Continuous evolution of endothelial keratoplasty changes field of corneal transplantation
Lamellar techniques have introduced a paradigm shift in corneal transplantation, especially in the United States and other Western countries. Endothelial keratoplasty has undergone rapid advancements in the last decade, becoming the most commonly performed corneal transplantation procedure in the West and relegating penetrating keratoplasty to a minor role.
Endothelial keratoplasty has evolved from deep lamellar endothelial keratoplasty to Descemet’s stripping endothelial keratoplasty to Descemet’s membrane endothelial keratoplasty in just more than a decade.
“The evolution of EK has been astonishingly fast from PK to DLEK to DSEK to DSAEK to DMEK in just 12 short years,” Mark A. Terry, MD, director of corneal services at the Devers Eye Institute and professor of clinical ophthalmology, Oregon Health Sciences University, said. “Even though DLEK proved far superior in patient benefits to the previous standard of PK, it was not widely accepted because it was too difficult a procedure for most surgeons and posed too great a risk of donor damage at the time of surgery. What this showed us is that it takes more than superior patient benefits by a procedure to make surgeons adopt it. The procedure has to be relatively easy and relatively quickly learned.”
In 1997, Gerrit Melles, MD, started with DLEK as the first technique to replace the endothelium.
Image: Legacy Devers Eye Institute
“This technique was relatively demanding, so we continued with Descemet’s stripping endothelial keratoplasty in 2001, in which only the host Descemet’s membrane had to be excised instead of a posterior corneal button. However, the corneal graft in both these techniques contains posterior stroma, which seems to somehow degrade the optical quality of a transplanted cornea,” Melles said. “To reach an anatomically ‘normal’ cornea, we worked towards Descemet’s membrane endothelial keratoplasty in 2005, which we thought should eliminate the image degradation caused by the donor stroma, since only Descemet’s membrane is transplanted.”
Today, DSEK, with the variation Descemet’s stripping automated endothelial keratoplasty, and DMEK represent one-third to one-half of the total number of keratoplasty procedures in Western countries, depending on the area. According to a statistical report from the Eye Bank Association of America (EBAA), endothelial keratoplasty was performed more often than PK in the U.S., 23,049 procedures vs. 21,422 procedures, in 2012.
“Penetrating keratoplasty has now been relegated to indications that do not qualify for endothelial transplantation,” Marianne O. Price, PhD, executive director of the Cornea Research Foundation of America, said. “In our practice, 90% of procedures for endothelial dysfunction are DMEK and 10% are DSEK. EK represents about 80% of the 500 transplants the practice performed last year, with anterior lamellars and penetrating grafts for non-endothelial dysfunction each making up 10% of the total.”
According to Massimo Busin, MD, the relative percentage of endothelial procedures in Europe is currently around 30%, but it is much higher for some surgeons.
“Of the 398 transplantations I performed last year, 60% were endothelial, 35% were anterior lamellar and only 5% were penetrating keratoplasty,” he said.
In Asia, numbers are still low, due to the late introduction of the surgery and the high costs of cutting tissues. Donald T.H. Tan, MBBS, FRCSG, FRCSE, FRCOphth, an OSN APAO Edition Board Member, estimated that the relative percentage is around 5% to 10%. However, some centers of excellence, such as in Singapore, are aligning with Western standards.
“In our practice, we do about 300 transplantation procedures a year, of which 50% are endothelial, 30% are anterior lamellar procedures and only about 20% are PK, reserved for end-stage stromal and endothelial disorders, which are still prevalent in Asia. My personal rates for EK are even higher, around 62%. This is also thanks to the availability of tissues from our local eye bank, which offers both precut EK and ALK grade tissue,” he said.
According to Terry, the leading indication for endothelial keratoplasty in the U.S. is Fuchs’ dystrophy, with almost 80% of all endothelial keratoplasty cases performed for this indication. Pseudophakic bullous keratopathy is also a leading indication. More rare indications are traumatic endothelial failure, herpes zoster endothelial failure and iridocorneal endothelial syndrome, Terry said.
Pseudophakic bullous keratopathy is the leading indication for endothelial keratoplasty in regions such as Asia and the Middle East, he said.
DSEK and DMEK advocates
Both DSEK/DSAEK and DMEK have advocates with differing opinions. Some surgeons have made a definite transition to DMEK and use DSEK only in specific cases. The main arguments in favor of DMEK are the superior visual outcomes and lower rejection rate. Other surgeons believe that the latest developments of DSAEK with ultra-thin donor discs have results comparable to DMEK, without the additional surgical challenges posed by DMEK.
“In our clinic, DMEK is now our preferred procedure. It feels much better controlled than DSEK/DSAEK, and the visual outcomes surpass earlier techniques. The rule of thumb is that about 80% of eyes reach 20/25 or better at 6 months,” Melles said. “Once the technique is mastered, complications are fewer and there is no need for large financial investments. Standard donor corneal rims can be used for harvesting the tissue.”
The thin DMEK grafts, which do not have much impact on the original corneal thickness, induce a minimal amount of corneal aberration and lead to better visual acuity and faster healing.
“The stroma that’s left on the donor in DSAEK has to conform to the posterior surface of the recipient, causing wrinkles and folds that degrade the image. In addition, the microkeratome cut produces irregularities from side to the center. With DMEK, we avoid all those distortions,” Francis W. Price Jr., MD, an OSN Cornea/External Disease Board Member, said.
Francis Price said that DMEK allows operating on the two eyes just 1 week apart, similar to what is done with cataract surgery. Thanks to the smaller DMEK incision, healing and visual recovery are fast, which allows for the shorter interval between surgeries, he said.
According to some surgeons, ultra-thin DSAEK has comparable visual results to DMEK while also offering the ease of preparation and manipulation of DSAEK.
“We now do thin donors, below 120 µm thick. In a series of 250 cases, we have found that the percentage of patients achieving 20/20 is equal, if not superior, to DMEK,” Busin said.
DMEK still results in a higher endothelial cell loss rate, approximately 30% to 35% at 1 year, whereas cell loss rates with newer DSAEK techniques and donor inserts continue to improve, Tan said.
“In our first series of 100 eyes, ultra-thin DSAEK with the use of our ultra-thin DSAEK inserter had a cell loss of 13.5% at 6 months and 15% at 1 year, and DSAEK still has a lower re-bubbling rate. However, DSAEK techniques continue to improve, and we hope to see cell loss and re-bubbling rates reduce further,” he said.
The significantly lower rejection rate is a key issue in favor of DMEK. In 2011, in his first series of 120 eyes of 105 Fuchs’ dystrophy patients, Melles and his group reported a rejection rate of less than 1% at 2 years. The same rate over the same period of time was reported in 141 eyes by Francis Price and colleagues in 2012.
“We compared retrospectively these patients with cohorts of DSEK and PK patients treated at the same center, with similar demographics, follow-up duration, postoperative regimen and indications for surgery. The relative risk ratio for immunological graft rejection at 2 years with DMEK turned out to be 15 times lower than DSEK and 20 times lower than PK,” Marianne Price said.
“I used to do more DSEK than DMEK, but once we found that rejection rate was so much lower, about 1.5 years ago, I shifted to DMEK and encouraged others to do so,” Francis Price said.
Tan suggested that the 8% to 12% DSEK rejection rate reported by Price seemed relatively high, saying that the rate is steady at 2% to 2.5% in his own patients, with both standard and ultra-thin procedures.
“Rejection rates are likely to vary depending on the extent and duration of steroid use after DSAEK surgery, and it may be that the tendency to greatly reduce steroid use after DSAEK as compared to PK may affect rejection rates. In our initial DSAEK series, we didn’t really reduce steroids. We therefore see a low rejection rate, but conversely, our glaucoma rates remain similar to PK,” he said.
Francis Price noted that the low rejection rate of DMEK may allow a significant reduction of postoperative steroids and steroid-related complications such as IOP increase.
“It appears that either the corneal stroma or the total amount of tissue transplanted affects the immune response and propensity to stimulate immune-rejection episodes. While many doctors are attempting to make thin-cut DSEK an alternative to DMEK, DMEK is the thinnest possible graft at this point and, therefore, the most desirable for the best possible vision and least immunologic reaction. We are evaluating in a multicenter trial the safety and feasibility of reduced steroids administration after DMEK,” he said.
For those who prefer DMEK, there are still indications for DSEK/DSAEK in specific cases.
“In complicated eyes with aphakia, previous posterior segment surgery and glaucoma tubes, DSEK/DSAEK may still be a valuable fallback option. In such eyes, obtaining graft attachment is a challenge and may outweigh the final visual outcome, especially because the visual potential of these eyes most often is relatively low,” Melles said.
“DSEK is preferable in complicated eyes with a lot of synechiae requiring anterior chamber reconstruction. Likewise, in eyes that are aphakic, a DSEK graft can be pulled into the eye with forceps or a suture and held in place until air can be placed beneath it, whereas a DMEK graft could go into the posterior chamber more easily,” Francis Price said.
The challenges of DMEK
DMEK has been thought to be a technically challenging surgery with a long learning curve. That perception has been the main limitation to gaining fast and widespread popularity.
“The challenge in making the transition from DSEK to DMEK is that it is a different skill set for DMEK than DSAEK, and most surgeons were concerned about destroying the donor tissue at the time of surgery while stripping it for the surgery,” Terry said. “That concern is now eliminated by using pre-stripped tissue, and the different skill set of DMEK is now so much easier than before. I believe we are at the point where most DSAEK surgeons can become comfortable making that transition from DSAEK to DMEK.”
The Yoeruek tap technique is an alternative to the traditional anterior air bubble technique. It also can be used with pre-stripped tissue, Terry said.
“The Yoeruek technique eliminates the anterior air bubble method of unfolding, described by Melles and others, and makes even our novice fellows quickly successful with DMEK surgery,” Terry said. “Once a surgeon learns the Yoeruek tap technique, DMEK can be done in just about any eye that one can do a DSAEK, and that is why DMEK is now our preferred method of EK.”
Patience, practice and donor corneas older than 40 years of age are the keys to successful surgery, Francis Price said.
“Some DMEK surgeons prefer donors over 50 years. Older donor tissue is easier to prepare and to uncurl inside the recipient eye, probably because the Descemet’s membrane continues to thicken with age,” he said.
Concerns about damaging donor grafts in the harvesting and implantation process can be overcome by using the “no-touch” technique suggested by Melles and colleagues.
“With our technique, there is no direct handling of the tissue. For harvesting, we leave a peripheral ring of trabecular meshwork tissue in situ, and the graft is trephined on an underlying soft contact lens. For implantation, we use a smooth glass injector and then manipulate the tissue by air or [balanced salt solution]. Endothelial cell loss is minimized,” Melles said.
The challenge of unfolding and positioning the graft has been evaluated. The classic “double roll” is the easiest approach, but if this cannot be done, several other unfolding techniques have been developed by Melles and colleagues.
Tan recently presented a new device for graft insertion, the disposable D-Mat carrier. Acting as a stromal carrier replacement, it supports the endothelial graft for enhanced ease of manipulation and prevents scrolling, allowing for surgical techniques akin to ultra-thin DSAEK to be adopted.
“The donor Descemet’s membrane adheres gently to the D-Mat surface and therefore does not wrinkle up, and a no-touch technique is employed as the D-Mat is held rather than the donor tissue, which can also be coiled into a DSAEK inserter and delivered into the eye. However, further work needs to be done before this becomes a viable technique,” Tan said.
DMEK cannot be performed on aphakic eyes and those with an anterior chamber IOL in place, Terry said.
“If a posterior chamber lens is substituted in each of these two scenarios, however, then DMEK can be done,” he said. “Cases that have had a complete vitrectomy are also more difficult to do with DMEK. For a surgeon’s very first DMEK case, it is reasonable to start with an eye that is already with a posterior chamber IOL, can have the pupil constricted very small, has a Fuchs’ dystrophy with a relatively clear cornea and a chamber depth that is not excessively deep. Finally, unlike DSAEK, which induces a significant hyperopic shift, DMEK is a better choice for eyes that have multifocal lenses already in place.”
Inserters have been a key feature in DSEK. The Busin glide (Moria) is a funnel-shaped device designed to fit into a 3-mm incision.
“The graft is pulled rather than pushed into place, grasping a preplaced nylon suture from the opposite side. Under continuous irrigation, the graft unfolds easily, with minimal manipulation and cell loss,” Busin said.
The Tan EndoGlide (Angiotech) was inspired by the difficulty of inserting the graft in small Asian eyes with high vitreous pressure and a tendency for anterior chamber collapse and iris prolapse, which induces a cell loss of about 60% with traditional taco-folding techniques.
“The EndoGlide provided essentially a much higher element of control. We had a much lower cell loss, between 13.5% and 15% at 6 months and 1 year, respectively, the lowest to date. An advantage is that this inserter is extremely useful in more challenging cases where other insertion techniques may be difficult, simply because of better anterior chamber and donor control,” Tan said.
Results in high-risk eyes and those with failed grafts, previous vitrectomy or implanted glaucoma drainage tubes showed an almost comparable rate of cell loss, around 18%.
“We now have produced a second version of the Tan EndoGlide for ultra-thin DSAEK, which makes coiling of very thin donor tissue easier and more reproducible,” he said.
Francis Price said that it is a great privilege for cornea specialists to be working at a time when surgical procedures are undergoing such dramatic changes and to be involved in this progress.
“The benefit to our patients is huge. With cataract surgery, we would not perform an intracapsular cataract unless people were 20/200 or worse. Now we do phaco at 20/25 or 20/30. The same is happening with transplant surgery. Not very long ago, patients had to be non-functional before we performed keratoplasty, and now we do it if people have problems driving or working,” he said.
Further improvements are expected in coming years. According to Tan, there is still a wide variation in techniques, results, dislocation rates and primary graft failures.
“We need to develop consistency in the procedure, and we will gradually achieve uniformly better results. But we need to routinely measure endothelial cell loss. Strangely enough, many surgeons today ask for donor tissue with a cell count but don’t do the cell count after surgery,” he said.
There is also the question of whether to use ultra-thin DSAEK or DMEK.
“We are trying to make DMEK an easier, more reproducible procedure, but at the same time, ultra-thin DSAEK is giving us results that appear to be nearly as good. What is certain is that the future is thinner with either technique, and less is the new more,” Tan said.
Melles has recently begun investigating a new Descemet’s membrane endothelial transfer (DMET) technique that might completely change the approach to corneal transplantation. The idea came from the observation that in some Fuchs’ dystrophy eyes, corneal clearance occurred despite endothelial graft detachment or subtotal attachment after DMEK.
“This may prove that host cells can start migrating again under the regenerating stimulus of the donor and recreate a healthy endothelium,” he said.
The possibility of performing DMET, ie, the implantation of a graft into the anterior chamber without positioning it to the host posterior stroma, may be useful in eyes that are technically challenging. Also, it may be of interest from a scientific point of view.
“If host cells play a main role in corneal clearance in eyes operated on for Fuchs’ endothelial dystrophy, graft surgery might be ancient history in a not too distant future, and stimulating agents may be used instead to reconstruct the diseased endothelium,” Melles said.
The main drawback of DMET at present is that corneal clearance is delayed to 2 to 3 months, and endothelial cell density is lower than after DMEK.
“Nevertheless, anatomical restoration is near perfect, and the risk of intra- and postoperative complications may be lower,” Melles said. – by Michela Cimberle and Matt Hasson
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Is precut tissue preferable to tissue dissected at the time of surgery for endothelial keratoplasty?
Pros outweigh the cons
There are certainly pros and cons of using precut tissue for endothelial keratoplasty. Still, the pros outweigh the cons for several reasons.
The tissue quality is excellent. A trained eye bank technician who cuts tissue numerous times in a week or even a day is highly likely to produce excellent quality tissue.
DMEK is easier to perform. Precut tissue eliminates two of the major barriers to surgeons performing DMEK, namely the uncertainty of obtaining an intact Descemet’s membrane and the fear of wasting tissue (and money) if the preparation is not successful.
There is less uncertainty in the OR. Precut tissue eliminates having to cancel a case due to problems cutting donor tissue in the OR.
OR time is reduced. The surgeon does not need to spend time fashioning the EK button, except to trephine it.
There is no need to buy and maintain expensive equipment to create DSEK buttons, nor is there a need to rely on OR staff to set up and care for the equipment to create DSEK buttons.
Precut tissue is clinically equivalent to surgeon-cut tissue. Numerous peer-reviewed studies have demonstrated no clinical safety or efficacy differences between surgeon-prepared and eye bank-prepared tissue for DSEK.
Finally, there is less stress on the surgeon and OR staff.
Christopher J. Rapuano, MD, is chairman of the Cornea Service, Wills Eye Institute, Philadelphia. Disclosure: Rapuano has no relevant financial disclosures.
Cons rise to the top when it comes to DMEK
If we go with the premise “surgery by surgeons,” then this would encompass donor tissue preparation. This aspect of the surgery is very important because it deals with the donor tissue. The healthy donor corneal endothelial cells are quite vulnerable to mechanical injury, and these cells play a vital role in the postsurgical graft survival and recipient corneal clarity.
Endothelial keratoplasty increases in complexity both in the donor tissue preparation and in recipient corneal surgery as we go from DSEK to DSAEK to DMEK, while the instrumentation cost drops (no microkeratome). The former two procedures allow the operating surgeon to titrate the donor disc diameter and thickness if he is preparing the donor tissue in the operating room. With DMEK, without donor corneal stroma, the donor Descemet’s membrane that is removed as a single disc will almost immediately roll on itself, with the endothelial surface on the outside.
This is a very delicate procedure, and who else is more suitable and knowledgeable than the experienced corneal surgeon to perform this segment of DMEK surgery?
When the surgeon performs the donor tissue preparation, there is a significant cost saving, as well. This saving will translate into preserving Medicare funds longer.
Thomas “TJ” John, MD, is an OSN Cornea/External Disease Board Member. Disclosure: John has no relevant financial disclosures.