Ophthalmology

Overview

Mayo Clinic Ophthalmology glaucoma surgeons discuss updates on glaucoma therapies, including medications, minimally invasive surgery and management of the ocular surface.

Speakers:

• Syril K. Dorairaj, M.B.B.S., M.D., Ophthalmologist, Mayo Clinic
• Cheryl L. Khanna, M.D., Ophthalmologist, Mayo Clinic
• Dave R. Patel, M.D., Ophthalmologist, Mayo Clinic
• Gavin W. Roddy, M.D., Ph.D., Ophthalmologist, Mayo Clinic

CHERYL KHANNA: Good afternoon and welcome. Thank you for joining us today for the Update on Glaucoma Therapies webinar. I'm Dr. Cheryl Khanna, an ophthalmologist and glaucoma and cataract surgeon at Mayo Clinic in Rochester, Minnesota. And I will be your moderator and one of the presenters for today's discussion. We are also very glad to have you with us today.

During today's presentation, you will hear from myself and three other board certified, fellowship trained glaucoma surgeons from our Mayo Clinic locations in Arizona, Florida, and Minnesota. Each speaker will present for about 10 minutes. We will then have time for a Q&A session at the end. With that, I'm glad to introduce our first speaker today, Dr. Syril Dorairaj. Dr. Dorairaj is an ophthalmologist and glaucoma and cataract surgeon at Mayo Clinic in Jacksonville, Florida. Dr. Dorairaj is speaking to us today about minimally invasive glaucoma surgery in the suprachoroidal space. Welcome Dr. Dorairaj.

SYRIL DORAIRAJ: Thank you, Cheryl. Thank you for the introduction, and thank you for moderating this session. Well, to start off, I would say that we are in one of our best times in our career, especially while taking care of our glaucoma patients. I have experienced a little more than 30 years, I've been taking care of glaucoma patients. I have more opportunities and more options to treat our glaucoma patients and give them opportunity just to choose more than what I had started initially 30 years back.

So 30 years back, probably like in 1997, this is what I used to do. I used to do just trabeculectomy. This is, towards the left side, my dissertation comparing 5-fluorouracil and mitomycin C, while doing trabeculectomy. So for mild, moderate, severe glaucoma, standalone, or along with cataract, this is the only surgery that I would do in 1997. Trabeculectomy, trabeculectomy, trabeculectomy. But, it is by far one of the most successful surgeries by efficiency. It's one of the most successful surgeries that I've seen in my entire career. But unfortunately, when I came here, there was a balance of safety and efficacy.

And so, a lot of new surgeries were introduced, something called MIGS, that's called minimally invasive bleb based surgery. There are two new devices were introduced, something like XEN and pressure flow. Pressure flow is not approved by FDA. But these two surgeries tried to mimic trabeculectomy and glaucoma drainage device. But again, the problem is it had the same complications as if you are doing a trabeculectomy. Almost 9% of this patients in their lifetime would have vision threatening complications. It would go to an extent, like within days, they will lose everything we worked for in our entire lifetime.

So that's where the concept of MIGS, that's the minimally invasive glaucoma surgeries, came into picture. The first is the angle based surgery, this was introduced, it's called the trabeculectomy in 2008. And from 2008 until now, then 15 years, there is a lot more options that's available for now. These angle based surgeries it can be cutting the angle, or excising a piece of trabecular meshwork, or having a trabecular meshwork bypass devices itself.

So basically what it does is it uses the conventional pathway. Conventional pathways, we think, that the major point of resistance is the trabecular meshwork. And once we bypass the trabecular meshwork, we have access to the Schlemm's canal. And then from that Schlemm's canal, we go to the distal collector channels. So that is the conventional pathway where 40% to 60%, I would say, the outflow pathway is dependent on.

But if you look at what this angle based surgeries [INAUDIBLE], this is my office. I took a picture just to show there is so many new devices that's been coming out in since last two years. If you have to do a goniotomy, you have five or six of them. Unfortunately, we don't know which one works how, where, and where exactly the resistance is, what is that we need to do to make the outflow channels work better in these patients.

But if you actually look at this diagram, where-- if you see from this orange line picture, to this to this, from scleral spur to Schwalbe's line-- it's like around 500 microns. The entire, all these devices that I showed you, kind of like, clumps together in this 500 microns. You have to be extremely precise, if you want to have a predictable outcome.

If you are doing a surgery, say, if you are doing a trabecular bypass stenting, you need to focus on going into the Schlemm's canal and placing that device exactly in the Schlemm's canal to have the right outcome. But unfortunately, if you look at the safety and efficacy, it has become more safer. But unfortunately, it's the efficacy is kind of like compromised. Basically, because we don't know where exactly the resistance is, and also we don't know whether the procedures that we are doing is doing the exact thing. Like, if you are trying to place the device in the Schlemm's canal, we are not accurately sure that if we are placing it in the Schlemm's canal. So that is the problem.

And also, all this angle based surgeries, which depends on opening the Schlemm's canal and the other routes, is dependent on the episcleral venous pressure. So in severe glaucoma, where the pressures have to come down in almost like less than 8 to 10, something like that, it's very hard for us to go to that point.

So in our updates on glaucoma therapy, this is where I want to go and touch base on. Probably we know the MIGS in the supraciliary region. Any MIGS that's placed in the supraciliary region doesn't conform to the limitation of being limited by the episcleral venous pressure. But you have to understand, this surgery that is creating a cyclodialysis cleft was like actually was done in 1900s. Previously it was tried, but basically because it causes fibrosis, it didn't come into picture.

So it has other advantages, especially when you are considering suprachoroidal space, the suprachoroidal space itself as a negative pressure gradient. So it is like around 4 millimeters less than the anterior chamber, so that any fluid in the anterior chamber just gets sucked in into the supraciliary space. The interstitium of the ciliary body is like a sponge. It absorbs the aqueous, and then pushes into the supraciliary, and then it goes into the suprachoroidal space. So the actual dimension-- it's like if you look at the trabecular meshwork, if you are taking a Kelly punch and just punching one or two, and then when you compare it to the surface area, it's almost like 160 times more area where the fluid can drain out. And more volume it can accommodate.

And we also have evidence from proven evidence before, that prostaglandin analogs, which depends on the outflow system with the uveoscleral outflow, is one of the most effective therapies that we have currently available. So based on this, so we need some device, or some procedure in the supraciliary space where it is not bleb dependent. Because bleb is like a ticking time bomb. Anything can go wrong. It might not work. You need to keep doing some work to keep it working. And we also know it has an hypotensive potential. There is, compared to traditional filtering surgery, it might have, but like it's not proven with any randomized control trial that it might be much more safer. But, the other major point is there is no bleb, so the surface of the eye is far more comfortable. The quality of life for the patients is better. Dave is going to touch base on that.

So, based on this, in 2016 CyPass was introduced by the FDA. So I'm going to show you a case that I did in 2016. I had an opportunity to treat on a patient, 80-year-old, ICD 10 classification, moderate glaucoma, pressures of around 22, and two medications. I went ahead and did a CyPass, placed the CyPass in both eyes, took out the cataract. And you can see, the CyPass was placed exactly where it needs to be. There were two rings, one of the rings has to be at the scleral spur and then it should not be protruding into the anterior chamber.

And if you see the other pictures, like here, most of the surgeries that I do, I take some pictures-- this is the transverse curves towards the left side-- to show where exactly the rings are, and then the supraciliary space where the fluid is collected. But if you notice, any-- if you make a cleft, if a cyclodialysis cleft, even if it's one clock hour, the fluid goes 360 degrees. Everywhere you will see fluid around.

So, unfortunately, what happened, this is the email that I got from FDA. 2018, it was withdrawn. So the device that we are thinking that we are looking as a possible potential to be used in the future, we tried it. We tried CyPass, and then they withdrew, because of endothelial cell loss.

This is my patient after 2017. The patient came back last week. Two weeks back, the patient came, and I took the endothelial cell count and compared from the pre-op to the post-op. And as you can see, there's not much of changes. According to FDA, the endothelial cell loss should be more than 30% to say that this is not good for our patients. But, remember, any procedure, any MIGS Schlemm's canal based, any device that you do, if it's done accurately, you won't see that a side effect. But it will also have the best benefit. That's what I'm trying to reach.

So, we learned quite a bit from CyPass, what's the problems. It should not protrude. We needed something which is much more softer, which can avoid endothelial cell loss, and also prevent fibrosis. And currently, there are three devices being evaluated from the FDA.

One of the device that probably you might be seeing in next few years, two to three years, is MINIject. So this is a device that's been approved in 2017, and they got the CE mark. And this is basically a medical grade silicone, where they use the pores. They create pores, so that there is a fluid flow unidirectional from the anterior chamber into the supraciliary space. It's almost like 5 millimeters in length. It's like around 1 millimeter wide, and then around 0.6 millimeters like around in the eye. So it can be used as a standalone, and so there's quite a bit of data available over that.

And you can see these are some trials that's been done, STAR-I, STAR-II, STAR-III. They had like around 66 patients and almost 77%-- they looked into almost three or four years-- and they looked at the efficacy. The pressure dropped from around like 23 to like around 15. It's almost like a 35% pressure drop. And the most important, towards your right side, you will see medication free patients. We forget, when we are thinking of just reducing the intraocular pressure, we also have to think, how many of these patients can go off medication and can they be stable. This is one of the very important part. Medication associated with glaucoma treatment can have a lot of problems. And so these are the other trials that's been conducted, and they have little more than three to five years of data.

And most important point is to compare the endothelial cell loss. And what we noticed compared to other devices, like the XEN, pressure flow, even the trabeculectomy, it's like around 6% to 9%, which is almost the same. What is the difference? The difference is the material itself. Instead of having a tube where the fluid drains continuously and it can suck these cells around, this device, which has like micropores, can help prevent the loss of endothelial cells in the long run. The other thing is it can also prevent fibrosis, because it's kind of like bio integrates with the eye. So like it's better to use a device which can cause less fibrosis. Because in our glaucoma surgery safer trab, or any surgery that we do for trab-- mean glaucoma-- fibrosis is one of the biggest problems that we face.

So having said, that where does it fit in? Because when CyPass was introduced, they gave it to cataract surgeons. So now they are thinking, probably as a standalone from moderate to severe, where you want to avoid bleb based surgeries. Where you want to have less complications, or keep the trabecular meshwork for later. Probably, you can try something like AB internal like this. But still now, there is a lot of studies being going on, FDA is trying to get around 350 patients' safety data for three to five years looking at the endothelial cell loss and also to prevent fibrosis.

So I think, probably, if you are thinking of an update in glaucoma therapies, we have a lot of MIGS that's already there for a little more than 15 years with data, variable data, especially saying it's much more safer. But efficacy wise, like we always compare with trabeculectomy which is, yeah-- with nothing can bring down the pressures to single digits. So this can be comparable to trabeculectomy, because it's not confined to limitations of episcleral venous pressure. And also the main advantage is the surface, you don't have a bleb, and you don't have to worry about long term endophthalmitis and other problems related to bleb. So this is some potential, and currently, we are doing a lot of studies on it. Probably, you might see in your practice in the next few years. CyPass might come in a different way.

Thank you. Thank you, Cheryl.

CHERYL KHANNA: Thank you, sir. Next, I will be presenting about when MIGS is not enough.

So as Syril mentioned minimally invasive glaucoma surgery has many advantages. They're less invasive, potentially lower risk profile, and many patients have a faster visual recovery. I want to point out a few scenarios when MIGS may not be appropriate, however. They may be less effective for a shorter period of time, and MIGS may not treat the specific glaucoma diagnosis at hand. In addition, in patients with advanced disease, MIGS may not lower the pressure adequately. Across the Mayo enterprise, our glaucoma subspecialists offer many MIGS currently, including selective laser trabeculoplasty, iStent, Kahook, Hydrus, canaloplasty, XEN, and in the past, as Syril mentioned, Trabectome and CyPass.

Today, I want to point out a few scenarios when MIGS may not be appropriate. For example, I saw 40-year-old woman who was referred with elevated intraocular pressure after having a selective laser trabeculoplasty in the right eye. Unfortunately, after the selective laser trabeculoplasty, she had a dramatic rise in her intraocular pressure. And on exam, on gonioscopy, she was noted to have peripheral anterior synechiae and many iris nodules in the periphery. She had a diagnosis called ICE, or Cogan-Reese syndrome, which was not amendable to an SLT. Fortunately, she went on to have a Baerveldt and did very well.

So selective laser trabeculoplasty, which is a very common MIGS that many of us use, is appropriate in patients with open angle glaucoma, secondary open angle glaucoma, such as exfoliation and pigmentary glaucoma, and we really use it for any stage of glaucoma, including as an initial therapy. SLT is also very effective for patients with steroid induced glaucoma. I tend to avoid SLT, however, in patients with neovascular glaucoma, ICE, as in the example that I provided in my patient with Cogan-Reese syndrome, inflammatory glaucomas, in patients after trauma, patients with aphakic glaucoma, and patients with angle closure glaucoma.

So I want to encourage everyone to treat the specific diagnosis and think about whether MIGS is appropriate. For example, this is a second case of a 58-year-old woman who was referred for elevated pressures at 27 in the right eye, and 40 in the left eye, and maximal medications topically. Of note, she had a history of high myopia in both eyes.

You can see on these slit lamp photos that she had a peripheral iridectomy and-- a peripheral iridotomy in both eyes. This patient did have cupping in her left eye, as well as retinal nerve fiber layer thinning in the left eye. Of note, her specular microscopy revealed a normal endothelial cell count, as well as normal endothelial morphology. She did have a mild glaucoma-- glaucomatous visual field deficit in the left eye. And so upon presentation, I thought, was this patient a mixed candidate? But first, why did she have a peripheral iridotomy in both eyes?

The answer was really in a test called ultrasound biomicroscopy. I obtained this after I looked at her angles on gonioscopy, and her angles were open. And because it wasn't clear why she had these performed, and she was a high myope and really should have open angles, it was noted that she had aphakic IOL, which wasn't actually evident on her slit lamp exam due to poor dilation. So she had her natural lens, as well as aphakic IOL with elevated pressures that were uncontrolled on maximal medications.

As we know, there's many mechanisms for glaucoma and patients with phakic IOL. In our patient, the mechanism was uveitis glaucoma hyphema syndrome. The phakic IOL was rubbing against the posterior, pigmented epithelium of the iris, releasing pigment and causing inflammation and elevated pressures which were uncontrolled. Phakic IOLs may also result in angle closure, inflammation, pigmentary glaucoma, or steroid induced glaucoma, since many of these patients have chronic inflammation necessitating steroid use chronically.

So in this patient, I offered cataract extraction, I removed the phakic IOL, and also placed an eye stent at the same time in both eyes. And fortunately, when the mechanism of the glaucoma was addressed, she had 2020 vision and normal pressures without glaucoma medications. So I encourage you to treat the mechanism of glaucoma, and sometimes MIGS does not allow us to do that.

Another example when MIGS was not quite enough is a 63-year-old woman who has open angle glaucoma, and I did place a XEN in this patient. Unfortunately, despite lowering the pressure from the mid 20s to the teens, she continued to progress by visual fields. After XEN needling, which was unsuccessful, I decided to remove the XEN and perform a trabeculectomy with mitomycin C, which fortunately was successful in lowering her pressure into the low teens and her glaucoma stabilized.

Similarly, I saw an 85-year-old woman with severe open angle glaucoma, who had pressures of 33 and 35 on presentation. She was on five topical medications. And her visual field revealed severe glaucoma and visual field loss. So in this patient, really performing MIGS would only delay definitive treatment, and she did well with trabeculectomies in both eyes.

Finally, I saw a Sturge-Weber patient who was a child, 14-year-old international patient, and she had received a Baerveldt locally. Unfortunately, upon presentation, it was noted that her Baerveldt tube was anteriorly positioned, and she had decreasing endothelial cell counts with an anterior located tube in the anterior chamber. Her pressure was also uncontrolled.

You can see on the slit lamp photo that her tube was anteriorly displaced. And this is a poor photo of her optic nerve-- photo of her optic disk appearance, but she was quite cupped in the involved eye. And this is specular microscopy, which demonstrated abnormal morphology of the cells, as well as a decreased endothelial cell count in the involved left eye.

As we know, there's a high bleeding risk with MIGS in Sturge-Weber patients. And I also wanted to avoid repeat general anesthesia in a child. So I went to a more definitive solution and I pursued cyclophotocoagulation, as well as placing the tube in the sulcus to protect the cornea and hopefully delay, or even avoid, a corneal graft down the road.

So in summary, the treatment for glaucoma should be based on the specific diagnosis. And at times, MIGS may not be appropriate or address the specific diagnosis. Gonioscopy and ultrasound biomicroscopy may be key to diagnosis and surgical planning. MIGS at times, however, can be combined with other procedures for better intraocular pressure lowering. In cases of advanced glaucoma, consider non MIGS interventions, such as trabeculectomy and glaucoma drainage devices.

Thank you.

So next I'm very happy to introduce Dr. Gavin Roddy. Dr. Roddy is an ophthalmologist and performs cataract and glaucoma surgery at Mayo Clinic Rochester. And today Dr. Roddy is discussing sustained release drug delivery for glaucoma. Welcome, Dr. Roddy.

GAVIN RODDY: Thank you, Dr. Khanna. So, as already has been discussed today, different treatment algorithms for glaucoma have been laid out, from drop therapy, to laser intervention, to MIGS, to incisional glaucoma surgery. Well, we still have many patients that progress in spite of these multiple therapeutic options. So what is the state of-- the current state of pharmacologic treatment for glaucoma?

Less than half of patients take glaucoma medications as prescribed. And this may be due to voluntary compliance issues, such as managing the various dosing regimens of the prescribed medications, to involuntary compliance issues, in that up to a third of our patients for anatomic reasons aren't able to adequately instill medications, from things like manual dexterity issues, to cervical spine issues.

Furthermore, fluctuation in pressure also contributes to glaucomatous neuropathy as an independent predictor. Our current approaches, we might give a drop once a day, up to four times a day, with a single bolus of medication. And so there is certainly a waning of drug dose. Furthermore, missed doses contribute to fluctuation. And as well, none of our current pharmacologic classes are able to really reduce diurnal curves, which contribute to fluctuation and progression. And finally, as will be discussed in the next talk in much greater detail, over half of patients taking glaucoma medications have ocular surface disease.

And so, when defining successful drop installation as not touching the tip to the ocular surface, instilling one drop and having the drop actually reach the ocular surface, anywhere from one quarter to one third of patients are able to successfully instill a medication. In my practice, if I have a patient that is unresponsive to two or more different classes in a row, I'll actually ask the patient to demonstrate instillation of a medication in clinic. And it's often a very sobering experience, in that we assume when we write the Rx that the drug will actually reach the patient's ocular surface, but many times that is an assumption that is not valid.

And so, I do believe that the medical management of glaucoma is headed toward this goal of sustained release, of sustained IOP reduction with minimal therapeutic treatments. In order to improve compliance, reduce fluctuation, and ultimately decrease progression, decrease blindness, and perhaps, decrease need for surgery.

And so anatomically, there are some different options that allow potentially a provider to provide a therapeutic that can be eluted in a sustained fashion. And so, with contact lens approaches, and most of these are still in experimental phases, but as one might imagine, when a topical drop is instilled, the contact time on the ocular surface is minimal, such that less than 5% of the drug is bioavailable. A contact lens approach, if a drug can be placed and then slowly eluted, can increase contact time and the viability can bioavailability can increase tenfold up to 50%.

Problems with contact lens delivery has been drug loading into the platform, as well as ocular optical clarity, and then of course, other issues inherent with contact lens use, including infectious keratitis and dry eye. Punctal delivery systems have also been approached scientifically and are not quite ready for prime time. But one of the reasons for this is that in current systems, only low drug doses can be loaded into the punctal delivery systems, making at least at the current time, prostaglandin analogs, but perhaps, the more useful medication class. And like other punctal occlusion approaches, side effects can include discomfort and epiphora.

Perhaps a quite hot topic moving forward are periocular delivery systems that might include subconjunctival approaches using various implant systems, microspheres, or even liposomes as various delivery vehicles to slowly release drug. And perhaps, really the two prototypes that I'd like to discuss just in a little bit more detail that have more data behind them are approaches using the conjunctival fornix with the bimatoprost ring in particular, and then the anterior segment approaches with the intracameral injection of Durysta. So we'll talk about those in a little bit more detail.

So the bimatoprost ring is available in different sizes, from 24 to 29 millimeters in diameter. The cross-sectional thickness is 1 millimeter. And there is a polypropylene center support structure, surrounded by a silicone matrix that is loaded with bimatoprost. And this can provide IOP reduction for up to six months per application. And you can see, down at the bottom, the schematic of inserting this, such that when the device is fully inserted, it's really only visible to a small degree at the medial canthus. One great advantage of this type of approach is that it's preservative free. And so our patients that are limited in their topical medication usage due to preservative allergies might benefit greatly from an approach like this.

There has been a Phase 2 study completed, and the results are promising with IOP reduction. All of the metrics did not fully meet non-inferiority compared to timolol, but it was suspected that this may have been a sample size issue. And another quite positive set of data from this round of experiments, compared to prior approaches of drug eluting devices in the fornix, there was much greater retention rates of this device in the 90% range, even at six months.

The bimatoprost implant, also known as Durysta, is FDA approved. And a single use, 28 gauge applicator-- you can see the size of the implant in reference to a coin-- is used to inject this biodegradable implant into the anterior chamber. Typically, on gonioscopy, these are visible in the inferior angle. And after injection, the device does tend to swell before it slowly, completely breaks down. And it is biodegradable, and does actually break down into CO2 and water.

Phase 3 data has been published, and this did show non-inferiority to timolol through week 12. Of particular note, an advantage is that both periorbital side effects and ocular surface side effects that had been previously observed with topical prostaglandin analogs, were not seen with this approach that places the implant directly into the anterior chamber.

We should note, however, as Syril mentioned with CyPass, in this post CyPass era, I think we were all quite concerned with corneal endothelial cell loss. And in the bimatoprost implant group that was seen in a higher proportion compared to the topical timolol group. Furthermore, being a prostaglandin analog, higher rates of uveitis was seen as well.

And so, sustained release approaches to IOP reduction certainly have the potential to reduce disease progression by minimizing IOP fluctuation, by improving patient compliance. And the leading candidates to date both elute a prostaglandin analog using a scaffold, one in the conjunctival fornix and one in the anterior chamber. And I think these approaches are very promising. Whether these two in particular are sort of proof of principle, and there might be newer approaches, including types of scaffolds, locations, or even drug eluted. But certainly, it's a very encouraging proof of principle for our patients that we might be able to minimize disease progression by improving compliance and reducing fluctuation.

Thank you.

CHERYL KHANNA: Thank you, Dr. Roddy. I'm happy to present our last speaker this afternoon who is Dr. Dave Patel. Dr. Patel is an ophthalmologist and performs cataract and glaucoma surgery, as well as corneal transplants at Mayo Clinic in Phoenix, Arizona. Dr. Patel is discussing the management of ocular surface in glaucoma patients. Welcome, Dr. Patel.

DAVE PATEL: Thank you, Cheryl. Very much honored to be here with my colleagues and learning a little bit as we go along. I'm the cleanup hitter, as they call it, and I have the driest topic. But it is a passion of mine, dealing with anterior segment and certainly some of the Renaissance in glaucoma that we're happy to be part of, as Syril was pointed out. And just as sort of a background, I finished training when Xalatan hit the market. So it's sort of a long ways back.

But we were so excited. We had a new class of drugs, highly potent, different mechanism of action, and I thought that was a game changer that everybody should be first line on Xalatan. Fast forward now, we're talking MIGS and we're seeing some of the detriment over the years, decades I would call it, of the side effects that we weren't aware in the beginning and the onset. So, we'll talk a little bit about the issues that we're experiencing.

So as we know that dry eye is an aging process. We deal with it commonly with our non glaucoma patients. But add to that the concept of glaucoma, which is also an aging prevalence, and you combine the two. So it's sort of a bad mix having dry eye and glaucoma. And in essence, there's a higher prevalence, but when you look at studies, universally they show that the glaucoma-- the dry eye situation is exacerbated with glaucoma and glaucoma treatments. So the conclusion is that the treatment of glaucoma induces or exacerbates dry eye disease.

And looking at that some of the highlights, or the pertinent studies showed that there's an increase in corneal staining, which is a risk factor and certainly a marker that we use in the clinical setting. But in addition to that, identifying the causative agent, most notoriously, the toxicity from preservatives and the topical medications that the patients are subjected to. BAK being the primary culprit, which has led to the development and advancement of preservative free formulation, the injectable medications that Gavin has mentioned, and slow release formulations that are at least investigated. But, you know, I want to highlight some of the direct and indirect mechanisms that contribute to the unstable ocular tear film.

So let me just show you a cartoon here. Biochemistry of tear films. So we kind of know the three layers of triple layer sandwich we call it. We have the lipid layer, the aqueous, and the mucin. Now, what glaucoma treatment-- topical glaucoma treatment-- does is it affects all three layers. Sometimes directly, but mostly I'll talk a little bit about the indirect mechanism.

So the lipid layer, predominantly from meibomian glands, when you have prostaglandin use, inflammatory disease leading to dysfunction, myoglobin gland deficiency, so you lose the lipid layer. Chronic BAK has been shown to cause goblet cell density loss, which is a primary component to elicit the mucin layer, so you lose that. And then the aqueous layer is typically the detriment with chronic, lacrimal gland dysfunction, or inflammation within the lacrimal gland, which is a precursor to aqueous deficiency. So you've got sort of all three hits in one way or another with topical medications.

We have some tools at our disposal. Quite commonly, and if you're not utilizing it, I highly recommend just looking at the surface of the eye and having the patient blink, and you'll see tear breakup time. In addition, again aging myself, we had to carry a bottle of rose bengal during our cornea fellowship. And staining every cornea, these patients left the office just beat up red. So that's all past now. The nice thing is that lissamine green is a very well tolerated stain. It's just-- I put a little anesthetic on this paper strip, dip it into the eye, and it washes away pretty readily. But you do see enhanced conjunctival disease, as well in addition to the corneal staining. So my preference is lissamine green.

Of course, if you have none and you can look at fluorescein staining, that typically will be more evident in severe dry cases. If it's mild, you may not pick up the staining with fluorescein. And then quite commonly, if you just watch the patient in consultation and look at their blink rate, you'll notice that some patients will have a poor blink rate, and that's exacerbating their underlying condition.

Objectively, we do Schirmer's testing, which is quite time consuming, but that is an objective means, especially for research protocol that we can analyze the Schirmer's testing. And of course, osmolarity and MMP testing is also a very good objective means of isolating the severity, or at least the stage of dryness in a patient, especially with glaucoma treatment.

One of the questionnaires that was popularized and still in use, but we've moved to the speed score, is the ocular surface disease index, OSDI as we call it. It looks at 12 questions, they're divided into three sections. One is based on symptoms. The other is vision and vision function. And the last is the environmental triggers causing their symptoms. So it's a subjective test, patients are asked to fill out the questionnaire, and they will give you a score relative, and categorize them as a low dry eye, or severe dry eye patient according to their test results. That is an objective means, or at least subjectively, to identify if their treatment or progression is identified.

I want to focus the tail end of it to the mechanism of glaucoma, which is still evolving in my mindset, but I've really grown into understanding it a lot more in depth being a primary surgeon now for glaucoma. And even when my glaucoma surgeries fail, I question, what is it, what could we do better, and how can we get ahead of the game. But, we have to think about our understanding of glaucoma and dry eye, and the common variable is inflammation.

So if you buy into the theory of inflammation leading to detriment of collector channels, trabecular meshwork dysfunction, obviously conjunctival fibrosis, that in itself can be exacerbating-- the treatment itself can be exacerbating the disease. So topical medications with their preservatives over a prolonged period again, it's not seen in the initial stages. But I think long term, you're talking about patients who've been on drugs 5, 10, 15, 20 years, even from the pilocarpine and timolol days, we still see them in their 80s and 90s, now.

But the inflammatory effects of prostaglandins, I think have accelerated, or at least increased that propensity, which is resulting in a lot of dysfunction in the meibomian gland, and leading to the evaporative dry eye state that we see on a clinical basis. But the poor tear film induces the optical disturbance, and that leads obviously, to patients having more difficulties with their day to day functioning and OSDI worsening.

This is a very complicated tree, but I want I want everybody to see where I see it from. And why I have a bias for intervention, or surgery potentially moving up to the scale of first line, as in the CIGTS study, if you will recall. So as you see at the top of the spiral, it's the initial stages where there's very little inflammation, and patients are given trabecular meshwork and high IOP. You introduce IOP lowering agents. Well, that triggers an inflammatory response, BAK effects, long term therapy.

Now you've got ocular surface disease, which induces more inflammation. So not only is the drug treatment, but now the reaction from the drug, the chronicity of use induces ocular surface disease creating more inflammation. So now you've got this downward spiral, as you can see. This leads to progressive toxicity, TM changes and TM damages, and inflammation further increases in the deeper tissues of the eye. Now you induce resistance to outflow, you're forced to add more medication to offset the rise in the pressure. Again, it feeds into the inflammatory cascade, and creates more progression of glaucoma. And then you get uncontrolled IOP, or very little benefit with drugs, and you you're forced to at least at this point, offer surgery.

Now, as we've talked about MIGS and the traditional surgery, as Syril started the conversation with 5-FU and mitomycin, well, we still resort to that, because unfortunately, that's the last resort. And the challenges are these patients who've been prolonged, or treated for long periods of time with these topical medications, do poorly with surgery versus a virgin eye who has an initial surgery. So that's where my bifurcation is, is the failure rates that we're starting to see with some of the therapies in patients who have prolonged use of topical medication. And in doing so, it really highlights some of the biomicroscopy, is a very good illustration of inflammation.

As you can see in the staining, there's a top left A panel, which has dendritic cells, or fibrotic cells, within the cornea with topical treatment and chronicity. And you'll get the staining pattern similarly in the slide B, where vimentin is the identified agent seen in histologic tissues. And you see that in the cornea, which is commonly seen in vivo, but you can also see it in histologic slides involving the trabecular meshwork which is panel C, where you get inflammation within the trabecular meshwork.

Now, these are patients who are treated long term, and you can see these inflammatory markers lighting up in the beginning, or at least drug therapy stages. And it leads to the spectrum. We have the spectrum of glaucoma, early, mild, moderate, and severe. Well, this is a spectrum of inflammation, if you want to call it. And it's overlapped with the propensity of glaucoma and severity of disease.

So you'll see on the top bottom left, you'll have microscopic, or histologic inflammation. And these patients are asymptomatic. They're doing their drops. They're on target pressure. Their glaucoma is on a plateau. We're not seeing any progress. Then you get the turbulence where the inflammation is beyond the scope of containment. You'll get mild symptoms. You'll get clinical signs of surface disease with corneal staining, conjunctival staining. So now, you're already behind the curve. That's what I think. I think that this reaction that we see in a clinical level is beyond our understanding, because it's happening at the cellular level.

Further on, as this develops, patients will be more symptomatic. We initiate treatment. Of course, multitudes-- a whole hour can be spent on management and treating dry eye disease with various modalities. But again, preservatives are going to be involved, artificial tears are preservatives, unless you're specifically doing preservative free. So you may be enhancing this cascade. And of course, as it develops and worsens, and age is again fighting against us, because now these patients are 10, 20 years older, you get severity of DED. So now you've got a really inflamed eye, and you have to entertain surgical treatments, which obviously create more risk, given that they've had chronic inflammation for prolonged years of use of topical treatment.

So it loops us back to, what do we consider. How do we evaluate managing a glaucoma patient who we already know are going to create dry eye. And so my considerations and food for thought, and I know we're doing a Q&A after this, but these are sort of possible scenarios where I would introduce the, I think, overall acceptance of SLT before meds. They've had robust safety data, efficacy data. And it's not uncommon that most patients are offered laser prior to meds, at least that's what I've been implementing. Of course, there's a discussion with the patient and their risk tolerance. But I do think that laser therapy would be a very good first line treatment, before drugs are introduced.

Having said that, when and if these things evolve, do we use meds as a bridge to surgery? Say, well, ultimately, surgery might be the best option, especially in an early stage, or virgin eye versus a eye that's had chronic treatment and it's progressive. So that's a debate that I think in the glaucoma world it's ongoing, but that's certainly something to consider until we can get the patient to a safe place or surgical stage. Meds can be used as a bridge with the ultimate endpoint of surgery.

The nice thing is that the MIGS are demonstrating at least a relatively good duration. Cheryl's pointed out some of the limitations, even despite the excitement that we're having. They're not always, they're not-- nothing's 100%, of course. But are there options unique to the patient, to the eyeball, to their disease state, to their stage in life, that can alleviate the drop burden and the side effects and the issues that dry eyes brings along with it. Demonstrating that MIGS could be a therapeutic intervention early on.

And I think lastly, and certainly something that we tend to do a lot more is, just like glaucoma is a very difficult condition to explain, or at least have patients-- you don't feel it, but dry eyes, you feel. People experience that, and it's symptomatic. So they don't equate the severity of glaucoma with severity of dry eyes readily. But you have to partner with the patients to understand that their treatment may be exacerbating the dry eyes, and we need to focus on both arms of their treatments to alleviate their day to day visual needs. Importance of ocular health may be omega fatty acids, hot compresses, lid hygiene, topical steroids to quiet down inflammatory markers. So those are, I think, ongoing ideas and areas of investigation into better manage some of the dry eyes that we're creating using topical medication.

So I leave that to the Q&A, but I appreciate the time and thank you for your attention.

CHERYL KHANNA: Thank you very much, Dr. Patel. So at this time we have a few moments for questions. And feel free to submit any questions that you may have. Maybe I'll ask Dr. Dorairaj about suprachoroidal space devices. We certainly have many comprehensive ophthalmologists who are interested in performing MIGS and maybe considering different devices. How would you advise them about suprachoroidal devices? Do you think that should be in the skill set of comprehensive ophthalmologists? Do you have special words of wisdom, or advice for comprehensive ophthalmologists who may be considering these steroidal devices that are soon to be on the market?

SYRIL DORAIRAJ: That's a very good question, Cheryl, because everybody has a different way of learning things. Some people just like during their residency might have done a few cases, here and there. And then once they come into practice, they can start doing their stuff on their own. Just because some industry is coming there, and then they're asking, let's do a new mixed device. And they will say let's do 10 devices, and then go ahead and let's start doing it.

People who stand on the podium and then they speak about their experience are extraordinary surgeons. But I'm an average surgeon. If you ask me a question regarding suprachoroidal device itself, we learned something from our previous experience with the CyPass. When CyPass was introduced, it was like graded for mild glaucoma along with cataract surgery. So what happened, people who used to do cataract surgery, we had no evidence of dealing with the angle, or dealing with any problems related to the suprachoroidal hemorrhage, or fluid, hypotony related problems. They had no clue about it. It's not only just doing the surgery, it's most easy. Like doing a surgery is like most easy, but dealing with the complications, dealing with what it comes after, having some problems is more important for us. This is where we need that support.

CyPass, in a matter of like two years, people started putting so many, and it started they started noticing changes in the endothelial cells. Because most of them, they didn't get a proper training. They had-- some people have a different learning curve compared to other people who have already working in the angle base. People, like, some people who are working in the angle, who knows about the supraciliary space, who know who knows how to deal with a cyclodialysis cleft, and if you give it to them, they will handle it.

So my point now is I would give a training to someone who's comfortable with the angle based surgery, and who knows how to deal with complicated glaucoma. Like in a bleb base, we do have suprachoroidal hemorrhage, or suprachoroidal fluid, they should know how to deal with hypotony. For me, believe me, it's easier to deal with higher pressures. I can deal with higher pressures, but hypotony, I'm like I'm one step behind. So I'm like, oh, what should I do, how should I deal with this.

So that is what I would recommend for a comprehensive surgeon, who is thinking of starting. A little bit of a longer learning curve might be needed, but this device might be a little more forgiving, compared to CyPass. But exact placement, the outcomes depends on the exact placement. The complications depends on the exact placement of the right anatomical place. So we need a little more hand holding this time, and giving it to the people who have a little bit of experience in angle based surgeries.

That's what I would say, instead of like, opening up the market to mild, moderate, everyone to do. Like I would give this device, which is like a little more in my hands, I would say, in my hands, it's a little more tricky. I need a little more experience doing this. And of course, dealing with the hypotony, dealing with the suprachoroidal problems, I should know how to deal with, and then I will give it to them. Because ultimately, what matters is our patients. What we recommend, what we promise our patients. A mild patient, like, who's undergoing a cataract, yeah. So that's what happens. Over time, if these procedures are not properly learned, you don't have proper support, and see them over time, we might lose that opportunity to learn from what we didn't learn from CyPass, is what I would say.

CHERYL KHANNA: Thank you so much. Dr. Roddy, you mentioned several alternatives to drops. Many of our patients are on multiple drops. Do you know of any technologies coming that would introduce multiple agents in an intracameral device, or conjunctival device to deliver drugs?

GAVIN RODDY: Yeah. They're in the experimental phases, but combination drop therapy. Folks have talked about maybe two or even three meds. I think that would be great for our patients. But you know, my guess is those are probably a couple of years down the line. For now, as I've alluded to, most of the approaches have used single use, single agent, using a prostaglandin, but think that would be wonderful moving forward.