Your Eyes and Chronic Graft-versus-Host Disease

Presenter: John Irvine MD, Doheny Eye Center UCLA

Summary:

Chronic graft-versus-host disease (GVHD) often affects the eyes, making it difficult to perform normal, daily functions.  It can be the only sign of chronic GVHD, or a signal that chronic GVHD is developing elsewhere in the body, as well.

Highlights:

• Graft-versus-host disease in the eye (ocular GVHD) can cause dryness, blurry vision and light sensitivity
•  Ocular GVHD can persist for a long time, and can impact quality of life
• A variety of treatments, ranging from eye drops to special contact lenses, are available to treat the symptoms of ocular GVHD

Key Points:

03:29  Symptoms of graft-versus-host disease in the eyes (ocular GVHD) 

08:18  A healthy ocular surface requires lubrication

10:25  Damaged tear film in the eye can cause infection (blepharitis)

11:13  When filaments form in the eyes, it can be very painful: 

12:19  If oil glands in the eyes don’t produce enough oil (lipid abnormality) you can have tear loss 

17:53  Lifestyle factors can aggravate eye irritation   

25:39  Pros and cons of using topical steroids, such as prednisone, to treat ocular GVHD

27:41  Serum tears can be an effective treatment for ocular GVHD 

32:15 Plugging the tear ducts (punctal occlusion) can help retain moisture in the eyes

33:32  Gasketed glasses can help retain moisture in the eyes

38:09  The PROSE® scleral lens provides lubrication to the eye and improves vision in patients with ocular GVHD 

Transcript of Presentation:

00:00  Overview of presentation:  Good afternoon. Pleasure to be here. This is a topic that I have grown into and have very much embraced over the last 10 years. Dry eyes, when I first started 30 years ago, dry eyes were considered to be the low back pain of ophthalmology. No one wanted to take care of it. And yet it is becoming more and more of an issue to deal with, certainly as we have become more proficient in our treatment of leukemia, lymphoma, various cancers with stem cell transplants.

The flip side of that, the success of that, is also mirrored by some of the problems that we encounter and that you guys are very familiar with —GVHD. My goal today is to go over some of the issues of ocular GVHD, try to explain what I feel are the issues. I'm always a big fan of educating about pathology, about physiology, so that the patients understand why certain things work and why certain things don't work. So that will be the gist of my talk and I will end up with going through a spectrum from the very simple to the more complex treatments for ocular GVHD.

01:42  Graft-versus-host disease in the eyes (ocular GVHD) can persist for a long time and negatively affect quality of life:  So the problem with ocular GVHD is really two fold. One, it's a chronic disease. It's hard to get away from. You can run but you can't hide oftentimes. And it can be extremely debilitating. On the other hand, it can be nothing. I met a man on the way down from my room this morning on the elevator and his account was, ‘I treat my dry eye with one drop a day of Refresh Tears®." And I said, ‘Congratulations.’

The frustration of it is that you get your life back. Nobody has told you when you're signing on for a bone marrow transplant what the flip side's going to be. And quite honestly, you don't care at that point. It's, ‘We've got to move forward with this.’ But your eyes hold you back once you get to a certain point and they become the quality of life limiting factor, or one of them.

You've all sat through a number of different seminars and great workshop about things that can bother you, and I don't mean to be so egotistical and think that the eyes are the only problem. But I do know, from my vantage, that I have patients who have recovered tremendously [from their transplant] and they are extremely debilitated and cannot move on because your eyes are right here, and they are the things that oftentimes keep us from being able to carry out our work and enjoy life to the fullest degree.

03:29  Symptoms of graft-versus-host disease in the eyes (ocular GVHD):  Well, the symptoms of ocular GVHD are very disabling. You can get foreign body sensation, burning or dry sensations, you can get light sensitivity. And I see from looking around that there are a few of you who are experiencing the latter. The surface related blurry vision comes because the eyelids need to act like a windshield wiper and wipe the surface of the cornea, keep it clean, keep it smooth. And if it's not smooth then certain things happen, which we'll go into.

04:17  Chronic graft-versus-host disease in the eyes (ocular GVHD) can cause dry eyes (keratoconjunctiva sicca): So you all know this in general, but white blood cells from the donor damage certain tissues in the eye. The tear glands and mucus producing cells, which are in the conjunctiva, which we'll go into in a few minutes. The conjunctiva is the thin, clear membrane. It's like the Saran Wrap that covers the white part of the eye and then folds up over onto the inner layer of the lids.

The word keratoconjunctivitis sicca, I've broken down here. Kerao’ means cornea; conjunctiv is self-explanatory, it stands for Saran Wrap; itis is inflammation; and sicca means dry. So keratoconjunctivitis sicca is dry eye as manifested by dryness of the conjunctiva and the cornea.

It comes from a combination of reduced volume of tears, reduced quality of tears and altered mucus, which allows the tears to stick to the eye. So the tear film is like a sandwich. There's two pieces of bread and a lot of water in between and that's the meat of the sandwich. But you can have water but still have dry eyes symptom because there's some part of the bread that isn't functional.

05:55  An explanation of the different parts of the ocular surface of the eye, and their function:  So we look at the ocular surface as a functional unit. It can be very complicated, I've tried to minimize that but you can see that the eyelids cover the surface of the lid. And here's muscle, you have lashes, which note, usually turn outward. If they turn inward they cause problems. There are glands in the lids and these are, if you've ever pulled your lid down, you can see the piano keys that are lining the inside surface. Those are the Meibomian glands and they secrete an oil that helps to reduce the evaporation of tears.

06:44  Tears are produced by the lacrimal gland:  The tears are produced by the lacrimal gland, which is up here in the upper outer part of the orbit. And they are distributed by the lids, drawn down and then exit through the nasolacrimal duct system into the nose through these little holes called puncta. And there's a negative suction that's created every time you blink that actually pulls tears into the nasolacrimal duct. So you can see that if your lids are working well and you have dry eyes, it's working against you in a way. Yes it's wetting it, but it's draining the tears that you have from your eyes. So that becomes one aspect of the strategy of treating dry eyes.

07:42  Network of nerves in the eyes: The other part is that we have very intricate nerve connections on the ocular surface. The cornea has probably one of the highest number of nerves of any tissue in the body, save for maybe our brain, hopefully. And consequently, if you have an abrasion or you have some sort of breakdown on the surface of the cornea, those nerve endings can be raw and exposed and be very irritated and that's what gives you pain and burning.

08:18  A healthy ocular surface requires lubrication:  So what's required for a healthy ocular surface? Obviously, lubrication. And that comes from the goblet cells. These are the cells in the conjunctiva that secrete the mucin which allows the tears produced in the lacrimal gland to stick to the eye. Without those goblet cells producing enough mucin of quality type, the tears can bead and roll off because the wettability of the surface is not adequate. It's like it's being Scotch Guarded, if you will. S,o you need those mucin cells, those goblet cells.

You need aqueous, which is the fluid produced in the lacrimal gland, and you need oil from the Meibomian glands that I mentioned before, and that creates the tear sandwich that we see here. With the mucin down below, the aqueous here and the oil up top and that decreases the evaporation of the aqueous to the outside world.

09:25  The ocular surface provides a protective barrier against infection and helps our eyes focus:   The function of the ocular surface the function of this ocular surface unit is two-fold: to provide a protective barrier, so that infection does not occur, and it also is a powerful refracting surface.

That is, the cornea has two thirds ... Your cornea is right here. The cornea and the lens together bring light to focus on your retina in the back of the eye. So they are the focusing mechanism. The cornea has two thirds of the power, the lens has one third. And of that two thirds power of the cornea, that most important part of that is the front surface. So if the front surface is irregular, it throws off your vision. It can give you glare, it can decrease the ability for the cornea, in and of itself, to accurately refract or focus light onto the retina.

10:25  Damaged tear film in the eye can cause infection (blepharitis):  The problem becomes one of dysfunction when you have an irregular tear film — decreased vision, discomfort and possibly infection because you have a break in the skin of the cornea. We have bacteria all around us, we have bacteria, normal flora, along our eyelids. The term blepharitis— bleph-, meaning lid, -itis inflammation— is very common in patients in all of us. And so blepharitis and dry eyes can be a very bad combination and you have to treat both in patients who have dry eyes because of the risk of infection.

11:13  When filaments form in the eyes, it can be very painful:  So you have volume abnormality, mucin abnormality, which can cause filament production. Now filaments are small little skin tags on the cornea, and you'll see a picture of these in a few minutes. They're like if you took silly putty and we used to go like this and make them long, stringy things. Well imagine those being stuck on your eye, that's what it looks like to me as I examine patients with filamentary keratitis. What I can't appreciate is how much pain these individuals are in. They're like rocks in your eyes.

I once had filamentary keratitis many years ago as a result of a viral infection that I contracted. And it was so bad that I asked my wife, who was a surgical ICU nurse, to put my magnifying glasses on and take them off, or wipe my corneas. To which she replied, I will put my hands in someone's chest but I will not touch your eyes.

12:19  If oil glands in the eyes don’t produce enough oil (lipid abnormality) you can have tear loss.  If you have a lipid abnormality, that is the oil glands are not producing enough oil, then you have an evaporative tear loss. And that can be just as bad because in our society what are we doing so frequently? We're looking at the computer. So many of my patients are on the computer at least four or five hours a day. Or if they're not doing that they're on their iPhone, their iPad. They're doing something. Or if you're driving, you're staring. You're trying not to get killed by the other guy.

12:55  Activities that cause you to blink less frequently, such as staring at a computer screen, can further reduce the amount of tears on the ocular surface:  So activities near and of concentration decrease your frequency of blinking. And that can be problematic when you have a low tear film or you have an evaporative tear film, because you're not restoring the ocular surface and then the surface cells underneath can break down and aggravate the problem. When you have a surface abnormality, you get decreased vision for the reasons I mentioned a few minutes ago.

13:28  Traditional approach to treating dry eyes:  What's our traditional approach to dry eyes? Thirty years ago we put lubrication on it, we corrected any malposition of the eyelid because remember, they have to act correctly to wipe the tears across the surface of the eye. And if we couldn't do that, and there was exposure, we would close the eye by sewing the lids together to preserve the integrity of the eye from evaporation, ulceration and loss of the eye.

14:03  Photo of someone with dry eye due to incomplete blinks:  So you can see here at the bottom, or in the top slide, there's a picture of an individual with a dryness. That red stain is called Rose Bengal, it stains dry portions of the eye. And you can see that the lower third of the cornea has been affected.

Now this comes because people have incomplete blinks. And you say, "How can you have an incomplete blink?" If you had high speed photography done of your blink reflex, you would see that, occasionally, you do go like this and blink completely. But frequently there are incomplete blinks. And if you have an altered tear film and you are at risk, then it will become manifested by that.

14:54  Photo of eye lid positioned improperly (malposition):  The lower picture shows a lid malposition. This occurs, this is called a ectropion, meaning it turns out. And therefore the lids aren't coming together and not wetting the cornea appropriately. This can come from chronic GVHD:  we have chronic inflammation and it can affect the skin, and the scarring can cause the lid to turn out. So these things have to be corrected in order to really address the picture as a whole.

So the goal is prevention, if possible. And there are a lot of strategies that have been evolving over the years to try to prevent systemic GVHD including conditioning regimens, tissue matching, trying to prevent local disease and eliminate sensitization. Even trying local immunosuppression before the graft. But it's not always successful. And these techniques are still being refined as we speak.

00:16:09  Chronic conjunctivitis – inflammation of the conjunctiva (pink eye) can cause vision problems:  What are some of the clinical manifestations about dry eyes that we're talking about. Well the first one is chronic conjunctivitis. Conjunctivitis, inflammation of the conjunctiva, your garden variety pink eye. But it's not due to a virus, it's not contagious. It's just that your eyes are irritated, red and angry. And it presents as red eyes.

You can develop dry spots on the cornea, as you can see here, and those dry spots as I alluded to before, alter the front surface, which needs to be smooth. Now it's irregular because of the dryness and your vision drops. You can get glare, and if it's bad enough, you can get confluent dryness which can essentially be a corneal abrasion, which is a geographical dry spot that can be very difficult to heal.

17:04  Photo of filaments:  Filaments, I mentioned. Here you can see on the upper slide, pictures of these tiny little skin tags on the surface of the cornea. They can be extremely irritating, as I mentioned.

17:22  Other areas of eye irritation that can develop as a result of chronic graft-versus-host disease (GVHD):   And then you can develop other areas of inflammation such as superior limbal kerato-conjunctivitis, which is inflammation of the conjunctiva on the upper surface of the eye, sometimes related to problems on the under surface of the lid. And as it bangs up and down over that surface it can cause chronic irritation. Rarely one develops a corneal ulcer, but it can happen.

17:53  Dry climate can aggravate eye irritation:    So what are some of the aggravating factors for all of this? Well as I mentioned there are extrinsic things. Weather. People who live in arid climates, dry climates, are more severely affected because there's no humidity. You want to live in a place where there are fish in the air. Temperature. Somebody living in Arizona is going to really have a problem with this.

18:25  Activities that decrease the frequency of blinking, such as driving, computer work and reading can aggravate a dry eye problem:  Some of the activities which require attention at near, like I mentioned computer work, reading, driving, all decrease your blink frequency. What do you do about that? I mean we all have to blink but who thinks about blinking until your eyes tell you to blink. And so we want to be proactive in this because, as I tell many of my patients, if you're putting drops in or you're doing something when your eyes bother you, you're already swimming upstream. It's already a problem and it's hard to recover.

So, what you'd like to do is figure out a way to be proactively blinking. And this is my suggestion to my patients.  One, if you're reading a book, make a book mark that says BLINK on the top and stick it a few pages back from where you are. It's in your sphere of reference and you may see it and it may help you blink.  Two, if you're on the computer, put a little dot or something up there on the side that means blink to you. I tell them, if you're working and you have a work station at work, do not put the word blink up on the computer because people think you're nuts. So it's got to be your message to you to help you remember.

19:55  Use tear drops or lubricants proactively and frequently, even if it is inconvenient, for best results:  If you find a tear drop or a lubricant that works for you, be proactive. Don't be afraid when the doctor says, "I think you should put these in hourly." And you go, ‘Doc, I got a life.’ Put them in hourly to see if it works. Or put them in every 30 minutes to see if it works. If it works, then you taper it back to the level where you get the most relief with the least amount of effort. But if you give up by only putting it in four times a day and say, ‘This doesn't work’ then you've short changed yourself on a possible solution.

20:37  Other medications you take may aggravate dry eyes:  And then remember that other medications that you may take can also aggravate your dry eye. If you have asthma, or you have allergies, or you have Parkinson's, medications for those also dry the ocular surface and can cause problems. And Parkinsonian drugs, not only Parkinson's itself, will decrease your blink frequency — some of the drugs that are used can decrease the tear film as well.

21:11  Chronic graft-versus-host disease (GVHD) can affect one or both eyes, and may occur with, or without, symptoms of GVHD in other parts of the body:;  So generally both eyes are affected but one eye can be more affected than the other. Typically, patients will say, ‘My left eye is bad but my right eye is just knocking my socks off’" So, you look at it and oftentimes you can see a correlation. Sometimes there's no evidence of dryness on the ocular surface. But they're symptomatic. And when that happens I have to be thinking, maybe it's the occult inflammation inherent to GVHD that's causing them their problems. And that leads me on a different way of treating them initially.

These can be independent of other manifestations of GVHD or they can be part of it. They can follow other manifestations such as your dermatologic or GI problems. And they can also, if the GVHD systemically is quiet and all of a sudden you start having a problem with your eyes, it can be the heralding of a flare-up of GVHD.

Now oftentimes oncologists are just looking at the systemic problems. And I have to say that I am a big advocate of working with the oncologists, and I regularly write letters to them letting them know how my patients are doing and when they're having flare-ups. But I have the luxury of having a really good relationship with City of Hope hematologists. And they know that having not had someone like my team to work with, who are as responsive — because before we came on the scene these patients were going into the community and their doctors were not as responsive, In part because the low back pain problem. Okay? It's throw drops on it. They didn't understand. A lot of practicing ophthalmologists don't understand GVHD, they don't understand the steps. They're oftentimes quite busy with surgical practices and they don't have time to spend with the patients and listen to them.

23:37  Treatment for graft-versus-host disease in the eyes may be local or systemic (treatment that affects the whole body):  How do you treat? Well you can treat either locally or systemically or both. And that's why it's important to communicate with the oncologists because the oncologists may be called upon— if I am not able to turn something around that I think needs, maybe, some increase in prednisone or something or I think it's heralding a GVHD flare-up — I need to communicate that with the oncologist. And frequently with that communication you get an understanding that I'm not crying wolf, I think you ought to try this. Whereas there have been situations where, and I still get this, where the oncologist will say, ‘I don't really think we need to bump this up. In fact I'm going to taper it.’ So, we see what happens and sometimes it's not good. But if you can do it locally, it spares having to use systemic drugs, which is always a good thing if possible.

The treatment goal is to treat the underlying disease if there is a flare-up, or to reduce the symptoms, and that's what we're doing locally with topical medication. And we can often do both at once, or may need to do both at once. So if you have a systemic flare or a site threatening problem, we add or increase systemic agents as necessary. And that may include corticosteroids or prednisone. Other forms of immunosuppression that spare the body the aggravation of prednisone include cyclosporine A, tacrolimus, sirolimus and mycophenolate. There are biologics and photopheresis as possibilities, but those are sequential steps down the road if the early ones do not work.

25:39  Pros and cons of using topical steroids, such as prednisone, to treat graft-versus-host disease in the eyes (ocular GVHD):  Let's talk a little bit about the local treatments. Topical steroids, they work well in many patients. You don't have to use them all the time. It may just need to be pulsed. We're looking at pred acetate as one, there's a number of other topic steroids. The downside of pred acetate, and some of the other ones, is that you can be prone to cataract formation if you are using them for a long period of time and you can develop glaucoma in a certain subset of the population who are called steroid responders. That is, if you put steroid on their eye, their interocular pressure goes up and they can be prone to glaucoma.

So anytime you go on that, you have to let the ophthalmologist know [if ] there [is] anybody in your family who has a history of glaucoma. Have you ever been treated for glaucoma and have you ever been treated with topical steroids before for any other reason, perhaps for cataract surgery or for some ocular surgery that you had as a younger person? And did you have problems with steroids? All have to be taken in account because you can make allowances for it by using certain types of steroids.  These can come in drops and ointment forms, so we have a little bit of leeway there depending on the individual.

26:59  Using cyclosporine A (Restasis®) to treat graft-versus-host disease in the eyes (ocular GVHD):  Another form of topical immunosuppression is cyclosporine or Restasis®. I'm sure many of you have heard of Restasis®, you've all seen the pictures of the beautiful woman with the twinkle in her eye that puts the drop of Restasis® in her eye for dry eyes. She does not have this problem [that] you have. And typically speaking, Restasis® has been disappointing for a lot of GVHD patients. I will tell you why it may need to be done as part of a sequence of events leading to the ultimate, hopeful victory in a few minutes.

27:41  Serum tears can be helpful for people with graft-versus-host disease in the eyes (ocular GVHD):  Serum tears are quite beneficial in a number of individuals. This is where your blood is drawn from your vein, it's spun down by a pharmacy, and the clear serum is put into eye dropper containers and you use those serum tears four times a day in your eyes. It's quite good for people with the filamentary keratitis and can be wonderful for other individuals who maybe do not have filamentary keratitis but have other symptoms, dryness and whatnot. Serum has a lot of beneficial factors in it that, we don't know why totally, but they seem to work.

The problem is they're hard to get. It has to be done by specialized pharmacies. Compounding pharmacies are becoming more and more difficult to: one, find; and two, to perform this task. I have been on a personal mission to try to get the hospital where I work to use, or to somehow develop the capability and the protocol for doing serum tears, because the patients are there regularly, they're getting their blood drawn regularly, take another pint and get it processed and that way they have. But it's not as simple as that, apparently. But it's something that if you can advocate for, either with your ophthalmologist or the oncologist. It can be worthwhile.

29:35  There are a number of artificial tear products on the market that can help some patients with graft-versus-host disease in the eyes (ocular GVHD):  There are a lot of artificial tears out there. There are more artificial tears than there are toothpaste products. And that just means that there is no one product that's good for everybody.

There are ones like Refresh® that are good for the individual that walked down with me this morning. And there are those that need something more viscous. but don't want something so viscous that it blurs their vision, because they want to work or they want to be able to see and whatnot. And there are others that will help the individuals who are so photophobic or light sensitive and just want relief, that they don't care about the decrease in quality of vision. To those individuals I will ask them to use the viscous solution, and then maybe chase it with something less viscous so you still get a barrier, a little coating but it dilutes it out.

One of the benefits of a lot of these tears is that most of these come in non-preserve form. And that's really good. A lot of people who are older, they don't like the non-preserve [form] because they have arthritis or it's too difficult to twist those things off and it looks wasteful. Many of the products, now, you can cap so it's not one use and you throw away.

31:13  In order for artificial tears to work, you have to know how to put them in your eyes properly:  Another point is to learn how to put tears in. Okay? A lot of people, they give you the instructions, ‘use artificial tears’ but they don't tell you how to put them in. And so, I see patients that are holding the drop way up here and they drop it in. Now we're intelligent. We know something's going to hit our eye and so we close our eye before it gets there, right? So the best way to do it, that I can think of, is to pull your lid. You use one finger to pull your lid down. You use that as a guide and you can figure out where the tip of that dropper or that bottle needs to be in your lower tear film to get it into that pocket. It's not irritating but it's soothing and it's much more economical.

32:15 Graft-versus-host disease in the eyes (ocular GVHD) is sometimes treated by plugging the tear ducts (punctal occlusion):  So what else can we do? Well we can try to keep the tears around longer— I alluded to that — by occluding the puncta, which is the entrance to the nasolacrimal duct where the tears drain. And we do that with small plugs like you see right here, there's a little plug. It's a silicon plug mounted on a stylus and you insert that into the puncta, and then you push a little button and the insert pulls back and it leaves the plug, which essentially is like a small toggle bolt, which goes in there and then it can't come out because there's an edge. It doesn't hurt but that's the effect of it. And it's designed to keep your tears around longer.

If that doesn't work then there are some that go way down into the nasolacrimal duct, they swell. You don't feel them, but they stay intact for about six months. And lastly, one can physically occlude the puncta by either sewing it closed or, traditionally, people will cauterize it under a little local anesthetic, as you can see down on the left.

33:32  Gasketed glasses can help some patient with graft-versus-host disease (GVHD) retain moisture in their eyes:  Do not underestimate trendy looking glasses, okay. There are a number of eyecare products out there that have gaskets around the backside that will fit to your face and keep the evaporation factor down to a minimum.

I have a patient who showed me the glasses, he introduced me to them, and you know where he got them from? A Harley Davidson web site. And you can write this down, if you go on the web site 7eye.com you will find a whole myriad of these types of glasses.  They're almost like Zappos. You can call the company and say, ‘I'd like to get some glasses,’ and the guy will say, ‘What kind of face do you have?’ ‘Well it's a good looking face.’ He said, “No, what size.” And, so, they said “take a picture of your face”. So he [my patient] took a selfie and he sent it to him, and he sent him three pairs of glasses which he thought might work and he said, "Send the ones you don't use back." And the gasket on the back is made of foam but you can pop it off so that you can wash the glasses and the pop it back on. And they come in a number of styles so there's something for everybody.

Pardon me? 7eye. E-Y-E. Pardon me? They do fog up. 7eye fog. Thanks. Gotta have this, this is why you ...

35:26  Bandage contact lenses can help people who have abrasions on their eyes due to graft-versus-host disease.  Okay, let's talk a little bit about contact lenses as we wind up. So bandage contact lenses are quite helpful for abrasions. They are named bandage because if you have an abrasion on your skin, nerves are exposed and it hurts. Wind bothers it, sun bothers it, rubbing up against things bothers it. If you put something over that, you're covering up the nerves and decreasing the stimuli to it. Well that's what a bandage contact lens does. It has no value as far as vision goes, in terms of correction. It's there to cover up the cornea and cover up the bare nerve endings.

The down side of these in dry eye patients is they are sometimes difficult to keep on the eye, and because they have a high water content, you put them on a dry surface and by osmosis the water leaves the contact lens and will dry up and tighten up on the cornea, which then makes taking the lens off a little bit problematic and can actually worsen your symptoms and predispose you to infection. So in really severe dry eye patients, it is not a really good option.

36:46  Scleral contact lenses can help patients who have graft-versus-host disease in their eyes (ocular GVHD):  However, there are scleral lenses which do provide a wonderful alternative to this and we'll talk a little bit about that. The problem with scleral lenses is that not all optometrists are facile in fitting them. And it does require a certain amount of sophistication to fit them. 

The goals of these lenses are one, to promote healing. To give mechanical support and protection. Because you put fluid in between, and I'll show you a diagram in just a second, you put fluid in them, it maintains hydration of the cornea, and it can actually heal some of the problems that we've seen on these pictures. It's covering the surface, so it's covering up those nerve endings and it, therefore, relieves pain. And hopefully, by virtue of all that, the side effect is good vision. Let me go back, so you can see here how big these are. This is the upper edge of this lens. And from here to the edge of the cornea it sits on the scleral and then it vaults over the cornea.

38:09  PROSE scleral lens provides lubrication to the eye and improves vision in patients with graft-versus-host disease in the eye (ocular GVHD):  I'm sorry, did somebody say something? So, one specific type of scleral lens that I have become quite familiar with, and have contributed some to in terms of clinical trials, is the PROSE lens. This comes out of the Boston Foundation for Sight in Boston, and it has gone through a number of name changes. It was the Boston Lens, I can't even remember the number of lens names they had, and they finally settled on PROSE, which stands for the prosthetic replacement of the ocular surface ecosystem. Why? Because they were having difficulties with insurance companies who wouldn't reimburse contact lens. A lot of exclusions are for contact lenses. Just straight off, ‘Is it a contact lens? We're not going to pay for it.’   So what the Boston Foundation for Sight has tried to do is to show and underline the importance of this as a therapy. And, so, it's to restore vision, to support the healing, all the things that we talked about, and it can be really, really helpful in this regard.

39:27  Photo of PROSE scleral lens:  Here's what it looks like. You can see the part that sits on top of the scleral, and then the optic vaults over the cornea and there's a fluid reservoir between the lens and the cornea. So you can see that: one, it's not touching the cornea so it'll fit well;  two, it's hydrating the cornea. It's healing it because of the hydration and it improves the vision because now this front surface has become the front surface of the optical system of the eye. It is no small device, you put fluid in here before you put it in. It's not like putting in a regular contact lens where you can watch yourself do it in the mirror. You actually have to bend over and learn how to insert it because you've got fluid. And if you did it the other way the fluid would drop out.

Question from audience:  Do they stay in like 24/7?

Dr. Irvine  : No. It's 12 hours at a time. So most people are not using it at night unless there are certain conditions where we've had to use it, in terms of trauma victims who have lost their eyelids and we're trying to preserve their ocular surface until we can do oculoplastic surgery to restore the normal function. So in those individuals we'll trade them out at 12 hours.

40:54  Photo of person’s eye before and after using the PROSE scleral lens:  So here at the bottom you can see filamentary keratitis before the lens went in and then four hours afterwards you can see how it's resolved with just the hydration.

Again, same picture and you can see how debilitative this individual is with photophobia, light sensitivity and decreased vision.

41:13  New generation of scleral lenses can be use with patients who have ocular surface irregularities due to glaucoma treatment:  Now, there are newer generations with these lenses. The problem with the PROSE lens and some of these lenses is that you can only customize certain quadrants of the scleral with its fit. Now there are individuals who will have had glaucoma surgery, or have little bumps and things on their sclera, which cannot be addressed in the usual way. And you can see this in this picture. This is a cornea, this is an imprint much as one would take when you do a dental imprint. And I'll show you a picture of it in just a second. But this was the glaucoma valve that was placed on a sclera. This would be very difficult to fit and you would get air in between on the sides if that were not overcome.

So it's individuals who have scleral irregularities that the next call for evolution has come. And this is an individual who places an ocular surface mold, like a dental implant, on the surface of the eye and when they take that off, they then go ahead and design the lens based on that imprint. And you can see on this next picture how some of these, you can see the irregularity, the elevated surface here as well as over here. And this picture, which is called an OCT, which is a cross section, here's the lens, here's the bump on the sclera and you can see how this has allowed it to mold right to it and overcome that. So this has expanded our ability to treat GVHD patients who may have other ocular surface problems separate and distinct from GVHD that predated their development of the dry eye.

43:07  Getting insurance reimbursement for therapeutic contact lenses can be a challenge, but can be done:  Insurance issues can be problematic, right? Therapeutic contact lenses are typically covered, cosmetic or not. And so it becomes a real process to try to educate the insurance companies that this is not a cosmetic lens, it is a therapeutic lens. And you have to advocate for yourself. The doctor has to advocate for you. There are many standard letters and templates that we use to write to the insurance to get pre-authorization so that you're not on the hook for the cost of these lenses, which can be high, before you know how much you're going to be on the hook for. They require appeal, you have to be stubborn, you've got to stay with it.

PROSE, in my opinion, is a medical treatment and should be covered. And I think that we will continue to evolve this as the insurance business becomes more educated about it. Now, the doctor needs to document the treatment steps. This gets back to the point I made about using Restasis®, even though we know Restasis® is not helpful in a lot of patients. Because they want to know, when the insurance people are looking at the record they want to say, ‘Have you used artificial tears? Have you used Restasis®? Have you used topical steroids? Have you had punctal plugs? Have you done this?’ Just all the things that lead up to this big ticket item, they want to know that you've done it rather than jumping straight to the big ticket item.

So when someone says, ‘You need to try these’ and you're saying, ‘I really want to get to the end point,’ there's a reason for this, and it's for the betterment of your pocket book so that it's not such a strain. Although there are ways to expedite this.

45:05  Survey of people with graft-versus-host disease in the eyes (ocular GVHD) found over 95% had severe discomfort that impacted their quality of life; scleral lens was the most helpful treatment.  There was an online survey that was done about the clinical experience of patients with ocular GVHD and you can see these here. You can see that over 95% of them had severe discomfort, of the people that had ocular GVHD, with difficulty reading, worried about eyesight, having problems with quality of living of their daily life, hobbies and with night driving. Treatment response, when it was asked, I didn't ask them, but when it was asked, was that with topical immunosuppression, punctal plugs, oral antibiotics, fish oil, flaxseed oil, all these things that we typically think of, the group that we interviewed said zippo. Didn't help a big. Lubrication alone helped 7% of them. Scleral lens therapy, 72%.

So the Boston Foundation for Sight—and I've heard this said a number of times—they consider ocular GVHD dry eye the low hanging fruit for the use of PROSE®, that there is such a great response rate, positively, with ocular GVHD in these patients and the PROSE®, that it's almost what they call a no brainer. So, it's always in my back pocket as a positive thing and when I speak to somebody the first time and am giving them the spectrum of what they can expect, I always say, ‘We're going to start with tears, we may end up over here.’ There are a whole lot of possibilities in the middle, but I want to be able to give them what the spectrum is, and [let them know that] there is light at the end of the tunnel, given the statistics that we have.

46:58   Future therapies:  So in the future, we expect better technology. And as we get better technology, it'll be less expensive. We'll enhance our fitting process. There will be decreased costs for manufacturing. We'll have better experience for which patients will be appropriate for which types of technology and treatments. I think there will be greater availability, as newer optometrists come online and develop interest in this. And that there will be an increased awareness of this therapy by both ophthalmologists, optometrists and oncologists. I've been doing this for 10 years with the PROSE therapy, and it is a constant discussion to let people know about this— other healthcare professionals —know that there is a possibility out there.

47:57   Summary of talk:  So in summary, just to reiterate, despite really good care and attentive lubrication, ocular GVHD patients with dry eyes can have foreign body sensation, discomfort, poor vision. And the important thing is seek treatment, seek it from those who have experience with it and who have an interest in helping you.

So in conclusion, I was in Chile a year and a half ago giving a talk about the scleral lens and it's evolution. And I went to lunch and I saw something that caught my eye and I thought, this looks vaguely familiar. So basically the scleral lens could be a scleral lens and a salad bowl. So you can get nutrition from it as well. Thank you.

48:55  Moderator opens up the floor for questions:  So we have some time for questions so if you have a question please raise your hand and we'll get the mic to you.

49:00  Eye drops with greater viscosity can help with light sensitivity caused by graft-versus-host disease in the eyes (ocular GVHD): 

Audience member:  I have GVHD and one of the things I have is light sensitivity. That's why I wear these covers on my eyes. But as well, do you know of any eyedrops that— because I've tried about six different eyedrops. I've used Restasis® and Xiidra® and none of them worked. So my question to you now is there any type of eyedrops or lubricant that are a little bit thicker than Sustain® and all those others?

Dr. Irvine:  Yes. So, the question is despite the use of Restasis®, which is an immunosuppressive drug to try to improve the volume of tears and a newer medication called Xiidra®, which is lifitegrast, which works along a different pathway, one can still not get the relief that you would like. And so what are some other, slightly more viscous drops that are available that might help you? And as I alluded to, I have no, my disclaimer is I have, unfortunately, no financial commitments to any of these companies or relationships, but I have found that something like Sustain Ultra®, which is a little bit more viscous [helps]. I carry a bottle of Sustain Ultra® in my pocket, and I reach down and I grab the patient's finger and I put a drop on there, and I have them notice the viscosity of it. Especially if they've been using Refresh® or something which is just like water.

It doesn't blur your vision. If you use Sustain Balance®, that, in my opinion, doesn't work as well, and regular Sustain® is a little to milky and will blur your vision. So the Ultra, in my opinion, I have dry eyes and it's my go to drop. There are others. GenTeal® is good. TheraTears® is a good one. There are all kinds of viscosities for these. So getting back to my first point, do not be discouraged, there's plenty of opportunity in the pharmacy, just keep track of the ones you use and tell the pharmacist you want moderate to severe dry eye.

Audience member:  Because the thing that I deal with is that I put the eyedrops in my eyes and probably within, say 20 minutes, 30 minutes, whatever, they go dry again. And I need something that's a little thicker that can kind of ...

Dr. Irvine:  The other trick, which I mentioned earlier, is to use something thick that will blur your vision and then chase it, a couple minutes later, with a less viscus one, which will dilute it but will still give you the lubrication of the heavy viscosity one that might last longer.

Audience member:  What's a thicker one?

Dr. Irvine:  Oh, not Lacralube but ... pardon me? Yeah, gel drops.

52:25  You can get PROSE and other scleral lenses in prescription strength:

Audience member:  I also have the eye issues. But I'm finding, especially this last month, I've had a very difficult time reading up close. And so I think I'm having some— I used to be 20/20 and I'm pretty sure that's not happening anymore. So, my question to you is are the scleral lenses or PROSE lenses, can you get those in prescription strength so they're also like readers or something like that? Or are they just clear and then you have to get glasses on top of that for the reading or for the far eyesight?

Dr. Irvine:  So the question is can you get refractive correction placed in some of these scleral lenses and the answer is yes.

53:13  When to use scleral lenses versus serum tears in patients with graft-versus-host disease in the eyes (ocular GVHD)

Audience member:  In terms of stages of relief, for your patients would you recommend if serum tears are available to do that first or would you jump over and do the PROSE lenses?

Dr. Irvine:  I would try first things first: lubrication, then punctal occlusion and that sort of thing. And it depends on the availability and the psychological makeup of the patient, what other issues they have going. Are they able to get to a pharmacy that can do the serum tears? Is there a scleral lens dispensary close to them? I have to explore those and make it more practical and then tailor my documentation accordingly.

But in the best of all worlds, I think that serum tears are probably— you're getting blood drawn anyway and if it's done in a reasonable fashion with an accredited laboratory, I think the risk of infection is low and I've seen dramatic results with it—so I would try that first. And if it doesn't work, then you've eliminated something that's not so invasive and not so obtrusive. Because the contact lens, while it works, it can be great. But then you can come up and get the foggy lens with mucus production and whatnot - that is something I haven't gone into. But while it improves your vision, it's not a panacea. There are some problems that they're still working on.

54:56  Where to find a PROSE® provider:

Audience member:  I have a question in regards to the PROSE®. Are there any doctors in Colorado that would be proficient in putting in the PROSE or do you have to go to Boston to do it?

Dr. Irvine:  In where?

Audience member:  In Greely, in Colorado.

Dr. Irvine:  In Colorado? There are more and more of the satellite centers. It wouldn't surprise me if the University of Colorado has one by now. If not the PROSE, it might have an optometrist who specializes in scleral lenses because they're a tertiary care facility, and that is becoming more and more of an issue. I think there are about eight or nine PROSE satellites throughout the country, there's one in Texas, in San Antonio, there are some in Miami, up in Michigan. There's one in Los Angeles. So they're around. You can go on the PROSE website and they'll tell you the locations.

56:04  Questions about using Restasis® versus serum tears after cataract surgery: 

Audience member:  I just had cataract surgery and we've talked about going back onto Restasis® but I also have the serum drops. I'm thinking that the serum drops would be better than the Restasis®. What is your feeling?

Dr. Irvine:  How did you do with the Restasis® beforehand?

Audience membere:  I did fine, yeah. But I have the serum drops too.

Dr. Irvine:  You what?

Audience member:  I have the serum drops.

Dr. Irvine:  You could try one or the other. If the Restasis® works, it's less hassle than the serum tears. If they stop working, you know that it's already working. Or if the state of your eye, the ocular surface is a little bit different— the ocular surface is always a little bit, the shape is slightly different after you've had cataract surgery, even minutely—sometimes that can alter the sensation of your eye. And so the tear film isn't quite the same, and you might find that serum tears are a little more viscous and they're more comfortable. So I would try the Restasis®, you know, and then the serum tears afterwards. See if one makes you feel better. You're lucky that both of them work for you.

57:13  Audience member’s experience with PROSE® was life-changing:  Hi, I was at Boston Sight® last week and I got my PROSE lenses. I got them a couple of weeks ago and I just went for a follow up and I have to say, after having gone through every single thing that you said— Restasis®, Xiidra®, punctal plugs, serum tears, it seems like 100 other things, amniotic patch in my eye, a million things— this is the only thing that worked and it is absolutely life changing. It's just like a miracle. I mean I can see, I can see 20/20. You still need reading glasses and I still have some light sensitivity, but it is absolutely amazing. I'd be happy to talk to anybody about it. Mine was covered 100% by insurance, over $10,000 for a pair of PROSE® lenses and you have to go for a week of training because it's a big, huge hard lens. The length and width of your eye and you have to be able to learn to put that in. But it's certainly worth looking into. It's absolutely amazing.

Dr. Irvine:  I'm glad you had a great experience.

Audience member:  Yeah. Boston Sight® is the best. That's where all the PROSE® lenses in the United States are manufactured, so wherever you go in the US, your lenses are from Boston Sight®.

Dr. Irvine:  So what happens is that the individual optometrist in the satellites have proprietary software on their computer. And while you're in there, it's like fitting shoes: they have a whole wall of these lenses that they've kept from people who haven't been able to wear certain lenses, because they give you a certain amount, and if it doesn't work then they put it up on the shelf here and then they use it again to fit somebody else. So, they make observations and they change the shape of the lens right there on the computer, and then once they decide that that's what they want to go with, that goes back electronically to Boston and that gets downloaded straight into their computer which runs the lathe which creates the PROSE® lens. And it's usually within about 24 hours that they FedEx® the lenses back so that you can have them for trial.

59:37  A downside of the PROSE lens is that you can get protein deposits on the lens:

Audience member:  I was going to say I had the same experience, went through everything, through cauterization. The scleral lenses were definitely a game changer. But I noticed very quickly, in the day, for me, I don't know if it's the same for everyone, I started to get protein deposits or other problems with the lenses. Is there any drops you can put in without having to take out the lenses that can clean off those deposits throughout the day?

Dr. Irvine:  That's a great question. One of the downsides of the PROSE® lens is that you can get protein deposits forming. Not only on the outside but sometimes people get them on the inside and it requires removal for cleaning. And the optometrist will say, ‘Well take a Q-tip and just clean them off.’ And fortunately they've come up with a new coating that is supposed to be somewhat resistant to that but it's not uniform. So this is still evolving.

I have wondered whether or not this protein deposit is in some way an allergic response to it. It's some kind of a response of the conjunctiva to the device, and so, in some individuals, I have tried using a non-sterile anti-inflammatory drop that you would use for allergy, which stabilizes certain cells that mediate the allergic response. I don't have enough data to really know if that works, but I know there are a lot of people that are really affected by it and it's really a concern, not only by the physicians and the patients, but also by BFS [Boston Foundation for Sight].

01:13  Treatment for peeling eyelids is moisturizing cream:

Audience member:  I get peeling in my eyes, on my eyelids and underneath and I was wondering what could I do for that?

Dr. Irvine:  Peeling?

Audience member:  Yeah, my skin peels in my eyelids, and underneath, when my eyes get very inflamed. It's on the outside but I get dry eye on the inside as well. I was wondering what I could do, I've been putting hydrocortisone cream on it but that's not ...

Dr. Irvine:  Yeah, I would use more of a moisturizing cream. Because as the— I don't know how many of you went to the oral medicine presentation this morning, but the eyelids are very thin, the skin there. And so you can get problematic thinning of the eyelids if you use it chronically. So I think moisturizing is the key thing. And remember, some of the drops that you're putting in can be irritating as well. So all the more reason to learn how to put the drops in. And forgive me if you already know how to put the drops in and you're putting them in selectively, straight into the fornix, that's the best way because you don't get as much runoff and then the irritation of the skin.

Using non-preserved drops, again, will decrease the irritation of the preservatives on the skin.

Audience member:  On the outside? On the lid?

Dr. Irvine:  Well if you're using the drops, they're always going to get on the outside. The extra. And if there's preservatives, that might irritate, possibly in a sensitized individual, the skin.

02:56  Treatment for crusting in corner of eye: 

Audience member:  Okay I was just wondering what would help with the peeling of the skin or the inflammation. And I get crusting in the corners of my eyes a lot.

Dr. Irvine:  The crusting comes from the irritation of the conjunctiva, and it oozes just like you would when you get a cold, because the conjunctiva is a wet membrane. And when it gets irritated it oozes. At night it accumulates on the lashes, just like if you had a cold. So, one thing you have to ask your eyecare provider is ‘do I have blepharitis’ and should it be treated with, say, an antibiotic ointment to kind of clear off some of the bacteria?’

There's another agent that you could use for lid hygiene. It's called hypochlorous acid. It comes in a couple different forms. One is Avenova® by Nova Bay® and the other is HypoChlo®r by OcuSoft®. And hypochlorous acid, in its dilute form, is the active ingredient in white blood cells which kill bacteria. So it can be very effective at cleaning off and sterilizing some of the bacteria around the eyelashes.

Audience member:  Thank you.