 Good morning! Happy Wednesday to all of you. Hope everyone's doing well. It's having a great week and enjoying some maybe some slightly early spring weather. It's starting to get a little balmy here in Salt Lake. It's my great distinguished pleasure to introduce our guest speaker who's our visiting professor, our first visiting professor for 2019 and also happens to be our keynote US speaker for this Friday for those of you that are attending. I can remember one of my favorite things to do at Askress is when everybody's left the hall is to sit at a little computer terminal and just scroll through videos. The Film Festival is one of the highlights every year and I can remember in 2016 I was looking through videos and I happened to come across this video by Dr. Yamani and when I saw the video before the voting had commenced I knew right away that this was going to be the winner. I just had a hunch that it was going to be the grand prize winning video and ever since then Dr. Yamani's been on a worldwide tour of describing his technique, sharing his tips and pearls but what we did know is that he happens to be an accomplished retinal surgeon as well. So today's topic is not what he's notably known for but I hope that you'll be able to enjoy his talk and be able to appreciate the innovation that he's bringing to this whole sphere. Dr. Yamani graduated from medical school from Yokohama University in 2002 and went on to become a staff lecturer there, senior attending and is now assistant professor there along with the senior lecturer at the Yokohama University. Please help me welcome Dr. Yamani to our grand rounds this morning. Good morning everyone. Thank you for inviting me and first I want to apologize of my poor English so if you can't understand or you have some questions please stop my talk and ask me. Today's talk is about an retinal surgeon not about IOL. I have no financial disclosures. I'm from Yokohama University. Yokohama is in the east part of Japan, near to Tokyo. Here is Tokyo and Yokohama is only 50 kilometers from Tokyo. This is our hospital and our hospital is mainly treated and retinal diseases. He is our professor, Dr. Karonosano, he developed ICG staining of ILM so we have many retinal patients. I specialized in both of cataract and retinal surgery. Yokohama is a very beautiful city with harbour, so please come to Yokohama if you have any chance. So today's talk is about CLAO, central retinal arterial occlusion. As you know this disease has very bad natural cause. Most of cases result in the B.J.R.R.K.T. less than counting fingers. We do massage or lower IOP for these patients, however no effect of conservative treatment was revealed. Systemic plasminogen activator, TPA use is a choice of the good choice for this disease, however the result is controversial. In addition, TPA has a severe complication that is a severe hemorrhage, so it's not easy to use. We developed micro needles before. The tip of the needle is only 50 micrometers, so we can directly inject TPA to the central retinal artery. So we started the pilot study to inject the TPA for CLAO. This is a prospective non-comparative interventional case series. We included CLAO with onset of symptoms less than 48 hours. We excluded the cases with an other retinal disease, glaucoma, joint cell arthritis, and liscent stalks. We performed 25-gauge parsprana biorectomy, then the TPA was injected using micro needle. We evaluated vigilakiti and blood flow, evaluated with an F-A-G, O-C-T-A, and LSFG, laser speckle fluorography. So micro needle is very thin, and the inner diameter is only 20 microns, so we cannot push by hand, so we use VSC system for injecting silicone oil. After biorectomy, we directly inject the TPA to the central retinal artery. So today I have five cases. The first case is 70-year-old female. Her vigilakiti is at 0.01. We can find a typical CLAO spot, and in O-C-T-A severe capillary defect was seen, especially in the inferior side. F-A-G showed very slow and blood flow, and upper side is not so bad, but inferior side is very severe. So this is surgical video. I penetrated the artery, central artery, and started to inject TPA. This procedure is very difficult because I can't move. In this case, very few hemorrhages because of the low blood flow. After injecting TPA, the artery a little improved, but not so significant. One month post-operative, F-A-G showed an almost normal blood flow, and the vigilakiti improved to 0.09. O-C-T-A showed improved of the macular capillary, however small capillary was still defected. The second case is 49-year-old male. His vigilakiti was hand motion. If F-A-G showed no blood flow, and F-A-G showed the same, no blood flow was seen. Then I started to inject TPA. They're completely occluded, so the arteries turned white. I injected TPA about one month, one minute, but no blood flow was seen. So I decided to inject another point from another artery, but it was so difficult. So I injected to the central artery again. I was so disappointed because of no blood flow now. Suddenly the hemorrhage was occurred, and I found the clot is moving. This is one of the most effective cases. Clot, if that was a TPA, all blood base cells goes white. So you can see TPA goes here. Now TPA is moving now. Very different from clot. Finally the blood flow was recovered. So we found the severe hemorrhage. So as you can see, spray injection, the artery was completely white, but it turned red after injection. One month post-operative vigilakiti recovered with 0.04. That was not so pretty good, but maybe if we did not do surgery this patient vigilakiti is almost like perception. FG showed a completely recovered blood flow, and SFG showed a recover of the blood flow, but the normal, the FLI has been about 30 to 40, so this part is not normal, about half of the normal. The third case is 72-year-old male. His vigilakiti was counting fingers. He has a serial artery, but it didn't cover the phobia. Only serial artery is remained, and the central retinal artery was completely occluded. Now the blood flow is almost completely stopped, and after injecting TPA, the artery turned white, because now the TPA is filled in the artery. So the blood flow was recovered. Plain injection, you can see the stop of the blood flow, and after injection, the blood flow was recovered. One month post-operative vigilakiti was 0.02. Still, capillary dropout was seen in OCTA. FG showed a recover of the inferior side of the artery, but superior side of the blood flow is not good. LSFC showed an almost normal value of the blood flow, but the upper side was occluded. Three months post-operative vigilakiti was recovered to 0.2, but LSFC showed a reduce of blood flow compared to one month. One month and the value is 28, but at three months it decreased to 9.4. We do not why, but we speculate the ganglion cell loss reduced the reduction of the decrease of the blood flow. Next case is 79-year-old male, the preoperative vigilakiti was 0.01. We can see cell loss spot, but in OCTA the blood flow of the macula is not so bad, but if I see the FBHG and LSFC, the blood flow is almost completely occluded, and this is about 10 minutes from injection, but for saying was not coming to the artery. In this patient, one month post-operative vigilakiti was significantly improved to 0.9, and amazingly at three months the vigilakiti was over 20-20. So now I think macular blood flow is very important for visual prognosis. The final case is 75-year-old male and he has no light perception, and OCTA showed almost no blood flow in macula earlier. We did the same surgery, but the blood flow was not recovered in this case. One month post-operative vigilakiti was hand motion and almost no recover of the blood flow. Three months post-operative vigilakiti was the blood flow was recovered, but the optic nerve was turned white. The vigilakiti remained hand motion. I performed this surgery on 15 eyes of 15 cases. The Abelage age was 70.9 and 12 cases of male and 3 cases of female. The vigilakiti was significantly improved to a week, one month, and three months post-operative vigilakiti. The Abelage baseline log more was 2.1 and it comes 1.4, three months post-operative vigilakiti. Three cases showed no change of visual acuity at three months, but others are recovered. We speculated ARIA surgery is better for patients, of course. However, the result was lepersed. This is a period from onset to surgery and this is a vigilakiti. Amazingly, the longer time case has better vigilakiti. We don't know why. The improvement of the vigilakiti is almost the same and not depend on the timing of surgery. The effect of surgery for blood flow may depend on the type, size, and position of the embryo. If the embryo is very large or very deep positioning, it's difficult to remove. The visual prognosis may be influenced not only by period after onset, but also by the macular blood flow and nerve damage. In conclusion, retinal and vascular surgery is effective for restoring blood flow and vision in CLAO. Now, we want to find which patient can recover and which will not. We think that OCTA is a good tool to find the patient with good visual prognosis. In FHAG, these two cases have a completely occlusion of central retinal artery. However, the OCTA showed very different macular blood flow. This case recovered to 2020, but this case is only hand motion. We now use OCTA for CLAO patients. We must think about using other drugs to remove the emboli. Plasmin is effective to remove the emboli, he said. Maybe prevention of apoptosis by new protective drugs are very effective. We want to combine with our surgery and new drugs in the future. So, retinal and vascular surgery can perform using micro needle and may effective for CLAO, but we have a limitation, so we should be combined with new drugs. Thank you for your attention. Questions? Yeah. Yes. No, this is not randomized. So, I think the issue that would be raised is that clearly you're showing that there's some improvement. Is that the most powerful evidence is in comparison to what results you're getting from treatment with what the natural history might be? Yes. And until people see that, then they're saying, well, it's hard to know how much was a treatment effect and how much was just a natural history outcome of the disease. Yes, but we have only small cases belayer disease, so we cannot conduct a randomized clinical trial. So, there's other ways of looking at this. I mean, if you're going to submit a paper, you would want to try to get a control group of some type of those who didn't have treatment. I mean, it's not nearly as strong, but some type of a cohort comparison that you consider doing that. What is the natural history of people who did not get this and try to get so that there is as comparable as possible to at least show that it would appear as though this is an effect above the natural history of the disease? So, if you've got it, I mean, there's clearly plenty of people who have not been treated with surgery or TPA, and those kind of curves, I think, would be extremely important to at least suggest that this is something that's important to be tried. Yeah. You have a time limit following when the patients have their onset of symptoms until you can do an injection. I mean, is there a limit of a certain amount of hours or days before you go in and try to do the injection? Yes, we defined 48 hours in this study, but as I showed, and the result was not... It's what we call counterintuitive. We would expect the longer you go, the worse your results, and you're showing that as you get out towards 48 hours, you actually had potentially better results, which is what we call a head scratcher. That's hard to explain that. Do you have any idea why? I mean, typically, and it's more than just theoretical. I mean, the evidence is pretty clear. If you're not getting blood flow, what we say is the clock is ticking and things are starting to die, and so you're going to get to a point where the damage is done and you can't resolve it anymore, and yet this would indicate that even up to two days later you have the potential for return. That's maybe just your number. What was your p-value for this? You know what the p-value for your regression line was? I'm not sure, but this is only a small case. With the p-value statistically significant, because this could just be random. In other words, it just so happened that on a few cases you have a line that doesn't fit with any particular theory just because it's not significant. It's a random outlier and there's going to be a regression to the mean, and over time that will get the line we expect, which is the longer you wait, the worse the outcome. I'm just looking at those numbers and what you have. I'd be surprised if that regression line is statistically significant. I think we probably need more numbers to know if that's a real finding. Paul, would you agree with that? Well, I would say that it might be statistically significant if you did the non-parametric tests, but I think the interesting thing that he showed and that you won't correlate is what the OCTA showed, because I think some of these people that have gotten macular blood flow going, right, they have kind of a stuttering onset, a little bit of blood's getting through. So they're surviving? Yeah, so I think that... So OCTA may explain you? Yeah, I really look at them very closely and see how stable is that, because are these true heart-stop CROs versus... Because if they were full heart-stop, it's hard to explain why they won't be getting... Yeah, so it's difficult to evaluate the macular blood flow by FHG, but OCTA showed a good data. Well, it's fascinating, and it's a disease that certainly... There have been lots of different things people have tried over time. I mean, back when I was a resident, it was not uncommon. You tried to tap the enter chamber to suddenly lower the pressure, and there were certainly anecdotal cases where that would work, but as a regular treatment, that's pretty well fallen and does favor. And so a better treatment for these medical emergencies, these ophthalmic emergencies would certainly be a real positive. It would be good to get more people involved and trying to get a better handle of larger numbers against natural, at least for a cohort study. I agree there are few enough now any single individual could not do a randomized clinical trial, but I think in order to consider one, there ought to at least be a pretty well-controlled cohort study of natural history without treatment to suggest that the effect is at least moderately robust. Yes. Yes? Judith. So just to sort of bring things into our local realm here, I mean, I think that there have been lots of studies of attempting to acutely treat central organ artery occlusion as if it's a stroke in the brain, just similar parameters. And there's a lot of controversy out there as to whether or not it's effective IV or intra arterial. They can cannulate the ophthalmic artery fairly easily and geographically. Obviously, an intra arterial injection intracranially carries significant risks, as does IV or intra arterial TPA given systemically because of risk of hemorrhage in various body parts. But I think that the current status is that if you have a patient with a central organ artery occlusion who turns up in the emergency room and you can get them examined quickly and confirm that that's what the diagnosis is, that many of the neurology stroke attendings are treating that as a stroke and they will give intravenous TPA as a sort of, kind of on a compassionate use basis. It's much harder to go to the intra arterial route, although some studies suggest that that might be more effective when the TPA, when the CRA was a little bit longer. But, you know, we're really talking just like stroke six hours for IV and maybe eight to ten hours after onset because of, as Dr. Olson was saying, you know, time is ratcheting, I guess, in this case. So, are we doing that here? I mean, right now that's happening and generally if it's within six hours they're doing intravenous and if you're sitting between six to ten, is that something you'd say that's routinely being happening now? It's not routine because they're, first of all, it's not very common for people to come in within a couple of hours of onset of their vision loss and then they do have to be examined and, you know, all of the stars have to be aligned to get this to actually occur. But it is something that can be done, basically calling a brain attack is what they call it. So, we've got a category of interventional radiologists now that are good at threading cantors up to the ophthalmic artery. That's how we deliver it to our children with therapy for retinoblastoma. And it may be, you know, something to think about, not if anybody's doing it, but using that to get TPA closer to where you need it, just a little bit upstream from what you're doing. So, that was what I was referring to, the inter arterial. They're delivering it there? Yeah. Okay. Not through the eye, but through the ophthalmic artery. Cool? That's good stuff. Unfortunately, it comes up so infrequently that it's a bit of a hullabaloo every time it happens. Right. But, you know, under the right circumstances it can occur. But it's a constant ongoing debate. I think that although there have been studies suggesting that it doesn't work, there are many people who say that those studies were not done properly and that they allowed people and who were well outside the realm of when there's even any possibility that it would work theoretically. So, that just like with stroke, time is of the essence. So, it seemed to me that because it is infrequent enough that maybe something, somebody, a group like Nanos, try to get together a group to answer with enough numbers to try to look at these different approaches to see if we can't get a better handle because it's my understanding that it remains a bit controversial and that it's out there and it's a big unknown. And so, it's a bit hidden, missed exactly what happens in association with this diagnosis, particularly when you pick it up acutely. But our policy is we do treat with TPA, typically intravenous and interarterial, if it's after six hours, but no less than 10. I think that's off the top of my head, the recollection, I could certainly, Dr. Katz has been involved in, quite involved in sort of forming the protocol with the stroke the stroke team. Do you remember, sorry, I'm sorry, I can't remember exactly the numbers, but I can certainly forward the policy to Susan so that she could maybe distribute it widely to the faculty and residents. Do any of the residents who've been on Congress recently remember or, I mean, just like I say, it just doesn't come up, you know, maybe once or twice a year where something happens early enough that it could even potentially occur, do you know, Gene? No, I mean, is what they want them to do. No, there was, there was a year ago that I read the articles on it and I think it was a two to four percent intracranial hemorrhage risk. Right. And so, the recommendation was not to do it because the visual QA gain was so low. Well, that's what some of the studies have suggested, it was not statistically significant. And so, exposing someone to a two percent risk of a brain lead wasn't worthwhile. So it sounds like now that we have this new technology and with the paper you have, which I would strongly recommend that you put a big emphasis on the impact of the OCTA picture of the macular association with outcome, that there's a new variable here that should be considered and this is something that, you know, someone ought to pick up as a multi-centered trial as a study to try to answer that question. There's no single center in the United States is going to have enough numbers to be able to, you know, answer that question in a timely fashion. The other problem is that, and I think that our retina colleagues could comment on this, is that generally speaking, fluorescein angiograms improve after centrioral artery occlusions. Anyway, you know, a month later you might not be able to use a fluorescein as a helpful tool for diagnosing a month ago centrioral artery occlusion, because blood flow does normalize, but where it does improve quite a bit, but it's a pure victory. Because the optic nerve is chalky white and there's nothing there. Right, and the retina is, I've called you. No, no, I agree, and I think, you know, since we have OCTA, I think both in neuroop and retina, that should be our first line, because you can get that and they can be done in five minutes and we can send it onto the emergency room, rather than in FAA and getting approval and getting it done. You know, that slows things down. OCTA is fast. And probably from what your work is done prognostically may easily be far and away more important. I think that should be standard now. I recommend that, for sure. Well, I think that if Brad's the one, let's have someone here to help us so that we've got a consistent policy on that, and then I highly recommend that somebody back at NANOS probably start talking together. Yeah, you know, they've had point counterpoints in, I can forward that stuff as well. I mean, this is obviously a huge topic of discussion when you get to the national meetings, and then you have sort of ongoing debate on our lists or discussions and things. Is there a national champion who's really been interested in this? Yeah, there are. Valerie Buce is a very strong proponent of treating arterial events in the eye like arterial events in the brain. Right, right. I know it's been a big debate in regards to preferred practice patterns and the academies involved. I think that you have I've gotten the middle of that about some almost knockdown drag out battles between different groups. Yeah, it's like that. But I think you have plenty of support for not doing anything because I think that there's plenty of naysayers in the literature. Mike? Yeah, on polls, we do have a protocol for the CRAO presentation, and it's called if it's less than eight hours, that it can be diagnosed like they get an ophthalmology console, and we say it is a CRNO, and that's what you call the brain attack. It doesn't say whether or not to give TPA. Mike, we should add OCTA to that. It at least erratically makes a lot of sense, and over time I think it should be pretty clear what it's going to tell us in regards to the prognosis. So this is where things get complicated because I would say that probably the majority of people with severe acute vision loss like that end up in the emergency room rather than coming to the retina clinic, and then when you start transporting them to the Moran for a whole bunch of diagnostics, then, you know, the clock is ticking. And so there's a huge debate or conflict or waiting of interest between time and diagnostic tests. So they don't have an OCTA in the emergency room, and, you know, even pausing for a dilated exam is, that's time. You know, that's a half an hour of, you know, of time that is going by. So, theoretically, yes. Practically, what you're saying is... Yeah, and that's one of the problems with these protocols is that, you know, that, oh, we're going to do a study of this, and then, you know, everybody gets involved in that, oh, well, while we're doing that, we should do this test, and we should do that test, and then, you know, tick-tock, you know... In an off-hour such a setting. Yeah, I've never been told to get an OCTA. I mean, with Brad and with the Stroke Neurology team, I've been told if I see a central retinolary occlusion or a red retinolary occlusion, even, I believe, it's within seven days that I should notify the stroke team, at least so the patient gets a rapid workup and not a delayed workup over a week. They can do the workup in 24 hours, you know, so... Well, we don't have Brad here. Listen, Brad, Brad, but it is a test made on relatively rapidly, and it would not surprise me that it has important prognostic implication. So, we're not going to solve that here, but I think Brad's... Well, you've got an OCTA for the Neurology ICU. There you go. Any other thoughts or questions? Thank you very much.