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Ten-year data promising in combined CXL approach for keratoconus


Clinicians evaluated the refractive, pachymetric, topometric, and visual rehabilitation changes with the Athens Protocol applied in patients with keratoconus. Joanna Kontari, MD, highlights some of the research findings and implications.


By Laird Harrison; Reviewed by Joanna Kontari, MD

Eyes treated for keratoconus with collagen crosslinking (CXL) combined with topography-guided excimer normalization maintain ectasia stability and good visual acuity with 10 years follow-up, according to researchers.

“Patients show a very dramatic improvement in their visual function,” said Joanna Kontari, MD, of LaserVision Clinical and Research Eye Institute in Athens, Greece.

Uncorrected distance visual acuity improved from 0.19 (decimal) at baseline to 0.53 (decimal) at 1 year on the decimal scale (where 1.0 is the equivalent of 20/20 and 0.1 is the equivalent of 20/200 on the Snellen scale). Their acuity was virtually unchanged at 10 years, reaching 0.55 (decimal) (Table 1).

Best-corrected visual acuity went from 0.59 at baseline to 0.80 at 1 year and stayed at 0.81 10 years later.

Keratoconus is a degenerative bilateral disorder characterized by corneal steepening, thinning and irregular topography that can cause refractive errors. CXL strengthens the cornea to halt this ectasia.

However, significant residual astigmatism may limit visual rehabilitation, and when contact lens wear is not tolerable, patients may benefit from an additional procedure that normalizes the anterior surface.


The first such combined procedure, the Athens Protocol, was developed 13 years ago by Dr. Kontari’s colleague at LaserVision, A. John Kanellopoulos, MD. CXL alone usually flattens the cones typical of keratoconus by 1 to 1.5 D, said Dr. Kontari.

Using the Athens Protocol, she and her colleagues achieve 3.5 D of flattening, a significant benefit compared with the standalone crosslinking. In 2009, the same team published a large case series comparison of sequential crosslinking combined with partial photorefractive keratectomy (PRK) done 6 months later that underlined the above benefit.1

Clinicians begin with a partial-topography-guided photorefractive keratectomy. Next comes a 7.5-mm phototherapeutic keratectomy to remove about 50 µm of epithelium. They apply mitomycin C 0.02% for 30 seconds, irrigate with a saline solution, then soak the cornea in a riboflavin ophthalmic solution for 2 minutes until the stroma is penetrated. Next, they expose the cornea to 6 mW/cm2 of ultraviolet light for 15 minutes to crosslink the cornea (Figure 1).


“We take into account in treatment planning not only what we have measured in refraction, but also what the topographer suggests in order to normalize the cornea,” Dr. Kontari said. “The topographer doesn’t have axial length data but it can provide more accurate data concerning the amount and axis of the astigmatism.”

The team then modifies the clinical refraction based on the amount suggested by the topography and moves the axis of cylinder. They have subsequently reported significant benefits to this principle even in routine myopic LASIK cases, a technique they call topography-modified refraction 2, where adjustment of the treatment cylinder amount and axis is done based on the topographic data.2 (http://bit.ly/2qIBnOZ)

To gauge the long-term effectiveness of the technique, Dr. Kontari and her colleagues followed 144 cases for 10 years. The procedure reduced the cone size in 97.9% of patients, and halted progression of keratoconus in all of them.

“We found no regression of the crosslinking effect,” Dr. Kontari said. “None of the patients went on to develop further ectasia.”

Central corneal thickness dropped from 468.74 µm at baseline to 391.14 µm at the first year, and held steady at 395.42 µm after 10 years.

The index of height decentration went from 0.117 µm at baseline to 0.072 µm at 1 year and 0.074 at 10 years.

“The index of high decentration is important because it measures symmetry in regards to the cornea vertex and is correlated to better visual functions,” she said.

Previous research has found this to be the best metric for cornea irregularity.3

K1, the flat axis of the cornea, changed from 46.86 D at baseline to 43.12 D at 1 year and 43.04 at 10 years.

K2, steep axis of the cornea, changed from 52.74 D at baseline to 47.62 D at 1 year and 47.51 at 10 years (Figure 2).


All these changes, including uncorrected visual acuity, were statistically significant (p < 0.01).

Seventeen patients functioned without corrective lenses. Another 21 needed either spectacles or soft contact lenses. Six patients required rigid or scleral lenses.

Normalizing the anterior surface can increase myopic error because the oblique cone is flattened and the central cornea is steepened, she said.

“In some eyes there is an increase in refractive spherical equivalent and these patients manage well with contact lenses, soft contact lenses or spectacles,” Dr. Kontari said. “The amount of the refractive change (flattening) that the crosslinking will achieve long-term was unknown until now.”

The refractive effect of crosslinking appears to depend on how uniformly the cornea is crosslinked, she said.

If the crosslinking creates differentials of fortitude it may this can have important refractive effects that can be even progressive through the years, she said.

Three cases developed cone over-flattening between years 1 and 10 (Figure 3).


“In some cases we have seen flattening of 10 D with crosslinking alone,” Dr. Kontari said.

Researchers are still investigating the reason for this over-flattening, and it is important to counsel patients about this risk when offering them the Athens Protocol, Dr. Kontari said.

In addressing the risk of ablating a cornea that is already thin, she said: “When we started doing these procedures, we had a 50-µm margin over the thinnest part of the cornea. In clinical reality, this limit reduces the amount of clinical error that one can correct with the partial PRK procedure.”

She pointed out that these were not refractive patients. They were patients in whom the partial PRK was employed therapeutically to normalize the cornea with the knowledge that it would still leave a refractive error and in some cases increase the myopic error.

“Because of the steepening of the central cornea the patients become more myopic,” she said. “So these cases can’t be compared with routine PRK or LASIK cases in myopic patients.”

As a next step in their research, Dr. Kontari and her colleagues plan to use ultraviolet light that has variable pattern and fluence in order to boost the refractive effect of the crosslinking procedure and reduce the amount of excimer radiation required to normalize these corneas and stabilize them.

“We feel that a great opportunity is present when we will be able to combine a less tissue-removing partial photorefractive keratectomy with photorefractive crosslinking (PiXL)4,5 (http://bit.ly/2D9PsYd; http://bit.ly/2melf2h) on the thinnest part of the cornea in order to get the same or even better results with less tissue removal, which we all appreciate is the only counterintuitive part of these cases,” she said.

Results so far have been good with this technique, which Dr. Kontari and her colleagues call the Enhanced Athens Protocol.

“We look forward to acquiring long-term data on this technique that could possibly replace our gold standard technique, the Athens Protocol, which we have used over 12 years in over 3,000 eyes successfully,” Dr. Kontari said.





1.   Kanellopoulos AJ: Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg. 2009 Sep;25(9):S812-8.

2.   Kanellopoulos AJ: Topography-modified refraction (TMR): adjustment of treated cylinder amount and axis to the topography versus standard clinical refraction in myopic topography-guided LASIK. Clin Ophthalmol. 2016 Nov 3;10:2213-2221. eCollection 2016.

3.   Kanellopoulos AJ, Asimellis G : OCT corneal epithelial topographic asymmetry as a sensitive diagnostic tool for early and advancing keratoconus. Clin Ophthalmol. 2014 Nov 18;8:2277-87.

4.   Kanellopoulos AJ: Novel myopic refractive correction with transepithelial very high-fluence collagen cross-linking applied in a customized pattern: early clinical results of a feasibility study. Clin Ophthalmol 2014;8 697-702

5.   Kanellopoulos AJ, Dupps W, Seven I, Asimellis G: Toric topographically customized transepithelial, pulsed, very High-fluence, higher energy and higher riboflavin concentration collagen cross-linking in keratoconus. Case Rep Ophthalmol 2014;5:172-180

6.   Kanellopoulos AJ, Binder PS: Collagen cross-linking (CCL) sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty. J Cornea 2007 Aug;26(7):p.891-5

7.   Krueger RP, Kanellopoulos AJ: Stability of Simultaneous topography-guided Photorefractive keratectomy and riboflavin/UVA cross-linking for progressive keratoconus: CaseReports. J Refract Surg. 2010 Oct;26(10):S827-32

8.   Kanellopoulos AJ, Perry S. Binder: 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. 2011;27(5):323-31

9.   Kanellopoulos AJ, Asimellis G: Comparison of Placido disc and Scheimpflug image derived topography-guided excimer laser surface normalization combined with higher fluence CXL: the Athens Protocol, in progressive keratoconus. Clin Ophthalmol 2013;7 1385-96

10. Kanellopoulos AJ, Moustou V, Asimellis G: Evaluation of visual acuity, pachymetry and anterior-surface irregularity in keratoconus and crosslinking intervention follow-up in 737 cases. J Kerat Ect Cor Dis, Septemeber- December 2013;2(3):95-103

11. Kanellopoulos AJ, Asimellis G.: Keratoconus management: Long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (The Athens Protocol). J Refract Surg 2014;30(2):88-92

12. Kanellopoulos AJ, Asimellis G: Corneal Refractive power and symmetry changes following normalization of ectasias treated with partial topography-guided PTK combined with higher-fluence CXL (The Athens Protocol). J Refract Surg 2014;(5):342-46

13. Kanellopoulos AJ, Asimellis G: Epithelial remodelling after partial topography-guided normalization and high-fluence short-duration crosslinking (Athens Protocol); results up to 1 year. J Cataract Refract Surg 2014; 40: 1597-1602

14. Kanellopoulos AJ, Asimellis G.: Novel Placido-derived Topography-guided Excimer Corneal Normalization With Cyclorotation Adjustment: Enhanced Athens Protocol for Keratoconus. J Refract Surg. 2015 Nov;31(11):768-73.

15.       Kanellopoulos AJ, Khan J: Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: Initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. J. Refract. Surg. 2012 Nov;28 (11 Suppl):S837-40.


Joanna Kontari, MD

e: jkontari@laservision.gr

This article was adapted from Dr. Kontari’s presentation at the 2017 meeting of the American Academy of Ophthalmology. She did not indicate any financial interest.


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