Refractive Surgery Outlook Feature: December 2010

A CXL Update from Athens

By Linda Roach, Contributing Writer

Eight years after he first began stabilizing keratoconic corneas with collagen crosslinking (CXL), corneal surgeon A. John Kanellopoulos, MD, credits the procedure with sparing many patients from undergoing penetrating keratoplasty (PK).

"Ten years ago this procedure was not even available. Today, crosslinking is definitely proving a godsend to people with keratoconus," Dr. Kanellopoulos said in an interview with Refractive Surgery Outlook earlier this month. "We see a lot of patients functioning better and their lives improving."

"As a corneal surgeon, I have happily seen my personal volume of cornea transplants for keratoconus drop by 80 percent, even though the number of keratoconic patients we are seeing has increased greatly," he said. "We also are finding that, if crosslinking is offered earlier, these patients do not even need refractive treatment with PRK at all, and their vision stabilizes."

More Than 1,100 Treated
At the LaserVision.gr Institute in Athens, Greece, where Dr. Kanellopoulos is medical director, more than 1,100 people with keratoconus and more than 50 with iatrogenic ectasia have undergone treatment with what is known as "The Athens Protocol": topical riboflavin and ultraviolet A (UVA) irradiation combined with topography-guided photorefractive keratectomy (PRK) to normalize the cornea's shape.1-7

Follow-up is nearing eight years in some of these patients, and the corneas remain stable, said Dr. Kanellopoulos. He also practices in New York City, where he is a clinical professor of ophthalmology at New York University Medical School. He says that it is highly important that surgeons are very conservative with excimer laser ablation when combining crosslinking and PRK.

"We have seen the Athens Protocol being applied elsewhere, and the PRK part is overly aggressive. But you don't want to overtreat the eyes because the corneas already are very thin and you have to anticipate a continuing flattening effect on these corneas from the CXL for several years," Dr. Kanellopoulos said.

Remove Less Than 50 Microns
Under his protocol, Dr. Kanellopoulos uses an Allegretto Wavelight Eye-Q Excimer Laser (Alcon, Inc.) to plan a customized partial PRK. Topography-guided PRK was introduced at the Laservision.gr Institute and has unique features. Doctors at the institute perform an eccentric small optical zone myopic PRK intervention, which is easily understood by most ophthalmologists. However, the unique part is their use of proprietary Wavelight software that combines this myopic PRK with a hyperopic correction that aims to steepen the flattened cornea adjacent to the cone. In this way, the irregular cornea is normalized with minimal tissue removal from the cone. To minimize tissue ablation, Dr. Kanellopoulos removes the epithelium with the excimer laser and decreases the effective optical zone to 5.5 mm, which is 1 mm smaller than in normal eyes.7-9

Using this protocol, he treats only up to 70 percent of the cylinder error and up to 70 percent of the spherical error in order not to remove more than 50 microns of stroma.

"The PRK part should be a very frugal treatment. It is not intended to be a refractive treatment," Dr. Kanellopoulos said. "Its purpose is to reduce irregular astigmatism and normalize the cornea, not to correct refractive error."

The goal, he said, should be improving the patient's best spectacle-corrected visual acuity.

"In fact, in some patients who are myopic before surgery, we have seen them becoming more myopic after the combined procedure," he said.

Less Haze from Combining Procedures
In the early days of crosslinking, Dr. Kanellopoulos introduced a partial topography-guided PRK treatment to follow by as much as 12 months successful stabilization of ectasia with riboflavin/UVA treatment.7,8 Combining the procedures, with partial PRK performed first, has been the norm for the last five years.

Other features of the Athens Protocol as currently practiced include:

use of balanced salt solution (BSS) as the carrier for 0.1% riboflavin sodium phosphate ophthalmic solution (Priavision, Menlo Park, Calif.). Dr. Kanellopoulos believes that this carrier diffuses into the cornea better than the dextran mixture used by a Dresden group.
slight hypotonicity (340 milliosmols) of the solution, which causes the cornea to swell slightly, further protecting the endothelium from the UVA irradiation.
halving of the UVA treatment time to 15 minutes by doubling the energy output of the UVA diodes to 6 milliwatts per square centimeter.
during combined procedures, performance of PRK first, followed immediately by crosslinking.

"For our patient population, we see a significant reduction in the amount of haze by doing them (PRK and crosslinking) together versus doing PRK in a crosslinked cornea," Dr. Kanellopoulos said. "In the patient population in which we did them sequentially separated by six months, we saw more haze than if we had done the procedures together."2

Culprits Might Be Keratocytes
Dr. Kanellopoulos suspects that one reason for this difference in haze levels, depending on whether or not PRK and crosslinking are performed together, is a reduced numbers of keratocytes after crosslinking.

"It is my impression that when we crosslink cornea, we throw into apoptosis a significant number of keratocytes. For three to six months, the cornea is depleted of these natural healing cells, which if they were present would release the collagen and healing growth factors that lead to haze after PTK (penetrating keratoplasty) and/or PRK," he said.

He explained why: "There is evidence that the more superficial crosslinked area is the strongest. If you were to crosslink the cornea first and then attempt to normalize the cornea with the excimer laser, you would be removing some of the most crosslinked layer that you just created.

While the Athens Protocol recommends combined procedures, if a surgeon nonetheless decides to perform the procedures six months apart, Dr. Kanellopoulos advises scheduling the crosslinking first. He says that otherwise, PK in an unstabilized cornea might accelerate the keratoconus.

What about Stability and VA?
Dr. Kanellopoulos has found that a crosslinked cornea behaves differently than a normal cornea. Consequently, if there is a months-long gap between the surgeries, the surgeon should reduce the refractive target of the ablation beyond the 30 percent reduction that the Athens Protocol recommends for combined procedures, he said.

The peer-reviewed literature on crosslinking has been sparse until recently, with studies of long-term stability even sparser. But, so far, the published results have been generally positive.

Caporossi et al. reported in April 2010 on a study in which 44 patients had unilateral crosslinking for keratoconus, with their fellow eyes serving as controls. All 44 treated eyes remained stable 48 or more months after surgery (mean, 52.4 months; range, 48 to 60 months). The untreated fellow eyes progressed by 1.5 D in more than 65 percent of the patients after 24 months.10

Vinciguerra et al. used objective measurements, including topography, tomography, keratometry and aberrometry, to show refractive improvements in 28 eyes 24 months after they underwent crosslinking but not PRK.11 They reported small but statistically significant gains in UCVA (P = 0.048) and BSCVA (P < 0.001). Twelve eyes showed a one-line gain in UCVA at 24 months, and 15 eyes gained two lines of BSCVA. Mean refraction showed a statistically significant decrease in sphere and cylinder (P = 0.03) at 24 months postop.

Preoperatively, the mean spherical equivalent was ?3.37 D, with a mean sphere of ?1.86 D and a mean cylinder of ?3.02 D. Two years after CXL, the mean spherical equivalent was ?2.56 D; mean sphere, ?1.22 D; and mean cylinder, ?2.68 D. Such refractive changes might appear small, but they are important to patients whose keratoconus is progressing and robbing them of BSCVA, Dr. Kanellopoulos said.

"It's unfair to view this procedure with the same standards as custom PRK for a healthy eye. What I always say to patients and colleagues is that I view these refractive results as a cornea transplant surgeon, not a refractive surgeon," he said. "For a cornea transplant surgeon, these would be very good results."

Unanswered Questions Remain
More research is needed to resolve the unanswered questions about crosslinking treatment, Dr. Kanellopoulos said. These include:

Would the treatment work as well or better if UVA was delivered in pulses in order to allow the power output to be tuned higher? This might be one way to make epithelium-on crosslinking more effective than it has proved so far, he said.
Is it possible to crosslink on very thin corneas without removing any tissue?
How can the treatment effect be made more predictable?
What is the best protocol for crosslinking?
What objective measures can be used to determine the relative effectiveness of different techniques for crosslinking?

References:
1. Kanellopoulos AJ, Binder PS. Management of Corneal Ectasia After LASIK with Combined, Same-Day, Topography-Guided Partial Transepithelial PRK and Collagen Cross-Linking: The Athens Protocol. J Refract Surg. Nov 5, 2010;1-9. [Epub ahead of print].
2. Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg. 2009;25(9):S812-818.
3. Krueger RR, Kanellopoulos AJ. Stability of simultaneous topography-guided photorefractive keratectomy and riboflavin/UVA cross-linking for progressive keratoconus: case reports. J Refract Surg. 2010;26(10):S827-832.
4. Kanellopoulos AJ. Cross-linking plus topography-guided PRK for post-LASIK ectasia management. In: Garg A, ed. Mastering Advanced Surface Ablation Techniques. New Delhi, India: Jaypee Brothers; 2007:204-214.
5. Kanellopoulos AJ. PRK and C3-R. In: Wachler BSB, ed. Modern Management of Keratoconus. New Delhi, India: Jaypee Brothers; 2007:219-228.
6.Kanellopoulos AJ. Cross-linking plus topography-guided PRK for post-LASIK ectasia management. In: Garg A, Rosen E, eds. Instant Clinical Diagnosis in Ophthalmology Refractive Surgery. New Delhi, India: Jaypee Brothers; 2008:258-269.
7. Kanellopoulos AJ. Cross linking plus topography guided PRK for post-LASIK ectasia management. In: Garg A, Pinelli R, Brart O, Lovisolo CF, eds. Mastering Corneal Collagen Crosslinking Techniques (C3- CCL/CxL). New Delhi, India: Jaypee Brothers; 2008:69-80.
8. Kanellopoulos AJ. Post-LASIK ectasia. Ophthalmology. 2007;114(6):1230.
9. ?anellopoulos AJ, Binder PS. Collagen cross-linking (CCL) sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty. Cornea. 2007;26(7):891-895.
10. Kanellopoulos AJ. Managing highly distorted corneas with topography-guided treatment. Paper presented at: International Society of Refractive Surgery 2007 Subspecialty Day; November, New Orleans
11. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010;149(4):585-593.
12. Vinciguerra P, Albe 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.

Financial Disclosures:
Dr. Kanellopoulos is a consultant for Alcon, Inc., maker of the Wavelight excimer laser that he uses for topography-guided photorefractive keratectomy.