Cornea
Fall 2024

by Liz Hillman
Editorial Co-Director

Both W. Barry Lee, MD, and Christopher Ketcherside, MD, have heard of (and, in Dr. Ketcherside’s case, experienced) the recent uptick in primary graft failures, and the data seems to confirm it, but the cause is still unconfirmed.

“I have a small text group of cornea surgeons across the country, and we ping each other with things. Before this came up, we had brought it up among ourselves because I had personally seen an uptick in rebubbles and graft failures in the first quarter, and it was definitely something out of the ordinary, something noticeable. When I brought it up to my colleagues in different places, they were seeing the same thing,” Dr. Ketcherside said.

The data

Dr. Lee said that recent data confirms this increase. “In analyzing the data published by the Eye Bank Association of America [EBAA] Medical Advisory Board meeting in June 2024, we see that 2018 showed a total of three reported primary graft failures or early regrafts, 2019 showed an increase to 32, and 2023 showed an increase to 45. The numbers certainly point to an uptick in these complications,” he said.

Dr. Lee defined a primary graft failure as a corneal transplant that does not clear after 8 weeks following the surgery and an early regraft as a graft that is either dislocated or thought to not clear so a repeat graft is placed in the early postoperative period. 

Elmer Tu, MD, said that the definition of graft failure is very different between penetrating keratoplasty and endothelial keratoplasty. In the latter, it is more difficult to identify the reason (surgical technique or tissue preparation). “Although the increase in primary graft failures for endothelial keratoplasty may be for the same reason, the increasing graft failures of penetrating keratoplasties is probably the best indication that something may be amiss,” Dr. Tu said.

Dr. Ketcherside, who is part of the EBAA Medical Advisory Board, said there was a decrease in reported graft failures in the fourth quarter of last year, after the uptick that had been observed, but anecdotally, there has been a perceived increase again, though the first and second quarter numbers of 2024 are not in yet.

“There are a lot of theories about this, but we don’t totally know why,” he said.

The potential culprit(s)

There are several areas of active research looking into this complication. Dr. Lee noted that there is an increased amount of DMEK tissue preparation being done at eye banks, rather than in the operating room with the surgeon. Amphotericin supplementation in tissue storage media is also being closely examined. Amphotericin use as an antifungal for cornea grafts began in the last 2–3 years.

Dr. Ketcherside also said amphotericin is what is most often being brought up and investigated in relation to these graft failures.

“We should have more on that fairly soon. We should have more definitive answers regarding whether or not this may be causing more graft failures,” he said, adding that investigators are also looking at the amount of time DMEK grafts are stained, volume of fluid the graft is in after being stained, etc.

Dr. Lee said surgeons have the choice of whether to add amphotericin B to the storage media or not. History has shown an increase in fungal infections after endothelial keratoplasty, a rare but potentially vision-threatening complication, and studies have shown amphotericin B can potentially reduce this risk of infection. 

“The problem is amphotericin B does have some degree of endothelial toxicity, and cell damage may be heightened by contact of the medicine with the endothelial cells from the time of tissue preparation until it is removed from the storage solution at the time of surgery,” Dr. Lee said. “While it is hard to prove, the amphotericin B supplementation is a potential for the increase in primary graft failures and early regrafts. Cases of graft failures with amphotericin B supplementation have shown an increase from 2.1% in 2018 to 28.5% in 2023, according to the EBAA data.¹ This is certainly an alarming increase and raises the question of whether the risk of adding amphotericin B to the media is worth reducing antifungal infections, although we still do not have unequivocal evidence that its supplementation statistically reduces the risk of fungal infections in keratoplasty.”

Dr. Lee said that it is safer to decontaminate donor corneal tissue with double betadine prep applied to the donor tissue during recovery. “Salisbury et al. have shown the double betadine prep does have statistical significance of lowering the risk of fungal infections and is a very effective method without adding any additional toxicity to the endothelium,”¹ Dr. Lee said. “While the double betadine prep does not completely eradicate fungal infections after keratoplasty, it does statistically reduce the risk of infection without the potential need for amphotericin B supplementation in the storage media. More studies must be done to assess what surgeons should do as far as adding the antifungal to their storage media or not.”

Dr. Tu pointed out that while the consequences of a fungal infection can be severe and devastating, the incidence of infection has fallen significantly over the last several years. He said that previous studies have shown supplementation is likely not cost effective.

“If there is an issue with toxicity, graft failures would only be the most obvious, immediate consequence; an expectation would be that even those exposed grafts that did not fail initially may have a significantly shorter lifespan,” Dr. Tu said.

The problem

“[A graft is] a gift from some person, and we have a responsibility to make sure that as many of those as possible are able to help someone.”

Christopher Ketcherside, MD

When you look at the individual numbers each year of primary graft failures, it might seem small, but Dr. Ketcherside said that when a practice that does 200 DMEKs a year, for example, goes from a 1% rebubble rate to 10%, that’s significant.

It’s significant from a practice resource standpoint, for the time it’s taking patients to drive back to clinic for treatment, and because of the increased infection risk due to more procedures being performed.

“There are small numbers on how often we get fungal infections with grafts and endophthalmitis as a whole, and people will tell you those tiny numbers involve a catastrophic event that is life changing for the patient and devastating for the surgeon. Graft failures aren’t on the scale of that because you can replace these with another graft, but each one of these is coming from a human being. It’s a gift from some person, and we have a responsibility to make sure that as many of those as possible are able to help someone,” he said.

Dr. Ketcherside said when it comes to corneal grafts, it doesn’t take much of a disruption in the success rate for it to be a big deal. “It will be interesting to see what these initial looks at amphotericin B in larger numbers of patients and their graft failure rates are going to show us,” he said.

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About the physicians

Christopher Ketcherside, MD
Cornea Specialist
Kansas City Eye Clinic
Overland Park, Kansas

W. Barry Lee, MD
Cornea Fellowship Director
Eye Consultants of Atlanta
Atlanta, Georgia

Elmer Tu, MD
Professor of Clinical Ophthalmology
University of Illinois College of Medicine
Chicago, Illinois

Reference

1. Salisbury CD, et al. Increasing povidone-iodine exposure in endothelial keratoplasty tissue processing and fungal infection impact. Cornea. 2019;38:1093–1096.

Relevant disclosures

Ketcherside: None
Lee: None
Tu: None

Contact

Ketcherside: cketch@gmail.com
Lee: wblee@mac.com
Tu: etu@uic.edu