Herpetic keratitis remains a leading cause of corneal blindness worldwide, yet can have a favorable prognosis if diagnosed early and managed properly. In this live webinar, we discuss the various types of herpetic keratitis, how it varies in presentation, and new methods for its prevention as well as treatment.

Lecturer: Doug Rett, OD, FAAO, Veterans Affairs Medical Center, Boston, USA

Transcript

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DR RETT: Hello, everybody out there! I hope you can hear me okay. My name is Doug Rett. I’m an optometrist at the Boston VA, Boston, Massachusetts. It is 9:00 in the morning here on Friday. And I was happy to see so many people from around the world tuning into this. I hope it’ll be an interesting talk. When I thought about — when I was asked to speak, I thought about what we could talk about. I wanted to do something that everybody could identify with, and everybody could use, and I thought: What would be more global than herpes? Herpes is in every country where humans are. It’s a globally ubiquitous virus. Where humans are the only reservoir. So I thought it would be important for us to talk about. The audience is kind of varied here, right? So I hope I don’t speak above some of you or below some of you. The lecture is set up as a review, and then we’ll get into some new things that have changed about herpes in the last generation. This whole talk came about, because I was interested in what’s changed lately in herpes. In America, we’ve been vaccinating our children for chickenpox, for varicella zoster virus over the last, say, generation, and over the last ten years or so, we’ve been vaccinating our adults against shingles. The question came to mind how this would change how we see herpetic eye disease in the clinic. If we see it at an earlier or younger age, if the numbers go up or down, so we’ll get into some of that. The lecture starts out with varicella zoster virus, then herpes zoster virus or shingles, and the ocular manifestations of those, and then herpes simplex virus and the ocular manifestations of that. But that brings us to our first poll question. How comfortable are you with managing herpetic eye disease? We have a number of people in the audience today. Some of us are experienced clinicians that have been treating herpes for years, and some are students just starting off, so I just wanted to get an idea of where people were in their level of managing herpetic eye disease. We’ll go ahead and click on the question and hit submit. We’ll wait a little bit for all the responses to come through. Slightly comfortable, but need to know more. That’s a nice level to be at. There’s always room for improvement, right? So we all have something to learn. And I think it’ll be a nice review for everyone, and we’ll get into some of the new things. So let’s get right at it. If you’ve ever listened to me speak or read anything that I’ve written, you know I like to talk about the etymology of the words that we talk about, when we’re talking about certain diseases. And if you’ve read the chapter in any cornea textbook about herpetic eye disease, it always starts, it seems to be mandatory, that you start the chapter by mentioning that Hippocrates was the first to mention herpes. Herpes is the Greek for crawling or spreading. If you think about the way the rash spreads on the skin, it’s a very fitting word. I didn’t know the word zoster, also a Greek word, which means belt. But not so much a belt or a girdle that you wear around your waist to keep your pants up, but more like you can see on the right hand side here, that would be worn over the torso or around the shoulder, in Greek society. And certain people had different colored zosters. And warriors were often given the red color zoster. If you think about the picture on the bottom about what a typical zoster rash looks like, you can imagine how it would look like this zoster belt, especially if it was red, this rash going around your torso, in this unique to one dermatome fashion. Varicella is Latin for pock, and that makes sense, and simplex is also Latin, meaning singular or simple. And that seems a little bit confusing, except when you think about it in contrast to zoster, this chickenpox rash over your entire face or something over your entire body, the simplex rash is more focal or localized. It’s something a little bit more singular. That’s where we get these terms from. We’ll jump into varicella zoster virus. I’ll go between chickenpox and varicella zoster. They mean the same thing. This is the primary infection in zoster virus. And when we refer to herpes zoster virus, we’re referring to shingles, referring to the reactivation of that latent varicella zoster virus. As most of us know, chickenpox is highly contagious. It’s spread via respiratory transmission. It’s less direct contact. If you’re touching these pox and touching your skin, it’s less of a big deal than the respiratory transmission. Most cases are children, 5 to 9. If you don’t remember when a child around you had chickenpox, it’s 1 to 4 days of prodromal low grade fever and malaise-type symptoms, and then you’ll start to see the rash. It starts as a papillary rash, kind of flat and a little bit strange-looking, and then a day later, you’ll see the classic vesicular or pock-like rash. And these vesicles last for about four days. The whole thing lasts about a week, give or take. The child will complain about a skin itch, and this overall feeling of unwell. But less severe pain than you’ll see in adults. Besides the viral skin infection, the most common complication in youth is a bacterial superinfection. The skin is broken from the viral infection, and that leaves it susceptible to a bacterial infection. This is why you’ll see some people when they have a dramatic chickenpox infection, it’s a superinfection from bacteria, and can leave those pox scars that last into adulthood. That’s when the bacteria can penetrate the basement membrane of the epidermis and get into the dermis and cause scarring. That’s in youth. The most common complication in adults is pneumonia. That’s why infection of varicella zoster virus when you’re an adult is much more serious. And we’ll talk about that. That was varicella zoster virus. Now talking about herpes zoster virus. This is a reactivation of latent varicella zoster virus. As we probably know, whenever we get this varicella zoster infection, it’s in our sensory nerves. Not our motor nerves, but our sensory nerves. When the virus subsides, it doesn’t leave the nerves. It retreats down the sensory nerves into the sensory ganglia. It can happen at any age, this reactivation of our old chickenpox virus, but it typically happens over 50 years old. We’re getting older, our immune system is slowing down a little bit, and it’s been a while since we were exposed to the original virus, and our titers are reduced. So that’s why you can get it at any age. We’ve all seen friends and family who have a zoster rash in their 20s or 30s, but it’s typically over 50 years old. Usually if you have a normal immune system you only get this reactivation — you only get this shingles outbreak once in your life. Immunocompromised patients can get it more often, though. But recurrent zoster is unusual in an immunocompetent patient. It doesn’t necessarily mean that you were recently exposed to chickenpox. Say you had chickenpox as a child, and now you’re an adult, caring for a child with chickenpox. You don’t necessarily have to worry about an outbreak of shingles because you’re exposed to this. It’s not thought to be related. The outbreak in shingles is more related — as we’ll talk about later — to certain stressors. Obviously stress, sunlight, fever, things like that. Just like chickenpox, the rash in shingles starts off as erythematous flat papules, and then turns into grouped vesicles. Usually limited to one dermatome, as we talked about in the beginning, with the zoster belt around your waist. The thorax area, and you can see in the picture on the bottom, is the most common area to be affected by shingles. In this way, as eyecare providers, we don’t necessarily see most of these. Up to 40% of all shingles rashes happen in your thorax and abdomen. But the second most common is the V1 distribution of the trigeminal nerve. When you get shingles, as opposed to chickenpox, pain is the number one symptom here, and it’s often described as a sharp burning, stabbing, throbbing nerve type of pain. Sometimes can be prodromal. The patient will come in and say… I have this pain in my forehead, pain in my eyelid, and you do an exam and palpate and can’t find anything. Keep shingles on your list, because this might be prodromal pain, before you actually see the rash. And then when you’re talking about shingles, the conversation usually goes to postherpetic neuralgia. This is the most common complication of shingles. It refers to pain that persists beyond four months from the onset of shingles. Right? And the adjective used in almost all of the texts, when you’re describing postherpetic neuralgia, is exquisitely painful. If you think about the stats of shingles, one in three human beings will get shingles in our lifetime. And 10 to 15% of everybody with shingles gets postherpetic neuralgia. So we’re talking about a lot of people who get postherpetic neuralgia. This is the main reason that these vaccines exist. Half of patients are over 60. As we get older, our immune system is waning and less able to fight this battle. It results in a reduced quality of life, physically and psychologically. And it brings us to our second poll question. Which branch of the trigeminal nerve is most affected by herpes zoster? V1 is the ophthalmic branch. Again, we’re talking about the fifth cranial nerve, the trigeminal nerve. V1 is the ophthalmic branch. V2 is the maxillary branch. V3 is the mandibular branch, and V4 doesn’t exist. Don’t choose 4! Yes! Nice job, nice job. V2, the most commonly affected branch in herpes zoster. We talked about the thoracic area as being the most common part of your body, but the face and specifically the first branch of the trigeminal nerve is the second most common. And that’s what we care about in the eye. I’ll move this over. So there’s three branches of the trigeminal nerve, just like we talked about. But somewhat confusingly, there’s three branches of the first branch. There’s the frontal branch, which supplies your forehead. The lacrimal branch, which obviously innervates the lacrimal gland, and the nasociliary gland, which innervates the globe, the ethmoid sinus, a lot of the lids, and that’s what we care about as eyecare providers. So the most affected branch of the first branch of the trigeminal nerve is the frontal nerve, and that’s what you can see from this. I’ll move my mouse around. I hope you can see it. This poor lady has pretty bad shingles. Right? But you can really tell the distribution of her nerves. I’m circling the frontal distribution, which is this nasty rash on her forehead. And here, nicely delineated, is a mapping of the nasociliary branch. And you can see she has ocular involvement. Her conjunctiva is very injected. So again, frontal branch — most affected. Nasociliary is the one we care about the most. When we talk about new changes in the way we manage herpetic eye disease, we’re taught about Hutchinson’s sign. The way I learned it is a lesion on the tip of the nose, like she has here, is Hutchinson’s sign. You’re concerned about globe involvement. You should assume there is globe involvement if you see a lesion on the tip of the nose. Now the literature is pointing more towards the new Hutchinson’s sign, a lesion on the side of the nose, towards the bridge here. This is the epicenter. You can see the worst part of her rash is right where the nasociliary nerve comes out of the skin. So just because you don’t see a lesion on the tip of the nose doesn’t mean you’re safe. Frankly, a lesion anywhere on the nose, and you think that the nasociliary nerve is involved, and you should triple check for globe involvement. What does globe involvement look like? It’s typically vessels on the eyelid in a non-specific conjunctivitis. But you can have lesions anywhere in the eye. We’re gonna stay away from retinitis and uveitis. We’re gonna focus more on corneal complications. But suffice it to say: The eyelids and the conjunctiva and the cornea are the most commonly affected in zoster ophthalmicus. We refer to it when it’s in the first branch of the trigeminal nerve. You can have it when you have a forehead lesion. Often we’ll see patients sent from the emergency room with a forehead rash that they think is HCO and they want to clear the eye. So it’s your job to make sure there’s no globe involvement. 10% to 20% of all shingles involves the ophthalmic branch of the trigeminal nerve. Here’s an interesting case that I found on the web. This lady was nice enough to post her shingles saga. As it went on. And she posted it in the hopes of getting people with early shingles rashes to identify themselves and head to the doctor. Because she didn’t do that, and her case ended up pretty bad. Here’s day one. She takes a picture of herself and describes her symptoms as a headache and a skin itch. We can’t see the left side of her forehead in this picture. But you kind of assume if we’re talking about zoster that it’s spared. But notice her rash is kind of papillary and flat. Her eye seems okay, right? And her symptoms are itch. But on day two, she describes excruciating skin pain. The rash has changed a little bit. It’s become a little bit more localized. And I think you can see, if I get my mouse, some vesicles here forming there. Whereas the rash on day one is very flat and broad, now we’re kind of firming up. And perhaps a little crocodile tear here. Day four, things have unfortunately gotten a lot worse for her. The rash is obviously vesicular, and looks very herpetic in my opinion. The eyelid is quite swollen. She describes the pain as burning, which would be horrible, I think. She’s posted pictures all day, but I’ll just skip to the end. Day 7, her eye is quite involved, you can see. She says that now she’s been to three specialists, just in these first seven days, and has retinal involvement, uveal involvement, and obviously conj and corneal involvement. The rash is starting to dry up a little bit, obviously, but the virus is still in the eye. She ended up with a bad case of acute retinal necrosis, and has good central vision but has lost a lot of her peripheral vision. This is kind of how the rash changes. When we’re worried about the cornea, the most common corneal involvement in zoster ophthalmicus is just some simple punctate epithelial erosions. They kind of coalesce together. Over time, they can form pseudodendrites. When I think of corneal involvement in zoster, I think of this phrase pseudodendrites that we learn in school. It’s confusing. Is it a dendrite? A pseudodendrite? All pseudodendrites means is there’s a collection of PEEs that come together, and heaped epithelial cells on top of that. The heaped epithelial cells are devitalized, just like you might see in a corneal abrasion that’s healing. These heaped-up cells on top. And so they’ll look linear, like you see in the picture there. But they stain very minimally, as opposed to a true dendrite. A true dendrite is one that is going to erode tissue and kill these epithelial cells, and possibly burrow into Bowman’s membrane and into the anterior stroma. That doesn’t happen in a pseudodendrite. And classically, they don’t have end bulbs. They’re just linear lines where the PEEs have kind of coalesced together. You can also get this nummular keratitis, from the term numismatist, like a coin collector. This nummular keratitis is essentially just subepithelial infiltrates. The nerve endings have protruded into the epithelial cells, and you get these PEEs in the epithelium. That infection in the epithelial cells creates a localized inflammation, just under the epithelial cells. In the anterior stroma. So this is this nummular keratitis, which is just the same as before, but it’s a localized reaction. Then you can get like this picture on the left, bad keratoprecipitates, disciform keratitis and uveitis. We’ll talk about that later, because herpes simplex keratitis has a presentation that’s somewhat similar. So how do we manage zoster? We try to prevent it or we try to slow it down. A lot of us think about chickenpox as a benign childhood rite of passage, and for most of us it is, but in the 1980s in America, there were three million cases of chickenpox each year, but it resulted in 11,000 hospitalizations and 11 deaths. That’s a relatively good ratio, but if that’s your child or your grandchild, that’s a lot more serious of a case. If you have immunocompromise or HIV, or if you’re just a kid taking steroids for your asthma, your chance of hospitalization and death is much higher. If you’re an adult, you have a 40 times higher risk of death than if you’re a child. Again, more susceptible to pneumonia from that. And our immune systems are not as good as when we’re a child. And then you have the unfortunate case of perinatal varicella infection. This is where the pregnant mother gets infection with chickenpox, right before they give birth. Transmits to the child during birth. And the mortality rate from that is quite high. So if we can prevent this, it’s the best treatment for this disease. There is morbidity and mortality from shingles. Perhaps not quite as bad as chickenpox, but a study from the National Health in Britain said shingles was responsible for an average of 12 days missed work. Presumably a lot of that is for a skin rash that you don’t want to go outside for and are in so much pain for. And then there’s postherpetic neuralgia, which is on average responsible for 12 days of hospitalization, and is unfortunately the most common cause of suicide in patients with chronic pain over 70 years old. So it’s a sad case. Something that we’re trying to prevent. In America, we started vaccinating our children for chickenpox in 1995. The first dose was intramuscular injection that’s just given once. It was found to be 80% effective in preventing any kind of varicella infection at all. And 95% effective in preventing any hospitalization. But then a couple years later, we switched to combining that vaccine with a measles, mumps, and rubella vaccine. And that was dosed twice, when the child was around 1 year old, and then around 5 years old. And that was found to be much more effective. 95% effective in preventing any varicella zoster infection. The best numbers I could find were from 2014, and they compared the numbers of varicella infections in 2014 versus the early ’90s, where it was before we started vaccinating children. They found that 95% of adolescents in America had received one dose of the chickenpox vaccine, and 81% of them had received two doses. So that’s pretty good. Room for improvement, but pretty good. And then you compare those numbers to the early ’90s, varicella deaths had declined by 87%, and hospitalizations had declined by 93%. So solid numbers. Solid numbers. That was chickenpox vaccines. Now, shingles vaccination has been happening in America for about 12 years. The first vaccine was called Zostavax. It was by Merck, and it was a live vaccine. And then just about a year ago, almost to the day, Shingrex came out in America. And this is a recombinant vaccine. They both work by boosting the cell-mediated immune response. Talking about T-cells. If you look at the average American over 50 years old, 40% of us have zero titers. These are people who had chickenpox infections as a child. 40% of us have zero titers to varicella zoster. This is why we’re getting shingles. Which leads us to poll question number three. Around what year did the first major herpes zoster vaccine become available? In America. This is 1986, 1996, 2006, or 2016. We’ve been doing chickenpox vaccinations since about 1995, and the question is: When did we start doing shingles vaccinations? 1996? The actual answer is 2006. So we’ve been vaccinating chickenpox a lot longer than we’ve been vaccinating shingles. One of the things that people wonder about, and one of the things that I wondered about is the rate of shingles increasing, now that we’re vaccinating our children for chickenpox. Right? Our adults and parents and grandparents not being exposed to the chickenpox virus when raising these children, and therefore not getting a titer boost and perhaps getting shingles at an earlier age or more aggressive shingles with postherpetic neuropathy. The answer is no, they don’t think that shingles outbreaks are caused by lack of exposure to chickenpox. But confusingly, shingles outbreaks are on the rise in America and across the globe. The reason they don’t think the shingles increase is related to the chickenpox vaccine is because in countries that don’t vaccinate their children from chickenpox, they still have seen an increase in shingles vaccination. And in America, that does vaccinate children against chickenpox, they’ve seen an increase in shingles outbreaks even before the vaccination happened. So shingles outbreaks are on the rise. The CDC in America is somewhat confused about why, but they don’t think it’s related to chickenpox vaccination. Talking back about shingles vaccination, Zostavax was the first one that came out in 2006. Hence the poll answer. This was an intramuscular injection that just needed one dose. And the CDC recommended this be done in all patients over 60 years old. Then a year ago, when Shingrix came out, the CDC changed their recommendations, and now recommend all adults over 50 years old get the Shingrix vaccination. This is a two-dose vaccination. The dose is spread out by at least 4 to 6 months. One of the reasons that they recommend Shingrix to people over 50 — and the other one was recommended over 60 — is that, one, Shingrix works a lot better, and it works a lot longer. In the Shingrix trial, they did a study with 15,000 patients in America, over 50, given Shingrix. Over three years, it prevented shingles in 90% of patients, compared to placebo, and 90% effective against postherpetic neuralgia. As far as duration of immunity benefits, Zostavax showed less than 50% efficacy after five years, and no efficacy after eight years. So that’s one of the reasons why they recommended it in people who are a little bit older, because they knew that after five to eight years, it wasn’t gonna be effective. If you compare that to Shingrix, it’s just come out. They’ve been studying it, they have long-term data for 4 years, but they found almost no waning immunity in Shingrix. I leave the zoster part with this last little icon that says: Do your part! And the sobering stat, I think, that one in three of us humans will get shingles sometime in our lifetime. And we as eyecare providers see a lot of complications from the zoster virus in the eye. And we talk to our patients all the time about systemic eye diseases. Diabetes, hypertension, cholesterol. Why not also talk to them about getting their zoster vaccination? I think it’s something that we can do. A small part to help these patients. Okay. That was herpes zoster and varicella zoster. Transition to herpes simplex. I hope you’re saving some questions at the end. We’ll have some time at the end. I thought we would bang through the whole lecture and take questions at the end. Okay. Most of us know herpes simplex virus has two parts, I and II. Herpes virus I is the one that affects the eye and lips and cold sores, et cetera, and II is mostly genitals. There’s a new terminology for this that you may have heard in literature. Human herpes virus I, human herpes virus II. This is just the same thing as simplex virus. It’s just that now they’re categorizing all the herpes viruses with the same name. So human herpes virus III is varicella zoster, IV is Epstein-Barr, and human herpes virus V is CMV. It keeps going, but those are the main ones for the eye. The zoster virus, varicella zoster, was spread by usually respiratory transmission. The simplex is almost always spread by direct transmission. Kissing people, or water bottles, or something like that. And just like varicella zoster virus, develops a latency in the sensory nerves, not the motor nerves, but the sensory nerves. And after the infection erupts, it travels retrograde back to the sensory ganglia. This is your classic picture of a cold sore. Close-up. Which is kind of gross. I hope no one’s eating right now. Classic triggers. These are called fever blisters in some parts of this country. Cold sores, lots of colloquialisms for them. They’re triggered by stress, but also fever, sunlight, and hormonal changes. Much more localized than the zoster rashes are. Hence the name simplex, like we talked about. By the time we’re 40, 90% of humans will have antibodies to herpes zoster virus. This is an ubiquitous thing. Now speaking of just the keratitis, when you get corneal involvement from herpes simplex, 90% of the time this is a unilateral phenomenon. And you will get recurrences of this disease. Recurrences, thankfully, almost always affect the same eye. So you’re not gonna get bilateral — you won’t often get bilateral blindness from this. But just like we talked about zoster recurring very rarely, simplex recurs very frequently. Ten years after your first simplex keratitis, you have a 60% chance of another recurrence. It’s likely within another decade that it will recur. In these patients, once you diagnose simplex keratitis, you need to diagnose them and follow them closely and stay with them. Okay. What happens? And why does it happen in simplex keratitis? You have essentially three problems: You have an active infection of the virus, infecting a certain part of the corneal tissue. And you can have an active infection on all three layers of the cornea. So when you’re talking about simplex keratitis, it’s not as simple as just looking for a dendrite in the epithelium. You can have an active infection in the epithelium, and then classically, you can have an inflammation in adjacent tissues. The example here is an active infection in the corneal epithelium, and then adjacent inflammation in the corneal stroma. Right? So when you’re looking at a patient with herpetic eye disease, try to think about: Is this active infection? Or is this recurrent inflammation? So one, active infection, two, adjacent inflammation, or three, an immune reaction from a past infection. There’s no obvious infection in the cornea. This is just all inflammatory delayed-type hypersensitivity. A bit confusing. The diagnosis of simplex is typically made by clinical appearance alone. You can do bloodwork on these patients, but almost every human being is gonna test positive for it, so it’s not helpful. You can culture these lesions. In my experience, this doesn’t work that well unless the corneal lesion is quite large. Maybe you can get enough sample to get a good culture, but especially when it’s a small dendrite, it usually doesn’t work nearly as well as you would hope for. And the cultures take at least 1 to 2 days to come back, if you’re in a clinical hospital. Generally, the best case here is just to diagnose it based on appearance alone. And keep simplex keratitis on your differential. A lot of these pictures that we’re about to show have very close similarities to other conditions. And you think you’re following a bacterial ulcer, but then you realize it’s a simplex — it’s a necrotizing stromal keratitis. Always keep in mind herpetic keratitis in a differential. So we’re gonna talk about how simplex affects the epithelium, the stroma, the endo, and the fourth category that doesn’t really fit as well is neurotrophic keratitis. And know that it can affect every layer of the eye. We’re just gonna focus on the cornea today. So number one, epithelial keratitis. This is the most frequent form of simplex keratitis. It’s basically a dendrite or a geographic ulcer. And we all know the look of the dendrite. But you can also get these larger dendrites, as they’re called, “geographic ulcers”. If you don’t treat an epithelial simplex keratitis, the dendrite and the whole disease will last about 17 days, but when it recurs, it lasts a lot longer. Up to a month. The symptoms of epithelial disease — photophobia. Your classic corneal problems. Photophobia, pain, watery discharge. The pain is not too intense, though. It depends on how big the dendrite is, but it’s typically more of a foreign body sensation. A small one. If you see the patient early enough, which is rare, you’ll see these small punctate epithelial erosions, and they coalesce to form vesicles in the epithelium that look a lot like the vesicles around your lips. But this is the first 24 hours, and the patient doesn’t often show up then. But those vesicles coalesce to form the classic dendrite. This is in the second 24 hours of the eruption. And that’s typically when the patient gets a little bit more pain, they realize it’s not going away, and then they come in to clinic to see you. So a dendrite is a true ulcer, in that it extends through the basement membrane, or at least has the potential to extend through the basement membrane, so the potential for scarring here is a lot more serious, which is why we take the simplex dendrites a lot more seriously than we do the zoster pseudodendrites, because we know the potential for scarring in the zoster pseudodendrite is very low. But here are some pictures. We’ve all probably seen these pictures. The one on the left is kind of cool-looking, and also you can see it a little bit better without the fluorescein. So dendron is the Greek word for tree. And you can imagine how it gets this term, right? It’s arborizing, a branching pattern. When I was in school, they taught you that a dendrite — the middle part will stain with fluorescein, because the epithelial cells are broken and gone and eroded. And then the end bulbs stain with rose bengal. I think clinically in the real world this is less important. It’s hard to get rose bengal in the clinic. We haven’t had any in a while. But the reason that was taught is because the end bulbs contain the active virus, and they are in the process of destroying the epithelial cells, but might not have broken through yet. And eventually the virus will break through and continue on. So the fluorescein staining happens when the epithelium is broken. In the beginning part of the dendrite, but not yet at the end bulbs. Next. Then you can get this thing called dendrite epithelialopathy. Which is kind of looking like ghost dendrites, right? And this is just abnormal epithelium that persists weeks after the dendrite has healed. It’s just basically swollen epithelial cells. Deturgescing after the infection. Sometimes people think that the topical antivirals that you have given play a role in retaining those cells, but they’ll eventually go away, usually about a week later. So that’s the regular dendrite. And then you can get this geographic epithelial simplex keratitis, which is basically just a really big dendrite. But this is 22% of all epithelial involvement. Turns out to be a geographic ulcer. Which obviously is worse symptoms, takes longer to heal, and something that you want to avoid. This is a bit of controversy in the literature. But some people think that this might be associated with use of steroids, right? So if you accidentally or mistakenly give steroids early on in the course of epithelial simplex keratitis, perhaps the patient has more of a risk of developing a geographic ulcer. So this one is kind of obviously like a dendriform… But you can imagine how you might see a patient with a geographic simplex ulcer that is a little bit more circular, and you think you’re dealing with a regular corneal abrasion, or a regular bacterial ulcer. So again, always keep simplex in mind, when you’re talking about differential diagnoses. That was epithelial simplex keratitis. This is stromal simplex keratitis. This was poorly categorized in the past, and they’ve changed — this is another thing that’s new in herpetic eye disease. Changing of the nomenclature. It used to be called disciform keratitis. Now they break stromal involvement into two terms. The necrotizing stromal keratitis and the reactivation of inflammatory disease, which is called immune stromal keratitis. So a primary stromal infection is pretty rare. Just 2% of HSK is the necrotizing infection type. But the stroma gets inflamed all the time. Whether it’s adjacent infection from epithelial disease, endothelial disease, or just reactivation of disease that happens to be in the stroma. So you have to think about the cause, because that would change your treatment, right? Whether it’s infectious or inflammatory. So the first one is the infectious one. Like I said, this is the most rare type, but it’s the worst type. You’ll see a dense infiltrate in the stroma. And then broken epithelium over top of it. But that could also describe a microbial keratitis. The big difference between viral versus bacterial etiology is that the viral keratitis moves much quicker. You’ll see advanced stromal thinning, and it can lead to perforation very quickly. Here’s a picture of it. It looks pretty nasty. You see the really large stromal infiltrate, and the broken epithelium over top of it. This patient needs heavy antiviral treatment and very close care, because the risk of perforation is strong here. It could mimic a bacterial keratitis, right? The second type of stromal involvement is the immune reaction. Otherwise known as interstitial keratitis. This is almost always a recurrence of herpetic simplex keratitis. And classically, they have epithelial keratitis, and then weeks or even years later, they have this reactivation of the disease, but it’s not in the epithelium. It’s in the stroma. And it’s 20% of all simplex keratitis, is this stromal reactivation. It’s a cell mediated, delayed-type hypersensitivity, to the viral antigens in the cornea. So this, as opposed to the necrotizing type — you’ll see intact epithelium, but you’ll still see that stromal infiltrate, right? And then classically, you see the stromal neovascularization that you think of when you think of interstitial keratitis. And this is under the epithelium. This branching, arborizing neovascularization that is really quite rare. And when you see interstitial keratitis, herpes simplex reactivation is high on your list. So this is bad, right? Because this neovascularization will bring a lipid exudate and bring scarring into the cornea. But it’ll also compromise the immune privilege of the cornea. Right? And make a potential prognosis for a future corneal graft. Something that you want to avoid. We talked about epithelial disease, stromal disease, and now endothelial disease. This is typically not a true infection, but an inflammatory reaction at the level of the endothelium. You can see the picture here — this corneal haze and corneal edema, but you can see the precipitates here. You can imagine especially on the bottom of the cornea — you can see the classic circle of the disciform keratitis starting. This is not in the stroma. Sometimes the scarring can reach the stroma, but it starts on the endothelium. They’re trying to get away from the term disciform keratitis, because it just means it’s circle-shaped. So try to refer to this as endotheliitis. It’s fun to spell because all the Is in a row. And it’s pathognomonic from the high pressure. In a viral etiology of uveitis, the intraocular pressure is higher. I think that’s due to a secondary trabeculitis, or maybe the keratic precipitates in the anterior chamber getting lodged in the trabecular meshwork and just clogging it up. The fourth one is neurotrophic keratitis. I think of this as essentially a diabetic foot ulcer of the eye. If you think about… When you have a diabetic foot ulcer, this peripheral neuropathy, the nerves just start to die, and the cells that they used to innervate change also. So this isn’t an inflammation or an infection. It’s just this corneal virus has been living in these nerves for so long that eventually the nerves start to die, and then the cells that they innervate stop functioning. So you have hypesthesia or complete anesthesia of the corneal nerve. That’s why it’s always important to check corneal sensitivity in patients with past or suspected herpetic disease. So when you lose this corneal innervation, you’ll start to get — the eye will start to dry out. And you’ll get these punctate epithelial erosions. Those will coalesce into these kind of non-healing epithelial defects. And then you’ll start to get this larger epithelial defect. So the eye is just drying out, and the nerves aren’t sensing that the eye is dry, and the eye isn’t sending more tears. So you’ll get these classic erosions and ulcers. Right? But they differ from your dendriform ulcer, because of the shape of them, the borders of them. The neurotrophic ulcer is always going to be relatively smooth borders, and circular or oval, as opposed to a dendrite. And it’s simply because the eye is just drying out. Very hard to treat these. Best to prevent them. So let’s talk about simplex keratitis treatment. Most of the treatment that we talk about when we’re talking about simplex keratitis was learned by the herpetic eye disease study. This was a study that came out in the early ’90s. That was a multicenter study across the world. That came out with just tons and tons of literature. We don’t have time to go into the herpetic eye disease study, but I encourage you to read it. When HEDS came out, the only topical treatment that we had for simplex keratitis was trifluridine, Viroptic. It’s not that great of a drug anymore. One of the things I wanted to talk about was to encourage you guys to use some of the new drugs. If you have epithelial disease, you’re dosing your patient nine times a day with Viroptic. It’s pretty toxic to the epithelium. So after you see a patient for several days, the epithelium will look a little worse, and you don’t know if it’s the virus or the cure. In 2009, in the United States, the FDA approved ganciclovir, which is a gel that’s dosed less frequently and helps compliance. That’s ganciclovir. There’s also an acyclovir ointment not in America, but used worldwide, and very well tolerated. So you have an ointment option, a gel option, and the old solution of Viroptic. Which brings us to our last poll question. In 1988 the Nobel Prize in medicine was awarded to scientists whose research led to the discovery of which of these medications? So it’s to talk about viruses, right? And acyclovir is on the list. It’s very tempting to choose that one. And most of us did! And you are correct! Except all of you are correct, right? It’s a bit of a nasty trick question. Because the answer is all of these drugs. Gertrude Elion and George Hitchens studied differences in DNA metabolism in the ’40s and ’50s. And they were the first to find that normal human cells and cancer cells and bacteria and viruses all metabolized DNA differently. And if you could identify a way to change that metabolism, you could change, in effect, just some of those cells, and not all of our cells. And so all of these drugs for cell rejection and viruses and bacteria and gout were all discovered by this research! So that drug, acyclovir, that won the Nobel Prize, was the only oral medication that we had in the HEDS study. And it’s not a great medication. It’s poorly absorbed in our stomach. The bioavailability is only 10% to 20%. By the time it reaches the bloodstream. So it’s not a great drug, because it doesn’t reach our bloodstream very well. But it’s nice that you don’t have to worry about renal function. You can just kind of give it to everybody. But in the last generation, there’s a lot better antiviral drugs that have come out, and I encourage you to use them. There’s Valacyclovir, that came out in ’95, and famciclovir, that came out about a decade later. The bioavailability is much better, but because it’s better, you have to worry about kidney function. If you have a patient with kidney disease, perhaps consider acyclovir, or consider one of these newer drugs, but just renally titrate the dose. It’s dosed much less frequently, so there’s better compliance, and it’s much more effective. So consider Valacyclovir and famciclovir. One of the things I was considering when putting this talk together, besides the question of vaccines and the question of treatment changes is what do we do about these procedures that we’re doing on patients? LASIK, corneal crosslinking. We talked about one of the triggers of simplex in all herpes, really, is sunlight exposure. And what is corneal crosslinking, except a lot of exposure to UV light? It got me thinking: What should we be telling our patients who are interested in these procedures, who have a history of simplex keratitis? And there have been reports of reactivation of herpetic simplex keratitis following laser, microkeratome LASIK, and corneal crosslinking. So the Academy of Ophthalmology recommends perioperative and postoperative antiviral therapy. There’s also prostaglandin therapy, typically for glaucoma. This is more controversial. There’s less of a consensus on this. There’s anecdotal reports of herpetic simplex keratitis worsening, that they think is attributable to prostaglandins. But there’s no large correlation. The results are still in doubt. To sum up, when you’re managing herpetic eye disease, the key is to make a timely diagnosis. Don’t make one diagnosis and assume it’s correct and see the patient back in two weeks. Bring the patient back soon and often, because this virus can change quickly. And it’s something that you want to stay on top of, because of all the differential diagnoses that it could be. And think about what we talked about with vaccines, in zoster patients. In the patients who seem at risk for it, perhaps monocular patients, immunocompromised patients, talk to them about getting the vaccine. And when you’re managing any kind of herpetic keratitis, think about the new medicines. Ganciclovir gel, famciclovir ointment, and the Valacyclovir oral medication. That’s all I have. We’ll pop it over to the questions. Up top, you can see an area to type in some questions. We have a little bit of time. So let me see what you’ve got. First question is from Ardy. Can we use HZV vaccine in adult patient who had history of chickenpox in childhood? This is herpetic zoster vaccine in an adult patient? Yes, you can assume that at least in this country almost everybody has had chickenpox. And that is the reason why you would have a herpes zoster outbreak, as an adult. And so yes, if you had chickenpox in your childhood, then we do recommend the herpes zoster vaccine, if you’re over 50 years old. Second question is Ahmad Ali. If we suspect keratitis is due to herpes, is it better to give or not to give an antiviral? Hopefully after this talk, the answer is clear that it is better to give an antiviral. The question is whether you want to give a topical or a systemic antiviral. One of the studies — one of the findings that the HEDS study came out with is that oral antivirals and topical antivirals are somewhat equivalent. So a lot of practitioners now are simply dosing oral antivirals to treat just corneal disease. Or sometimes doubling up with topicals and orals. But if we learned anything from the HEDS study, it says you don’t need to do that. But yes, give antivirals. A question about preventing recurrences. It’s a little bit hard to talk about this, because I’m not sure if you mean recurrences from zoster or simplex disease. But one of the things I’m not sure I mentioned is that in zoster disease, you don’t get a lot of recurrences, but in simplex disease, you do get a ton of recurrences. Say you have a patient with a history of simplex keratitis today. And you manage that patient with, say, oral antivirals, for a certain course. And then the keratitis resolves. What should you do about preventing recurrences? And one of the things that the HEDS study came up with is that you should dose this patient with an oral antiviral, for at least a year. Because their chance of recurrence in that year is quite high. And these antiviral medications are quite safe medications. There’s not much of a risk to just keep these patients on antiviral medications. We didn’t go into the dosing of the patients today. Because we only had like an hour. But when you’re dosing a patient for an active infection, it’s a relatively high dose of antivirals, and then when you’re treating it for prevention of recurrence, it’s a lower dose. Feel free — if you manage a simplex keratitis patient, and keep that patient on oral antivirals, the question is: How long you keep them on. That’s a bit more controversial. But most people recommend at least 6 to 12 months. Dr P asks: Percentage of glaucoma. This is a hard question for me to answer. Say you have a simplex or a zoster keratitis. I guess the question is: How likely is it that this patient is gonna get glaucoma? I think the only reason they would get glaucoma is because they would develop a uveitis because of this infection, and that changes the trabecular meshwork and causes their pressure to go high. A uveitis from any kind of herpetic disease is somewhat rare, but if they get that uveitis, then the percentage of glaucoma is much higher. Is dendritic ulcer contagious? No, it’s not thought to be contagious. Perhaps if you take scrapings of a dendrite and inoculate someone else’s cornea, but besides doing something artificial like that, it’s not thought to be spread. A dendrite is reactivation of a systemic disease in these nerves. Rachid B said when should we give steroids in HSK? This is a good question. I couldn’t go into all the treatments and all the layers. It’s pretty complicated. But to answer your question briefly, you should not give steroids in simplex keratitis. If the epithelium is broken. So if you have epithelial keratitis, and you give steroids without antivirals, the risk of creating an infection is worse. So it’s tough. Right? It’s tough, and you have to identify what layer. For your average epithelial simplex keratitis, you should give antivirals, until the epithelium clears. And then consider dosing steroids to prevent scarring. The question from Ravi M is how you manage chronic stromal inflammation. The answer is: Very carefully with steroids. Every patient is a little bit different, right? One of the things we talked about is: The best thing is to prevent this from happening in the first place. Patients who have epithelial disease can keep them on an antiviral regimen, so they don’t get reinflammation or involvement. But you can get them on oral steroids or topical steroids, depending on severity. Is there any cause of neurotrophic keratitis, not herpetic? Any kind of neuropathy. You can have neurotrophic keratitis from diabetes. Just like you can have peripheral neuropathy from diabetes. There are myriad diseases that affect the corneal nerves. But those are the two most common ones. But you can also have it from, say, something like limbal stem cell disease, or any kind of chronic corneal disease. Huawei asks: In which type of viral keratitis should we add systemic antiviral medication to treatment? Is it essential in all types? I would say in all kinds. Is it essential for epithelial disease? The compliance is better for topical treatments. If your patient has normal kidney function… I wouldn’t hesitate to put patients on oral medications. This question is from anonymous. We find dilute steroid very effective when the epithelium is intact. What is your impression? I haven’t tried dilute steroid. Interesting thought. Next question from anonymous. How long should oral or topical antivirals be given for herpes keratitis? This depends on what layer it is, or the severity of it. I would direct you to the textbooks for this. But it depends on the severity. The dosing of acyclovir and ganciclovir — we didn’t get into that, based on time. But I don’t like to just spout these numbers in lectures, because I find it’s not really great listening to just listen to certain milligram dosage. But suffice it to say it’s a higher dose. I have many patients with a chronic anterior herpetic uveitis that I can’t stop the topical steroids and valacyclovir, and I don’t know what to do. That’s a tough one. Some of these, when they become deep in the eye with uveitis, then it’s tough, because the pressure is rising. Is the pressure rising because of the uveitis? Or is it a steroid response? Or is it a combination of both? I wish I had a great answer for you. What is prophylactic dose of systemic Valacyclovir? I’ll just ask you to look that up. Do we use systemic antiviral in adenoviral infection of the eye? This is a good question. I presume you’re not talking about herpetic infection. You’re just talking about regular adenoviral conjunctivitis. Or keratitis. And most of the literature says no. I think most of the treatment is against this. The potential for serious infection or visually limiting disease is rare here. We do not usually recommend doing this, because it’s a self-limiting phenomenon. How long do you prevent oral acyclovir in recurrent stromal keratitis? This is a great question. I would say at least a year. After a year, you assess the patient. And it’s kind of patient-dependent on that. If it’s a really severe recurrence, or the patient is monocular for other reasons, and you’re really worried about it, maybe they’re on other antivirals for life. These are low doses, where it’s just the recurrence rate, and they’re safe drugs for the kidneys. I wouldn’t be afraid to keep these patients longer rather than shorter. Ahmad Ali asks: Can we give topical antiviral instead of oral one as a preventative against recurrence of viral keratitis? This is, again, for recurrence. Not talking about active disease, but recurrence. It’s not recommended. I think the reason why it’s not recommended is because even the good topical antivirals have some ramifications and toxicity to the epithelium. So it just seems to be safer to give oral ones. It’s not typically done. Samantha A asks: When do you introduce the topical steroids in epithelial keratitis? The answer is when the epithelium is closed. Or after you have the patient on a high dose of antivirals. The only reason to start steroids is to prevent scarring. You have to make sure the patient has been on antivirals for long enough that the disease is slowing down. How do you manage neurotrophic keratitis? The best way is to prevent it from happening in the first place. Heavy lubrication is the answer to that. Topicals, sometimes orals. Heavy lubrication. Sometimes a blepharoplasty to close the ocular surface. How long can we give steroids in stromal herpetic keratitis? How long can you give them? As long as the patient needs it. Some patients are on corneal transplants for life. So you give it as long as you can. What is the protocol for cataract surgery in healed herpetic viral keratitis? We talked about the risk of LASIK, and corneal crosslinking. There is thought to be little risk in activation. I don’t necessarily recommend putting the patient back on oral antivirals. Some surgeons will do that. But it’s thought to be relatively little risk. Because the incisions are so small. If lesions healed without a scar, is it due to simplex or not zoster? No, the only time they create a score is if there’s a bacterial superinfection and the bacteria burrows deeper into the dermis. French sources recommend preventative oral antiherpetic medication if there are more than 3 epithelial recurrences or 2 stromal recurrences. Per year. Do you follow similar recommendations in the United States? Yes. I would say yes. And we’re probably more aggressive than that. Two stromal recurrences in one year is kind of a lot in my opinion. These medications are safe and we shouldn’t hesitate to use them. We’ll do two questions. Management of persistent nummular keratitis after adenoviral keratitis. I would say topical steroids. Nummular keratitis is simply the inflammation. You treat this with steroids. If you’re worrying about the adenoviral keratitis flaring again, you can give an oral antiviral after that, while you give topical steroids. Just so you have less concern about the virus flaring up. And we’ll do the last question. Let’s do it from Phison. Aside from the HEDS study, what resources would you recommend to read further on treatment and dosage for herpetic keratitis? That’s a great question. I love… Up to date is a great website. A somewhat expensive website that you need to subscribe to, but if you can get a subscription to it, it’s the best reference we have, at least from the American studies that we recommend treatment from. I’m holding up a textbook right now called Cornea, by Mosby Printing. This is great, and the Bible of cornea textbooks. I think that will do it for me. I appreciate everyone tuning in, and all the great questions. I’m sorry I couldn’t answer them all. You have my email address on the first slide. If you want to email me these questions, I would be happy to respond to you guys. Thanks. I hope you enjoyed it. I enjoyed it, and we’ll see you around.

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October 26, 2018

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