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ANDREA TOOLEY: Welcome to the Mayo Clinic Ophthalmology Podcast, a weekly podcast on all things ophthalmology 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: Today, we're joined by Dr. John Chen, a professor of neuro-ophthalmology and neurology here at Mayo Clinic. We're talking all things papilledema, how to tell papilledema in conditions like IIH versus other, more atypical causes of papilledema. We're also talking about the role of AI, artificial intelligence, looking at the optic nerve. Finally, we'll test it on astronauts and conditions their optic nerve may suffer while they're in space.

ERICK BOTHUN: John Chen is an M.D., Ph.D., and professor of ophthalmology and neurology here at the Mayo Clinic in Rochester, Minnesota. He serves as president of the Minnesota Academy of Ophthalmology, chairman of the Upper Midwest Neuro-Ophthalmology Group, and is an editorial board member of neuro-ophthalmology. We frequently see his editorials on Neuro-Ophthalmology through AAO. Additionally, John Chen was just awarded an R01 for his work to investigate structural changes in eyes with papilledema.

ANDREA TOOLEY: Welcome, Dr. Chen.

JOHN CHEN: Well, thanks for having me. Excited to be here.

ANDREA TOOLEY: We're excited to have you. So we're talking papilledema today. And whenever I think of papilledema, I immediately think of IIH, idiopathic intracranial hypertension. So could you just quickly take us through the traditional papilledema we see with IIH versus other, more atypical types of papilledema?

JOHN CHEN: Absolutely. So in a scenario when you have a patient with bilateral swollen optic nerves with intact vision, that's typically going to be papilledema from raised intracranial pressure.

I think the first thing you have to do is determine, is it truly papilledema? Because some patients can come in with nerves that look elevated from optic disc drusen or other causes, and that's pseudopapilledema. So that's my first branch. Is this papilledema? Is this pseudopapilledema?

Once you determine it's papilledema, then you've got to go and truly investigate to make sure it's truly idiopathic, intracranial hypertension, so entails getting an MRI, an MRV. And if that's normal, other than indirect signs of raised pressure, then you proceed with a lumbar puncture to confirm you've got an elevated opening pressure. Make sure the fluid shows no signs of infection or inflammation. Then you can make your diagnosis of idiopathic intracranial hypertension.

Of course, some of these other causes of raised pressure may have neurologic deficits other than just the vision. So if they've got problems with balance or weakness in the arm, obviously you're not thinking this is going to be idiopathic intracranial hypertension. But sometimes you don't know.

We had a patient a month ago who was a female in her 30s who came in with headaches, bilateral swollen optic nerves. Looked like it was going to be idiopathic intracranial hypertension. Got an MRI, and there was a massive tumor there causing midline shift. And that was a mass that was doing that.

So just looking at a patient alone isn't enough. You really have to do that imaging to make sure everything looks OK, the lumbar puncture to make sure there's no signs of inflammation or other things like that.

ERICK BOTHUN: When such patients come in and they're complicated, I think most of us as ophthalmologists can recognize there's something potentially more going on. It's so critical to stop and think about what you're referring to as other signs and symptoms to help us diagnostically. You bring in a phenomenal skill set, not just as an ophthalmologist but also as a neurologist.

So help the rest of us in terms of giving us a quick and dirty list of things we should do that would be a neurological examination in our eye clinics to help us evaluate patients.

JOHN CHEN: That's great. I think a lot of it's going to come from the history. And so oftentimes with patients, I'll just kind of rattle off some symptoms to see if they have any-- I'll say, do you have any numbness, tingling, weakness, imbalance? I just kind of rattle that off on almost every patient I see. So that's one thing that's helpful.

I just see them walk in the room because you're looking for problems with imbalance, ataxia, problems with incoordination. You can see that in their gait. And then if they do say they have problems with coordination, just a simple nose-to-finger kind of test to look for crude problems with coordination are some of the main things I do.

The great thing about being at the Mayo Clinic is we have some phenomenal neurologists. And so I often refer our patients to our colleagues in neurology if they have any of these symptoms or any of these signs of any deficits. And so it's great to have colleagues that have expertise beyond what we have. And again, it's good to build those relationships, no matter where you are.

ANDREA TOOLEY: There's been a lot of talk about AI and grading disc edema and how that's kind of the new frontier. What do you see with the role of AI in terms of how we look at the optic nerve, how we grade disc edema? And how would that kind of fit into your practice?

JOHN CHEN: Yeah, artificial intelligence is pretty amazing. And I do think it's going to be having a large impact. We actually had a collaborative study with Dan Milea in Singapore, and he's got this amazing setup to look at AI for looking at swollen optic nerves versus not swollen optic nerves.

And so he has this trained algorithm to differentiate papilledema from pseudopapilledema. And then a group of us sent in photographs of optic nerves, some that have papilledema, some that have ischemic optic neuropathy, some that are normal, some that are drusen, and tested this algorithm essentially blindly.

So essentially it was trained on these other photographs, and we sent them 1,500 photos that it had never seen before. And essentially, it was 90% accurate in being able to detect papilledema versus non papilledema.

ANDREA TOOLEY: That's unbelievable.

JOHN CHEN: So it's just going to, I think, revolutionize the way of being able to pick things up. And then what's exciting even beyond that is we then sent two of the best neuro-ophthalmologists in the US, Valerie Biousse and Nancy Newman-- sent them to Singapore to challenge the AI computer.

It was sort of like the chess versus chess master computer. And the results were striking. Essentially, they were about the same. And the time it took the AI to do the analysis was 25 seconds, and our experts, it took over an hour. And this was the best of the best and still ended up with about 90% accuracy based on the fundus photos.

And then we've got a future study looking at AI versus non-neuro-ophthalmologists-- so ophthalmologists, neurologists, optometrists, ER physicians. And essentially AI is beating them.

So I see AI potentially being in the ER. So if we've got a fundus camera in the ER, a patient comes in with headaches, blurred vision, take a non-mydriatic, non-dilated picture of the fundus photo, and then just run it through the AI. And the AI is going to be able to pick up papilledema and alert what's important or not.

So I think it's exciting. It's right around the corner. And I think we'll revolutionize the way we care for these patients and avoid missing patients that could have significant problems.

ERICK BOTHUN: Yeah, it's such a condition that pattern recognition of subtleties are so valuable. So it's wonderful to think about some of these tools helping us because most of us that look at a swollen optic nerve get nervous because we don't have the expertise in pattern recognition built up like neuro-ophthalmologists do.

So you make a diagnosis of IIH based on your own expertise and/or teamwork and/or AI. Tell us, just over the last 10 years, what's changed in the classic paradigms or treatment of IIH for a patient than you once diagnosed?

JOHN CHEN: Yeah, actually a lot. And we've known about IIH for a long time, but some things have changed. We've always treated with acetazolamide, and clinically we knew it worked. But in 2014, we actually had a randomized clinical trial showing that acetazolamide is superior than diet alone. It not only led to faster recovery of the papilledema but also actually ended up with better visual outcomes.

So it's really nice to have that clinical trial data showing that things that we've done for a while does work. And so it just proves that these treatments are effective. It allowed us to know what dose we can go to. A lot of patients can tolerate as high as 2,000 milligrams twice a day-- so 4,000 milligrams of acetazolamide a day. And again, outcomes were excellent.

The other large shift is there's been-- in terms of surgery, traditionally, we reserved surgery for vision-threatening disease. And our options were optic nerve sheath fenestration and a VP shunt. Over the past five years or so, there's been a little bit more exploration of another surgery called venous sinus stenting.

So patients with IIH typically have a stenosis or squishing of their transverse venous sinus. And with this surgery, endovascular surgery, we're able to put in a stent to open up that stenosis. And it allows the blood to essentially escape the brain. And it has been working very, very well.

We've done about 100 cases of venous sinus stenting at the Mayo Clinic. And essentially, I don't think there's really been any patient who had normal IIH who did not respond in terms of the papilledema grade to the venous sinus stenting. And complications rates are quite low.

So I think that's been a large paradigm shift is how much more venous sinus stenting we are doing compared to a VP shunt in some of these other surgical options. Again, it still remains a medical disease. But if you need surgery, it's nice to have that extra treatment.

And then most recently-- this was done actually at the UK. They did a randomized clinical trial comparing bariatric surgery to weight loss alone and its response in patients with IIH. And this was just published in the summer. And they found that patients who underwent bariatric surgery, of course, had more weight loss, but they also had lower intracranial pressure, faster resolution of papilledema.

Obviously, you're not going to do that in a patient who comes in with fulminant IIH, who's going to be blind in a week. That's going to take time, but it's nice to know that is an option. And we weight loss works, and bariatric surgery certainly helps with that. So a lot of new treatments, a lot of new data. And I'm sure, in the future, we'll probably have randomized data on venous sinus stenting as well. But I am very confident that it's going to work.

ANDREA TOOLEY: Yeah, it's amazing the new treatment options that we can offer our patients. It's terrific. This is clearly a passion of yours and a research interest of yours. You actually just got an R01-- congratulations-- looking at structural changes in eyes with papilledema. Can you tell us about your research and your R01?

JOHN CHEN: Yeah, of course. I find papilledema very fascinating. One of the most fascinating things is the fact that it's so variable. You see a patient who's got an opening pressure of 35, which is high, and they've got grade 4 papilledema. You'll see another patient who has an opening pressure of 50, which is two times normal, and they've got grade 1 papilledema. So why is there not a direct correlation between how much pressure you have in your head and the amount of swelling?

And even sometimes we'll see a patient with papilledema in one eye and none in the other. And obviously, again, the pressure is high everywhere in the brain. And yet one nervous one. One's not. So there has to be something that either predisposes an eye to papilledema or something that prevents the papilledema from happening.

And one of our theories is that there may be structural differences within the eye itself. And so in collaboration with Xiaoming Zhang and Arthur Sit, we're using this technology called ultrasound elastography. So essentially it's an ultrasound that we typically kind of see.

But on top of that, we have something called a shaker that actually just gently vibrates the eye and kind of moves it a little bit. And then what it does is it causes little waves of propagation through the eye. And depending on how fast the tissue moves, you can actually determine how stiff it is using ultrasound elastography.

And what we did is we measured the posterior sclera of eyes. And this was a mini grant through the Mayo Clinic ultrasound team. And we found that the posterior sclera was actually stiffer in eyes with papilledema compared to normal controls. And in eyes with unilateral papilledema, the eye with the papilledema was stiffer than the other eye, so they almost had an internal control.

And so essentially there's two theories in terms of what might be going on. One is you've got a stiff posterior sclera. And we can't measure the lamina cribrosa, where the actual pressure is being transmitted. But if you've got a stiff posterior sclera, you could see that there's less flexibility there. So all that pressure is getting transmitted to the lamina cribrosa, and then you've got a more swollen optic nerve.

And then if you had a softer posterior sclera, pretty much if you've got pressure going in the back of the eye, the entire area can move up. And that may kind of protect you. So that stiffer sclera may predispose you to papilledema.

The other option is that-- what we're measuring is there's more pressure getting to the eye with more papilledema. And that's why it's stiffer because everything's just kind of pressing on the eye. I think both those explanations will be helpful. One, we could potentially predict which eyes are predisposed to papilledema. Or two, we can actually detect that there's pressure getting to the eye, so we can help differentiate papilledema from pseudopapilledema.

So with the R01, we've got funding now to enroll about 50 to 100 patients with IIH to confirm our finding. And also what's great is we're going to get baseline measurements while there's papilledema. We're going to treat them medically or surgically if they need it.

And when the papilledema is gone, we're going to remeasure those exact same eyes and see what happens to that stiffness. And then we'll be able to answer, is this secondary to pressure getting transmitted to the eye? Or is this that predisposition that allows that eye to develop more papilledema?

ANDREA TOOLEY: That's fascinating-- kind of a chicken or an egg situation.

JOHN CHEN: Correct. But I think both answers are going to be helpful clinically.

ANDREA TOOLEY: Yeah, I really like it. And you're also looking into structural changes in the optic nerve in astronauts or types of changes that we see in spaceflight?

JOHN CHEN: Yes, yes.

ANDREA TOOLEY: Tell us about that.

JOHN CHEN: Absolutely. So it's really fascinating. So astronauts, when they go to space, will actually develop-- some of them will develop papilledema choroidal folds. It'll look like our terrestrial IIH. But these are not your demographics of IIH. So IIH is going to be typically females. 90% are going to be obese or overweight.

Our astronauts are the fittest men and women we've got. And yet they develop these structural changes that look like IIH. And it's going to be from the microgravity. Essentially, on Earth, we've got gravity kind of pulling that blood back down to our heart. In microgravity, that doesn't exist. So that's how I think they develop the papilledema and IIH.

We've been collaborating with a group at NASA, Scott Smith and Sarah Zwart. And what they found is that astronauts that develop more papilledema tend to have a polymorphism in the one-carbon metabolism pathway. And so what we're doing now is we're looking at our patients with IIH to see if they may potentially have those polymorphisms as well because that may be a shared phenotype that predisposes to papilledema.

Also, in Germany, there's this amazing cohort. We're trying to come up with some kind of on-Earth, I guess, mechanism of mimicking papilledema in space. So in Germany, they have normal, healthy volunteers that lie 6 degrees head down for a month at a time. And actually, within one or two weeks, they start developing papilledema and choroidal folds. So that's our terrestrial model of spaceflight is people just 6 degrees head down.

And Scott Smith and Sarah Zwart looked at the ones that developed more papilledema, and they had the same polymorphisms in there. And so we're now going to extend ultrasound elastography to see if we can predict and help predict which of the astronauts that might develop papilledema or some of these patients that are 6 degrees head down.

They're looking at the one-carbon metabolism pathways to see if we could potentially alter this by diet. We're looking at OCT angiography in both astronauts and these healthy volunteers in Germany. So it's exciting to try and be able to get this sorted out.

This is important because we think that there's more papilledema the longer you're out in space. So if we do want to send our astronauts to Mars, we've got to get this figured out because the last thing we want to do is have our astronauts unable to see while they're piloting these incredibly intricate space shuttles.

ERICK BOTHUN: That's fascinating. Well, thank you so much for the tour, both locally, nationally, and globally, and outer space through optic nerve-- or swollen optic nerves and papilledema.

JOHN CHEN: Of course. Happy to be here.

ANDREA TOOLEY: Yeah, thanks so much. Wonderful.

JOHN CHEN: Thanks, everyone.

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 next week.

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