HISTORICAL PERSPECTIVE: EVOLUTION OF ENDOTHELIAL KERATOPLASTY TECHNIQUES
Compared with penetrating keratoplasty (PK), endothelial keratoplasty (EK) is a disease-specific surgery in which only dysfunctional corneal endothelium is replaced. The smaller incision makes EK much safer for patients than does PK. In addition, EK achieves better vision sooner. As EK has evolved, the implanted donor tissue has become thinner, leading to the implantation of only endothelial cells on a Descemet membrane (DM) scaffold without other corneal layers.
EK was long the dream of many surgeons. The first reported attempt by Tillett1 in 1956 was both a surgical and postoperative disaster. Barraquer and Rutlan2 attempted it as well without success. Jones and Culbertson3 built on Barraquer's ideas of using a microkeratome to make a flap, trephining the residual stromal bed, replacing the posterior cornea with a sutured graft, and repositioning the anterior cap in a technique called endothelial lamellar keratoplasty. However, none of these attempts worked well, because the sutures shortened the cord lengths of the donor tissue relative to the overlying host cornea, causing distortion and separation of the interface.
Melles et al4 had the insight to place the donor graft into a pocket dissected into the posterior surface of the host cornea using just the surface tension of air to hold the donor in place, rather than sutures. Melles et al5 also had the key insight that the donor graft could adhere to the bare posterior surface of the host stroma after removal of DM and the dysfunctional endothelium, without removing any host posterior stromal tissue. This technique became known as Descemet stripping endothelial keratoplasty (DSEK).6 Melles et al7 further realized that donor DM and endothelium could be implanted without any stroma, a technique he called Descemet membrane endothelial keratoplasty (DMEK). Use of a microkeratome to perform the donor lamellar dissection for DSEK significantly facilitated EK adoption. This was first reported by Gorovoy,8 who called this iteration Descemet stripping automated endothelial keratoplasty. Adoption of EK further accelerated after eye banks began to prepare the donor tissue for surgeons.9 Other refinements are too numerous to mention and include tissue insertion methods designed to minimize endothelial cell damage.10,11
A DMEK myth has been that the donor preparation is the limiting step in the surgery. With technique refinements, multiple sites have reported donor loss rates of approximately 1% with surgeon-prepared tissue,12–14 and numerous eye banks now prepare DMEK tissue for the surgeon. The limiting factor is developing the pattern recognition for understanding how the DM graft moves within the anterior chamber and determining which way it is oriented. Two basic approaches are used to determine donor orientation. One is to assess how the tissue is curled in the anterior chamber using a slit-beam, intraoperative optical coherence tomography (Fig. 1), or even a cannula, before the tissue is flattened against the host stroma.15–17 The other approach is to mark the tissue with gentian violet or to punch out small areas along the edge in a specific pattern to determine the orientation after the tissue is unfolded,14,18 although there could already be endothelial damage, and it could be difficult to flip the tissue over and reposition it if it is oriented incorrectly.
The future of EK may involve injecting cultured human corneal endothelial cells into the anterior chamber as is being done in initial safety studies at Kyoto University,19 or stimulating endothelial regeneration pharmacologically.20 New approaches are being researched by multiple groups.
EK'S CONTRIBUTION TO EVOLVING UNDERSTANDING OF THE CORNEA AND GLAUCOMA
However, the more important evolution with EK has been our increasing understanding of both the cornea and glaucoma. The speed of this evolution has been amazing. The fifth World Cornea Congress held in 2005 had 1 invited article on an early iteration of EK called deep lamellar endothelial keratoplasty, 3 free articles on deep lamellar endothelial keratoplasty, 1 free article on endothelial lamellar keratoplasty, and one on DSEK. That meeting proved to be a tipping point for EK with approximately 300 doctors attending a DSEK symposium and wet-laboratory hosted by Moria (Antony, France). The Eye Bank Association of America began tracking the number of EK procedures in 2005, when it represented 4.5% of corneal grafts. Within 10 years, it represented over 50% of all grafts performed in the United States.21
Common beliefs at World Cornea Congress V in 2005 were:
- Guttae did not decrease vision in Fuchs dystrophy—edema decreased vision
- Patients with Fuchs dystrophy could have cataract surgery, but keratoplasty should be delayed until vision decreased to about 20/200 with the use of a hair dryer
- Keratoplasty should be delayed as long as possible because the visual/refractive results with PK were unpredictable and the physical limitations were quite restrictive
- Bilateral grafts should be performed a year apart to minimize the risk of graft rejection
- The corneal endothelium was the most important layer for stimulating immunologic graft rejection
- Young donors were better than old donors
- Eyes with glaucoma had poorer visual and graft survival outcomes after corneal grafting
- Glaucoma tubes and trabeculectomies were similar in their effects on the cornea, problems with tubes were short term and usually related to positioning, and a tube might be preferable to a trabeculectomy as a first-line surgical treatment for glaucoma.
EK has provided new insights into corneal grafting and glaucoma by removing many of the confounding factors with PK that made it difficult, if not impossible, to accurately assess cause and effect.
HOW EK HAS CHANGED THE FIELD OF CORNEA
Lowering the Visual Impairment Threshold for Keratoplasty
The progression from PK to DSEK to DMEK has mirrored in many ways the progression of cataract surgery from intracapsular to extracapsular to phacoemulsification. As the incision size has decreased, the safety and visual results have improved. EK leaves 95% of the recipient cornea intact, including the structurally important stroma, thereby providing greater stability and faster visual recovery with fewer activity restrictions. Instead of facing a life-time risk of easy wound rupture after PK,22 DMEK patients have an essentially normal-strength cornea and can return to work and full daily activities in 1 to 3 weeks.
Just as with modern phacoemulsification, the visual impairment threshold to undergo surgery has dropped substantially with DMEK. Patients may have Snellen acuity of 20/20 in a darkened room but qualify for surgery because of disabling glare that prevents night driving or discrimination of small print and details needed to work. The reduced surgical threshold has dramatically increased the number of patients having EK relative to PK. With DMEK, many patients have 20/20 to 20/50 vision by the fifth postoperative day and an increasing number of patients are opting to have their fellow eye transplanted just 1 week after the first.23
Increasing Appreciation of How Guttae Affect Vision
Do guttae without edema affect vision? As residents, Dr Theodore Schlegel taught us that anything that distorts the red reflex degrades vision. Guttae distort the red reflex, and removing them during DM stripping improves the clarity of the cornea. Figure 2 shows an eye in which DM has been partially stripped. The increased clarity of the red reflex in the stripped area and the haze in areas where DM is folded over on itself is notable. This suggests that DM is not clear in Fuchs dystrophy; rather it is semiopaque, but very thin. With the predictable visual improvement achieved with DMEK, there is no reason to wait for corneal edema to recommend grafting for Fuchs dystrophy—visual disability is sufficient. Likewise, if patients have confluent guttae over the pupil, the surgeon is not doing them a favor by only performing cataract surgery; the guttae also must be removed for clear vision.
Minimizing Duration of Edema for Best Visual Outcomes
When PK was the only option, there was no urgency to graft eyes with stromal edema because the entire corneal thickness was discarded anyway. With EK, the host corneal stroma is retained, and prolonged edema or long-standing Fuchs dystrophy may lead to anterior stromal degenerative changes that can degrade final visual quality, as shown by Patel et al.24,25 Likewise, 2 studies have suggested that eyes with DMEK regrafts have poorer vision than those with primary DMEK grafts, but the interval between the development of edema and regrafting was lengthy in those studies.26,27 We and others have found that when DMEK is repeated promptly to minimize the duration of edema, the visual results match those achieved with primary DMEK.28,29 Although the host endothelium can sometimes regenerate after stripping DM and the endothelium without implanting a graft, we have found that the prolonged edema can lead to permanent visual decrease.30 Together these findings suggest that long-standing edema should be avoided whenever possible for best visual outcomes.
Modifying Risk Factors for Graft Failure
EK has revolutionized graft survival for endothelial diseases. Ocular surface disease has been virtually eliminated as a cause of graft failure because the host corneal stroma and innervation are retained with EK. In an analysis of 10-year PK graft survival, we found that ocular surface disease accounted for 20% of our PK failures, whereas it is rarely, if ever, associated with EK failure.31,32 Additionally, we found with DSEK grafts under failed PK that preexisting corneal neovascularization did not increase the risk of DSEK graft failure, whereas it is a known risk factor for PK failure.33,34
Reducing the Risk of Immunologic Rejection
Immunologic rejection is a leading cause of PK failure.31 Fortunately, the risk of an immunologic graft rejection episode is significantly reduced with EK.35,36 When we compared our cumulative 2-year rate of possible immunologic graft rejection episodes between PK, DSEK, and DMEK, we found the rates to be 18%, 12%, and <1%, respectively.35 Thus, the relative risk of rejection was 20-fold less for DMEK compared with PK and 15-fold less for DMEK compared with DSEK. Importantly, the 3 keratoplasty groups all had the same steroid dosing, demographics, and rejection criteria. Some centers have had a lower incidence of DSEK rejections36; however, these newer series are typically with donors thinner than those initially used in DSEK. Earlier series had similar rejection rates to our 12%.37,38
Since 2008, our center has performed over 1800 DMEK grafts with only 20 possible or probable immunologic graft rejection episodes and only 2 graft failures after a rejection episode (unpublished data). Higher reported rates of stromal rejection after deep anterior lamellar keratoplasty than after DMEK suggest that the stroma/keratocytes and/or the amount of tissue transplanted may be more important than the endothelium in stimulating immunologic recognition.35,39
Decreasing Topical Corticosteroids and the Risk of IOP Elevation
The standard steroid dosing regimens used for PK were designed to balance efficacy at preventing graft rejection against unwanted side effects of intraocular pressure (IOP) elevation and delayed wound healing. Wound-healing issues are no longer relevant with EK, and DMEK has dramatically reduced the risk of rejection, suggesting that steroid dosing regimens need to be rebalanced. As a result, our center undertook 2 prospective randomized studies comparing different steroid dosing regimens in the first year after DMEK. The first compared brand name prednisolone acetate 1% and fluorometholone 0.1%.40 All eyes received prednisolone 4-time daily for 1 month, and at month 2 they were randomized to either of the 2 study drugs with dosing of 4-times daily for 2 months, 3-times daily for 1 month, twice daily for 1 month, and once daily for 7 months. There were no rejections in the prednisolone group and 2 in the fluorometholone group (1.4%, P = 0.17). The proportions with IOP elevation (defined as ≥24 mm Hg or a 10 mm Hg increase over the preoperative reading) were 22% in the prednisolone group compared with only 6% in the fluorometholone group (P < 0.0001). The proportions that exceeded an IOP threshold of 30 mm Hg were 12% in the prednisolone group and 1.5% with fluorometholone (P = 0.0022).40 Importantly, any eye on long-term topical steroids can get a high IOP spike.
We next compared prednisolone acetate 1% to loteprednol etabonate 0.5% gel, using the same dosing frequency and IOP elevation thresholds as in the earlier study. No rejection episodes occurred with either treatment; IOP elevation was significantly less likely with loteprednol (P = 0.016).41
As a result of these 2 studies, we have changed our recommended postoperative steroid dosing for whites to prednisolone acetate 1% 4-times daily for 2 months, followed by either fluorometholone or loteprednol at a decreasing dose of 4-times daily for 1 month, 3-times daily for 1 month, twice daily for 1 month, and once daily for the rest of the year. For African Americans or those with increased skin pigmentation, we increase the initial steroid dosing to prevent any inflammation before tapering because we previously found with DSEK that African Americans had a 5-fold higher relative risk of immunologic graft rejection episodes compared with whites.42
We are currently conducting a study to evaluate the risk of rejection episodes if topical steroid use is discontinued 1 year after DMEK, with over 450 eyes enrolled so far. In previous randomized studies with PK, immunologic rejection rates ranged from 9% to 40% when topical corticosteroids were stopped at 6 to 12 months.43,44 DMEK allows us to assess steroid discontinuation with a much lower risk of graft rejection.
HOW EK WILL CHANGE GLAUCOMA SURGERY?
EK's impact on glaucoma may be just as significant as it has been on the cornea. By eliminating the confounding variables of ocular surface disease and slow visual recovery seen with PK, EK allows us to more precisely assess the affects of glaucoma and glaucoma treatments on the cornea.
Preexisting glaucoma has long been associated with poor visual recovery after PK.45 In comparison, after DSEK, we found that neither medically managed nor surgically treated glaucoma impaired visual recovery, presumably because we can reliably check both IOP and visual fields quickly after EK.45
Preexisting glaucoma also is associated with increased PK failure rates. In an analysis of almost 4000 PK's from our center, we found that a preexisting diagnosis of glaucoma doubled the risk of endothelial decompensation either with or without immunologic graft rejection, and it tripled the risk of failure from ocular surface disease.46 Likewise, the Corneal Donor Study found that medically treated glaucoma doubled the risk of PK failure, previous glaucoma surgery tripled the risk, and a combination of both medically and surgically treated glaucoma increased the failure risk by 7-fold.47 The increased PK failure rate in patients with medically treated glaucoma was presumably from the chronic inflammation caused by the topical preservatives in the glaucoma medications.48
Fortunately, medically treated glaucoma does not have such an adverse effect on EK survival. We found that 5-year DSEK survival was just as favorable in patients with medically managed glaucoma as it was in patients without glaucoma.49 EK survival may be better than PK in patients with medically managed glaucoma because EK virtually eliminates ocular surface disease as a cause of graft failure by maintaining corneal sensation and not requiring long-standing sutures.
On the other hand, previous glaucoma surgery is a major risk factor for both EK and PK failure.47,49,50 As shown in Figure 3, our 5-year DSEK survival rates were 96% for eyes without glaucoma, 90% for eyes with medically managed glaucoma, 59% for eyes with previous trabeculectomy, and only 25% for eyes with a previous aqueous shunt.49 In cases where DSEK was used to treat failed PK, our 4-year survival rate was 96% in eyes without an aqueous shunt versus 22% in eyes with an aqueous shunt (Fig. 4).50 In these DSEK studies, previous glaucoma surgery (tube or trabeculectomy) was the most significant risk factor for graft failure, with no other donor or recipient factors being significant in a multivariate analysis. Aldave et al51 have also shown that DSEK graft survival is poorer in eyes with previous glaucoma filtration surgery.
When we compared our 5-year graft survival rates for PK and DSEK performed for Fuchs dystrophy, we found no difference (95% vs. 96%, respectively), whereas in grafts performed for pseudophakic corneal edema, the respective rates differed (90% vs. 72%, respectively).31,32 Notably the DSEK series was more recent, when pseudophakic corneal edema was increasingly associated with previous filtration surgery. In the earlier PK series, performed between 1982 and 1996, only 3% of the eyes had a filter, whereas in the DSEK series performed between 2003 and 2005, 33% of the pseudophakic edema eyes had a filter. Corneal edema after glaucoma filtration surgery is becoming an increasing cause of corneal grafting.
In fact, corneal transplants may be the canary in the mine for filtration surgeries. More bluntly, the type of filters implanted today may determine how busy corneal surgeons will be in the future.
In our series of grafts with tubes, the graft failures with corneal decompensation were not caused by the tubes being too close to the cornea or by long tubes dangling in the anterior chamber because we reposition all abnormal tubes, usually a month ahead of time, to make sure they are away from the cornea and not too long. Our preferred method of placing tubes is the Alvarado technique,52 which is done without a patch graft for scleral reinforcement but rather prolonged tunneling of the tube in the sclera, so there are no elevated areas above the sclera within 4 to 6 mm of the limbus. This may also decrease lid movement or pressure on the tube with blinks.
The presumable cause of corneal failure after filtration surgery may be related to a loss of the blood-aqueous barrier and dramatic increase in the protein content in the anterior chamber. We first reported this in 2011,53 and more recently submitted for publication a more detailed study showing that eyes with a trabeculectomy or Express shunt (Alcon, Ft. Worth, TX) have about a 5-fold increase in protein concentration in the anterior chamber, whereas eyes with a tube have approximately a 10-fold increase in protein content. It is not yet clear whether changes in specific proteins mediate an adverse effect on the endothelium or whether the overall increase in protein concentration and pervasive alterations of relative protein concentrations generally pollute the aqueous environment causing cell loss. The bottom line is that tubes should not be a first-line surgical treatment for medically uncontrolled glaucoma. Just as a canary in a mine dies sooner from toxic air than men in the mine, we think these EK grafts are a warning of future endothelial failures of virgin corneas. Corneal grafts seem to have less robust endothelial cells than virgin corneas, and we predict that there will be a lot of corneal decompensation from tubes in the coming years.
Probably, every glaucoma surgery has some short- or long-term effect on the cornea. Even laser peripheral iridotomies have been associated with corneal decompensation and decreasing endothelial cell density in eyes without a history of angle closure.54–56
In the future, we may treat corneal endothelial decompensation by ordering a syringe of cultured endothelial cells for in-office injections. We may even be able to collect a person's own adult stem cells, reprogram them to become corneal endothelial cells, and inject them into the eye. We may prescribe topical drops to stimulate endothelial cell regeneration without the need to learn complex surgical procedures such as DMEK.
At World Cornea Congress IX in 2025, will a major focus be how to manage all of the decompensated corneas that had tubes placed 10 years earlier and now require regrafting every 3 to 5 years? Or will we find a way to negate the effect of tubes on the endothelium?
Our long-term dream is that people can come to a center to receive a graft such as DMEK along with a depo-injection of a corticosteroid in which the release of medication is programmed so as to prevent rejection yet not stimulate IOP elevation, and the patient will not need to return for follow-up for 3 to 6 months. This dream will produce better vision, fewer lost eyes, and reduced expense for the health care system.
Looking back at the 7 “beliefs” from 2005, we now know that:
- Guttae decrease vision
- Fuchs dystrophy and corneal edema can lead to structural changes in the stroma and anterior surface of the cornea
- Fuchs dystrophy patients with confluent guttae and cataracts need to have the guttae removed to improve vision and reduce glare. Just removing the cataract is not doing the patient a favor
- Bilateral DMEK grafts can be performed a week apart without increasing the risk of rejection
- The corneal endothelium is not the most important component of the cornea for stimulating immunologic graft rejection
- For DMEK, older donors are currently better than younger donors
- Eyes with glaucoma have excellent visual results with EK
- Glaucoma filtration tubes are the most significant risk factor for EK graft failure and should not be considered for first-line surgical treatment of uncomplicated open-angle glaucoma.
In conclusion, EK is amazing. It provides better and faster visual recovery, improved safety, a reduced risk of immunologic rejection episodes, decreased need for corticosteroids resulting in less induced IOP elevation, and better understanding of the cornea and glaucoma.
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. Am J Ophthalmol. 2007;144:318–319.
45. Vajaranant TS, Price MO, Price FW, et al.. Visual acuity and intraocular pressure after Descemet's stripping endothelial keratoplasty in eyes with and without preexisting glaucoma
. Ophthalmology. 2009;116:1644–1650.
46. Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol. 2003;121:1087–1092.
47. Sugar A, Tanner JP, Dontchev M, et al.. Recipient risk factors for graft failure in the cornea donor study. Ophthalmology. 2009;116:1023–1028.
48. Anwar Z, Wellik SR, Galor A. Glaucoma
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50. Anshu A, Price MO, Price FW. Descemet's stripping endothelial keratoplasty under failed penetrating keratoplasty
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51. Aldave AJ, Chen JL, Zaman AS, et al.. Outcomes after DSEK
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52. Alvarado JA, Hollander DA, Juster RP, et al.. Ahmed valve implantation with adjunctive mitomycin C and 5-fluorouracil: long-term outcomes. Am J Ophthalmol. 2008;146:276–284.
53. Anshu A, Price MO, Richardson MR, et al.. Alterations in the aqueous humor proteome in patients with a glaucoma
shunt device. Mol Vis. 2011;17:1891–1900.
54. Ang LP, Higashihara H, Sotozono C, et al.. Argon laser iridotomy-induced bullous keratopathy a growing problem in Japan. Br J Ophthalmol. 2007;91:1613–1615.
55. Lim LS, Ho CL, Ang LP, et al.. Inferior corneal decompensation following laser peripheral iridotomy in the superior iris. Am J Ophthalmol. 2006;142:166–168.
56. Park HY, Lee NY, Park CK, et al.. Long-term changes in endothelial cell counts after early phacoemulsification versus laser peripheral iridotomy using sequential argon:YAG laser technique in acute primary angle closure. Graefes Arch Clin Exp Ophthalmol. 2012;250:1673–1680.
Keywords:Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
penetrating keratoplasty; Descemet stripping endothelial keratoplasty; Descemet membrane endothelial keratoplasty; DSEK; DSAEK; DMEK; DLEK; glaucoma; aqueous shunts; trabeculectomy