In this lecture, Dr. Roberto Pineda talks about the evolution of Keratoprosthesis, the results of the studies conducted and its uses.

(you can also view a Keratoprosthesis surgical demonstration here.)

Lecture location: on-board the Orbis Flying Eye Hospital in Chittagong, Bangladesh

Lecturer: Dr. Roberto Pineda, Massachusetts Eye and Ear Infirmary, Harvard Medical School, USA

Transcript

(To translate please select your language to the right of this page)

Dr. Roberto Pineda: It’s always a pleasure to be here on Orbis. This is actually my 14th Orbis program since 1998. And I’m going to talk today a little bit about a subject that we’re not really doing any demonstration surgeries for or doing this week, but probable is a subject in which many of the patients in Bangladesh could potentially benefit from. So, this is more of an educational lecture about the Boston keratoprosthesis. This is a device — let’s see if this works here. Nope. Let’s try this. One second.
It must be an easier way to do this. Let me try this. Okay. These are my financial disclosures, can which are not relevant to today’s talk. But Dr. Dohlman, who is basically the inventor of the Boston keratoprosthesis, he doesn’t receive any financial interests in the device and all the money that’s collected for the device actually goes into research for the device. Let’s see if this works.
Jay, do you know if I’m — do I have to do this every time? For advancing? No. But anyways, so — so, you know, there’s been a lot of different keratoprosthesis that have been kind of promoted over the years, but really the Boston keratoprosthesis down here — I don’t have — there we go — down here in the lower right-hand corner. It’s not working. Is really the most commonly used.
So, and why is this device so — become so popular? Well, it really has to do with the survival curve of the device. Very many — very early in the development of the keratoprosthesis in general there was a lot of failures. And what’s made the Boston keratoprosthesis kind of different from a lot of those other ones is that it’s a little simpler to use. But the survival curves are quite impressive. This is a set, actually, from over ten years ago. But really showing for non-autoimmune, multiple graft failures, I mean, the survival — this is just a 2-year survival. I’ll show you some other, longer ones, is quite good. Those that have either chemical injuries or autoimmune-related disorder like Stevens-Johnson or ocular cicatricial pemphigoid have a much lower survival rate. We’ll talk about that.
This is the actual utilization of the device currently. And you can see from about 2006 on there’s been a much larger global use of this device. And, you know, the pink here kind of represents those international usage of the device. And you can see that’s, you know, primarily representing almost 40% of the devices now that we share globally. And this little yellow line here is our own institution. So, you can see that’s kind of remained constant or actually dropped a little bit as more and more people learn how to use the device.
So, this is a paper that was published also a few years ago by Tony Aldave group looking at the international experience. So, it’s great when you have all the resources in western countries to manage the keratoprosthesis. But what about when we look at the global picture and the use of the keratoprosthesis outside the U.S., for example? And you can see that basically the results are very, very similar in managing repeat grapt failure and chemical injury categories outside the U.S. With very similar rates of retention and post-operative complications compared to what we have in the U.S. So, that’s for encouraging. That’s from about five years ago.
So, let’s talk about the device itself. The device itself basically comes as either a two of-piece or three-piece design. It has a front plate. It has a back plate and it has a locking ring. We’ve since gone to a two-piece design that the back plate is the lock — locks on to the ring. And how we put this together is the front plate goes on first — I’ll show you that. We then put on a carrier, which is corneal tissue, and then we put on the locking ring — back plate and the locking ring — if we have that model.
And this particular design comes as boast an aphakic and pseudophakic model. The aphakic model basically requires a knowledge about the axial length of the eye. And the pseudophakic, we assume it’s targeted for emmetropia, so it just comes as one power. And this was — this has been approved in the U.S. since 1992.
This is, again, another representation of the device. The back plate has either been made of polymethyl methacrylate or trivium depending on your interests. And this is how it’s put together. So, we usually start with a seven and a half to eight and a half millimeter donor that’s punched. Centrally we use a 3-millimeter dermal punch to punch out the center of the graft. This is, then, placed over the front plate here. It has a stem on it. And once it’s placed over the stem, then we basically apply the back plate. Again, this can be made of polymethyl mecrylate or titanium. And that’s pressed down. And in this case we have a king which is then pressed on the back here. And then once that’s assembled, you have what’s essentially a corneal grapt. You can see the locking ring here. And this is from the front looking back. But you essentially have a structure that can now just be sown in as you would a normal PKP graft.
So, this is one of the reasons that it’s easy. This is what it looks like after it’s been applied. And usually — you can see there’s a contact lens here as well to help with dehydration of the surface of the device. But essentially you have the same 16 interrupted sutures to hold the graft in place. So, we’ve had a number of updates to the design since 1992. As I mentioned before, we have a snap-on ring which eliminates this locking ring which was a problem for some people.
And then we have — we’ve added holes to the back plate. And what that’s done is improved the nutrition of the device so there were issues with the cornea melting prior when there was fewer or no holes in the back plate. And we’ve since moved to a titanium model because that’s demonstrated better tolerance or biocompatibility compared to the polymethyl methylacetate. And in addition, titanium is much, much thinner than the PMMA.
So, this is — we’ve also — one of the things that’s bothered some people is the kind of metallic appearance of the titanium. And we’ve learned to basically color-code — color-coat, or modify, the surface to give if a blue or more brownish tint to the back plate. So, we’re doing that by using some titanium oxides to change the color for cosmetic purposes. This is the most recent design which is more widely used. You can see we have a slit here now. Which actually allows it to be snapped on as a two-piece design, which is the most popular.
You can see a profile of it here. And I’m not going to talk specifically about the type two keratoprosthesis, but this is what we currently use for the — Stevens-Johnson and ocular cicatricial pemphigoid patients where the prosthesis actually goes through the lid as you can see here. And really, it’s for these cases of severe dryness. One of the issues with using the Boston type one keratoprosthesis is that it does require basically some hydration or lubrication on the ocular surface as well as a good blink reflex. So, if there’s bad exposure or these very dry ocular surfaces, we recommend the type two keratoprosthesis which you can see here.
And this is the new model that we’re working with right now. And it works very similar. But you can see the stem is much longer. What are the indications for the Boston keratoprosthesis? I’ve already kind of mentioned multiple graft failure. I mentioned chemical injuries. But things like chronic herpetic keratitis where the patients have chronic ongoing inflammation. These patients do quite well with the Boston keratoprosthesis. And more recently, aniridia is another condition which we’re using as a primary treatment for these patients. We’re to the grafting the aniridic patients. They usually have severe limbal stem cell deficiency. And we know if we graft these patients, most of them will lose the graft within three to five years. But the keratoprosthesis is retained quite nicely in these cases with very good follow-up.
Here is a case of aniridia, count finger vision, post operatively, 20/60 at seven years. And, again, these patients may have other retinal conditions which — or macular conditions — which limit their vision. But basically, you know, they get very, very good vision with this device as a primary device. And this is a case of post-herpetic kind of neurotrophic kind of cornea with kind of chronic breakdown with the keratoprosthesis. You know, the inflammation goes down and the patients actually do quite well with this device. Usually they’re on chronic antivirals such as acyclovir.
So, you know, one of the questions that people always ask us is, like, why is the keratoprosthesis improving? Why are we getting better results? And, you know, part of it is, is we use the — a carrier graft for these patients which we’ve included both allografts. Sometimes we use the patient’s own corneas as a carrier which helps save money. And we use gamma radiated tissue for these patients. The posterior back plate has the holes which have improved. We have better contact lenses to help keep the surface hydrated. And, you know, we’ve modified the antibiotics for these patients and have new glaucoma technology which basically has improved some of the long-term complications of the device.
So, if you look at large studies of the keratoprosthesis, it’s interesting to see which groups do well and which other groups don’t do well. And if you look at this case where 17% of the Kpros implanted were for autoimmune disease in this 252-patient study, if you look at the number of patients that lost the Kpro, it’s only about 8-9%. But 50% of these patients were autoimmune disorders. So, you can see this is a very high risk group of patients for this device.
And usually when we go and do these programs where we’re working with the Boston keratoprosthesis, patients, you know, the doctors, the local doctors often bring their worst patients to us for help. And usually those are the Steven-Johnson patients, which are the worst group. So, usually we do not recommend this group of patients for the keratoprosthesis except under special situations because they do have a lot higher complication rate.
And, again, this is a longer follow-up almost four years out. And, again, you can see the survival, again, for the multiple graft failure, which is in this gray line here versus the autoimmune which, you know, dropped to almost 50% by less than two years. So, again, this group you have to be very careful with. We’re potentially offering these patients systemic immunosuppression. Much more complicated management issues. But for those with chemical and multiple graft failure issues, you can see the retention at four years out is 80% or better which is quite impressive because these are patients that, if they had a regular graft, they would fail. 100% would fail. So, this is very good.
And, again, if you look at the kind of predictive factors about who is going to do well, again, it’s going to be patients — patients who are older than 65 and have graft failure. Here you can look at the rate of loss was only 1.5% in this group versus the autoimmune groups less than 65 where you have over a third of the patients losing their keratoprosthesis. So, this is very important to remember on how we apply this device to different clinical situations.
And, again, this is just what I mentioned overall. But if you take out the non-if you just include the non-autoimmune and chemical burn patients, we have a success rate of, you know, 90 — nearly 95 plus percent which is very impressive. So, I just want to talk about other things that are really important for use of the keratoprosthesis. One is these patients do require contact lenses in most situations. It’s basically to keep the surface hydrated.
And they do need to be changed out every — you could have a monthly disposable. If you have some other ones, such as the contour, you could leave these in if for three to six months. Many of them — but not all of them — many of them do need chronic steroid drops every day to keep the inflammation under control. But they do need chronic antibiotics. So, these can either be locally available antibiotics. Do you have — let’s see. I mean, we typically in the U.S. will use either Vancomycin, which is compounded, or we’ll use Polytrim or polymyxin B, trimethoprim and a fourth generation fluoroquinolone. These are what’s most commonly used in the U.S. But other — we like to rotate the antibiotics to prevent — to prevent resistance of the antibiotics to the different — the bacteria to the different antibiotics. And the other thing we do that’s really important is when the patient comes to see us in the clinic — which they are every few months, we put in a 5% drop of povidone iodine to sterilize the fornices, mostly for fungal-related issues, which has been quite helpful.
But since we’ve modified this, really the incidence of panophthalmitis, which was much more common prior to the Vancomycin, has become much less of an issue for the patients. The nice thing about the keratoprosthesis also is that, you know, the — the failure rarely occurs immediately. It’s really something due to usually long-term management of the contact lenses. Either people develop deposits on the cant lens, melting, as I mentioned, is improved, infections. But the real problem — this has all gotten better. But the problems have been retroprosthetic membranes, petrositis or cystoid macular edema and glaucoma, which is probably the biggest issue with the device.
And you can see we don’t discriminate. This is a 93-year-old man with a keratoprosthesis who is, you know, enjoying very good vision. But we typically see this with soft lenses. We’ll get some patients who will develop precipitates on the contact lens that require additional management. In this case, we used a hybrid lens. So, hard center, soft periphery. Obviously not an easy solution, but it prevents the deposits from developing on the surface of this patient. So the patient can retain good vision. Many times the patient will also develop deposits on the surface of the keratoprosthesis that require us to kind of take a sterile sponge and wipe off those deposits.
Again, we’ve added these back holes. We’ve gone from one ring to two ring of holes now to help improve the kind of hydration of the graft, which has been quite helpful. And basically, again, most patients do have a contact lens. Patients have a very, very wet ocular surface. They may not require a contact lens. Again, for the melts, which we’re seeing less of, we are using immunomodulation in high-risk groups to prevent melting. And we’re also looking at cross — we’re actually doing this right now — is we’re cross-linking the cornea tissue to make it more resistant to melting and also using — also using gamma radiated tissue to see if that makes a difference as well.
Again, this, you know, this is probably one of the other issues is just patients using — staying compliant with the medication. The best way to do that it so make sure the patient comes in every few months. Most patients are being — this is on a timer. I apologize. Most patients are coming in about every three or four months to get seen after a year from the keratoprosthesis. But obviously endophthalmitis is still something we look for, we watch for. And typical drop in pressure, maybe increasing eye pain. And we’re looking for fungal infection. That’s really what we see more commonly. So, again, this kind of haze around the stem or here are the things we see with fungal infections. But most of these are superficial and can just be treated with topical antifungals.
We’re also looking at impregnating the contact lenses with antibiotics and coating the actual keratoprosthesis with anti-microbe — antibacterial coating to minimize infection. Sorry. It’s going a little too fast. And then, again, the 1% povidone iodine in the clinic is shown to be very helpful in reducing kind of chronic colonization of the fornices. Retro prosthetic membranes, which are essentially fibrosynthetic membranes that form on the back plate — or the back stem of the keratoprosthesis occur very regularly. Up to two-thirds of patients. And we get them in more eyes that are inflamed or eyes that have had infections on aniridic eyes. They can be Yagged, just like you would a normal posterior caps laryngectomi pacification. Sometimes they’re thicker. Sometimes that’s vascularized. If they’re very thick, you may need to consider a pars plana vitrectomy in order to remove the retro prosthetic membrane. And they can also reoccur.
But most cases can be handled with a simple yag capsulotomy and that usually helps restore vision quite a bit for patients. Again, we’ve switched from PMMA to titanium because of better biocompatibility and tolerance. And as you can see here, this is a larger, kind of oversized back plate which I’ll talk about in a little bit which has been helpful for maybe reducing this retro prosthetic membrane. If we look at — this is a small study — but looking at the PMMA versus titanium, you can see the incidence of retroprosthetic membrane incidence was much smaller in this study.
Now, we also think that maybe the retroprosthetic membranes, where are they coming from? Well, we think they’re coming from the host tissue that’s exposed peripherally. And that maybe the graft host junction serves as a site of initiation for formation of the retroprosthetic membranes. So, one thought was to oversize the back plate so it actually covers the graft host junction on both sides to see if that would reduce the incidence of retroprosthetic membranes for these patients. And you can see here, this is a histopathology of the donor cornea, the host cornea, the graft host junction and the formation of this fibrous membrane, or retroprosthetic membrane. So, you know, this makes sense. Usually this tissue is inflamed. There’s probably activation of TGF beta I with transformation of the keratocytes here to produce — to produce abnormal collagen and tissue.
So, again, we started oversizing these back plates. So, this is an 8.5 back plate. Normally the tissue would be about 8 millimeters. And then half a millimeter oversizing. And you can see here from this study — this is looking at with OCT, and your segment, OCT — you can see here we have the back plate and graft host junction. And you can see how much thicker this area is compared to when the back plate extends beyond the graft host junction, that it’s much thinner and you can actually measure that. And we can see in the study here that when we had the oversized back plate, we were almost 200 microns less thick. And this was also associated with a lower incidence of retroprosthetic membranes.
Again, glaucoma is really the one hurdle that we have not improved on as much as we’ve liked to. And so, a lot of reasons people might retain the keratoprosthesis but they lose vision because glaucoma. And many of these patients, I would say at least half of these patients, need a secondary glaucoma surgery or have a shunt placed at the time of the surgery or shortly after surgery because of worsening of their glaucoma. We know — no. We know that many of these patients have progression of their glaucoma after keratoprosthesis surgery. And the problem that we have with the device is we have no way of really measuring eye pressure.
So, you can’t do oppilation, you have to do digital palpation. We have the patient close their eye and we press on it, compare it to the other eye, compare it to our own eye to try a get a sense of what’s happening. We can still now — we can look at OCT, look at the cup-to-disk ratio, and see — then, that’s been helpful. But we are also looking at ways of measuring interocular pressure for these patients because it’s been very difficult. Personally, we — I put all patients on a glaucoma medication whether I think they need to be on it or not because of the progression of glaucoma in these patients.
So, fen, we have a low threshold for using like CTONs or tube shunts with these patients. And why is that? Because we can see that certain groups of patients, their cup-to-disk ratio, we look at the change in the cup-to-disk ratio, certain groups have big problems. The autoimmune patients, the burn patients seem to have a much faster rate of progression over a two to three-year — four-year period. These patients, you know, basically cup out and lose their vision.
So, the patients with no previous surgery seem to do the best. But, you know, the autoimmune and burn patients do much worse. Or patients with one or more penetrating keratoplasty do much worse. Okay.
So, again, as you saw from this previous one, the rate of, like, compared to primary open angle glaucoma is about seven and a halftimes faster when you have a keratoprosthesis in place. So, these are important things. I mean, glaucoma progresses rapidly in these patients. They do need to be checked every three to four months. And, again, for myself, I put everyone on a glaucoma eye drop even if they have no signs of glaucoma. And obviously early intervention is very important to help slow progression. We’re still trying to understand exactly why this occurs. And, you know, I think we’ll be hearing more about this topic in the future.
The other thing we’re trying to do is use technology and putting in sensors in the eye that will allow us to measure pressure over time. And we have done some preliminary studies using these sensors to help monitor pressure. Also, something else we’re using is anterior segment OTC to help us look for membranes and see how the — how the keratoprosthesis is performing over time which is nice. You can look for thing or science of extrusion of the device which are very, very helpful.
So, this is good technology that will help us manage — make some clinical decisions and management decisions for these patients. Also, we’re developing international protocol for use for the device. Kind of makes recommendations for medications and clinical strategy for the device because it’s really hard — no one has, you know, hundreds and hundreds of these patients. They may have a few patients and don’t have the full clinical experience to manage these. So, this is really a compilation of many decades of experience with using the device that we’ve come up with.
you know, some of this — this is part of the study group. I do a lot of international work. Principally in Africa. But in many Ethiopia — I have been going there since 2008, and Sudan since 2009 — to work with these patients. And we have done issues with the consent process, with patient education and microbiology surveillance. Obviously physician training and education. And then some of the medical management and data outcome reporting for these patients.
These are the centers that I have been working with for a number of years. And we have — these numbers are very low. I don’t have an update of these numbers. I probably have about 50 or 60 patients we have been following with this issue.
So, Dr. Dohlman again, our fearless leader, who has helped develop the device. And Mr. — really? Okay. I was told 45 minutes. That’s okay. We’ll work on it. And Dr. Choto who joined us in 2008 is made some big clinical contributions.
Obviously one of the big issues with the keratoprosthesis is cost. It’s a very expensive device. We charge $5,000 in the U.S. But outside of the U.S. it’s used on a sliding basis with the price as low as $500 for countries usually based on GDP. But obviously cost — at that price, it’s still a barrier. And, of course, the tissue itself is also a barrier for requirements. We’re working on a low-cost device called the LUCIA keratoprosthesis. It’s a two-piece device. It’s not quite custom made, but it can be molded, which makes it cheaper. The idea that this would be $100, which now starts to move the device into a much more applicable range. It would only become available as a phakic model, but can be used with many different types of carriers. And it would be essentially sterilized locally. And it’s going through the FDA process right now. This is not for the United States. This is for outside of the U.S.
So, this hopefully will be available by next year. Again, it’s made of the same material, the same quality material, but it’s just molded instead of lathed, and that reduces the cost for production. So, this is what this device is hopefully be available in the near future. This is the latest design of the Lucia, and we’re excited to potentially launch it next year. Again, this is a low-cost device. Can be used with multiple different types of grafts.
And this is a paper that we published now several years ago showing utilization of the patient’s own cornea. So, we basically took — this is a patient who had measles keratitis, basically took off his cornea and punched out the center of it and reassembled the keratoprosthesis and put it back in place. And for patients — in this case from Ethiopia or Sudan — with either trachoma or measles, they were able to achieve good long-term results using their own corneas as a carrier which greatly reduced the cost.
This is just one case here using the Lucia. Someone who had bilateral IK. I’ll just skip through this because it’s not really that important. But the device works very well. And, again, I’ll just — this is using an allograft. This next patient here actually had her own cornea used with severe limbal stem cell deficiency from VKC. And, you know, day five she’s 20/80 and has been doing well. I have been following her for a few years in Sudan.
Of course, we realized cornea tissue is a precious gift. And we have been able to use one — one cornea for three different purposes. Taking the central purge out for the Kpro, using it for a patch graft, and then using the rest for a corneal — for a tectonic graft in the case of Morin’s ulcers. If you’re going to be using tissue, you may have other uses for it at the same time. Our protocol here, again, is in version three, which has been requested by Orbis and should be on the way shortly.
And these are just our recommendations that we’ve come up. Which is actually available on our website. I’m going to skip through some of these. But these are just examples of some of the patients we’ve used the Lucia keratoprosthesis for with either fresh graft and kind of their immediate follow-up. And this is the most recent trip in January of this year. Sorry. Next. For patients either using radiated tissue or allograpt tissue with different reasons for limbal stem cell deficiency, infectious keratitis, failed grafts, et cetera. And this is the more recent trip I did to Egypt for aniridia and for actually an OCP patient.
And the daughter was quite excited and the patient was very excited as well. They did well. Her vision was 20/60 the next day. And they actually sent out — sent out a message on Facebook and got — kind of went viral in Egypt. So, this device has a very powerful impact for patients, but does require long-term follow-up. And we know that the issues and barriers for successful transplantation in particular keratoprosthesis are both social and economic. These are often the poorest patients coming from areas that are far away. And difficulty with follow-up and post-operative management are challenges for these patients.
And we feel that one of the screening criteria for using the device has to be resources that the patient has as well as maybe proximity to the medical center so they can get the proper follow-up. It should be at places that offer kind of a full range of ophthalmic care, including glaucoma specialists, retinal specialists, cornea specialists. You need to have a multi-specialist center in order to be offering this device to patients. It does require a team. It’s not just one doctor taking care of one patient.
So, some concluding thoughts. You know, we have academic collaborations to show that the Kpro is sustainable in countries that are not necessarily the U.S. And we have the Lucia keratoprosthesis which we can look for. That it is both effective and sustainable solution for patients who do not do well with routine keratoprosthesis. And that there is a particular growing interest in this technology with recent developments and follow-ups with improved clinical results and decreasing complications.
So, we hope the Lucia keratoprosthesis will reduce that financial barrier to allow cornea surgeons and patients an opportunity to use this device when it’s appropriate. So, thank you very much. And I’m happy to answer questions.

 

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December 1, 2017

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