Lecture: Cornea on the Cutting Edge

With an explosion of research and technologies focused on corneal disease, we as ophthalmologists must keep up with an ever-accelerating innovation cycle. In this lecture, we will look at the Top Five Discoveries/Technologies in the last 10 years and look ahead at what is in the pipeline for our future practice. We will look ahead at the latest techniques and technologies for corneal imaging, drug treatments/delivery, genetics, and surgery, especially transplantation and refractive surgery. At the end of this session, the audience will have an engaging assessment of the current corneal landscape and have an interactive session at the end to ask questions and have discussions on where we will be in the next 5-10 years to better treat our patients.

Lecturer: Dr. Balamurali Ambati, Cornea Specialist, Pacific ClearVision Institute & Professor & Director of Ophthalmology & Visual Science, Knight Campus, University of Oregon, USA

Transcript

[Balamurali] Good morning and good afternoon and good evening! My name is Bala Ambati. Thank you for joining us. Today I’d like to share my thoughts on a dozen key innovations, both past, present and coming up. There will be a little bit of history in how innovations have arisen and been incorporated into practice and a look ahead to the future. That’s why I call these the dazzling dozen of cornea on the cutting edge.

First, I’d like to really thank and say what a privilege it’s been to work with some fantastic mentors over my career. There have been many more than this group of five, but these group of five mentors in my residency and fellowship helped me become the doctor that I am.

Looking backward, more than 80% of what I do now didn’t exist when I finished fellowship in 2002. And so all of these things I’m going to talk about have been things that we’ve adopted and incorporated into our practice. I’d like to spend some time with you looking at how cornea has evolved in the recent past, in terms of how we’ve figured out how to resurface the back of the cornea, repair the surface of the cornea, advances in refractive surgery, and key contributions in biomechanics for the treatment of keratoconus.

My mentor Claus Dohlman from my residency, unfortunately passed away about a year ago, told me, “Cornea is the most noble of specialties.” Because we can do so much for patients, we have so many things to offer.

Let’s start with endothelial keratoplasty. This was first attempted by Dr. Barraquer in the 1950s, but there were a lot of technical challenges in terms of astigmatism and neovascularization. And until the 1990s, it really did not gain traction. Dr. Melles from Holland developed a technique for a posterior stromal pocket and then use of an air bubble to help secure the endothelium. And then this was worked on by Dr. Terry in the US to develop great instrumentation to enable what he termed DLEK. And then shortly thereafter my mentor, Dr. Carlson, told me in 10 years we’re all going to be doing a lamellar surgery almost exclusively. And this was in an age where we were only doing PKs in the late 1990s, early 2000s. And so coming out of fellowship, I knew I had to continue to add to my skill set and continue to learn new techniques.

New techniques are incremental often. They require collaboration among the community of surgeons. Dr. Melles used descemetorhexis to peel the back of the cornea and then Dr. Price added the technique of venting incisions. And then Dr. Gorovoy developed a way to use microkeratomes, that are traditionally used in LASIK, to remove anterior stroma as a free cap on the donor. And that enabled preparation of grafts by eye banks. And by taking the donor tissue preparation out of the operating room and into the eye bank, that made DSEK much more simple and much more standardizable allowing us to use thin grafts. Ultrathin DSAEK, less than 100 micron tissue and now nanothin DSEK which is about 50 micron tissue, is now routinely available from eye banks that have the capacity to prepare tissue in a standardized way.

And the innovation doesn’t stop. Why put stroma in at all? Dr. Melles adapted descemetorhexis for donor corneas to allow preparation of just Descemet’s membrane and endothelium from the donor. And now US eye banks can prepare DMEK grafts as well. One of the main challenges of this is maintaining orientation and then that is addressed by using Trypan blue dye and then stamping the stromal side of the graft.

I’d like to share a video from my partner, Dr. Anthony Grillo, who’s doing a DMEK. He’s a great surgeon and this is a preloaded DMEK tissue that’s inserted through about a three and a half millimeter wound that has two safety sutures. And this preloaded tissue, remember it scrolls endothelial side out. You have to be very careful to manipulate it. It does not behave like DSEK tissue. You don’t really want to touch the graft once it’s inside the eye.

Dr. Grillo’s basically unfurling this using tapping on the surface of the cornea and getting the graft to unfurl inside the eye. You want a shallow chamber and also use fluid currents to get this to orient properly. This configuration of a crepe or a dosa inside the eye allows proper unfurling. That triangular crepe work, for my friends in India, a dosa-type configuration really enables this to unfurl. And so it does take some patience. This is a lot more involved than DSEK, it takes a lot more intraoperative time than DSEK, and it does require sutures. But it looks very elegant when it’s all complete. One of the other things about DMEK tissue is you should only use tissue over the age of 50. If you have a very young patient, you may still want to use DSEK tissue because you can use younger tissue in DSEK.

He’s finishing up here and put in the air bubble, you can use filtered air, you can use SF6. Also note he’s prepared an inferior PI, that’s very important to prevent pupillary block. DMEK does achieve a little bit better visual acuity, 20/20 versus 20/25 on average for DSEK. And it does generally have a faster recovery usually within a week, rather than four to six weeks with DSEK. But it’s a lot more technical challenge. Because of that steep learning curve, because of the much higher rebubbling rate with DMEK, you just have to let patients know there’s a high chance that they’re going to need a rebubble in the office. That is a barrier to DMEK adoption. Both DSEK and DMEK are great surgeries. In our practice we use DMEK frequently with patients who have great visual potential who want advanced or multifocal lenses and so on. And for patients who are willing to wear glasses, DSEK is a perfectly good option.

Next up I’d like to talk about what’s happening in surface repair or what’s happened in surface repair in the last 20 years. Amniotic membrane first came about in the 1940s. But again they went into deep storage because they were hard to use. In the 1990s, they became easy to use. Dr. Batlle from Bascom Palmer and Dr. Scheffer Tseng from Miami made significant key advances in harvesting amniotic membrane and then cryo-preserving it which allowed long term storage and ease of distribution. Now it’s used for a whole bunch of things: pterygium repair, corneal ulcers, even bad dry eye. There’s many different companies that prepare either fresh tissue, which I like for pterygium repair and severe ocular surface disease or freeze dried tissue which I use for treatment of epithelial basement membrane dystrophy and Salzmann’s nodules with office-based procedures.

Limbal stem cells are something that we take for granted. But when you lose them, it’s major problems. You get severe pannus, neovascularization. And treatment of limbal stem cells initially when you had bilateral eye injury, was using keratolimbal allografts, taking donor tissue and then sewing it onto the host limbus. If you had single eye disease you could do conjunctival limbal autografting. And then most recently in the last decade, we’ve developed techniques for simple limbal epithelial transplantation.

The classic way of dealing limbal stem cell deficiency was taking cadaver donor eyes and harvesting just the limbus, and making crescent halves, and then sewing them onto the patient’s eye. Big surgery, you have to give them systemic antirejection medication. But if you have a bilateral chemical burn this is probably what you’re going to end up needing to do.

With unilateral disease, you can take tissue from the donor eye and then just conjunctiva and limbal corneal epithelium and suture that onto the host eye. You can take two clock hours from superior and inferior limbus and sew that onto the patient’s cornea.

Dr. Sangwan from India developed a very elegant technique about 10 years ago called SLET which makes treatment of unilateral limbal stem cell disease even easier. Here, let me show you a video from them and it will explain things. This is a video from Dr. Sangwan who moved from LVP to Jackie Shroff’s clinic in India. First he’s going to harvest a normal limbal conjunctiva from the good eye of the patient and you just want conjunctiva. And he’s doing a nice dissection. There will be some blood at the donor site, that’s okay, that will heal. And then on the bad eye, remove all of the disease, scar, and pannus. And this takes time. This is going to require patience to get a good cut down. Then he puts some fibrin glue onto which there’s an amniotic membrane. And then in the meantime, he’s cut that limbal conjunctiva from the other eye into these small pieces. I call this fairy dust, he cuts them into these small, fine pieces and scatters them on the amniotic membrane bed and then puts fibrin glue. You put another amniotic membrane on top if you want. Everything is trimmed to fit and it becomes a really elegant way to repair a single eye disease.

What else has been going on besides back of the eye and front of the eye. Refractive surgery has continued to advance from PRK in the 80s to blade LASIK in the 90s and early 2000s to now all laser LASIK. My residency mentor, Dr. Azar, taught me the importance of the word “perfect.” Both in terms of something which we should aspire to and in terms of something we should keep the patient calm during surgery. When he was teaching me surgery, I would put in a suture and ask him if it was okay. Even if I didn’t do it right he would say, “Perfect.” He would remove it, put in a new suture and say, “Now it’s even more perfect.” And that word “perfect,” both during surgery and after surgery is so reassuring to patients and helps keep them calm and that’s an important pearl to keep in your clinical practice.

In the pursuit of perfection, femtosecond laser has allowed us more precise flap thickness and architecture. It has removed a lot of the flap complications of microkeratomes and it’s enhanced visual outcomes.

Beyond LASIK, now we have SMILE which just got approved a few years ago in the US, has been in Europe for much longer than that. And with SMILE this is all femtosecond refractive surgery. This can treat up to 10 diopters of myopia, up to three diopters of astigmatism in the US, and up to five diopters overseas. And by using SMILE, this has been advanced for patients with high myopia because there’s no flap, there’s less biomechanical impact. And an advance for patients with significant dry eye, the surface incision is so much smaller.

This is a video from Dan Reinstein in London using the Zeiss VisuMax laser. You first make a deep cut, and then a refractive cut, and a side cut that links the two. Then there’s a small two to three millimeter incision through which the dissecting tool separates the lenticule that’s prepared by the femtosecond laser. And you’re separating that from the cap of the overlying cornea, as well as the underlying bed. And then you take it out and you’re done. You just have to make sure you got all the lenticule out. But much smaller incision, corneal nerve recovery is faster, and this is a very elegant procedure that I think is really going to make a huge impact in refractive surgery.

Femtosecond laser also does elegant astigmatism correction. This has been great for the treatment of astigmatism at the time of cataract surgery, before cataract surgery, or after cataract surgery. And so it can be used for treatment up to about one and a half or two diopters, even, of astigmatism correction at the time of cataract surgery. You can use it in lieu of toric lenses or to complement presbyopic toric lenses when they have a lot of astigmatism. On a corneal transplant patient when we have lots of astigmatism, if you bring the femto incisions down to a zone of seven millimeter optical zone, you can even correct about seven diopters of astigmatism on a post-PK graft.

Next up is biomechanical reinforcement. In keratoconus, traditionally we do glasses and contacts but they don’t treat the disease. Intracorneal ring segments, which are PMMA implants, can be implanted into corneal channels to provide support. And there’s a whole bunch of implant technology. Intacs is the only one available in the US, but there are other ones: Keraring, Ferrara ring, Mediphacos, Myoring, which have a variety of different arc lengths, configurations and thicknesses, and inner and outer diameter. Some of them can get pretty close to the pupillary center when somebody has really bad astigmatism.

And by using intracorneal ring segments, if you use two of them you can achieve a significant amount of corneal flattening. If you use a single 450 Intacs, you can knock down astigmatism by five to seven diopters. There’s very importantly a reduction in higher order aberrations. Coma can be very disabling to keratoconus patients and by reducing the coma, by symmetrizing the cornea you reduce the coma and help improve the visual quality.

In the management of keratoconus, Intacs is beneficial to lowering astigmatism. And to stabilize the cornea you want to do corneal crosslinking. Crosslinking represents the convergence of biochemistry and biomechanics. It’s deficient in keratoconus patients because there’s a deficiency of an enzyme called lysyl oxidase. Starting in the late 90s, Dr. Spoerl and Seiler from Germany at Dresden, used ultraviolet light and a vitamin B2 solution to induce photooxidation. By doing photooxidation that crosslinks the collagen fibers in the cornea, the riboflavin keeps the UV light from going beyond the cornea. And this helps stabilize the cornea, prevents progresseive ectasia of the cornea, and strengthens the cornea. It’s used in keratoconus, post-refractive ectasia, even corneal ulcers and marginal degeneration.

The classic Dresden protocol involves epithelial debridement, there are risks of pain and infectious keratitis and scarring. But those are worth it given the dramatic reduction of the need for corneal transplant. The places such as Holland and Finland that have registries show that corneal transplant for keratoconus has declined by about 50% since the advent of crosslinking. These risks of the crosslinking procedure are worth it when weighed against the dramatic benefit and reduction of need for corneal transplantation.

In the last several years, people have wondered can we crosslink without removing the epithelium? Different companies are working on riboflavin formulations that have enhanced permeability as well as using accelerated and pulsed and oxygenation techniques to enhance efficacy of crosslinking and reduce the time. You can imagine 30 minutes of holding a light over an eye, that can be burdensome on physicians. And now with these accelerated techniques we can get that time down to 10 or even five minutes.

This is a picture of crosslinking. You want a nice, even application of riboflavin. Some of the more modern machines you can adjust the aperture size to match the aperture to the largest diameter of the cone so you can focus the treatment on the weak cornea.

Epi-on versus Epi-off. A recent meta-analysis show that Epi-off works better. Great reduction of Kmax. But Epi-on had a much better safety, a much lower significant and non-resolving complications. Bottom line, there was no difference in uncorrected or corrected distance visual acuity. In my practice, generally we use Epi-on because there’s a fast visual recovery and less risk and the procedure can be repeated if there is progression. And very importantly, it can be combined with simultaneous Intacs. When you’re doing Epi-off there’s a lot of inflammation and generally it’s recommended to separate Intacs from the crosslinking. With Epi-on, you can combine it with Intacs and that leads to a much happier patient much more quickly.

These are just examples of Intacs and Epi-on combined surgery in our practice. And you can see that the difference maps of pre-op versus post-op show significant flattening throughout the cornea and more symmetry and less astigmatism compared to baseline.

Looking ahead, there’s a lot of continued innovation and intellectual ferment in the world of cornea. This is just a partial list of some of the things that are exciting. There’s a lot of other things going on cornea. But I wanted to give you a taste of what to look forward to in this decade. We talked about surgical crosslinking. There’s a company called iVeena, which I’m the co-founder of, that’s developing an eye drop for pharmacologic crosslinking. There’s advances in nerve regeneration, endothelial cell replacement, and gene therapy. There’s new intraocular lenses that will be very beneficial for corneal patients. And then femtosecond IOL or corneal modification and then allogenic implants.

My mentor, Tony Adamis, who’s a physician, scientist, and corneal surgeon, he was the founder of Eyetech which brought Macugen, the first anti-VEGF drug to the market. He inspired me to become a researcher and to help contribute to the evolution of practice by working in basic science. I’m very grateful to his training, emphasizing not just becoming the best doctor you can be but also contributing in the lab. Because you don’t want MDs not to understand science and you don’t want PhDs not to understand clinical problems. And that interface between laboratory and science is a fertile interface for advancement.

I mentioned this enzyme, lysyl oxidase. This is a copper dependent enzyme that catalyzes collagen crosslinks. It’s diminished in keratoconic corneas, there’s great work from Rohed Shetty in Bangalore and others who have shown that it’s reduced in both the epithelium and in the stroma. There’s also a lot of work on genetic mutations and the lysyl oxidase gene in keratoconus families. And copper, the requisite cofactor of lysyl oxidase, is reduced in keratoconic corneas.

In 2015 in my lab, we found that copper could enhance lysyl oxidase activity in both normal and keratoconic corneas compared to normal and keratoconic corneal fibroblasts without copper. This was an in vitro experiment that we did in corneal fibroblasts. And as you’d expect, the keratoconic corneal fibroblasts had the lowest baseline LOX activity compared to normal. But both benefited from treatment with copper.

Soon after that, I did co-found iVeena, so now I want to do the financial disclosure that I’m president and co-founder of this company that’s developing IVMED-80 which delivers copper as an eye drop to the cornea. Arturo Chayet, in Mexico, completed a Phase 1/2A study, a clinical study report in January of this year. This was in a pool of 31 patients and we had three subarms. About a third of the patients received vehicle eye drops, a third received six weeks of IVMED-80 eye drops, and a third received 16 weeks of IVMED-80. Everybody was followed for 26 weeks so that way we could assess the impact of duration of therapy as well as cessation of therapy.

And we found that as you’d expect, the placebo-treated patients had a slight progression at six months. The patients that received IVMED-80 for six weeks didn’t really benefit that much, no significant effect. And the patients that received IVMED-80 for 16 weeks found a diopter of reduction at 16 weeks and that was mostly preserved at about .78 diopters of flattening of Kmax and 26 weeks, and that was statistically significant.

In addition, we decreased corneal astigmatism at both the week 16 and 26 time points. And improved stress strain index and surface point highest curvature, which are biomechanical parameters that can be tested in vivo in patients over time. And that was done by Dr. Chayet’s group on the Oculus Corvis.

Most importantly, there were no adverse events. There’s no surgery. There’s no adverse events from this eye drop. The only adverse event that we saw was in the placebo group. There was a little mild, marginal keratitis that self-resolved. But there was not a single treatment-related adverse event from IVMED-80.

We think this is going to be the first pharmacologic treatment for keratoconus and we’re very happy that the FDA has given us guidance that we need to show one diopter of flattening at one year. We’re confident that we can achieve that with our phase three studies that are upcoming. And we feel that longer treatment will yield more flattening that hopefully will be durable.

Next topic beyond keratoconus is corneal nerve regeneration. Neurotrophic keratopathy is a big problem. When you have damage to the trigeminal nerve, there’s chronic epithelial breakdown, ulceration, perforation. And there are now both pharmacologic and surgical treatments for these patients. Historically all we could do was supportive care: bandaged contact lenses, amniotic membranes, tarsorrhaphy. There wasn’t a whole lot we could do to treat the loss of corneal nerves.

A couple of things on the pharmacologic side. My good friend, Hynda Kleinman, who was an NIH scientist for decades working with Gabe Sosne, a cornea specialist, developed an eye drop called Thymosin Beta4 that reduces inflammation and promotes re-epithelialization of these patients with neurotrophic keratopathy.

Oxervate was approved a few years ago and is starting to gain traction in the cornea community. It’s a recombinant human nerve growth factor. It relies on work done by Nobel laureate Rita Levi-Montalcini who survived World War II and went on to become a great scientist in neurology and physician in neurology. And so she isolated a nerve growth factor that’s been developed into cenegermin eye drops.

The results with this eye drop are striking. You can see rapid closure of neurotrophic keratopathy epithelial defects. And they’ve also shown improvement in corneal sensation.

On the surgical side for nerve injury, there’s been a technique developed called neurotization where you can translocate donor nerves to the perilimbal cornea. This is a slow process and can be done from either ipsilateral or contralateral nerves. There’s a lot of different options. You can do supraorbital, supratrochlear, intraorbital, or auricular nerves and translocate them to the cornea. You want them to be tension-free after growth.

And so these results of direct nerve neurotization have shown that you can close the cornea and improve corneal clarity.

And more recently there’s been indirect nerve transfer either using allograft or autograft tissue. And you can use sural nerves, antebrachial nerves. And so this opens up things tremendously if you can just graft nerve tissue or never segments from other parts of the body.

Both direct and indirect neurotization achieve 80% or more of corneal sensation restoration and improvement of numbness within six to eight months. Earlier you do it the better the results, in terms of reduced scarring. And if they have significant scarring then you’ll still eventually need to do a cornea transplant but wait a couple of years after the neurotization to give the graft the best chance to succeed.

On the back of the cornea we talked before about the state of the art, DSEK and DMEK. But there’s still continuing advances in restoring endothelium that’s been damaged. As you know, the corneal endothelium is a hexagonal monolayer that creates a flux of ions to maintain corneal clarity. We talked about transplantation but there’s going to be non-transplantation therapies. One of the things Dr. Kim, my fellowship mentor, taught me is to spare your motions. The more you can make each surgical movement count, the more you can make each surgery count, the better off you and your patient will be. Doing unnecessary things in surgery and getting things out of the operating room into the office, both are cornerstones of continued evolution of corneal care. The non-transplant approach is to restoring the endothelial monolayer and include both cell-based and gene therapies.

Dr. Kinoshita of Japan published a landmark article in the New England Journal a few years ago where he took cultured human corneal endothelial cells from donors and then developed a suspension, supplemented it with a ROCK inhibitor, and then injected it into the anterior chamber and had the patient lay face down for about three hours. Within a matter of 24 weeks, this increased endothelial cell density, improved visual acuity and decreased corneal thickness.

You can see the series of patients where within two years you have a striking improvement in corneal clarity in these patients with Fuchs or pseudophakic bullous keratopathy or both. And this was a durable effect lasting up to five years. And there was normalization of corneal curvature as well. Substantial benefit to the patient and much less surgical risk because this is essentially an outpatient procedure.

On the gene therapy side, since the human genome project concluded in the last 1990s, we’ve been able to identify key genes for several different corneal dystrophies. Starting in the front of the eye, Meesmann’s dystrophy, there’s now a mouse model for it which can be cured using CRISPR-Cas9. This was done by Dr. Courtney and more and their group.

And on granular dystrophy, for TGF beta-induced dystrophies, there’s been in vitro demonstration that you can take human corneal keratocytes from a patient and fix them by CRISPR-Cas9 repair. This opens up a whole slew of opportunities where you can treat granular, and lattice dystrophy, and Reis-Bücklers dystrophy, anything that’s TGF beta-induced. And potentially, you can take a sample of a patient’s keratocytes, take them out, culture them, modify them ex vivo, and then reinsert the patient’s own cultures keratocytes back into the cornea. You’re avoiding the risks of rejection while fixing the gene defect in their cornea. This is really remarkable work coming out of Japan.

In my laboratory, my lead scientist, Hironori Uehara, was at the University of Oregon, developed a gene therapy for the treatment of early onset Fuchs dystrophy. We got mice from Dr. Albert June in Johns Hopkins that had a collagen VIII A2 mutation. And by disrupting the start codon with CRISPR-Cas9, then we were able to rescue endothelial function and prevent endothelial cell death.

These are some pictures from Dr. Uehara and the laboratory team where the mice that have the exact same mutation as early onset Fuchs dystrophy. You can see they develop polymegathism and cell loss and treatment with a viral vector that knocks down that mutant start codon, can significantly improve endothelial density by preventing endothelial cell loss and reduce the guttate formation on corneal OCT in these mice. Furthermore we were able to improve central corneal thickness, reduction in osmotic stressed challenge. Untreated mice are much less able to deswell the cornea after an osmotic challenge. And the treated mice were able to deswell their cornea comparable to untreated mice. This work just got published in “eLife” in June.

Moving from endothelial cells to intraocular lenses. This is a cornea talk but intraocular lenses are very important to cornea patients. Especially in patients who’ve had post radial keratotomy or corneal scarring, they still have a lot of glare and problems after cataract surgery. The AcuFocus IC-8, which is in phase three studies currently, promises a lot of benefit to these patients. Initially the underlying technology was a pinhole from the camera implant which didn’t gain much traction because synthetic corneal inlays have had problems in the treatment of presbyopia. However, it was adapted and put onto an IOL platform and this seems to give an extended range of vision and accommodate through a good amount of pre-existing astigmatism. For corneal patients who have had prior radial keratotomy or corneal scarring, the pinhole effect achieved by this IOL can give them a much better depth of focus.

This is a video of an IC-8 injection. Standard phacoemulsification has been done and then it’s then injected through a standard wound. And you can see it’s just an acrylic lens that has this pinhole in the center. You center it, you do want to center it on the visual axis, so that’s important to bear in mind in terms of where you center the pinhole. But it’s otherwise a straightforward cataract surgery that I think will make a big difference for post-RK patients who are now getting into cataract age.

And what about patients who’ve had intraocular lenses and aren’t satisfied with their outcome? There’s a couple of companies working on refractive index shaping. One is called PerfectLens. This can change a multifocal lens into a monofocal lens or turn a monofocal lens into a multifocal lens. The femtosecond laser modifies the IOL inside the eye using this principle called refractive index shaping that changes the properties of acrylic lenses.

There’s a different company called Clerio that’s using this approach on the cornea. Scott MacRae at University of Rochester is using femtosecond laser to change mid stromal cornea. And you can see this pattern of small rings and arcs to induce treatment of presbyopia or hyperopia by using a refractive index change. In the central cornea there’s no flap, this is just small femtosecond bubbles delivered to the mid stromal cornea so there’s no incision. But you can imprint different patterns onto either the cornea or the IOL. I think this is going to be revolutionary when this comes out in the treatment of presbyopia in the post-cataract surgery modification of intraocular lenses. This is going to open new treatment modalities.

I mentioned that synthetic corneal inlays have experienced a lot of challenges. And that’s the thing with innovation, you try some things, they may not work but then you have to approach it from a different angle. There’s a company called Allotex that’s developing acellular corneal lenticules. This is corneal tissue that’s been shaped by an excimer that can be placed into the mid stromal cornea under a standard LASIK flap. This is being done for the treatment of presbyopia but you could use it for other conditions as well.

A related technique, Dr. Frank Price is one of the main proponents of this, is something called LIKE: Lenticular Intrastromal Keratoplasty. Where you do a LASIK flap and then you order a premade lenticule from Indiana Eye Bank, or in Europe a company called Gebauer, that can be placed onto the central cornea and the flap repositioned. This is basically eye bank donor tissue that’s been shaped by an excimer and then you can fine-tune for refractive correction about two months later with the excimer. This is something that will be useful for keratoconus patients as well as very high hyperopia patients who currently don’t have good options.

In conclusion, I just want to say that we’re all very blessed to be in a field that has a great community of surgeons that work together and is a very dynamic field. And that innovation, if you remember nothing else from this talk, innovation depends on understanding history, approaching it and the current challenges with humility, but persistence and bravery in collaboration as well. The willingness to try new techniques to always keep the field moving forward and keep developing better options for our patients.

I know I’ve covered a lot of material today. But I hope I managed to fit it all in. And I’d like to thank Orbis, it’s been a tremendous honor working with Orbis on over 10 programs in my career in four different continents. I’d like to thank Roberto Pineda who was my residency mentor who introduced me to Orbis way back when. And my good friend, Hunter Cherwek, who’s the heart and soul of Orbis and has been a great friend to me for almost 20 years.

And I’d like to thank all the folks who, Andrew Thomson, and Quyen Luong, Bonnie Archer, and Sarah Molokhia who helped me put together this presentation. Thank you all for your attention, I’d be happy to take any questions.

We’d like to know about liquid cornea for surface repair on the cornea. There are companies and US military grants developing suspensions of corneal cells with hydrogel. I’m answering this live, so. With hydrogel suspensions of corneal cells to place in battlefield injury. I think work of that nature, that is in research labs, both here and in Japan where you have self-surface suspensions, I think will be coming out within, hopefully, five to 10 years.

Next question, was the future of chemical crosslinking? I mentioned to you we’re developing IVMED-80 to enhance lysyl oxidase. And that is going through phase three studies next year and hopefully will result in FDA approval by end of 2025, assuming those phase three studies are successful.

How will we remove opacities in lattice corneal dystrophy? Currently for lattice corneal dystrophy, if it’s significant in terms of visual degradation or pain, the standard of care is probably anterior lamellar keratoplasty or deep anterior lamellar keratoplasty. In the future, hopefully there will be gene therapies but currently transplantation is necessary for lattice.

Any experience with artificial endothelium with EndoArt? I did not. I will have to learn about that technology.

Next question is multifocal versus trifocal IOLs? In the US we currently use PanOptix, Vivity, and Synergy lenses. Those are probably the three most advanced lenses that are available to us. And I try to match those to the right patient depending on what their near point is, depending if they have any other pathologies in their cornea or in the retina, and their visual needs and lifestyle. I really do take time to understand each patient and their goals to decide what lens is best for them.

Next question is, may I use this presentation in this classroom? Absolutely, I’m sure Cybersight would be happy to send you the slides you can email me and I’d be happy to send you the slides.

Which technique would you use in a newborn baby with Peters syndrome bilaterally with adhesion between lens and cornea? Pediatric corneal disease is a very challenging thing. I’m certainly not an expert on this. I would say Jonathan Song at Hopkins is probably the foremost experts in pediatric corneal disease. For Peters babies I’ve done corneal transplantation in these babies in the pre-DSEK time. And it was very challenging, doing a PK in an infant is very challenging. There’s a lot of issues post-operatively in terms of rejection, suture management, and glaucoma. Currently, I would say that if you’re able to separate the lens from the cornea and can get young DSEK tissue, I’ve used DSEK successfully in patients with CHED. That’s worked very well for CHED patients. I would expect that if you can separate lens from the cornea, then put DSEK, again, that would be a good first procedure for a Peters patient and then deal with the cataract later. That would be my recommendation in the absence of further information.

For advanced keratoconus, if surgery is not possible what should we do? Scleral lenses are a great benefit to these patients. There’s been a lot of advances in custom geometry lenses as well as scleral lenses for keratoconus who are not surgical candidates.

Alternative to fibrin glue for a simple limbal epithelial stem cell transplant? You can do a double layer amniotic sandwich. And so if you don’t have access to glue you can put a membrane bed, put the fairy dust on the simple limbal epithelial cells, and then your amniotic membrane.

And then crosslinking in patients with corneal thickness less than 400 microns? When you’re doing Epi-off crosslinking, you can use solutions from Avedro in the US that swell the cornea, so that’s Photrexa Viscous. That can swell the cornea to more than 400 microns. Overseas there’s a lot of other companies, Peschke, New Vision and so on, that develop other hypotonic solutions that can swell the cornea.

Is bandaged contact lens and tarsorrhaphy possible for SLET when fibrin glue is not available? Sure, absolutely.

Pinhole pupilloplasty? I don’t have experience with that but it would probably be a very good technique as well.

In which age do you advise PK for a baby with bilateral CHED? It’s a great question. When you have unilateral eye disease, you want to treat early to reduce the risk of amblyopia. With bilateral CHED, if it’s symmetric and there’s no glaucoma issues, the surgery just becomes easier technically at six to 12 months of age. I would wait a little while to let the eye grow.

As far as my email, I’ll type it, but anyone who wants to email me they can. My email is very easy: BAmbati, so my first initial B, my last name: Ambati, at gmail.com. Feel free to email me any questions and I’d be happy to send the slides.

There’s time for a few more questions. But I really appreciate everybody’s attention. It’s been great spending time with you.

Oh, here’s another question. Plenty of keratoconus cases with cornea thinner than 400 microns. In the US, I think there’s Photrexa Viscous, I believe Avedro has representatives in other countries as well. Overseas, there’s Peschke H solution which is hypertonic solution from Peschke, that’s a Swiss company. That’s a very solid riboflavin product. They also have Peschke TE, which is transepithelial solution.

Great. I will stick around for a few minutes. I have clinic at eight o’clock, but happy to answer any other questions that are there from this worldwide audience. Lawrence, I’d like to thank for his smooth walk through with putting this presentation together. And anyone from the Orbis family, it would be good to see you again, whenever and wherever we can. It’s been a long time since I’ve seen the Orbis crew. It’s a fantastic organization and I encourage anyone who’s able to to get to know them and contribute in whatever way that you can. That makes a big difference around the world every day.

For endothelial rejection and graft, what is alternative treatment? Graft rejection management is a big discussion. If you catch it early, very often graft rejection can be taken care of with hourly steroids. If there’s any neovascularization I do a subconjunctival Avastin right next to the neovascularization and that works like magic. If you need to, you can do a five-day course of oral prednisone. If this person is on corneal transplant number three or four, and they’ve had multiple surgeries before, then I’ll do prophylactic treatment with tacrolimus ointment as well as oral tacrolimus, five milligrams once a day. Which can be very beneficial in preventing rejection in patients with chemical burn or multiple prior corneal transplants.

If the transplant is not salvageable and essentially the endothelium has died, you could do DSEK post PK. You would want to undersize the tissue, so if you have an eight millimeter original PK you can put a seven millimeter DSEK to get it to stick. My colleague, Dr. Grillo, does do DMEK in post-PK patients who’ve had endothelial failure, and that seems to work as well. But he cautions that there is a very high rebubbling rate in those situations.

What is my opinion about descemetorhexis stripping only procedure? This is where you have Fuchs dystrophy and you have focal guttata that are affecting central vision and you can do a three or a four millimeter, maybe a five millimeter descemetorhexis. And I’ve done it, personally four times, twice it worked, twice it didn’t. It’s certainly worth a try, you don’t really have anything to lose. It also depends on your patient, are they a patient person or are they expecting rapid visual recovery? In the US context, patients really want rapid visual recovery so it’s hard to position descemetorhexis. If you have somebody who’s patient and worried about transplantation and long term rejection risks, it might be worth a shot if you can do a focal removal of the guttate and then see if they heal.

What’s your opinion about using topical anti-VEGF drops for reducing neovascularization? They work, it’s been shown to work. It’s just that a monthly injection of Avastin is cheap and topical preparation of Avastin to use continuously can be fairly expensive.

Gene therapies, which center does it? That’s not clinically done yet. Those are all research studies that I presented. Will it replace keratoplasty for corneal dystrophy? I certainly hope so!

We talked about DWEK, descemetorhexis without corneal transplantation and so in a particular patient who’s patient in terms of visual expectations and timeline to recovery, yes it is an alternative.

Transepithelial PRK. That’s not available in the US. I don’t have experience with it. Dr. David Lin in Vancouver is probably the world’s expert on transepithelial PRK.

I think we’ve answered all of the questions. It’s been great spending time with you this morning.

[Speaker] Dear participants, as World Sight Day is being celebrated, we recognize the impact you all have. And use this day to shed light on blindness, vision problems, and impairment, and their impact on education, employment, quality of life, and poverty. The burden of the vision impairment falls more heavily on low and middle income countries. And that is why eye care health professionals in these regions continue to play a key role, providing a ray of hope through the delivery of eye care services. We also seize this opportunity to celebrate Qatar Creating Vision, a joint initiative of Qatar Fund for Development and Orbis, created to reduce childhood blindness across India and Bangladesh. The program also evolved to support the Rohingya and local host community in Southeast Bangladesh.

We take great pride in its achievements. It has so far delivered access to vital eye care to more than six million people, without which they may have been forced to drop out of school, leave their job, or be left unable to break the cycle of poverty. Achievements, such as these, are made thanks to the dedicated healthcare professionals like you, who work tirelessly to provide high quality eye care to your patients. I wish you all a fruitful and insightful webinar. Thank you.

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October 15, 2021

Last Updated: September 12, 2022

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