Crosslinking has several applications in ophthalmology that are exciting for the refractive surgeon. First, corneal collagen crosslinking (CXL) slows keratoconus progression in early and more advanced stages of the disease. Second, it can stop progression of postrefractive surgery ectasia in a large percentage of cases. Third, it can improve UCVA and BCVA in eyes with keratoconus by producing a flattening effect on the cone and triggering a reduction of simulated keratometry, corneal asymmetry, and coma-like corneal aberrations.
However, CXL affects the corneal surface in other ways that are not as beneficial. For instance, the corneal thinning effect of T-dextran (the solute for riboflavin) and the corneal dehydration that occurs as a result of the crosslinking are temporary side effects.1 Additionally, there has been evidence of asymptomatic stromal opacity development after CXL in eyes with steep corneas and keratometry values higher than 54.00 D.2-4 This has led several authors to consider corneal maximum steepness and corneal pachymetry as major parameters to evaluate the effectiveness and safety of the procedure for cases with specific indications.2-4
On the other hand, Raiskup et al demonstrated that infusion of a hypoosmolar riboflavin solution for CXL protected corneal tissue from stromal opacities, even in severe keratoconus cases with ultra-thin corneas.5 Furthermore, there was no reduction in the effectiveness of CXL when a hypoosmolar riboflavin solution was used to soak the cornea. We recently observed the same phenomenon in post-LASIK ectasia patients who had ultra-thin corneas due to previous refractive ablation and stromal thinning induced by ectasia.
In our study, the corneas of patients with post-LASIK ectasia were plumped with hypotonic riboflavin (hypoosmolar solution with riboflavin-5-phosphate) before CXL irradiation.6,7 No stromal opacities developed in these eyes, despite the fact that mean central corneal thickness (CCT) was less than the recognized safe cut-off depth of 400 μm in all cases. We noted, however, that the usual development of deep stromal opacities after CXL was related to a reduction of CCT measured at 1 month after CXL.
Based on our initial observation in post-LASIK ectasia patients, we decided to study CCT behavior after CXL in 45 patients with keratoconus (mean age, 27 years; range, 19–37 years). Each patient underwent a complete eye exam including UCVA and BCVA assessment, slit-lamp biomicroscopy, Goldmann tonometry, endothelial biomicroscopy (Konan Specular Microscope; Konan Medical Inc.), corneal topography, aberrometry (Nidek OPD-Scan, Optical Path Difference Platform; Nidek Co., Ltd.), optical tomography (Pentacam; Oculus Optikgeräte GmbH), corneal hysteresis (Ocular Response Analyzer; Reichert Ophthalmic Instruments), and anterior segment optical coherence tomography (OCT; Cirrus HD-OCT; Carl Zeiss Meditec). Corneal topography, corneal pachymetry, corneal hysteresis, and corneal resistance factor measurements were repeated during the procedure. Posterior stromal opacity formation was evaluated by anterior segment OCT up to 12 months postoperatively.
Pain medication was administered and 2% pilocarpine drops were instilled in the eye 30 minutes before the procedure to reduce the thermal and photochemical ultraviolet-A (UV-A) light irradiation potentially harmful to the lens and retina. After topical anesthesia with two applications of 4% lidocaine drops and oxybuprocaine HCl 0.2%, the patient was draped, the ocular surface was rinsed with balanced saline solution, and a lid speculum was applied. The corneal epithelium was abraded in a central, 9-mm diameter area with the aid of an Amoils brush.
Before beginning UV-A irradiation, photosensitizing riboflavin 0.1% solution (10 mg riboflavin-5-phosphate in 20% dextran-T-500 10 mL) was applied to the cornea every minute for 30 minutes to achieve adequate penetration of the solution. Using a slit lamp with a blue filter, the surgeon confirmed the presence of riboflavin in the anterior chamber before initiating irradiation.
After 20 minutes of soaking with 0.1% riboflavin solution, all corneas with a CCT of less than 350 μm were plumped to 400 μm with a hypoosmolar solution (riboflavin-5-phosphate) for a mean of 8 minutes. Intraoperative CCT measurements (Figure 1 and Table 1) were taken with ultrasound pachymetry after epithelial removal (t1), after 20 minutes of riboflavin infusion (t2), after corneal expansion (t3), and at the end of irradiation (t4).
The cornea was exposed to a UV-A light source emanating from a solid-state device (CBM XLinker; C.S.O.) that emits light at a wavelength of 370 ±5 nm and an irradiance of 3 mW/cm2 or 5.4 J/cm2. Exposure lasted 30 minutes, during which time riboflavin solution was reapplied once every 5 minutes. The cropped light beam has a diameter of 7.5 mm. A calibrated UV-A meter (LaserMate-Q; Laser 2000) was used before treatment to check the irradiance at 1 cm. Fixation during irradiation was achieved by instructing the patient to focus on the central green light of the probe. During the procedure, the surgeon also controlled for centration of treatment. Both topical anesthetics were added as needed during irradiation.
Postoperatively, patients received cyclopentolate (Ciclolux; Allergan, Inc.) and levofloxacin (Oftaquix; Tubilux Pharma) drops, and a soft bandage contact lens was applied until reepithelialization was complete. Topical levofloxacin was given four times daily for 7 days, dexamethasone 21-phosphate 0.15% drops (Etacortilen; Sifi) three times daily for 20 days, and 0.15% sodium hyaluronate drops (BluYal; Sooft) six times daily for 45 days. Additionally, all patients received oral aminoacid supplements (Trium; Sooft) for 7 days. Patients were examined every day until reepithelialization and at 1, 6, and 12 months thereafter.
No significant difference in CCT was seen after epithelial removal (P=.003); however, a mean reduction of 102.11 mm in CCT was measured after 20 minutes of riboflavin infusion (P<.00001). No significant change in CCT was measured at the end of corneal expansion (P=.51) or at the end of irradiation (P=.016).
Eyes were also divided into three groups of 15 according to preoperative CCT (group 1, fewer than 450 μm; group 2, 450– 500 μm; group 3, greater than 500 μm). The decrease in CCT after the first 20 minutes of riboflavin infusion was significantly higher in group 3 (28% vs 22% in group 1 and 25% in group 2). No complications were seen intraoperatively, and no early or late postoperative complications, such as deep stromal opacities, were seen for up to 1 year after CXL treatment.
We concluded that CCT reduction during the soaking phase could be a predictive factor for the potential development of stromal opacity after CXL.
Because CCT can be measured throughout the CXL procedure, we recommend testing each cornea, including those with postrefractive surgery ectasia or severe keratoconus, after the soaking phase. If the CCT is less than 350 μm, the corneal thickness should be increased using a hypoosmolar riboflavin solution to avoid stromal scar formation and visual impairment. It is also interesting to note that the thickest corneas thin at a higher rate than the thinnest, probably because thick corneas have more interlamellar and interfibrillar spaces and become more dehydrated during the CXL procedure.6,7
Elena Albé, MD, is a consultant in the Department of Ophthalmology, Cornea Service, Istituto Clinico Humanitas Ophthalmology Clinic, Milan, Italy. Dr. Albé is a member of the CRST Europe Editorial Board. She states that she has no financial interest in the products or companies mentioned. She may be reached at e-mail: firstname.lastname@example.org.
- Salomão MQ, Chaurasia SS, Sinha-Roy A, et al. Corneal wound healing after ultraviolet-A/riboflavin collagen cross-linking: A rabbit study. J Refract Surg. 2011;27(6):401-408.
- Hafezi F. Limitation of collagen cross-linking with hypoosmolar riboflavin solution: failure in an extremely thin cornea. Cornea. 2011;30(8):917-919.
- Spoerl E, Hoyer A, Pillunat LE, Raiskup F. Corneal cross-linking and safety issues. Open Ophthalmol J. 2011;5:14-16.
- Raiskup F, Spoerl E. Corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas. Am J Ophthalmol. 2011;152(1):28-32.
- Vinciguerra P, Camesasca FI, Albè E, Trazza S. Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg. 2009;22:1-12.
- Mencucci R, Marini M, Paladini I, et al. Effects of riboflavin/UVA corneal cross-linking on keratocytes and collagen fibres in human cornea. Clin Experiment Ophthalmol. 2010;38(1):49-56.
- Vinciguerra P, Albé E, Romano MR, et al. Stromal opacity after cross-linking. J Refract Surg. 2012;28(3):165.