Marginal keratitis is an inflammatory disease of the peripheral cornea. It is usually associated with the presence of blepharoconjunctivitis, and is thought to represent an inflammatory response against S. aureus antigens. The objective of this lecture is to understand the physiopathology of this presentation and the different alternatives for diagnosis and treatment.
Lecturer: Dr. Carlos H. Gordillo, Corneal Specialist, Instituto Zaldivar S.A., Argentina
DR GORDILLO: Okay. We are ready to start. I’m Dr. Carlos Gordillo, from Mendoza, Argentina. Thank you, Cybersight, for the invitation to be sharing with you this webinar, regarding marginal keratitis. As I was telling before, I’m Carlos Gordillo, from Argentina. I’m actually working at the Zaldivar Institute, and we’re settled in Mendoza, Argentina, Buenos Aires, and I’m also working in my family practice in the North of the country. So just for you to know where I am right now. The objectives of this presentation is to share with you some knowledge about this disease, the marginal keratitis. For you to understand and identify also the disease and the physiopathology. To learn how to make the differential diagnosis, and also the alternatives for treatment. I have been reading all your questions, and the idea was to answer all the questions that you have sent during this presentation. Regarding background, the marginal keratitis is an inflammatory disease of the peripheral cornea. And it’s usually associated with the presence of blepharoconjunctivitis. It’s thought to represent an inflammatory response against the staph aureus antigens. As you know, the majority of the patients have symptomatic staphylococcal blepharitis or conjunctivitis in association. It can be asymptomatic colonization of the eyelid. So this is something to be aware, from the very beginning. So it’s hypothesized that the marginal keratitis is the product of anatomical and chemical variations between the central and the peripheral cornea. So let’s remember a little bit about the staphylococcus aureus. It’s facultative anaerobic bacterium, Gram positive. Coagulase production. It’s immobile and non-sporulating. So regarding some epidemiology, things that we should know, because this is part of the way to understand the physiopathology, and also the diagnosis for later. Staph aureus is the major human pathogen. The data from the United States and from Europe indicates that it’s the predominant cause of cutaneous and invasive infections, and the leading cause of morbidity and mortality in the industrialized world. Of course, we’re talking in general about staph aureus, but if we talk about how it affects our eyes, this bacteria can coexist with a human as a commensal. Between 20% and 30% of the population has colonized the mucocutaneous surface, and much more significantly, a higher proportion of the population have been exposed to it. The isolation of the staph aureus from the eyelids of normal subjects has been previously described. And as we’re gonna see later, there are some patients that have had the infection previously, and then the culture can be negative. So the acquisition of resistance against a variety of antibiotics reflect the adaptive capabilities of these bacteria, that have shaped its ability to cause continually shifting patterns of disease. And one of three people are colonized with the bacteria, but not infected. So after this information, we’re gonna talk a little bit about the physiopathology. So it’s the product of an inflammatory reaction against the staphylococcal antigens. The presence of the bacterial antigens in the peripheral area of the cornea possibly triggers a type III hypersensitivity reaction. What does it mean? In this reaction, the immunocomplexes are formed and deposited in the peripheral corneal stroma. As you can see in the pictures, you have the antigen and the immunoglobulins together, and the antigen-antibody complexes are preformed in the circulation, before they’re deposited in the tissues. So what is the type III hypersensitivity reaction? It occurs when there is accumulation of immune complexes, antigen-antibody, as you were seeing in the picture before, that have not been cleared by the immune cells, giving rise to an inflammatory response and attraction to the leukocytes, as you can see in the picture. So this is the type III reaction graphic, where you can see the complement, immunocomplex deposition, and the tissue basement membrane. So these reactions may progress to immune complex disease, and the complement activation leads to the recruitment of inflammatory cells. These cells that release lysosomal enzymes and free radicals at the site of the immune complexes, cause damage in the tissue. But it’s not only the type III reaction that’s involved during the process. There are many papers regarding the physiopathology of this disease. The marginal keratitis has been studied for many years. And described in different papers. The presence of another kind of reaction is a type IV. The incidence of the marginal keratitis and the isolation of the staph aureus from the lids were not significantly different in some studies in patients with and without enhanced cell-mediated immunity. This suggests that the presence of delayed-type hypersensitivity, as I was telling you before. So what is a type IV delayed type hypersensitivity? It’s a reaction that takes several days to develop. It’s not antibody-mediated, but rather is a type of cell-mediated response, and it involves the interactions of T-cells, monocytes, and macrophages. So this graphic and the other one is gonna help us to understand these kinds of reactions. And also to understand why in some patients that we have the inflammatory reaction. We don’t have a positive culture for the staphylococcus. This is really clear in the paper, regarding the role of superantigens in the pathogenesis of the marginal keratitis. The term superantigens is described as a group of molecules produced by the pathogen, the staph aureus organisms, and capable of inducing activation of T-cells and B-cells also. So the aim of this study was to establish whether superantigen producing staphylococcus are present on the eyelid margins and consumption of these patients. When you don’t have enough culture of the eyelid, you may suggest that there are toxins in the pathogens of the marginal keratitis that have been already in contact before. So after this, we’re gonna talk a little bit about the symptoms. The patient can appear with pain, photophobia, foreign body sensation, eye redness, blurred vision, and watery eyes. All these symptoms can be together, or you can have one or two of them. It’s really important for us to think about this disease, and the personal and family history, and if it’s the first time or not. Usually the personal history is gonna show us a patient with chronic blepharitis. There are complement activation and neutrophil attraction with the formation of peripheral stromal opacity, also called catarrhal infiltrate. This lesion may evolve with epithelial damage, forming a marginal ulcer. Here you can see the first picture of a marginal keratitis. You can see here you have three different lesions in the inferior part of the cornea. And then you have the fluorescein image. What about ocular examinations? We always need to see the visual acuity without correction, the visual acuity with correction, the pinhole is gonna help us, ocular motility, slit lamp evaluation, intraocular pressures, the pupils of course, and confrontation visual fields. Why is all this information important? Because it’s part of our diagnostic. You always need to take — to think that this patient is gonna come with blurry vision, in pain, photophobia, so sometimes it’s difficult to evaluate, but it doesn’t mean that it’s not really important. So maybe you need to use anesthetic before the evaluation. So the slit lamp evaluation. I’m sorry for this. So we’re gonna think from outside to inside. So the lids, the lashes, are gonna be the first thing to evaluate. And we’re gonna see erythematous and edematous lids, as you can see here. Blepharitis with collarettes. I don’t know if you’re able to see in this picture. The meibomitis is also going to be there. Acne rosacea is often present, but not always. You’re gonna see some telangiectasia in the eyelids, but please take a look at this. Understand why this is important. You can see from here, we’re in touch with these areas, and the cause, the principal cause of this blepharitis. Of this reaction. Then we need to go to the conjunctiva and the sclera, where we’re gonna be able to see conjunctival injection. As you can see here. What are the most important signs? Unilateral or bilateral peripheral curvilinear infiltrates in superficial cornea. As you can see here. Where the lid crossed the corneal periphery. As I was telling you before, it’s a place where there’s contact between the eyelid and the cornea. You have lots of corneal epithelium, ulcerations in the marginal zone. That’s why we call it marginal keratitis. And it’s separated from the limbus by a clear corneal zone. As you can see here, the limbus is not involved. A little bit of safe cornea. And usually the lesions are circumferential, and you have progression of associated marginal infiltrates. With limbal hyperemia and conjunctivitis. There also can be associations with keratitis also, which presents as small, flat punctate lesions on the corneal epithelium. But it’s not always there. So depending on the time it’s being diagnosed, you can see also the infiltrates all together. Forming just one lesion. You have both possibilities. Here we go. So some important signs. The curvilinear infiltrates in the superficial cornea are subepithelial, and in the anterior stroma. Be aware of that. And you’re gonna be able to find them at 10, 2, 4, or 8 o’clock. Why is that? Because those are the places where you have more contact with with the eyelids. Ulcerations are located in the marginal zone and separated from the limbus, as I was telling you before, can by a clear area of cornea. Fluorescein stains often show epithelial defects that are smaller on the infiltrate area. Because this is subepithelial, as I was telling you before, and in the anterior stroma. So this can be single or multiple. The infiltrates. Which subsequently can be all together or coalesced, with overlying epithelial breakdown of the corneal epithelium. So here you can see another patient with the lesions usually appearing in areas of direct contact between the peripheral area and the eyelid margin. So this is usually the way they appear. As you can see here. This patient has many lesions, and some occur from previous infections. So although it’s unusual, in severe cases you can have hypopyon. You may think about another cause that can be infectious. Or not. This scenario is kind of scary. But you have to be aware of the history of the patient. And a proper examination is gonna help us to diagnose if it’s a case of endophthalmitis or not. Now we’re gonna be able to see the difference between infectious and non-infectious pathology. So I’ll give you some tips or notes for the signs of the cornea that you’re gonna be able to read after the class. So up to here, we’re gonna stop for a few seconds, to think about the marginal keratitis. And please remember: It’s associated with blepharitis. The marginal keratitis is a common cause of red eyes, the patient comes with uncomfortable eye, often presenting bilaterally, with peripheral, discrete infiltration, with circum-limbal sparing. Remember, the staphylococcus is involved, and it’s not infectious, and results from an enhanced cell-mediated immunity at the limbus to the antigens of the staphylococcus aureus on the lids. So it’s important to understand why it’s coming. And also it’s inflammatory. The treatment is therefore with a combination of topical antibiotics and steroids. Usually results in a rapid resolution of the signs and the symptoms. Why am I telling you this? Because usually what we see with patients that are coming from some doctors that don’t want to give them steroids, because they are afraid of the steroids and the infection, so these patients, if you don’t treat it properly, you’re gonna have complications. Just a picture of the Aconcagua mountains here in Mendoza. Just for you to know where we are. And this is the highest mountain in Latin America. And we’re gonna advance with a question for you. So in reference to the staphylococcus aureus marginal keratitis, which of the following options is not correct? So I’ll give you the opportunity to answer. It’s an inflammatory reaction. It’s a type III and IV immunity process that has been described in the physiopathology. It is usually associated with a previous trauma and corneal ulcer. Usually has a self-limited course. And last, topical corticosteroids are recommended as the treatment of choice. So please give your answers. Let’s see. Perfect. 69% has given us the right choice. It’s usually associated with previous trauma and corneal ulcer? No, it’s not. Great. Let’s go on. So how do we deal with the diagnostic? With all the information we have seen before, it’s enough. So if you understand how important it is to make the interrogatory, the semiology, the clinic, and the slit lamp evaluation, it’s enough to understand the pathology. So it’s usually based on patient history and the slit lamp evaluation findings. Of course, you can use different diagnostic alternatives. But you don’t need anything else. For example, if you have a tomography opportunity, you’re gonna be able to see how deep is the infiltrate in the anterior stroma, or if it’s subepithelial or not. But with a good slit lamp evaluation, it’s enough. Gonna show you a few cases after this. What about the laboratory biopsy? It’s gonna be sterile. Because it’s not infectious. So the ancillary testing can be useful for us. Especially in atypical cases. As I was telling you before, if you have hypopyon, and if you’re not sure if it’s a superinfection with another germ, that can be helpful. But for the pure lesion, it’s gonna be sterile. As I was telling you before, you can check the presence of the staphylococcus in the eyelids, but in some patients, it’s gonna be absent also. So how do we make the differential diagnosis? This is the best information we’re gonna have. Other causes of ulceration of the peripheral cornea are gonna be microbial keratitis, contact lens associated corneal infiltrates, rosacea keratitis, Mooren’s ulcer, peripheral keratitis associated with rheumatoid arthritis, corneal phlyctenulosis, Terrien’s marginal degeneration, and marginal herpes simplex keratitis. So we have infections and non-infections, but all of them are affecting the peripheral cornea. How do distinguish if it’s infected versus non-infected? This is the most important thing, and this is a great paper, published by some colleagues from India. They have a huge experience in infectious keratitis. All my friends from India. Some of them are connected here. And I have learned a lot regarding this infectious keratitis. So check this paper. And you’ll be able to see different tables. You have infective keratitis. In the case of those patients, you can think of bacteria, Gram positive or negative, fungi, the filamentous — mostly filamentous fungi. Viral with herpes simplex, or parasites. Once you have this chart, all of these, you know that you have different symptomatology and way of presentations. So to be able to know the presentation of the non-infective keratitis, you’re gonna be able to understand if it’s a PUK, if it’s a phlyctenular keratitis, a vernal ulcer, or if it’s our marginal keratitis, or maybe contact lens-related sterile infiltrates. So I did this table for you to see the sterile versus the infectious. What to consider? In the sterile ulcer, usually it’s smaller. Less than 1 millimeter. But it can be confluent. Usually less than 2 clock hours extension. It’s more peripheral, and you have minimal epithelial damage, the defect size, compared with the underlying infiltrate. Usually you don’t have mucous discharge, and it’s less painful. You have the patient with photophobia — that’s why it’s difficult to get pictures of these patients in the first moment. And usually you don’t have anterior chamber reaction, or a little one. Against infectious keratitis, you’re gonna have bigger lesions, and usually they’re more central. And not peripheral. So let’s go with the next questions. One of the following signs is mandatory in the marginal keratitis. You’re gonna be able to answer also. It’s: Unilateral or bilateral peripheral curvilinear infiltrates in superficial cornea, where the lids cross the corneal periphery. It’s an absence of epithelial defects and subepithelial reaction. Anterior chamber reaction and hypopyon must be there. Radial keratoneuritis. It’s mandatory. And central corneal abscess is described. Let’s see your answer. Perfect. 80%. Great. This is a good sign that the concepts are being clear. Then we have another paper here. It was published in 2017. With a group of doctors. It’s also in my references. Where you can see the differential diagnosis of the peripheral ulcers. And how to distinguish one from the other. So the most important thing to know is that in the rest of these differential diagnoses, with sterile corneal ulcers, you need to be aware of the systemic area. So you need to be in contact with the rheumatologist and the clinic. And if you are under suspect of a peripheral ulcerative keratitis, don’t be afraid of calling our colleagues. Because these patients are gonna need systemic treatment. With the marginal keratitis, the treatment is gonna be responding pretty quickly, in the first two, three, or five days after you give the steroids. The big difference with the other ones that are not gonna be answering to the topical treatment — you’re gonna be needing more than that. So what is the prognosis of this marginal keratitis? The natural course of the disease is spontaneous resolution in two or three weeks, with few to no long-term sequelae, such as anterior stromal scarring. Maybe some astigmatism. But as it’s peripheral, it usually is not that big. The recurrences are common, especially in the concomitant blepharitis. If you don’t treat it, you’re gonna have it again. And the only dangerous thing here is when you don’t treat it properly. The corneal thinning in the periphery can go, and you can have another infection with fungal or bacterial keratitis in the same area. So I’ve seen many cases of these in different places all over the world. I’ve been working all over, and I’ve had the opportunity to see different reactions, and the main problem, no matter where you are, is not thinking about the staphylococcus. Because sometimes you are in some places where you don’t have the resources to do the culture, or to do the different examination. But the main problem there is not that you don’t have the resources. The main problem is that you don’t think about this. So regarding the differential diagnosis of the peripheral sterile corneal ulcer, you should consider all the following options, except: Peripheral ulcerative keratitis. Marginal pellucid degeneration. Mooren. Terrien. Or herpetic keratitis. So all of them should be in our differential diagnosis except one. Let’s see your answer. Okay. This is not correct. The option is B. Marginal pellucid degeneration. I guess there was a mistake here. No problem. So the thing is that this is the only one. It’s been described lately with keratoconus. But it’s not — we get type III or IV inflammatory immune mediated. So let’s go to the treatment. The treatment of this condition focuses on addressing the two main components of the disease. So the sterile corneal inflammatory reaction with topical corticosteroids at least 4 times a day, for one or two weeks, you can use also low dose of prednisolones, 0.12%, with an antiinflammatory effect, or stronger concentration, 1%, with an immunosuppressive effect. Also, mostly you need to think about this, depending on how bad is the patient. How many lesions and the symptomatology you have. Don’t be afraid of using also antiinflammatory — topical antiinflammatory for the pain. The most important here is that if you know the diagnostic is gonna take a few days, in addition, you can add topical antibiotics for prophylactic or therapeutic benefit, especially in cases where there is epithelial breakdown. Because as I was telling you before, you can have superinfection on the epithelial breakdown. So here you have a patient, the first day after she arrives. She has a lot of vessels and inflammatory area. And you can see here the limbus. It’s clear. Then you have the lesions. So it’s important to reduce the antigenic burden by treating the bacterial lid disease. So this treatment involves the usual blepharitis regimen, which commonly includes warm compresses and improved lid hygiene, with frequent eyelid scrubs. The topical and/or systemic antibiotics are often added in acute presentation. With the oral antibiotic that can be macrolide, azithromycin or tetracycline. So these questions were also — one of the most popular questions you made to me were things about the tetracycline, the doxycycline, I really like this treatment, so the tetracyclines have been shown to decrease the lipolytic activity of the staphylococcus organisms, which is presumed to be one of the ways the bacteria alters meibomian gland function. This is a historic case I had in Africa, when I was on a mission over there in Congo. There were plenty of patients with pain and red eye. And with these lesions. So in this area, they really don’t have much access to eye drops. And they do have access to doxycycline. So you can see here how deep has been going the inflammatory lesion. And you can see — as I was taking these pills for the malaria prophylaxis, I was able to know that it was for free in the hospitals for the patients. So you can give them these as a treatment. And you can see how it’s almost healed. I know it’s not gonna be enough for these patients. But if you have problems with topical treatment, you need to understand that the doxycycline is gonna help you with the staphylococcus, but not with the inflammatory reaction. So this is really nice to be aware. Because it’s gonna inhibit the matrix metalloproteinase activity in the cornea and in the eyelids. What about the azithromycin? It’s also good. You can use it topically or you can use it orally. Orally, I would rather prefer the doxycycline, because you can give it more days. You can use it for one pill a day, 100 milligrams, for 14 to 30 days. But if you have a patient with a good tolerance, you can use it for longer. Well, there were some other questions regarding surgeries. If you can do surgeries in patients with previous marginal keratitis. We have some papers that have been describing activity after intravitreal injections, after surgery, but the most important thing is that if you treat the blepharitis and the staphylococcus, you’re not gonna have a problem. So be aware of that. And you’re gonna be able to do any surgeries or procedures you need. If you have a lot of lesions in the periphery, probably it’s not gonna be a good idea to make a flap there, because you’re gonna have association with inflammatory reaction in the stroma. There was another question, between the interrogatory you made to me. What about treatment in children? So here we are used to treat after we teach the parents to make the cleaning of the eyelids. You can also use topical ointment of tacrolimus. It’s a way of having an immunomodulation of the patient’s lid surface. So we prepare tacrolimus 0.1% ointment. It’s very good for the patient, but it’s kind of itchy. So as a conclusion, marginal keratitis may represent different clinical features of the same disease process. The laboratory investigation for underlying systemic disease may be warranted in patients with the appearance of peripheral corneal disorders. Be aware of that, please. The chronic antiinflammatory therapy may be effective in limiting the progression of the corneal thinning in these diseases. So thank you very much for your attention. Another picture of Mendoza in Argentina. You’re welcome to visit us. These are my references. And my contacts. We’re gonna see some questions that I have here. Is catarrhal infiltrate the same as phlyctenule? It’s not the same, but it has the same immune response. What is best precautions for bacteria, virus, and fungus infections to the eye? The best precaution for bacteria, virus, and fungus is, I guess… Well, it’s pretty different. The etiology of all of them are different. But be aware that your patient has a really clean area in the eyelids. Is keratitis only involved in the inferior peripheral cornea? No, it’s not only involved in the inferior. You can have it 360. But usually you’re gonna have inferior and superior, if you have a contact of the eyelid with the cornea. Remember that you may have 360. Okay. Describe the keratitis and precautions in 10 lines. The precautions of the keratitis is having a clear area of the staphylococcus. And the precaution is to be aware… So once you made the diagnosis and you explain to the patient how to deal with it, you’re not gonna have more problems. Let’s go for another one. Okay. The prescription of azithromycin and doxycycline — as I was telling you before, azithromycin, you only can have 500 milligrams by day during three days. And then you have to be aware of this prescription, because you have to wait one week or two weeks to repeat. Usually we don’t use azithromycin orally, because we are gonna be more than three days of treatment. So that’s why we use doxycycline. 100 milligrams a day, during 14 to 30 days. As I was telling you before, myself, I was taking this pill for three months. In Africa. As a prophylaxis of malaria. And it was perfect for me. I didn’t have any problem at all. What are the best combinations of treatment of marginal keratitis? As I was telling you before, Philip, you need to treat the inflammatory disease with steroids. That’s the first line. If you only have steroids, use it. Doxycycline orally and topical steroids. If you have the opportunity to add antibiotics, usually we use moxifloxacin. Is tacrolimus indicated for all children? Why tacrolimus in children? What about topical steroids? Yes, you can use topical steroids in the moment of the reaction. But to prevent the future reactions, like in chronic patients that are not responding only to steroids, you need to decrease the inflammatory reaction. As you know, in medicine, Moulid Omar is your name — we don’t say “all”. Because you need to treat every case as unique. We have the experience — very good experience — with tacrolimus for some kids that are not responding to the topical treatment and to the cleaning of the eyelids. For how long the treatment of blepharitis? Usually when it’s — when the patient learns how to deal with that, they do it themselves. Because they don’t want to have the blurry eye again. Do the type IV immune reaction present in the same way in the peripheral cornea? Yes, it’s the same reaction, but the lesion is different. Okay. Contact lens for marginal keratitis? Do you advise future use? Always. Azithromycin eye drops. Do you recommend it? It’s gonna help, and I do recommend it. Because it’s easy for the patient to use it. Twice a day, in the morning and the afternoon. And it’s really good. But it’s going to be preventing the blepharitis. It’s not gonna be useful for the activation of the immune process. More about PUK? We need a special class for PUK, because it’s really huge. The most important thing and concept to be aware of PUK is that you may have a treatment — you need to have the treatment with with systemic steroids. And sometimes we need to give the patients systemic immunosuppression. Because otherwise you’re not gonna have a good answer. So I think we are done with the time. Thank you, everyone, for joining us today. I’ll be answering the rest of the questions in… The website. I think we’re done. Thank you very much for your help and support.
February 19, 2021