During this live webinar, the fundamentals of aqueous humor formation and outflow will be reviewed. Methods for the accurate measure of IOP will be discussed, including potential sources of error. The anatomy and pathophysiology of the anterior chamber angle and outflow system will be illustrated and reviewed, including recent advances in our understanding of the aqueous outflow system.
Lecturer: Dr. Louis Cantor, Indiana University School of Medicine, USA
It’s wonderful to gather in this format for this morning here where I am. And in previous talks we’ve talked about a lot of different things and advanced topics, surgical topics. But today I thought it would be fun and useful to go back to the basics. To really go back and review what we know about aqueous humor dynamics, how intraocular pressure is controlled, and how we evaluate the anterior chamber angle. That’s going to be our focus this morning. Again, please, if you have questions make sure to get those in mind and prepare them for the Q&A and submit them and we’ll try to get through everyone’s questions at the end.
What is glaucoma? We talk about this group of diseases that have in common this characteristic, optic neuropathy that we all can recognize with characteristic associated visual field defects for which elevated intraocular pressure is a risk factor. Certainly not the only risk factor, by any means, but it’s the only modifiable risk factor that we have.
We know a lot of things about risk factors but we’re still learning all the time. And it’s still clear that elevated intraocular pressure remains the primary risk factor that we have to keep in mind for our glaucoma patients. But other things such as family history, African American in our country or Hispanic descent or others, are also important risk factors. Other risk factors have been identified as well and are important. And I think we’ll understand these more and maybe even be able to modify some of these risk factors. But today, intraocular pressure remains the only modifiable risk factor.
In terms of intraocular pressure, if we look at various studies we always talk about a pressure of 21, which isn’t a magic number. That’s just based on some population averages and statistics. But if we look at that, about 4% of persons with pressures over 21 will develop new glaucoma damage. And on average, less than 1% of ocular hypertensive patients develop glaucoma damage over time. And about ⅓ of glaucoma patients, on the other hand, don’t have consistently measured pressure over 21. Our so-called normal tension glaucoma, which is very common in certain areas of the world, particularly Asia, for example.
Let’s talk about intraocular pressure. How is intraocular pressure controlled, what is the physiology and pathophysiology that happens in glaucoma that affects intraocular pressure?
This is the classic drawing with all these arrows showing where aqueous is produced in the ciliary body and the different ways that fluid can get out of the eye. And we know that it’s that interchange between inflow of the eye and then resistance to outflow that ultimately determines the intraocular pressure at any steady state. Pressure inflow and outflow equal each other.
Where is aqueous produced? Here is our cartoon drawing of the ciliary body with the ciliary muscle and iris as shown on the top figure. On top of the muscle, which has its different fibers: the longitudinal fibers and the circular fibers. There’s the ciliary stroma. And the ciliary stroma is divided and is covered by two layers of epithelium. The non-pigmented epithelium is shown below which is on the inner side and where aqueous is produced. And underneath that is the pigmented epithelium of the ciliary body and the ciliary processes. But it’s this non-pigmented ciliary epithelium that ultimately leads to aqueous production into the anterior chamber of the eye. And here’s just showing that.
Here are some electron microscopic photographs showing the same thing that show that the non-pigmented ciliary epithelium is on the side that faces the inside of the eye and where aqueous is produced, under which is the pigmented ciliary epithelium.
Let’s have a question real quick here just to get us awake for the morning. Which mechanism below accounts for the major component of aqueous production? Diffusion, secretion, passive flow, ultrafiltration, or concentration? You can enter in A, B, C, D, or E and we’ll see what the group decides. Hopefully you’re all getting your… So we have the secretion seems to be the majority opinion, but there’s a lot of different answers here. Diffusion, passive flow and so forth.
The answer is secretion. And if we look at aqueous production, diffusion, which is the net movement of molecules from higher to lower concentration. Ultrafiltration is where there’s a pressure or concentration gradient across a somewhat semipermeable membrane, which means it won’t let some things through but it will let other things cross. That’s ultrafiltration. And then there’s this active transport which is secretion. Diffusion and ultrafiltration are more passive. But it’s the active filtration that requires cellular activity to count for the majority of aqueous production.
The non-pigmented ciliary epithelium, which is where the business end is of aqueous production, contains numerous mitochondria. Why? Well, because it’s a very highly active, constantly in motion, constantly producing aqueous fluid cell layer. And that requires a lot of energy. And mitochondria are the engines that run our cells and provide all the energy. Microvilli are on the surface of the cellular epithelium and those provide for a lot of surface area. And between cells there’s a lot of tight junctions. And these tight junctions help control what can move and what really makes up the blood aqueous barrier, which we’ll talk about a little bit more. But it prevents certain things from diffusing into the aqueous and allows for primarily, secretion with some of the other effects contributing smaller amounts to the overall aqueous production.
As I said, plasma substances accumulate between and behind these tight junctions. So they can’t diffuse and we’ll see how that’s important in just a minute. And as I said, that acts as the blood aqueous barrier. When we lose these tight junctions, that’s when a lot of protein and things can then move into the aqueous, such as what we see in inflammation. The active transport is across barriers with sodium, potassium, ATPase that moves sodium ions and potassium ions. There’s also active transport of chloride, bicarbonate, ascorbic acid, which we’ll see is important, and amino acids that might be necessary.
There’s this osmotic flow of water because where a sodium ion goes, it increases concentration, so it will pull water in with it. When you put various ions into as the non-pigmented ciliary epithelium cells pump these ions across its membrane, water naturally goes with it in the production of aqueous.
Here’s something to remember about aqueous humor. And this is all controlled, again, by those non-pigmented ciliary epithelial cells. Compare the plasma, our blood plasma, aqueous is hypertonic, it has more sodium. It’s slightly more acidic to neutral, the average pH of aqueous is about 7.2. Plasma is a little bit higher than that. It’s very high in ascorbic acid compared to plasma, 15 times higher. Ascorbic acid is really being pumped into the aqueous and why? Well, ascorbic acid is a potent antioxidant and has other important effects for eye health and health of the anterior segment. And the aqueous is very low in protein, 0.02% versus 7% protein in our plasma. And that’s so that the aqueous remains clear. When we get a lot of protein, that’s the flare that we see in uveitis because there’s leakage of protein into the aqueous, which can affect not only the health of the anterior segment, but maybe even the clarity of the aqueous.
Aqueous production, we have this rate of inflow. It’s about 2-3 microliters per minute on average. These are in normal eyes. The turnover takes about 100 minutes. A little over every hour and a half we are completely turning over the aqueous in our eye. There are diurnal variations and aqueous production decreases up to 45%, in some studies even a little more, during sleep. And that becomes important when we consider some of our therapeutic options, which I’m not going to talk about. But for example, how effective might an aqueous suppressant be at night versus being given in the morning when aqueous production is more robust? If our aqueous production is already going down by nearly half at night, does using a beta blocker at night even do anything, for example. Just one of the things to think of as a clinical corollary to what we know from the basic science. And we know that aqueous production also decreases with age.
How does aqueous then get out of the eye? That’s how it gets in, those are some of the things. Which of the following, our next question, which of the following regarding the conventional (trabecular) outflow system is false? It’s pressure independent, it accounts for the vast majority of the outflow capacity, it’s increased by miotics, decreased in most glaucomas, or increased by rho-kinase inhibitors? Go ahead and make your choice. Again, which is false? Results should be popping up here shortly. The majority were saying pressure independent, but a lot of variety in the answers here without an overwhelming answer. The incorrect choice was pressure independent.
In fact, in aqueous outflow the conventional trabecular outflow pathway, which accounts for the majority of outflow, at least 80%, although it varies in some studies, but it’s pressure dependent. Meaning that with higher pressure, there’s more outflow through the trabecular system. It is increased by drugs like miotics, rho-kinase inhibitors, and to some degree even by the prostaglandins, although the majority of their effect may be uveoscleral. And conventional trabecular outflow is what is decreased in most glaucomas except for in eyes with normal pressure, like low tension glaucoma.
The unconventional or uveoscleral outflow pathway accounts for a smaller percentage of total outflow. It is pressure independent. Regardless of what the pressure is in the eye, this stays relatively stable. It is decreased by miotics and it’s increased by drugs like alpha agonists, cycloplegics even, and prostaglandins, as examples.
Back to our drawing, here’s the anatomy of where everything goes. We have resistance to outflow at the trabecular meshwork we know. But we don’t really have much resistance except for maybe some tissue resistance through the ciliary body or through the sclera for uveoscleral outflow.
Since trabecular outflow is the majority, let’s look at it a little closer and make sure we understand the basics of the anatomy. In the angle, as is shown here, we have the corneoscleral meshwork and uveal meshwork that is then followed by the Schlemm’s canal and the juxtacanalicular network. Fluid has to flow through all of these pores through the corneoscleral and then uveal meshwork and then through the juxtacanalicular zone to get into Schlemm’s canal. These pores not only remove some products that may be in there, these beams that are shown here are lined by endothelial cells that phagocytize, that are actively metabolic. It’s not just bare beams of collagen it may look like in the pictures here, these are actually columns of collagen covered with endothelium.
Once the fluid gets in the Schlemm’s canal, there’s then an outflow system of collector channels. And ultimately the aqueous connects with the episcleral venous plexus on the surface of the eye and is drained away from the eye with the blood system.
If we look at the trabecular outflow in a little bit more detail, like I said, each of these trabecular beams, this is one shown here in this electron micrograph. It has a collagen connective tissue core, but it’s got an endothelial cell layer lying around it. And it synthesizes GAGs, which are glucosamine and glycans, glycoproteins, collagen, to help maintain the health of these beams. And it does phagocytize and degrade foreign substances.
When we get into Schlemm’s canal, the Schlemm’s canal also has an endothelial lining and fluid. After it’s passed through the trabecular meshwork has to then cross this endothelial cell wall. And these endothelial cells contain vacuoles or pores and aqueous passes both through and between these cells by active transport. And a variety of mechanisms that are quite honestly still being defined today and are not completely known.
When we look at aqueous humor dynamics though, at the trabecular meshwork, it seems as though the primary site of resistance is at the juxtacanalicular. That’s the zone just outside the canal or inside toward the inside of the eye, but right next to the canal, which is the final barrier and where a lot of changes occur in glaucoma. In glaucoma we see a buildup of glucosamine and glycans and extracellular matrix and the tissue there actually becomes not only thicker but more stiff and less compliant. And it takes more pressure for fluid to get through that. The pores that are there in some of the endothelial cells, some of them appear passive, some of them are energy passive and independent. But there are others that appear to be pressure dependent and maybe more active to get fluid out.
The other thing that’s been shown by work done by Murray Johnstone and others for years, is that Schlemm’s canal in glaucoma can start to collapse. And that it has very much a pumping mechanism, almost like a heart valve, to get fluid out of Schlemm’s canal. We can also have resistance in Schlemm’s canal when it collapses and doesn’t allow fluid out. And the final layer of resistance is the outflow system, the trabecular canal system that gets fluid out of Schlemm’s canal. And then finally, there’s the episcleral venous pressure. Whatever fluid is getting out of the eye, it has to go against this episcleral venous pressure which is normally around eight to 11, normally. It can be elevated in certain conditions if there’s an artery or venous malformation involving that area, then the episcleral venous pressure will be high. And the intraocular pressure can theoretically, if you’re going through the system, can never be lower than that.
The uveoscleral outflow system, it’s less well-defined but it’s just once fluid gets into the eye, and after it’s produced, some of it can backflow through the iris, interstitial spaces of the ciliary muscle and ciliary body. And it ends up going into the suprachoroidal and supraciliary space and then finds its way out around pores in the sclera, around vessels and nerves that are penetrating the sclera. Or through the sclera itself or into blood vessels via passive flow and osmosis. It’s a much more diffuse system, and again, it accounts for the minority of aqueous outflow. But if you increase this, such as we do, say a prostaglandin drug, to where this is not just 15 or 20% of the outflow, but 50 or 60% of the outflow, that makes a big difference.
What about intraocular pressure? We know that this, we’ve talked about the aqueous fluid and how it gets into the eye and how it gets out. If there’s resistance to it getting out that builds up pressure. And we know if that builds up inside the eye because it’s a closed system. And we also know that the weak spot in the eye, if you will, to the effects of pressure, is the optic nerve. That’s what causes glaucoma in many patients. We have lots of equations here. I want you just to bear with me. But for intraocular pressure when it’s steady state, when inflow equals outflow, Goldmann, many years ago came up with the Goldmann equation. Not to get lost in all the figures here, but Po is just the intraocular pressure in millimeters of mercury, equals the rate of aqueous formation over the outflow facility plus the episcleral venous pressure. Because of every millimeter of episcleral venous pressure that goes up, the intraocular pressure goes up. You can also calculate a figure of resistance downflow which is one over the outflow. But it’s a very simple equation, really, that tells us conceptually what’s happening in the eye.
Now the problem with intraocular pressure from a clinical standpoint is that we know in most populations the average intraocular pressure is about 16 and if you go two standard deviations one way or another, that gives us an upper end of around 21 for two standard deviations. But we know that pressures can be much higher than that in the normal population and that the distribution of pressure is still slightly skewed towards the high end. If we look at the glaucomatous intraocular pressure, it’s even obviously more skewed to the right. But there seems to be no pressure at which glaucoma can’t occur or always occurs. But this is what those curves look like from an epidemiology standpoint.
Intraocular pressure we know has a lot of variations to it. Short term factors such as diurnal variation, exercise, valsalva, postural, just with respirations, anesthesia can affect the intraocular pressure. We know that genetics plays a role, the intraocular pressure is higher in relatives of POAG patients, even if they don’t have glaucoma in these relatives. Intraocular pressure increases with age and there may be some racial and in myopes, there may be some issues as well.
How do we measure intraocular pressure? Maybe some of you have seen this device, you don’t see it much anymore or at all, but it’s often pronounced “shee-otz”, but I’m told by someone who spoke to the individual who developed this, it’s Dr. Schiotz “Shutz”, which was the Dutch pronunciation. Anyhow, this was a way of using a simple mechanical weighted arm to try to assess the pressure with this type of tonometer.
Applanation tonometry, which is what we primarily do today with Goldmann tonometry and things, is based on a principle called the Imbert-Fick Law which applies to an ideal thin-walled sphere. And it merely says that the force against the sphere is equal to the pressure within the sphere, times the area that’s being flattened or applanated. But that formula assumes what’s called an ideal thin-walled sphere that has no resistance to it. Which, as we know, the eye isn’t.
That would be what the idealized thing here, you’re putting something against the eye and the force and area correlate to the pressure that’s inside that. Measuring it from the outside. However, we have to modify that Imbert-Fick Law from physics for the eye. And Goldmann modified the equation still looking at the external force against the sphere, but he knew there was another force. And that’s the surface tension of the tear film which actually tends to pull the tonometer tip against the eye more. It actually adds to the external force that you’re applying. Then we’ve got the pressure in the sphere and you’ve got the area of applanation so the pressure resists flattening. But then you’ve got the force to bend or flatten the cornea. He knew the cornea wasn’t without some resistance. So there’s a force there that you have to overcome with corneal rigidity, corneal thickness come into that.
But he made an assumption. He said the resistance to corneal flattening, in other words the corneal rigidity, would be canceled out by the capillary attraction of the tear meniscus for the tonometer head. That was an assumption which may hold true in a very narrow range, but certainly isn’t true across the board. But it was a very big assumption that was made to help develop the tonometer.
This is what he did, he just took that same formula and he calculated out that when the diameter of the tonometer tip was 3.06 millimeters, what the standard Goldmann tip size is today for a Goldmann applanation tonometer, that these forces of surface tension and resistance to the corneal rigidity would equal out. We know that’s not entirely true but it kind of gets closer to what is reality.
With the Goldmann applanation tonometer, we have this flattening force and it’s grams and it’s multiplied by 10 to get millimeters of mercury. It displaces a small amount of fluid. And if we look at the diagram now, it’s a little bit more complicated. We’ve got the resistance to flattening, what they call the spring force of the cornea, to not be flattened. You displace a volume, there’s a tear meniscus and all of that going on when we’re measuring the pressure by applanation tonometry.
And there’s a lot of sources of error. Lid squeezing, breath holding, valsalva, pressure on the globe, sometimes a tight collar. If they’ve got tight muscles for some reason. If you have too much or too little fluorescein, if the cornea’s distorted in some way, if you have a lot of astigmatism. But primarily by central corneal thickness and corneal rigidity.
Just to present a couple of cases. Here’s a 57-year-old Caucasian woman with ocular hypertension for the past five years. She has pressures from 22-25, she has 0.4 cups, her fields are normal, and her corneal thickness is around 600, approximately, in both eyes. Contrast that with another patient who’s a 32-year-old African man with no past ocular or medical history. Presents with good vision, pressure’s of 19, he looks ok on slit lamp and gonioscopy. But he’s got large cups, he’s got what appears to be some early visual field loss and his corneal thickness is 492 and 493. Two very different presentations, even lower pressure than in the first case. But because of the very thin corneas, we know the pressure is higher than what we’re actually measuring. That there’s an error with our Goldmann applanation tonometry that we have to account for.
And various studies have looked at trying to correct the intraocular pressure for corneal thickness and across the range of pressures and apply a correction factor. Some estimate that it’s two to three millimeters for every 50 micron difference in central corneal thickness from 535 microns. A lot of this came from the Ocular Hypertension Treatment Study. And the variation was thought to be less for healthy eyes, greater for eyes with chronic disease. But the problem is, it’s not linear. And it doesn’t apply across the spectrum.
And this is just one study that was done many years ago where they looked at eyes that have various degrees of corneal thickness down there on the X axis. Measured the intraocular pressure by tonometry and then by canulating the eye and getting an exact monometric reading, and seeing what the error was. And you see it’s kind of all over the place. You can draw a line through it but it’s not like all those error dots line up along that line, it’s all over the place. There’s a lot of variability. That’s why it’s very hard to apply any formula to this, you just have to know that qualitatively when the cornea is thin, the pressure is going to be in your mind a little bit higher than what you’re measuring. And if it’s a thick cornea, just the opposite. And take that into account when you start to think about how you’re going to manage that patient. I would urge you not to get hung up on a calculator that says it’s going to tell you what the pressure is based on what the corneal thickness is because they’re not accurate. And they only maybe get you partly there.
We know that there’s a variation also in central cornea thickness during the day. The cornea varies some, because it depends on when you measure people. We measure most people during the daylight hours, but even during daylight hours it can vary a little bit. Maybe not enough to have a big effect, but it does vary.
When we’re measuring it, what happens? This is, on the left, what the correct reflex looks like for the edges of the mires, just touch each other, that means you’ve applanated the correct area with that 3.06 millimeter diameter. Fully applanated and they’re just touching, so there you’re good. But if you have too much or too little fluorescein, you’re going to overestimate or underestimate the pressure. You’ve got to have just the right amount. And again, here’s another diagram that shows that.
There are other types of tonometers. There’s the tonopen, is what’s called a Markey-Marg type of tonometer. It’s useful for, especially in scarred or edematous, or irregular corneas but it can be used in the clinic if need be. There’s pneumatic tonometers, there’s portable tonometers, there’s dynamic contour tonometers that try to take into account and minimize some of the corneal factors that can contribute to error that can be used, but are not widely used.
I’d like to move on now to how we classify glaucoma and think about it and what the anatomy looks like and talk a little bit about gonioscopy for the next few minutes. When we evaluate any new glaucoma patient, especially in adults, our number one responsibility when we know they have glaucoma is to determine is it open-angle or angle closure? Because that will determine potentially different treatment courses. It has a very applicable, clinical, relevant issue associated with it. If you misdiagnose somebody as open-angle who really is angle closure, for example, you won’t apply the correct treatment.
Open-angle, the resistance in an open-angle, the resistance can be in the pre-trabecular on the interior side of the meshwork, it can be within the meshwork like most are, or they can be post-trabecular, such as elevated episcleral venous pressure. You can think a little bit about mechanism there. And for angle closure, they’re going to be pulling or pushing methods are etiologies as we call it. Pushing is what we’re used to, mostly, where there’s pupillary block pushing the iris forward, closing off the angle. But you can also have an anterior pulling such as in secondary glaucomas with neovascular glaucoma. Then, of course, there’s the whole category of childhood and developmental glaucomas and juvenile glaucoma, which we don’t talk much about.
This is a complicated screen. I just put it up just to show some of how this is broken out. And we keep doing better. The one symptom that causes some challenges for us is plateau iris down at the bottom. How to exactly diagnose it between the mechanism of pulling and pushing, it’s probably a little of both in some cases. But these are some of the diagnoses then that fall out when we think about whether it’s trabecular, post-trabecular, and where the area of resistance is.
This brings me to gonioscopy and the Spaeth Gonioscopic Grading System, which I use on every patient. I don’t know how many of you are familiar with this. But I think if you’re not familiar with it I hope you’ll pay attention and maybe consider using this system. Because it tells you a lot about the appearance of the angle better than saying we’ve got an open-angle or the angle’s two plus open, three plus open. I never know what that means when somebody says that. But I know what it means when somebody describes the angle according to this system.
What’s the goal of gonioscopy? It’s really to distinguish pathologic aspects of the anterior chamber angle from infrequent, but normal, variations. And there were a lot of systems developed over the years. And the Spaeth System is the most recent and it’s undergone some modification. But it was really developed by Dr. Spaeth in 1977. The penlight, it can be a quick screening way to look for angle closure. It’s quick, it’s not very sensitive.
And then we can use the Van Herick system where we look at the slit beam and look at how much, how the peripheral anterior chamber depth compares to the corneal thickness. And here’s an example. Here we have the slit beam near the limbus, coming in at about a 45 degree angle. And we see the light going through the cornea, the parallelepiped reflects that we see in the cornea of the light. Then there’s a gap before it hits the iris and that gap, of course, is the anterior chamber. And we can see that that gap is almost as thick as the cornea. It’s likely, at this angle, just by this quick screen is still open. As opposed to this eye, where we do the exact same thing and there’s no gap. That just means the iris is already not even in the angle, but out away from the angle a little bit, already up against the back of the cornea. So that angle is closed. Just a very simple Van Herick.
Spaeth proposed a system that doesn’t rely on any single part. But it described three parts of the anatomy of the iridocorneal angle that are important. Where the iris inserts. The point where the iris contacts the internal lining of the eye. At what angle does it approach the angle of the eye? And what’s the peripheral iris contour? Which can be different and we’ll look at that.
Iris insertion. We just call this ABCD and E. Does the iris insert very anteriorly? Anterior usually at or in front of Schwalbe’s line, behind scleral spur, ciliary body, or way deep in the ciliary body? Here’s a schematic. That just shows the meshwork drawn there and where’s the iris inserting? Here would be a drawing of an A angle where the iris is completely covering the trabecular meshwork and up to probably Schwalbe’s line and then you have the anterior chamber. Versus at the other end of the spectrum an E angle, we have a very posterior iris insertion. On gonioscopy you would see a lot of the angle. And this is just that sort of whole chart showing the different levels of which the iris can insert in the eye.
You then have to define the angular approach. This is a little more subjective in many ways, but it’s not as difficult as it seems. You just draw two lines. One through the middle of the iris and one through the meshwork. And they look like this. You draw one line through the middle of the iris, that’s a tangent. And you draw another line that’s through the meshwork and you estimate how many degrees apart those would make that angle. And normal would be about a 40 degree angle, say.
And then there’s the peripheral iris configuration. The iris can approach right at the very periphery, it can be relatively flat, it can be concave and bow backwards, such as we see, for example, in pigmentary glaucoma. It can be bowed forward or convex, such as we see in pupillary block, or it can have a plateau where it has this little hump and then flattens out. And that can have consequences. Here’s just normal iris bowing into the angle. You can see there on this ultrasound biomicroscopic picture. Here’s three different eyes that have maybe similar angular approach, but very different in the periphery into how much of the angle you might see.
And there’s also, and I don’t want to make it too complicated. But then there’s also indentation gonioscopy where you compress the central corneal if you’re using a small gonioprism to determine is that the actual insertion or is it just where the iris looks like it’s inserting, but in fact the insertion is more posterior because the iris is bowed forward.
Here’s an example of a gonioscopic photograph of looking across at the angle. And you see in this picture, part of the angle is closed, it’s an A angle. And then it all of the sudden deepens where it’s open. Very easy to see that zone of distinction. You can also then look at pigment and grade it and other things.
And this is what the whole system looks like. Again, the ABCDE for the iris insertion, what is the angular approach? It’s usually somewhere in the range of 30 to 40 in normal, but a very bowed forward, or very pushed forward can be 50. And if it’s very flat, or posterior, it can be very small angle. And then what does the peripheral iris look like and pigmentation.
Here’s a case, I’m just going to illustrate with ultrasound biomicroscopy. Here’s a case where the angle structures, you really can’t see. The iris is pushed forward over it for some reason. But the anterior chamber in front of it looks fairly deep. This is angle closure. What’s our first thing in angle closure? Let’s do an iridectomy. A hole was put in the iris and things kind of open up a little bit but you still see that the angle is mostly covered. And why is that? If you look posterior to the iris, there’s all this ciliary body here, this patient has a very anteriorly displaced ciliary body and has plateau iris. What do we do next? We do iridoplasty to thin out the peripheral iris and now open up the angle.
And here’s a gonioscopic picture with indentation of a patient with plateau iris. And if you look at the light as it traverses over the iris, it’s still got this double hump pattern. Because out here in the periphery it’s being pushed forward by the ciliary body. It won’t go straight back. But we could still open the angle in this eye without indentation, no angle structures were visible.
This patient, we always do an iridectomy, laser iridectomy usually first in these eyes. And if the angle doesn’t open, then that confirms the diagnosis of plateau iris so then we do iridoplasty.
We can do other things with gonioscopy too. Here’s an eye that seems to have a good filtering bleb after trabeculectomy. But the pressure’s 25, why? We can look at the sclerotomy. And in this case, it may not be very clear in the picture but there was a membrane that had grown over the sclerotomy that was causing increased resistance internally.
This is an example of pigmentary glaucoma with that heavy pigmentation in the trabecular meshwork. Here’s an example of an angle recession with a very deep angle and we’re seeing behind the ciliary body, actually, here.
This is a photograph of where I get to work at our eye institute at Indiana University. It’s a pleasure to have brought this to you today. I’m now going to stop sharing and we’ll go to the Q&A.
We will go to the questions first. I’m not going to try to pronounce the name, but I’ll say the first name, Marlene. I’ve tried to change aqueous humor dynamics in Wistar rats by episcleral vein cauterization and injection of magnetic microbeads in the anterior chamber. It didn’t work properly. It only elevated pressure about 48 hours. Do you have any clue why it didn’t work? It seems not to affect the aqueous dynamics. It should work, it depends on, I’m not an expert in these models. And I think you need to talk to other basic scientists who do these. There are models, I know, that do work by either lasering the trabecular meshwork and laser the aqueous veins and closing them off and using microbeads in the anterior chamber also to plug the meshwork. It may have something to do with the type of beads that you’re using or the technique. A lot of these things are very technique-dependent. I would encourage you to contact some of the, if you do a literature search with scientists who are doing these sorts of models, and ask them about how they do their model. Most scientists are very open to sharing their knowledge. If you have trouble, I do have colleagues, basic science colleagues, who work with me that I’d be happy to put you in touch with.
The next question was, can we decrease episcleral venous pressure? Not the normal episcleral venous pressure but if someone has elevated episcleral venous pressure. And for example, has an arterial venous fistula such as a cavernous sinus fistula, that they get closed and treated, yeah, that can bring the secondary elevation of episcleral venous pressure down. The one new thing in that area besides treating elevated episcleral venous pressure is that our rho-kinase class of drugs seems to have some effect on the episcleral venous system and may open some of the episcleral venous system a bit, which could lower episcleral venous pressure. We may be able pharmacologically now begin to perhaps lower that. I think there’s still some work to be done in that area. But if it’s just normal episcleral venous pressure, the only way we have to possibly lower that is with a rho-kinase class of drugs. But if it’s secondarily elevated, then treating the primary cause can lower the episcleral venous pressure in that patient.
The next question is, is there any condition of aqueous over secretion? The answer is no. We really don’t have hypersecretion glaucoma. We only have over secretion relative to outflow. Anything that raises pressure in glaucoma is an outflow problem, not an overproduction problem. The eye just keeps making that two to three microliters per minute unless we give aqueous suppressants to lower it.
The next question. Does the aqueous humor rate change in eyes with glaucoma compared to normal eyes? And the answer is no. It keeps making it unless we, again, interfere with that by using drugs such as beta blockers or other drugs, carbonic anhydrase inhibitors, that would lower aqueous humor formation. But there isn’t a good feedback. If the eye had good feedback mechanism where the trabecular meshwork or something sense that the pressure’s too high and sent a signal to the ciliary body, well, turn down the faucet, the eye doesn’t need anymore fluid. But we don’t really have that kind of feedback it seems, or at least we don’t have that kind of feedback in glaucoma eyes. There’s loss of that loop.
More people with ophthalmic hypertension than with glaucoma? Prior the cause of glaucoma is not ophthalmic fluid but in the state of the lamina carbosa. Thank you, good day from Ukraine. Oh wow. First of all, thank you for joining us and I hope you’re safe if you’re in Ukraine. We are all watching and praying for the Ukrainian people. Hope that this war ends soon.
It is true that the majority of patients of individuals who have ocular hypertension don’t get glaucoma. Why is that? Well, there’s a lot of reasons probably for that. And it has to do with glaucoma is a very complex disease. Maybe it has something to do with their optic nerve being more resistant, some postulate that maybe it has something to do with their CSF pressure. The cerebral spinal fluid pressure, if it’s up a little bit and the eye pressure’s up, then the overall translaminar pressure gradient isn’t so great. And may even be normal. In low tension glaucoma patients, what’s going on there? Is it some weakness in the lamina carbosa? Is it loss of autoregulation and ocular blood flow? I think there’s a lot of things.
When we talk about glaucoma we simplify it way too much because it’s a very complex disease. Glaucoma is just this optic neuropathy. This characteristic form of optic neuropathy. What I like to tell our residents, not to go on a tangent here, is that the optic nerve can respond to insult in one of three ways, and that’s all it can do. It can swell, it can get pale, and it can cup. If I showed most, even medical students a swollen optic nerve, they’d come up with a big differential diagnosis of things that can cause optic disc edema, swelling, all the way from inflammation in the nerve to intracranial pressure and all sorts of things, tumors, big differential. If I showed them a pale, atrophic optic nerve, big differential of all the things that can cause them. You show them an eye with cupping and they just say glaucoma. Well, there’s obviously a lot of diseases that cause that optic neuropathy and I think we’re just beginning to be able to separate that out. Some of it’s going to be based on genetics and other things. And I think we’re going to understand a lot more. But there’s a differential diagnosis under glaucoma. It’s not just one disease.
Is there a postural change of aqueous secretion? Good question. I’m not sure that there is, maybe if you hung someone upside down by their feet for a while and you increase all the pressure around their head. Or what happens to astronauts when they go out into space they have this neuro ophthalmic system where they get cephalic fluid shift toward their head, does that change aqueous secretion much or at all? My guess is if there’s any effect it’s little and it’s probably limited and the eye compensates. But I don’t know the full answer to that.
The next question is, can you describe the basic mechanism of malignant glaucoma or aqueous misdirection as we more commonly call it? It’s a very complex question, actually. And I don’t think we yet fully understand all the factors that lead to it. But the basic mechanism is that aqueous humor flow accumulates in the vitreous and the vitreous volume increases. And therefore, fluid cannot get in relative amounts, it’s not absolute like a pupillary block would be if you had your pupil pretty firm. But over a period of time the vitreous hydrates more and more and it pushes the anterior segment structure forward, closes off the eye angle, and leads to a spiral of progressively increasing pressure because fluid can’t get out properly because it’s accumulating in the eye. The treatment for that, which wasn’t part of the question, is to get things reestablished. There’s a whole series of steps to do that. Oftentimes ending up just trying to convert the eye to a unicameral system. Because you can’t have malignant glaucoma or aqueous misdirection, unless you’ve got two chambers that are competing against each other. If you can convert the eye to a one-chambered system, then it doesn’t matter where the aqueous goes, it’s always going to go out in the path of least resistance.
During the gonio section, Spaeth classification seems very comprehensive. But during the PAS view and slit lamp, determining the angle seems difficult. Why not just document the most posterior structure in each quadrant and then details like PAS, et cetera, can be added? You do want to identify the most posterior structure. But you want to know why and that’s what the Spaeth System tells you. Is the most posterior structure that you can see visible because there’s a big bow in the iris at the periphery or because the whole iris is bowed forward because there’s PAS or not? The Spaeth System gets you into the mechanism of why you’re having trouble seeing what you’re seeing. You do want to know the most posterior structure, that’s the first part, the ABCDE of the Spaeth System. But then the rest of it is looking at the peripheral iris contour and the relative angular approach of the iris to the angle to help you figure out why. And it’s primary for angle closure, of course, but also can be useful in very deep angles and pigmentary or angle recession to some degree as well and other things. Just identifying the most posterior structure doesn’t tell you why, it just tells you what you can see. And what we want to know is why.
Next is diabetes-related glaucoma treatment please. Diabetes, first of all in primary open-angle glaucoma there is some associations where diabetes seems to be a risk factor. But that doesn’t show up consistently but it’s just primary open-angle glaucoma. You treat it like you would any. If you’re talking about complicated diabetic eye disease with neovascularization and bleeding and all of that, the primary treatment of diabetes-related glaucoma, number one is to treat the diabetes. And control blood sugar, do all the retinal treatments, laser, injections, steroid, VEGF, whatever it takes, to control the retinal disease is always the mainstay of glaucoma treatment. And then we treat the pressure so we get the patients when now they’ve already got glaucoma. If it’s neovascular glaucoma, you still need to do all the retinal treatments but most likely that’s going to require a tube shunt. I hope that answers the question.
Would you do gonioscopy on every patient as part of your standard workup, or is it a tailored procedure? My personal bias is that every new patient should have their angle looked at as part of their initial exam. We look at all sorts of things on every patient, why not look at their angle? If they don’t have glaucoma and they’ve got a wide open-angle, you don’t need to repeat it. But in glaucoma patients, the appearance of the angle can change over time. I think it is important in glaucoma patients to also do repeat gonioscopy maybe annually or every other year, or after any intervention that you’ve done or surgery to see what the angle is doing.
There was a study done in the US a few years ago by Anne Coleman that looked at glaucoma patients undergoing surgery. And over 50% of them had no documented gonioscopy ever billed for through our Medicare system, which was a shocking thing that half of glaucoma. We don’t know whether they were gonioscoped and it just wasn’t billed for. But we have a separate code where we get reimbursed for doing gonioscopy. I think it’s an important thing to do on every patient and important to do follow up gonioscopy in glaucoma patients.
Next question. We’ll do a few more questions. I don’t know if we’re going to get through all of them, unfortunately. But hopefully we will. Has anyone looked at what changes in aqueous composition before and after trabecular meshwork filtration? Do cytokines get sequestered in the TM? Great question. I haven’t looked at aqueous composition after filtering surgery. The problem with looking at cytokines and things in eyes that have had successful filtering surgery is that most often those eyes are on multiple medications preoperatively, which affects a lot of things and cytokines as part of them. And then post surgery, if they’re successful, they’re not on glaucoma medicines. There’s always the role of what the medicine is doing that’s difficult to account for. But it’s a good question and I don’t know the answer.
Next is, is there a system of standardizing the differences in hyperopic and myopic eyes in interpreting gonioscopy finds with Spaeth or any other system? I think the Spaeth System does a wonderful job in differentiating hyperopic and myopic eyes. Hyperopic eyes usually is going to be smaller eyes, there’s going to be more iris bowing. One of the characteristics of hyperopic eyes is that the lens/eye volume ration is a little bit off. The lens tends to be, take up more space in an eye. Hyperopic eyes tend to be small eyes but the lens tends to be normal size. And you can tell that by looking at the iris bowing and the angle of the iris and whether or not it’s enough to induce angle closure. But I think that’s a great way of doing it. There are also other systems that are using OCT, anterior segment OCT, to assess the angle, that I think are useful. I didn’t go into those systems just for time. But there are some interesting anterior segment OCT applications that can also help us understand the anatomy and physiology of the anterior segment and the angle.
Next is beta blockers are typically twice daily with long-acting gels or Tiopex, which is daily. Should we instruct patients to use this in the morning rather than at night? Most times beta blockers are prescribed twice daily, I don’t. I prescribe beta blockers once a day. It’s been shown that you don’t need long-acting gels. Back in the early days of beta blockers, they were equally effective once a day or twice a day in clinical trials, a long time ago. When I prescribe beta blockers, I prescribe them once a day in the morning. I think that’s what we should do for all patients. Because again, I think beta blockers have less effect at night and all it does is increase the risk of side effects. Beta blockers can lower your blood pressure at night, which normally drops at night anyway. Could that cause some perfusion issues with the eye? I think it’s an important question. I always try to minimize side effects and benefits. And I only use beta blockers, or try to, about once a day in the morning.
How many options do we have for treating closed-angle apart from iridoplasty? For closed-angle, iridectomy is the first choice. Iridoplasty, if it appears to be plateau iris. In other words, the central anterior chamber looks fairly deep, it’s not all bowed forward. You do an iridectomy, it’s still that way and the angle, then we can do iridoplasty. And then lastly, there’s increasing use of cataract surgery in eyes with angle closure especially if they have an early symptomatic cataract. I think we’re getting a little bit more aggressive about considering cataract surgery in eyes that have angle closure.
Can you throw more light on the use of carbonic anhydrase inhibitors and diurnal variation in aqueous production? Carbonic anhydrase inhibitors do decrease aqueous production and lower the diurnal production of it as well. It affects both day and night but there will still be diurnal variations because aqueous production will pick up in the morning. So as a percentage, it doesn’t completely flatten the diurnal variation, if that’s what the question is. It will blunt it to some degree and lower it but there’s still diurnal variation.
Next, are there any drugs to increase the intraocular pressure? Well, the most classic one is steroids. But that’s not a very good thing to do long term unless we need a steroid. There had been some other drugs that had been looked at without much success for eyes that have chronic hypotony, to try to reverse the hypotony by somehow increasing the aqueous production or doing something to the meshwork. But right now, no.
I think we’re getting down to the bottom of the questions. In my clinical practice, I encounter a majority of patients with VH grading one to two, but I’m performing gonioscopy the angle is found to be open. How can I rectify the situation, any suggestions from your end? I”m not sure what the VH grading is. Maybe that’s with the slit lamp? I think if you just employ, and you can look up the Spaeth Gonioscopic System or if there’s some way through Cybersight, I’m happy to share some of those pictures, slides that I showed with you. I think if you apply just a reproducible gonioscopic system you’ll be able to better manage.
The next question is, can you explain glaucoma suspect? Glaucoma suspect is a whole other talk. Patients can be a glaucoma suspect because of ocular hypertension, they could be a glaucoma suspect because they have a funny looking optic nerve, such as a myopic patient may have a nerve that looks glaucomatous but isn’t or may be congenital differences in the nerve. Or sometimes someone can be a glaucoma suspect because they have a field defect that somehow looks like it’s from glaucoma, but maybe from something else. Might be optic nerve bruising or some other cause. There’s a broad category of glaucoma suspect. The majority are ocular hypertensives, but there’s certainly others.
Can you explain the mechanism of resistance to, I think they mean maximum medical therapy while at the beginning it responds well to glaucoma drops? A lot of patients do develop resistance to therapy over time. Some of that can be compliance and they’re just not using the drops. But there’s true tachyphylaxis develops many of our medications. Beta blockers probably being the classic. About 25% of patients who are on a topical beta blocker for more than two years, the beta blocker stops working because they build up this drug resistance where it just isn’t effective anymore. And the other reason why glaucoma therapy fails over time is glaucoma gets worse. The outflow gets worse so the pressure goes up. And it’s part of the natural course of the disease.
I would like to know why prostaglandlogues are majoraly administered at night, are there specific reasons? First of all, it doesn’t have to be at night. It can be any time. The only reason why they were initially recommended at night was because they caused some hyperemia. By the morning it was hoped that some of that would be going away. But in terms of how the drugs work, and some patients have trouble using a drug at night because they fall asleep or whatever, they don’t go to bed at a specific time. What I tell patients the most important thing is to find that time during the day, whenever that is, that you’re most likely to use the drug consistently. Within an hour or so of the same time every day. Consistency is more important than the time of day.
Is there any damage to the eye when a non glaucoma patient uses a glaucoma eyedrop when he’s not supposed to. Not really. All of our glaucoma drops as they’re developed, they’re always tested in normal patients first, actually, just to develop some of the early phase one and two safety data. There is little downside to a patient getting a drop in. I even have some patients where I have a husband who’s on a prostaglandin and he gets really nice eyelashes. And his wife likes those eyelashes so they use his prostaglandin drop every once and awhile. No downside to it, really, but obviously no indication for it either.
Next is a long question. In case of a patient with visual acuity of hand movements because of macular scarring for more than 20 years and developed glaucoma, even after three kinds of topical medication, the IOP is around 30 with complaints of mild discomfort. The other eye is good. What is the next step for the right eye? Can we tolerate IOP because of the scarring and visual acuity? I would not. That’s a question of do you let an eye go because it has hand motion vision because of macular scarring. But what about the peripheral vision? Is that of use to the patient? What I do is I have the patient cover, when they have bad vision in the eye and we’re not really successful and how aggressive should we be with that eye. I tell them to cover that eye so they can’t see anything and say, “Would you miss that vision if you didn’t have it?” And it’s surprising how often the answer is yes. Because they’ve got a temporal island or some other peripheral vision that they rely on. Or I have them cover the good eye and say if you lost that. I have them test and you’d be surprised how often the answer is yes, they would miss that vision if that vision went to NOP. So then you go ahead.
Does changes in diet have any effect on aqueous secretion and development of glaucoma? Not that we know of. There’s really no dietary, we know that exercise can lower pressure, but nothing in diet that I’m aware of.
Does translaminar pressure in any way have a relationship with intraocular pressure? Not exactly. The translaminar pressure is just the pressure on the other side of the lamina. And it depends on what the pressure is in the CSF and in the intraocular pressure. Translaminar is just the relationship between those two but doesn’t affect the intraocular pressure.
Next was a thank you. Thank you very much for the thank you. (laughs)
How can some people react better to SLT to others? Because we’re all different. Laser trabeculoplasty, just like some people respond to medications better than others. We are different beasts, all of us, and that’s why we have to individualize therapy and unfortunately we can’t always predict before we do something, what the outcome is going to be.
Again, there was another nice thank you. I appreciate that. I appreciate everyone being on and we’ll close shortly.
What is your opinion on paired Schiotz rigidity using an indentation tonometer as a better measurement of IOT than GAT? I haven’t done Schiotz tonometry for years. I did do it 30-some odd years ago in patients and some studies. I don’t think it’s a better measurement, I don’t think it’s going to replace Goldmann. But I think we need better ways still.
Again, another thank you. Oh yes, good evening from Nepal, nice to see a second time. Thank you for joining a second time. Thanks for the interesting presentation, illuminating.
In your practice, which is the best drug for open-angle glaucoma? We really didn’t talk about therapy. But our usual first line drug is a prostaglandin today. That is the gold standard.
Next, what is the indication for shifting to surgical options? Once diagnosed, especially open-angle, should be managed surgically. Well, it depends on the patients. and we have studies looking at medications versus laser versus surgery as initial management and it depends on the surgery. We have no perfect treatment. I generally will start with medications in the majority of my patients and/or laser. And generally save surgery for if they’re progressing or failing.
I think the rest are thank yous. I think with that I think we will close this session. Again, I want to thank all of you for your attention. I hope this was useful and you gained some useful information to help with your patients. Thank you very much.
March 25, 2022
4 thoughts on “Lecture: Glaucoma, Back to Basics: Aqueous Humor Dynamics, IOP & the Anterior Chamber Angle”
Great lesson. Thanks so much for the lecture
excellent presentation. covered most of the practical aspects.
great presentation thank you very much
It was clear and understandeble presentation I got many things about Glaucoma