Descemet’s membrane endothelial keratoplasty slowly on the rise

Lamellar techniques have almost entirely replaced penetrating keratoplasty. They have undergone progressive refinements and have more recently evolved toward minimizing the presence of allogenic tissue in the eye to prevent rejection and graft failure.

“Overall, if we can work toward smaller grafts or no graft at all, this is going to benefit the patient in many ways. On the other hand, if we can multiply the number of grafts we can obtain from the same donor, we can reduce the costs and the problem of tissue shortage in some areas of the world,” Gerrit Melles, MD, PhD, said.

Melles, a pioneer and innovator in lamellar keratoplasty, recently opened a branch office of his Netherlands Institute for Innovative Ocular Surgery in San Diego. In the U.S., he said, he has found a more open environment that welcomes innovation and is eager to pursue new projects.

Image: Melles G

“We have many partners in the U.S., and it is easier for us to work together if we are closer. Our main goal is to design techniques and to design the eye banking techniques that support them. Eye banks and clinics will make decisions together and work synergistically,” he said.

Slow penetration despite superior outcomes

Descemet’s membrane endothelial keratoplasty is not the mainstream procedure for endothelial transplantation in the U.S. or Europe. In the U.S., DMEK currently represents only 13% to 14% of all endothelial keratoplasty cases.

“According to 2016 statistics of the Eye Bank Association of America, out of 28,327 cases of EK last year in the U.S., only 6,459 were DMEK,” Mark A. Terry, MD, said.

Contrary to poor adoption of DMEK, results in terms of visual recovery and quality of vision are significantly better with DMEK. In a study Terry presented at the American Academy of Ophthalmology meeting in 2016, in patients who had one eye operated with DMEK and the contralateral eye with Descemet’s stripping automated endothelial keratoplasty, with 20/20 vision in both eyes, the vast majority of patients cited having significantly better quality of vision in the DMEK eye.

“More than 60% of our patients are 20/20 or better at 6 months. Our published re-bubble rate is about 6%, graft failure is less than 1%, and endothelial cell loss is generally less than 30% at 6 months. DMEK gives better and faster vision, so why are people still so hesitant to do DMEK?” Terry asked.

Crucial steps increase success

Although some crucial steps of the procedure have been standardized, concerns about technical difficulties in harvesting the tissue and unfolding the graft in the eye restrain some surgeons from switching from DSAEK to DMEK.

“We always explain to people that it is important to have a double roll. Once it is correctly positioned, scrolls up, you gently tap the cornea to open it a little bit and then put the air bubble in between and completely unfold the graft over the iris. It is much easier to unfold it over the iris than over the posterior cornea,” Melles said.

Variations are possible and come with experience, but following a proven step-by-step technique at first is important. Later, surgeons will learn to adjust their technique to the behavior of the graft, which is never exactly the same from one case to another.

“Even if you drive different cars, you do the same thing at some point,” Melles said.

Terry does not use an air bubble to unfold the graft, but rather prefers a standardized “no-touch technique” of tapping on the corneal surface and limbus to generate fluid waves with a shallow anterior chamber that gently unscrolls the tissue.

One of the important discoveries Terry has made is that the time taken to unscroll the tissue does not affect the health and quality of the graft.

“We did a study on 93 eyes that underwent uncomplicated DMEK surgery and found no correlation with our technique between unscrolling time and endothelial cell loss at 6 months postop. Provided that a no-touch technique is used, you can unscroll the tissue comfortably and not be under pressure and stress. If you need 10 minutes, it is just fine. There is a point when the stain, and therefore the visibility of the tissue, will decrease, but up to 10 to 12 minutes there is nothing to worry about,” Terry said.

He advises DMEK novice surgeons to start with an eye that is already pseudophakic or an eye that does not need cataract surgery at the same time so that there is no need to dilate the pupil preoperatively.

“It is critical that the pupil be very small during the time you are manipulating the tissue. With a large pupil, the graft is exposed to damage during unscrolling from contact with the underlying IOL or crystalline lens,” Terry said.

More experienced surgeons should perform cataract surgery at the same time as DMEK but also modulate pupil size during the procedure.

Preloaded grafts

Another reason why surgeons may be reluctant to undertake DMEK is the difficulty and risk involved in the manual preparation of the graft.

“The risk of losing the tissue, wasting the money and canceling the surgery are understandably unacceptable,” Terry said.

Now that several eye banks are able to provide preloaded, pre-stained and pre-marked tissue, he foresees a fast increase in DMEK acceptance.

“Preloaded grafts reduce all the risks and the expenses. Since the tissue is pre-stained, we don’t have to use trypan blue; since it is precut, we don’t need to use a trephine; and since it is preloaded, we don’t have to buy an injector. Last but not least, we save time. Rather than spending 10 to 15 minutes or more in the OR staining the tissue, trephining it and loading it into an injector, we can spend 1 minute taking the injector out of a container,” he said. “In our initial series of over 50 cases, the dense stain of the preloaded tissue is fantastic, and we found no difference in cell loss or complications using preloaded tissue in Optisol.”

While Terry now uses pre-stained, preloaded Optisol tissue in all his patients, Melles prefers to prepare his grafts manually.

“We did a lot of studies on pre-stained, preloaded grafts some years ago. They undoubtedly give you the comfort of not having to do anything with the donor in the OR, but the problem is dealing with complications due to the preloading,” he said.

The culture medium must be thoroughly rinsed out or else the graft may not attach or may detach after surgery, Melles explained. On the other hand, by rinsing the tissue well, a lot of the staining will be removed, and it might then be difficult to visualize the graft in the anterior chamber.

“It is not that you cannot preload or pre-stain, but the question is whether you are going to gain from it from a surgical point of view,” he said.

“We place the double-roll graft in a glass bowl on the surgical table and flash it a few times because by flashing it you already have a good impression of how the graft is going to behave inside the eye. If it is a tight roll, you know it is going to be challenging, and this information is extremely important for the rest of your surgery. With preloaded grafts, you are missing this information. You introduce it sight unseen. If you have a graft that is fairly tight, you can do a lot by flashing it before to open it up a few times, and this helps it unfold in the eye,” Melles said.

Graftless approaches

A few year ago, Melles and his group observed that spontaneous functional recovery of the corneal endothelium had occurred in some patients even though the DMEK graft had failed to attach. The conclusion they reached was that the host cells were involved in repopulating the posterior stroma, maybe stimulated by the presence of a graft — hence, the idea of reproducing this situation intentionally, inserting a free-floating graft in the anterior chamber after Descemet’s stripping and just waiting.

“This is what we called DMET, Descemet membrane endothelial transfer. After a few years, I see that there are two aspects to consider. From a purely scientific point of view, it was extraordinary to discover that the host cells are involved because this may lead to an entirely new way of treating Fuchs’ dystrophy through regenerative processes. However, from a clinical point of view, DMET is not a big gain because it takes too long for the cornea to clear. Patients get worried with no detectable improvement for months, and it is too much of a contrast in visual recovery with DMEK,” Melles said.

Descemetorrhexis-only takes the graftless approach one step further. No donor tissue is used, and only a small area of Descemet’s membrane is removed over the visual axis. Over time, cells migrate from the periphery and repopulate the area, forming a new layer of clear, healthy tissue.

Results are inconsistent so far, but the technique has strong advocates who regard it as a great opportunity. Last year, Kathryn Colby, MD, PhD, published in Cornea her initial series of 13 eyes, of which 10 cleared and three were successfully converted to DMEK at a later stage.

“Patients are incredibly enthusiastic. I have people coming from all over the country to see me. If only we were able to predict which patients would or would not respond to the treatment, acceptance would increase greatly,” she said.

What she knows at this stage is that the treatment works best for patients with Fuchs’ dystrophy with central guttae and a preserved peripheral endothelium.

“If you can offer these patients a surgery that is very quick, does not use foreign tissue, has no rejection risk and no risk of long-term glaucoma because of steroids, that’s very appealing. I tell these patients that I cannot guarantee that the procedure will work, but if it does not, they can have EK,” Colby said.

During surgery, thorough removal of the guttae increases the chances of success, she said.

Recently, Colby has been complementing surgery with the use of a ROCK inhibitor. Gregory Moloney, MBBS, FRANZCO, FRCSC, was the first to use it for this indication and reports a twofold faster recovery.

“In my original series the average clearing was in 3 months, and now it looks like I am getting it in 6 weeks or so. I have had people clearing as quickly as in 2 to 3 weeks,” Colby said.

Smaller grafts

Currently, Melles’ technique of choice is quarter-DMEK, a hybrid technique combining the advantages of DMEK and DMET. A small 6-mm diameter circular graft is attached in the central cornea to cover the visual axis. This will clear quickly, providing useful visual acuity, while the peripheral area is progressively and slowly populated by host cells.

“The first advantage is that you are transplanting a smaller amount of tissue, with a lower risk of complications as far as allograft rejection and response is concerned. In addition, a smaller graft will require less steroids, lowering the chance of pressure-related complications,” Melles said.

The surgical technique does not differ from standard DMEK, although the graft might have a slightly different behavior. Melles’ team has treated a dozen patients, with some of them having reached 1 year of follow-up. Visual outcomes are comparable to those of a DMEK graft, but endothelial cell count appears to be slightly lower.

“We need further investigation on this because we are measuring cell density in the area around the edge of the graft, which is not a fair comparison because we measure density at the center of the DMEK graft. In this way, at 3 months the cell count seems to be lower but tends to remain stable at later time points,” Melles said.

Comparing outcomes

In a study, Oganes Oganesyan, MD, PhD, analyzed the results of descemetorrhexis-only, DMET, conventional DMEK and partial DMEK (quarter-DMEK and hemi-DMEK) in patients with Fuchs’ dystrophy and pseudophakic bullous keratopathy.

“We had a unique opportunity to compare different surgeries in two eyes of the same patient as in a few cases we performed descemetorrhexis-only on one eye and DMET on the other eye, or DMET and partial DMEK. The average follow-up was 38 months. We studied the dynamics and value of BCVA, corneal thickness, endothelial cell density and corneal optical density,” Oganesyan said.

Of seven cases of descemetorrhexis-only, only one had improved BCVA. The patient was young and phakic, with good visual acuity before surgery. In two cases, visual acuity did not change, and in four cases, visual acuity worsened. In all cases, even 2 years after surgery, BCVA, corneal thickness and endothelial cell density were worse than after DMEK in the fellow eye.

DMET had better results than descemetorrhexis-only but still not as good as with DMEK. In four of five eyes with Fuchs’ dystrophy, visual acuity increased, while in the one eye with pseudophakic bullous keratopathy, visual acuity remained unchanged. In all DMET cases, endothelial cell density was greater than after descemetorrhexis-only but less than after conventional or partial DMEK.

“I think that DMET and descemetorrhexis-only represent primarily a big scientific interest. These techniques are precious for studying and understanding the mechanisms of cornea re-endothelialization, but I don’t believe they will ever replace DMEK,” Oganesyan said.

“I have been doing DMEK for 9 years already, in very different and sometimes extremely complicated clinical cases. But every time I am fascinated like a child by the results of this elegant and beautiful surgery,” he said.

Bowman’s layer transplantation

Moving to the anterior part of the cornea, an innovative approach was developed by Melles in 2010 for patients with advanced keratoconus. The implantation of a donor-isolated Bowman’s layer graft in the stroma allows these patients to wear their scleral contact lenses again, which often become uncomfortable with ectasia progression.

“Patients often outgrow the ability to wear contact lenses because the cornea becomes too steep and the lenses don’t fit, pop out or are too uncomfortable to wear. As a result, vision precipitously declines,” Jack S. Parker, MD, said.

Bowman’s layer transplantation is a lesser invasive alternative to corneal transplantation and is also an alternative to corneal cross-linking, which may not be an option at the advanced stages of the disease. Like CXL, this transplantation seems able to halt disease progression in about 90% of patients and enables them to wear their hard scleral contact lenses again.

“The Bowman’s layer is less than 20 µm thick. It stabilizes the cornea and makes it more regular, with a positive effect on vision. It is isolable, and you can pull it off by itself from the donor. Unlike the rest of the stroma, it is acellular and therefore minimizes the risk of allograft reaction and graft rejection,” Parker said.

Harvesting is tedious and time-consuming and involves delicate peeling, using fine forceps.

“Currently, we are trying to use the femtosecond laser,” Parker said. “We haven’t done any study on patients; we are at the initial stages, and it seems possible. The laser would obviously make harvesting much easier, quicker and more reproducible.”

Implantation is similar to manual deep anterior lamellar keratoplasty, with a different location of the corneal pocket.

“We dissect a pocket in the middle of the cornea and place the Bowman’s layer graft inside. It is not where the Bowman’s layer usually is; it is simply within the stroma, in the easiest possible site for implantation, and it seems to work well there,” Parker said.

Balance of new and old

The unanimous advice from the experts is to be open to innovative techniques, learn them and use them, but to also maintain the ability to perform all other techniques when needed.

“My recommendation is that surgeons should learn how to do DMEK for best vision and quality of vision, but they need to keep their skills with DSAEK because there are still many complex cases that are better off with DSAEK,” Terry said. “When patients have an anterior chamber IOL, I prefer DSAEK. When they are aphakic and are going to be left aphakic, I prefer DSAEK. When they have a filtering tube in the eye, I prefer DSAEK. It is not that you cannot do DMEK in those cases; it is just that DMEK surgery does not offer the same advantages. It is a much more difficult procedure in those situations, and the more difficult the procedure is, the more harm you do to the tissue. In the long term, it is better to have a healthy DSAEK in a complex eye than an unhealthy DMEK.” – by Michela Cimberle

• References:
• Baydoun L, et al. Am J Ophthalmol. 2012;doi:10.1016/j.ajo.2012.06.025.
• Borkar DS, et al. Cornea. 2016;doi:10.1097/ICO.0000000000000915.
• Dirisamer M, et al. Am J Ophthalmol. 2012;doi:10.1016/j.ajo.2012.02.032.
• Dirisamer M, et al. Cornea. 2012;doi:10.1097/ICO.0b013e31821c9afc.
• Hamzaoglu EC, et al. Ophthalmology. 2015;doi:10.1016/j.ophtha.2015.07.003.
• Hooijmaijers HCM, et al. Ophthalmology. 2017;doi:10.1016/j.ophtha.2016.11.024.
• Lam FC, et al. Curr Opin Ophthalmol. 2014;doi:10.1097/ICU.0000000000000061.
• Lam FC, et al. JAMA Ophthalmol. 2014;doi:10.1001/jamaophthalmol.2014.3328.
• Liarakos VS, et al. JAMA Ophthalmol. 2013;doi:10.1001/2013.jamaophthalmol.4.
• Müller TM, et al. Cornea. 2017;doi:10.1097/ICO.0000000000001008.
• Palioura S, et al. Cornea. 2017;doi:10.1097/ICO.0000000000001039.
• Parker JS, et al. Eur J Ophthalmol. 2017;doi:10.5301/ejo.5000990.
• Parker J, et al. Eye Contact Lens. 2017;doi:10.1097/ICL.0000000000000396.
• Sales CS, et al. Cornea. 2016;doi:10.1097/ICO.0000000000000771.
• Terry MA. Cornea. 2012;doi:10.1097/ICO.0b013e31823f8ee2.
• Terry MA, et al. Cornea. 2015;doi:10.1097/ICO.0000000000000479.
• Tran KD, et al. Cornea. 2017;doi:10.1097/ICO.0000000000001150.
• van Dijk K, et al. Cont Lens Anterior Eye. 2013;doi:10.1016/j.clae.2012.10.066.

• For more information:
• Kathryn Colby, MD, PhD, is chair of the department of ophthalmology and visual science at the University of Chicago. She can be reached at Department of Ophthalmology and Visual Science, The University of Chicago Medicine & Biological Sciences, 5841 S. Maryland Ave., Chicago, IL 60637; email: kcolby@bsd.uchicago.edu.
• Gerrit Melles, MD, PhD, is founder of the Netherlands Institute for Innovative Ocular Surgery. He can be reached at NIIOS, Laan Op Zuid 88, 3071 AA Rotterdam, Netherlands; email: melles@niios.nl.
• Oganes Oganesyan, MD, PhD, is a senior researcher at the Moscow Helmholtz Research Institute of Eye Diseases, Moscow, Russia. He can be reached at email: oftalmolog@mail.ru.
• Jack S. Parker, MD, can be reached at Parker Cornea, 700 18th St. South, Suite 503, Birmingham, AL 35233; email: jack.parker@gmail.com.
• Mark A. Terry, MD, is director of cornea services at Devers Eye Institute. He can be reached at Devers Eye Institute, 1040 NW 22nd Ave., Suite 200, Portland, OR 97210-3065; email: mterry@deverseye.org.

Disclosures: Colby, Melles, Oganesyan, Parker and Terry report no relevant financial disclosures.

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