This live webinar will focus on differences in aqueous humor dynamics in the diurnal and nocturnal period along with clinical implications for the treatment of glaucoma. New devices that can collect data throughout the day and night will be explored along with discussion of scientific data obtained using these advanced sensors. A live question and answer session will follow to address clinically relevant pearls for practice with open chat available to all those who attend.
Dr. Malik Kahook, UCHealth Sue Anschutz-Rodgers Eye Center, Denver, USA
Dr. Kaweh Mansouri, The ELZA Institute, Zurich, Switzerland
Dr. Arthur Sit, Mayo Clinic, Minnesota, USA
We’re lucky enough to have, as I said, two great speakers. The first talk is going to be given by Dr. Arthur Sit who’s professor of ophthalmology at the Mayo Clinic in Rochester, Minnesota. He leads the glaucoma service at the Mayo Clinic. Arthur is a mechanical engineer by training, so hopefully he won’t get too mathematical on us (chuckles) during this discussion today. Many publications in the field of aqueous humor dynamics, that’s going to be the focus of his talk today so I look forward to that.
The second talk is going to be given by Dr. Kaweh Mansouri who is a consultant ophthalmologist at the Glaucoma Center Montchoisi Clinic. Hopefully I said that okay, Kaweh. He’s also part of our faculty here at the University of Colorado and has been for quite some time. A very valued member as an adjoint professor of ophthalmology. Kaweh’s one of the world leaders in monitoring devices centered on 24-hour IOP. He did a lot of the early work with Triggerfish, Sensimed, more recently with ImplanData. Very excited to hear what he might have to offer. Not just from a novelty standpoint about devices, but also practical implications from a clinical application standpoint. What do we do for patients when we want 24-hour IOP data?
To go through both of their CVs would take most of this hour. I invite you to take a closer look. One thing I do want to mention is that. I’m going to hand it over to Arthur for the first talk. Welcome, Arthur, to Point-to-Point.
[Arthur] Thank you, Malik, for that very kind introduction. I don’t know how much of it is deserved, but it’s very nice to hear. My talk today will be on 24-hour IOP and a bit more specifically why does IOP vary? And this is going to be an aqueous humor dynamics viewpoint. Really getting into what causes the variations that we see over a 24-hour period of intraocular pressure. And as Malik mentioned, Dr. Mansouri will then go on to talk about some of the devices and some of the clinical implications of these IOP variations over a 24-hour period.
These are my disclosures. Some of which are relevant. All of us deal with IOP and most companies in the glaucoma space deal with IOP.
Just to start off, all of us have seen statements such as this. Reduction of intraocular pressure is currently the only effective treatment for glaucoma. And that’s true. And we see this written in a lot of papers and really with glaucoma that is still what we’re primarily focused on. But how much do we really know about intraocular pressure? We know that it’s dynamic, we know it changes over time. But really how dynamic it is was shown to use very clearly 25 years ago now, by Jay McLaren and Richard Brubaker, when implanted telemetric monitoring devices into the eyes of rabbits. And this allowed them to 24-hour patterns in these rabbits and see what really happens. And what they found was remarkable. They found that intraocular pressure varies constantly, varies rapidly, and by very large magnitudes. And you can see here in a single rabbit that there was a circadian pattern with the pressure being lower during the light phase and higher during the dark phase.
And then more recently, Crawford Downs and his group has updated this technology and placed it into the eyes of non-human primates. And they’ve found really the same thing, IOP varies constantly, rapidly, and by large magnitudes. Interestingly, non-human primates do not seem to exhibit the circadian pattern.
Over the decades where we’ve been looking at intraocular pressure, there have been a lot of things that have been implicated as contributing to the variations. And this is just a small list. We’re not going to go through all of this list today since we don’t want to be here for the next two weeks. Really I want to focus on a couple of things: body and head position, and circadian rhythms, the 24-hour pressures.
Let’s first talk about the circadian pattern of intraocular pressure. A lot of this seminal work was done by John Liu and Bob Weinreb at the University of California in San Diego. And what they did was they set up a sleep laboratory where they brought in subjects and patients and they measured pressures using a pneumotonometer in the habitual position. That means you measure it during the daylight period while patients are sitting upright. And then during the nighttime period, you do it while they’re lying down. And what they found was that over the course of the day the intraocular pressure tends to start a little bit higher in the morning and gradually decrease as the day goes along. But then when individuals lie down to go to sleep, there’s a marked increase in intraocular pressure. And that was certainly true in normal individuals.
And then in untreated glaucoma patients, they again found a similar pattern where intraocular pressure decreases slowly over the course of the day and then increases significantly when individuals lie down to go to sleep. Interestingly, they also measured supine pressures throughout the entire day and what they found is if you eliminate these changes in body position, then the nocturnal spike, nocturnal rise, largely disappears. And certainly in the case of normals, it seems to flattens out. And then in the case of glaucoma patients, the nocturnal pressure actually ended up being a little bit lower than the diurnal pressure when you look at the supine only position.
What does that tell us? It tells us, first of all, and most importantly, that body position matters for intraocular pressure. How much does it matter? Some investigators have gone to extremes and they’ve looked at things such as the yoga headstand position. And if you were to take this extreme body position, pressures can increase by a factor of two, it can double and that happens immediately after taking that position. It happens if you sustain that position, but then when you go back to a normal position it does return pretty quickly to the normal pressures you would see sitting upright.
It’s not just the very extreme body positions that can affect intraocular pressure. A more recent study looking at various different yoga poses found that pressures can increase from 25% with just a leg up position, 28%, and 48%, and then 79% with this common downward dog type of position in yoga.
Looking at these variations we decided a number of years ago to try and systematically try to understand what were the head and body positions that actually affect intraocular pressure. We got a group of young, healthy volunteers and we measured them in a number of different positions. First of all, we know that intraocular pressure will tend to decrease if you measure it repeatedly. What we did was that we looked at a number of sitting positions and a number of recumbent positions, we randomized those. And then we randomized the sitting positions, and then we randomized the recumbent position. We eliminate the effect of repeated measurements and we measured by pneumotonometry, gave five minutes in between measurements. And this is what we found.
First of all, head position does matter. If you have neck extension that results in a increase of intraocular pressure compared to sitting with your head in the neutral position at the slit lamp. If you measure neck flexion, that also causes an increase in intraocular pressure compared to having the neck in the neutral position. And then neck flexion seems to increase the pressure more than neck extension. And then body position matters as well. All of the recumbent positions that we measured had a greater pressure than sitting upright with your head in the neutral position. In the recumbent positions, we did not find a difference between supine or right and left lateral decubitus as a whole.
When we look at the lateral decubitus positions though, it does seem even that position can affect which eye has the higher pressure. In the right lateral decubitus position, there was a trend towards having the right eye, the lower eye, having a higher intraocular pressure. And then in the left lateral decubitus position it did show that there was a significantly higher pressure in the left lateral decubitus position in that left or lower eye, in the dependent eye. And subsequent investigators have also looked at this in other populations and confirmed that the dependent eye, the lower eye, has the higher pressure.
This does bring up a number of questions. First of all, if the pressure is higher in the recumbent position, should we have glaucoma patients sleep with their head elevated? Another question is a lot of patients will tell me that they sleep with a couple extra pillows. Is that actually detrimental by putting the neck into flexion? And then third, is the lateral decubitus positions, we see many, many patients with asymmetric glaucoma. Is this potentially contributing to that?
And just to give you some data from a more recent study. This is a study looking at pattern ERG. And what they looked at was the pattern ERG amplitudes in different body positions. And they actually found that in the lateral decubitus positions, the dependent eye, the lower eye, had a lower amplitude compared to the non-dependent eyes. There does seem to be some functional implications to even that small pressure change in the lateral decubitus position.
That being said, the clinical significance of IOP changes with body position still remains to be determined. And that will get into some of the devices that we hope are coming down the road. What I want to talk about next is what actually causes these changes in intraocular pressure.
Let’s talk about aqueous humor dynamics and body position. We know that aqueous humor flow follows two pathways, there’s the trabecular pathway where aqueous humor exits through the trabecular meshwork into Schlemm’s canal, out through the episcleral venous system. And there’s also the uveoscleral pathway where it goes across the iris route to the ciliary body and then out through vessels in the sclera. And this can be modeled with the modified Goldmann equation which relates intraocular pressure to aqueous humor flow rate, uveoscleral flow rate, outflow facility, and episcleral venous pressure.
How do we actually measure these? Outflow facility is measured with tonography. Typically it’s been measured with an electronic Schiotz tonometer and those no longer exist. We built a digital version of that. It can also be measured with pneumotonography. Especially what we’re doing is replacing a weight on the eye, raising the pressure, and looking at that K of pressure over time. And then using the Friedenwald equations and tables we can then calculate outflow facility.
Aqueous humor flow rate is measured with fluorophotometry. We place a drop of fluorescein, or a few drops of fluorescein, in the eye forming a fluorescein depot in the cornea and the anterior chamber. And then over time with aqueous humor flow, that depot decreases. And then using a fluorophotometer, we can scan the eye and look at the change in fluorescence over time. And that allows us to calculate the aqueous humor clearance and aqueous humor flow rate.
Episcleral venous pressure we measure using our device that you see here. We place a balloon on the eye and that compresses the episcleral veins. And you can see that vein right there, that’s an episcleral vein blanching as the pressure increases. And we do some image analysis to find out the pressure at which that vein just starts to collapse which corresponds to episcleral venous pressure.
And then uveoscleral flow cannot be measured noninvasively. In humans we calculate that from the modified Goldmann equation based on the other parameters that we can measure.
What do we know using these techniques? Dr. Brubaker had, for a number of years, a tilt table where we took medical students and put them into interesting and uncomfortable positions. And then he measured the effect of this in one study on aqueous humor flow. And what we found is if you had a slight tilt it really didn’t affect the aqueous humor flow rate. But when you have that tilt head down position, intraocular pressure does increase as you would expect. And then if you had a very large tilt you have a very large increase in intraocular pressure. But again, really not much of a change in aqueous humor flow rate. In fact, if anything there was a small decrease in aqueous humor flow rate, which would suggest that the pressure should go down but instead it goes up. Clearly the aqueous humor flow rate is not what controls changes in pressure with body position.
We also looked at outflow facility. And we got some volunteers and we measured outflow facility in the supine position and in the sitting position. And we didn’t find any difference in outflow facility between those two postures. Although we did find a significant difference in intraocular pressure as we would have expected.
And what about body position? EVP currently, with our previous device, could not measure EVP in the true supine position. But we did manage to get a group of volunteers who could take this uncomfortable, semi-prone position where they put their head in a slit lamp and we did measure episcleral venous pressure and intraocular pressure. And what we found was that in that semi-prone position, intraocular pressure increases. But episcleral venous pressure also increases. And that change in IOP and EVP were similar and that suggested to us that the change in intraocular pressure with body position was due to EVP changes.
We do have a new device where we can start to measure in the true supine position and we’re just starting studies with that device.
Just getting back to the circadian pattern of intraocular pressure. Again, just to remind the audience if you measure the intraocular pressure over a 24-hour period in this supine-only position, it stays relatively stable through the 24-hour period. And that’s actually very curious because when Dr. Brubaker and others, and our group as well, have looked at the aqueous humor production rate, that actually drops by about 50% at night time. If everything else stayed constant, we would actually expect a marked decrease in intraocular pressure and not this relatively constant pattern that you see once we eliminate body position.
Again, a number of years ago we started to try to understand what causes this. And we took a group of healthy volunteers with regular sleep patterns. We measured aqueous humor pneumatics using pneumotonometry from IOP, anterior chamber fluorophotometry for flow rate, digital Schiotz tonography for facility, and our venomanometry technique for EVP. And we measured their aqueous humor dynamics during a mid-diurnal period from two to four PM and a mid-nocturnal period from two to four AM. And we compared those using generalized estimating equation models.
And this is what we found. First of all, aqueous humor production does drop by about 50% at night time and that was expected based on previous studies. Intraocular pressure does not change significantly from daytime to night time when you eliminate the body position changes. And that’s true in the seated position as well as the supine position. Outflow facility, however, does decrease at night. Not a huge amount but by about 15% and it was a statistically significant decrease in outflow facility so that definitely can contribute to increasing IOP.
EVP, there’s a lot of variability in this type of measurement. But there was no difference between day and night time. And then plugging all these parameters into uveoscleral flow calculations. What we found is that during the daytime, we have about 38% of flow through the uveoscleral system, which is typical for healthy adults. During the night time though, it dropped down to 5.6% and the actual decrease in flowrate through the uveoscleral system was very significant and it’s over 90%. And that was a significant change.
What this tells us then, is that episcleral venous pressure really does not change from day to night time. But the pattern of pressures that we see where the intraocular pressure stays essentially the same over the 24-hour period when you eliminate body position, is due to a decrease in outflow facility and a decrease in uveoscleral flow rate at night time. And what that does is it compensates for that very significant 50% drop in aqueous humor production. IOP, therefore, stays stable throughout the 24-hour period, essentially, when you eliminate body position changes.
Just to summarize a little bit. IOP elevation with body position seems to occur due to changes in episcleral venous pressure and elevation in episcleral venous pressure which mirrors the change in IOP. There is a circadian pattern to intraocular pressure with IOP being highest at night time in most individuals when measured in the habitual positions, sitting upright in the daytime, and lying down during the night time. And that IOP elevation is due to body position, decreased uveoscleral flow rate at night time, and decrease in outflow facility.
Thank you very much and I’ll stick around, of course, for Dr. Mansouri’s talk and happy to answer questions afterwards.
[Malik] Great. Thanks, Arthur. Lots of information and lots of questions coming up that we’ll have to go over after Kaweh is done. Just another mention here that I think is worth connecting the dots. We heard a lot of mention of UCSD and the time that Arthur spent with Weinreb and that 24-hour lab there, the sleep lab there. Kaweh had similar experiences. He spent a couple of years in San Diego learning from Dr. Weinreb and I think you’re going to see some of the influence here. We’re going to get into a more clinical-based discussion. 24-hour IOP in our patients and also novel devices that can be used for getting those measurements in an accurate way. And I’ll hand it over to Kaweh for his talk. Welcome, Kaweh.
[Kaweh] Thank you very much, Malik. I’d like to again, also to thank you for organizing this event and thank Orbis for the invitation to speak here.
Arthur has prepared so nicely the terrain, giving you a very comprehensive overview of where he stands about aqueous humor dynamics and physiology. I will speak, as was mentioned, a bit more about where we stand now with practical measurements. And if the devices which are ready for the clinic and which we can use and how we interpret the data that we get.
These are my disclosures. Two of them are relevant. I have been a consultant to Sensimed which produced the Triggerfish and a consultant to ImplanData.
When we speak about glaucoma, we speak about three pressures, of course IOP. But we also speak about intracranial pressure, the pressure behind the eye, and the ocular perfusion pressure which is also the result of the two, if you like. For the time being, IOP is still only the treatable pressure and the only treatable risk factor in glaucoma.
Our best method to measure it has many shortcomings. And it was no one else than its founder, Hans Goldmann, who knew about the many limitations of its applanamous tonometry technique. The most important one is that GAT provides just a snapshot of IOP, a few seconds out of a whole year of glaucoma, repeated maybe several times a year. And we know, as Arthur beautifully showed, that IOP’s a very dynamic parameter and it varies from minute to minute according to a host of extrinsic and intrinsic events and parameters.
Unsurprisingly, because of the instability of IOP, we measure peak IOP in probably more than two thirds of our patients. And as a direct result, we see axonal injury occur at what we consider to be normal IOP levels in 50% of cases, or maybe even more.
One reason why IOP varies is that contrary to these beautiful animals from the zoo in San Diego, when we humans go to sleep, we change our body position from upright to supine. And this itself creates an IOP increase and the mechanisms behind were just mentioned by Dr. Sit.
IOP, therefore, is a sleeping giant. And I think it was Arthur who coined this term. It’s a sleeping giant because it’s often at its highest level during the night time period. In all kinds of people, healthy, young, healthy, old, and glaucoma patients. Very few of us have a different circadian rhythm. I say very few because not all of us react in the same manner, we cannot all be considered as averages and it’s our individual rhythms that change also over time, and that can change according to our occupation, according to our pathology, according to our glaucoma treatment.
Therefore, having devices that can measure IOP for 24 hours, and ideally longer, are important. You’ve all heard about the Triggerfish contact lens. I will speak about it briefly. And some of you may have heard about the implantable sensors. And I will speak about the EyeMate device for where we have clinical data.
The Triggerfish was developed by two young PhD students from my city, Lausanne, in the 2000 years, they started a start-up. And the device was based on the principle that strain gauges in a silicone contact lens can measure IOP changes. We found out that they measure also volume changes in the eye, which are different from IOP changes. And that they are very much affected by biomechanical properties of the cornea. Those were some limitations and some advantages too.
The main limitation was that the device did not provide IOP in millimeters of mercury, however it was deemed important enough of a breakthrough to be featured in “The Economist” journal back in 2011.
The bench testing showed great results. One to one comparison with manometry and the device readings. But humans are not animals, are not created equal, they’re much more complex. You need to come up with data to prove your point. And data was forthcoming.
In many studies from different centers that showed the device to be safe, that started to be quite reproducible. And here’s an example of what the device provided you. It provided you relative changes of IOP-related events in the eye over 24 hours. Often the highest measurements were during the sleep period. This is the gray zone in the middle, patient’s sleep, and grows higher as Arthur just showed.
But not everybody reacted that way. The problem was, how do you interpret those data if they’re not in millimeters of mercury scales? Nevertheless, the FDA approved the device after the studies were conducted. But gave it a challenged indication of views which I’ll read to you here. The Triggerfish is a prescription device indicated to detect peak patterns of variation in IOP over a maximum period of 24 hours which then however were needed to identify the window of time to measure IOP by conventional, meaning Goldmann, for example, methods.
In essence, you could use a contact lens, then you would see where the peak IOP is, usually at night time. And then you would need to confirm it with GAT. This was an impossible formula, the device didn’t really catch on clinically wide. We still use it in our center for some select cases.
The need to have a device which is easier to use, easier to interpret. And this is maybe where the implantable sensors come in also.
The EyeMate device, that’s a German start-up company, is an implantable sensor that can be used during cataract surgery and could be implanted into a sulcus just in front of the lens. The device was CE marked many years ago. And quite a good number of studies show that it is safe to use. This is how it looks, that’s the ASIC. You have pressure sensors embedded in what looks like a small computer. It’s implanted in the eye. The patient has an external reader that when powered, sends energy to the device to power it and it receives a measurement in return. Importantly there is no battery in the sensor which would need to be replaced. No battery, the device can stay in the eye forever. Actually there are some patients in Germany now that have had the device in their eyes for up to 10 years.
The first generation had some adverse events. It was a bit bulkier and it created some pigment disruption immediately during after surgery. That wasn’t ideal because the pigment could self clog the angle, of course. As the device was miniaturized, the surgical technique was improved, this did not seem to be happening.
Patients have it in their eyes, and they’re about 70-80 patients worldwide in Europe who have the device in their eye. Some of them, as I said, up to 10 years. Do they obtain measurements once the study period is over? Look at this case. This was a patient over 950 days. And patients for the first year, the study year, that advised, asked to measure four times a day at least. If you look at this graph you see that beyond the 30, 50th day or so, patients still continue to measure at least four times, some of them more than four times a year. Patients believe that the device measurements are useful for them, not just for science. That’s important.
How do those measurements correlate now to Goldmann Applanation Tonometry? These are different studies and methods, but what you see here is that the concordance between EyeMate and GAT is very high. And it’s somewhere between 78 and 88, very good correlation. You may even ask the question, well is GAT the right device? Is it the real gold standard? Which device measures the real IOP? The one that’s in the eye, the sensor, or the one that’s outside the eye that has to go through the cornea and through muscle pressure and scleral rigidity issues and so on? But that’s another discussion that we won’t have here. The measurements seem to be very reliable.
Again, look at the same case of the patient I presented before who measured over three years and beyond. And you see how a typical IOP curve can look like for the long term. You can pick any single day and you see the wide variation of the measurements obtained. Any single day, essentially, the pressure could be as low as 10 and as high as 20 or 22 in a well-controlled glaucoma patient. It shows you the variability of IOP. And the importance to have more data so that you can average out and get a better image of the patient’s real 24-hour IOP variations.
Here we looked in the same patient whether there were differences in daytime throughout those three years. And yes, what we see here is, if you look at the circle on the left, that the highest measurements occurred around 4AM. And this is very comparable to what we have seen previously using the contact lens sensor here in the middle. Where, again, the highest IOPs were between 3-4 PM. Or what the sleep laboratory in San Diego obtained over many years. Again, peak IOP on average around 3-4PM. Thanks to Arthur’s talk before, we understand now why IOP’s higher, sometimes much higher at night time in the majority of people.
Because the first generation and the first approach was only for cataract patients and made cataract surgery slightly more complicated, we wanted to have another sensor for glaucoma patients who do not need to undergo cataract surgery or who had it before but needed glaucoma surgery, filtering surgery. And here we came up with the so-called EyeMate SC for suprachoroidal. It’s essentially the same approach but it’s a rectangular shape and the idea is to place it during non-penetrating glaucoma surgery as a space maintainer. It was earmarked recently.
Here is the video from my first patient from two years ago. We’re doing a deep sclerectomy here, you see here we have opened the conjunctiva, the mitomycin is being applied. We take it out, we rinse, of course, and then we will dissect our regular five by five millimeter scleral flap. And we jump. Here we’re going all the way into clear cornea. Now we are dissecting our deep flap, four by four millimeters. So far, so regular. Once we go to the cornea we take it away. And then we will dissect the trabecular Descemet’s membrane. And then after we have done the regular part, this is the new part. We create a small opening into the suprachoroidal space, as you can see here. We inject a viscoelastic device to create the pocket where then we will insert our SC device.
You see the sensor, it’s the first generation, the current generation is a big bulky, 3.5 to 7.5 millimeters in length. But as you can see here, although this was my first case, it’s not much of a challenge to insert it. You have the posterior part that will be in contact with the choroid, which measures IOP, and this is the external side of it. It has been put in place. Okay, my video is jumping here. It’s put in place and then we close our flap, we close our conjunctiva, as we usually do. The surgery itself is very similar to a regular surgery. Instead of using an inert space maintainer, such as a collagen implant or the Esnoper implant, you put these smart space maintainer.
A multicenter study was conducted, five centers, Germany and Switzerland. And the results were very positive. This is, again, the same case that you just saw. The first postoperative day, the eye looks good, just as any regular eye would do. This is a Swiss source OCT image where you see the device in sito. You see it creates a nice opening inside the sclera. And this is the patient on the first day, happy and smiling. And we could, right away, after the patient went home, see how the measurements were. Because the patient could now use himself, his external reader, to obtain IOP measurements at home.
And here you see the comparison between the first six months and a GAT measurement on the Y-axis. And then the Bland Altman method as well with the SC. And you see that the correlation between the two was very good and it was plus/minus five millimeters of mercury from each other on most occasions.
Is the device safe? That was, of course, an important issue because you’re using a new, big space maintainer. Fortunately we did not have any serious adverse event. We had one case of choroidal detachment which resolved under medical treatment without surgery intervention and otherwise we have very similar adverse events that we usually see with non-penetrating glaucoma surgery.
With the sensors we get a lot of data. And what you see here is the biggest treasure trove, the biggest collection of IOP data of all times. From 22 eyes that had the EyeMed sensors in their eyes, we had 92,000 measurements, over 15,800 or so measurement days. We wanted to know now if IOP, even when you have so much data, if IOP is repeatable over the short-term, less than three months. And what we found was that the repeatability of IOP measurements was moderate with an ICC of about .5-.6. Even the short-term IOP measurements are not very repeatable. Even if you see your patient every three months, and you’re doing GAT, or you’re doing the diurnal tension curve, it’s still not very repeatable.
What about long-term? Long-term repeatability is even less, it’s very poor. You see that the ICC values for long-term, meaning over a year, are repeat measurements are .2-.5. What does that mean? It means our current practice of measuring IOP every 4-6 months really provides this very poor snapshot of real IOP. We need much more IOP measurements, we need continuous measurement.
Something we could also learn from all these measurements, is whether in our sample of patients there was a difference between weekdays. No, we didn’t find any, neither for average IOP or for peak IOP. However, we found a significant difference between seasons. We found that the lowest IOP measurements were the summer months: June, July. And this difference to winter was significant. Essentially, IOP in winter turned out to be about 7% higher than in summer. You may say this is not huge, this doesn’t have a practical implication. Well, probably it does. These are averages, again, and there may be patients where the difference between summer and month is larger. Or imagine studies in new medications comparing one to another. In large pharmaceutical studies, this difference between seasons may have implications.
Another lesson we learned is that now we can study what happens in the eye in patients who undergo intravitreal injections for retinal problems. Here we had a patient who had glaucoma, that’s why he had the sensor in his eye, and he had to go regular intravitreal injections. And we were worried initially that his IOPs would go very high. But once he measured at home with his IOP sensor, we found that he went the other way. After each injection his pressure went down, sometimes to zero. And then he recuperated over the two, three days following. And it almost never went high as we had expected.
Giving him Diamox preventively in this case doesn’t make sense. That’s another advantage when the patient can measure his own IOP and this can have practical management advantages.
Dr. Kahook asked me to provide you some actionable pearls. It’s not very easy because most of these devices are not available outside parts of Europe for sure, but even to most of the glaucoma specialists or ophthalmologists. But we have implantable sensors which we can use in some select centers. And I’m hopeful in the coming days they will become more available.
In the absence of these sensors, and by the way, I presented only two approaches, but there are other approaches. I presented a tube where we have published clinical data. Fortunately we have other approaches to injectables. One such company Injectsense, active in the US, is a promising start-up as well and we hope to see clinical data soon. But in the absence of routine access to these devices, we can perform a diurnal tension curve. It’s better than just obtaining a single IOP measurement, it’s better than nothing. But ideally you would expect your patient to be sitting in your waiting room and be happy from eight to six PM, but that’s not the case. It’s cumbersome for patients to wait the whole day and see other patients come and leave. They get tired, they have other things to do. They may not appreciate to spend the whole day in your clinic for a few data points. But still, I would say it’s worth trying if patients are willing to undergo this diurnal tension torture.
We have access to home tonometers. The iCare HOME tonometer, this is generation two, is such a device which has been approved which works reasonably well. However not every patient can use it. About a third of patients will never manage to use it because of arthritis problems or other problems. But that’s another approach which provides us additional IOP data points outside clinic hours at the patient’s home, during different activities. It’s still better than not obtaining any more measurement.
I think these are actionable pearls. Try to get more IOP data while you’re waiting for sensors. What do I hope with these technologies provide us? Well, I think we can obtain better management of glaucoma. If we really go to using sustainable release IOP medications more routinely where patients might not come to the clinic as often as we would like to, or as often as they did because they don’t need to renew their prescription. Having a home monitoring of the IOP would be useful. What I personally think is now the biggest advantages of patients measuring their IOPs at home, is that now they can visualize the disease which is abstract, glaucoma. It becomes less abstract by having measurements themselves. And I’m sure it will improve their adherence to medications. And by improving adherence to medications, by being able also to see if there’s an IOP peak or not, they may feel better in control, empowered, and have a better quality of life.
By the way, it’s been about what we can do with home monitoring. During the first lockdown phase of COVID where in Germany, in Switzerland, many countries, patients were supposed to come for routine visit. Those patients who had the sensor in the eye could still measure at home and transfer the data to their physicians. And we look at these patients, 34 of them, and we found that their physicians were very happy to have access to the data. During two months of lockdown, these patients could benefit from better glaucoma management without leaving their home. In some cases even, the data led to immediate treatment change, different medications, or one case of surgery was deemed urgent to be conducted. These were patients who otherwise would have lost probably two, three months.
And finally, there will be challenges, of course. We need to be sure that these implanted devices are safe for the long-term, not just five, not just 10 years, but longer. We will need to learn how to better use the data, how optimally to interpret the data. And we will need probably to change ourselves and reevaluate our practice patterns. I’m sure that reimbursement of all these challenges could be a new formality.
Thank you very much.
[Malik] Two great talks and I think it tells a whole story from the basic science start all the way through to what are the things that you could do during a pandemic with IOP monitors? Which I think is introducing new questions but it might be accelerating the science as well as the clinical application because we’re starting to recognize the benefits in a more real-world way.
I have a ton of questions. A lot of them came in before the meeting. I’m getting texted and messages on WhatsApp from some of the attendees. A lot of hellos to you from around the world, which is one of the nice parts of doing a Cybersight session. We get people from all over the world attending.
I’m going to start off with a question for Arthur that Kaweh just touched on which was asked several times pre-meeting by the attendees. Which is, it’s great to have these nice, fancy toys that we might get our hands on in the future, but Arthur, what do you do in clinic? I think Kaweh described it as DTC torture. (laughs) Do you do diurnal tension curves or what do you recommend to people in private practice, maybe in low resource areas? What can they do?
[Arthur] And I think Kaweh really did touch on it and address it. And unfortunately there isn’t anything that’s great right now. I actually perform diurnal tension curves much less frequently than I did 10 years ago. There’s been some good work, one study from Tony Realini showing that the repeatability of diurnal tension curves is poor. And the work that Kaweh showed again, the repeatability of IOP measurements from day-to-day is poor. I just didn’t know how to interpret diurnal tension curves in most patients. There’s a very small number of patients where I still get that, just to see if there really are very, very large swings in intraocular pressure.
And then obtaining home IOPs as again Kaweh mentioned, is difficult for most patients. The iCare HOME, I really don’t use outside of studies right now. And for studies, looking at select patient groups I think it’s great. But it is, again, difficult for a lot of patients to use. And then they don’t see the data immediately so it’s a potential disattisfier for patients continuing to use this on a clinical basis.
There are some things that could potentially be done. There are some individuals, Remo Susanna in particular, is a very strong advocate of provocative tests such as the water drinking test. And that does show that there’s an increase in IOP when you drink a large volume of water. And there definitely are some studies that show more of an increase in patients with pleurotus glaucoma. Again, I don’t do that clinically just because it’s too cumbersome in a routine clinical basis.
Unfortunately the answer right now is stay tuned, the technology is coming fast. Clearly the work and the devices from Sensimed and ImplanData have been pioneering, but there’s a new generation of devices that are coming that I think will get us to the next stage and Kaweh mentioned Injectsense and there’s other companies as well.
[Malik] Kaweh maybe you can touch a little bit on iCare. Are you using it in clinical practice or studies? Clinical practice routinely? How do you think of iCare?
[Kaweh] First of all, I agree with Arthur’s points. Also in my practice the diurnal torture curve is not widely used. We may use in 5% of our patients because it’s cumbersome, because they don’t like it. And also, again, because the data is only small use. The cost-benefit is not wide. The iCare is a device which we’ve had in our clinic, the iCare HOME and we rent it or we give it to patients so far free of charge, but we may need to revisit this issue because it’s costing us. We give it to them for about a week or two to measure at home after they undergo about a half an hour training session in our clinic.
To whom do I give it? It’s mostly patients where we see glaucoma progression already despite low pressures during the clinic. We either do it for ourselves, more for academic reasons because I mentioned the progression is there, so you know you need to change your management. Or we give it to them because they’re hesitant to change their management or to undergo surgery because they tell me, “My pressure is 15, it’s 14, you tell me it’s low pressure. So why operate?” We provide to them and then if they manage to measure at home oftentime they see that there are swings. They see that pressure’s not always stable and low.
But again, the reliability issue comes up. Because you can never be sure that the patient at home measures just as correctly as you show it to him here in the clinic. You don’t know if the value that they measure are reliable. And frankly, you know, it’s hard to do. We haven’t had a good study where it’s measured, for example, compared to the EyeMate often enough to be able to obtain those measurements. Again, this is better than nothing. Back to what I said, the more data you get the better. As long as you can assure that the quality isn’t bad.
[Malik] I think the more data might be better, that question, I found myself in the clinic scratching my head saying, “Maybe I have too much iCare data, because I don’t know what to do with it and it’s not giving me the information that I thought.” I will tell you we do use iCare here routinely and we found a way to actually plug patients into getting the device and getting trained on the device outside of clinic. That’s one of the major issues. We’re all busy in clinic, how do you educate the patient on how to use it? We have several technicians that are trained, we actually use it as part of our electronic medical record to get them plugged in, just like for an MRI or a CT scan. They go and get trained and then use it for a week. Cost is an issue. We’re lucky to have some devices that we can cover the cost of for some patients. but for others it is an issue.
One question that came up was the reliability of iCare. And maybe I’ll go back to Arthur here. Do you see iCare as being as reliable as Goldmann, is there a difference between the two?
[Arthur] There’s a difference. And this gets into another area of ocular biomechanics. iCare clearly has some advantages in certain patient populations like a pediatric population where you can measure pressures without putting anesthetic and patients who maybe have blepheral spasm and this is a good way of getting those intraocular pressure measurements. But it does seem to be more affected by central corneal thickness. Goldmann clearly is but iCare appears to be even more affected by central corneal thickness.
I think it’s very useful and I definitely use iCare a lot in my clinical practice. But those measurements are good for longitudinal measurements but it’s sometimes hard to compare if you’re taking some with Goldmann, some with iCare, those pressures can be a little bit hard to compare in some patients.
[Malik] What about?
[Kaweh] I think the pressure between the iCare taken by the physician in the office and the iCare HOME taken by the patient, we really don’t know. The one we take in the clinic we know is quite reliable compared with the GAT. The one that patients took at home probably is less so, maybe even much less so.
[Malik] Yeah, that’s part of once you give it to the patient and they have it in the home environment, many things can happen. What about pneumotonometry? Are either of you using pneumotonometry routinely in clinic on patients? Maybe we could start with Kaweh. Nope?
[Kaweh] We use it for studies. We think it’s wonderful, it’s the gold standard. And it’s really a reliable device, you get a print out, you can measure in supine position. For research purposes, it’s a perfect device. It’s a very good device.
[Malik] Arthur, maybe a little bit of a twist for you. For KPro patients, for example, what type of approach do you have or patients with issues that might affect corneal approaches? PKP patients, or patients with corneal irregularities, what would you do?
[Arthur] I actually do use pneumotonometry. Not on every patient but for those types of patients where I think Goldmann’s going to be unreliable, who have irregular corneas. And KPro patients you can’t measure on the KPro, of course, but you can measure on the limbal sclera. And there is a good correlation with corneal intraocular pressure. Again, doesn’t tell you what the pressure actually is, but it allows you to monitor it over time.
[Malik] Arthur, there’s some people who want to know if your EVP measurement device is commercial?
[Arthur] It’s not, no. It’s such a small market for it (laughs) there’s probably, the number of people around the world who’d be interested in measuring an EVP I could probably count on one hand. (laughs)
[Malik] Me and Kaweh, so, we’re both (laughs) in line to buy it when it’s available.
Let me ask Kaweh and actually this could be for both of you because you both worked extensively with John Liu and Bob Weinreb. We have a lot of studies that actually the three of us in some ways have tried to mimic with different settings. A lot of us are following in Bob’s and John’s footsteps. When it comes to 24-hour IOP control, maybe we’ll start with Kaweh, can you talk a little bit about the efficacy of SLT and MIGS for 24-hour IOP control and then Arthur if you can add anything after Kaweh’s done?
[Kaweh] Sure. To my knowledge, the first 24-hour study looking at the effect of SLT on IOP was done at the sleep laboratory by John Lieu and Bob Weinreb in San Diego about 20 years ago, 15 years ago. And they showed that there was a clear reduction of night time IOP which was more than we see after all medication classes except for prostaglandins. And this is something we later could confirm using the Triggerfish. We also found the significant reduction of night time by SLT.
Concerning MIGS, to my knowledge, Malik, there hasn’t been a real 24-hour study done with MIGS. And we have had some data after glaucoma surgery but this is standard glaucoma surgery with the Triggerfish, but not after MIGS. But this is definitely an important thing to do.
[Malik] What do you think, Arthur?
[Arthur] I agree and just to elaborate on the study that Kaweh mentioned. It was done while I was a fellow, so it wasn’t quite 20 years ago, I’m not getting to that era quite yet. But it was actually an ALT study. And what was really interesting about that particular study is that in that patient group there was no change in pressure during the daytime. If you were to look at those patients you would have thought that they failed laser treatment. But if you looked at the 24-hour pressures there was a clear flattening of that nocturnal peak.
[Kaweh] Arthur, that’s a very important point. Actually I end up mentioning that regularly when I do SLT and I do a lot of SLT. And I tell my patients we determine SLT success after two months. And then after two months if I don’t see these 25% IOP reduction, which we usually would then consider an SLT failure, I often end up telling them, “Well, we put you on medications, but the laser wasn’t in vain, it probably reduced your nighttime pressure, but we don’t pick it up because we don’t measure it.”
[Malik] And I often use that same line probably because I heard you saying it at some point. (laughs) We don’t have a ton of time left but I do want to get a rapid fire to a bunch of questions. Dr. Susanna’s name was mentioned earlier. He’s listening in, he sent a question about how to measure peak IOP in clinic. I think there are different ways to do it. I’m just wondering if Kaweh, do you try and get to peak IOP through different maneuvers in clinic or do you not do that?
[Kaweh] I probably inadvertently do it all the time by asking my patients to do a visual field before they see me. Seriously. Anyway, that’s one inadvertent way to do. The water drink test, which is sometimes used not often, just for practical purposes, is a validated method to measure peak IOP. It really has been shown by different studies from different places. That’s it.
[Malik] Okay, Arthur, do you do anything? There’s this talk about supine and that might mimic the peak pressure. There’s some papers on that earlier on. Do you do anything like that?
[Arthur] Not routinely. The supine measurement was something from Sameh Mosaed when she was with Bob Weinreb again. Showing that rise in supine pressures did parallel the rise in nocturnal pressures in a lot of patients. But it’s not something I do routinely.
[Malik] How often, Arthur, do you talk to your patients about sleep position and the effects on IOP? Supine versus laying on one side or the other?
[Arthur] The supine, I think, is trickier because we don’t know how it parallels to the other physiologic changes such as the change in CSF pressure, change in blood flow. But I do talk to them a lot about the lateral decubitus position. There is a clear increase on the one side. But even more significant, if patients are sleeping on their side and pushing their head against the pillow, you can have very, very large increases in intraocular pressure. And that was shown in a study, I think, from Hopkins. I do counsel patients if you’re sleeping on your side, make sure your face isn’t squished into the pillow.
[Malik] This is when being a doctor and knowing some of this may not be a good thing. When I see my son sleeping on one side, I’ll often go and check that his eye isn’t next to the pillow or push the pillow down a little bit. Just an insight into some of my mental issues. (laughs)
I have one question for Kaweh and then I’m going to ask a final joint question for the two of you. Kaweh, there’s a question about different environments and when some of these implants might work. Space travel was mentioned in a question, scuba diving, will the implanted IOP sensors work in different environments?
[Kaweh] Good question. If a year to two years ago, if I get a question for space travel, I’d say, who’s the crazy person asking me? But you saw just yesterday we have two new tourists of today sent into space. The question’s become relevant much faster than we think. Honest answer, we don’t know, we haven’t studied that. Scuba diving, also, we haven’t studied that, we don’t know. The whole scuba diving and IOP issue is not very well understood. How high does IOP go? Should we advise our patients against scuba diving? We had a whole course here, it was done awhile ago, and we don’t really know. What I tell my few scuba diving patients is, I want a patient who goes for 30 days a year. I don’t want to prevent you from doing it, I know how important it is for you, let’s check your pressure afterwards, after your scuba diving week. And maybe if you want to take a Diamox or two during that week, don’t hesitate. But we don’t really know. There’s no consensus.
Things that we know more often about environments are if patients have a sensor in the eye, the EyeMate, if they undergo laser, the YAG laser for capsulotomey or goniopunctures, suture lysis, then you need to remeasure the pressure and sometimes you need to calibrate the device. The laser in the eye in a sensor can have an effect, not destroy it, but you need to recalibrate it.
What about daily activities? That’s another issue. If you have a few patients who play wind instruments, we have them come into the office and play here with a silencer for half an hour and we would measure IOP again. I usually ask my patients of high pressures or fluctuating pressures, how much coffee they drink. Often they say 8-10 cups of espresso, I advise them to reduce it if they can. Yes, Malik, please, reduce. (laughs) And we know from beautiful studies from Tanuj Dada in India that meditation has validated IOP reducing effects.
[Malik] If you haven’t, to the audience, had a chance to pick up the paper by Tanuj, I think it’s really interesting and might expand an area of research. And that reminds me of another question that came in about yoga, which is similar to the answer that you gave about scuba diving. If you think about it as everything in moderation, and Arthur showed the pictures of the different positions that could influence IOP in yoga. But there are many, many others that wouldn’t influence IOP. I don’t tell patients to stop yoga, I tell them to watch out for certain positions but continue to do what they love to do. We have ways to educate patients on ways to continue living even with the disease process that they have.
For the sake of time, I want to ask both of you a question and I’ll start with Arthur. Maybe a little bit of a controversial question, but I think one that all ophthalmologists and all patients are going to be thinking about. If you look at the video that Kaweh was showing, in the early stages these implants can be quite invasive when you’re putting them in. There are different versions of course, there’s Triggerfish contact lens, which maybe gives you a slightly different kind of data set. There’s Injectsense which maybe isn’t as public with some of the procedural things that they do, but it’s a smaller device, and maybe placed in a minimally invasive way. Arthur, how do you think patients are going to receive these devices? Will it be something that all patients will be lined up to do and you would want all patients to do, will it only be coupled with surgery in the operating room? What is the patient population that will actually see these devices and get use for them?
[Arthur] That’s a good question and I think that it will change over time. Certainly with larger, more invasive devices it will be coupled with other surgeries. It would be a hard sell to try to convince a patient to undergo a significantly invasive surgery just to place a device. But as the devices get smaller, I think there will be a shift. It won’t be an immediate shift, of course, because there’s going to be a learning curve on the part of providers, and a level of comfort that needs to be achieved. But I think that as the devices get smaller and less invasive.
I think the long term goal is I’d like to see this in all my glaucoma patients. To use the analogy with diabetes, we can monitor diabetes, blood glucose at home. There’s implantable blood glucose monitors. Once we can make that jump in glaucoma, I think we enter a completely different era of disease management and what we’ll learn and the level of care that we’ll be able to provide to our patients will be unlike anything that we can do now.
[Malik] Yeah, what do you think, Kaweh?
[Kaweh] I fully agree with Arthur. I think it will be a gradual change but ideally every patient should have access to routine IOP monitoring. Practically speaking, in our center since the new EyeMate suprachoroidal sensor got it’s CE mark in Europe, which means we can use it clinically, we have given our first orders for them. And the idea is to offer it to every glaucoma patient who undergoes filtering surgery. We haven’t gotten reimbursement, so it will be out of pocket. But we believe it’s useful enough and safe enough to offer it to every patient who has deep sclerectomy, for example.
[Malik] It raises other questions, of course, because you mentioned reimbursement, cost is a big issue. We’re going to introduce a whole new issue of health equity when some populations are going to have access to these sensors and others won’t. Organizations like Orbis, Cybersight are definitely at the forefront of trying to get to a better place from a health equity standpoint. This will be another challenge for organizations like Orbis, for sure. And hopefully we can figure out a way that everybody benefits from the technology and the data that we get from the technology. Because that’s going to be a whole new area of what does it mean to have constant pressure checks and what kinds of medications and surgical devices might actually come to play when we have all of that data?
I’m going to start off on the end of concluding this by saying thank you to Orbis, thank you to Cybersight for hosting. Thank you to all of you who Zoomed in today, because everybody’s busy, certainly night hours in many places of the world where people came in to visit with us today, so I’m thankful for that. We will continue to do these Point-to-Points hopefully every quarter, and I welcome suggestions for the next Point-to-Point. So you can send them in to Cybersight and they’ll pass them along to me. And I want to finish off by thanking Lawrence for doing a lot of the audio/visual stuff for us. And, of course, Arthur Sit and Kaweh Mansouri for spending time and sharing a lot of your past research and maybe future outlook on how we’re going to take care of patients with constant measurement of IOP. Thank you guys, I hope we can do this again live where we see each other and grab coffee afterwards. But I appreciate the time and please have a great rest of your day.
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September 16, 2021
1 thought on “Lecture: 24-Hour Intraocular Pressure: Basic Principles and Actionable Clinical Pearls for Practice”
Excelente curso e iniciativa. Importante e de grande impacto projeto educativo. Por favor agradeçam prof Malik por citar meu nome