Graft-versus-Host Disease: Eyes

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Graft-versus-Host Disease: Eyes

Monday, May 1, 2023

Presenter: Jessica Ciralsky, MD, Weill Cornell Ophthalmology

Presentation is 34 minutes long with 17 minutes of Q & A

Many thanks to Sanofi whose support, in part, made this video possible.

Summary: The eyes are one of the most common sites for graft-versus-host-disease following stem cell transplantation. This presentation describes the most typical forms of ocular GVHD and the wide array of remedies to effectively treat symptoms of this problem. (Note: In this presentation, when the speaker uses the term bone marrow transplants, it includes stem cell and cord blood transplants as well.)

Highlights:

• About half of transplant patients will experience ocular graft-versus-host-disease (GVHD) after a transplant using donor cells and up to 90% may experience it if they have GVHD elsewhere in the body.
• Ocular graft-versus-host disease can lead to disabling pain and blindness if not treated. Early detection, diagnosis and treatment are important in preventing long-term complications.
• Dry eye is an inflammatory disorder than can be a severe, burdensome form of ocular GVHD. Treatments for ocular GVHD can decrease this inflammation and improve sight.

Key Points:

(02:53): Ocular GVHD affects the ocular surface of the eye, tear glands, and oil glands.

(06:56): Rapid evaporation can limit tear production or quality and produce dry eye.

(15:15): Lubrication for ocular GVHD gets more tears to the surface through several types of artificial tear products.

(15:44): Preservative-free tears are preferable for ocular GVHD and they come in different viscosities.

(17:49): Nighttime ocular GVHD can be treated with ointments, moisture goggles, or punctal plugs.

(21:10): Serum tears, made from a patient’s own blood, act more like natural tears in treating ocular GVHD.

(22:10): Scleral lenses are made for dry eye patients and can be an effective treatment for ocular GVHD.

(27:41): Surgical options are possible for ocular GVHD when all else fails.

(29:38): In the most severe cases of ocular GVHD, corneal transplantation is an option.

(31:36): Self-care remedies for ocular GVHD include artificial tears, warm compresses, and night goggles.

Transcript of Presentation:

(00:01): [Becky Dame]: Introduction.  Hello, my name is Becky Dame and I will be your moderator for this workshop. We'd like to welcome you to the workshop, Graft-versus-Host Disease of the Eyes.

(00:11): Before we begin, I'd like to thank Sanofi, whose support helped make this workshop possible.

(00:18): It is now my pleasure to introduce our speaker, Dr. Jessica Ciralsky. Dr. Ciralsky is an associate professor of clinical ophthalmology at Weill Cornell Medical College and a cornea specialist with a special interest in severe ocular surface disease. She works closely with transplant teams, both at Weill Cornell Medical Center, as well as the Memorial Sloan Kettering Cancer Center, to provide comprehensive care for patients. Her practice focuses on early diagnosis of ocular GVHD and both traditional and novel treatments. Please join me in welcoming Dr. Ciralsky.

(01:04): [Dr. Jessica Ciralsky]: Overview of Talk. Thank you so much. What a pleasure to be here and to speak with all of you. I am going to be talking about ocular graft-versus-host and how it affects eyes. I have no relevant disclosures for this talk.

(01:20): A recent study showed that 40-60% of patients who are transplanted with donor stem cells experience ocular graft-versus-host-disease (GVHD) after transplant. I'd like to start by thinking about how common this is. This is a little bit of a difficult question to answer because the studies are so widely variable. Some studies show it's in 10% of patients and others show it's up to 90%. There was a more recent study that showed 40% to 60% get ocular graft-versus-host. But if you have graft-versus-host anywhere else in the body, and that's chronic graft-versus-host, the amount of graft-versus-host in the eyes jumps to a 60% to 90% chance. So essentially what I tell my patients is about half of all comers are going to get ocular graft-versus-host, but if you have chronic graft-versus-host elsewhere in the body, that number's going to jump to 60% to 90%.

(02:10): Mainly when we're quoting these numbers, we're talking about chronic graft-versus-host, not acute. Acute is a much smaller subset, less than 10%.

(02:20): GVHD of the eyes may be the first affected organ of the body. And interestingly, ocular graft-versus-host disease might be the first affected organ. So you might not have graft-versus-host elsewhere in the body and it might just come out in the eyes. There was one study that showed 22% of new dry eye patients after a bone marrow transplant presented with dry eyes and inflammation of the conjunctiva, the white part of the eye, without any other graft-versus-host. So it's possible that it can be your first presenting symptom.

(02:53): Ocular GVHD affects the ocular surface of the eye. How does it affect the eyes? Well, essentially it's an ocular surface problem. And when you think about what the ocular surface is, it's the surface of the eye, the parts that you can touch. In the picture, you can see the eyelids, you can see the white part of the eye. We call that the conjunctiva. And you can see there's sort of this clear dome that goes over the colored part of the eye, we call that the cornea. That's the surface of the eye, the parts that you can touch.

(03:23): Ocular GVHD can also tear glands and oil glands. There are also parts that you see in the left picture, that can affect how this ocular surface is affected. The lacrimal gland, which lives in the upper outer part of the eye is the tear-producing gland. And then towards the nose we have the tear ducts, nasolacrimal ducts, these are where your tears drain to go down your nose.

(03:48): Ocular graft-versus-host can do a lot of things to the eye, but essentially, it's mainly affecting those surface parts of the eye. So, on the eyelids you can get what's called meibomian gland dysfunction, which is where the oil glands are clogged, and we'll see a picture of this in the next coming slides.

(04:05): Sometimes the eyelids can turn in or out.

(04:09): The conjunctiva, which is the white part of the eye, can have redness, what we call conjunctiva and sometimes even membranes on it.

(04:17): The cornea, which is that clear dome at the front of the eye can have dry spots. And if you see in that top picture, those are called filaments, they're almost like stuck on dry spots, you can have a lot of discomfort with those. You can even have a scratch on the eye, which you see in the bottom picture, and in the most severe cases it can go on to even create more severe thinning and openings of the eye.

(04:45): Lacrimal gland dysfunction means that that gland that lives on the upper outer part of the eye is not producing tears correctly. And then there is a much lower percent possibility of it affecting things deeper in the eye. Inflammation in the eye is what we call uveitis.

(05:02): Dry eye can be a severe, burdensome form of ocular GVHD. The burden of disease can be really severe. So, essentially when you have ocular graft-versus-host, it's like having dry eye, and many times severe or very severe dry eyes. And they've done lots of studies to compare the impact of severe dry eye on a patient's life compared to moderate-to-severe chest pain. For the most severe cases, it's thought to be worse than a disabling hip fracture. So, this can be really burdensome for a patient and really affect their everyday life.

(05:37): So, when you come to the eye doctor, what are they going to do? When I have a patient for the first time, I like to do a full exam. So, you'll get a vision [test] and we'll check for things like prescriptions and glasses, and we'll dilate you and look for all other problems. But the big thing I'm looking for are problems with that ocular surface.

(05:59): Doctors use dye to diagnose ocular problems. And so, the most common thing we do is put a little dye in the eyes. Sometimes it's what's called fluorescein dye, which is more of a yellow drop that you may see. Sometimes something called lissamine green, which is green. These are vegetable dyes. They're nontoxic. They go on the eye and what they do, if you see in the bottom two pictures, they stain parts of the eye so we can see what's going on. The bottom right picture is staining the cornea so we can see dry spots. The bottom left picture is staining of the conjunctiva so we can see dry spots on the white part of the eye, the conjunctiva.

(06:37): The upper right picture are the oil glands that I was referring to, what we call meibomian gland dysfunction or blepharitis. These oil glands almost have a little whitehead or a cap on them, and those are abnormal oil glands.

(06:56): Rapid evaporation can limit tear production or quality, and produce dry eye. The upper left picture is something we look at for evaporation. And evaporation of the eye can be important because if you put tears on the eye or your eye has tears and they evaporate too quickly, you can get dry eye. So, two ways to get dry eye, you cannot have enough tears, and so, low production, or you can have tears, but they're unhealthy and so, they evaporate too quickly.

(07:23): So, many of the tests we do are with simple testing modalities like these dyes that we put in the eye. They're not painful and it just gives us a lot of information to examine the eyes.

(07:38): Not all doctors that you go to may have all of these testing modalities, but there are other ways to look for dry eye and ocular graft-versus-host. The upper left picture is something we call tear osmolarity, and it checks how salty the tears are, right? If they're really salty, the eye is going to be very dry. If they're not so salty, there's enough tears and so, the eye won't be so dry. It's a nice way of telling us how dry an eye is.

(08:06): There's something on the upper right called topography that gives us a sense of how dry the eye is. You get these sort of blank spots on the eye when the eye is very dry.

(08:16): Dry eye is an inflammatory disorder. Moving down to the bottom left, there's a test, it almost looks like a little pregnancy test with the two little lines that tell you how inflamed the eyes are. Dry eye is an inflammatory disorder.

(08:27): There's a test called Schirmer's where they put this little strip in the eye and they measure how many tears you make in five minutes, and that tells us about what's called your basal tear secretion, how many tears do you make in general.

(08:41): And then there are tests that can look at the oil glands. We talked a lot about the oil glands, and we can actually image them to see if they're complete, if they're atrophied, which means sort of dying or not there anymore or even foreshortened, where they need to be opened up more.

(08:59): Acute GVHD in the eyes is uncommon but can be severe. So, once we have all of this data and we're looking at a patient, how do we grade this or stage it? Well, it's different for acute and for chronic [GVHD]. Acute, like I was saying before, it's very uncommon, but when you get it, it can be severe. Many of the treatments that we will talk about later on apply to both, but when we do acute treatments, they're going to be for shorter periods of time, whereas chronic is probably going to be a chronic treatment.

(09:28): Acute GVHD has four stages from simple redness to actual scratches on the eye. So, the four stages of acute GVHD staging. The first one is what we call conjunctival hyperemia, which just means redness. The second one is that redness with some swelling, we call that chemosis. The third one is redness with membranes, and you can almost see that little scarring in that inner membrane. And then the fourth one is scratches on the eye as well. And you can see that staining with that yellow dye.

(09:58): Chronic GVHD has different staging models or scores based on patient symptoms. When we get to chronic GVHD there's a lot of data and different staging groups that have worked on how to think about chronic GVHD staging. The first one that I want to mention is from the NIH, and this was from 2014. And the way that they think about staging is first, the dry eye has to be confirmed by the ophthalmologist and then they want to think about symptoms. Does the patient have no symptoms? Then they're probably a score of zero. If it's mild, moderate, or severe, the scores go up. They also think about how many times a patient has to use a lubricant eyedrop like an artificial tear, and if it's impairing their vision.

(10:42): There is another grading scale that I often use more commonly, and this was done by a bunch of experts in ocular graft-versus-host. They met a bunch of times and decided to come up with different variables so that they could give patients different diagnostic categories. So, they could tell them, no, this isn't graft-versus-host, or it's probable or it's definite graft-versus-host.

(11:07): Staging chronic GVHD is based on corneal staining, patient questionnaires, and tear production. And what they do, in this slide, is they look at corneal staining. And the corneal staining is going to look at how that yellow dye, what we call fluorescein dye, stains the cornea. So, in grade zero there's no staining. Grade one, a little bit, grade two, a little more and grade three even more. Essentially what that injection score shows is how red the eye is. Score zero is no redness, score one looks a little bit pink and score two looks pretty red.

(11:47): The next one looks at a questionnaire. And so, this questionnaire is going to ask the patient a bunch of questions. Are you sensitive to light? And if you are, can you grade that? - all the time, most of the time, half of the time, some of the time or none of the time?

(12:05): And then what this grading scale does is bring all of this together so that you have the different components. They're also adding in the Schirmer's test, which is that strip of paper that tells you how many tears you make, and then they give you a grading scale to tell you if you have graft-versus-host or not.

(12:25): But importantly, what we need to think about is what do we do with patients once we think they have [ocular GVHD] or are even borderline, probable or definitive graft-versus-host disease? How do we treat it?

(12:38): Treatment for ocular GVHD modulates or changes the tear film. Well, in order to explain this best, I want to take a step back and think about the tear film, because what we're modulating or changing when we do treatment is this tear film. And this tear film has three major layers. The inner layer is called mucin, and this is like mucus of the eye. The middle layer, which is the bulk component of it, is the water layer. And the outer layer is called the lipid layer.

(13:06): So, when we think about this, the inner layer comes from little cells on the white part of the eye we call goblet cells. This is not affected that much in graft-versus-host [disease], unless you get more severe or to the end stage most severe, which is very, very rare.

(13:24): This treatment for ocular GVHD affects the water and lipid layers so tears last longer on the eyes. So the main things that we're dealing with when we deal with treatment are affecting the water layer and the lipid layer. That water layer comes from that lacrimal gland, that gland in the upper outer part of the eye that produces tears. The lipid layer is coming from those oil glands that line the lid, and we showed that in an earlier picture. If you look upper right, those oil glands are producing oil. And when the oil is unhealthy, that tear is going to evaporate too quickly because the oil is not keeping it on. So, you do want to get your oil healthy so that your tears last on your eyes longer.

(14:04): Treatment for ocular GVHD will also decrease inflammation but is usually organ specific rather than systemic immunosuppression. So, when we think about treatment, our three goals are to lubricate the surface and bring back the water. Control evaporation by affecting the lipid layer, the oil layer. And then all dry eye is inflammatory, so we do want to decrease any inflammation. What I like to emphasize with my patients, and we talk about this with the other doctors as well, is that most ocular management can be treated with what we call organ specific treatments, meaning I can give eyedrops or treatments that are just for the eye. I don't have to reach to increase your systemic immunosuppression or put you on oral steroids. I can typically control it locally with eye treatments, which is important.

(14:49): So, as I think about treatments, I put them into those three buckets. Again, lubrication, how do I get more tears to the surface? Control evaporation, how do I help the oil to be healthier so that tears don't evaporate too quickly? And how do I treat inflammation? For most patients, I will tell you that we're doing a combination of all three because most patients have multiple things wrong with the tear film.

(15:15): Lubrication for ocular GVHD gets more tears to the surface through several types of artificial tear products. So, let's start with lubrication. I'm sure all of you are familiar with artificial tears. This was a picture I took when I walked into a drug store just to look at the crazy amount of possibilities you have when you have to decide on a tear. It can be overwhelming to look at the tear aisle and try to figure out which artificial tears I can get. And furthermore, there's been recalls recently which have made this an even more complicated story.

(15:44): Preservative-free tears are preferable for ocular GVHD and they come in different viscosities. So, what I tell my patients is, I break this down into two different ways of thinking about it. Number one is they preserved or non-preserved? Preserved tears typically come in a bottle and non-preserved tears typically come in the individual vials like you see over on the right part of the screen. I prefer preservative-free tears in my graft-versus-host patients because the preservatives can be irritating and a little toxic, especially if you use them often throughout the day. Four times a day is a common amount of time to use, or less, and for those patients you may be able to get away with something preserved. But for anything more than that, I recommend preservative-free, and I like to recommend preservative-free for almost all of my patients.

(16:38): The other bucket that I separate the tears into is what's called the viscosity or the thickness of the tears. I like to think about tears in three viscosities. There are tears, there are gels and there are ointments. Tears are what you probably think of as traditional tears, water drops. Gels have a little more thickness to them. What's nice about that is that it lasts a little longer on the surface, but it may blur your vision temporarily. And then ointment is viscous, almost like a cream that you're putting in the eye, and that can absolutely blur your vision, which is why we recommend it at night and not during the day, but it does last a lot longer.

(17:23): So, bringing us to our next slide, A lot of patients come to me and tell me about morning dryness or middle of the night dryness, and they put in tears before they go to bed. Well, often that's not enough, just to put tears in. Tears are only going to last maybe 15 or 20 minutes. So, you have to think about how to conserve that water in the eye and keep the eye lubricated all night long. An ointment will do that for you.

(17:49): Nighttime ocular GVHD can be treated with ointments, moisture goggles, or punctal plugs. So, there's many different nighttime ointments on the market, over the counter. You put just a tiny bit, a quarter inch I tell patients, which is the size of a piece of rice, you put it in and close your eyes. You don't want to put it in and go read because you're not going to be able to read and it's going to evaporate off your eye if your eye is open. So, you want to put it in and go to bed. But I will tell you that a lot of my patients hate ointments, and that's common.

(18:14): There are other options for nighttime lubrication. One of them is called moisture goggles, and this is just an example of one of the moisture goggles on the right picture. These goggles form almost a seal on your eyes and that keeps the tears in longer. So, you may add a regular tear in before you put the goggles on before bed. What's nice about these is they don't blur your vision. When you need to get up to go to the bathroom or get up to do something, you just take them off, you can see and then put them back on to go back to bed.

(18:46): What about punctal plugs? Well, I will tell you, these aren't my first choice of treatment for patients, meaning when I first see a patient, I don't put them in as a first step. I use a lot of them, but I use them after I've controlled the inflammation. Because what they're doing is blocking any outflow from the eyes. So, what I do is I treat the inflammation and then I add the punctal plugs.

(19:10): And so, if you think about the anatomy and you see in that right picture, your eyes make tears and then they go through this tear drainage system that goes through the eyelid and then will drain back through the nose. There's a bottom and a top. Usually, we plug the bottom one first because if you think about it with gravity, 80% of water is going to go through the bottom. Only 20% is going to go through the top.

(19:34): I find that with a lot of graft-versus-host disease patients, these plugs love to fall out. So, usually we put in the silicone plugs because they stay well in most patients, but in graft-versus-host, sometimes they must turn to what are called collagen plugs, which go in internally because they don't fall out. They do dissolve, so they have to be replaced, but they don't fall out.

(19:59): Anti-inflammatory medications can also help with ocular GVHD. We also use a lot of medications to help with dry eyes. So, dry eye is inflammatory, and you want to use anti-inflammatories. So, there's different formulations of cyclosporine and lifitegrast. I don't have a favorite in this group, but often we can do a little bit of trial and error and trial different ones. What they do is help produce more tears and decrease inflammation. But it does take a little bit of patience. These medicines take time to reach peak efficacy. Some of them take three months to really work well. Some of them work a little faster. But all of them have a little bit of a build to them, so you're not going to feel instant relief, it's going to be over time.

(20:45): And most of them can be associated with some irritation or burning upon installation. So, when you put that drop in, it can burn. If it burns, there are a lot of different things you can do to help with that. Sometimes I tell patients, putting it in the fridge, cooling it off can help a lot. You can also put some tears in maybe five minutes before or five minutes after to help with the sting.

(21:10): Serum tears made from a patient’s own blood act more like natural tears in treating ocular GVHD. But for some patients, all the things we've talked about, thus far, are not enough. And so, there are drops that can be made called serum tears, and these are drops made from your own blood. They take your blood; they drop the clear part of the blood called this serum. They sort of spin it down, add it to some artificial tears, saline, and they make it into a little dropper. You keep it in the freezer until you're going to use it. Then you keep one bottle in the fridge and use it until it's gone. And then take another one from the freezer so you're not drawing your blood every week. You get about a three-month supply at a time.

(21:47): What's great about serum tears in very dry eye patients is that they're going to simulate or act like your natural tears a lot more than the ones that you buy over the counter. They have growth factors and nerve factors and a lot of healing factors that you're not getting with the over-the-counter drops.

(22:10): Scleral lenses are made for dry eye patients and can be an effective treatment for ocular GVHD. For many of the severe dry eye patients, as well, we can go into what's called scleral lenses. Many patients come to me, and we start talking about contact lenses and they say, "I've worn contact lenses before, but I'm too dry for contact lenses." And that's probably true for traditional lenses, but these are not traditional lenses. These are lenses made for dry eye patients. They are hard lenses and they're scleral, which means they sit on the white part of the eye, not on the cornea like traditional lenses.

(22:42): What's cool about them that you can see in the upper picture is they're filled with artificial tears. So, you put water in them and then when you put that on the eye, it suctions on the eye. So, in essence, your eye is bathed in a liquid bandage all day long. It's as if you're putting tears on your eye 24 hours a day. These are not something you can sleep in, so you put them in in the morning and you take them out at night, but they are something that you can put on the eye to help throughout the day, help with pain, help with light sensitivity, and help with vision. So, it can help with all of those things.

(23:22): So, the one thing I want to just pause here and talk about are symptoms of graft-versus-host in the eye or symptoms of dry eye in general. So, things that we think of for symptoms are pain. Sometimes people describe it as an irritation, a sticking sensation, like a little pinprick. Some people tell me foreign body sensation, they feel like something's in the eye, grittiness, burning. The eye can look red, but it doesn't have to. Fluctuating vision is another one where you feel like every time you blink, the vision changes. And some people describe it as tired eyes.

s So, I want to move on to the second bucket, which is to control evaporation. If you remember, we're thinking about those oil glands and how to get healthier oil out of them. So, traditional first line treatments that we think about are sort of warm compresses or heat masks. Sometimes, as I explain this to patients, it can sound a little hokey, but the idea is you want to get the oil that is hardened and has become abnormal, melted and expressing better.

(24:34): So, sometimes when we're pushing on your oil glands, we're grading it, does it look like olive oil? That's actually a good thing. We want it to look like olive oil. Oil is good for the eyes. But if it looks like toothpaste and it's really hardened, that's abnormal. So, where the heat, the warm compresses, or the over-the-counter heat mask that you can put in the microwave work is to melt some of that oil.

(24:56): Lid hygiene is washing the eyes with topical antibiotics or products to clean or warm the oil glands. Some people have done the traditional baby shampoo scrubs where you make your own little scrub. You can also buy these as pre-made scrubs. They almost look like little makeup remover pads and there are many different brands on the market, but essentially, they clean off any of the excess oil and clean the eyelids to help express the better oil.

(25:21): We sometimes use topical antibiotics for this. There's one with azithromycin, there's one with tobramycin. And even oral antibiotics like doxycycline can be used to help improve the oil glands.

(25:36): There are also procedures. So when the things that I was talking about on the previous slide aren't working, there are procedures that can help with the lid hygiene. So, there's something called BlephEx, which you see in that left picture, it's almost like a deep clean for the eyes. There's a rotating brush with shampoo that can sort of really deep clean those oil glands.

(25:57): Or the picture on the right is called LipiFlow, where it has a heat mechanism that heats up the oil glands so that it can melt the oil, and then it has a mechanism that pushes on the eyelids so you can express all of that oil. There are many other eyelid procedures on the market, and these are just some examples of what's out there.

(26:20): Steroid can be used to decrease ocular inflammation but they have risks with long-time use. You also want to work to decrease inflammation. So, I'm sure a lot of you are familiar with steroids, because you may need to use these systemically or by mouth for other reasons. In the eyes, they are a wonderful treatment, but they are a double-edged sword. They work really well for dry eyes, but we don't like them as a long-term option because they can lead to an increased risk of cataracts and glaucoma.

(26:48): Cataracts are more of a cumulative thing. The more you use steroids, the higher your risk is. You can actually get cataracts from other forms of steroids. So, it's not only topical steroids. But cataracts can be treated, so we do think about this and monitor for it.

(27:07): Glaucoma is something we must monitor more closely. It's not common to get glaucoma with steroids, but it is possible. So, we watch patients. But I like to use this as a pulse therapy, which means if you get a flare up over the year, we need to use 10 days of steroids, that's fine. Or maybe if we're starting a medicine like the Restasis® or Cequa®, we need to use a little steroid to get your eyes quiet to get you there. That's good for me. So, pulse therapy is common. I don't like it as a long-term option.

(27:41): Surgical options are possible for ocular GVHD when all else fails. So, when conventional medical therapy fails, there are other things we can do. The goals of surgery are often to help bring more lubrication to the eye. Maybe you have a scratch on the eye that won't heal, and this will help with that. Or maybe you had a scratch, or an infection and it led to scarring and we have to clear that view and restore vision.

(28:08): One simple thing we often do is a tarsorrhaphy. A tarsorrhaphy means we close the eyelid. We can do that with tape, as you see in the right picture, and this is usually when it's temporary. Or we can do it with a stitch. And you can even do it with something longer than this kind of stitch that I'm showing where it becomes more of a permanent fix. But often we do it just as a temporary treatment to help with a scratch on the eye.

(28:38): There's also something called amniotic membrane. Amniotic membrane comes from the inner layer of the placenta. This is a wonderful material that has a lot of biologic properties to help heal different parts of the eye. So, it promotes re-epithelialization, which means it helps scratches heal. It helps decrease inflammation and scarring and can serve as a biologic bandage. When we put it on the eye, it brings all of these good properties that your natural tears and natural surface should bring to the eye.

(29:13): It can be sewn on, as shown in this picture where you have to go to the operating room. Or it can be done as a standalone, it's almost like a contact lens that has the membrane draped over it. We call it a symblepharon ring. It's a little ring with this draped over amniotic membrane that can be done in the office. It gets put in like a contact lens and then gets removed.

(29:38): In the most severe cases of ocular GVHD, corneal transplantation is an option. When it's really severe, sometimes we have to go as far as corneal transplantation. This is rare, but we sometimes need to do it when we have to give a patient better vision for a multitude of reasons. Maybe they have scarring, maybe they have haziness on the cornea, and many times it has to be combined with other treatments so that you get a good result.

(30:04): Some patients may be pre-treated for ocular GVHD before transplant, but a baseline exam before transplant is always advisable. So, the timing of treatment is also a little bit unclear. There have been a couple studies to look at 'should we be pre-treating patients?', meaning starting treatment before you have the bone marrow transplant. There's been one big study, but it was retrospective, meaning they looked at patients after the fact, that showed that patients that got something like Restasis before the bone marrow transplant versus patients that didn't get it till at least six months after the transplant, that the patients did better when they got it beforehand.

(30:39): What's hard about this is we probably need some bigger studies to try to figure this out, and what complicates the pictures for ocular graft-versus-host is a lot of us get dry eyes as we get older, and a lot of that dry eye could be preexisting. So, I always tell my patients, if you can come ahead of time to see the eye doctor, it's always better to get a baseline exam so we know where you start and where we're going afterwards so that we have a form of comparison. I don't routinely start patients on treatments beforehand, but it is something that I think about. I think it's just important to talk to your bone marrow transplant team to get in touch and looped in with an eye doctor who's familiar with graft-versus-host so that we can carefully monitor you to figure out if you get it, and if you do, how early we can treat.

(31:36): Self-care remedies for ocular GVHD include artificial tears, warm compresses, and night goggles. So, before I get to the summary, I just want to talk about things that you can do for self-care. Artificial tears are one thing that I think are easy to do. They're over the counter. I do prefer preservative-free. One of the reasons I prefer it is there is a bit of toxicity to preservatives, and although most patients don't use it in high enough doses to get to a preservative irritation, which is usually if you use it more than four times a day, even still, the patients with graft-versus-host or patients that have had bone marrow transplants often have a more fragile ocular surface. So, if we can do anything to minimize preservatives and any toxicity that may come from drops, I'd like to do that. So, that's why I recommend preservative-free. And I recommend starting with two to four times a day if needed. And if needed would be if you come in and you have burning or irritation or dryness, that's when you would put it in.

(32:36): I think another safe thing to add is a warm compress, and you can do this with a washcloth, just keep it warm five minutes a day. I often tell my patients, do it in the shower when you're in there anyway, you've got that warm water coming on constantly so it can keep it warm.

(32:54): There are also glasses and night goggles, as I showed in the picture, that can be really helpful for patients. Many of my patients have a lot of dry eye when they go outside. It's cold, it's windy, and when that hits the eyes, they tear a lot, or they get irritation. There's a website called dryeyeshop.com that has a great selection of day and night glasses that can help protect the eyes. And so, I think those are things that patients can do even before seeing the eye doctor as simple ways to treat graft-versus-host without any medication or any prescriptions necessary.

(33:32 Ocular graft-versus-host disease can lead to disabling pain and blindness if not treated, but early detection, early diagnosis, early treatment are really keys to preventing long-term complications. We can do a good job as a team if we see you early and we treat you appropriately based on what's going on. I like to evaluate patients as early as possible and even pre-transplant if that's feasible. So, that is everything I have for you. Please let me know if you have questions.

Question and Answer Session

(34:13): [Becky Dame]:  All right, thank you Dr. Ciralsky. This is an excellent presentation. We will now begin with question-and-answer session. So, our first question today is once a GVHD patient has severe dry eyes, does this ever get better or is it permanent?

(34:46): [Dr. Jessica Ciralsky]: That's a great question. I would have to see the patient to be able to answer that accurately, but I can tell you when the dry eye has affected the lacrimal gland, that's the gland in the upper outer parts, that that can't come back. So, the patient may always have dry eyes, but it can be tolerable and treated so that you can live your life normally. Sometimes when it's the acute graft-versus-host disease, some of that can be reversed, but many times with the chronic GVHD, if the lacrimal gland has been affected greatly, that cannot be completely reversed. So, some of it can be, but not all of it.

(35:27): [Becky Dame]: Thank you. We have another patient who's asking does GVHD of the eye eventually lead to vision loss? That they've been struggling for two years with a lot of different treatments and drops, and they really can't tell if their vision is worsening just due to the constant pain and that they just really hate to open their eyes. So, again, can it lead to vision loss?

(35:58): [Dr. Jessica Ciralsky]: So, the answer is yes, it can lead to vision loss, but it is rare for it to lead to vision loss. Usually when there is vision loss, it's because they have a scratch on the eye or they have scarring on the eye from either an infection or from a scratch. And that kind of vision loss can be treated eventually with a corneal transplant.

(36:23): But many times, patients feel as if they have vision loss because they have such a struggle to open the eyes. One way to tell is for a doctor to put in a numbing drop in the office. And if you can see well with the numbing drop, then that means your vision is probably okay, although you may still have the dryness, so it's not a perfect test. But at least it will have you open your eyes and see where your vision is. You also, if you're struggling that much, with treatments aren't working and you can't even open the eyes, that's when I would turn to something like a [scleral] contact lens. That would be a severe case of graft-versus-host in the eyes, and I think something like a [scleral] contact lens would be something I would recommend to help with both vision and dryness at the same time.

(37:11): [Becky Dame]: Thank you. That was a difficult question. Actually, another question from our patients, and I see this as we're also starting to transplant patients a little later in life, but also secondary to other treatments. So, this patient is on glaucoma drops, as well as using a Bruder mask and cleaning their eyelids. They were wondering about your suggestion of the drop gel drops at nighttime. What kind of process would that need to be? Would they need to do their glaucoma drops and then wait a couple hours and do the gel? Or what's the process there?

(37:48): [Dr. Jessica Ciralsky]: Great question. Yeah, five minutes between drops is all you need. You always want to put the thickest one in last. And I prefer ointments at night versus gel drops just because they last longer, but five minutes is plenty of time. One other thing I want to bring up with glaucoma drops is they often have preservatives. And so, for patients where the dryness is severe, even on glaucoma drops, you do want to wonder, are the glaucoma drops contributing? I'm not sure that was this patient's question, but if they are, they do make preservative-free glaucoma drops. Going back to why we like to get rid of preservatives, they can have an effect on the dryness.

(38:31): [Becky Dame]: Very good. Didn't know about the preservative-free glaucoma drops, so that's good to know. All right, perfect. Our next question is their tear ducts no longer work. What can they do about that?

(38:46): [Dr. Jessica Ciralsky]: I'm not sure if I know exactly what they're talking about. So, there's two ways that many times patients talk about the tear ducts. If the tear ducts are the drainage system, and they're having too many tears because the drainage system isn't working, and I may have them clarify to make sure I'm answering this correctly, but if the tear ducts, which are the ducts for the drainage system aren't working and the patient has too much tearing, sometimes those ducts can be opened.

(39:16): If the tear ducts, they're talking about are the lacrimal glands, which are the glands that are producing tears, [and they] aren't working anymore, that is sort of back to our first question, which is, is it sort of reversible? And if the lacrimal glands aren't producing tears anymore, many times we cannot reverse it. And then, what we have to do, is bring tears to the surface externally. And so, that's where we bring things like artificial tears in or maybe that is one who needs to be in that scleral lens to bring the tear on the surface every day.

(39:47): So, I hope I answered that one well, but if that patient can maybe clarify what they were asking if I didn't answer it correctly.

(39:54): [Becky Dame]: Sure. Thank you. And so, here's another question I think is also relevant for a lot of our patients. A lot of patients, either due to age or the therapy they've gotten, have cataracts. So, is it advisable to have cataract surgery if a patient is on immune suppression?

(40:12): [Dr. Jessica Ciralsky]: So, that doesn't bother me at all. From a cataract standpoint, the eye has its own immune system, which is nice, we have what we call immune privilege. And so, I do cataracts all the time in [patients with] graft-versus-host [disease]. Obviously, we need your doctor to sign off on it to say that you're healthy enough to have it, because you do have to have some anesthesia, it's a mild anesthetic. But I'm not at all worried about the immunosuppression part of it.

(40:37): I will say the part that worries me the most, and I am a cataract surgeon who does a lot of GVHD cataracts, is that I'm going to make you drier with cataract surgery. And so, for about three months after cataract surgery, all patients, GVHD or no GVHD, are going to be more dry than they were to begin with. And so, if you're starting with dryness, and then you get drier, this can be really difficult after cataract surgery. This can limit your outcome; this can make for a longer course. And so, what I always tell my patients is we have to optimize that ocular surface before we go to cataract surgery. And so, that's really important to mention.

(41:21): [Becky Dame]: Okay, perfect. So, we have another question here is how does the physician differentiate ocular neuropathy from ocular GVHD?

(41:35): [Dr. Jessica Ciralsky]: Yeah, that is a hard one. Ocular neuropathy, and I think what you're asking is what we call neuropathic pain, is a more complicated one. Ocular neuropathy, or neuropathic pain, usually means that a patient looks good, they come to our office, and they have nothing on exam. All those tests I was showing, where we look at all the different pictures, they look great. There's no staining, there's no red eyes, there's nothing, but the patient is miserable.

(42:09): What's hard about this is we see that sometimes, the dry eye symptoms and signs don't correlate, so a patient can feel terrible, and we don't see much. But ocular neuropathy is rarer in this group of patients, in my experience, than other patients. Patients who have had LASIK or patients who've had surgeries where we cut nerves, it's more common to have ocular neuropathies.

(42:37): But the way that you differentiate this, for me, is when they come to the office, I put that numbing drop in them and I ask them if their pain goes away. If their pain goes away with that numbing drop, that means that it's on the surface, that surface, which is the part you can touch of the eye. If the pain goes away, that means I can use some of my treatments that we talked about to help you. If they still have pain despite that numbing drop, that means that the pain is coming from somewhere deeper, maybe a nerve is being triggered, and then they have to think about systemic medicines that treat neuropathic pain.

(43:11): [Becky Dame]: Perfect. All right. Thank you so much. One of our other questions is does the preservative in Systane® eye gel increase the chance for possible inflammation if you use it at night?

(43:31): [Dr. Jessica Ciralsky]: It should not. No. Many times with the gels, they are using such a nice preservative, I think you even put it in there. It's not what we call BAK. BAK, it has a much longer name, but that's the preservative that's in many eyedrops that is the most irritating of the group. The gels, the ointments, they often carry a preservative that is very gentle on the eye. So, when I think about gels and ointments, you don't need to find them preservative-free. I stress that more with the artificial tears.

(44:05): [Becky Dame]: Okay, very good. Another question comes with, is it safe to have shunts put in for glaucoma after a bone marrow transplant?

(44:17): [Dr. Jessica Ciralsky]: Yeah, I mean, if you need it for glaucoma, then you need it. And I always tell my patients that I'm in charge of the front of the eye. Yes, it has a lot of problems that can be had in terms of symptoms, in terms of vision, but for the most part, I have treatments. I can fix things. Even as far as a corneal transplant if I need to. You don't go blind from the front of the eye problems typically, but you can go blind from glaucoma. And so, if you need a shunt for glaucoma, I am always for it.

(44:52): Can it increase the dryness? The answer is yes, and sometimes we need to be more aggressive, but I always, if a patient needs retinal surgery, glaucoma surgery, I think it's important to treat that regardless of the dry eye. We just have to be more aggressive with the dry eye.

(45:08): [Becky Dame]: Perfect. I have a patient here who is noting that they have worn contacts for decades. Is there any comment on wearing standard contacts with dry eye that comes and goes?

(45:25): [Dr. Jessica Ciralsky]: Again, this may be a little bit of an individual answer for each patient in that I have seen plenty of patients that have mild dry eye after bone marrow transplant, and they can wear their standard contacts and that's fine. And maybe for a week a year they have a little irritation. We take them out of contacts, treat them maybe with a week of steroids, and then they go back to their soft contacts. But if soft contacts work for the patient and you're being evaluated and everything looks fine, that is okay. I only leave those specialized contacts for patients that fail other treatments.

(46:05): [Becky Dame]: One of our patients is actually, this is good for HCP communication. So, once you return to your regular optometrist, how do you address the dry eye portion since they are not usually familiar with graft-versus-host disease?

(46:21): [Dr. Jessica Ciralsky]: That's such a hard one. It may be something where you have an ophthalmologist who's a specialist in graft-versus-host disease who's sort of the captain of the ship, and then maybe the optometrist who is someone that sees you regularly. And what you may do is just have good communication between the two because the optometrist... I guess it depends how comfortable your optometrist is.

(46:49): We have an optometrist at our practice who's amazing at dry eye, and she actually fits our patients for that scleral lens. And then there are optometrists that may have no experience with it. So, I think it's a little bit individualized in this question, but I would say that if they are unfamiliar, you probably need someone that is familiar to be driving the ship. And so, maybe an ophthalmologist who's maybe a cornea specialist or does dry eye, even if it's not only GVHD dry eye, to see you once a year to sort of check in and then interface with the optometrist.

(47:25): [Becky Dame]: Okay. So, we have five minutes left in our question and answer, so I'll try to get to a maybe one or two more. So, what are your thoughts on intense pulse light, IPL, for meibomian gland malfunction?

(47:42): [Dr. Jessica Ciralsky]: Yeah, sure. I don't have an IPL here, so I didn't show it. But similar to the two that I showed up above, the BlephEx and the LipiFlow, I think it's another tool in our toolbox. I've seen some patients have wonderful results and others have okay results. So, it's a mixed bag, but I think it's safe and it's a good treatment.

(48:04): [Becky Dame]: Okay. And I think we can get to another one here. Let's see. Is accurate detection and staging a limiting factor in prescribing effective treatment? Would improved diagnostic and tracking techniques improve the long-term patient outcomes?

(48:25): [Dr. Jessica Ciralsky]: Absolutely. I think that we need a more systematic way of detecting these patients, staging them, and then putting them into treatments. And so, more and more work needs to be done to do this. I think we absolutely need better diagnostic and tracking techniques and more of a universal system so that we can follow our long-term patient outcomes and then change what we need to do or put them into buckets so there's more of a treatment regimen that's more standardized. So, we know how to treat patients. A lot of what we do is somewhat of trial and error, or everybody has their own treatment regimen that they put patients through. But absolutely, I think if we had more diagnostic and tracking techniques, it would be better.

(49:23): [Becky Dame]: I don't generally like to use meds but needed Restasis for dry eye. It got better, so I stopped, per doctor. Once it came back, I restarted. Any comments about this?"

(49:37): [Dr. Jessica Ciralsky]: It only works when it's on there, so there's no cure for the dry eye. So, I understand many patients are hesitant to be on drops. I do think though it will only work when it's on there. And so, stopping and starting is not the worst thing, but it takes almost three months for it to work. So, you don't want there to be low grade inflammation ongoing when you're not using it.

(50:09): For somebody that really hates meds, sometimes I will go straight to something like serum tears, which are made from your own blood or scleral lenses, which don't use drops. And I think both of those are nice and don't have any active ingredients if someone is hesitant to use them.

(50:23): [Becky Dame]: Okay. So, let's do one more. We won't get a complicated one, but let's see. How can you tell if the lacrimal gland has been compromised? Is there a test for that?

(50:37): [Dr. Jessica Ciralsky]: Yeah, that Schirmer's test, which I'll pull up as well. You can see when I'm pulling the pictures up. So, this middle bottom picture is called a Schirmer's test, that tells you sort of about your basal tear production, how many tears you're making in a given five minutes. That's a good test for your lacrimal gland.

(51:02): [Becky Dame]: Closing. Very good. I think that was our last question. So, on behalf of BMT InfoNet and our partners, I'd like to thank you Dr. Ciralsky for all your helpful remarks. And thank you to the audience for your excellent questions. Please feel free to contact the BMT InfoNet if we can help you in any way.