Corneal ulcers are the commonest sight threatening ocular emergencies presenting in the clinic. This Live Lecture discusses the common causative organisms, typical presenting features of bacterial, fungal, viral, acanthamoeba keratitis, microbiology evaluation and management strategies
Lecturer: Dr. Aravind Roy
DR ROY: Hello, everybody. It’s exciting to meet all of you yet again. On this topic of the evaluation of corneal ulcers. This is a fairly long topic, so I would like to be clear on all the fundamentals of the management of corneal ulcer, and take your questions towards the end. So… Yeah. So before we start, as usual, would you please state your position? As to the level of expertise that you belong to. While we go through this, the topic is obviously of considerable importance, because this is of significant public health importance. Especially so from the developing countries. And the number of new cases are close to 8 million. We have about 65% of ophthalmologists, in the audience, both practicing and in training. So there is a fair amount of corneal ulcers in the community. With close to 8 million being from the Southeast Asia region only. And it is a cause of considerable ocular morbidity. It’s a significant sight and eye-threatening condition. And it has almost reached epidemic proportions in the developing world. So the next question that I would like to pose to you is: how often do you manage a case of microbial keratitis? While the audience answers this question, there are several learning objectives that we need to understand, that is of importance to this topic. The risk factors. Good. So most of us have voted that they have about… Zero to five cases per month is what they see commonly. So it’s quite important to understand the nuances and history taking, evaluating the risk factors of ulcers, understanding the diagnostics involved, documenting the ulcer, using the appropriate color coding, when someone is noting down the ulcer or making a drawing of the ulcer, and of course the management decisions and outcomes. So as you can see here, there are several clinical scenarios that are available. The following five pictures on your screen right now are typically the ulcers which are kind of pathognomonic for one particular variety of maybe fungal, bacterial, viral, or parasitic. So there are several nuances, several important things that, as an examiner, you should understand about each particular ulcer, and try to elicit the history from the patient. For example, this patient had a chronic ulcer of a couple of weeks’ duration, and margins which are very fuzzy, with satellite kind of lesions. And there are some areas of thinning here too. And the adjacent conjunctiva is quiet. So it’s important to look at diabetes, immunosuppression, existing steroid use, or polypharmacy. However, every type of keratitis has a typical kind of pathognomonic signature. We are going to discuss subsequently what and how each particular type of ulcer looks like. Similarly, this ulcer progressed very rapidly. In the matter of a couple of days, to almost a week, which almost melted away most of the cornea. It has a very wet-looking appearance. So one needs to be alerted about a possible CMV infection over here. Whether there was any nosocomial infection, whether the patient has immunosuppression, whether this patient was admitted to a hospital, and subsequently there is an ulcer, which spread very fulminantly in a matter of days. And it obviously has a wet-looking appearance, with a very inflamed eye. This is a case of a middle aged farmer, who used to have annual recurrences. There was a very mild kind of edema of the cornea, some scars and ghost lesions, and annual recurrences with scars alerts you to (inaudible) and whether it could be of viral origin. So this is the case of a viral stromal keratitis. And this patient responded dramatically with steroids and antivirus. This patient is again interesting. It’s interesting, because this is a chronic ulcer, extremely painful. Superficial ulcer. And there is no history of contact lens. In fact, in the Southeast Asian region, there is no history of contact lenses for most parasitic ulcers. So what is important is a chronic ulcer, with a history of injury with contact with soil. And often they are sustained by people working in the agricultural sector. It’s a dry, feathery-looking lesion, with clear margins, restricted to the anterior stroma. With a lot of pain in the eye. One should look towards the peripheral cornea and see if there are radial inflamed corneal nodes. So this again tends to ask questions and you should elicit the history as appropriate so you can go one step closer towards the diagnosis and management of these conditions. This is a case where the patient presented two weeks after cataract surgery. We can see that the clear cornea has a fungal infection. There are some kind of membranous lesions in the pupillary area. And there is the hypopyon. So the vision had dropped down, so one should also ask about surgery and also drop in vision. Which will alert the clinician about any possible endophthalmitis that might have occurred in these cases. So in a nutshell, every clinical case, including every type of ulcer, would have its typical clinical presentation, and it is important that we elicit the specific history, which will help us getting one step closer to the diagnosis and the subsequent management of these cases. So when we summarize the important risk factors, the most important risk factor is trauma or vegetative injury. Unsolicited corticosteroid use. Polypharmacy or over the counter medications. And poor ocular surface, immunocompromised patient, uncontrolled diabetics, and lack of patency of the lacrimal passages, and contact lens use. So an important article that is relevant here is the review of epidemiological features, microbiological diagnosis, and treatment outcome of microbial keratitis, experience of over a decade, published in the Indian Journal of Ophthalmology, and available for download from our group. This talks about the analysis of close to 2,000 patients, and of most of the risk factors, trauma was found to be the most important predisposing risk factor in fungal, microbial, and parasitic keratitis. And in addition, most of the patients who presented were inappropriately treated or indiscriminately treated. 41% had indiscriminate therapy. And less than 50% were appropriately treated prior to presentation at the tertiary care center. So here I will break for a while and ask if you have appropriate microbiology lab support for the management of corneal infections. And maybe you can quickly answer the other question too. So the group is divided almost equally. Among people who have and do not have the lab support. And can you quickly answer the other question too? So as an ophthalmologist, as a cornea surgeon, sometimes it is useful to perform a smear examination, and then get on with the results, and it will help us manage the corneal ulcers that we are treating. It will make a more rational management, and also provide probably a rational way of approaching and ruling out those conditions which are not there, and actually specifically targeting the organism in question. So we have quite a bit of colleagues who are not very comfortable, or rather, you can say that you have not initiated into these, but it’s actually quite easy. All you have to do is you can instil a drop into the infected eye, and take a little bit of the sample with a number 15 plate or a heat sterilized spatula. Having taken that, you can put one drop of 10% KOH, which can be easily available at any of the labs, and from that, you can actually see whether this sample contains or does not contain fungal filaments. So the traditional microbiology setup for any ophthalmic microbiology service will typically consist of smear examination of the particular slides. One of which is the white 10% KOH wet mount, the Gram and Giemsa stains, and the culture in 5% sheep blood agar, chocolate agar, potato dextrose, and brain-heart inclusion. So once you have the inoculate in your lab, you can actually send it across to the microbiologists. In the absence of any of them, you can simply do a smear examination over common available lab microscope, and get on with your treatment. So we will be discussing the different clinical scenarios over the course of our talk where we will explain and discuss about the management of ulcers when we do not have a microbiology setup. So that can still put us in a rational way of managing these difficult clinical conditions. Now, it is important here to understand the sensitivity and specificity of these conditions. Whenever we are interpreting ulcers, from the microbiological point of view. Now, if you look at the specificity for the acanthamoeba group of ulcers, it’s pretty much in the 90%s, when the gram is positive. Or parasites. Which means that it rules in all the ulcers which are caused by fungus and acanthamoeba. And in addition to the other tests that we have, another test of importance is the confocal microscope. Now, confocal microscopy is something which will typically be available in a research setup, but having said that, it is something which can help us diagnose in vivo or live conditions. So do you have access to confocal microscopy? Okay. So quite understandably so… It’s something which is very rarely available. But just for kind of an update, confocal microscopy is basically something which is like an applanation tonometry, but it tends to give in vivo, live data, about the layers of the eye. And as you can see on your screen, this is how it would appear. The anterior stroma would appear much more cellular, as compared to the posterior stroma here, which would have much lesser degree of similarity, with oval or bean shaped nuclei. The endothelium would have a monolayer of hexagonal cells, and these nodes would have a reticular appearance. The stromal nodes would have branched, linear lines, and it’s important to understand that these lines, which are the subepithelial plexus nodes, are in the range of 3 to 4 microns, and these are in the range of 10 to 5 microns. Why is it important? When you see acanthamoeba, it would be about 10 to 15 microns. So you can compare the acanthamoeba cyst to this. And see that the size is comparable to the size of that node. And fungal filaments would be about this thin. The thinness of that would be that of the upper epithelial nexus of nodes. So what we’re looking at is probably the fungal filament. Now, how would it look like? So if you look at the next few couple of slides, here you can see that this is how a fungal filament would look like, in confocal microscopy. So it would look like irregular branching patterns of septate filamentous double walled fungus. So that would be of the size of 3 to 4 microns, and they would be irregular. They would be in bundles. And they would be branching. And in addition, bacterial keratitis would have these keratocytes. They would have a lot of developing inflammatory cells. Acanthamoeba cysts would appear as round double walled particles of 10 to 20 microns. You can look at the node that is there in the corneal stroma. With viral keratitis, it would be characterized by ovoid dendritic cells in the subepithelium. So apart from that, it’s very important to draw the ulcers in your examination sheet, so it is a way of accurately documenting the ulcer, but also where residents in training can really benefit a lot by appropriately color coding the corneal ulcer, and also progressively seeing how the ulcer changes, over a period of time. The standard notation that we have here is black for scars and degeneration, blue for edema, brown for pigment, blood would be red, and fluorescein is green. All the infiltrates are orange. So in addition, when there is a suture, it’s a solid black line, contact lens by dashed black line. All the Descemet’s folds are denoted by wavy blue lines, and epithelial edema by small circles, which are made in blue. Similarly, superficial vessels are traditionally denoted by small wavy branching red lines, and broad straight red lines are stromal vessels. The ghost vessels are dashed red lines, and anywhere that is vitreous, such as in a corneal tear, that would be denoted by green. A landmark article on color coding of cornea, which is, again, freely available, is from this ophthalmological publication. I strongly advise all residents in training to go through this article about color coding of the cornea. So now we’ll go to the most interesting section of our talk, which is the management of corneal ulcers. Now, it poses several challenges. Especially in developing countries. Where the epidemiological patterns are far different than elsewhere. So we will learn about the rationale of management. I would like to crystallize our talk into etiological diagnosis, based on examination, the initial treatment, when we do not have access to microbiology, the guidelines for referral, and the role of antibiotics such as fluoroquinolones, the role of cortical steroids, and the role of antifungal agents such as voriconazole. So the best way to make the clinical diagnosis is probably on a good clinical examination, a detailed history, a good slit lamp biomicroscopic examination — is crucial. It’s important to pay attention to the size of the epithelial defect, the size of the infiltrate, the depth of the infiltrate, and edges. And how does the surrounding cornea look like. And quite obviously it’s important to understand whether there is any associated pitting or any impending perforation. Now, there are several clinical scenarios here. Such as a rapidly progressive disease with generalized infiltrate, and it could also be a slowly progressive lesion with localized infiltrate, as in the pictures there. So each has very different connotations. A rapidly progressive disease with suppurative infiltrate could be of bacterial origin or it could be of mixed origin. And the following group of bacteria, like aureus, pneumoniae, et cetera, can be implicated. The slowly progressive disease could be fungus or protozoae. However, there are bacteria that could be associated too. Such as epidermidis, actinomyces, et cetera. Gram positive bacteria typically are very well demarcated lesions. They are localized. The margins are very well defined. And they also tend to progress in a short duration and also tend to respond quite quickly too. In addition, the Gram negative bacteria tend to cause a lot of melting of the cornea. And it may be rapid deterioration of the clinical picture, which leads to large suppuration of the cornea, which leads to penetrating keratoplasty. And there are several slow growers, such as moraxella. As compared to the picture on the right, which can in a very short duration cause a big melt and a complete loss of the eye, with all the intraocular tissues. Nocardia has a typical appearance, such as this pattern, multiple pinhead-like lesions, and a slow, indolent, chronic course. NTM is typically seen in the setting of refractive surgery, where the LASIK interface is involved with these organisms. That’s too stereotypical. It can also happen without refractive surgery also, and it can also be a very slow grower. It typically has a cracked windshield kind of appearance. Fungus is typically important in the setting of a warm, humid, tropical climate. And in addition, they tend to grow very slowly. There is often an antecedent history of trauma, or vegetative injury. And the persons are typically working in the agricultural sector. And the lesion tends to just sit quietly on the cornea, and it appears as a dry, raised, feathery margin, with dry-looking infiltrate and very irregular margins, and sometimes the corneal ulcer may have kind of a raised, pigmented appearance. Kind of like a mushroom sitting over there. So these are typically caused by dematiaceous fungus, where there is a lot of fungus on the ulcer. This dry-looking lesion, sitting on the cornea, with irregular, feathery margins, which will have, typically, satellites, and it tends to exist for quite a long time, with a very chronic course in the eye. And it doesn’t respond to any of the treatments. Sometimes it will just progress into a deeper intraocular place. Acanthamoeba has had a resurgence, mostly due to contact lenses in the developed world, and due to other factors. Contact lens is not very important in the developing countries, where injury with soil or injury with trauma, like cattle tail, tail of cows or buffalo hitting the eye, or injury with any innocuous material, can actually inoculate this organism, which typically proliferates in the muddy water, or in the soil, into the cornea. This has a very painful, chronic, indolent course. It tends to form a ring infiltrate. It tends to have radial keratoneuritis. There’s a lot of surface inflammation. There’s a lot of limbitis. And it often leads to loss of vision. Unless appropriate steps are taken to diagnose it and treat it. However, once treated well, the prognosis is good, and vision is restored in a large number of cases. So when we can make so much sense from the history, with the classic clinical picture, why should we need to do an appropriate microbiology? Now… Having said that, there are a lot of ulcers which present to the clinician after they have been treated by somebody who is not having the level of expertise to treat somebody who is probably a traditional medicine man, or somebody who is just taking treatment from over the counter. So in these cases, whenever there is an indiscriminate polypharmacy, whenever there is some corticosteroids that have been instilled in the treatment of this condition, the clinical picture changes from what is pathognomonic to something which can be interpreted as… You know, very puzzling. And in these kind of scenarios, it’s not really easy to say what is the appropriate line of management that one should take. For example, take these two cases, that are on the screen now. The ring infiltrate that you can see here can belong to a person who has a fungal keratitis or somebody who has Gram negative bacteria, or somebody who has an edema. The treatment is radically different in these three scenarios. So microbiology is a way of making a rational diagnosis whenever possible. So it is strongly recommended that one should do whatever possible with access to microbiology, send corneal scrapes, and then go ahead with management which is based on laboratory work. So for that, you need a well equipped laboratory staff, and there are costs and logistics involved. Most of us in our practice may or may not have access to such a service. So then what do we do? Do we go for an empirical treatment? Or do we strictly follow a microbiology-based treatment? We would like to understand that — what should one do when microbiology backup is unavailable? There is an excellent source on the internet, which is a document of guidelines for the management of corneal ulcers, at primary, secondary, and tertiary levels, in the Southeast Asian region. This document is available for free download on the internet. You can refer to it. It very typically identifies those conditions that can be treated at the primary level, compared to those that can be treated in the secondary level, and then those which need urgent referral to a tertiary care practice. So as we were discussing some time back, the specificity of a 10% KOH mount is in the 90s. So all that you need to start off with is just to do a light microscopic examination. And if you see something like this, where you see double walled septate filaments which are branching, you can be pretty sure you are dealing with a case of fungus. And if you’re dealing with a non-severe ulcer, with very well defined margins, it is unlikely to be fungus or acanthamoeba. If it is smear negative, then also one can start empirical broad spectrum antibiotics and see how the treatment goes. So I would like you to quickly answer this question, before we move with the rest of the discussion. Okay. So I believe there is a fair mix of our colleagues who are treating with broad spectrum antibiotics, and also with the newer generation fluoroquinolones. Okay. So in the treatment of bacterial keratitis, either one can use a fluoroquinolone, or one can use an aminoglycoside with the fortified cefazolin. Which will increase the spectrum, until the response is arrived at, or until we can get microbiology. Or one can also use the newer generation fluoroquinolones, such as moxifloxacin or gatifloxacin. So a non-severe ulcer, which has a dry, feathery margin, and which typically clinically looks like fungal, actually, one needs to do the microbiology, and assess the smear. So if your smear is positive, start treatment with antifungals. If the smear is negative, and you strongly suspect that it is fungal, and you do not have access to microbiology, refer to a tertiary center. Treatment with antifungals and antiacanthamoeba drugs must be started only after the organisms have been documented. So what are the referral guidelines? All severe keratitis must be treated at tertiary care. All cases which are clinically suspected to be fungal keratitis and where you cannot find fungus in the smear or culture needs to be referred. And where the cases are worsening on empirical therapy, you need to refer these cases. So what is the role of the newer generation drugs? Such as the fluoroquinolones, corticosteroids, or voriconazole? So broadly, the Gram positive and Gram negative organisms are susceptible to a wide variety of antibiotics. It is also based on the identification of the organism, and the sensitivity profile. Now, whether one should use fortified antibiotics or use commercially available preparations, there are pluses and minuses of each. The fortified antibiotics may be less expensive. But then, they are much more cumbersome to prepare too. They are not commercially available. They have limited shelf life. There are issues with storing the drugs, issues with pH, tonicity, and toxicity of the drug. Fluoroquinolones are commercially available, their shelf life is not an issue, and it is safe and comparatively less toxic. So with this, there was an important study that was published, which studied the role of — or the efficacy of fluoroquinolones versus the fortified antibiotics. And it was found that they are very similar. But having said that, the problem of drug resistance, antibiotic resistance, has raised its head. And researchers have found that a number of the percentage of bugs which are susceptible to the newer generation of fluoroquinolones are on the rise, and they have consistently progressed over the last decade. So a study which was done in the US has found that the ciprofloxacin-resistant organisms are also more often than not resistant to gatifloxacin and moxifloxacin. As you can see from the table here, the Cipro sensitive staphylococcus aureus, and the pneumococcus, are most susceptible in 70 to 40% of cases to gatifloxacin, with a slightly better response to moxi. So with a small infiltrate, the fortifieds are a rational choice. Whereas in a larger infiltrate, the aminoglycosides can also be used. The antibiotics should be continued for as long as necessary, and then should be abruptly stopped. You should never for any reason taper an antibiotic. Because it tends to induce resistance. Now, what is the role of corticosteroids in the management of keratitis? Or corneal ulcers? So the ophthalmic world is rife with debate as to whether corticosteroids are proven and effective or ineffective and dangerous. So it has been found in a Cochrane review that there is no actual significance in terms of the best visual acuity, the healing time, the time to epithelialization, or the scar size, in terms of patients who are treated with or without corticosteroids. So in spite of several available literature, the evidence is not sufficient to conclude that corticosteroids have a grossly important role to play in the management of corneal ulcers. And they are best avoided. So consider this clinical case of a 37-year-old male who had 21 days of history of pain, watering, and redness. And on your scraping, you have found — this is the white mount, and this is the KOH wet mount. So you have found filaments of fungus. So obviously this is a case of fungal keratitis. We have several groups of drugs to act on fungal keratitis. Commonly the polyenes, the conazoles, et cetera. Now, what would be the first line topical management that you prefer for the management of fungal keratitis? Okay. So most of our colleagues would prefer to start with natamycin as the first line management. Some of us would also prefer other antifungal drugs, such as fluconazole or amphotericin. What is the role of voriconazole? It is not uncommon to see in several meetings in the scientific community where there have been several anecdotal or published reports of benefits of newer generation antifungals, such as voriconazole. And it is not uncommon for several colleagues to use oral antifungals in the management of fungal keratitis. Now, what does the published evidence say about the role of these drugs in the management of fungal keratitis, apart from whatever the perceptions are? So an important study from the eyecare system, the mycotic ulcer treatment trial. Comparing the effect of natamycin versus voriconazole. They did not see any significant benefit from adding voriconazole to the management of fungal keratitis. A recent Cochrane review on the medical intervention for fungal keratitis also failed to find that any study was adequately powered to find benefit of voriconazole. In fact, there is no good evidence for comparison of any antifungal drugs. And in summary, when we compare natamycin versus voriconazole in three major trials, the percentage of clinical cure and the microbiological cure and the best visual acuity is similar or better in the arm that was treated with natamycin. So the risk of adverse events with topical voriconazole has been found to be more. So from this, we can overwhelmingly conclude that natamycin is currently the best drug for both mold and yeast at this point in time, and contrary to popular belief, voriconazole was found to be inferior, especially against fusarium, and was associated with more adverse events. So when we summarize our discussion here, there is a science of managing the corneal ulcers. There is an art of making the diagnosis, based on the clinical examination. When one does not have microbiology, then it’s important to refer to the established WHO guidelines. And one needs to understand the role of fluoroquinolones, the role of corticosteroids, and should be cautious when they are using the new generation of antifungal medications. So with this, I would like to gratefully acknowledge the contribution of colleagues such as Dr. Prashant Garg and Pravin Krishna for their help with the slides. I would like to thank you all and I will take some questions before I end the session. So I will be going with the questions, and you can add to them, you can give your feedback, so I think that one of our viewers have asked whether it is safe to use steroids in treating a corneal ulcer. The evidence is not sufficient, and probably steroids are best avoided in the management of corneal ulcers. Okay. So the WHO recommendations for management of corneal ulcers are the set of guidelines which are available for free download on the internet, and one can go through those. One of our viewers have asked: how do you get KOH? Whether it’s commercially available — any chemistry lab would have it. And you need to prepare a 10% weight by volume preparation in the lab. And it is quite easy to make a 10% preparation, using distilled water and pellets of KOH. Commercial natamycin is quite commonly available. So that is one. And can you give systemic steroids? Probably you should avoid steroids in all forms, in the management of corneal ulcers. Systemic antibiotic… Again, when we give antibiotics, topically, the minimum inhibitory concentration of the antibiotics in the ocular tissue is very good. So unless the lesion is much more deeper — say, such as a concomitant endophthalmitis — then probably systemic antibiotic is not recommended. Is there a role of systemic or topical NSAIDs? Very limited. Probably only to manage pain. Crosslinking is a very exciting thing that is happening now. The results are mixed. And I think the verdict is still out. Is there a role of povidone-iodine? There has been studies where they used povidone-iodine in a smaller group of patients under very controlled conditions. The results have been found comparable to antibiotics and natamycin. But that’s, again, not concluded. What is the best regimen for antibiotics? Okay, subconjunctival injections when you give an hourly regimen, probably it’s not necessary to give subconjunctival injections. Okay. So culture negative is again something which is very difficult to treat. And one needs to actually make a decision tree based on whether the ulcer is responding to treatment. And if it is refractive to treatment, stop all the antibiotics for a period of two to three days, and then reassess. And if the patient is responding, then go ahead with the line of treatment ’til resolution. If the patient is not responding, then if the patient is worsening, probably one needs to look at surgical management, and if he is responding, one has to treat per etiology. Intrastromal injection of antibiotics — again, there have been reports of intrastromal injection, and there is some benefit. But then there have been papers which have been published that said that intrastromal versus topical doesn’t really make a difference. How to diagnose acanthamoeba? Probably history of injury with soil or contaminated water, chronic ulcer, severe pain, limbitis, inflammation, edema. But again, very difficult. Okay. Carbolization — probably not done anymore. Shelf life of fortified medications are typically within the week. One of our viewers has asked — hourly or five times ointment? Hourly regimen is given for 48 hours, followed by every two hourly, until resolution. And then you have to abruptly stop it. Combination of antibiotics with antifungals are best avoided, unless you have positive microbiology. One should not use antiparasitic or antifungal drugs. And they are not to be used in combination. Intrastromal infiltration of amphotericin B. It’s a very toxic drug. Some authorities believe it has some benefit, but probably it’s not recommended. When do we consider corneal transplant as a viable treatment option? Corneal transplant is typically done in a condition where there is a refractory ulcer, which is chronic, and there is medical failure, and it is progressing or worsening. Because certainly to involve the limbus, or it is tending to perforate the cornea — it is these conditions where it would be good to do a penetrating keratoplasty. Send the tissue partly for histopathology and partly for microbiology, and await response based on the diagnosis that you have. But in case of large perforations of more than 2 millimeters, it would be recommended to go ahead for a full thickness penetrating keratoplasty. So whenever you have perforation, it is probably better to refer to a tertiary center, and do a treatment based on the size of the perforation, and the severity. Amniotic membrane has been used in the treatment of ulcers. But amniotic membrane in the setting of inflammation can melt very quickly. And will not provide much help. Systemic antibiotics, as we discussed earlier, has no role in the management of corneal ulcers. And the systemic antifungals used in the treatment of fungal keratitis in addition to topical antifungal medications, have been found not to be useful. Meaning that the recent studies that are published have not found any advantage of using oral antifungals in addition to topical antifungals for the management of fungal keratitis. Okay. In LASIK and PRK, how should one treat suspected corneal infection? This is going to be quite a challenge, because one needs to rule out whether it is inflammation such as interstitial keratitis, or lamellar keratitis, versus something which is of an infectious etiology. If it appears to be progressing fast, with reaction in the anterior chamber, it’s probably important to do a scraping and rule out the infection, before it tends to progress fast to involve the vision. (inaudible) probably have a very limited role in the management. (inaudible) keratitis needs to be treated with antivirals and also corticosteroids. And one also needs to look into the study guideline in the management of keratitis. Bandage contact lenses and patching has a very limited role in the management of corneal ulcers. So probably best avoided. After therapeutic keratoplasty, how long should we continue antifungal treatment? So typically, the antifungal regimen needs to be continued for at least two weeks after therapeutic keratoplasty, for fungal keratitis, following which, if there is no evidence of residual recurrence, you should start corticosteroids. There is no role of cryotherapy. Or vitamin C. Adenoviral keratitis is often self-limiting, and that needs to be treated with topical antivirus. Any ulcer which is resistant to treatment and is also worsening, they are best managed with a therapeutic keratoplasty. Indiscriminate use of drugs can cause thinning of the cornea, cause a melting drug toxicity. So sometimes it is important to review the regimen and see if you are using a rational regimen, and whether there is not a drug toxicity due to frequent drug use. So yes, all antibiotics and antifungals when they are used excessively can cause a drug toxicity, which can cause thinning and worsening of the ocular condition. For prevention of recurrent keratitis — there are well defined guidelines for the management of herpetic keratitis. One should go to the trial and follow its conclusions. Viewers have asked — is there a role of debridement in corneal ulcers? That’s an interesting question. Actually, debridement not only decreases the load… It is important in a fungal keratitis. It’s important because it decreases the load of the fungus, and it also facilitates penetration of the drug into the corneal stroma. So it’s important to debride that. Lubricants have limited role in corneal ulcer. Mooren’s ulcer — best managed by ruling out if it’s a penetrating keratitis due to vascular disease or any other disease. Mooren’s ulcer is a diagnosis of exclusion. If you have ruled everything else out, treat with bandage contact lens and steroids. Tarsorrhaphy, again, depends on exposure. Whether there is an exposure keratopathy. Amniotic membrane transplantation — it has been tried in ulcers, but it has a limited role. So as I answered the tarsorrhaphy — it could be lagophthalmos or exposure keratitis. It definitely helps in the treatment of neurotrophic keratitis. Acanthamoeba management is best done by antiparasitic medications. And before one starts an antiparasitic regimen, there should be direct evidence of the organism in the smear. Corneal transplant is the standard management for refractory ulcers. And there is definitely a risk of endophthalmitis for any surgical option that we take, including corneal ulcers. Crosslinking for herpetic keratitis — well, crosslinking is still a newer modality. And as I said earlier, some time back, there is the… The opinion is again out there. Crosslinking is a newer modality. It should not be the standard of management for corneal ulcers. Corneal ulcers — how long should you treat a fungal keratitis? You should treat fungal keratitis for as long as it is not worsening or threatening to perforate. And until resolution. And then stop the medications two weeks after clinically you see that it has resolved. The buds of the fungi tend to stay in the tissue for at least two weeks. So that’s why the two-week margin beyond which you should continue antifungals without stopping. Hyphema usually does not lead to corneal ulcers. Herpetic ulcer not responding to treatment (inaudible)… (audio unclear) I’m sorry. There is something (inaudible). So it was nice to (inaudible) with all of you.