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Another View of Corneal Crosslinking
By Linda Roach
Less enthusiasm and more skepticism is the prescription that German ophthalmologist Jorg Krumeich, MD, says ophthalmic surgeons worldwide should bring to the evaluation of riboflavin/UVA collagen cross-linking (CXL) as a treatment for keratoconus.
Dr. Krumeich, who is the author of a widely-used system for classifying and treating keratoconus based on four stages of severity, worries that corneal cross-linking is entering clinical use even though its effectiveness remains unproven, potentially putting patients at risk for long-term complications that have not yet become apparent. He has begun speaking out about this issue, urging his colleagues to resume “medical thinking” about CXL.
“My primary concern is that corneal cross-linking has insufficient clinical proof,” said Dr. Krumeich, who practices at his outpatient surgery hospital in Bochum, Germany. “Its use is not based on controlled clinical studies. In particular, CXL results are not based on studies in which the stages I to IV of the cone have been separately evaluated.”
Cross-linking proponents are relying largely on the weight of the total numbers of CXL procedures being done — rather than on scientific rigor — to support the technique’s clinical use, he said in a recent interview.
“I want to alert people about how little we do know about corneal cross-linking, especially about the long-term effects on the cornea,” he said.
Not Doing Any More CXL
Dr. Krumeich said he performed 20 corneal cross-linking treatments at his clinic about four years ago but stopped offering the procedure because his patients’ visual acuity improved very little.
“I would not say they didn’t benefit at all. But it’s a question of how you define benefiting,” he said. “The primary goal of any keratoconus treatment is stopping progression of the disease, and you must be able to assure that the radii do not become steeper. Secondly, BCVA must improve, which I could not prove in my own series nor in the dissatisfied cases that came to see me after CXL elsewhere.”
“To me, results looked borderline, and we honestly could not tell the patients that CXL treatment would lead to a permanent stop of the cone or to a visual improvement,” he said.
Some frequently-cited papers in the field also appear to demonstrate borderline efficacy, he said. For instance, in 2009, Vinciguerra and colleagues reported results in 28 eyes that were followed for 24 months after CXL. They found that mean topographic astigmatism was -4.27 D preoperatively and -3.80 D at 24 months (P = 0.03). 
“Measurements on an irregular surface don’t allow you to be that exact,” Dr. Krumeich said. “What you can justify saying in that case is that the astigmatism has not worsened. But you can’t say it has improved.”
Questions about Data Reliability
A 2010 review published by the British Journal of Ophthalmology called corneal cross-linking a promising therapy but questioned the robustness of the accumulated scientific data.
“The study methodology, in terms of inclusion and exclusion criteria, treatment parameters, outcome measures and analysis are very variable among the studies,” the authors wrote. 
The number of PubMed citations related to the therapeutic use of intrastromal CXL has ballooned in the last few years to nearly 200, according to a recent keyword search.  That compares with 34 relevant citations that Koller and Seiler found when they did the same keyword search during preparation of a review paper published in 2007. 
However, fewer than 10 of the clinical papers in the current citation list meet safety and medical efficacy gold-standard criteria of being prospective, randomized and controlled. [5-10] The remainder consist of case reports, case series and large observational studies, some conducted over several years, that lack controls.
In addition to his questions about study methodology, Dr. Krumeich criticized the fact that CXL treatments are not being tailored to the disease state of individual patients.
“Cross-linking using the same doses of riboflavin and UV just cannot work the same for every kind of disease stage. But I see no controlled studies for the four stages of the disease. They all are treated the same,” he said.
“This does not seem to be a clinical results-oriented procedure when we don’t know in what percentage of stage II keratoconus we can expect what BCVA improvement,” he said.
Safety Record Questioned
Although some large prospective observational studies have reported few adverse events, Dr. Krumeich is concerned when he hears corneal cross-linking characterized as a safe procedure.
“It’s not that there are no complications after cross-linking,” he said. “There have not been enough large, well-controlled studies completed, and the duration of follow-up has not been long enough for us to know the answers.”
For instance, one prospective study of 117 eyes with primary keratectasia that were followed for two years reported treatment failure (continued progression) in 7.6 percent of eyes. Sterile infiltrates were seen in 7.6 percent of eyes and central stromal scars in 2.8 percent. The percentage of eyes losing two or more Snellen lines was 2.9 percent (95% confidence interval, 0.6%-8.5%). 
Case reports have documented other complications with corneal cross-linking, including:
- Persistent stromal haze, sometimes visually significant; [11,12]
- Postoperative infectious keratitis; [13-15]
- Late stromal scarring and loss of VA; [16-18]
- Corneal melt requiring penetrating keratoplasty; [16, 18] and
- Damage to the corneal endothelium, even though the preoperative cornea met the recommended minimum thickness of 400 microns. [17, 19]
In the latter instance, Dr. Krumeich wonders about the degree of certainty that a surgeon can have when measuring corneal thickness preoperatively.
“I think the preop evaluation measures we have are not so accurate in all cases that we can rule out that some areas of the cornea are too thin to protect the endothelium,” he said.
Aging and the Cross-Linked Cornea
It is estimated that CXL has the same stiffening impact on the cornea as 30 years of aging, he said. But no one knows how the combination of this artificial “leathering” and the cornea’s natural aging will impact it over a lifetime.
“I think that we might really hinder the possibilities of other treatments later,” Dr. Krumeich said. “To me, this is something that is really a reason to question this procedure.”
For instance, he has encountered four corneas that required lamellar transplants within the first year after cross-linking and which then had inexplicable difficulty accepting the new tissue.
“It does not look like this is an immune reaction. Two of the eyes just did not accept the new tissue at all, and they were totally opaque after three weeks,” Dr. Krumeich said.
“The other two eyes are fighting and have recurrent epithelial slough-offs, which you never see in non-CXL treated eyes,” he said.
Such cases suggest to him a need for caution. “Looking at cases like these, we must conclude there are important questions unanswered. At present, I think we should tell the patient before CXL that we might be performing on him a subprime procedure,” he said.
1. Vinciguerra P, Albè E, Trazza S, Seiler T, Epstein D. Intraoperative and postoperative effects of corneal collagen cross-linking on progressive keratoconus. Arch Ophthalmol. 2009;127(10):1258-1265. PubMed
2. Ashwin PT, McDonnell PJ. Collagen cross-linkage: a comprehensive review and directions for future research. Br J Ophthalmol. 2010;94(8):965-970. PubMed
3. Search conducted on Nov. 8, 2011, in the U.S. National Library of Medicine’s Medline/PubMed database, at http://www.ncbi.nlm.nih.gov/pubmed/. Keywords: “cross-linking” + “cornea.” Search limits: “Published in the last 5 years.”
4. Koller T, Seiler T. [Therapeutic cross-linking of the cornea using riboflavin/UVA]. Klin Monbl Augenheilkd. 2007;224(9):700-706. [Article in German] PubMed
5. Search conducted on Nov. 8, 2011, in the U.S. National Library of Medicine’s Medline/PubMed database, at http://www.ncbi.nlm.nih.gov/pubmed/. Keywords: “cross-linking” + “cornea.” Search limits: “Randomized Controlled Trial.”
6. Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(7):1282-1290. PubMed
7. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(4):691-700. PubMed
8. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg. 2011;37(1):149-160. PubMed
9. Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg. 2010;36(12):2105-2114. PubMed
10. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24(7):S720-S725. PubMed
11. Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg. 2009;25(9):S824-S828. PubMed
12. Herrmann CI, Hammer T, Duncker GI. [Haze formation (corneal scarring) after cross-linking therapy in keratoconus]. Ophthalmologe. 2008;105(5):485-487. [Article in German] PubMed
13. Sharma N, Maharana P, Singh G, Titiyal JS. Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. J Cataract Refract Surg. 2010;36(3):517-520. PubMed
14. Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal cross-linking with riboflavin and ultraviolet-A. J Cataract Refract Surg. 2009;35(3):588-589. PubMed
15. Rama P, Di Matteo F, Matuska S, Paganoni G, Spinelli A. Acanthamoeba keratitis with perforation after corneal cross-linking and bandage contact lens use. J Cataract Refract Surg. 2009;35(4):788-791. PubMed
16. Lim LS, Beuerman R, Lim L, Tan DT. Late-onset deep stromal scarring after riboflavin-UV-A corneal collagen cross-linking for mild keratoconus. Arch Ophthalmol. 2011;129(3):360-362. PubMed
17. Eberwein P, Auw-Hädrich C, Birnbaum F, Maier PC, Reinhard T. [Corneal melting after cross-linking and deep lamellar keratoplasty in a keratoconus patient]. Klin Monbl Augenheilkd. 2008;225(1):96-98. [Article in German] PubMed
18. Labiris G, Kaloghianni E, Koukoula S, Zissimopoulos A, Kozobolis VP. Corneal melting after collagen cross-linking for keratoconus: a case report. J Med Case Reports. 2011;5:152. PubMed
19. Gokhale NS. Corneal Endothelial Damage After Collagen Cross-Linking Treatment. Cornea. 2011: 30(12):1495-1498. PubMed