Optimizing Corneal Cross-Linking in the Treatment of Keratoconus: A Comparison of Outcomes After Standard- and High-Intensity Protocols.

PURPOSE: To evaluate and compare the safety and efficacy of accelerated (AXL) and standard corneal cross-linking (CXL) protocols in patients with progressive keratoconus. METHODS: Progressive keratoconus patients (14-40 years) received either standard-intensity CXL or high-intensity CXL (AXL). Corneas were exposed to ultraviolet-A 365 nm light for 30 minutes at an irradiance of 3.0 mW/cm in the standard CXL group and to ultraviolet-A 365 nm light for 10 minutes at 9.0 mW/cm in the AXL group. Changes in uncorrected visual acuity, best spectacle-corrected visual acuity, refractive astigmatism, Kmax, and Kmean were used to determine treatment efficacy. Safety was determined by the incidence of adverse events and occurrence of loss of 2 or more lines of best spectacle-corrected visual acuity. Outcomes for CXL versus AXL were compared to determine differences in safety and efficacy between treatment groups. RESULTS: Thirty-six eyes of 34 patients (mean age, 27.9 ± 7.6 years) underwent AXL; 66 eyes of 53 patients (mean age, 30.0 ± 8.0 years) underwent standard-intensity CXL. There was no significant difference in any outcome measures between the groups. For AXL, there seemed to be more corneal flattening, with a statistically significant reduction in Kmean at 6 and 12 months postoperatively, when compared preoperatively (P < 0.01). There were no adverse events or complications in any patients. CONCLUSIONS: There was more corneal flattening in AXL patients 6 to 12 months postoperatively, suggesting that AXL may be a promising alternative to CXL in stabilizing corneal ectasia.

Rate of riboflavin diffusion from intrastromal channels before corneal crosslinking.

PURPOSE: To determine the diffusion of riboflavin from intrastromal channels through the effective diffusion coefficients compared with traditional axial diffusion with epithelium on or off. SETTING: Advanced Optical Imaging Laboratory, University College Dublin, and Wellington Eye Clinic, Sandyford, Dublin, Ireland. DESIGN: Experimental study. METHODS: The rate of diffusion in whole-mounted porcine eyes was monitored for a 30 minutes using an optical setup with a charge-coupled device camera and a bandpass filter (central wavelength 550 nm and 40 nm bandpass) to image the fluorescence under ultraviolet illumination (365 nm wavelength). For comparison, an isotropic corneal stroma with an annular channel was modeled numerically for different diffusion constants and boundary conditions. RESULTS: Numerical and experimental results were compared, allowing determination of the effective diffusion coefficient for each case. Experimental results for 6 different riboflavin solutions were in all cases found to be higher than for the common crosslinking (CXL) riboflavin protocol, where the diffusion constant is D0 = 6.5 × 10(-5) mm(2)/sec. For the intrastromal channel, 2 isotonic solutions containing riboflavin 0.1% correlated with a diffusion constant of 5D0 = 32.5 × 10(-5) mm(2)/sec. Hypotonic solutions and transepithelium had a higher diffusion coefficient approaching 10D0 = 65.0 × 10(-5) mm(2)/sec, which is an order-of-magnitude increase compared with the typical diffusion coefficient found in standard CXL. CONCLUSIONS: In this study, riboflavin had a faster stromal diffusion when injected into a corneal channel than when applied as drops to the anterior corneal surface. Further numerical modeling might allow optimization of the channel structure for any specific choice of riboflavin.

Second-harmonic reflection imaging of normal and accelerated corneal crosslinking using porcine corneas and the role of intraocular pressure.

PURPOSE: The aim of this study was to investigate morphological changes, using second-harmonic (SH) optical imaging, in the corneal stroma after normal- and high-intensity collagen crosslinking in postmortem enucleated porcine eyes at controlled intraocular pressures (IOPs). METHODS: Reflection-mode SH optical imaging of the stroma was realized after standard collagen cross-linking (CXL) and accelerated crosslinking (AXL) of porcine corneas, and the results were compared with the results for untreated controls. Ultraviolet-X lamps (365 nm) were used during riboflavin crosslinking with intensities of 3, 10, 30, and 100 mW/cm2 for constant 5.4-J/cm2 exposure doses. The IOP was varied using saline solution injected through the optic nerve and monitored using a Schiotz tonometer. SH optical imaging was realized with an in-house build multiphoton microscope using an ultrafast dispersion-compensated Ti-sapphire laser. RESULTS: SH reflection images of CXL and AXL porcine corneas obtained at IOPs of 8, 11, 16, and 26 mm Hg showed a similar fibrillar structure of collagen lamellae. All crosslinked corneas showed an increased fibrillar contrast in comparison with untreated baseline images. At low IOPs, strong variations in the scattering were observed that reduced with an increase in the IOP, when fibrils tended to straighten out. At low and normal IOPs, no significant difference between CXL and AXL results could be observed. At very elevated IOPs, however, the impact of AXL was found to alter the fibrillar structure of the collagen becoming less apparent in SH images when compared with that of CXL. CONCLUSIONS: We found a strong influence of the IOP on SH reflection imaging of postmortem porcine corneal stroma. CXL and AXL led to similar SH images indicative of a similar tensile strength. Only at very elevated IOPs (26 mm Hg) did the results for AXL deviate from those of CXL, suggesting an IOP-related threshold for reliable applications of AXL.

The theory and art of corneal cross-linking.

Before the discovery of corneal cross-linking (CXL), patients with keratoconus would have had to undergo corneal transplantation, or wear rigid gas permeable lenses (RGPs) that would temporarily flatten the cone, thereby improving the vision. The RGP contact lens (CL) would not however alter the corneal stability and if the keratoconus was progressive, the continued steepening of the cone would occur under the RGP CL. To date, the Siena Eye has been the largest study to investigate long term effects of standard CXL. Three hundred and sixty-three eyes were treated and monitored over 4 years, producing reliable long-term results proving long-term stability of the cornea by halting the progression of keratoconus, and proving the safety of the procedure. Traditionally, CXL requires epithelial removal prior to corneal soakage of a dextran-based 0.1% riboflavin solution, followed by exposure of ultraviolet-A (UV-A) light for 30 min with an intensity of 3 mW/cm2. A series of in vitro investigations on human and porcine corneas examined the best treatment parameters for standard CXL, such as riboflavin concentration, intensity, wavelength of UV-A light, and duration of treatment. Photochemically, CXL is achieved by the generation of chemical bonds within the corneal stroma through localized photopolymerization, strengthening the cornea whilst minimizing exposure to the surrounding structures of the eye. In vitro studies have shown that CXL has an effect on the biomechanical properties of the cornea, with an increased corneal rigidity of approximately 70%. This is a result of the creation of new chemical bonds within the stroma.

Newer protocols and future in collagen cross-linking.

Corneal Cross-Linking (CXL) is an established surgical procedure for the treatment of corneal disorders such as corneal ectasia and keratoconus. This method of treatment stabilises the corneal structure and increases rigidity, reducing the requirement for corneal transplantation. Since its development, many scientific studies have been conducted to investigate ways of improving the procedure. Biomechanical stability of the cornea after exposure to UV-A light, and the effect of shortening procedure time has been some of the many topics explored.