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.

Model for Optimization of the UV-A/Riboflavin Strengthening (cross-linking) of the Cornea: Percolation Threshold.

To achieve the maximum level of collagen strengthening within the shortest treatment time possible, we have developed a mathematical model which is used to optimize the process of corneal cross-linking. This model is able to predict the temporal and spatial distribution of generated cross-links within the corneal stroma and hence the increase in the elasticity modulus. Theory predicts corneal strengthening at low radiation intensities and the absence of the strengthening effect at radiation intensities above the threshold level, which agrees with the experimental results. The model takes account of the initial riboflavin concentration and bleaching, light intensity and time of illumination.

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.

Current status of accelerated corneal cross-linking.

Corneal cross-linking with riboflavin is a technique to stabilize or reduce corneal ectasia, in diseases such as keratoconus and post-laser-assisted in situ keratomileusis (LASIK) ectasia. There is an interest by patient as well as clinicians to reduce the overall treatment time. Especially, the introduction of corneal cross-linking in combination with corneal laser surgery demands a shorter treatment time to assure a sufficient patient flow. The principles and techniques of accelerated corneal cross-linking is discussed.

Corneal higher order aberrations after myopic wavefront-optimized ablation.

PURPOSE: To analyze the induced corneal higher order aberrations (HOAs) after wavefront-optimized ablation. METHODS: Sixty-four myopic eyes that underwent wavefront-optimized myopic LASIK were divided into three groups based on spherical equivalent (SE): low myopia group (23 eyes with SE <-3.00 diopters [D]); moderate myopia group (27 eyes with SE between -3.00 and -6.00 D); and high myopia group (14 eyes with SE >-6.00 D). Total corneal HOA, corneal spherical aberrations, corneal coma through a 6-mm pupil size, and corneal eccentricity were measured with a dual Scheimpflug imaging device preoperatively and 3 months after surgery. RESULTS: An overall increase in total corneal HOA was observed with a mean of 0.18±0.18 µm (P<.01), although this induction was not statistically significant in the low myopic group with a mean of 0.006±0.15 µm (P=.85). Root-mean-square spherical aberration varied the most after myopic ablation, with an overall induction of positive spherical aberration of 0.27±0.25 µm (P<.001). CONCLUSIONS: Although the wavefront-optimized profile was designed to preserve the preoperative HOAs of the total eye, a significant induction of the corneal HOAs after myopic treatment was observed. The magnitude of the induced corneal HOA was related to the amount of intended correction. Corneal wavefront profiles do not reflect the visual performance; however, they provide relevant information, which may help in optimizing new laser treatment algorithms.

The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time.

PURPOSE: Standard treatment in cases of progressive keratectasia is UV-triggered corneal cross-linking. For irradiances larger than 10 mW/cm(2) and treatment times below 10 minutes, the scientific proof of a biomechanical strengthening effect is insufficient. The authors investigated the biomechanical strengthening of ex vivo corneal tissue treated with irradiances between 3 mW/cm(2) and 90 mW/cm(2) and illumination times from 30 minutes to 1 minute, respectively. METHODS: A total of 100 porcine eyes received riboflavin + UV treatment (constant irradiation dose of 5.4 J/cm(2)) with different intensities and illumination times and were randomly assigned into 10 groups. A control group (80 eyes) was not irradiated but underwent the same treatment otherwise. Young's modulus at 10% strain was determined for each strip after uniaxial stress-strain measurement. A Kruskal-Wallis test was used for statistical analysis. RESULTS: A statistically significant difference (α = 0.01) was found between the median value of Young's modulus of the treatment groups up to 45 mW/cm(2) (illumination times from 30 minutes to 2 minutes) compared with the control group. There was no statistically significant difference between the treatment groups from 50 mW/cm(2) up to 90 mW/cm(2) (illumination times of less than 2 minutes) and the control group. CONCLUSIONS: The ex vivo results of corneal cross-linking performed in porcine corneas show that the Bunsen-Roscoe reciprocity law is only valid for illumination intensities up to 40 to 50 mW/cm(2) and illumination times of more than 2 minutes. Further experiments are necessary to validate these results for in vivo human corneal tissue. Additionally, safety aspects at high intensities must be investigated.

Initial surface temperature of PMMA plates used for daily laser calibration affects the predictability of corneal refractive surgery.

PURPOSE: To investigate the relevance of initial temperature of the polymethylmethacrylate (PMMA) plates used as a target for photoablation during calibration of excimer lasers performed in daily clinical routine. METHODS: An experimental argon fluoride excimer laser with a repetition rate of 1050 Hz, a radiant exposure of 500 mJ/cm², and single pulse energy of 2.1 mJ was used for photoablation of PMMA plates. The initial plate temperature varied from 10.1°C to 75.7°C. The initial temperature was measured with an infrared camera and the central ablation depth of a myopic ablation of -9.00 diopters (D) with an optical zone of 6.5 mm was measured by means of a surface profiling system. RESULTS: The ablation depth increased linearly from 73.9 to 96.3 µm within a temperature increase from 10.1°C to 75.7°C (increase rate of 0.3192 µm/K). The linear correlation was found to be significant (P<.05) with a coefficient of determination of R²=0.95. Based on these results and assuming a standard room temperature of 20°C, optimal plate temperature was calculated to be 15°C to 25°C to maintain an ablation within 0.25 D. CONCLUSIONS: The temperature of PMMA plates for clinical laser calibration should be controlled ideally within a range of approximately ±5°C, to avoid visually significant refractive error due to calibration error. Further experimental investigations are required to determine the influence of different initial corneal temperatures on the refractive outcome.

Optimization model for UV-riboflavin corneal cross-linking.

PURPOSE: To develop a theoretical model for riboflavin ultraviolet-A cross-linking treatment that can predict the increase in stiffness of the corneal tissue as a function of the ultraviolet intensity and riboflavin concentration distribution, as well as the treatment time. METHODS: A theoretical model for calculating the increase in corneal cross-linking (polymerization rate) was derived using Fick's second law of diffusion, Lambert-Beer's law of light absorption, and a photopolymerization rate equation. Stress-strain experiments to determine Young's modulus at 5% strain were performed on 43 sets of paired porcine corneal strips at different intensities (3-7 mW/cm²) and different riboflavin concentrations (0.0%-0.5%). The experimental results for Young's modulus increase were correlated with the simulated polymerization increase to determine a relationship between the model and the experimental data. RESULTS: This model allows the calculation of the one-dimensional spatial and temporal intensity and concentration distribution. The total absorbed radiant exposure, defined by intensity, concentration distribution, and treatment time, shows a linear correlation with the measured stiffness increase from which a threshold value of 1.7 J/cm² can be determined. The relative stiffness increase shows a linear correlation with the theoretical polymer increase per depth of tissue, as calculated by the model. CONCLUSIONS: This theoretical model predicts the spatial distribution of increased stiffness by corneal cross-linking and, as such, can be used to customize treatment, according to the patient's corneal thickness and medical indication.

Clinical results of topography-based customized ablations for myopia and myopic astigmatism.

PURPOSE: To evaluate clinical outcomes after primary treatments for myopia and myopic astigmatism with topography-based ablation profiles on the Allegretto Wave Eye-Q platform (Alcon Laboratories Inc). METHODS: Records of patients who underwent topography-guided, Q-adjusted LASIK were retrieved and analyzed. Patients with mean refractive spherical equivalent up to -16.00 diopters (D) and cylindrical errors up to 6.00 D were included (2051 eyes). Refractive outcomes and visual acuities were analyzed preoperatively and 3 months postoperatively. RESULTS: Manifest spherical refractive error decreased from -5.05 +/- 2.33 to +0.04 +/- 0.35 D. Manifest cylindrical refractive error decreased from 0.83 +/- 0.75 to 0.23 +/- 0.22 D. At 3 months postoperatively, 86.1% (1766 eyes) had a spherical equivalent refraction within +/- 0.50 D of targeted refraction. The number of eyes with uncorrected distance visual acuity of 20/16 and 20/20 was 851 (41.5%) and 1495 (72.9%), respectively. At 3 months, 0.10% (2 eyes) lost more than 2 lines of corrected distance visual acuity and a loss of 2 lines occurred in 0.24% (5 eyes). All patients who lost lines of visual acuity were found to have corneal erosions related to dryness and recovered vision on further follow-up. CONCLUSIONS: The results of this retrospective study demonstrate refractive predictability, efficacy, and safety comparable to other treatment modalities such as wavefront-optimized and wavefront-guided treatments. Results are also similar to those reported with other topography-guided systems.

Optical ray tracing-guided laser in situ keratomileusis for moderate to high myopic astigmatism.

PURPOSE: To assess the efficacy, safety, and predictability of an individualized laser in situ keratomileusis (LASIK) ablation profile based on an optical ray-tracing algorithm to treat moderate to high myopic astigmatism. SETTING: Ophthalmology centers in Zurich, Switzerland; Dublin, Ireland; and, Cologne, Germany. DESIGN: Multicenter clinical trail. METHODS: This 3-center study enrolled eyes with a manifest refraction sphere ranging from 0.50 to -10.25 diopters (D) and/or astigmatism ranging from 0.00 to -4.50 D. The intended outcome was plano in most eyes, undercorrection of 0.50 D in 1 eye, and undercorrection of 0.25 D in 2 eyes. Refractive outcomes were analyzed preoperatively and postoperatively at 1 day and 1 and 3 months. RESULTS: The study enrolled 127 eyes (71 patients). The mean manifest refraction was -5.92 D ± 1.72 (SD). By 3 months postoperatively, 15 eyes had been lost to follow-up and 1 eye was excluded from analysis because of early retreatment. Of the remaining 111 eyes, 93 (83.8%) had an uncorrected distance visual acuity (UDVA) of 20/20 or better. The mean manifest refraction spherical equivalent (MRSE) in all eyes was 0.03 ± 0.30 D. In 97 (87.4%), the MRSE was within ±0.50 D and in 107 (96.4%), within ±1.00 D. No eye lost 2 or more lines of corrected distance visual acuity. CONCLUSIONS: The new optical ray-tracing algorithm for individualized LASIK ablation profiles to treat moderate to high myopic astigmatism was efficacious, safe, and predictable. The UDVA in eyes with high myopic astigmatism was better than in those treated with wavefront-guided LASIK.

Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation.

PURPOSE: Ultraviolet (UV) corneal cross-linking is an accepted method for treating corneal ecstatic disorders. The authors evaluated whether a rapid treatment protocol (higher intensity and shorter irradiation time) could achieve the same increase in corneal stiffness as the currently used standard protocol. METHODS: Stress-strain measurements were performed on porcine corneal strips. The corneas (n = 72) were cut into three strips, each randomly receiving a different treatment: rapid (10 mW/cm(2), 9 minutes), standard (3 mW/cm(2), 30 minutes), or no (control, 0 mW/cm(2)) irradiation. After irradiation, the Young's modulus of each strip was determined. The results of the stress-strain measurements were analyzed statistically. RESULTS: Statistical analysis showed that, after irradiation, the median value of Young's modulus from both active treatment groups (rapid, 3.83 N/mm(2); standard, 3.88 N/mm(2)) was significantly higher (P < 0.05) than that of the control group (2.91 N/mm(2)). Treatment increased Young's modulus by a factor of 1.3. However, there was no significant difference (P = 0.43) between the rapid and standard groups in the median of Young's modulus. CONCLUSIONS: Rapid UV cross-linking treatment can be regarded as equivalent to the standard procedure in terms of increase in corneal stiffness. The new rapid protocol shortens the treatment duration by more than two thirds, from 30 to 9 minutes. The safety of the higher intensities must be addressed in further clinical studies.

Effect of air-flow on the evaluation of refractive surgery ablation patterns.

An Allegretto Eye-Q laser platform (Wavelight GmbH, Erlangen, Germany) was used to study the effect of air-flow speed on the ablation of artificial polymer corneas used for testing refractive surgery patterns. Flat samples of two materials (PMMA and Filofocon A) were ablated at four different air flow conditions. The shape and profile of the ablated surfaces were measured with a precise non-contact optical surface profilometer. Significant asymmetries in the measured profiles were found when the ablation was performed with the clinical air aspiration system, and also without air flow. Increasing air-flow produced deeper ablations, improved symmetry, and increased the repeatability of the ablation pattern. Shielding of the laser pulse by the plume of smoke during the ablation of plastic samples reduced the central ablation depth by more than 40% with no-air flow, 30% with clinical air aspiration, and 5% with 1.15 m/s air flow. A simple model based on non-inertial dragging of the particles by air flow predicts no central shielding with 2.3 m/s air flow, and accurately predicts (within 2 µm) the decrease of central ablation depth by shielding. The shielding effects for PMMA and Filofocon A were similar despite the differences in the ablation properties of the materials and the different full-shielding transmission coefficient, which is related to the number of particles ejected and their associated optical behavior. Air flow is a key factor in the evaluation of ablation patterns in refractive surgery using plastic models, as significant shielding effects are found with typical air-flow levels used under clinical conditions. Shielding effects can be avoided by tuning the air flow to the laser repetition rate.

Laboratory measurement of the absorption coefficient of riboflavin for ultraviolet light (365 nm).

PURPOSE: Corneal cross-linking (CXL) is an increasingly used treatment technique for stabilizing the cornea in keratoconus. Cross-linking (polymerization) between collagen fibrils is induced by riboflavin (vitamin B2) and ultraviolet light (365 nm). Although reported to reach a constant value at higher riboflavin concentrations, the Lambert-Beer law predicts a linear increase in the absorption coefficient. This work was carried out to determine absorption behavior at different riboflavin concentrations and to further investigate the purported plateau absorption coefficient value of riboflavin and to identify possible bleaching effects. METHODS: The Lambert-Beer law was used to calculate the absorption coefficient at various riboflavin concentrations. The following investigated concentrations of riboflavin solutions were prepared using a mixture of 0.5% riboflavin and 20% Dextran T500 dissolved in 0.9% sodium chloride solution: 0%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.08%, 0.1%, 0.2%, 0.3%, 0.4%, and 0.5%, and were investigated with and without aperture plate implementation. An additional test series measured the transmitted power at selected riboflavin concentrations over time. RESULTS: In diluted solutions, a linear correlation exists between the absorption coefficient and riboflavin concentration. The absorption coefficient reaches a plateau, but this occurs at a higher riboflavin concentration (0.1%) than previously reported (just above 0.04%). Transmitted light power increases over time, indicating a bleaching effect of riboflavin. CONCLUSIONS: The riboflavin concentration can be effectively varied as a treatment parameter in a considerably broader range than previously thought.

Technical aspects of the WaveLight FS200 femtosecond laser.

PURPOSE: To demonstrate the feasibility and technical features of the WaveLight FS200 femtosecond laser (WaveLight GmbH) in refractive and corneal laser surgery. METHODS: The reproducibility of femtosecond laser-created flap dimensions and channels used for corneal ring segment implantation were measured by means of an optical coherence tomography system in porcine corneas. The increase in the intraocular pressure (IOP) during applanation with the corneal interface was measured by means of an IOP sensor. The possibility of creating a channel for gas diffusion within the stroma was investigated to minimize opaque bubble layer formation. RESULTS: The technical features, such as optical design, pulse energy, and scanning algorithms at a high repetition rate, allow reproducibility for tissue cutting with a standard deviation of <10 µm in depth and 0.1 mm laterally. Intraocular pressure increases up to 150 mmHg during applanation. The use of a gas channel minimizes the creation of an opaque bubble layer during the femtosecond laser procedure. CONCLUSIONS: The WaveLight FS200 femtosecond laser provides a high reproducibility for cutting three-dimensional tissue structures. The IOP increase is comparable to other microkeratomes and femtosecond lasers. The minimized opaque bubble layers allow the surgeon to perform an excimer laser treatment immediately after FS200 flap creation.

Experimental setup to determine the pulse energies and radiant exposures for excimer lasers with repetition rates ranging from 100 to 1050 Hz.

PURPOSE: To evaluate the feasibility of surface profiling for central ablation depth measurements and determine experimentally the required single-pulse energies and radiant exposures to achieve equivalent central ablation depths on bovine corneas for a myopic correction of -6.00 diopters (optical zone 6.5 mm) performed with laser repetition rates ranging from 100 to 1050 Hz. SETTING: Institute for Refractive and Ophthalmic Surgery, Zurich, Switzerland, and WaveLight AG, Erlangen, Germany. METHODS: Freshly enucleated bovine corneas and poly(methyl methacrylate) (PMMA) plates were photoablated. The shot pattern for the myopic correction was maintained during all experiments; the pulse laser energy was adjusted to achieve equal ablation depths for all repetition rates. Pulse energy, radiant exposure, and pulse duration were monitored to determine the required laser parameter. RESULTS: The variations (standard deviation) of the profile measurements were +/-0.45 microm or less for PMMA and +/-1.50 microm or less for bovine corneas. Measurements with bovine corneas should be performed within 3 minutes or less to avoid larger variations in profile measurements. Increasing the repetition rate from 100 Hz to 1050 Hz required an increase in peak radiant exposure from 400 mJ/cm(2) to 530 mJ/cm(2) to achieve equal ablation for the myopic correction. The required increase in the mean radiant exposure ranged from 190 to 260 mJ/cm(2). CONCLUSIONS: Higher-repetition-rate excimer lasers require increased radiant exposure. Further experimental studies should be performed to determine the relevance of spatial and temporal spot positioning, ablation-plume dynamics, and temperature increases during high-repetition-rate laser treatments.