Corneal collagen crosslinking (CXL) is a minimally invasive surgical technique used for the management of ectatic corneal disorders such as keratoconus, pellucid marginal degeneration (PMD), and post-LASIK ectasia.1-4 The main principle of action of CXL is the formation of new chemical bonds between collagen fibrils that can increase corneal resistance and rigidity and inhibit ectatic progression.1,2 The use of riboflavin, also known as vitamin B2, in conjunction with ultraviolet-A irradiation facilitates the formation of links between collagen fibrils in the corneal stroma, producing a stiffening effect capable of halting the progression of ectasia.1,2
Management vs Treatment
CXL was introduced into routine clinical practice during the past decade. Before that time, the management of keratoconus included spectacle and contact lens correction and intrastromal corneal ring segment (ICRS) implantation.5 All of these interventions are purely symptomatic and aim to improve visual function without addressing the pathophysiology of the ectatic disorder. Before CXL, the only actual treatment for keratoconus was lamellar or penetrating keratoplasty, which was performed in advanced cases.6 CXL has given patients with keratectasia the chance to postpone or even avoid corneal transplantation by arresting the progression of the primary disorder.
The goal of CXL treatment is restoration of the tectonic integrity of the cornea to increase corneal biomechanical rigidity and inhibit the progression of the ectatic disorder. Following the early work by Wollensak et al,1 several others have reported extremely promising results with CXL; clinical measurements have been shown to improve after CXL due to its stiffening effect and regularization of corneal curvature.7-10 Nevertheless, in some cases, patients do not achieve visual acuity improvement sufficient to provide functional vision after CXL treatment.
Several adjuvant therapies in combination with CXL treatment have been proposed in an effort to develop a technique that can offer patients with keratectasia corneal stability together with improved functional vision.11 CXL treatment in combination with ICRS implantation can be an effective treatment because the synergic influence of the two procedures can partially reverse the progressive irregular astigmatism and result in favorable outcomes for the patient.12-14 Nevertheless, to date, topography-guided PRK in combination with CXL seems to be the most effective approach to optimize the CXL results.15-20
A. John Kanellopoulos, MD, and Perry S. Binder, MD, proposed a two-step procedure with CXL performed first and PRK after a 1-year interval—an approach that had some limitations.15 First, crosslinked corneas may have a different ablation rate from normal corneas, which could lead to unpredictable PRK results. Moreover, there is an increased possibility of haze formation after PRK. Last, and probably most significant, is that the removal of the crosslinked corneal tissue by the PRK procedure could decrease the stiffening effects of the CXL treatment.
Topography-Guided PRK and CXL
Due to these limitations, we hypothesized that the best option for optimizing the result of CXL in the treatment of keratoconus is simultaneous topographyguided PRK followed by CXL. In 2009, we reported promising results with this approach.16,17 First, we described a patient with PMD that showed significant improvement in UCVA and BCVA and in topographic values after simultaneous topography-guided PRK and CXL.16 Second, we reported that a series of keratoconic patients treated with simultaneous topography-guided PRK followed by CXL showed significant improvement in all parameters evaluated (spherical equivalent, defocus, UCVA and BCVA, and keratometric values).17 The main advantage of simultaneous topographyguided PRK and CXL is that laser ablation does not interfere with an already crosslinked cornea. Kanellopoulos showed that this approach is more effective than sequential CXL with later PRK in the visual rehabilitation of keratoconus.18 In his study, the simultaneous group performed superiorly in all fields evaluated, with improvement in UCVA and BCVA, a greater mean reduction in spherical equivalent and keratometry, and less corneal haze.18 Kanellopoulos used mitomycin C 0.02% after laser ablation. In our case series, we did not use mitomycin C; we posited that crosslinking of the ablated stroma offers the advantage of depopulating keratocytes in the anterior stroma, which may reduce the possibility of haze formation.17
Stojanovic et al19 reported improvement in patients’ visual, refractive, and topography outcomes after topographyguided transepithelial surface ablation followed by CXL performed in a single combined procedure. In that study, transepithelial surface topography-guided custom ablation was chosen instead of standard surface ablation to avoid potential custom ablation planning error due to epithelial remodeling.
Recently, we published long-term results of simultaneous topography-guided PRK followed by CXL in a series of keratoconic patients.20 All parameters evaluated (spherical equivalent, UCVA and BCVA, and keratometric values) showed a significant improvement that remained stable throughout follow-up.20 All patients showed marked improvement of corneal irregularity and visual acuity. An example of topographic improvement after simultaneous topography-guided PRK followed by CXL in a keratoconic patient using iTrace technology (iTrace; Tracey Tech) can be seen in Figure 1.
None of the patients in our study showed topographic or clinical signs of keratoconus progression during followup. 20 In 50% of patients, however, a posterior linear stromal haze corresponding to the central treated area of the cornea developed that was detectable by slit-lamp biomicroscopy. 20 The posterior haze gradually moved anteriorly and became less dense during follow-up.20
The major consideration in the planning of this combined procedure is postoperative corneal thickness. In our cases, PRK was planned based on the patient’s corneal thickness; expected corneal thickness after PRK should be more than 400 μm.17,20 Treatment modifications (attempted correction and percentage of customization) were based on preoperative corneal pachymetry, BCVA, and manifest refraction to arrive at a maximum ablation depth of 50 μm.17,20 A maximum ablation depth of 50 μm has been chosen in all our cases to not only remodel corneal curvature and achieve a decrease in irregular astigmatism but also to avoid removing a significant amount of tissue that would jeopardize the biomechanical integrity of the cornea.17,20 Kanellopoulos also reported a maximum ablation depth of 50 μm in his study, but with corneal thickness no less than 350 μm after PRK.18 Stojanovic et al19 reported a maximum ablation depth of 60 μm and minimum postoperative corneal thickness of 400 μm. Whatever the criteria chosen, postoperative corneal thickness plays a significant role in planning the combined PRK and CXL procedure. It must be noted that thin corneas limit the possibility of tissue removal by topography-guided PRK, and therefore this combined procedure may not be performed in eyes with advanced keratoconus.
CXL alone is effective in achieving a halt in progression of keratoconus, but the improvement in visual acuity that has been reported is not always sufficient for functional vision and better quality of life. Combined treatments seem to be the way to optimize the result of CXL treatment for keratoconus. To date, simultaneous topography-guided PRK followed by CXL seems to be the most effective approach for optimum results in the treatment of keratoconic patients, as it is capable of offering functional vision with stabilization of the ectatic disorder. Further studies with longer follow-up are needed to confirm the promising results of this approach.
George D. Kymionis, MD, PhD, is a Lecturer in Ophthalmology at the Institute of Vision and Optics, University of Crete, Heraklion, Greece. Dr. Kymionis states that he has no financial interest in the products or companies mentioned. He may be reached at tel: + 30 281 0371800; fax: +30 281 0394653; e-mail: email@example.com.
Michael A. Grentzelos, MD, is a clinical and research fellow at the Institute of Vision and Optics, University of Crete, Heraklion, Greece. Dr. Grentzelos states that he has no financial interest in the products or companies mentioned. He may be reached at e-mail: firstname.lastname@example.org.
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620-627.
- Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356-360.
- Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2007;33:2035-2040.
- Spadea L. Corneal collagen cross-linking with riboflavin and UVA irradiation in pellucid marginal degeneration. J Refract Surg. 2010;26:375-377.
- Siganos CS, Kymionis GD, Kartakis N, Theodorakis MA, Astyrakakis N, Pallikaris IG. Management of keratoconus with Intacs. Am J Ophthalmol. 2003;135:64-70.
- Frost NA, Wu J, Lai TF, Coster DJ. A review of randomized controlled trials of penetrating keratoplasty techniques. Ophthalmology. 2006;113:942-949.
- Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34(5):796-801.
- Coskunseven E, Jankov MR 2nd, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg. 2009;25:371-376.
- Vinciguerra P, Albè E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology. 2009;116:369-378.
- 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;149:585-593.
- Kymionis GD. Corneal Collagen Cross Linking - PLUS. Open Ophthalmol J. 2011;5:10.
- Chan CC, Sharma M, Wachler BS. Effect of implantation of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg. 2007;33:75-80.
- Kamburoglu G, Ertan A. Intacs implantation with sequential collagen cross-linking treatment in postoperative LASIK ectasia. J Refract Surg. 2008;24:S726-769.
- Coskunseven E, Jankov MR II, Hafezi F, Atun S, Arslan E, Kymionis GD. Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus. J Cataract Refract Surg. 2009;35:2084-2091.
- Kanellopoulos AJ, Binder PS. Collagen cross-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty. Cornea. 2007;26:891-895.
- Kymionis GD, Karavitaki AE, Kounis GA, Portaliou DM, Yoo SH, Pallikaris IG. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. J Cataract Refract Surg. 2009;35:1298-1301.
- Kymionis GD, Kontadakis GA, Kounis GA, et al. Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus. J Refract Surg. 2009;25:S807-811.
- Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topographyguided PRK for treatment of keratoconus. J Refract Surg. 2009;25:S812-818.
- Stojanovic A, Zhang J, Chen X, Nitter TA, Chen S, Wang Q. Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration. J Refract Surg. 2010;26:145-152.
- Kymionis GD, Portaliou DM, Kounis GA, Limnopoulou AN, Kontadakis GA, Grentzelos MA. Simultaneous topography-guided photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. Am J Ophthalmol. 2011;152:748-755.