 So welcome welcome to our Grand Rounds series. It this is one of our special Grand Rounds, which is our visiting professor series We have a unique opportunity. I will not be Having me I will not have the honor of introducing John will leave that to Alan Crandall here in just a moment But suffice it to say that John is someone who is one of the bright minds in ophthalmology Beyond being a bright mind. He's also an incredible person quality of person I'm sure he doesn't want me to tell you this. He actually Just donated his entire honorarium for coming here to our resume education fund, which is quite an extraordinary gesture. So No, it's really a great honor for me to introduce John John has done some Even as young as he is has done some major major work in glaucoma Anybody that knows anything about the the astronauts at all every single astronaut has some form of Opinir pathology, whatever you want. I'll let you I see we're going to talk a little bit about that Related to being in space and and it's his Roll he went through thousands of of Records to discern how what's the problem and possibly how do we fix and make sure because if it if it was like It is now everybody would be blind by the time they got to Mars and Obviously, so there's a lot of work to do with his work with that in the central nervous system of connections Which will be very interesting for Judith. I hope she's yeah because he'll be talking about right up your alley So and also they have a great fellowship Our feet is Resident Russ who's up in up in? Up in Montana They've they set up an office for him up there and they take great care of their fellows And also their patients. So it's really a great honor to have him here to talk about the future Very interesting stuff. So we thank you very much And before we get started One of the things that I'd like to say is this place is incredible you guys have some of the most Accomplished most caring teacher mentors of any institution in the United States and as a from a fellowship director standpoint I think that the best training of residents occurs here and the University of Iowa of any place in the United States And so for those that are in training. I said this when it was just our small group, but I'll say it again You have a responsibility to our profession. That's bigger than just going out and doing a good job That's the absolute ante for you guys, but being at the best residency program in the best Specialty within medicine and medicine is one of the best jobs in the world in the most prosperous company or country in the world Is a is a real? Responsibility it's a it's a little bit of a burden, but it's really an opportunity and I'm really excited to see what the great things that all of your trainees do and and you've got like I said some of the best people in the world So this talk might be a little bit different than some of the talks that you've gotten in the past But how many people have heard the phrase the dark side of the moon? Not just the best Pink Floyd album ever And it's got special significance now because China just recently landed on the dark side of the moon What is the dark side of the moon one of the residents tell me what the dark side of the moon is what does that mean? So it's the side of the moon that's facing away from Earth. That's right. Most people that's right Most people say that the dark side of the moon is the side that doesn't get any sun That's incorrect. It's the side of the moon that we never see from Earth So it turns out that the moon's day and the moon's year So the day is how long it takes to do a rotation the moon's year is how long it takes to do the revolution? They are identical so it does one rotation in Exactly the same amount of the time that it takes to do one revolution And what that means is the same side of the moon always faces the earth and has Forever and I think that glaucoma is not unlike that We as ophthalmologists quickly forget that the eyeball is connected to the rest of the body and We spend all of our time in our one cubic inch of the world And we don't think about it in terms of the greater pathophysiology And so I'm gonna make an argument that The dark side of the moon is analogous to the dark side of the optic nerve and we need to think about that Here's my financial disclosure. So, how do you take some? crazy idea that you have and Actuated Ideas are really really fun and they get your juices going and there are One maybe if you're lucky 2% of the work and they're the fun 2% of the work The rest of it is just work and most of the time what happens to a brilliant idea is it ends up like this Once the work actually starts how many have started a research project that you're excited about and Four months later after you've you know Written down a paragraph of the proposal. We haven't made any progress right that kind of stuff happens and the other thing about ideas and taking Taking a stand on something is that it requires real risk not fake risk but real risk reputational risk risk of how you view yourself if you fail and you thought that you were brilliant and unstoppable and Risk of other people's dollars that have invested in you Especially if you're doing that from a venture capital standpoint people invest millions of dollars and you did you deliver on that? Trust that they put in you But what happens in academia better than anywhere else is that you have an opportunity for lightning to strike If you're just going through your day from cataract to cataract to cataract to cataract to cataract plus makes to cataract There isn't an opportunity for that conversation with a colleague for lightning to strike another thing that happens in a university setting is you've got specialists that are Not in your field that can give you ideas. I think that most of the ideas in medicine Get translated are discovered and if we can apply them to us or we can take Discoveries we made and apply them to other areas of medicine There's huge opportunity there. I remember when I was a medical student at Mayo Pediatric oncologist came and told me that he thought for retinopathy of prematurity That may be some of these new anti-veget, anti-cancer drugs Could be helpful. This is in 2002. I'm like, I don't get it and you know, and that's I don't know how far along they were Before they were injecting medicine in the back of the eye But the point is that there is somebody somewhere that's thinking Across specialties and if you can take that and translate it somewhere else you can find real big Opportunities so my idea came when I was scuba diving. This is my family. This is taken last year Not when I had the idea, but this is my son Who's tennis my wife and that's me And so I'm down scuba diving and I'm down under the water And I'm a first-year resident at Duke at this time and I'm thinking What's going on with the pressure inside my eyeball if I'm down 30 feet underwater? How many scuba divers do we have in here? How much This isn't a pimp type question, but does anybody know at 30 feet how many millimeters of mercury your pressure the water's putting on you 10 meters what? One atmosphere at third at 30 feet 30 meters would be three atmospheres. Yeah So one atmosphere of pressure. Does anybody know how many atmosphere one atmosphere of pressure is how many millimeters of mercury? 760 somebody said it but didn't want to get credit for it because they whispered it They're gonna be really accurate. They would have said it's about 610 in Salt Lake in Salt Lake City So 760 millimeters of mercury of pressure pushing on my eyeball Now if someone comes in today with the pressure of 60, we're gonna drill a hole in their eyeball today, right? So how can I be experiencing 760 millimeters of mercury of pressure on my eyeball and And not have glaucoma. How can I profuse my eyes? So I'm sitting on my one vacation I get during my first year of residency And I'm thinking about this and my wife is pissed because this is what I'm thinking about on the beach instead of enjoying a corona and paying attention to her and so When we're confronted with Something that we can't make sense of I think we have to zoom out and think about the perspective And I like this picture because this is true. You shine a red light from over here. This is true If you shine a whatever color this is aquamarine light from here This is true, but it does not represent the totality of truth And if we can zoom back out and start to make the puzzle pieces fit together We can get a broader view of what Is so the common belief is that glaucoma is a one-pressure disease the pressure inside the eyeball The more likely truth is that glaucoma is a two-pressure disease Or at least I believe the more likely truth is that glaucoma is a two-pressure disease a balance between the intraocular pressure and The intracranial pressure Okay, so when you look at the optic nerve head and you do a histology slide and this comes from Yoast Jonas Here's the intraocular pressure. There's the lamina Croprosa Here's the cerebral spinal fluid pressure bathing the optic nerve all the way to the back of the eye and we've spent a century talking about this pressure that affects the optic nerve and Very little time talking about this pressure the CSF that bathes the optic nerve We'll talk about one millimeter of mercury difference here And what's happening at night and all of this stuff when the disease occurs here at the optic nerve head? How is it possible that this pressurized fluid doesn't matter? You know that it matters You know it does because what do we see in high CSF pressure? That Vladimir the optic nerve bows forward it swells excellent will transport gets stuck on this side of it What else do you see? That looks like papillodema in high intra-cranial pressure papillodema. Hi potty the optic nerve swells Right if this pressure differential is one where CSF pressure is higher than IOP the optic nerve bows forward it swells If IOP is higher than CSF, what would we expect to see? cupping and The optic nerve gets pushed backwards right so This is just basic physics if you have two equal and opposite forces those forces cancel each other out No net force is generated Nothing happens, but if you have a force on one side That's higher on the force that's higher than the force on the other side cupping can occur glaucoma can occur So when I'm sitting there scuba diving what's happening? Yeah, my eye pressure went up 760 millimeters of mercury But so did my CSF pressure so did my blood pressure so did my tissue pressures all the pressures work in lock steps so to the point of having it having atmospheric pressure being 610 millimeters of mercury in Salt Lake City a 150 millimeters of mercury less than it is in San Diego people in Salt Lake City still get glaucoma even though the Absolute pressure in their eyes 150 millimeters mercury less It's got to be absolute. It's got to be relative pressures that matter not absolute pressures that matter But that's not how we think about glaucoma We think about it as an absolute pressure inside the eye and that's not actually the truth when we measure the pressure across the Cornia we're measuring a relative pressure We're saying what's the pressure inside the eye? How much force do I have to add to the cornea to flatten it? Aplenate it and that's the pressure and so we should really call IOP We really should call it the trans laminar cornea pressure difference, so I go back and I Go back to one of the other glaucoma specialists at Duke and I say hey, I have this idea I think that it might redefine what glaucoma is He says you're wrong go back on call So I do just what you learn to do with your parents. I find it different professor And I say hey, I got this idea about what I think glaucoma might be and And he says well, I think you're wrong go study it and that was Randall and him and so he's one of my six heroes in Ophthalmology because he took a risk on this with me and he was a wonderful mentor and he just died earlier this year And so so I'll cherish this picture You know with him forever me making some argument about some crazy idea and him seeming to buy it So I went to the Mayo Clinic. I talked my way out of one week of my glaucoma residence or my glaucoma rotation I went to the Mayo Clinic in January. I looked at 55,000 lumbar punctures over a 20-year period with Doug Johnson Doug Johnson was also one of the great people and glaucoma specialists and he died a year after we did this project from liver after having a liver transplant and And boy, he was one of the good guys. So our original paper has me Randall and him and Doug Johnson And I'm all that's left and that really rocked me a little bit. Our time is short Make sure that you're spending it on things that matter with people These were people that I cared about so we looked at 55,000 lumbar punctures and We found that indeed they have a low CSF pressure the patients that have a glaucoma glaucoma have low CSF pressure I'll talk about that in a second. So we get the paper submitted. I We submit it to ophthalmology. I'm here in this building interviewing for fellowship 10 years ago and It was the day I learned that I was not tough enough to be an academic Because it's the day that this paper got rejected And I remember getting the email saying There's not a whole lot you can poke in this thing and I was Dejected, I mean I was like, oh my gosh two people Anonymous people have this much power over me and my day And and I was I knew honestly no kidding. I knew in that moment that I wasn't tough enough to be an academic I'm interested enough to be an academic. I like to do it But my underbelly is too soft to take that kind of rejection for so for those of you that are tough enough to do that kudos to you because it really was It really was hard on me and so I went back to Allingham and I'd whined to him that I thought that this should get Accepted and he called up Henry Jampel and said how about you have one more reviewer look at it and it ultimately did get accepted in ophthalmology Peer the peer review process is not quite as Unassailable as you think that it is And it ultimately did get accepted to ophthalmology and was the lead article in their journal And so here's what we found we found that patients that had um That were normal had an average CSF pressure of 13 millimeters of mercury and people that Had glaucoma had a CSF pressure of 9.2. That was lower and so Highly statistically significant We then went back and said well, what about Ocular hypertension what about normal tension glaucoma right doesn't this explain all of it? Because 30% of glaucoma in the United States is normal tension glaucoma 70% of glaucoma in Japan is normal tension glaucoma and 83% of glaucoma in China is normal tension glaucoma Most people that have a high eye pressure don't get glaucoma Many people that have normal eye pressures do get glaucoma What's the big picture that we're missing? So if it's this that normal is eye pressure say 15 or 16 CSF pressure of about 13 Glaucoma primary open-angle glaucoma is a high eye pressure a little bit lower CSF pressure You get that pressure differential across the optic nerve Normal tension glaucoma is a normal eye pressure, but a bottomed out CSF pressure an ocular hypertension is a high seat without glaucoma a high eye pressure and a high balanced CSF pressure So that's why they don't get the disease So we went back and looked at that and that's what we found indeed the patients that had normal tension glaucoma had a lower CSF pressure patients that had ocular hypertension had a high CSF pressure and so I bring this back to Dave Epstein who was the chair at Duke who also you know passed away a year and a half ago and And and it was so fun to have a chair that would Light up and take joy in your successes and he was And so he would have these rounds Monday night and he poke at me about this stuff and he ultimately came to believe So then the questions start flying once you have this insight. What happens to CSF pressure with age? Are there diurnal CSF pressure curves does BMI affects CSF pressure? What about experimental models? Can we raise CSF pressure? Can we measure CSF pressure not invasively without doing a lumbar puncture? So what does happen to IOP with age? How about some of the residents? Let's start with an easier question This is maybe a PGY to question What happens to glaucoma incidents with age does it go up go down or stay the same? Answer the easy question first because they only get harder Goes up Okay, make sense right what happens to IOP age if say it goes up residents. How many people say it goes up? How many people okay somebody saw somebody raised their hand they said I'm following Raise your hand if you say it goes up Raise your hand if you say it goes up raise your hand if you say it stays the same Raise your hand if it stays goes down raise your hand if you don't have hands Okay IOP Increases with age to the sixth decade after which a decrease in IOP is seen with further age IOP really doesn't go up That much with age even though glaucoma in incidents is going up with age. That's curious, right? After adjusting for blood pressure there was a trend for IOP to decrease With age Okay, so IOP Stays the same if anything it goes down with age That's curious since glaucoma goes up with age. No doubt about it What happens to ICP with age? How many people say that it goes down? How many people say that it goes up? People say it stays the same. Okay, so you're right. So this is a paper that we published in I OVS 14,000 points make up this curve Here's what's how here's what happens to CSF pressure with age When you're young and you know these little babies getting taps You know, maybe they're sick or something like that, but basically it stays really really flat until about age 65 And then it falls off the cliff So CSF pressure no doubt goes down with age and not only we're not the only ones that That showed that other papers show that ICP seems to decrease with age across all ages Okay, what about BMI? What happens to CSF pressure with BMI? CSF pressure goes up. This is another paper that we published Luke Aswale published a paper in ophthalmology showing that obese women were protected from glaucoma even if they had a high IOP So glaucoma is one of the few diseases that it's good to be chubby. Enjoy your cheeseburger I think we've all seen the reverse of somebody who's had stable glaucoma and it loses a lot of weight And and the glaucoma just goes just that's right And we were talking just yesterday about when you see normal tension glaucoma patients How many of them are slender females a Lot of them are slender females and it starts to tie this story Together so here's past Wallace paper among women high BMI was associated with a lower risk of primary open-angle glaucoma Low BMI low BMI was associated with an increased odds of glaucoma Okay. Now, um, I didn't show one other study. I don't think maybe I'm showing it later Where mainly Wang from Beijing Tongren Hospital He did a prospective study looking at this and did spinal taps on patients that had That had glaucoma and he found the same step out that oculohypertensives were the highest and controls then glaucoma then normal tension glaucoma He published that in the very prestigious Chinese Journal of Forest Experimentation And That's the kind of prospective study that you can get away with but not everyone believes so so I just enjoy this study And this is where reputational risk comes out and this is fun This is where you get in the arena and you get to fight for what you believe in don't take offense Get in there and fight for what you believe. Sohan. Hey ray has a his from the University of Iowa He has a history of writing pretty Pointed letters to the editor. So we publish our letter to the editor. He's also an iconic last He doesn't mind taking shots he's 92 years old he still goes into the office And so I published we publish our paper in ophthalmology He writes a letter to the editor to ophthalmology. They don't publish it So he writes a letter to the editor to graphe's which he's the editor-in-chief of which is kind of not the typical way So I just happened to come across this and he's saying, you know that he thinks that I'm wrong So let's go through a little bit of this He says a recent study claims CSF pressure may play an important contributory role in pathogenesis a glaucoma But in that study the difference in mean CSF between the groups was only four millimeters of mercury the concept that a Translimiter pressure difference of only three point eight millimeters of mercury produced by low CSF is strong enough to call bowing back the dense compact Connective tissue has little scientific credibility So he comes at me with like a jab. That's probably the nicest one that he's ever written I reply with a little harder jab and say we appreciate and recognize the tremendous Contributions that dr. Hey ray has made to ophthalmology in particular is understanding the ha optic nerve Thus it's with humble respect that we disagree with his conclusion This is the jab scientific validity is assessed by a well-controlled study to address a hypothesis not expert opinion He replies with a roundhouse This is this is him now saying this is speculation and simple armchair philosophy I just love this and sorry to take so much time bird on colleagues site Yablonsky in support of the hypothesis in 1978 dr. Yablot 40 years ago dr. Yablonsky and I discussed this at a conference He told me that the entire concept of the pathogenesis of optic disc and demon rays CSF was based on my studies He wanted me to Wanted to ask me about the concept of optic disc cupping in glaucoma He told me that if rays CSF pressure causes optic disc swelling the naturally a fallen CSF must cup Cause the reverse I tried my best to explain to him that this was not true at all Because the pathogenesis of optic disc swelling was totally different However, he was not prepared to accept any scientific evidence contradicting his belief He presented a paper on this at Arvo, but that was never published Birdall and colleagues states none of the colleagues dr. Hayre sites are designed to address whether a chronic pressure difference across the lamina cabrosa would lead to glaucoma disc cupping I do not waste my precious time researching topics that have no scientific logic in merit in conclusion therefore It's evident contrary to the hypothesis by birdall and colleagues that there is no scientifically valid theory that CSF pressure Plays a role in disc cupping It's what Thomas Henry Huxley called the great tragedy of science the slaying of a beautiful hypothesis by an ugly fact But the facts are what we need even if they are ugly and unwelcome. I have tried to present in this editorial facts Okay, so how much fun is this we get to try and establish truth And if you're gonna try to be a truth Establish her you're gonna have to fight for it Nobody has ever not had to fight for it when they're changing how people think and you know all we care about is truth If we're wrong, we're wrong and these kind of things test us and help make us better There is a little bit of disconfirming evidence. So our see it our ophthalmology papers been said you know 300 times down with only a couple of papers that have shown that maybe CSF pressure wasn't low This one actually got there's one that got published in ophthalmology that showed that Norm and the title of it was that CSF pressure is not low and normal tension glaucoma And what they found was that it was lower by a millimeter of mercury in a prospective study of 11 people And so it was lower and for their title was that it's not low And so there's um, you know some disconfirming evidence, but I'll tell you Hey Ray wasn't alone. If you ever want to be humbled apply for an AGS grant So I was applying for a young investigator grant. It's for the people that are in the first five years of practice that have Outside of the box idea. So I feel like this qualifies and so I apply for the grant and Um, and here's what I got in response It would be unethical to proceed given the complete lack of scientific evidence that would be achieved based entirely on flawed judgment And my favorite rabbits wouldn't wear goggles. How do you who says? Rabbits wouldn't wear goggles. Okay, so so let's think about this for a second What type of disease is glaucoma? Is it a mechanical disease of vascular disease of metabolic disease? A combination what is it and when we don't know we always say it's a combination of a bunch of things multi-factorial to me that usually just means we don't know So Harry Quigley and Doug Anderson wrote a classic paper And I think that this was in 1978 as well looking at axonal transport and monkeys and This will reveal how geeky I am, but it's really fun to go back to some of the real old You know 40 year old literature and read it because how they wrote was way different then and it was often much more Speculation was allowed and and it really is fun to to read how these papers sound different And we're looking at axonal transport and what he showed was that indeed if you raise eye pressure in monkeys Exonals transport stopped at the level of lamina crebrosa Okay, and and then the apoptotic mechanism occurs but what he also showed which was really interesting was that if you lowered the eye pressure for just four hours for one hour about half to seventy percent of the Metabolic accumulants were gone if you lowered it for four hours. It was 100% gone So what I wonder and I don't know that I'm right about this, but I wonder is glaucoma really a 24-hour disease Or is it a disease where if you can normalize that pressure gradient for a period of time You allow axonal transport to resume you deliver the metabolic needs you remove the metabolic waste. It's like Getting a breath. It's like kidney diocese it prevents the apoptotic signal from being sent and people ultimately don't end up getting glaucoma so if you think about The eye bone being connected to the brain bone by the optic nerve and that axonal Transport is a two-way mechanism and you have a normal eye pressure and a normal brain pressure You go up that pressure gradient. No problem Kind of like just the salmon swimming up the river If the pressure in the eye is higher or the pressure in the brain is lower It's a little bit harder to get up that pressure gradient But you get there, but if the eye pressure is really high or the CSF pressure is really low Then axonal transport is stopped. It can't get up that pressure gradient the accumulants Backup the metabolic needs aren't met the apoptotic signal descent and the optic nerve dies and the same is true in reverse With our ortho grade axonal transport If CSF pressure is high the axonal transport can't get up into the eye and that's been shown and now it's been shown in more and more studies experimentally this is an experiment An animal experiment where they showed that indeed if you lower CSF pressure Axonal transport stops the level of the optic nerve Even more so than if you raise IOP the same amount So there's lots of studies that have been done. This has been done This was done by Bill Morgan in Australia He showed that indeed there is a pressure gradient that exists across the optic nerve Had he cannulated the vitreous then the anterior optic nerve Lama crebrosa the posterior optic nerve the subarachnoid space and showed that indeed there is a pressure gradient that does exist There this is an experimental study in monkeys showing that if you lower CSF pressure, there's thinning of the optic nerve and neural retinal rim thinning this is that study by Rujan Ren and Ningli Wang showing similar data to what we have in their prospective study On on this in humans that they lower CSF pressure Optic nerve sheet diameter has been shown to be smaller in glaucoma patients Indicating that perhaps the retro laminar CSF pressure is lower there and so When I think about all of this work I think back on some of these people that that believe that we should try to find out if it was true or not Even before they did and the risk that they took on So I come out of residency and I'm feeling really good and I remember actually sitting in in Dr. Olson's office Talking about this and he said you seem really passionate about this and I was and and that meant Something to me and he said you can tell a difference between a research project Where somebody is just doing it to put it on their CV and a research project actually Because they're interested in trying to accomplish something. Okay, so I get done with residency. I'm feeling pretty good I'm applying to fellowships. I get accepted to fellowship with Dick Lundstrom and Dave Hardman and Tom Samuelsson at Minnesota eye consultants and And it was a wonderful place with wonderful humans and three more of my of my heroes and So a couple months in I scheduled an appointment to sit down with Dick to tell and for those of you That don't know dick. He's one of the real Amazing people that you'll ever meet he is loyal and he is Smart and he cares about the good and sometimes he takes some arrows because like you because You don't have to take any arrows because everybody loves what you do but but But he cares about what's doing right and because he's such a big person in our profession He he does take those arrows, but he's amazing So I sit down with him and I put together this ten minute PowerPoint to make the argument the CSF pressure matters in glaucoma And I get done and he says in his really deep voice John. I think you're right What are you gonna do about it? Like what do you mean? What am I gonna do about it? I'm gonna get credit for it people are gonna think that I'm smart And that's what I'm gonna do and he says well I live in a world where we like to take these scientific discoveries and translate them into something that can actually help people And I said well, I don't know what I'm gonna do and he says that's okay Opportunity favors the prepared mind be prepared for when that opportunity presents itself So what so what am I gonna do so I go through the next four or five years thinking what can I do to? Help treat people that have glaucoma because they've got a low CSF pressure And so I'm laying in bed one night, and I'm reading the Wall Street Journal on my iPad And there's an article that says astronaut shortage, and I say I'm always looking for a job I wonder what the skinny is, you know, why are What's the problem and they talk about how astronauts are losing vision up on the International Space Station during long-term spaceflight and I'm like and they talked about you know the path of the demon I say I think I know why It's because their CSF pressures high because there's no gravity pulling their CSF pressure down So it's amazing what you find in Google I find the highest ranking persons at NASA's email address that I can find who's in charge of astronaut help And and I email and I say hey, this is John from South Dakota. I think I can help you and No kidding he emailed me back and so we set up a call and then Ultimately, I got invited to be a part of the vision from ours program So I get to go down and meet all these astronauts and so this is the that syndrome. It's now called sands It used to be called the IIP and it's really four things. It's Coroidal folds. It's a hyperopic shift It's globe flattening and it's papillodema So what does that sound like? Sounds like hypoteny, right? Well hypoteny If you look at it through the lens of CSF pressure is just when IOP is lower than CSF So it's that same kind of scenario So this is what the this is one of the astronauts eyes after he got back and these are the four things That you see in that so what would be a treatment for that? gravity would be a great treatment Or raising eye pressure right so that it balances out CSF pressure So I was luring or lowering CSF pressure something like maybe Diamonds but diamox will also lower IOP. So maybe maybe a differentially lowers it Ventricular peritoneal shunt Could maybe do that maybe astronauts don't want one of those So and they're pretty particular about experimenting invasively on astronauts while we're up in space So the idea you know is really a simple one It's this as we're all sitting here our CSF by gravity is pulled down into our caudal spinal column CSF pressure at eye level is Lower in space. There is no gravity pulling the CSF down it redistributes up And so at eye level CSF pressures higher they never saw it on short-term space flight because it wasn't enough time to cause the problem of the accumulance of metabolic and external transport But I'm up at three months in space about 50% of the astronauts are experiencing some of these Symptoms women less likely to experience it than men Probably because they have lower CSF volumes a lower Column of fluid because they're shorter and they have lower CSF pressures to start with okay so we go down to NASA and we We get a hundred thousand dollar grant for this crazy idea that I have about raising eye pressure And we'll talk about that in a second and we publish a paper in this journal and I would highly recommend this journal I love this journal the Journal of Medical Hypothesis because you don't need any data To publish in this journal all you need is a hypothesis So you can come up with your idea try to support it That's what this journal is intended for and and I really I really do like it So I'm sitting in my office and this is my partner Vance Thompson And these are the planes of South Dakota with the Missouri River in the background The answer is one of my other heroes and ophthalmology and one of the really really good guys and for your for residents That are choosing a job we talked about this but join somebody like him Join somebody who is going to take as much joy as in your successes and be rocket fuel for your career Like he has been for me not someone who wants to suppress you And so we're sitting in the office and we're talking about all right What can we do so what that the CSF pressure thing is there and we were talking about astronauts and Says well, what if we just put them in a pressurized room and we pressurized the room and I said well Vance That's going to pressurize their eye, but it's also going to pressurize their CSF so it'll move and lock step That's not going to work. He's like, okay What if we use a helmet and pressurize a helmet well Vance It's gonna pressurize the eye and it's gonna pressurize the head and they're gonna move and lock step and so I say well What about a pair of goggles? What if we could just pressurize the eyeball, but not the CSF? so That's what we did. We went down and we looked at We I bought a bunch of stuff off Amazon and a little pump and put a pressure goggle together We got a hundred thousand dollars from NASA. We got $450,000 to study it from friends family and fools that said hey I'm willing to invest in your crazy idea And and we're on the way to a company that we've now raised 17 million dollars for and if you think that there's Pressure in academia from so on. Hey ray writing that so nice things about your idea in a paper try taking 17 million dollars from venture Capitalists that's real pressure. So the idea is this atmosphere is like a cosmic thumb pushing on our body It's pressurizing our entire body okay, and So all we're gonna do is release a little bit of pressure over the eye by drawing a vacuum now The atmospheric weight is not pushing down as hard in our eye But it's pushing down the same amount everywhere else in the body if I pushed my thumb on your eyeball will go What happens to your eye pressure? What if I release my thumb what happens to your eye pressure? Goes down Pretty simple concept, right? I mean it's really really straightforward. So the idea is this if you think about it in absolute terms Atmospheric pressure is 760 millimeters mercury the eye pressure is 16 millimeters of mercury higher than that 776 an intracranial pressure say 12 so that's 772. We think about it this way ambient is zero I pressure 16 CSF pressures 12 you got a pressure different differential right here of four no big deal you put on Glaucoma and that 16 goes up to a 22 that 12 goes down to a 9 Now you have a pressure differential here of 13 millimeters of mercury and the optic nerve doesn't like that and it slowly Deteriorates so if we took an applied negative 10 millimeters of mercury to the eye take that 22 down to a 12 Leave the CSF pressure at 9. We've now normalized that pressure gradient Pretty straightforward Okay, so the first thing that I did is I went and went over to Germany And there's a company that has wireless eye pressure sensors inside the eye We took my kind of Amazon garage created once we went over there We dialed the pressure down two millimeters of mercury it went down two millimeters of mercury Dialed down two more and went down two more. I got the phone call. I wasn't there when they did it I got the phone call at 4 a.m. Laying on my couch saying we can dial and I'm We presented this paper for this data for the first time at the AAO conference this year Here's what we saw. This is 51 patients in a consistent cohort One eye with goggles with vacuum one eye with goggles that didn't have vacuum as a control Pressure was 16 millimeters of mercury beforehand. We dialed in 25% of their baseline So think of this as we're dialing in 25% of that minus 4 we take their 16.2 down to 13 Control eye stays more or less where it was We dial in 50% so dial in minus 8 we take it down to 11 and a half We dial in minus 12. We take it down below 10 millimeters of mercury And so we just can dial in the eye pressure To where we want it to be After you take the goggles off the pressure goes back up to normal in a week later. It's normal interestingly We've been seeing this kind of positive after effect Of a little bit lower eye pressure afterwards I don't have a good way to explain it if I'm not willing to hang my hat on it But I am willing to hang my hat on the fact that we can lower eye pressure So we believe that this technology will be helpful during a vulnerable time Which is nighttime night times the time where IOP goes up medications and surgeries don't work as well Blood pressure goes down and it's a third of our existence. So we think that this will be an adjunctive Treatment to glaucoma or especially for hard to lower IOP somebody that's had it to Somebody that's got normal tension glaucoma and they're at 13 and they're still getting worse and we think what a CSF pressure Do during the night? You'd think it would go up. It does Go up a little bit at night Just like IOP goes up and so I think about CSF pressure and aqueous, you know cerebral spinal fluid and aqueous as very similar Embrilogically, they're similar compositionally. They're pretty similar and they have a tendency to go up and down together I thought CSF during the daytime was about five and at night it's about 15. That's a three-fold increase Yeah, so CSF pressure during the day is about 12 millimeters of mercury and it raises an interesting And it raises an interesting point One thing that you could ask is why haven't we thought about this before? Usually what are the units for CSF pressure measurement clinically that we use? centimeters of water or Millimeters of water one of those two and so here we have millimeters of mercury and so because we were comparing units that weren't Comparable we maybe didn't see a connection that we would have seen otherwise, but CSF pressure during the day is about 11 to 12 millimeters of mercury Okay, so when you're trying to take an idea and execute it What do you need what you need to Solve a real unmet need and we think that there is an unmet need here We think that we have good control of IOP We're going to be able to monitor this in the future So the pump has a 4g antenna built in to monitor clients and also to monitor whether or not People are actually getting worse over time. So how often do you have to wear it is eight hours a night? Meaningful or is it not? So this is where we hope to end up But once you get bit by some of these ideas, it's hard not to keep It's hard not to get bit by these ideas so we've got a couple other companies That we've started and I would encourage you to go after these things because it's really fun and icing on the cake One is really easy. This was a stigmatism fix. I was a math teacher and When I was a fellow Dave Hardin said you're a math teacher. I've got a torac lens that's misrotated figure out where I should rotate it to Okay, so I put together this big ugly wonky spreadsheet with a lot of arch tangents in it And and then I got sick of emailing this to everybody And so we put it on the website for free or put it on the web for free in a thousand surgeons a month Go and it's a real issue is is residual stigmatism after cataract surgery So a thousand a month Alcon licensed it. They're potentially going to put that in some of their New diagnostic devices. This one's kind of fun too. So, um, this is the MKO melt What it is is versed ketamine and sofran underneath the tongue for sedation for cataract surgery So we don't start an IV in 98% of our cataract patients We just give them this the ketamine is really nice because they have a tendency to gaze and stare at the light They get a little analgesia and they get a little euphoria And they don't have to have an IV and so This is going to get spun out of imprimise into its own Company and they're going to go for an FDA approval and we're really excited about that having meaningful impact Not just an ophthalmology, but maybe in the emergency rooms or minor surgical procedures elsewhere And then the final one is this thing that we just started which is a way to get online second opinions Um And so right now you have a person in rural wherever and their local doctor says you got foods dystrophy And you should have cornea transplant, but they didn't have a good connection This um tries to introduce a marketplace to medicine where you can say I want an opinion from alan krandall and it costs acts i'm pretty sure you would probably charge five bucks because Maybe that's a little steep because i'm giving you are but really say I want access to some of the world's best doctors I want them to review my records. I don't want to have to travel. I want to be able to get in with them doctors set their own price Patients choose which doctor they want and we're going to see if we actually get people to transact or not So when you're thinking about how you start your own company There's a couple of things that you need to look at you need to look at a market markets are real And so if it's going to be a company it has to have a market Um, how are you going to protect yourself? What's your motivation? What are you really doing this for because it's hard get mentors that are going to help you? And ultimately you're going to have to have some capital And i'm going to squeeze through the last five minutes really quick because I think it's the most important stuff And this is usually the favorite Talk that I give it's the next parts with my dad usually but he couldn't be here today So my question for you about whatever ideas that you have is don't be a dwi That's a doctor with an idea be a doctor that does something with it and execute So what are you going to do about it? Okay So when's the last time you felt vulnerable all of this stuff is because We serve patients. So when is the last time that you felt really Vulnerable, you know, we're all kind of bulletproof, especially the younger trainees But when did you feel like something beyond your control? could Shatter your life And so my dad Came in to see me when I was a first year resident and I was at the VA at Duke And I did an eye exam And I'm just staring at this thinking I'm not sure that I know what I'm seeing here, but I'm pretty sure you have fuchs dystrophy So dad you have fuchs dystrophy. You're probably going to need a corny transplant someday This is my dad and I think this is interesting insight to what patients do. He said he's never heard of fuchs dystrophy So he goes home And he says Am I the only person that has this obviously not because it has a name And who are other people that have this Mandy Patinkin? Is one of those people that had a cornea transplant. He had it for care to come And so he was diagnosed in fuchs dystrophy and then in 2010 he was hired by our local eye bank to evaluate corneas And um, that's when things became real because every cornea. He was evaluating He was thinking should I would I want this cornea? in my eye And so his vision wasn't bad only 2025, but he's driving around at night and now he is The outreach coordinator, so he's driving around the state of South Dakota at night And he can't drive and my mom's with them He's writing his tests down to 2400 fuchs dystrophy is the poster child for visual acuity not being a complete measure Of visual function because a lot he's seeing his acuity is good, but he can't function And so I say dad are you seeing okay, and he says no I'm not We need to do something about this so I'm going to talk real quick, and I'm going to move through it quickly So we're done by nine, but I'm going to talk about three people my dad my mentor and my father in law And so when so I end up Saying dad you want me to do this surgery or do you want somebody else? And I'll get you to The best people in the world. He says no. I want you to do my surgery. So does anybody know who this is This is Felix Baumgartner And he held the record for the highest From space to earth And when you're about to do surgery on your dad it kind of feels like this when you're going to do a cornea transplant And right about here you feel committed To the plan that you have but uh, you know, especially to the trainees Rely Rely on your training Take that plunge do things that make you feel uncomfortable But acquire the skill to get comfortable because inevitably things will start spinning out of control And when they spin out of control you have to be able to control yourself in order to end up with um With a happy landing and and that's what ultimately ended up for him So i'm not going to show you his his video. This is his eye, but his cataract surgery and cornea transplant went great And um, and this is what he looked like one week afterwards And he's got this tiny little partial detachment. So we put an air bubble in this is what his endothelial cells looked like After his d-mech. That's what they looked like before his d-mech So the second time around you could tell how nervous he was. He had gotten one of those mko melds and um, you know He uh That's before surgery And he's just sitting there snoring away right before going into the operating room So he ended up 2020 minus 2. I'm corrected. I actually did the second eye with a little bit of mono vision Um, so he doesn't need glasses for intermediate or distance. He just needs them for up close Um, I'll skip through a couple of these things a little bit But as the outreach coordinator, he reaches out to all of the recipients and he got this card one day Listen, I opened um I opened two gifts this morning. They were my eyes. What we do here is sacred and people value that And this is a letter that he got from one of One of those recipients and I am going to read it quickly first and foremost. I'm deeply sorry for your loss I send my sincerest condolences to your family. So these go get distributed through the eye bank to the donor family I've been legally blind since I was 15 with care to conus. I'm 32 years old now and over the years My vision got very bad. I recent a recent turn of events led me to look into eye surgery before then I was in a hopeless state of mind and just never In may of 2016 I underwent my first cornea transplant and to date it has been very successful I still have ways to go before I get my right eye done Needless to say my hope has been restored and I'm working on turning my life around I will be completing my GED soon and entering the work field. I am told 32 years old I'm told that there's a chance I will be able to drive after my next surgery I can't express enough how forever grateful and thankful I am to your family It goes without saying that if at all possible, I would give this all up For you to have your lost loved one back. I wanted you to know that with this opportunity All of this will not be for nothing. Thank you so much for helping restore my hope And I will do my best to make the most out of life In the daily grind of what we do This is lost a lot of times and reminding ourselves of how sacred it is His 32 years old didn't have a GED didn't have hope. He got his life back Because somebody made a donor and so eye banking is really a special Thing that allows miracles to happen and there are unsung heroes and ophthalmologists are not part of that We are sung heroes, right? We get so much credit, but there's people every Night they get up in the middle of the night drive through snowstorms to recover tissue So that we're not annoyed that we get it five minutes late when we're in the operating room And it's really really Special the work that they do So as we transition to this I get an email from Dick Lindstrom A few years ago at john in his deep voice. I would like to come and see you do d second d mac I especially want to see how you use sf6. I still have more rebubblings than I would like So time for you to be the teacher. What days do you operate if we planned ahead? Could you bunch up some cases would also be fun to see you in the or an action? Maybe send me your d second d mac op report and any reading you think I might find useful Best for me is a Wednesday or Thursday, but I can do anything I'm available October 7th 8 28th and 29th at those work Your friend tickle Okay, so I feel like I get an email from the king and he's coming to watch me and I'm so impressed with myself And when I got over myself three days later what I realized Is that this is a guy who loves the process of being great if someone doesn't need to transition from d sec to d mac It's the 70 year old dick Lindstrom But he says if he's going to do it he's going to do it as good as he possibly can and he came And he was the single best observer that I ever had in in the operating room. It was incredible And so now Isn't this amazing? My mentor teaches me a skill That I use on my dad And then get to go back and help him Become better and Alan was talking about how He's having a fellow that was trained by his son And and it is just this circle of life that we get to go through that is so Incredibly special and then I'll end with this And this is a little personal and a little Insane, so this is the most powerful thing that happened to me in medicine. This is my father-in-law. His name's tom dirks This is him dressed up He is a redneck and he delivered newspapers all of his life And and he was a great guy and he was the pillar of his community and a poor community and people just went over to him And and he would pay somebody to mow his lawn so that he could so that guy could pay his rent or get food This is my son Tommy who he's named after And so he died four years ago five years ago, maybe now and um And he died and my wife gave the eulogy and she gave an amazing eulogy and afterwards I go out and one of his friends is just bawling his name was Steve and Steve Um, I said, how you doing? I gave him a hug. He said i'm doing terrible. I miss tom so much I've just been sitting here all day long listening to the song spirit in the sky because it was one of his favorite songs I said i'm sorry So now fast forward a week later. I'm in the operating room And i'm getting ready to do full thickness corny transplant and I look at the donor sheet And on the donor sheet It's his cause of death and it's his time of death And it's his date of death and it's my father-in-law's cornea That I get to implant into somebody else and so he gets to live on through me Through that and so I sit down at the microscope And um and i'm sitting there And no kidding 10 seconds. Oh shoot the music didn't yeah, so 10 seconds after I start the surgery The song spirit in the sky comes on the ring And i'm like oh boy Is that for real and who knows if it is or if it's caught but what we do Is bigger than the moments that we're in every day. So don't let the grind in the moment um Delude the sacredness and the trust that patients put in so in closing Be committed to what you do like Felix Baumgartner jumping out of that You know space capsule Fall in love with the process of becoming great not greatness itself do the work to be awesome um You are a hero, but there are so many other people that are heroes And and don't forget the power that your words have and how you can influence somebody's day And finally what we do is sacred. So it's really a huge honor for me to see you guys today and thank you for listening So john that's fantastic and uh, obviously great lessons for us all to remember. We often get locked up in our detailed life Don't get back and get a chance to look at the bigger picture. So, uh Following only what you've said and there's boogie still here So when we do an optic nerve sheath fenestration, obviously because we're concerned about permanently lowering The um icp Do those people who have that then are they at greater risk for glaucoma? Is that an unknowable? We don't know that. I don't think we know it yet. Um, we do know that Ventral peritoneal shunts have shown acceleration of glaucoma after people have shunts And so actually when I was at mayo doing this study I call rand alling ham after I analyzed the dad and I say look he said I saw a patient yesterday I couldn't believe it. They had a vp shunt placed three months ago and their glaucoma fell out of the table Yeah, so it's randy those fenestrations. Of course you're going from an extremely high csf to a lower csf And ultrasound studies roger roger's here. We we published this a while ago. It shows that you get a filtration But then the filtration sees up So it's not like you're creating a witch you're not creating on an abnormally low You're just rigging back to a normal level. So the estimate was about three months It sort of sees itself off That buys you the time to get But but here we're inducing pressure from extremely high to a lower level John it's interesting when you talk about the astronauts captain kelly who spent a year in the space station Prover is a really interesting book and They have chronic problems not only with the button and I broke you but he says you chronically feel like your head It's totally full and you can't think and you have a chronic headache and they're putting them in pressure suits now And having them do exercise and he was saying that when they were doing that subjectively he was feeling tremendously better So it'd be interesting to see What that does to any kind of uh, you know an ultrasound or an oct of their optic nerves and their posterior That's right. And they also have negative pressure body suits that kind of create a negative pressure So fluid comes down and if you look at an astronaut before Before takeoff and five days afterwards. You will see that they look um, all almost like Well, they've got swollen faces and and they look like they're you know got too much steroid Right because all of almost cushionoid because all of that fluid redistributes upward And and you know interestingly, you know our valves and our veins and stuff You know, we have valves down below our legs, but not always up above and so we're designed for gravity We're not designed for no gravity That guy killer. I think yeah hans peter killer. Yeah. Yeah. Yeah. He did some really interesting studies of csf flow csf flow, but and the possibility of Lockulation and entrapment of csf around the optic nerve during elevated screen pressure specifically with regard to the potential Sort of nutrient stasis In the csf around the optic nerve. That's sort of an interesting Thing that has also not been kind of brought into this number two There is a phenomenon of people who have chronic papillodema Long term who get shunted for all the right reasons and then who rapidly go blind in one or both eyes over the course of a couple weeks Completely mysterious have no idea why that happens. It's just the most devastating because they're they go seriously blind Is the nerve dying off and then what yeah, they just it becomes chalky way Is there a cupping associated with it? Eventually. Yes as with many Because their intracranial pressure is great The question is what the possibilities have been raised by this ICP iop thing is whether their iop their icp is too low Which as far as a neurosurgeon is concerned is not an issue Right why would low icp be a problem? But and a third thing is there have been a couple of cases of people who Their shunts for other reasons their shunts are over draining and it can get a progressive optic neuropathy And you can not reverse it but halt it by readjusting their icp And to me, I think that a lot of this is around the pressure differential You know another question is do we have a compartment syndrome going on? Is there a segmentation of the intra orbital part of the nerve from the intracranial part of the nerve? And if the csf pressure is too low, maybe it can't just get into that backwater area That's surrounding the optic nerve head and I think that Hans peter killer's work is really, you know fascinating But but I still think that it I still bet that most of this can be explained by what is the retro laminar tissue pressures And how much flow do we have there? sleep apnea Yeah, so sleep apnea has a Some studies show that it is associated with glaucoma and some other studies show that it It's not You know, it's interesting to me because you know, people are probably hypoxic and having issues But they're also probably large and would have a higher csf pressure So in my mind the jury's still out of what cs Sleep apnea and glaucoma is real association and that group in germany measured that during the sensors Yeah, they could measure what happens to iop During during sleep and sleep apnea patients and I don't know what the answer to that is And you know, you kind of wonder if they actually have balsalva a little bit when they're sure They have they can have profoundly Interesting and there are some studies suggesting a relationship between sleep apnea and elevated Thank you, sir