John J. Chen, M.D., Ph.D., is a neuro-ophthalmologist at Mayo Clinic in Minnesota, and Arthur J. Sit, M.D., M.S. , is an ophthalmologist at Mayo Clinic in Minnesota. Dr. Chen and Dr. Sit join our podcast to discuss their fascinating research on ocular biomechanics and the implications for both glaucoma and papilledema.
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Welcome to the Mayo Clinic Ophthalmology podcast brought to you by Mayo Clinic. I'm your host, Doctor Andrea Tooley and I'm Doctor Eric Botham. We're here to bring you the latest and greatest in ophthalmology medicine and more in today's episode, we are joined by two clinician scientists. Doctors, John Chen and Arthur sit, Doctor Chen, a Neuroopthalmologic and Dr sit a glaucoma specialist, combine their interest in optic neuropathies and their backgrounds in biomechanics to study glaucoma papy edema and more. Doctor John Chen MD and phd is the professor of ophthalmology and neurology here at the Mayo Clinic. He is internationally recognized for his work with optic neuropathy and we have hosted him and featured him in our program here at the podcast previously discussing optic neuritis and papy Edema. Doctor Arthur sit is a professor of ophthalmology at the Mayo Clinic and he is our research chair for the Department of Ophthalmology. Together. Doctor John Chen and Arthur sit were recently awarded in RO one for their work involving the biomechanics of the eye in glaucoma and Papy Edema. Welcome, Doctor Sit and Doctor Chen. Thank you very much. It's just a pleasure to be here. We're so excited to have both of you here to talk about your collective research together. I think that's pretty unique to have a research team here together for the podcast. So, first of all, congratulations on your ro one. That's really exciting news. Thank you. Thank you so much. We want to talk about um how your research bridges both glaucoma and neuro-ophthalmology because those are two totally different specialties. So to start, um let's talk about ocular biomechanics. I know doctors say you have a mechanical engineering background from mit so you're an engineer kind of at the heart of everything. How did you guys bridge this together and really what is ocular biomechanics? That's, that's a great question. And I, I'll start off by saying that I'm not going to put up any equations for, for you to look at today. So, um so, first of all, I do have to acknowledge our, our collaborator on this uh Doctor Xiao Ming Zhang who is a phd in the Department of Radiology. And, and this is really a collaborative project in the best and the best spirit of, of Mayo Clinic. Um And um and uh we've developed a technology uh called uh ultrasound, bro. Eas, I'll get that to get to that in a little bit. But first of all, in terms of what is ocular biomechanics, that's really just to look at the structures of the eye and how strong the tissues are and how does it support pressure because the eye is, is a pressure vessel. And the eye really is meant to allow us to see and to do that, it has to hold the pressure so that the tissues are in a constant shape. But the eyes act on acted upon by a lot of different forces the forces inside the eye from the pressure within the eye, the intraocular pressure, but also behind the eye, um the eye is connected to the brain. So we have the the the intracranial pressure acting on it and then we also have muscles pulling on it. We have blood vessels connected um and veins. And so there's a lot of different forces acting on the eye. So olear biomechanics is to try to understand uh the tissue properties and how well those tissues can support all those forces that are acting upon it and preserve healthy vision. John, you're such a true Neuroopthalmologic because as soon as Arthur said, the eyes connected to the brain, you immediately had this big smile on your face. It was so perfect. I just had to point that out. You're like, yes, the brain, I love it. No, that's a great explanation, but very complex. It, it is uh you know, ocular biomechanics is, is a very complex issue because the eye is, is um as we all know, here is made up of different tissues, uh there's different parts of the eye and again, with all these different connections to the eye. Um there's, there's, it's a very complex organ and, and it's also a very delicate organ. So, um it's difficult to measure ocular biomechanics. So, you know, in some other parts of the body skin, for example, if you want to measure its properties, you might just take a skin biopsy. We can't do that in the eye. So we need to find ways to measure it non invasively. And that's what our project, our, our research leading up to this grant has been focused on developing that core technology. OK. So we're measuring the stiffness of the eye essentially. And why is that important in either glaucoma or optic neuropathy? Why does that even matter? So, so I'll start with glaucoma and then, and then, and John will can explain pap edema far better than I could. So with glaucoma, glaucoma is uh an optic neuropathy uh where um there's a characteristic change in the appearance of the optic nerve. And, and the key factor is is intraocular pressure. And so there's something about the pressure in the eye that uh uh combined with all the other forces that act on the eye that, that cause some patients to, to lose um nerve cells, retinal gangling cells and and eventually lose vision and, and some patients even go blind. So uh one of the, one of the uh puzzling things though is that um in interactive pressure is what we treat in glaucoma. So we lower the pressure to try to prevent further damage. But most patients who have high pressure, never get glaucoma. And a lot of patients, probably up to half of patients have glaucoma with in, in what we would consider a normal range of pressure. So, so we think that that it's, it's more than just pressure. It's, it's about whether the tissues in the eye are strong enough to support the pressure that you actually have. Ok. And then from a papilloma standpoint, it's interesting. So Arthur gets glaucoma and as a ophthalmologist, I get all the other optics, it's way better being a neurop. But in terms of paloma, essentially paloma is a swollen optic nerve from raised intracranial pressure. And just like Arthur said, with glaucoma, you can have varying amounts of eye pressure and still get the um glaucoma with pil edema. You can have some patients who have, you know, just mildly elevated intracranial pressure and they've got a good amount of pil edema and some that actually have elevated opening pressures, elevated intracranial pressure and they don't have pil edema. And ultimately, we think it all boils down to the biomechanics of the eye. And then our really, our goal is to try and predict um why some patients develop piled Dema. One don't um are there some protective features in the eye that might either predispose or prevent papilloma development? So how do you measure this? I mean, obviously in ophthalmology, we have different diseases that we're a little bit becoming more and more used to being sensitive to, for keratoconus in the cornea. But you're talking about the globe itself and structures way in the back that you can't just push on like a tonal p or like other a abnormal or conditions where you might blow a puff of air and see the cornea vibrate, share with us. How do you measure rigidity of the eye in different locations, especially in the back of the eye near the optic nerve in which you guys are most interested? A absolutely. And that, that really gets to the core of the, of the uh of the technique, the technology that we're we're developing. Um And uh so essentially what, what, what we do is we can uh cause a small vibration uh with a mechanical shaker at, at the uh at the front of the eye. So uh through closed eyelids, we put the shaker uh on the, on the eye and it causes a small vibration that vibration uh propagates through the eye. So it actually propagates um starts at the cornea, then propagates to the sclera and eventually makes it back to the optic nerve. And using ultrasound. Uh we can uh visualize that that wave propagation. And by visualizing that wave propagation, we can then look at how fast that wave propagates and the speed at which that wave propagates is actually related to uh more traditional measures of, of, of tissue mechanics uh like like the modulus of elasticity. Um And so that's really what we're trying to get at by looking at this wave propagation, the speed of the propagation in different tissues. We can then infer um more conventional measures of, of uh of uh tissue biomechanics. And this is, is this independent of age or other patient related factors. Because I would think that potentially age would be something that uh that would obviously play a role in this, either the vitreous changes or the scleral rigidity changes. But it's not, no, no, no. It's a great question and, and, and it definitely does change with a number of different factors. Age. Um, there, there's uh, um, work that predates us that shows that the, the, the, the tissues of the I do become stiffer with age. Uh, it changes with pressure, which is, um, a confounding factor. So it's, it becomes very complex. Uh, that's a chicken or egg situation. Exactly. And then, um, and then things like, um, myopia there, there's some evidence that it changes with that. So, really a very complex situation. So, um, um, um, in our R one, we've tried to focus down on something that's gonna give us the most information. And so from the glaucoma side, we're focusing on normal tension, glaucoma patients. So those are patients who get glaucoma without having raised intra pressure and we're looking at them before they've had any treatment with medications, which can also change the ocular biomechanics. It's interesting, you know, I like analogies. It's almost like you're creating an an orbital earthquake and watching the ripple effects. Because truly in that most of us are well aware of the prediction and understanding that we have measuring when the earth trembles. In this case, you're creating an orbital, you know, uh echo wave and studying it how and appreciating how tissues will respond differently in different conditions. What was the thought or how did you strategically package both of these into an ro one? Yeah, it's, it's actually very interesting. So you've got Paloma on one end, you've got glaucoma on the other completely, they seem totally different, different um different demographics. Glaucoma, elderly patients, patients with paloma are typically young females that are obese, but it's actually sort of like 22 ends of a coin. You know, it, it all boils down to something called the trans lame gradient. So in the eye, it's connected to the brain and then they right there at the a nerve. If you've got a high eye pressure, there's something called the um the Lamin Arosa. And if you've got a high eye pressure, the eye, the pressure actually causes a backbone of Lambic cu bosa and potentially stretching and damage the epic nerves. And then you've got a high pressure in the brain, you've got an upturning of that Lamar Cubo and you got the Plomo and then there's a lot of stretch of those optic nerves. So it all goes down to this trans limit gradient, the difference between the eye pressure in the eye and the pressure in the brain. And that differential is potentially what contributes these opic neuropathies. And so that's how we kind of patch these together to see how did the biomechanics of the eye actually influence the changes to eye pressure and changes to pressures in the brain. So is the rigidity of the Lamin arosa where it all meets because is a stiffer lamina better or a more or a floppier lamina? Is that, is that what we're finding? That is an amazing question. So that really the the whole grill is really measuring that Lamma Kibo, the drawback is it's such a small structure. We can't measure it with the ultrasound. So essentially what we're doing is we're measuring the posterior square right adjacent to it with a potential assumption that it may mimic what's going on in Lamber Cabos or alternatively, it may not, but we're actually measuring the posterior square kind of in the area of the macula. But we actually can't measure that optic nerve lambic cur Bosa itself is just too small with our technology we have right now. And then in terms of your preliminary data, you, I would think that either stiff lamina or more floppy. I don't know what the better term is looser lamina is, is either more pathologic or less, but you're finding the opposite that in one, in one condition, it's good to have a stiffer lamina and then in the other in Glaucoma, it's better to not, is that right? Uh So, so not necessarily, I think you're talking probably getting to some of the preliminary data that we presented or published. Um So it's, it's again, very complex because um if you have a stiff sclera, for example, um you could actually concentrate deformation into the lemma. Uh the converse might be true or if you have a stiff sclera, if you, if you, you might have larger pressure fluctuations. So it's, it's, it's a, it's a very complex issue that we're really just trying to, we're really starting to, to try to understand. Uh but we did have some um work in a previous study where we um use this technique to look at the properties of the cornea. And we didn't find any difference in the corneal properties in glaucoma patients versus normal patients. But we did find something, a difference in something called ocular rigidity, which is an older measure of ocular biomechanics and essentially looks at the change in uh pressure for a given volume change for the whole eye. So we can't isolate where it happens. But for the whole eye, glaucoma patients seem to have a lower ocular rigidity or a more compliant eye. Ok. So that's for the whole eye in terms of ocular rigidity. And what are you finding now with your ultrasound? Um looking at posterior sclera in those glaucoma patients. Well, we're very early so we don't have um results that we can present yet. This is fascinating to me. It's remarkable you think about other uses and other conditions that, you know, might shed light on this. And I just, you know, in your thought process, you, we're gonna learn about the way it sounds going forward, the glaucoma cohort and the Palomas cohort. What other conditions might this open us up to treating or understanding? I I think there's a lot of diseases in the eye that depend on biomechanics. You know, one that kind of relates to paloma is is corot faults. So in addition, when patients have raised intr pressure, their optic nurse swap, but addition, sometimes their, their posterior Clare will get pushed forward, they get hyperoptic shift and you'll get these kind of curves in the, in, in, in the posterior sclera corot folds. And of of course, we think that biomechanics is gonna play a role there. If it's softer, maybe it's gonna be more compliant there and you get more folds and then outside of race in pressure, other diseases as well, we probably gonna be dependent on it like myopic degeneration. You know, perhaps if you've got a softer eye might predispose patients to more myopic generation and that kind of elongation of the eye. And obviously, there's this, you know, huge shift toward higher myopia around the world and really the ocular mechanics of the eye may be that predisposing factor and then other things, even the cornea with Konas crosslinking treatments, all those things are all dependent on ocular biomechanics. And I think ultrasound Lati Gray has a large role and try to understand these diseases and trying to predict which patients are more predisposed to some of these diseases in, you know, thinking long term, in addition to identifying which ones might have a harder course, are there thoughts or hopes that this would lead to treatment changes or new options in our paradigm? Yeah, I I think absolutely certainly in terms of knowing which patients are good, viable options for treatment. And also I think following treatment effects, I think would be helpful as well. You know, did that cross the link truly kind of stabilize that cornea? Um So I think it can help monitor treatments in terms of paloma. Um Preliminary data showed that eyes were actually stiffer that had paloma again, not entirely sure if that's because as Arthur said, the posterior sclera stiff. So it doesn't allow that flexibility. All that pressure is getting transmitted to laminar carbos and pap edema or are we actually measuring kind of pressure getting transmitted to that um back of the eye and causing stiffening and then using ultrasound elastography, we can see we can actually determine if which one that is by getting the baseline, treating the pap edema, making it go away and seeing if that changes So again, ultrasound elastography can be used to help monitor treatments, monitor response, scleral windows. Things I just thinking about rigidity. There are surgical techniques in the past that have been used to change the sclero permeability and thought that they would give new life learning more about the sclero rigidity in these sort of technologies. I think that's a great question. And um you know, for glaucoma, as we all know, there's, there's a lot of patients who uh despite our best efforts continue to have disease progression. Um and, and, and that may be just fundamental uh to their, their eyes and their tissue properties. They just may have tissues that are unable to support the pressures that we're able to um achieve without uh extreme measures. Um So, you know, we can certainly think that if, you know, if, if a, if we need to stiffen the tissues to better support that, then maybe we can do something, you know, probably not crosslinking as we know, but there may be a way of stiffening those tissues to better support the pressure. And the uh on the flip side, if it turns out that we need a more compliant eye that better absorbs pressure fluctuations, then maybe there's ways of of decreasing that ocular rigidity. Uh But it's a great question and, and uh you know, it's, I think, I think um it's definitely an area that we want to look for, look into as we continue our research as somebody who does optic nerve sheath fenestration. I kind of thought the same question. I wonder if having fenestrated the nerve, even though it's not affecting the actual eye would have any kind of relation in, in those pressure mechanics that we're measuring, I think certainly could. You know, the whole idea behind optic nurses penetrations is, is to create that window allow that fluid to drain out. And, you know, perhaps that's preventing some of that pressure, getting the eye and then obviously its effect on the back of the eye, whether it's, it's less stiffening. II, I think it's, it's probably having a role. So I think we should definitely investigate those eyes that are undergoing opic Ns men and get a baseline ultrasound. Last geography, do the surgery and then do it again two weeks later and see how it changes the rigid. That's very interesting. I know historically, people used to go in and sort of try to cut the cuff in some way. And for different conditions is, I know fenestrations are back in the nerve. Are there any procedures done to date that would affect the rigidity of the laminal cuff itself? You know, I think you're talking about radio optic neuro neurotomy. And um, yeah, and, and you know, the the clinical results from those were, were never very good. So, um I'm glad they're not being done anymore. Um, because, you know, certainly from a glaucoma standpoint, I can just see that weakening the lamina and, and exposing the lamina to even greater deformations. Uh So, uh um um yeah, I think likely, but it certainly fits. I was just thinking about other surgical things that are done in that area that would change with your, your measurement tool. What I love is that this is such a relatively early field in terms of research that the questions are endless and there's so many different potential avenues. And I love the collaboration because it's applicable to so many different areas with ocular pathology, which I think is tremendous about your research. And at least someone who's more junior. And sometimes you think all the questions have been answered, all the data has been collected. It's hard to think of something new that hasn't really been investigated. And that's exactly what you've done. Can you maybe talk to some of the younger ophthalmologists out there who have research questions or how you stumbled upon a collaborative effort or what your advice would be to those interested in asking those big questions? I'm sure I can start. And, and um I think that uh again, um um being open to those, those interesting questions is, is first and foremost, the, the the key thing. Um And then, uh uh so I can actually tell you how our collaboration started. It was um it was through one of Mao's um internal research conferences where people came and put up posters who, who had uh some internal funding through mail. Um And so I was one of those participants and uh Doctor Zhang was also one of those participants. So I was just walking around through, looking at the different posters. And I saw his poster where he was uh originally using this, of this technology to measure much larger, larger organs like liver and skin. Um But then I said, have you used that in the eye? And that was um over 10 years ago. So, you know, it's, it's uh it's been a very interesting process. So definitely keep, keep an, keep an open mind. Um Look for those interesting questions, but also look for opportunities to collaborate because people want to collaborate. Um And uh and, and uh uh work on things that you're interested in. I, I think that's key if, if you're never, if you're working on something that um that someone else told you to work on, but you're not interested in, that's never gonna work out well, find something that you're interested in. No, I agree completely. It's, it's all about collaborations and we only have so much time in the day. I don't think any of my research projects are ever just me doing the research. It's really um kind of finding other people, you kind of collaborate with their expertise and it makes for a better project and it actually makes it more fun to, to, you know, get a chance to go to conferences with your, your colleagues and kind of build these research projects together. That's great advice, exciting. It's, you know, it's in the spirit of academic medicine that we're sharing cross pollinating, you know, working together for, you know, the common goal and advancing what we are able to do for patients and the whole spirit of this podcast, just bringing voices to the table sharing and encouraging and enlightening each other in our practices and patient care. So, I thank you both for being here and for sharing your insight uh and your vision regarding this, your, your grant in your ro one, but also this new technology to measure our eyes in a special new way. That's a pleasure and, and, and thank you for having us. It's, it's, it's great talking with you. Congrats guys. Thanks so much. Thank you. You can find all episodes of the Mayo Clinic ophthalmology podcast on our website. Thank you for listening and we definitely look forward to sharing more.
