy. The crystals in this tend to be deeper in the retina and even sub-retinal and then often stay isolated in the arterials themselves. You can get the exact same picture with ethylene glycol ingestion as well. The maculopathy is not reversible in this. The primary treatment for this is prevention. So we don't use methoxy fluorine. Hardly at all, I don't think anymore. I think it's just about becoming extinct. And you definitely don't wanna use it in patients who have renal dysfunction. They've tried dialysis to get the improvement of the crystals without any benefit. This patient here, this is a very pronounced picture. This was a patient who was abusing cocaine, so he had really damaged his kidneys from that and then was also abusing methoxy fluorine on his own on the side and that's how he came up with such an impressive picture. And we won't typically see a picture like that, but a very pronounced crystalline deposition in his arteries there. Other one is nitroferantoin. Very rare, just a couple case reports in the literature and usually associated with people who were using it chronically as prophylaxis for recurrent urinary tract infections. Again, patients had both superficial and deep intranetal deposits that were in a surcinate pattern in the posterior pole. We don't know just how reversible it is because it's just two patients that I could find. A cessation was recommended in both of those. Talk retinopathy. Talk, in order to develop the retinopathy, typically that's associated with the history of chronic IV drug use. Most common one is Ritalin. So I was doing a little research on how people are getting the Ritalin and I guess with the most common form, you can hop online and Google it and all sorts of formulations out there for how to do it, and the most common method that I could find looking at it was that they seemed to crush the Ritalin in cold water, let it dissolve, try to filter it using a Q-tip head, the cotton end of a Q-tip head to filter out the particles. Ritalin is very guilty of it because there's a very small amount of medicine to the filler. The pill itself is almost all filler and so a lot of Talk filler in there that they filter with the cotton head they inject it either intravenously or intramuscularly and it's a lot of filter that ends up flowing around in there. So what happens is the unfiltered suspension flows in and it deposits most commonly in the lungs. It can also deposit in the liver and heart valves but from the lungs, over time it's developed and you develop an abe fistula and then that allows access to the eye and you get these deposits that flow to the eye and kind of give you a spread out pattern typically in the macula. Sometimes the deposits themselves can be small enough to move right into the lung on the first usage or of course if there's any heart defects such as a patent frameral valley or something like that you could get Talk that goes right to the eye but typically it requires repeated usage and time to develop the Talk pattern. And then what you can see in the retina is very similar to what you would see with diabetes or radiation or hypertension where you get cotton wool spots you can get capillary dropout, neovascularization very similar to sickle cell. So here's another picture of a patient. This was a 56 year old woman who on retinal exam had these crystals on history. She admitted to injecting some IV drugs quite a bit in the past. She ended up having a bilateral lung transplant and so this is her actual pathology slides from her lung and what's interesting you can see these these are form body particles here and she's got epithelioid granulomas as well in her lungs. She had COPD as well so it's hard to know how much of the lung damage that the authors thought it was mostly due to the COPD but that the Talk probably didn't help the cause and on her other slide here you can see these are all polarizable form bodies very consistent with Talk seen throughout her lung there. So that's kind of what her lung looks like when your retina looks like this. As far as treatment for it if you see Talk retinopathy you should probably follow them at a pretty regular interval because and you could a wide field floor seen in geography would be helpful to look for peripheral capillary dropout which would put them at risk for developing neovascularization. If you see it you would treat them with PRP. There's not really any good treatment for the macular ischemia that can result from this. They can also get cystoid appearance on the OCT like we've seen on some because these Talk molecules can go right to the macula and you get loss of nutrients to part of the macula and so loss of mular cells and you left with these little empty cystoid spaces in the macula. Next macular telangiectasia so it probably assumed to be more common than we originally thought. When they went back and looked at the Beaver Dam study data they said 0.1% of the adults or one in a thousand over 45 had evidence of mac telangiectasia and that was just looking at color photos. If they'd looked at, if we'd had SDOCT we probably would have raised that number to a higher number. There is some element of genetic inheritance associated with it although we really don't understand it. It's not autosomal dominant. It's not autosomal recessive. It's not X-linked. We don't understand exactly how it works but our own Dr. Bernstein was involved with a study that demonstrated that about one in 10 family members of people with mac tel will demonstrate mac tel changes even though we can't figure out the gene as of yet and we're not sure exactly how the inheritance works there. Most often it's seen in healthy people but there seems to be a predisposition of those who have glucose resistance such as diabetes for other risk factors. So first described by gas in early 1980s and then gas and bloaty in the early 1990s classified mac tel into three different groups. Yannoussi came back later and made it two groups which is easier for retina fellows all around the world to remember. I just think of it as type one and type two now. Type one and the easy way to remember is type one is unilateral. Type two is bilateral. So it tells you how many eyes are involved but type one almost always unilateral and it's a coach-like symptom where you have a male predisposition. You see the telangiectasias and you get these inter-retinal surcinate exudation right around the macula in one eye. And then type two is bilateral. So in this one it's 98% bilateral, a slight female predisposition and usually seen later in life, 40s to 60s. Changes that you see typically early you see loss of the transparency of the retina, sorry, then you'll start to develop retinal crystals in about 50% of people. We'll end up developing those. You'll start to develop inter-retinal cystoid spaces and then later at stage three and further on you'll start to see leakage on the fluorescein angiogram. Late changes are you'll start to get retinal thinning. You'll get pigment plaques like you can see here on these photos, plaques usually in the temporal macula and you can also get sub-retinal neovascularization, late atrophy, that would be stage five, the latest stage of mactail. The retinal crystals can be hard to see, as I mentioned earlier, about 50% of people with mactail will develop them. They do tend to aggregate temporally and are seen in the inter-retina right along the neurofiber layer or just below there. You also get these cystoid spaces that develop again. The thought is, so if you look at this FA here you'll see the hyper fluorescence here. The first stage is you get thickening of the capillaries, you get more leakage and you get loss of the nutrients that the Mueller cells need there. So the thought is you start to get Mueller cell drop out and then as a result of that you start to lose the photoreceptors underlying and the RPE as well. When you lose the RPE that allows some of the other RP cells around it to move up through where the photoreceptor drop out is and that's what's thought to give you the pigment plaques that you see associated with it. Other things you'll see is a lack, a loss of macular pigment optical density, retinal transparency and then of course leakage on the fluorescent angiogram. The most recent paper I saw, which was put out by the Mactail study group, hypothesized that these crystals are actually composed of retinoids from the triangular cells. And so this is our patient, again, this is an OCT I showed before, but you can see these crystals, superficial, along the nerf fiber layer, loss of ISOS junction. And that same paper said that the loss of the ISOS junction is a big risk factor for demonstrating crystals in patients with Mactail. Red free and confocal blue light reflectance are the best imaging modalities to see those crystals on, whereas you see less on infrared and you really don't see them at all on fluorescent angiogram or fundosodal fluorescence or ICT images. Management is somewhat controversial at this time. There's quite a few people doing different things because none of it works great. For type one, you can think of it like coats and it responds very similarly to coats. Laser photocoagulation can be beneficial and anti-veget, they tend to respond pretty well to those, whereas type two seems to be a complete different disease. It doesn't respond at all to laser and I know there's a lot of disagreement amongst different retina specialists on whether or not they're injecting this with Avastin, even amongst our own community, but in general it doesn't seem to respond at all to Avastin injections. And it's because the edema you see isn't true edema and leakage as much as it is. Empty space is left from loss of Mueller cells, although you can see leakage on the fluorescein. So Byeddy's first described by Dr. Byeddy in 1937. He had three original cohort patients he described and they all had this triad of posterior pole retinal crystals along with the tapitol retinal degeneration of the chloride and crystalline dystrophy of the cornea. Most cases of this demonstrate autosomal recessive inheritance, although there is some autosomal dominant inheritance shown as well. Usually it starts to develop after 20 years of age and it's slowly progressive. Very rare here in the United States from the West to see it, quite common in China. The central visual acuity early is pretty mildly impaired and late becomes quite severely reduced and nyctalopia often is associated with it. Crystals are present in all layers of the retina and ERG shows progressive loss of both photopic and scotopic amplitudes. The FA itself you'll see loss of the coriocapolaris quite late in the disease as well and the visual field you'll see in annular scatoma. So the biopsies of it have shown crystals that resemble cholesterol and so one thought is this just a lipid metabolism disorder but we don't know for sure exactly the mechanism behind it. The management currently there really is no treatment for it. Dr. Burson, he wrote an article where he recommended treating it similar to retinitis pigmentosa with high dose vitamin A which he thought might slow the ERG but it's really not good data with that. It's not very well substantiated that you get much improvement with that and genetic counseling of course given the nature of the inheritance of it. And then cystinosis retinopathy is another autosomal recessive disease. It comes in three forms. All forms you get cystine accumulation within lysosomes. If you check the serum levels you usually don't see elevated cystine levels. The most severe is the infantile or nephropathic cystinosis and they present pretty severely with loss of growth in the first year of life and then they have pretty profound symptoms of photophobia and paired vision and then conjectival, corneal and posterior pole deposits of crystals and the ERG is usually reduced in them. And then in the non-nephropathic form it's not quite as severe. You get the corneal crystals without the retinopathy and without as much of impaired vision. For the most part, those patients do pretty well and they don't have the renal dysfunction associated with it either. Most of them, those patients survive into adulthood and do well. And then the intermediate or adolescent form these patients usually present in their teens and they usually have only corneal and conjectival deposits although they can have some in the retina as well. And then, of course, variable involvement of the kidneys, the retina and other symptoms. So treatment of it, there's no specific treatment for cystinosis itself. It's associated with acidosis that you can treat with bicarbonate. It's associated with renal failure in many cases and you can do renal transplant for that. The renal transplant itself doesn't stop progression of eye involvement and other systemic involvement as well. And then, of course, cystiumenide drops are very useful for the corneal itself or the crystal deposition. Next, oxalosis. This is another autosomal recessive disease associated with an air and glycoxylate metabolism so they have increased production of oxalate. Usually these patients, they know when they have this by the time they're seeing us for the most part. In childhood, they usually have repeated episodes of ureolithiasis. By adulthood, they usually have kidney transplants due to kidney failure associated with such frequent ureolithiasis with so many kidney stones. The retinopathy seen in these patients is usually seen in childhood and you get these crystalline deposits that are in the outer retina and in the RPE deep in the retina. The definitive test is demonstrating increased oxalate on 24-hour urine samples. They'll get severe visual impairment, but usually that's associated to optic nerve head pallor not due to the maculopathy and the crystal deposition. That usually just causes mild vision loss. There are a couple of papers recommending treatment with pyridoxine and oral citrate with very mild improvement but not great improvement there. And then the regression of the retinal deposits has been seen in patients who had renal transplantation. These are X-ray diffraction photos here showing these crystalline deposits along the area of the RPE there. Chocon-Larsen, I've never seen this personally, very rare in the US. Quite common in Sweden, 1.3% of the population is heterozygous for this gene there and so more common there. But it's an autosomal recessive disease again. They often have congenital cataracts, almost always have retinal crystals. Usually these patients are almost always, I should say these patients are severely mentally handicapped. They have spastic dipleisure or straightening and stiffness of the legs. They have very profound ichthyosis, dryness and skelling of the skin, short stature, speech deficits. You usually know there's one case report of an adult who did pretty well, who had this genetic test done and had this, but for the most part all these patients when you're seeing them, they're handicapped patients in your room and it's known that there's some sort of genetic abnormality. It's associated with an enzyme deficient, fatty aldehyde dehydrogenase and they'll get these glistening dots in the periphobeal area. Histopathology's shown an increase in lipofucine granules around that. Again, genetic counseling recommended, especially those from the Swedish area where the gene is so prevalent and then dermatology, neurology management for skin lesions and associated seizures. As far as the eyes go, there's some thought that supplementation with median chain triglycerides might improve the visual potential in the eyes. We're getting there, I promise. Druzen, not really classic crystals, but you do get crystals late in the disease process. I wanted to cover Druzen quickly, the Druzen to build up between the RPE and the coreocapillaries, you can get Druzen build up basal laminar Druzen, basal linear Druzen, depending on which side of the Brooks membrane it's on. I'll remind y'all, I know a lot of you don't look at OCTs frequently, but here's your photoreceptor junction, your RPE, so you get Druzen development right in this area here. Early on, Druzen I think are pretty easy to differentiate from retinal crystals. Late in the process, as Druzen regress, you can get some brilliant crystal and formations in the retina. Here's just a patient with profound Druzen throughout, you can see the deposition of these Druzen just under the RPE there. And of course, it's associated with macrity generation and geographic atrophy. West African crystalline maculopathy is a newer one, this was described in the 90s. In this, you can get bilateral, asymptomatic yellow green crystals within the arcades in patients from West Africa. The original paper described six patients, 12 eyes, who all had this. The question is what caused it? There's a lot of questions on it, we don't have a lot of answers. So something that crystals pass through damaged blood retinal barrier, most of the patients with this have some sort of associated vasculopathy, whether it's diabetes or history of vein inclusion or fever. And the other question is it, due to ischemia that reduces flow through the axons unless the crystals build up. Toxic causes have been looked through, at first they thought it was colon nuts, all the patients who used it seemed to have a history of eating a lot of colon nuts, which is this addicting nut found in the West African area and it has xanthines in it, maybe they're getting a lot of it. But lately there have been a couple case reports of patients having it from West Africa and not having a history of any colon nut ingestion, I should say, I guess. Other things that they think might be associated, you can see the list there, but don't have a good answer yet as far as what causes it. Again, this is the patient seen before, here's his funesodal fluorescence, you don't see any crystals on that, which would be consistent with some sort of carotenoid or other process leading those crystals. And here on the OCT you can see the subtle crystals here in Henley's layer, the outer plexiform layer here and along the inner nuclear layer. Couple other things, just for the sake of completeness here, chronic retinal detachment can give you a classic crystalline retinopathy, superficial deposits of crystals, usually greatest in the macula and no deeper than the ILM. Frequently seen with dialysis tears, any resident want to tell me where the most frequent dialysis tear would be seen? Infra-temporal, you got it, exactly. Infra-temporal, so this is a patient with an infra-temporal dialysis tear, you see the retinal crystals here and further examination of the peripheral retina demonstrated that. This is one with a detachment leading up, I think this one might be seen even in the cornea clinic, it might pick up that detachment, but there's some retinal crystals associated with this one as well. Thought that maybe it's undigested photoreceptor cells. Again, two more pictures, of course the treatment would be surgical repair of the detachment, you could do that in many different ways, you could even laser barricade a dialysis tear, they've done that in many cases and the crystals usually hang around although they're not known to be the toxic in any way to the retina. Iotrogenic, so triumphsynolone is a newer one we've been seeing since we've had the big increase in triumphsynolone injections in the eyes. And with it, this is a patient who had a cronovascular membrane received a triumphsynolone injection and you can see these fine crystals throughout the macula. On OCT of the same patient, you see these crystals sitting on the surface of the neurofiber layer, they're subhyloid and you can get them with kennelog and also with triessins injection. It's thought to be associated more with the insoluble components of the triumphsynolone itself, not with the preservatives that are in it. So you can see it with either one. In this case, this is an article out of the Indian Journal of Ophthalmology, but they followed this patient for six years. The crystals never changed at all and it didn't get any better, it didn't get any worse. The author on the first paper recommended doing vitrectomy with membrane pill in order to get rid of them, but probably definitely excessive since they're not really associated with any visual problems. And then Iotrogenic, this is the TANO Diamond Dusted Scraper here. They've definitely been noted on the retina or in the retina following membrane pills in which the TANO was used. So TANO knew this when he first designed this scraper. He saw that these crystals would come off. These are diamond crystals. So I think any woman would love to have diamonds in her eyes. You could sell it at that. But they're about 30 microns in size and he saw them come off. So he, as part of the production of this, he would put it in an ultrasound machine to try to shake off the loose crystals. They're just loosely held on with a non-toxic silicone glue. And so, for the most part, they stay on, but there's definitely crystals that can come off when you're scraping it along the surface of the retina and be left on the retina. The recommendation, this is a patient who has two obvious crystals here after a membrane pill. The recommendation is to, you can just remove them with a soft tip during surgery if you see them, after surgery if you see them, probably just leave them. They're not toxic at all. So our patient, we checked the serum creatinine, that was normal. Good-looking patient. And we did urinoxilate levels, 24-hour collection, the patient canceled that twice. So we don't have those for sure, although it would be very unlikely in the patient. CNP was normal. Sent to Dr. Bernstein, because we think this patient has macular telangiectasia, sure seems consistent with it. So Dr. Bernstein, did you wanna, I know you're involved right now with the MacTel project. Did you wanna mention briefly anything about that? Any other questions or comments from anyone?