Cornea Tissue: How Old Is Too Old?

Download PDF

If you perform endothelial keratoplas­ty, are you comfortable accepting cornea tissue that’s 10 or 11 days old? Although the FDA has approved hypo­thermic storage of donor cornea tissue for up to 14 days, most U.S. surgeons are offered tissue that is three to seven days old because of the typical surplus of cornea tissue in this country.

However, the future of that surplus is uncertain. The U.S. population is aging, and there is a concomitant increase in demand for cornea tissue, noted Jonathan H. Lass, MD, at Case Western Reserve University School of Medicine and the University Hospitals Eye Insti­tute in Cleveland, Ohio. In addition, the donor pool is at greater risk from emerging infections—and the current opioid epidemic means eye banks need more time to screen donors.

Extending storage time gives eye banks greater flexibility to evaluate and distribute donor corneas, significantly expanding supply. But U.S. surgeons have become so accustomed to the current practice of shorter-term storage that “many are reluctant to go beyond seven days should the need arise,” said Dr. Lass, who also served as chair of the Cornea Preservation Time Study (CPTS).

COMPARISON. These images are from the same patient. (1) Right eye, two months after DMEK (Descemet membrane endothelial keratoplasty). Best-corrected visual acuity (BCVA) was 20/20; the edges of the graft are not visible on direct diffuse illumination. (2) Left eye, eight months after DSAEK. BCVA was 20/25; the nasal graft edge is visible (red arrows).

Evidence From the CPTS

For evidence-based guidance on storage times, cornea surgeons can turn to the CPTS for assurance.

Question of preservation time. The NEI-sponsored CPTS was the first to study whether endothelial keratoplasty using donor corneas preserved for eight to 14 days could be as successful as sur­gery with donor corneas that had been preserved for up to seven days.

The CPTS enrolled 1,330 study eyes that underwent Descemet stripping automated endothelial keratoplasty (DSAEK) for corneal conditions associ­ated with endothelial dysfunction and moderate risk for graft failure (Fuchs dystrophy or pseudophakic/aphakic corneal edema [PACE]).¹

The objective of the CPTS was to provide scientific evidence regarding best practices for preservation time and usage. The noninferiority design rigor­ously demonstrated that donor corneas can be preserved for up to 11 days and still have a greater than 90% probability of graft success at three years.¹ Data on endothelial cell loss at three years mirrored these findings.²

“A big question in eye banking has been the optimal timing for using tis­sue,” said Jennifer Y. Li, MD, at the Uni­versity of California, Davis. “The CPTS gives us an evidence-based approach to deal with misperceptions about the ideal ‘freshness’ of donor corneas and should increase our eye banks’ ability to place tissue,” said Dr. Li, who also holds an advisory position with the Eye Bank Association of America (EBAA).

Of note, the three-year success rates were still high in the 12- to 14-day preservation time group (89.3%, versus 94.1% in the one- to 11-day group).¹ When logistics dictate, surgeons should be encouraged to accept corneas stored 12 to 14 days, Dr. Lass said. “The mini­mal reduction in survival translates to a clinically acceptable level.”

Impact on surgeons’ attitudes. “As with any scientific discovery, dissem­inating the findings of the CPTS and influencing practice patterns will take some time,” said Anthony J. Aldave, MD, at the Stein Eye Institute in Los Angeles. “The effort to influence or change surgeon criteria for donor tissue begins at the cornea fellowship level because it is easier to shape practice patterns as opposed to changing them.”

The CPTS appears to have had an impact on the preservation time that surgeons say they are willing to accept.³ However, in practice, it hasn’t been fully tested, given the domestic supply. “Now, as eye banks ramp up in the shadow of COVID-19, we might see more corneas offered that will be over seven days old at the time of surgery. That will show if surgeons are truly comfortable accepting tissue with longer storage times,” Dr. Aldave said.

Predicting Graft Success

The CPTS was also designed to study the effect of factors other than preser­vation time on DSAEK outcomes. It prospectively tracked over 50 factors that might impact graft success or fail­ure and endothelial cell loss three years after surgery.⁴

Risk: diabetic donors. The most re­markable finding, according to Dr. Lass, was that diabetes in the donor correlated with lower graft success and greater endothelial cell loss at three years, as well as more graft dislocations over­all, particularly among patients who experienced primary or early graft fail­ures.^1,2,4 “Prior to the CPTS, there were conflicting studies on whether diabetes in the donor could affect transplant success and cell loss,” said Dr. Lass.

Going forward, researchers need to define and study disease severity in do­nors (e.g., from prediabetes to diabetic nephropathy, neuropathy, and periph­eral vascular disease). “Given that this country has an epidemic of diabetes,” Dr. Lass said, “we need to establish” whether tissue from particular subsets of diabetic donors can be used.

Risk: recipients with PACE. Failure was more likely in PACE recipients than in recipients with Fuchs dys­trophy, with a significant difference in late failures, but not in primary/early failures.⁴ This may be due to the PACE group having a lower peripheral endothelial cell reserve than the Fuchs group, said Dr. Lass, who noted that further study is needed.

Risk: operative complications. By far the strongest predictor of failure was operative complications. These included an inverted graft, unplanned vitreous loss, posterior capsule rupture, and significant hyphema. They also comprised difficulty with unfolding and positioning tissue with/without use of a positioning hook, a difficult air fill and retention in positioning, and/or reinsertion of the donor tissue after extrusion.⁴ “The most important thing to focus on for your patients is mini­mizing iatrogenic donor tissue damage by any means possible,” said Dr. Aldave.

Not a risk: donor age. Aligning with prior findings from the Cornea Donor Study on penetrating keratoplasty (PK), CPTS found no evidence to suggest that advanced donor age is correlated with DSAEK survival.⁵

Not a risk: additional factors. In addition, no evidence suggests that pre­operative donor endothelial cell density or donor DSAEK diameter is associated with graft survival, according to Dr. Aldave.

Dr. Aldave further noted that out­comes were not affected by donor gen­der, race/ethnicity, or cause of death. In addition, they were not affected by death to preservation time, time from dissection to surgery, gender mismatch, or type of injector used.

Unclear: lenticule thickness. In the CPTS report on graft dislocations, much of the data mirrored the reports on graft success and endothelial cell loss.³ Operative complications and diabetes in the donor were two of three predic­tors of failure. But the third factor—one that Dr. Aldave called a mystery—involved lenticule thickness. That is, a donor cornea with thicker precut thickness, despite the postcut lenticule thickness (ranging in eyes from 14% under 100 μm to 31% over 150 μm), was more likely to be associated with complications.⁶

“Much focus has been placed on lenticule thickness and graft disloca­tion, but why, if the eye bank is able to prepare lenticules of a given thickness from donors of variable thicknesses using different microkeratome heads and preparation techniques, should the original thickness matter?” Dr. Aldave asked.

Additional nuances regarding graft rejection. The only statistically signifi­cant factor associated with graft rejec­tion was recipient age. Older DSAEK re­cipients had a lower rejection risk than younger recipients (defined as those younger than age 50), Dr. Lass said.

Factors identified by two major PK studies (the Cornea Donor Study and the U.K. Registry Study) as being asso­ciated with a higher risk of rejection—gender, gender mismatch, prior use of glaucoma medications, and a history of glaucoma surgery—were not found to be significant with DSAEK.^5,7

Practical Advice

When discussing the freshness and safety of donor tissue, Dr. Li empha­sized that EBAA-accredited eye banks require donor tissue to meet a rigorous standard of quality and safety. In her personal practice, she has never ques­tioned or sent back a donor cornea to her eye bank. “Accreditation is not just a rubber stamp. Standards are updated on a regular basis, including amidst the COVID-19 pandemic. As long as a surgeon works with an accredited eye bank, freshness and safety of donor tissue are not factors he or she should need to think about.”

Thus, she and Drs. Aldave and Lass said, surgeons should worry less about donor tissue quality and more about minimizing operative complications. They offered the following suggestions:

Patient age. Surgeons should care­fully monitor patients younger than age 50 because of their higher risk for rejection, Dr. Lass said.

Other considerations. In addition, it is prudent to be cautious with patients who have had prior glaucoma surgery, Dr. Li said. (Only 31 eyes in the CPTS had a history of glaucoma surgery, and eyes with previous tube shunts were not included. Though not statistically significant, eyes with prior glaucoma surgery had a lower graft success rate.³ As noted above, in PK studies, prior glaucoma surgery was associated with a higher risk of rejection.⁷)

Dr. Aldave added, “For eyes at high­est risk for donor detachment, rejection and/or failure, such as hypotonous eyes or those with prior glaucoma surgery, maybe it would be justified to request tissue from a nondiabetic donor whose corneas are of normal thickness. I’ll probably get a lot of flak for suggest­ing that, but these are the only factors within the surgeon’s control besides operative skills.”

___________________________

1 Rosenwasser GO et al. JAMA Ophthalmol. 2017;135(12):1401-1409.

2 Lass JH et al. JAMA Ophthalmol. 2017;135(12):1394-1400.

3 Hannush SB et al. International Journal of Eye Banking. 2018;6:1-12.

4 Terry MA et al. Ophthalmology. 2018;125(11):1700-1709.

5 Mannis MJ et al., for the Writing Committee for the Cornea Donor Study Research Group. Ophthalmology. 2013;120(12):2419-2427.

6 Aldave AJ et al. Am J Ophthalmol. 2019;203:78-88.

7 Stulting RD et al. Am J Ophthalmol. 2018;196:197-207.

___________________________

Dr. Aldave is professor of ophthalmology, Walton Li Chair in Cornea and Uveitis, chief of the Cornea and Uveitis Division, and director of the Cornea and Refractive Surgery Fellowship at The Jules Stein Eye Institute in Los Angeles. He is also chair of the Policy Position and Review Commit­tee for the EBAA in Washington, D.C. Relevant financial disclosures: None.

Dr. Lass is Charles I. Thomas Professor and Vice Chair for Academic Affairs in the Department of Ophthalmology and Visual Sciences at Case Western Reserve University in Cleveland, Ohio. He is also a member of the Center for Anterior Segment Diseases and Surgery at the University Hospitals (UH) Eye Institute, medical director of the UH Cornea Image Analysis Reading Center, and medical director of Eversight Ohio. Relevant financial disclosures: NEI: S.

Dr. Li is professor of ophthalmology and chief of Cornea and External Disease at the University of California, Davis. She is also chair of the Medical Advisory Board for the EBAA in Washington, D.C. Relevant financial disclosures: None.

For full disclosures and the disclosure key, see below.