Richard and Leonora Hill Lecture Series

DR. ZADNIK
So, as you know, Dr. Brunstetter received a bachelor's degree in molecular biology from Grove City College, and then his optometry, master's and PhD degrees here. He also has an executive MBA cause he didn't have quite enough letters after his name from the Naval Postgraduate School, Graduate School of Business and Public Policy. So he served as principal investigator at the Naval Aerospace Medical Research Lab in Pensacola, Florida, studying night and dynamic visual acuity, eye movement patterns of aviators, and G tolerance and endurance. He revised the US Navy's unaided night vision training course, and that system permitted students to dark adapt in real time and experience visual illusions and disorientation unique to the night flight environment. At the Naval Air Systems Command, he was the systems engineer for the almost $8 million Joint Service Advanced Laser Eye Protection Advisor program. He also served as research director for the US Navy refractive Surgery Program. His studies in that role permitted data-driven decisions in the Department of Defense regarding optimal refractive surgery protocols for service members. And the results of his 500 subject LASIK in naval aviation study directly led to the approval of LASIC for US naval aviators and aircrew. So imagine the people who thought they couldn't pursue that kind of career and thanks to Dr. Brunsetter's work found that they could. That's page one. Not double-sided.

So amidst all the other achievements, he was detailed to the NASA Johnson Space Center Space Medicine Operations Division as a Department of Defense Aerospace Medical liaison officer to support the investigation and mitigation of a unique condition affecting the eyes, which I think is what he's going to talk about today, The eyes, brains, and vision of astronauts during spaceflight, spaceflight associated neuroocular syndrome, and I know you've all been thinking about space and astronauts of late, so I couldn't believe how great it was that Tyson was going to become our speaker, but I will tell you that I think the other thing Dr. Brunsetter has done, which isn't, wouldn't be reflected in his formal bio sketch, is he's put optometry front and center in front of all these various military studies and work, and now he's retired, but he's at NASA. And I think that I, when I think about optometry and our graduate program and Ohio State University being represented by Tyson Brunstetter, to the Department of Defense and military colleagues, kudos, young man. It's just absolutely fantastic. So please join me in welcoming Dr. Tyson Brunstetter.

DR. BRUNSTETTER
Thank you so much, Karla. can everyone hear me? OK. I don't like my bio. I don't like having it read right next to me, but I understand it. And, so thank you so much for the, the warm welcome and thank you so much for this incredible honor. to be a speaker for a Hill lecture is, is really the pinnacle that I think folks strive for. for me it goes further than that. when I was here at Ohio State sitting in similar seats but much older seats I was privileged enough to pursue a master's degree under Barbara Fink, but immediately beside, Dr. Fink was Dr. Hill. He spent so much time with me, this, this young person who really had no idea how to conduct research and he showed me the way. He showed me the path, he showed me how to publish and I desperately looked for photos that I could, I could show here today. Then I realized that I'd moved 7 times. Since I graduated and pictures were in boxes everywhere, so I did find this, this handwritten note from Dr. Hill, letting me know that our publication was on the way. It was, it was not accepted by this point, but received by the Journal of the American Optometric Association back in '99, and of course we had some revisions to do. So, you know, he was the dean when I first arrived here in 1993, so this being here today means a great deal. So I really do appreciate that.

It was about at this time, when, life was in black and white, as you can see, I don't think we had color film back then, But I swore into the US Navy. I don't have a military background. It was a leap of faith. I thought, well, this will reduce my student loan debt. It'll ease up my financial burdens. And so I signed up and I thought, well, I'm just going to do one tour. I'll get out. I'll probably come back to Ohio and see patients. But at that time, the Navy said, Well, we would like you to pursue a PhD, and I thought, well, Maybe, you know, I've learned a lot from Drs. Fink and Hill. Maybe I need to look into another area that may be a little more applicable to military, especially military aviation. And so, I then worked with Dr. Fogt who you know, it must have been more recent because it's in color here, but, what a, what a great experience to be, working with Nick for those years, in another incredible mentor. So armed with this, I then went to the US Navy. I realized that I didn't quite understand, I couldn't understand naval aviation without wings, and so I was able to go through the naval aerospace optometry course. I got my wings. It allowed me to fly any DOD aircraft with two sets of controls. I worked mainly research, development, tests, and evaluation during that time. and eventually in 2016, I was approached to, to serve at Johnson Space Center, which of course I said yes.  so, I arrived there, but.

We also had the opportunity to come back to Ohio State on different occasions. One of those was helping to validate a new goggle-based visual field device that had been developed for NASA. So Jenny and Nick Fogt and team came together and helped to validate that system. And then we on the other side took it on the vomit comet and used a few bags in, in the process, but, just one example of those great collaborations over the years of, of us all working together. I would not be where I am today. I would not certainly not be at NASA if I didn't have my OD, my PhD, and my wings, without a doubt.

So anyway, we're not here to talk about me, but I wanted to give a little background. I wanted to definitely show that connection, appreciation for Dr. Hill and all the experiences that I gained from Ohio State. So, as you know, you might recognize a few of these people here as the folks, excuse me, who recently went around the moon, the Artemis 2 crew. so as you know, astronauts are now venturing outside of the Earth's protective magnetic cocoon and outside of the Earth's gravitational. Fields, so that return to the moon is called the Artemis program, as you're probably very, very well aware, we had just a really successful mission here in the last couple weeks. But from there, from the moon as a base, the plan is to go to Mars, humans to Mars.

Now the critical difference here is the duration of the mission will drastically change to a period of time that humans have never been outside of Earth's atmosphere. Duration will be between 2.25 and 3 years, but keep in mind you have no option of an early return. When you're when you've left, you're gone for the next 2.25 or 3 years. You can't pull over at the nearest urgent care facility. If you get a foreign body in your eye, well, it's on you. You, you and your crew have to figure out how to solve that problem. So you can imagine there are absolutely unprecedented challenges in engineering, but also in health and human performance. And so I've listed some of the the top human risks to these exploration missions. One is radiation. Uh, this one will be a big one. What about behavioral health? Could you imagine being a small tin tin can with your spouse for three years? Your dog, your cat, I mean, fill in the blank. Could you imagine being in a very small enclosed space for 3 years? That will be a great, great challenge. What about in-flight medical conditions? What if you develop appendicitis, what will you do? Or what if you develop a venous thromboembolism, which we have diagnosed in more than 1 crew on board the ISS, uh, particularly in the left internal jugular vein. This is considered to be one of the two top risks to human spaceflight, as well as spaceflight associated neuroocular syndrome or SANS, and that is the area where I study.

So over the years I've collected various SANS headlines, and if you take a look at at all the headlines, they're a little bit negative. I think the more important one is a Mars mission showstopper, eye problems, eyes at risk, blinded by space, vision problems, eyeball squashing on the ISS. Spacemen on the way to Mars will have to wear swimming goggles to save their sight. interesting, but there's a little bit of truth in there. So, The eyes and vision of astronauts have been examined at pre-flight and postflight in all crew members ever since the mid-1960s of the Gemini era, and for the decades since then there have been many anecdotal reports from crew members of in-flight vision changes. It never really rose up to the level of great concern, but keep in mind these missions were all for the most part, short duration missions, usually 14 days or less. But hundreds and hundreds of people have flown in space in short duration conditions.

Everything changed in 2005. That's when the very first SANS case was discovered in our optometry clinic at Johnson Space Center. It took, as you can imagine, it took a few years to realize that this wasn't a condition affecting one crew member. It was affecting the population. So it took, you know, we don't send that many people to the ISS, so it took quite a long period of time to realize this affects the population. The result was in 2010, the establishment of a new series of ocular visual tests and beyond, including MRI. These occurred not only pre-flight and postflight but also in flight, critically in flight for the first time. And I will say the current core battery of tests that we perform in flight have been performed since 2013, so roughly 12 or 13 years or so. And you can see in the pictures at the bottom, some examples of some of the ocular testing that we perform, like visual acuity, ocular ultrasound, the fundus photography, and, and OCT. There are 4 primary signs associated with SANS. I call them the big four, optic disc edema, chorioretinal folds, glowbe flattening, and hyperopic shifts in refractive error So if you take a look at the at the image here, the color photo, you can clearly see this area surrounding the optic nerve head that's blurred. it's blurred because of optic disc edema, and actually that optic nerve head is protruded towards you from the screen, if you could see it in, 3 dimensions. Over here is an OCT cross sectional image right through the foveal area of a crew member, and you could see the, the jagged chorial folds at the bottom and some retinal folds at the top. you can imagine that one of the risks, due to foveal choroidal folds would be metamorphopsia or distorted central vision. Luckily we haven't detected that yet in any crew members. Down here in the lower right are postflight MRI of the globes, and you can clearly see the flattening that can occur in our crew members.

Now, what about the symptoms of SANS? Well, unless you as a crew member notice vision changes, you're basically asymptomatic, no issues whatsoever. So, here's an actual SANS case. So this is a pre-flight image. These are multicolor images that we capture with OCT and you can see normal optic nerve heads here, both the right eye and left eye and the crew member. This we published back in 2024, so if you're more interested in a full case report, you, you can find that. But take a look.

I will jump from pre-flight to in-flight. So, notice any changes there. so for the right eye, which is on the left side, you can see uh optic disc edema, you can see that blurring of the optic nerve head margin. You can also see what almost looks like a fingerprint here. Those are retinal and chorioretinal folds On the left eye, you can see an actual protrusion of the optic nerve head with a blurred margin, as well as some, chorioretinal folds as well. These were taken, around flight day 90 to to flight day 150, while in flight. So I'll go back to pre-flight normal to in flight there in one of our more severe, cases. So the prevalence of SANS, now this covers all levels of severity. This goes from just a trace of, say, optic disc edema all the way up to severe levels. So and these these are composed of just NASA, ISS long duration crew members, data collected from July 2000, around the beginning of the ISS to May 2025. So 69% of all these ISS crew members are diagnosed with some level of optic disc edema, again, from very mild trace up to more severe, 25% diagnosed with chorioretinal folds, 37% with significant globe flattening. And then 20% with refractive error shifts greater than half of a diopter. Overall, the prevalence of SANS, one or more of these findings are found in 81% of crew members, so the vast majority of crew members who fly long duration space flight. But Clinically concerning SANS is only diagnosed in about 16% of ISS long duration crew members. What does this mean? Well, they've reached the level of, let's say, optic disc edema that meets our threshold of clinically concerning. That means they might have chorioretinal folds encroaching in the macular foveal area. they may be reaching the point where their refractive error shift is getting close to the maximum amount of prescription power that we've given them in their backup bag. so at this point it requires additional monitoring.

So we typically see them, about once a month. We oftentimes perform OCT and multicolor imaging in them. Sometimes we perform amps or grid if they're chorioretinal folds in the phobia. This would also be the flag for countermeasures. We'll talk about countermeasures and treatment in a moment. Now we do see other ocular signs in crew members during flight. We occasionally see cotton wool spots. You can see an example of that in the upper right here. We don't see that very often. I've seen one case in the last 10 years. We occasionally see retinal hemorrhages. Not very often I've seen one case in the last 10 years. We see very frequently signs of venous overload choriopathy. and that would include retinal cystoid spaces like the red asterisk here on the right, or, retinal pigment epithelial detachments or PEDs. We see these two, the cysts and the PEDs. I'm guessing somewhere around 20 to 25% of crew members. That indicates that there's something going on with choroid, pachychoroid in particular, And that's causing some issues in the ability of the RPE to pump fluid back into the choroid from the retina.

Very rarely we'll see Serous chorioretinopathy. we have seen it one time in flight during my 10 years there and, one time postflight which occurred in a crew member who had a PED in that location in flight. And there is some evidence, some suggested evidence that there are choroidal anastomoses that form in crew members due to long duration space flight. We're about to perform a study to look more closely at that. What that would tell us is that if there are anastomoses formed in these locations that you and I probably don't have, it indicates a physical and anatomical modification to the vascular system of the choroid in response to. What we'll talk about in a minute, but most likely some type of a venous outflow obstruction or resistance.

Now if we see Choroidal anastomosis. What else could be happening, say, in the brain, because we do see brain changes with long duration spaceflight as well. we have diagnosed retinoschisis in one case due to ocular ultrasound on orbit, and then we routinely see just a small amount of optic nerve sheath distention. Now, some of these may or may not be associated with SANS, but we have to keep an open mind at the possibility. So why do we think this is happening? Well, let's, let's focus on long duration missions. So on board the ISS it's typically 6 to 12 months of duration.

So we're all astronauts, we fly up on our spacecraft and we go into microgravity. And so the very first thing that happens, you get a headward fluid shift. So, about 1 to 2 liters of fluid wants to move from your lower extremities when you're in gravity. Gravity is pulling that fluid down. Once you're in microgravity, the fluid can move upward, and it tries to uniformly distribute within the body. So that means 1 to 2 fluid liters of fluid moving from your lower extremities up towards your head.

And so, my really terrible joke that I've been using for a decade is this weekend when you get your Domino's pizza and your 2 liter of Coke, imagine trying to shove 2 liter of fluid into your skull. Something's gonna give. So what gives? Well, you can see right there, these two crew member examples, Peggy at the top, of course. Pre-flight is on the left for both, and in-flight is on the right. If you look at Peggy, she almost looks like she has an ocular allergy. Her eyes are a little bit puffy, but that's the fluid shift. If you take a look at Chell, good looking guy on the ground, but he kind of puffs up like a, like a watermelon, and this is one of the better pictures, Chell's an awesome guy, but I, I do pick on him for his fluid shifts, but he is a very good example of all that fluid going up into the head.

So what happens is we know for sure this fluid shift causes vascular congestion. Your internal jugular vein expands greatly. It's very, very increased in diameter. the choroid thickens in all crew members on average. You may have little areas where it thins, but overall, on average, the choroid thickens. which of course can, can cause the PEDs, the, the cysts, etc. etc. What we don't know for sure is, and that's why there's a dotted line there, is what happens to intracranial pressure. Our best guess based on terrestrial data and parabolic flight data, is that intracranial pressure may mildly elevate, but it's sustained. What I mean by that is there was a parabolic flight study that used 0 G's in folks who had an Amira reservoir implanted in their ventricles. They were able to directly measure intracranial pressure.

What they found was when the subjects were on the ground, like for example, when we were asleep last night laying in bed, our intracranial pressure is pretty much maximum at that point for the day. But as soon as you get up and you start moving and standing, gravity pulls fluid down, your intracranial pressure goes to basically a minimum. So you get relief. It's high at night and then low during the day, you get relief. Well, what they found in this parabolic flight study is that the intracranial pressure in these in these subjects was somewhere between supine high and vertical terrestrially, somewhere in the middle, but the difference is they can't stand up in space, you can't get that relief. So our best guess is that. Intracranial pressure is mildly elevated, not the pathological levels like uh idiopathic intracranial hypertension, but mildly elevated and sustained. You don't, don't get that relief. Regardless of the path, the big four signs of SANS is what's produced, and keep in mind, like, like we saw with the prevalence numbers, it can be an a la carte. You can, you can pick and choose kind of what SANS signs you want to have, and they are so random in many ways that it doesn't allow us to kind of figure out what causes what are they caused by the same source or. it makes it very interesting, very challenging, but very, very frustrating, and at such low sample sizes compounds the issue.

So the very first manuscript on SANS was written in 2011, and, I've told this story today to some folks, but, I was in my navy khakis in San Diego and I read the manuscript and I thought this is, this is amazing, this is, I need to learn more about this, and then I laid it down and I told myself, but it's NASA, they'll figure it out in six months. And obviously it's not that easy.

It's not, it's not just intracranial pressure, it's not just venous congestion, it's probably multifactorial. And there are also brain structural changes that I won't go into today because of the amount of time we have, but the lateral ventricles, for example, will increase in size by about 10 to 15% due to long duration space flight, and the brain position will actually shift upward in the skull. If you take a look at MRI's pre-flight to in-flight, so there are brain structural changes as well. The changes are not visible on short duration crew members, so duration plays a role. And there may be other factors, altered sleep like sleep apnea on the ground will elevate intracranial pressure, when you're up in space, if you don't have good circulation, you can create CO2 pockets right there in front of your face that that doesn't move, convection doesn't occur in space, and if you breathe in high amounts of CO2, that's a potent vasodilator, can compound these issues. And then there's a one carbon metabolism theory from a genetic standpoint that is also being suggested as a factor in SANS, and we'll talk a little bit more about that in a moment.

So you've probably already put this together in your own mind, but there are in-flight and long-term health risks associated with SANS. You can have visual field defects because of the optic disc edema. Those can be temporary or permanent. You can have central vision distortions due to the chorioretinal folds and the phobia. You can have retinal atrophy because of chorioretinal folds disrupting the RPE. chordal neovascularization because of the same reason. Potential cognitive decline and neurodegenerative disease as well, for example, Alzheimer's or dementia. Luckily, we have not detected any permanent loss of vision in any crew members, and we have not detected retinal atrophy or anything at that level in crew members for durations of 6 to 12 months with a limited sample size. So let's talk about how we collect those data. So this is just a general overview of some of the primary tests that we perform. I thought this audience might be, might be interested in that, so you can see them listed on the left hand side. On the right hand side, I list when exactly we perform these tests. So we've got, of course, pre-flight, we collect all the data on pre-flight, all the data on post-flight. But we, we can't send an MRI into space, so, um, it'd be a little heavy and the whole magnet thing could cause some problems, and so some of these tests are only performed on orbit, and, some aren't.

So, Oh, yeah, real quick. So FD 30, that stands for flight day 30, flight day 90, and then R minus 30 is 30 days before return. So return minus 30 days. So 3 tests of MRI of the brain in orbits. comprehensive eye exam, you can see what we do. I think most people agree that this is a reasonable list, and that includes optical biometry, and the OCT, of course, which establishes our baseline OCT for follow-up imaging, on board the ISS. Multiccolor imaging is used, on orbit as our basic retinal photography method. It saves us a lot of time from having to pull out the traditional funduscope. And we found that it allows us to diagnose any of the same SANS signs that we would diagnose normally with color photography. Visual field, we do it, you know, traditional 24-2 so the standard Humphrey pre-flight and postflight, but we just recently were able to deploy the Oculussmart field that you see on the right hand side to the ISS because it's a relatively small footprint device. So we've sent that up there to determine whether or not we actually see visual field defects due to space flight in that environment. it got up there in, September and we ran it through its paces. We call it, activation and checkout, in October, so it's ready to go for any clinically concerning cases.

Vision screening, Christina, actually, this is, she just went around the moon, but this is a photo from her days on board the ISS several years ago, and I just love her, her post, "float right there." Words I never thought I'd hear my eye doctor say.  It wasn't me. I'm not a remote guider for visual acuity, but how cool would that be? And you could tell we have solved the problem of test distance for near. We use a string. It works really well for distance, a little bit harder because you have to float right here and that's not exactly easy sometimes, but we get, we get decent data. We measure visual. At distance and at near, corrected and uncorrected, and we do a vision questionnaire as well. What symptoms are you experiencing? Have you changed your glasses to a higher power? Do you hear pulsatile tinnitus or other signs that would suggest elevated intracranial pressure? And we also perform Amsler grid because of the chorioretinal fold risk. OCT, this is our workhorse. We love the OCT. It gives us definitely the best quality data that we obtain. Retinal photography, you can see our old school, retinal camera there, but as I mentioned, we have since moved over to multicolor imaging from the OCT and it works extremely well. Very, very happy with that ocular ultrasound, you can see Johnny Kim, who flew, I guess that was last year. He is performing ocular ultrasound on himself and, this is.

I love giving this example here. So, When you think about space flight, you almost always have to spin your brain. You have to think a little bit differently. And so this at this one ocular ultrasound session many years ago before I was at NASA in 2016. There was an astronaut on board the ISS about to perform ocular ultrasound, and his name is Don Pettitte. When you think of astronauts, you think smart people. They're here. Don Pettit is up here. He's freakishly smart. He has designed, this is a total tangent. He has designed a totally open coffee mug that you can use in space. It doesn't spill the coffee. You can float around, you can go upside down, you can do whatever you want. The coffee does not come out, and you can sip it like you normally would on the ground. So you can look it up. I think he has a patent on it. In case you want to buy one for your next space flight I'm not sure it's a big moneymaker at this point, but, but that's the level of thinking he, he is at. So, so imagine you were the remote guider, you're the person remotely guiding Don Pettit inocular ultrasound. You're down to mission control, he's up on board ISS and Don says, hey, why are we using ultrasound gel for this? And of course the remote guider said, well, you need a medium, you can't just use the probe, it doesn't work that way. And Don said, well, I understand all that, why aren't we using water? And the remote guider thought, wait a minute, that's a really good idea. Sure enough, you take water in space, you squirt it right here in front of the eye, and it stays. It adheres just like ultrasound gel would, it's a little less messy, and it gives beautiful images, and so we always use water now.  

But you know. It's $35. What's the big deal? You could $35 to buy a 12 pack of ultrasound gel from Amazon. What's the big deal? You order it and you have it delivered. Well, the problem is shipping and handling. It is $150,000. It's about $10,000 to $20,000 per pound, and you can't use ultrasound gel for really any other purpose. So the point of the story is that you have to be very careful what you deploy, and it has to, you know, to the best of your abilities, it has to be useful in other ways, not just ultrasound gel. Now, the good news is if we spent all that money, the good news is there are free returns, so. Maybe we'll get that money back.

And then tomography, we, you can see the note there. ESA is the European Space Agency. That's the only agency that requires us to measure intraocular pressure routinely, otherwise it's as clinically indicated in everyone else. Now why is that? Why wouldn't we measure intraocular pressure? It's important, right? We measure it all the time in eye exams. So here's where the balance is. We don't just walk up to the NASA engineers who run NASA. We don't just walk up to them and say, we have an OCT device we'd like to deploy it and we'd like 40 minutes of your crew member time,  

Actually that happened in about 2012 and the engineer said, well, what are you gonna give up? So all the, all the SANS people got together and they thought, well, we're not seeing a whole lot of significance with our Tomography data, so we can give up that time in order to deploy OCT and get that time. I've heard estimates of the amount of money per hour for one astronaut is about $100,000. So you know, you think you make some good money. It's about $100,000 per hour per crew member, and for many of these you can see we have two crew members performing tomography. So there we have to worry about cost.

Crew member time is probably the most precious commodity up there, and in space we have to be able to pack these devices away, and ISS is relatively big, so we can, we have the luxury of sending an OCT up there. We won't be able to send Spectrallis to the moon, I don't think, or to Mars, so we're developing miniaturized OCT device for that. So that's why we don't perform tomography all the time on NASA crew members.

So countermeasure strategies, so we have the same flow chart. Honestly, the only true effective countermeasure we have are space anticipation glasses. Those are glasses of extra positive power that we send with the crew members for their mission. So on the ground, Bob Gibson is our clinical optometrist. He is the astronaut's optometrist. He will do a cycloplegic refraction. He'll look at the age of the crew member, look at the previous missions that they have, and he'll decide how many pair of space anticipation glasses to deploy with them. The very first pair of space anticipation glasses is 0.5 diopter more plus than the baseline. And if you have more, it's plus a half, and then plus a half We send up to 3 pair per crew member if if we feel that they need it, and it works. If you notice your vision is changing, it's always in the hyperopic direction, so you put on your first pair of SAGs and see if it works, and if it does, you're good to go. So it is an effective countermeasure.

No one has lost visual acuity due to SANS if they have the right prescription in front of their eyes. All of these other ones are unproven or currently under investigation, so you can see lower body negative pressure in the upper left. You can see how big it is and someone is a crew member is not able to move about the cabin space and do their job if they're in a device like that. The Russians on their side of the station, they actually have a lower body negative pressure device called the CIBs, but it's literally bolted into the ground.

So maybe someday we find that it is an effective countermeasure. We haven't gotten to that point yet, but, but the logistics of, you know, the crew members being able to do their job is, is greatly affected by that, so. Veno-constrictive thigh cuffs is another option where I call them loose fitting tourniquets that you wear high on your, on your thigh. What it does is you, I think we're around 30 millimeters of mercury. it's enough to allow arterial flow down into your legs, but it restricts some of that venous return up to the heart. And, again, we haven't found the prescription that actually works yet, so we're in the process of that. Hopefully it will be an effective countermeasure, but we're not there yet. B vitamin complex, that if the one carbon metabolism theory is correct, the correction is as simple as taking B vitamin complex. So we have an in-flight study going on, where crew members just take B vitamins, and then we're me, excuse me, we're measuring them with OCT and all the other tests to see if it's effective, and, so we'll, we'll see what the results show. We also have thigh cups up there right now as well, running a study to see if they're they're effective if they're worn for 6 hours a day. 6 hours a day.

Pharmaceuticals, Diamox, of course, lowers intracranial pressure, but as you know, it also lowers intraocular pressure. So if SANS is a translaminar pressure gradient issue, and we give them Diamox, is it going to make SANS better or worse or not have any effect at all? And you all know how evil Diamox is, no one likes to take Diamox, especially in therapeutic dosages. it's not like uh we're talking, symptomatic crew members here. They're happy as clams for the most part. so imagine trying to convince your crew member to take Diamox when they don't notice any problems at all, but you're making it worse with this drug There is some suggestion that a GLP-1 receptor agonist, xenotide in particular, might lower intracranial pressure modestly.

So we're about to run a strict head down tilt study in Cologne, Germany next year to see if it's helpful. that 6 degree head down tilt analog is a, it's. It is a research setting that has produced SANS-like optic disc edema and chorioretinal folds, so it seems to be a pretty good research analog. And then this device called an ocular pressure adjusting pump, it looks like you might have a hard time seeing it. It does look like those swimming goggles that I mentioned at the beginning. These are FDA approved to treat glaucoma if it's used to cause a vacuum in front of the eye, so you wear it for a certain period of time every day, a vacuum that in turn lowers the intraocular pressure, which in theory stabilizes the translaminar pressure gradient and reduces glaucoma effects. If SANS isn't a mild elevation in intraocular pressure, we actually need to increase the intraocular pressure to match. And so we have a version of this, the OPAP plus, that provides positive pressure, that we just did a head down tilt study to see, in a pilot study to see if it's it's helpful. So that one's TBD but we hope to deploy it in the next year or two.

So predicting SANS. So there's a huge, huge variability across crew members from a SANS perspective. Some are more severe than others, some of them don't seem to have any signs at all. if we talked about 8 years ago, I would say that SANS is a male-only condition. We know now that's absolutely not true. It's males and females, that we were a victim of small sample sizes, especially, a relatively low number of females flying. About that same time period 8 years ago, I would have said SANS is a right eye biased condition. We know that is not true either. Again, small sample sizes. We diagnose it in novice and veteran crew members across various ages, body types, body weights, BMIs. You can pretty much name it, and we have not found any way to predict who will develop SANS on their first mission.

AUDIENCE MEMBER
Yes, Jeff, it consistently develop, they develop. Or them off and er.

DR. BRUNSTETTER
Great question. So the question was, do they repeat this? Do they repeat SANS on subsequent missions?

Well, we were thinking along the same lines, and so we performed an analysis. This wasn't meant to be hardcore research. This was just looking at a small sample size, just looking at how SANs repeats. We didn't expect to find anything.

So at the time 16 US crew members had flown one long duration mission followed by a subsequent long duration mission, both on board the ISS. So you can see the graph here, 16 crew members flew twice. The typical separation between the missions was about 5 years. That's kind of typical. So let's take a look at the 16 crew members as they fly their first mission. 6 out of 16 were diagnosed with SANA, 10 out of 16 were not diagnosed with SANS. So now, let's focus on the SANS cases, they flew their second mission.

How many do you think were diagnosed with SANS? How many do you think were non-SANS cases? So every single one of them was diagnosed with SANS again. So let's look at the non-SANS cases from the first mission. They flew again. How many do you think were diagnosed with SANS? Just one, 1 out of 10. So, we ran the stats. The probability of this happening completely by chance is less than 0.001, with a sample size of 16. So we were amazed by this. So the bottom line here is, if you were a previous SANS case, you will be another SANS case in a future flight, and if you were a non-SANS case, you are highly, highly likely of being a non-SANS case in the future.

Then we took it a step further. We looked at our OCT data and the, we all created a metric objective measurement of optic disc edema, we call it delta TRT. What that is, is we measure the total retinal thickness immediately around the optic nerve head, look at that thickness pre-flight, and then compare it to how it changes in flight, and that's our direct measure of optic disc edema. So we call it Delta TRT, the change in total retinal thickness, pre-flight to in-flight to post-flight.

And so if you look at the graph here, notice we only have 5 crew members on this. We only had 5 crew members with good quality delta TRT data from mission 1 on the X axis to mission 2 on the Y axis. If you look closely, you know, it's 10 eyes from 5 crew members. What you notice is that we've got 3 crew members down here. Those were non-SANS cases and then up here towards the upper right we had two SANS cases and if you, I mean it's pretty clear that the level of optic disc edema of the first mission is highly predictive of the second mission within I would say 10 to 15 microns. It's incredibly predictive. And you could see the correlation value of 0.94 again 10 eyes and 5 crew members. So that that was, that was a big, I think a big finding. And so we're using that now. We now are able to talk to crew members and say, well, this is what happened on your last mission, so we expect the same thing to happen on your future mission and so far it's holding up very, very well. So with that, it seems like people actually have a SANS fingerprint. What you look like on your first mission will be very similar to your subsequent mission, you know, across the repeat flights, and it applies to crew members who have an asymmetry. So, they weren't included in that analysis, but we've had a couple of crew members. One of them had more SANS signs on the right side. They flew again and it looked identical. We had another crew member that was the opposite. It was a left eye bias. They flew again and it looked exactly the same, yes.

AUDIENCE MEMBER
Right, and then they're having the exact effect or is there kind of a residual.

DR. BRUNSTETTER
That's a great question. I wish we could talk for 3 hours, 8 hours. Give me 8 hours.

So the question was, is there residual signs left over between those missions, or does it all resolve?

So the optic disc edema in all crew members does resolve depending on the severity. It takes between weeks to months to a little bit more than a year in the more severe cases, but they resolve. They get back to baseline. If you have mild globe flattening, shifts in refractive error or chorioretinal folds, if they're mild, they will resolve in between missions, but if they're moderate to severe, they will probably persist. They might, they might backtrack just a little bit, but they will persist. And Bob Gibson, our clinical optometrist, he actually diagnosed chorioretinal folds in a NASA crew member who last flew in Skylab in the mid-1970s. So we presume that was due to long duration space flight back then, even though we didn't have OCT of course back then. so the fact, well, so in this case when we diagnose SANS, it's gotta have a delta, it's gotta have a change. So if someone has chorioretinal folds before their second mission, they have to get worse before we flag that as a SANS case. And of course the edema comes back, um, so it's gotta be a delta. From that new baseline. So everyone seems to have the SANS fingerprint across repeat flights, and if it's asymmetric, it still respects that asymmetry flight to flight.

And so this distinct repeatability suggests, at least to me, that there's some physical, some anatomical factor or factors that is a primary driver of SANS pathophysiology. My personal guess is it's venous anatomy that is driving it could be optic canal diameter. I mean it could be anything, but at least we know that this is a fingerprint and we need to look at these anatomical differences, but. You know, we've got that wide variability, so how do we tease apart these anatomical differences between people? It makes it very difficult, especially with the sample sizes.

So this is brand new, I think this is the 2nd time I've presented this, these data. it's not published yet, but it will be later this year. We looked at clustering of SANS optic disc edema. What do I mean by that? Well, we looked at 54 ISS long duration crew members, and we looked at data from 2013 to 2025. In other words, as long as the OCT's been up on orbit, we use those data. And for the sake of time, I won't get into the full analysis, but the first analysis was to look at the data, the objective optic disc edema data over the period of a mission and determining if there's any clustering. Do we see any groups? And then number 2, if we find groups, then let's take a look at the trajectory of those groups over the period of the mission and see if there's any trajectory that we can that we can see.

And so, lo and behold, we identified 3 distinct clusters of the crew member population for optic disc edema. And we call them SANS resistant. Mild responders and SANS susceptible crew members. Each of these clusters displays a very distinct course throughout their mission. And so here they are. So on the x axis you can see pre-flight is the baseline, so that is zero because we're looking at delta TRT, the change in total retinal thickness. So baseline is by definition zero for everybody. And then in flight you can see the days going by there.

The green represent the SANS resistant group. Now if you look at the gray band on the lower portion of this, that is the test variability for OCT and crew members. We put them in various different poses, measure them four months, separation and time on the ground. We figured out the test variability is plus and minus 20 microns, and you can see that this group stays typically within the variability of the test itself, so we do not consider them to be developing optic disc edema.

The mild responders, you can see they have a slightly different trajectory. It's kind of a gentle progressive increase, almost a linear increase over time, but it never gets above this green area which we call the earliest indication of SANS. So it's mild. It's like you have a temperature of 99 degrees. Technically that's a fever, but is it really? Are you really concerned? No, you just monitor that a little bit more closely because you may get worse. So that's kind of our 99 degree group there in the yellow.

Then the red represent the SANS susceptible folks. Those are the folks who by flight day 30, which is the first time point for us for data collection. They are already in the clinically concerning zone, and they tend to follow a trajectory where they peak in optic disc edema around flight day 90 to 120, and then they may slightly come down in severity. Never goes down to the point where it's benign, without risk, but for some reason, some physiological change occurs where or some compensation occurs where the edema reduces slightly.

And then we also have folks who that might be hard to see, but we call these the SANS outliers. We do measure delta TRT up here in the over 200 microns and above, and they're in kind of a realm all by themselves, but anyone who is SANS susceptible, we instantly know who they are by flight day 30.

So how do we put this all together? Well, we look at that SANS fingerprint. We need to find that anatomical or physical difference between crew members, but the data are all noisy. So what we found here is what we need to do is to combine that information. We need to look for a physical anatomical difference, but we need to remove some of that noise. And so what we plan to do, this is our next step. Is to compare the SANS susceptible to the SANS resistant, what makes them different, and we eliminate all these folks, the majority of crew members here in the middle who add a lot of noise to the analysis, and with that we hope to find that critical difference between the groups that drive SANS pathophysiology.

So bottom line messages. Currently no evidence of cognitive impairment due to those brain anatomical changes or any permanent vision loss in any crew members. However, about 81% of ISS crew members are diagnosed with SANS of all severities, from mild to more substantial. Only about 16% develop what we call clinically concerning SANs. Predicting SANS, we still can't predict it reliably in folks who have never flown before. However, we do know that SANS repeats or non-SANS repeats, and so that has helped us out a great deal. Terrestrial analog. I mentioned that strict head down tilt studies is a great terrestrial analog. We typically run these for at least 30 days or 60 days. If you live in Russia, maybe 6 months. We haven't gone that long, but it does produce SANS-like signs optic disc edema, chorioretinal folds, and it allows us to very rapidly test potential countermeasures or to figure out what Prescription is necessary for a particular countermeasure for a particular person. We might be able to use this to accelerate our knowledge.

SANS severity is related to mission duration, so for short duration missions, by definition that's 30 days or less, so that would be all space shuttle, all Apollo, Gemini, all those, that's a green risk. In fact, we don't even collect data for missions less than 30 days because by the time we decide that this is a SANS case, they're already coming back to 1G, and that's the ultimate countermeasure. It's considered a yellow risk for long duration missions greater than 30 days, up to 12 months. There are still outliers. There are still people who definitely could use a countermeasure once we determine them, but most of the crew members are not at substantial risk at this point in time.

It's really a red risk for Mars, and so we need to figure out SANS, I think, from an ethical standpoint before we ever consider sending our astronauts to Mars. And we do truly believe that all the efforts that we're putting into SANs will benefit you all in terrestrial medicine. So what we're doing are like advanced analytics with OCT for example, we're miniaturizing devices like the OCT. We're working with Heidelberg to miniaturize a device to the size of a large pair of binoculars. We're actually testing it out right now at JFC. and keep in mind that, you know, they have to be small in order to go in small capsules, or else it, it won't go at all, and they have to be semi-autonomous because, crew members on the way to Mars may experience a round trip calm delay of 45 minutes. So I could be sitting down on the ground saying. OK, press the button on the on the tono pen, and it'll be 45 minutes before I get confirmation that they've pressed it, and of course it'll time out before, before that time. You get my point, we can't remotely guide them. They've got to be able to do this themselves. we have new objective-based definitions of optic nerve head disease, and of course NASA is incredible at telemedicine, technology and techniques.

All that of all my looking for headlines, this is the only positive one I've found. Researchers are learning more about eyes thanks to astronauts. That's the only positive one I have.

So, thank you so much for your attention and for the opportunity to be here to talk about something I really love and to be a part of, the Hill lecture series is, I would never expect that. So thank you so much. I have no, OK.

DR. ZADNIK
Good, OK. Thanks for asking. I've been real fun.

AUDIENCE MEMBER
first of all, congratulations on that tremendous body of work. It's really very impressive, and I wonder if your new SA's fingerprint will be used to select astronauts for Mars. Because you wouldn't want to send any of the ones who are going to get severe SANS.

DR. BRUNSTETTER
Yeah, so the question was, since we know that SANS repeats that, would we use that knowledge to inform us as to who we should select for Mars missions, I will say right off the bat that is like the first question the crew members ask. They're a little concerned about that. My response is that my intent is that we will develop countermeasures that will allow anyone to fly. That's my goal. Now I can't control those above me. Maybe someone at some point may take that position, but my goal is to develop countermeasures so that anyone can fly. However, what we do recommend is anyone that goes on extended duration missions beyond 12 months, especially the Mars, they should be on at least a 30 day mission, maybe in low Earth orbit. so that we can diagnose them with SANs or non-SANs, and then that way we'll at least know what to expect if, you know, if and when they go on that extended duration mission. I try to take a positive approach on that. Yes.

AUDIENCE MEMBER
You look at all the severity or susceptibility of the stands for they're like refractive error or accident. Yeah So the question is have we

DR. BRUNSTETTER
I'll, let me, I'll make sure I understand. So have we looked at how refractive error is, how that shift occurs? Is it the flattening, or, oh. Oh, a risk for the development states. Oh, got you. Does refractive error, baseline refractive error, play a role in SANS severity? We have not detected any red flags that indicates that, say a 5 diopter myope, will develop more severe SANS than a 2 diopter hyperoppe or anything like that. That again, I go back to the statement that it's fascinating, it's exciting, but it's so frustrating because. Questions that seem like they make sense and it it should be fruitful if we investigate this. We have not captured any red flags, so no, we have not, we have not determined that, we have not detected that.

DR. ZADNIK
Tyson, I will have to say that I believe Dr. Hill is quite proud at this moment looking down. I, if he showed you the way, you took the way and ran down that path, and I think for many of you thinking, well, that was a master class in how to give a 1-hour talk and tell a compelling story. you had a compelling story to tell, but you're a compelling storyteller. So with that, this is the 2026 Hill Medal. Congratulations. So I can ship it home for you. Congratulations. Thank you so much. and thank you all for coming and attending online. Thank you for joining us. and everybody have a nice rest of your evening.
 

DR. WALLINE:
We'll start with a formal. It says Dr. Quigley, the A. Edward Maumenee Professor at Wilmer Eye Institute, Johns Hopkins has been CEO of ARVO and editor in chief of IOVS. His 450 publications are the most cited in the ophthalmic literature with over 100,000 citations. He received the Friedenwald, the Joanne Angle and Epstein Mentoring Awards by ARVO, uh Doyle, right? it is Doyne Doyne Medal and multiple awards from RPB and Alcon, as well as the Lewis Rudin Prize. He's a life achievement honor awardee of the Academy of Ophthalmology, having given 50 named lectures, including the American Academy of Ophthalmology Jackson lecture.

So that's the formal introduction, just to give you an idea of some of the breadth of work that, that Dr. Quigley has has done over his career so far.

But I wanna talk a little bit about Dr. Quigley and sort of what I learned today. He is what I would call sort of the quintessential clinician scientist. So he's an excellent clinician, and you may or may not know that he's a glaucoma specialist. And that means that he treats everybody from adults to pediatrics. There aren't very many specialists who treat both adults and pediatrics, but he's one of them. So that tells us a little bit about the breadth of his clinical care. He also has a wide breadth in terms of his research. So if you know some of his papers, you know that he's done research in glaucoma all the way from sort of the mechanisms of glaucoma to the effects of glaucoma on the patients. And it's from these perspectives that he's gonna give us a wonderful lecture tonight. So if you would please join me in giving Dr. Harry Quigley a warm Buckeye welcome, I would appreciate it.

DR. QUIGLEY:
Well, thanks, I really appreciate being asked to be here. And first and most importantly, Dick Hill, who was your dean and somebody who contributed massively to the field relating to contact lens use. Now, if you're one of the younger people sitting toward the back there, you can say, well, how could somebody have time to be a scientist, a clinician, and a dean and all that. Well, it doesn't happen to you immediately. You build up to it over time. But he was asking some really fundamental questions about the cornea and whether a contact lens maybe cut down the oxygenation. How do you build a contact lens that better oxygenates the cornea. If you all are contact lens wearers, if there's any of you non-LASIK treated young people out there, you'd know that when you take them off at the idea of contact lens blur, and that's due to the anoxia caused by hard lenses of the time. And so Dr. Hill's contributions over time for 20 years worth of papers that I kind of reviewed to come here ahead of time, were special at the time because there weren't very many people doing work of that quality.

Glaucoma is a major problem in ophthalmology and optometry. You will be seeing it in your clinics. And for the next few years, we have the opportunity to improve dramatically in how patients are cared for. So I'm gonna do a flyover tonight of a lot of things about glaucoma. That way, you can't get bored cause it'll change, the slides will change pretty quickly. when it comes up, I'm gonna tell you where any financial interactions that I have with companies may impact your listening to what I'm saying about the particular subject matter.

Very interestingly, you might say, well, you know, you're so you're an expert on glaucoma. What is glaucoma? How do we define it? And believe it or not, the most common definition in randomized clinical trials, very important, big time, randomized clinical trials is, cause I said so. Cause three guys sat down and looked at the picture of the optic nerve head and said, you know, we agree that's optic, that's characteristic glaucomaous optic neuropathy.

I call that the three guys in a smoke-filled room method for diagnosing glaucoma, and I'll tell you that it doesn't work. And the reason it doesn't work is Bal Shahan, a OD PhD from Dalhousie, has done a study at which I was a part. And they took 1,000 glaucoma patients, clinical photos, OCTs, and fields. And they asked 100 glaucoma specialists around the world online to look at these pictures and to rate the patient's chance of glaucoma from 0 to 100%. You will see that at the far end of this, way up at 100% of glaucoma, the, the spread in the assessments was pretty tight. And down here near zero doesn't have glaucoma. They agreed about that. Take a look at the vast majority in the middle here. There were patients being rated from 25% to 75% of having glaucoma.

So what we needed, what we need now and what we actually have in your hands is an objective definition of glaucoma that's based on OCT and field. And if you match up a quadrant of abnormal OCT in the case of this patient, it's the inferior quadrant, with a typical definable objective visual field test in the upper visual field. In other words, they match because the world's upside down, right? That gives you a chance that that patient would be agreed to by a large number of ophthalmologists and optometrists as having open-angle glaucoma, glaucomatous optic nerve damage. And the chance that it's not a glaucoma patient is under 1%. So if clinical studies that you see in the future, say we had a definition of glaucoma, it was the three guys in a room, you wouldn't be able to do a study to duplicate that study and be sure that you had the same crowd of people in your study that they had in theirs. But if they also said, oh, and by the way, we diagnosed the glaucoma dystopic neuropathy by this objective definition, then apples would be apples instead of something else.

Now we know that in Columbus and Baltimore and around the world in developed country cities, We miss half of the glaucoma patients. They're walking the street outside here, and you don't know who they are yet. So how do we stop diagnosing glaucoma outside. And the answer is in part because in our heads, we've been using a magic number that I'm not going to say it's on the slide. You should look at it and then you should please forget it. It has nothing whatever to do with your patient having open angle glaucoma, though it is true that the higher the pressure is, the more likely they are to have the disease. Stop thinking that you need to use that number to decide what else to do. You want to take a look at the optic nerve head and more importantly, do more visual field tests on people with a family history, on people who are myopic, people who have risk factors, including ocular hypertension. And if we do that, we're gonna find more patients with glaucoma.

But we still need, as I heard today from one of your investigators, better ways of screening for glaucoma, maybe with binocular field testing or other methods that will help us to identify it quickly and easily. I personally think that a system that our medical students are using in their screening program in Baltimore is a very good way to go, and that's to take an OCT instrument into the field and take OCT images of people. You can see AMD and diabetes and the RNFL and the optic disc features, all with an instrument that's portable. Not terribly portable, but you can take it apart and put it back together, and we've done it in screening programs every Saturday in Baltimore for a lot of times. AI, everybody's favorite word, don't get too used to it because Time Magazine will have a new special thing next year that's gonna solve all of our medical problems. But AI has had a lot of trouble diagnosing glaucoma, and the reason is cause there's no ground truth. They don't have 10,000 pictures of people where all 10,000 had somebody do an OCT in a field. But if you don't do that, you're stuck with comparing AI to three guys in a room. And that means that you're comparing it to a very wishy-washy kind of definition. It is a lot easier to diagnose diabetic retinopathy. That's already an FDA approved screening method in medical offices around the country, but little diabetic hemorrhages are easy to see. Figuring out if the disc is glaucoma from a color photograph is a lot harder.

If you were to prescribe a glaucoma eye drop, what's the chance that the patient is actually taking their eye drops? Now I think we know that it's probably not ideal. I didn't know it was this bad until we electronically monitored a crowd of patients, and we actually knew how many how many drops per week they were taking of a prostaglandin eye drop. And the answer is that patients who were in a study, signed a consent form knowing they were going to be monitored electronically, were given free eye drops that they didn't have to go to the drugstore to take. We're on average taking 73% of the drops per month. And noticed that there were people down there at the 20% and 30% range. Were you to ask these patients, are you taking all of your eye drops? Most of them would have said yes. Doctor, I'm religious with my eyedrops, and they're not lying to you, they actually believe that. They think they're taking their eyedrop, cause they're looking at a bottle and they can't see they have leftover pills at the end of the week, cause they need a pill. So we've begun asking a question that it turns out in our electronic monitoring, has identified the patient you need to worry about with regard to adherence with eyedrop therapy. And that question starts with saying to the patient, you know, I know how hard it is to take eye drops. You know, I'm supposed to be taking a pill every day, and I, every so often, I notice I've got too many pills and I must be forgetting them, you know, it happens to all of us. What are you doing? You're opening the door. You're saying, even though I'm in an optometric office and I look like I had all these fancy instruments and stuff, I'm human and so are you. Do you think in the last two weeks, maybe you missed your drop once or twice? If they answer that question, yes, I think I might have missed some. Their average in this testing that you're looking at was 50%. They were taking half of their drops or fewer. If they say, doctor, I never miss. I know I took all of them, you have no idea what they're doing. But if they admit it, that's the patient who needs to help you by working, you work with them on electronic monitoring.

Now, the reason why eye pressure in the clinic is poor is shown on this slide. This is what the adherence was with patients who were electronically being monitored. And if you look here, the, the, the visit that they had was over here, and the next visit was over here. And these folks are the worst adherent patients, and notice what happens right before the visit. They start taking their drops again. How many of you fail to floss before you see the dentist? How many of you fail to floss the other six days of the week or month or year? It's, it's human. That's, that's fine. But that means that their pressure looks great, but their glaucoma is being poorly controlled. And it's the single biggest cause of gee whiz, the pressure is being treated, but glaucoma patients still lose some vision. It must be something else other than the eye pressure. It might be, but that's the biggest cause of the pressure looks good, and the patient's getting worse.

We used electronically bugging people on their cell phone or their computer. To juice them into taking their drops, and that works. And more and more of us are walking around. How many of you people don't have an iPhone on you at the moment or a Samsung phone, right? And believe it or not, 70 year old patients of ours, 75% of them. Look at email or a text every day. So all you gotta do is send them the text or call their phone at 9 p.m. It's time for your prostag gland and eye drop. Did you take your drop? Press 1. Did you have to go back to the the bathroom and find it and take it and press 2, right? That improved adherence very significantly in a large number of patients that we were doing.

The ultimate answer for the next 10 years is finally to develop sustained delivery, and I don't mean Durysta. That's the one that's injected into the anterior chamber because that's completely impractical and somewhat dangerous. Perhaps sustained delivery of subconjunctival delivery, which might be actually very practical for technical staff to do. If you had a sustained delivery drug that was only half as good as an eye drop. It would be there all the time and it would be as good as the eye drops for the patients taking 50% of their drops. And they wouldn't have to go to the drugstore, etc. etc. So I'm very hopeful that we can finally convince a drug company or two. We know what agents will work. Dorzolamide works, subconscious subcons delivery, nanoparticleized, so it's sustained delivers over an extended period of time.

We were part of the Durysta study. This was approved by the FDA for one injection into the eye. The Durysta implant damaged the cornea in some patients in the study. One of our patients suffered significant corneal damage from only the 2nd injection. In that study, there were multiple injections. And Ophthalmologists are not going to be injecting patients bilaterally. On a multiple basis every 3 months. It's just not gonna happen.

So this is not going to be the solution for us, subconscious type of delivery work, it was done by Ian Pitha, now at the University of Utah, and showed that in a rat model, we could lower the eye pressure in a long sustained fashion, but it hasn't yet been tested in humans, hasn't been because drug companies don't necessarily want to pick this up. Why? They're gonna lose their eyedrop market. It's a $2 billion a year for Latana Prost alone. What if this works, and they don't have to take drops. So we may have to have a different model for this, or later I'll tell you about stem cell work. We may have to have a different model outside the capitalist system, uh, whereby a nonprofit corporation starts doing this kind of thing.

What we'd like to have, and we were very close, is to have something where when the patient is taking their drop, we would know whether they were adhering with therapy or not electronically. And the device that you see on the right, the Calicare drop, unfortunately, this company has presently been bought and probably killed by a larger corporation. That's a buy it to kill it phenomenon in our system. Another of the wonderful things about systems. This thing, when the patient takes the drop, it records the time and date, and when it's placed into its dock, it sends it to our office. So we're sitting there watching the patient's adherence with therapy. And one of the things that we were first told when we did electronic adherence treatment therapy monitoring was, yeah, but you didn't prove that it actually benefited the patient to take those drops. You didn't prove that their field didn't get so worse when they were better adherent compared to worse adherent, you don't have an outcome measure of actual proof.

So we began doing a variety of things, one of which was monitoring people at home with the home eye care pressuring device. And if you've seen this one, the newer version lets the patient see what their pressure is, and once again it sends it to us. So, within the time period of your optometric practice, I will predict that you will have on the patient's eye drop bottle. And the patient ability to monitor their pressure at home, the ability to see are they taking it? And is it lowering their pressure? You'll have software which says, oh, Mrs. Jones hasn't taken a drop in 4 days. Send her the call, or better yet have a human call her from your office. Mrs. Jones, are you OK? We noticed that you, oh yeah, you're off at vacation and you left your bottle at home. OK, we'll get to the pharmacy. Mrs. Jones, we noticed that you're taking your drop dutifully, but your eye pressure is not going down. Are you sure you're getting it in your eye? Did you look at that chapter in Quigley's book on how to put drops in your eye? Or if you are sure and your husband swears that he watches that drop hit your eye, that drop's not working, and I don't want you to wait 6 months till the next visit. We need to see you next week. Imagine the effect that those simple measures, which are presently technologically feasible, are gonna have on glaucoma care, it'll be as good as measuring your blood pressure at home. Except even better, cause the internists don't know if you're taking your pills.

We are very close to being able to put a device through the sclera. implanting it in an office or in an operating room. And the device, the one that's in the lower picture here, is a company that I work with at no charge. I'm a I'm an unpaid consultant to this company. In an attempt, we've seen it now in rabbits, and the device can measure the eye pressure inside the eye and telemeter that to something that's say, on the eyeglasses. And from there to our software in the research zone. It works in rabbits. They need to continue working on it to get an FDA approval. And the first series of these are gonna go in when people have cataract surgery who have glaucoma. Cause you're in the operating room anyway, you're already sterile, you're already instrumenting the eye, and you leave behind the ability to have a battery operated tenometer that's rechargeable. But it's in the eye. So you know that it's actually accurately measuring eye pressure. There's another company, the EyeMate, it's a German company. They're also attempting to produce something like this. it's gonna have to be small, and the one by EyeMate is a quite large device into the super coroidal space, and I'm quite worried about putting things in the super coroidal space.

Bob Derek and I were just talking about the vascular causes of glaucoma and the mechanical causes. We'll get to the mechanical causes in a minute. But if blood flow is important in glaucoma, blood flow to the optic nerve head, and we know that it is, there's epidemiologic evidence, there's clinical evidence for that. What can you do as a clinician to improve the blood flow to the optic nerve head? Well, first, we know that blood pressure falls at night, and so people who take their blood pressure pills should take them and have its maximum effect in the morning. So if your patient is taking blood pressure pills at night, you want them to take it in the morning only. You want them to take Timolol in the morning, because Timolol doesn't work very well during the night. So why take that second drop? And an investigator and I, a woman who's done orthokeratology on herself for many years, she's a space engineer who's involved in some of the telescope things that you read about. She and I use the triggerfish device, which is a contact lens that instruments the limble flexibility. It's an interpretation of what the eye pressure is, and you can wear it 24 hours. What we did was have people sleep. Laying down, your pressure goes up. But if you bury your face in your pillow and your eyelid is pressing on the eye, the trigger fish alerted us that the pressure goes up and it went up more in glaucoma patients than it did in controls. That's a biomechanical effect. Dr. Luke can tell you about that. That means that their eye potentially in the front of the eye, where the trigger fish is, might be stiffer. We're gonna find out that glaucoma patients' eyes, in fact, are more compliant, not stiffer.

So what can you do for blood flow? Well, if you get somebody to take 5000 steps a day or more, Their glaucoma does better and my colleagues, including Dr. Priti Bramalou, who's our head of glaucoma, has demonstrated this and there's a randomized clinical trial beginning now where patients are going to be given an exercise bike and the control group doesn't get an exercise bike, except the exercise bike is instrumented so we know if they freaking used it. And will then follow their visual field tests and show whether more exercise actually improves visual fields.

But you gotta get people up off the couch. It's better for their glaucoma, we suspect, and we'll hopefully still prove, but it's also better for their general health and other things.

SLT laser therapy, that's gotten a lot of press recently. There's a study by Dr. Gazzard and colleagues that suggested that it's as good as eye drops, and it may very well lower it certainly lowers the eye pressure in early glaucoma. It is ineffective in moderate or severe glaucoma. It often requires not one session of laser treatment, but two  And unfortunately, while some, a large number of eyes are drop free, they don't need eye drops, they achieve the target pressure with the SLT alone. Patients have two eyes. And if one eye is drop free, but the other one isn't, the patient's still going to the drugstore or getting a mailed in prescription every month. And so while we offer SLT now as initial therapy, As an alternative to or in addition to eye drops, patients don't choose it. And the reason is, patients don't trust procedures, and they do trust eye drops, even though, as I just told you, they're not taking them as much as we'd like. They think they are, and a procedure could hurt me, whereas just taking an eye drop, that can't hurt me. Well, yeah, it can cause it has side effects. Most of them are mild. But the interesting thing is in this SLT study, the study was called the light study L I G H T right? They for three years had patients take the eye drops or have the laser treatment. At the end of three years, they concluded SLT was pretty good and they said to the eye drop treated patients, Wouldn't you like to have an SLT now? 2/3 of those patients who were in the study, they'd agreed to be randomized. They were told the SLT was really good and they ought to think about it. 2/3 of them said, no thanks, I'm continuing my drops. Why? Because people would rather do a non-procedural thing. So, whether SLT is going to have a huge effect or not, it's not quite strong enough, still leaves some patients taking eye drops, but it's a great thing for the non-adherent patient. Or for patients who don't respond to eye drops initially and have relatively early disease.

Now, surgery in glaucoma is changing fairly rapidly, although probably not permanently. An awful lot of what you're hearing about that are new procedures are not very effective, and we're dispensing with them. There are 2 or 3 that are really relatively good. One of the things we'd like for the more advanced glaucoma patient, the one who didn't respond to medicine, who has significant damage, is a better tube shunt. The tube shunt is a good procedure. But it has some difficulties. And as first surgery, in other words, for the patient who's going to have an operation, the tube shunt surgery against tuberculectomy came out pretty well. Except for those glaucoma patients who needed a very low eye pressure, and there the tuberculectomy won, but tuberculectomy had more side effects of too low in eye pressure, requiring a revision to bring it back up again. The tube shunts, on the other hand, uh, did well at lowering patients who had a high pressure. But had double vision With a fairly high rate, and had a problem that the tube shunt can extrude, can come out through the surface over a period of years afterward. And while that number is relatively low, it's about 7 or 8%. If you're the 7 or 8%, doesn't go any good to tell you, oh gee, that doesn't doesn't happen very often. Yeah, but doctor, it happened to me.

We've been working and I am a paid consultant for the company Gore. How many of you have Gore-Tex on a running suit or some kind of equipment, right? OK. Gore also makes stints for cardiac use. When somebody says, oh yeah, I had a, I had a car and Catherine and I had a stint. That was a Gore-Tex stent. The Gore-Tex folks came to us and said, we think we can build a better reservoir at the end of the tube, and we're gonna make it out of Gore-Tex material that's water permeable. But not permeable to cells. Except on its one surface, so it'll adhere to the sclera. But otherwise, the water will just percolate through it. They now have 20 patients who've been treated in a phase one clinical trial. The complication rate is as low or lower than a standard tube shunt, and the pressures are doing reasonably well in the majority of the patients. But there's a way to go. I think this is one of a number of potential improvements, including an adjustable tube shunt where even after surgery, you could use a magnet to open or close the flow. Right up next to the patient's eye. They may have to worry about getting an MRI to change their flow through their tube shunt, but we can deal with that if we had an actual adjustment that was possible.

There are quite a number of new glaucoma surgeries. They are referred to generically as MIGS surgeries, minimally invasive glaucoma surgery. They are not minimally invasive, they are invasive of the eye. Overall, none of them has as yet in any randomized true clinical trial been as good as tuberculectomy or tube shunt surgery. They are, however, lower in terms of side effects. So if you need not that much pressure lowering, And you want something that's low risk. You can do it, and it's very often that this is being done combined with cataract surgery. There's unfortunately many more of them being done with cataract surgery than are actually justified. In terms of the patient requiring something to be done and achieving a useful and beneficial effect. That's my opinion, I can back it up with data. Early glaucoma cases are by and large the ones that are being treated. And the cost to Medicare and other insurers of these surgeries is a dramatic improvement in the overall cost of glaucoma care, and our country has what's called a zero-sum game for medical care. There's a certain amount of dollars that Medicare is going to put out there, and it's not gonna go up. It's very likely even the present situation, it's gonna go down. And if we're taking up a lot of that cost with procedures that don't do a lot for the patient, then we're doing the wrong thing. In fact, the newest best surgery that lowers eye pressure in glaucoma patients is cataract surgery alone.

In every one of the randomized clinical trials where cataract surgery was compared to cataract surgery plus a new procedure. The major effect on lowering eye pressure was in the cataract only group. And a slight improvement with one of the procedures called Hydrus, which is a stent that's put in. It's a titanium metal-based stent. But we now know that cataract surgery alone can help the glaucoma patient. We can't promise, we don't tell them you'll be off eye drops, but it's, it's something that can be beneficial. You all test visual fields in the clinic.

How often should you be doing that on a patient with glaucoma? We did a medical chart review of large insurance database work, and we showed that in Medicare patients, and the patients in our clinic, it was on average about once a year. So what is best though, to detect if the patient's doing well, is once a year OK?

Here's a a graph. It shows whether glaucoma patients were progressing or not. If you were not, if you were not progressing, You were over here at 0. And if you were progressing and getting worse, you're over here. If you were getting better, you're over here. Now, unfortunately, glaucoma patients don't get better. So, measurement of getting better means that's a false positive rate. So, pretend that's a Gaussian curve. What you've got is these folks over here were the ones who were getting worse under treatment by Canadian glaucoma specialists. And some of them were getting worse catastrophically. And that was under careful observation. They weren't lost to follow up, they were in care. And so what we need to do is be able to identify. The glaucoma patient who's gonna be getting worse dramatically, they're about 10 or 15% of the patients. And you can find out in the 1st 18 months that you see them. By doing 5 visual field tests. You might say, oh my God, the patient's gonna hate me.

Patients hate doing visual field tests. But Bal Shahan from Dalhousie University in Canada, and Andrew Hale did a study that showed that if you only do a field test every year, You're gonna take about 5 or 6 years to be able to detect the rapidly progressing patient. By then, they've already lost 10 dB in their field, and they're functionally severely impacted in one eye. Whereas if you've done those 5 fields in the 1st 18 months, on everybody who's new, most of them wouldn't have to do another field except a year from now, and a year after that, cause you've already proven that they're not rapid progressors. And then you've found the rapid progressors and those need more aggressive treatment, they need more frequent visits, they may need multiple drops or laser or surgery.

So the real field new patient, do more field tests. Now, we definitely need better biomarkers for whose gonna get worse faster. There's a lot of research in that field, and I'm gonna show you some pictures of one method. there's a, there are 2 or 3 randomized trials right now going on, giving vitamin B3 in massive doses to see if you can get a reversal of some of the visual field loss. We'll, we'll see if that's gonna work out. We can hope that there is some DNA that identifies the rapid progressor floating through the blood. I know a young man named David Quigley, who's done a liquid biopsy showing metastatic prostate cancer patients and what's wrong in their cancer. So it's not unreasonable to think that we might be able to do that. Measuring the susceptibility to biomechanical stress is another thing that Dr Lu and our lab are working on in terms of identifying what's going on.

This is a picture of the optic nerve head, the lamina fibrosa. It's a scanning EM picture here on the upper left, and you can see that there's an area of the optic nerve, it's the inferior part of the optic nerve head, where there's less supportive connective tissue. This is a 30 year old picture. Since then, we were able, due to Vicky Nguyen, my colleague, and Dan Midget, a doctoral student, able to show and measure how the optic nerve in a dead eye, a postmortem eye from the eye bank, how it flexes when you raise and lower the eye pressure. And what we found was that it flexes more in the areas with less connective tissue. If you were to look at an optic nerve from a glaucoma patient, you'd find that that area has lost the myelinated nerves from that zone much earlier or more. And if you looked at the visual field, you would find that area corresponds to the area that we know is the very typical early or moderate glaucoma visual field damage. So, the biomechanical endowment. And its behavior are very likely to predict for us if we could measure that in some useful way.

So what Dr. Nguyen and we have done is to take OCT images with Heidelberg Spectralis. They loan us the instrument. I don't get any money from Spectralis for doing this research. And what you see are pictures of what's called biomechanical strain. These are eyes of people where we change their eye pressure. In the case of these people, we did suture lysis after tuberculectomy. We, the pressure was too high and we cut a suture and lowered it. We've done it also with starting an eyedrop to lower their eye pressure. So, if you were to start a patient on an eye drop, you could take an image of the patient, start the drop, bring them back in 3 weeks, measure them again with Spectralis at the lower eye pressure, and generate these images of what the biomechanical strain was in the lamina cribrosa This is the lamina right here.

And interestingly, what we have found is that persons with glaucoma, if you lower their eye pressure, Their lamina cribrosa goes from a tuna fish can to a tomato juice can. It gets narrower and higher. And there's also an effect of, if you imagine taking the Tomato juice can and tilting it's called shear. The world literature says that glaucoma patients have stiffer eyes, and that's why they get damage from glaucoma. Every bit of evidence we have so far, and it's been corroborated by another group, so we may be right. Glaucoma patients have a more compliant eye at the time that you evaluate them with their glaucoma. That doesn't mean they had a more compliant eye at the start. But it does mean it's more compliant now. So the disease process itself is unlikely to be causing the eye to get stiffer, it's more likely to be causing it to try to accommodate the effect of pressure on it, and I didn't say high pressure. Half of the patients we study have glaucoma at baseline untreated at normal pressure. So their eyes are not tolerating normal pressure. That's why you can't use that magic number that we're not gonna talk about.

If you were doing a clinical exam, and you wanted to identify an angle closure patient, You might try to use something called the Van Herick test, which means a diagonal slit beam is coming from the outside, and you're trying to judge how close is the iris to the back of the cornea. We did what we thought was a pretty definitive study comparing faculty gonioscopy, faculty Van Herick test, resident ophthalmologist, gonioscopy, and Van Herick test. The residents and the and the faculty agreed really well. The problem was that the Van Heerrick test didn't identify the angle closure patients. It missed 30% of those who had true angle closure by gonanoscopy. And only 1 in 15 of the positives by Van Herick actually had primary angle closure disease. So I'm not telling you don't do it. I'm just saying please do more gonanoscopy.

There have been some recent studies that suggest that we're doing a lot too many laser iridotomies. The study called the ZAP study, you have to have a cutesy acronym for any study, right? This study was done in Zhongqiong, South China, so that's where the Z comes from. And I was part of designing some of the study, but Heming Wang and Dave Friedman and others deserve credit. They followed 900 Chinese persons from this area. Many of them were selected from the population previously untreated. So this means that they were actually representative of the population. That's the way to do a study. And when I got a laser iridotomy and the other one didn't, was left untreated, even though they all had gonanoscopy that showed the iris against the trabecular meshwork throughout 270 degrees of the angle. You would have said that's an an eye in a positional closure. And in the United States right now, that person would be told you're gonna go blind tomorrow from angle closure, you have to have youridotomy immediately, don't even wait till next week. So the zap study didn't wait till next week. It waited now for 14 years. In the initial report of the study, fewer than 1% of those suspects who were untreated had anything bad happen. And mostly what happened was they developed one clock hour of PAS. They did not. There were 2 or 3 acute attacks of ankle closure glaucoma. They were in part induced by the exam that was done because we dilated everybody once a year. Just to prove that we couldn't make their pressure go up. And during the course of those exams, there were 2 or 3 people who had pressures go up, and they of course got an immediate iridotomy. We've now done the 14 year follow up, and that finding hasn't changed a wit. So you can tell someone who has oppositional angle closure that I can follow you without sending you to somebody to do a laser iridotomy, or if you all will begin, but who knows what the future is gonna hold to get the capability of doing laser irididotomy, please do it only on people who are, who has a family history of angle closure glaucoma. Or present to them the low chance that they need this treatment, but if they're gonna go home tonight, unable to sleep cause they think it's always me, I'm always gonna be the one who has something happen. Fine, the iridotomy was quite benign, it speeds the development of cataract. Not a lot, but enough that it was statistically significant. But it's a pretty benign treatment. It's, it's not that hard to go through. So doing it though to 900 people instead of a few people, is not what we should have been doing.

The 14 year follow-up also showed something that was interesting that the irises of people who develop acute attacks and ankle closure glaucoma. are sponges that don't dump fluid off into the anterior chamber. And we found this by measuring iris area change with pupil dilation. And it's a pretty good biomarker for who's going to develop angle closure. There was a study called the Eagleri. It also deals in angle closure. The eagle trial did the following. They took a bunch of people who had real angle closure disease. Their pressure was above 30, or they had field loss and angle closure. And they were offered cataract surgery. Or laser iridotomy. Now, the study conclusion, which was in The Lancet, big journal, right? Remember, even the Lancet has to retract things once in a while. The, the, the study, I'm not asking that the legal study be retracted. I'm suggesting they had the wrong endpoint. They ask patients. Do you think you're you're better off now? It was a quality of life measure. If you take a + 3 hypero. And you make them plaino. Are they gonna be happy? Yeah, I've had to wear glasses all my life, and now I just have to put on some reading glasses and I can drive and do everything. That wasn't the question. The question should be, how did their glaucoma do? And while doing cataract surgery does definitively treat pupillary block, so does laser eridotomy, and it's safer and cheaper. And so We don't wanna be doing cataract surgery on people who don't need cataract surgery just because it might help their Angle closure disease.

So as I mentioned, the iris is a sponge. You probably know that if you look at the slit lamp, you can see all the holes in the surface of most irises, not thick dark brown irises, which don't have crypts, but most irises do have crypts. And when we measured the area of the iris from position of light with a small pupil to positioned in the dark with a large pupil, and then you measure the area of this portion. You'd say what's the iris, it doesn't change, does it? Yeah, it loses 50% of its area going from small people to big people. What do you mean area? Well, it's a sponge, it's full of water. Where did the water go? Went into the anterior chamber. And then when the pupil comes down small again, the water goes back in again. You've seen the holes. I just showed them to you. It's going in and out of the holes. But if the iris can hold on to that water and the angle happens to be narrow, when the pupil dilates, it's gonna be much more likely to occlude either chronically, much more commonly, and PAS develop, and asymptomatic primary angle closure disease starts or an acute attack happens. And now, 3 different groups on 3 different continents have shown that that phenomenon is important. Uh, unfortunately, Viante, which one of your investigators and I talked about today, uh, has been largely killed by the company, and we need to be able to make this measurement effectively with an an segment OCT like device.

So, iris area loss per millimeter of pupil enlargement is less than those. Who have an attack. Their their iris doesn't dump off water. And when we looked at the zap study, this is the study I mentioned, laser rootomy in one eye, no no treatment in the other eye, and you look and see who developed PAS or the few who developed an attack. The loss of iris area was lower in the ones who developed the disease. So this is the prospect of proof that that was an important phenomenon.

We're gonna talk about positive pressure. Positive pressure means that when you operate on somebody, Let's say you're doing, one is doing cataract surgery. The lens of the eye all seems to want to come forward and shallow the anterior chamber quite dramatically. And that's been a bit of a puzzle over the years as to why was that happening. And these are people, many of them who already had an iridotomy. They weren't having angle closure due to pupillary block, cause they had a hole in their iris. What they have is choroidal expansion. They have an expansion of the extracellular space of the choroid. It happens when somebody pokes a hole in the cornea and produces atmospheric pressure in the anterior chamber, and the choroid in these people is hyper responsive to the pressure difference in the back of the eye to the front of the eye, and the choroid starts to expand, and that brings the lens forward, that brings the iris forward, gives the surgeon a bit of a pain in the. Backside, trying to do the cataract surgery. And in fact, opening through the sclera, to let some of that fluid leak out to orbital pressure is the way that we treat this when it's happening in the operating room. But it turns out that persons with primary angle closure disease, typical ankle closure patient, Have expanded choroids on a regular basis, and this was one of the couple of the papers that show that that phenomenon is actually very operative in potentially the majority of persons with primary angle closure disease. So we need more work on what causes the choroid to expand. I'm gonna propose to you that it's a breakdown in the blood choroid barrier at the choreo capillaries. It's probably related to something called emmatropization. Oh yeah. Anybody get myopia in your practice around here? Any of your faculty studying myopia? Well, myops have a poor development of the back of the eye because blurred retinal images signal to the choroid. To tell the sclera to change its development, so the eye gets too big. That's at least one hypothesis, it's the dominant hypothesis for what's going on. They have some kind of, what if you had that mechanism? That became deranged in adulthood, and the choroid for no reason that it should, decides to expand or on being stimulated by lowering the front of the II pressure, the choroid hyper responses. So if we were to understand that phenomenon better, We not only work on myopia, we could work on angle closure glaucoma, even though one of them has big eyes and the other one has small eyes. There's probably a similar mechanism in each.

Getting to, we're gonna talk about something called malignant glaucoma, that may or may not be something that each of you has seen. It's a situation where the anterior chamber goes flat, and it is said to be due to aqueous misdirection. That means that the aqueous humor sometime, somehow goes to the back of the eye, can't get back to the front of the eye, and because aqueous is misdirected, the chain, the pressure is very high. And the patient has to have surgery to get out of it. The surgery is to remove the vitreous gel. It turns out that vitreous abnormality combined with choroidal expansion is the cause of this disorder. If fluid could go from the front of the eye and get misdirected to the back, it could come back forward again. Where's the one-way valve? The pressure elevation is coming from choroidal expansion. And in these people, the fluid can't transmit across the vitreous gel, which is why vatrectomy removal of the vitreous works.

And we now have, thanks to Coroidal thickness measurements on OCT direct evidence that eyes with malignant glaucoma have choroidal expansion. Before they get the disease in their fellow eye of the eye that had malignant glaucoma in the right eye, these are pictures of the left eye. So an expanded extracellular space of the choroid perhaps breakdown of the blood choroid barrier is not only in general angle closure important, it's probably one of the primary causes of malignant glaucoma.

So how close are we to neuroprotection? We're lowering the eye pressure. We ought to keep doing that. That works. But we still would like to also protect retinal ganglion cells. I mentioned the vitamin B3 clinical trials, and by the way, don't go out and tell your patients to take these doses of vitamin nicotinamide pyrovate there are two patients so far who have developed liver failure, neither died, fortunately. But that the dose of vitamin B3 that's in these trials, they now have to monitor very carefully the liver function studies. And I think there's some possibility that it maybe might improve things a little bit, and of course it'd be wonderful because the stuff's cheap. It's not an expensive drug.

We've done work that gets back to that biomechanical thing. Remember the biomechanical thing? And what we did was to study agents that would change the biomechanics of mouse eyes that were given experimental glaucoma. We raised the eye pressure in the mouse by putting beads in the front of the mouse eye, the pressure goes up, and in some of the mice, we treated them with an agent that blocks transforming growth factor beta. If you've studied the physiology of connective tissues. You know the TGF beta can cause lots of change in connective tissues and losartan, a well-known blood pressure medicine effects as an inhibitor of a particular receptor infected by transforming growth factor beta, and it was neuroprotective in mice. Well, that's mice. So who cares? You know, there have been lots and lots of experiments of neuroprotection that was supposedly helpful in mice, and it never turned anything in humans. So, Pappelis and Jansonius in Europe, looked at a group of patients they'd followed for 13 years in excruciating detail, visual fields, OCTs, and at every visit, they logged what blood pressure medicine the patient was taking. Not a single blood pressure medicine was associated with either better development of glaucoma. In other words, they didn't develop glaucoma. Except one. The same one that was neuroprotective in the mice, Losartan. Once again, I'm not telling you to go tell your patients until there's a randomized clinical trial that Losartan is what they ought to be taking for their blood pressure, but I always smile when one of my patients is on it because I kind of suspect that it's going to turn out to be beneficial. We need a randomized trial.

At the present time, there are two ways of doing neuroprotection by delivering something called a neurotrophin, brain-derived neurotrophic factor or ciliary derived neurotrophic factor. These, these are agents that ganglion cells eat up, they love it. Pumps up your ganglion cell, but to deliver it, Keith Martin working with us and now in Australia. Took a viral vector, the AAV2 vector, and tagged it with BDNF or CNTF, and in a rat glaucoma model similar to the mouse one I mentioned, it was beneficial to protect ganglion cells from dying at the same pressure elevation that the non-treated. Control animals did. This can now be done in humans. It's being done by a Japanese company in what's called phase one, which means they're testing to be sure it's safe. This viral vector is the one that is FDA approved for the treatment of labor's disease. So we know that humans can have this done. We know it's already benefited somebody with an eye disease. And this vector continues delivering the neurotrophic agent for years. That's also now known. So it's not, oh, didn't he tell me at the start of this talk, he didn't want to inject the eye in the office? Yeah, but what if I only had to do it once? Like once when they were having a cataract or glaucoma operation. Or just one time.

In addition to this way of doing it, there is a capsule that's already been in human eye that has cells in it that deliver this chemical, CNTF and and an incision is made in the sclera. This is sewn to the sclera, the capsules inside the eye. The patient can't see it. And these have been in human eyes for 3 years so far, and continue to deliver the same chemicals, CNTF. Didn't benefit retinal disease, that's what they tested first. It is now about to be tested further in glaucoma eyes. Hasn't been in enough eyes to tell us for sure that it actually works. But Jeff Goldberg has a paper in Ophthalmology Science in 2023 that shows that at least it didn't hurt anybody to put the thing in.

Our colleague David Derrick Wellesley has nanoparticleized an inhibitor that blocks one of the chemicals that kills ganglion cells, it's called DLKinase, dual lucy zipper kinase. It's the injury signal that when an axon and the optic nerve head gets squished or runs out of nutrition, the signal goes up to the cell body to say you've been injured. You better set off your survival mechanisms or you're gonna die. What Derek gave to animals in the studies was an inhibitor of that injury signal. And it was dramatically effective, whether you crushed the optic nerve or produced experimental glaucoma. he and my colleague Don Zack now have a company that is working on the initial human trials of a sustained delivery effect using tozasertib or sunnitinib, which are actually cancer drugs. If you gave it to persons as a pill, they get terribly sick. You just put it in the eye. If you had a long prolonged effect, you might very well block their glaucoma.

The final step in the future, of course, is to restore vision. You're going to get very tired of telling glaucoma patients,  Mrs. Jones, I'm really sorry that we can't do anything to restore your vision. We can block it from getting worse. But we can't put it back. So my colleague Tom Johnson is one of the leaders in the field of putting it back. We aren't close. But we've taken the 1st 5 steps in having stem cells to replace vision. Let me tell you where Tom is at the moment. The cells will be gotten from one of 3 sources. There are retinoids, that's growing an eyeball from a stem cell. They might be generated from fibroblasts in the skin, turned into retinal ganglion cells. What Tom has been working with are embryonic stem cells from those embryonic lines that were just barely saved from being killed off during the Bush administration. And Don Zack figured out how to take embryonic cells from, let's say an 8-cell embryo and turn them into a retinal ganglion cell-like cell, producing everything that a ganglion cell produces, 8 major chemicals. You put them in culture, they grow dendrites and an axon. However, they are from somebody else. So when you put these into an eye, there may very well be a need to block immune rejection. They wouldn't be from the patient themselves, but you can get a ton of them. We can make thousands and thousands. The second is Tom and I worked on transplanting these cells into the eyes of mice. We put them in the vitreous, and they wouldn't go into the retina. They don't get in the retina, they're not gonna work. The blockade was the internal ending membrane. So we digested the internal membrane, the cells went into the mouse retina. Integrated into the retina. And grew dendrites in an axon.

This is how Don Zack developed those cells. We don't need to look at that. Here's where we disrupted the internal limiting membrane, and the, the, the maroon color that you see here are the injected cells growing into the retina, and interestingly, they know where they ought to go. They go to the ganglion cell layer, and they don't go further than that. If you put them in the vitreous. Interestingly as well, these cells now have incorporated enough. With bipolars and amacrines. Such that when you flash a light on one of the injected stem cells that has been given a calcium signal indicator. That when you, when a light is shined, a neuron has a calcium internal signal that says, oh, I saw a light. So Watch what happens in the mouse eye. When the light goes off. That would not just happen from the intrinsic ganglion cells that we talked about a little bit earlier with one of your investigators that are intrinsically sensitive to light. These guys are not, they don't have the molecules of an intrinsically sensitive ganglion cell, so they have to be connected. In the retina. So OK, so now we've got the cells. We've got them into the retina. We know there's synapsing in the retina. Tom has some additional evidence that shows they actually are making immunofluorescently identifiable synapses. Now we got to get them to grow an axon.

So here they are in a monkey eye, we've moved moved, now we need to work in bigger eyes. So we now have worked in monkeys, and what you're looking at is a monkey eye in which the membrane, the internal limiting membrane was peeled surgically, retina surgeons do this all the time. It's a little trickier in a monkey, it turns out, but our premier retinal surgeon figured out, they peeled the internal membrane, Tom put a bunch of the stem cells, like I just showed you, they're red. And you can see them In the retina and growing axons and very interestingly, look where the optic nerve head is on that arrow. The axons seem to know that's where they want to go. They're not just going randomly all over the retina, like spaghetti. So we may get saved in the stem cell work by the fact that the internal program of the cell, once it becomes like a ganglion cell, is gonna recapitulate what happened in embryologic development. That's the only way we're ever gonna get there. But the problem now is those axons aren't going through the nerve head out of the eye. So we're gonna have to figure out how to induce them to do that, and that's the next step.

Tom has a consortium of 130 scientists around the world, all of whom are pooling information on the stem cell work. And it's a unique academic interaction because they're telling each other what they know. The usual deal is you don't tell anybody. So you publish it, cause I gotta publish it first. And this time, everybody's saying, look, for us to get anywhere, we have to share every bit of information that we can. And so that group is doing that.

Through the talk, I happen to mention the book about how to take an eye drop. If you happen to want to be interested, we have a website called diagnosisglaucoma.com. It has 45 podcasts for patients. It has this book which Mona Kaleem, who, uh, Christina Mona had the baby yesterday. My colleague, uh, Mona Kaleem had her second child yesterday, and she and I, she helped me edit the second edition. There'll soon be a 3rd edition. Of this book, we find that patients really benefit after you've spent time with them in the clinic, talking about why are you taking eye drops and how do I, they want to read stuff. And all of this is free. We don't benefit financially from any of it. And there's an audio version, if somebody wants to listen to the book, we actually dictated the book. So if, if that's you we can also buy it as a book on Amazon if you want. It's like $35.

I work with a lot of people, a lot of what I've talked to you about, um, is done by somebody other than me. This is the team, Vicky Nguyen, helping me presently doing the work on biomechanics. Tom Johnson is the tallest guy in the back there doing the stem cell work, I think that the future for you all is that we're going to be doing a lot better with glaucoma therapy. We're probably, I don't wanna finish my career still prescribing eye drops, but it's looking tough at the moment. We may get there. And finally, we'll open it to questions and see if there are anything that any of you want to ask about uh um a few things that we talked about about glaucoma. Thank you.

DR. WALLINE:
Right, so people have joined us online. If you have any questions, you can put your questions in the Q&A and we will try to um get to those as they come through. But now we're gonna open up to the audience here for any questions that they might have for Doctor Quigley.

DR. QUIGLEY:
Don't be shy, sir.

ATTENDEE 1:
So you mentioned the uh the vitamin B3 studies being beneficial, but there seems to be some momentum in the other direction. The calcium channel blockers are particularly bad for patients with glaucoma in an IOP independent fashion. What's your thoughts on your patients with calcium channel blockers?

DR. QUIGLEY:
Yeah, I think, uh, in general, some of the cal especially the short acting calcium channel blockers were originally touted as being neuroprotective for those with the lowest pressures. And the side effects of calcium channel blockers are now kind of coming to the fore. If it's the only medicine that helps the person's high blood pressure, or if they're not a glaucoma patient, they have no risk for glaucoma, then there's certainly nothing wrong with taking amlodipine or other things. Could two members of my family take the that that agent uh itself, right? Um, and on the other hand, without any question, it's not beneficial for glaucoma. And I can think of several reasons why it's actually not beneficial, and that deals in lowering the diastolic blood pressure, which it's very effective at doing. But unfortunately, Could have been, you know, not beneficial effect. So, we often see glaucoma patients who come in and you look at their med list, and there's four blood pressure medicines there. How did those patients get on four blood pressure medicines? Now, some of us need more than one But what if the patient takes the first, gets the prescription for the first one? Comes back, first blood pressure medicine looks great. OK, keep taking that. A year and a half later, they come back and they weren't adhering with their pill. Did the doctor identify poor adherences, work on that, and find out that if she just took the blood pressure pill, she'd be fine. No, what's the standard behavior? You had the 2nd pill. And that's why a lot of people wind up on 3 or 4 blood pressure medicines. So in addition to suggesting to the internal medicine doctor, maybe somebody ought to look into taking all these in the morning. Maybe the internal medicine doctor ought to look into a trial, especially with a home blood pressure monitor, of stopping one or more of those. And if I were gonna say which one to stop first in a glaucoma patient. be the calcium channel blocker. June. So amazing. Yeah, I know, but what was wrong with it? This is, this is the US of A, and if I give a lecture in Japan and I say to people, what did you think was weak about your talk? Oh, it was perfect. Everything was fine. That doesn't help me. She's gonna ask a tough question.

ATTENDEE 2:
Yeah, I think it's amazing of everything you're doing here, but of course my focus is more related to the biomechanics, and I'm extremely interested in your work in Losar. Um, and the biomechanical, um, implications of that. I, know in your class one paper, and you guys did test, the sclera properties. And if I remember correctly, it does affect the sclera properties in those experimental models of mouse glaucoma or rat glaucoma, I forgot.

DR. QUIGLEY:
At the time, we did not have the technology to measure. The effect on the astrocytic laminocribrosa of the mouse. Some of you may know that mice, the eye is not only really small, it's 3 millimeters, but there's no connective tissue in their optic nerve head. The astrocytes function as the, the thing that holds the optic nerve head from just blowing out the back of the eye. We didn't have a chance to measure astrocytic compliance, but we did measure whether axonal transport was affected. Now that's a surrogate measure for the biomechanical effect on axons, and losartan affected the axon beneficially affected axonal transport.

ATTENDEE 2:
Yes, I, I wanted to get your comments on your, this study. I'm thinking about the, the sclera, you know, also the laminar part. So, so in that study, I believe that the sclera was um stiffened or more compliant after losartan.

DR. QUIGLEY:
you may be thinking of another experiment that's very similarly related. It was the prior experiment. We, we thought, well, gee, if you want to block the effect of intraocular pressure in the eye, why don't you just keep the eye from expanding. Make it rigid. So we looked into chemicals that do that safely without killing nerve cells, and the chemical we used is glyceraldehyde. If you had a Prepared food today of any kind, it probably had glyceraldehyde in it. It's a well-known chemical. It's not a fixative like glutteraldehyde, which is really, really a potent turns eye tissue into concrete. But glyceraldehyde stiffened the sclera, and we proved that it stiffened the sclera. And then we stiffen the sclera by injecting it around the eye of mice with experimental glaucoma and injected saline in other mouse eyes. And instead of protecting the eye, it made the glaucoma worse. And I was so startled by that result that I did the whole experiment again. Because sometimes, you know, you do something and it doesn't come out the way you thought, but it was just a fluke, you know, let's do it again. I'm sure it's gonna work the second time, and it was even worse the second time. Both times significant. And what we think is going on is you make the sclera rigid, so you're intensifying the translaminar pressure gradient, which any good engineer could have told me ahead of time, and I would have spared myself a year and a half years of work, right? Except you got to do the experiment, and otherwise you won't know what's actually going on. So I would not, for any reason, want to treat the eye for a permanent stiffening one-time treatment, even though Bryce Chang, who's working with me right now, is doing exactly that. In a pig explant model, where we have a laminar cribroso, and like your human work, the pigs are cheaper, somebody was gonna have bacon anyway, so why don't we just take the eyes. I know, get a bag full of them and then we've proven that you can actually do axonal transport studies in the pig explant model that's gonna be published quite soon. So, what I wanna do though is to establish and maintain the equilibrium behavior of the peripapillary sclera and lamina cribrosa in the face of change and pressure. That doesn't mean make it stiff, and it doesn't mean blow it out, so it is totally elastic. Cause neither of those is physiologic. I wanted to simply respond to the eye pressure and stay there. Until the axon everything is fine, and we think that the systemic treatment with losartan. Did that closer to the ideal, because it was blocking the effect of transforming growth factor beta, which itself is producing changes in the nerve head, which probably in the human, and now I'm really speculating that that are Causing the eye to become more compliant. Both peripapillary sclera and the lamina corros, but definitely the lamina corrosa, uh, in glaucoma patients. We have the sclera papers coming out, human sclera, living human eye sclera, and we can measure that just barely now.

ATTENDEE 2:
Yeah, I was just thinking how do we reconcile that, right? Losartan's effect of making it more compliant, which is, Well,

DR. QUIGLEY:
I don't know that it made it more compliant. I, I just know that it blocked axonal transport. So we could do the losartan experiment again in the mice with fluorescent astrocytes and measure. The compliance of those astrocytes. Um, I don't think that, I don't think that it's actually measuring astrocytic behavior though. It's measuring an effect in the peripapillary sclera in the mouse, but it's why we're going to pig and it's why your human work is so much more valuable right now. We can do, we can do, you know, large scale drug treatment stuff first in a mouse, but it doesn't have an optic nerve head that's close enough to the human. Hi.

ATTENDEE 3:
So it seems to me like you know there's quite a bit of evidence about BDNF being helpful. And I, I noted your um treadmill study. I'm curious, are you going to be measuring, we know that exercise actually increases the amount of BDNF. Yes, it does. Yeah. And I don't know, treadmill versus I know lifting weights in particular does, but I'm curious, are you going to also be measuring something quantifiable in the blood, something like a.

DR. QUIGLEY:
It was part of the trial. Yeah, they're, they're gonna be looking at a whole bunch of things in the blood, um. the neurotrophins are certainly one. Whether the level in the blood is going to be highly relevant is a pretty, that's it's a speculative leap, isn't it? I just reviewed a paper where somebody studied skin fibroblasts of glaucoma patients. And said, oh gee, there's all kinds of gene expression in these skin fibroblasts that are different from controls. And they were talking about oxidative damage. In a fibroblast from the skin. How's that related to the eyeball? Where the cells in the eyeball that are being damaged by oxidative damage, the neurons, are they fibroblasts? How similar are those? And there's a couple of studies that show that Circulating white blood cells, which have been studied as a surrogate for brain tissues and eye tissues in terms of gene expression and methylation, which is one way of studying, you know, the gene expression. That what you get from the white blood cells is absolutely unrelated to the same degree of methylation in the in the eye tissue. So, we gotta try to hope that we can maybe measure something in eye tissue as well. But it's, it's a good first step and you can do it. So, you know, why not do it to find out.

DR. WALLINE:
OK one question, online and two comments. I'll just go through those real quick and we got another question here.

First, the question from online is from one of our colleagues at the University of Houston, and she asks, have the results of the life trial changed your recommendations for initial therapy for light therapy?

DR. QUIGLEY:
No, we were, we were recommending SLT or ALT, um. But recommending SLT now, cause that's what everybody has in the office as a, as a laser. We were recommending SLT or drops to every new patient. 85% of them or more pick drops. Even though I think we're presenting a, an, uh, a balanced viewpoint of the two things, and the usual statement is, well, but you're not guaranteeing me with the SLT that I'll be off drops, right? I said, no, I can't guarantee you that. Well, OK, well, let's start the drops. But I think it's a reasonable first treatment. A couple of comments online and we'll get to a

DR. WALLINE:
A question right over here. one comment is from an alumnus of ours who's now with Wilmer, Bryce Sinclair sends his regards, and he asks.

DR. QUIGLEY:
One of our favorite colleagues, yeah, he actually asked a

DR. WALLINE:
question too, if you could just spend just a moment with it, he asks about the evolution of the ODMD relationship and, and how you see that.

DR. QUIGLEY:
Yeah, when you look at the next edition of the book that I wrote for patients. 15 years ago, I wrote a chapter, and then the chapter was titled "Who Should Care For Your Glaucoma?" This was in an era where not the majority of states in the United States had a drug capability for optometrists. And the new chapter is going to say glaucoma care at the Wilmer Institute is a team approach of optometric and ophthalmological colleagues. That uh your care will be done by people who are specifically trained about glaucoma and all of us uh feel that that's the best way for us to manage your disease. And my Every week colleague who is uh in the room next to me, seeing my patients and her patients with glaucoma, and I interact all the time, and Corinne Casey, that faculty member, uh helped me rewrite that chapter. And she's She's an optometrist.

DR. WALLINE:
And then uh one comment comes from Cindy Hill, and she says, thank you, uh, for an informative and enjoyable lecture. My father, Richard Hill would have very much enjoyed it. Yeah.

DR. QUIGLEY:
Thank you, Cindy. OK, um, so there's been a lot of talk about

ATTENDEE 5:
OCPA, and I thought I saw a quick sentence. About like monitoring the progression of glaucoma, even like a rotation. What is the like, will OCTA be used in honoring for progressive glaucoma?

DR. QUIGLEY:
Can I make money if I give the right answer? No, it was, it was just a handshake. Oh, OK. Well, that's, that's fair. Right. So when OCTA, when David Wong first brought out OCTA, he had a flow index on it. And they were claiming that OCTA was measuring blood flow. It does not. It measures the presence of capillaries, and it does it beautifully. For if you wanna see whether capillaries are physically present or not in the retina. It's an incredible technique. He deserves all the kudos for for developing the methodology, and we find it to be fun and useful. There is a paper that's either in press or about to appear. It's from the Diggs study, which is a longitudinal study at University of California San Diego. Linda Zangel, and a junior colleague of hers named Bob Weinreb, um. And they have done OCT and show that it tracks very well with the degree of injury and with the degree of progressive injury. What hasn't been shown, and Bob Derek and I were just talking about this earlier, is the prospective, did the OCTA change in capillaries occur before there was the visual field loss? Did it predict it, or was it an effect? Now, bear in mind we're talking about the retina. We're not talking about the optic nerve head. The damage starts at the optic nerve head. There is damage in the retina and retinal capillaries. Auto regulate away as the ganglion cell there disappears. You don't need as much oxygen, you don't need as much glucose. There's an auto regulatory system and they involute. And I showed that in the optic nerve head like quite a number of years ago, same phenomenon. So we know that they're disappearing. But we don't know if it's cause or effect. That doesn't mean it's not a decent biomarker for what's going on. And what they did in this most recent study was try to say which is better, counting nerve fibers in the RNFL or doing OCTA. At the present time, we don't have anything like decent software for measuring OCTA effect. It's gonna be complex, because now you're out in the retina, looking at the variation with myopic eyes are bigger and smaller eyes are smaller. Um, you don't often know what the baseline state is. There's a vascular index of the number per unit area that's out there. I think it's gonna be interesting to watch what value OCTA has, but the purpose of what I put on that slide was, you're not measuring nutritional blood flow. And frankly, also you're not measuring it in the lamina quadrosa, because the capillaries in the lamina are completely encased in collagen. And I doubt that what we're seeing in OCT of the optic nervehead is actually laminar corrosive blood vessels. I think they are more superficial, and they may be a good surrogate. So it's worth very worthwhile research, not presently clinically useful in my opinion.