[MUSIC PLAYING]

ANDREA TOOLEY: Welcome to the Mayo Clinic Ophthalmology Podcast brought to you by Mayo Clinic. I'm your host, Dr. Andrea Tooley.

ERICK BOTHUN: And I'm Dr. Erick Bothun. We're here to bring you the latest and greatest in ophthalmology medicine and more.

ANDREA TOOLEY: In today's episode, we are joined by two clinician scientists, Drs. John Chen and Arthur Sit. Dr. Chen, a neuro-ophthalmologist, and Dr. Sit, a glaucoma specialist, combine their interest in optic neuropathies and their backgrounds in biomechanics to study glaucoma, papilledema, and more.

ERICK BOTHUN: Dr. John Chen, M.D. And PHD, is a 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 papilledema.

Dr. Arthur Sit is a professor of ophthalmology at the Mayo Clinic, and he is our research chair for the Department of Ophthalmology. Together, Dr. John Chen and Arthur Sit were recently awarded an R01 for their work involving the biomechanics of the eye in glaucoma and papilledema. Welcome, Dr. Sit and Dr. Chen.

ARTHUR SIT: Thank you very much. It's just a pleasure to be here.

JOHN CHEN: Absolutely.

ANDREA TOOLEY: 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 R01. That's really exciting news.

ARTHUR SIT: Thank you. Thank you so much.

JOHN CHEN: Absolutely.

ANDREA TOOLEY: We want to talk about how your research bridges both glaucoma and neuro-ophthalmology because those are two totally different specialties. So to start, let's talk about ocular biomechanics. I know, Dr. Sit, you have a mechanical engineering background from MIT, so you're an engineer kind at the heart of everything. How did you guys bridge this together, and really, what is ocular biomechanics?

ARTHUR SIT: That's a great question. And I'll start off by saying that I'm not going to put up any equations for you to look--

ANDREA TOOLEY: Please don't.

ARTHUR SIT: --at today. So first of all, I do have to acknowledge our collaborator on this, Dr. Xiaoming Zhang, who is a PhD in the Department of Radiology, and this is really a collaborative project in the best spirit of Mayo Clinic. And we've developed a technology called ultrasound vibro-elastography. I'll 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 a pressure vessel, and the eye really is meant to allow us to see. And to do that, it has to hold a pressure so that the tissues are in a constant shape. But the eye is 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.

The eye is connected to the brain, so we have the intracranial pressure acting on it. And then we also have muscles pulling on it. We have blood vessels connected and veins, and so there's a lot of different forces acting on the eye. So ocular biomechanics is to try to understand the tissue properties and how well those tissues can support all those forces that are acting upon it and preserve healthy vision.

ANDREA TOOLEY: John, you're such a true neuro-ophthalmologist because as soon as Arthur said, "the eye is connected to the brain," you immediately have 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.

ARTHUR SIT: It is. Ocular biomechanics is a very complex issue because the eye is-- as we all know, the eye is made up of different tissues. There's different parts of the eye, and, again, with all these different connections to the eye, it's a very complex organ. And it's also a very delicate organ, so it's difficult to measure ocular biomechanics. So 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 noninvasively, and that's really what our project, our research leading up to this grant has been focused on, developing that core technology.

ANDREA TOOLEY: OK, so we're measuring the stiffness of the eye, essentially.

ARTHUR SIT: Exactly.

ANDREA TOOLEY: And why is that important in either glaucoma or optic neuropathies? Why does that even matter? So I'll start with glaucoma, and John can explain papilledema far better than I could.

So with glaucoma, glaucoma is an optic neuropathy where there is a characteristic change in the appearance of the optic nerve, and the key factor is intraocular pressure. And so there's something about the pressure in the eye, combined with all the other forces that act on the eye, that cause some patients to lose nerve cells, retinal ganglion cells, and eventually lose vision, and some patients even go blind.

So one of the puzzling things, though, is that intraocular 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 in what we would consider a normal range of pressure. So we think that it's more than just pressure. It's about whether the tissues in the eye are strong enough to support the pressure that you actually have.

JOHN CHEN: And then from a papilledema standpoint, it's interesting. So Arthur gets glaucoma, and as a neuro-ophthalmologist, I get all the other optic neuropathies. So it's way better to be a neuro-ophthalmologist. But in terms of papilledema, essentially papilledema 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 glaucoma-- with papilledema, you can have some patients who have just mildly elevated intracranial pressure and they've got a good amount of papilledema and some that actually have elevated opening pressures, elevated intracranial pressure, and they don't have papilledema.

And ultimately, we think it all boils down to the biomechanics of the eye, and really, our goal is to try and predict why some patients develop papilledema, when don't. Are there some protective features in the eye that might either predispose or prevent papilledema development?

ERICK BOTHUN: So how do you measure this? Obviously, in ophthalmology, we have different diseases that we're a little bit-- becoming more and more used to being sensitive to, for instance, 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 Tono-Pen or like other 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.

ARTHUR SIT: Absolutely, and that really gets to the core of the technique, the technology that we're developing. And so essentially, what we do is we can cause a small vibration with a mechanical shaker at the front of the eye. So through closed eyelids, we put the shaker on the eye, and it causes a small vibration. And that vibration propagates through the eye.

So it actually propagates-- starts at the cornea, then propagates to the sclera, and eventually makes it back to the optic nerve. And using ultrasound, we can visualize 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 more traditional measures of tissue mechanics, like the modulus of elasticity, 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 more conventional measures of tissue biomechanics.

ANDREA TOOLEY: And is this independent of age or other patient-related factors? Because I would think that potentially age would be something that would obviously play a role in this, either the vitreous changes or the scleral rigidity changes, but it's not?

ARTHUR SIT: No, no, that's a great question, and it definitely does change with a number of different factors. Age-- there's work that predates us that shows that the tissues of the eye do become stiffer with age. It changes with pressure, which is a confounding factor, so it becomes very complex.

ANDREA TOOLEY: That's a chicken-or-egg situation.

ARTHUR SIT: Yeah, exactly. And then things like myopia-- there's some evidence that it changes with that, so really a very complex situation. So in our R01, we've tried to focus down on something that's going to 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 intraocular pressure, and we're looking at them before they've had any treatment with medications, which can also change the ocular biomechanics.

ERICK BOTHUN: That's interesting. I like analogies. It's almost like you're creating 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 echo wave and studying it.

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 R01?

JOHN CHEN: Yeah, it's actually very interesting. So you've got papilledema on one end, you've got glaucoma on the other completely. They seem completely--

ANDREA TOOLEY: Totally different.

JOHN CHEN: --different, different demographics. Glaucoma is elderly patients. Patients with papilledema are typically young females that are obese. But it's actually sort of like two ends of a coin. It all boils down to something called the translaminar gradient. So in the eye, it's connected to the brain, and then right there at the optic nerve, if you've got a high eye pressure or something called the lamina cribrosa-- and if you've got high pressure, the pressure actually causes a backbone of lamina cribrosa and potentially stretching and damage the optic nerves.

And then you've got a high pressure in the brain. You've got an upturning of that lamina cribrosa, and you get that papilledema. And then there's a lot of stretch of those optic nerves, so it all boils down to this translaminar gradient, the difference between the eye pressure in the eye and the pressure in the brain. And that differential is potentially what contributes to these optic neuropathies, and so that's how we kind of package 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.

ANDREA TOOLEY: So is the rigidity of the lamina cribrosa where it all meets? Because is a stiffer lamina better or a floppier lamina? Is that what we're finding?

JOHN CHEN: That is an amazing question. So that really-- the Holy Grail is really measuring that lamina cribrosa. 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 sclera right adjacent to it with a potential assumption that it may mimic what's going on in the lamina cribrosa. Or alternatively, it may not, but we're actually measuring the posterior sclera kind of in the area of the macula. But we actually can't measure that optic nerve, lamina cribrosa, itself. It's just too small with our technology we have right now.

ANDREA TOOLEY: And then in terms of your preliminary data, I would think that either stiff lamina or more floppy-- well, I don't know what the better term is-- looser lamina is either more pathologic or less, but you're finding the opposite, that 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?

ARTHUR SIT: So not necessarily. I think you're probably getting to some of the preliminary data that we presented or published. So it's, again, very complex because as if you have a stiff sclera, for example, you could actually concentrate deformation into the lamina. The converse might be true where if you have a stiff sclera, if you-- you might have larger pressure fluctuations. So it's a very complex issue that we're really just trying to-- we're really starting to try to understand.

But we did have some work in a previous study where we used 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 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.

ANDREA TOOLEY: OK, so that's for the whole eye in terms of ocular rigidity. And what are you finding now with your ultrasound looking at posterior sclera in those glaucoma patients?

ARTHUR SIT: Well, we're very early, so we don't have results that we can present yet, so.

ANDREA TOOLEY: This is fascinating to me.

ERICK BOTHUN: It is. It's remarkable. You think about other uses and other conditions that might shed light on this, and I just-- in your thought process, we're going to learn about, the way it sounds going forward, the glaucoma cohort and the papilledema cohort. What other conditions might this open us up to treating or understanding?

JOHN CHEN: I think there's a lot of diseases in the eye that depend on biomechanics. One that kind of relates to papilledema is choroidal folds, so in addition-- when patients have raised intracranial pressure, their optic nerves swell up. But addition, sometimes their posterior sclera will get pushed forward. They'll get hyperoptic shift, and you'll get these kind of curves in the posterior sclera, choroidal folds. And of course, we think that biomechanics is going to play a role there. If it's softer, maybe it's going to be more compliant there, and you get more folds.

And then outside of raised intracranial pressure, other diseases as well are probably going to be dependent on it, like myopic degeneration. Perhaps if you've got a softer eye, it might predispose patients to more myopic degeneration and that kind of elongation of the eye. And obviously, there's this 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 keratoconus cross-linking treatments-- all those things are all dependent on ocular biomechanics, and I think ultrasound elastography has a large role in trying to understand these diseases and trying to predict which patients are more predisposed to some of these diseases.

ERICK BOTHUN: And 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?

JOHN CHEN: Yeah, 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. Did that cross link truly stabilize that cornea? So I think it can help monitor treatments.

In terms of papilledema, our preliminary data showed that eyes were actually stiffer that had papilledema. Again, not entirely sure if that's because, as Arthur said, the posterior is sclera-stiff, so it doesn't allow that flexibility, all that pressure's getting transmitted to the lamina cribrosa and papilledema. Or are we actually measuring pressure getting transmitted to that back of the eye and causing stiffening?

And then using ultrasound elastography, we can actually determine which one that is by getting the baseline, treating the papilledema, making it go away and seeing if that changes. So again, ultrasound elastography can be used to help monitor treatments, monitor response.

ERICK BOTHUN: Scleral windows, things-- I'm just thinking about rigidity. There were surgical techniques in the past that have been used to change the scleral permeability. Any thought that they would give new life, learning more about the scleral rigidity, in these sort of technologies?

ARTHUR SIT: I think that's a great question, and for glaucoma, as we all know, there's a lot of patients who, despite our best efforts, continue to have disease progression, and that may be just fundamental to their eyes and their tissue properties. They just may have tissues that are unable to support the pressures that we're able to achieve without extreme measures.

So we can certainly think that if we need to stiffen the tissues to better support that, then maybe we can do something-- probably not cross-linking as we know it, but there may be a way of stiffening those tissues to better support the pressure, and 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 decreasing that ocular rigidity. But it's a great question, and I think it's definitely an area that we want to look into as we continue our research.

ANDREA TOOLEY: As somebody who does optic nerve sheath fenestrations, 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 those pressure mechanics that we're measuring.

JOHN CHEN: I think certainly it could. The whole idea behind optic nerve sheath fenestration is to create that window, allow that fluid to drain out, and perhaps that's preventing some of that pressure getting to the eye. And then obviously, its effect on the back of the eye, whether it's less stiffening, I think it's probably having a role. So I think we should definitely investigate those eyes that are undergoing optic nerve sheath fenestration, get a baseline ultrasound elastography, do the surgery, and then do it again two weeks later and check for the change.

ANDREA TOOLEY: Yeah, absolutely, see how it changes the rigidity. That's very interesting.

ERICK BOTHUN: I know historically people used to go in and try to cut the cuff in some way for different conditions. 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?

ARTHUR SIT: Yeah, I think you're talking about radial optic neurotomies and--

ANDREA TOOLEY: It sounds terrifying.

ARTHUR SIT: Yeah, and the clinical results from those were--

ERICK BOTHUN: --poor.

ARTHUR SIT: --never very good, so I'm glad they're not being done anymore because, certainly from a glaucoma standpoint, I can just see that weakening the lamina and exposing the lamina to even greater deformations. So I think--

ERICK BOTHUN: Unlikely, but it certainly fits. I'm just thinking about other surgical things that are done in that area that would change with your measurement tool.

ERICK BOTHUN: 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 within ocular pathology, which I think is tremendous about your research. And at least someone who's more junior entering, 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?

ARTHUR SIT: I'm sure I can start, and I think that, again, being open to those interesting questions is, first and foremost, the key thing. And then so I can actually tell you how our collaboration started.

ANDREA TOOLEY: Yeah, tell us.

ARTHUR SIT: It was through one of Mayo's internal research conferences where people came and put up posters who had some internal funding through Mayo, and so I was one of those participants, and. Dr. Zhang was also one of those participants. So I was just walking around, looking at the different posters, and I saw his poster where he was originally using this technology to measure much larger organs, like liver and skin.

But then I said, have you used that in the eye? And that was over 10 years ago, so it's been a very interesting process. So definitely keep an open mind. Look for those interesting questions, but also look for opportunities to collaborate because people want to collaborate. And work on things that you're interested in. I think that's key. If you're never-- if you're working on something that someone else told you to work on but you're not interested in, that's never going to work out well. Find something that you're interested in.

JOHN CHEN: I agree completely. 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 finding other people, collaborating with their expertise. And it makes for a better project, and it actually makes it more fun, too, to get a chance to go to conferences with your colleagues and build these research projects together.

ANDREA TOOLEY: That's great advice.

ERICK BOTHUN: It's exciting. It's in the spirit of academic medicine that we're sharing, cross-pollinating, working together for the common goal, and advancing what we were 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 in patient care. So I thank you both for being here and for sharing your insight and your vision regarding your grant and your R01 but also this new technology to measure our eyes in a special new way.

ARTHUR SIT: It's a pleasure, and thank you for having us. It's great talking with you.

ANDREA TOOLEY: Congrats, guys. Thanks so much.

JOHN CHEN: Absolutely, thank you.

ANDREA TOOLEY: You can find all episodes of the Mayo Clinic ophthalmology podcast on our website.

ERICK BOTHUN: Thank you for listening, and we definitely look forward to sharing more.