Compaction of very thin corneas from ultraviolet A riboflavin-vitamin E transepithelial cross-linking.

The purpose of the study was to determine the decrease in pachymetry of very thin corneas with advanced keratoconus due to corneal compaction from the ultraviolet-A (UV-A) irradiation phase of transepithelial (epi-on) cross-linking. Twenty removed corneal buttons were obtained from patients who underwent penetrating keratoplasty for advanced keratoconus. Removed corneal buttons selected from among the post-surgical specimens for this study had intact epithelium, no scarring or surgical cautery, endothelial cell density >2500 cells/mm2, and average pachymetry over the measured points of below 400 µm. Corneas were mounted in a Franz chamber. Each epithelial surface was soaked in isotonic riboflavin and D-alpha-tocopheryl polyethylene glycol 1000 succinate (Ribocross® IROMED Group, Italy) for 15 min. Pachymetry was measured at three points over both the shielded and unshielded corneal halves for each corneal button. Surfaces were then washed in saline to remove the Ribocross®. Shields from UV-A irradiation over half of each cornea were then fixed to stand 5 mm above the test corneas. UV-A irradiation using the custom fast cross-linking (CF-CXL) protocol was then performed for the typical 10 ± 1.5 min, for a total energy of 1.08 ± 0.6 J/cm2 after which pachymetry was re-measured. The average percent change in pachymetry was -0.43% ± 0.38% (maximum -1.06%) in the shielded half. Pachymetry change was -6.2% ± 2.2% (maximum 12%) in the cross-linked halves. In conclusion, we estimate that the change in corneal thickness from corneal compaction due to the cross-linking reaction itself was -5.8% ± 2.2%. Scanning electron microscopy of cross-linked corneal segments showed stromal fiber contraction.

Topography and Pachymetry Guided, Rapid Epi-on Corneal Cross-Linking for Keratoconus: 7-year Study Results.

PURPOSE: To evaluate custom fast cross-linking (cfCXL) treatment of keratoconus. METHODS: "Custom fast cross-linking" or "cfCXL" is a keratoconus treatment algorithm featuring no epithelial disruption, 15 minutes of corneal presoaking with a riboflavin-vitamin E TPGS solution, and a 370-nm ultraviolet A radiation beam centered on the most highly curved corneal region. Ultraviolet A radiation beam fluence, total energy, and exposure time are significantly less than those in the Dresden protocol. In this study, refraction, spectacle-corrected distance visual acuity, Kmax, and corneal hysteresis were monitored in 81 eyes of 81 patients for 7 years with 100% follow-up. Pretreatment Kmax and patient age averaged 53.01 ± 4.87 D and 25.9 ± 4.7 years, respectively. RESULTS: Average refractive cylinder magnitude was reduced by 26.1% at 1 month postoperatively and by 44.2% at 7 years postoperatively. Logarithm of the minimum angle of resolution average spectacle-corrected distance visual acuity (best spectacle-corrected distance visual acuity) improved from +0.26 ± 0.34 (20/36.4) to +0.15 ± 0.23 (20/28.25), +0.05 ± 0.20 (20/22.4), and +0.06 ± 0.20 (20/22.96) at 1 month, 1 year, and 7 years postoperatively, respectively. Best spectacle-corrected distance visual acuity improved in 54.3%, 74.1%, 84.0%, 87.7%, 84.0%, 84.0%, and 82.7% of patients at postoperative months 1, 3, 6, 12, 24, 48, and 84, respectively. Kmax did not increase in 96.3% of patients at 1 month, 97.5% at 1 year, and 98.8% at 7 years postoperatively, with average corneal apex flattening at 1 month and 7 years of -2.79 ± 1.70 D and -4.00 ± 2.40 D, respectively. CONCLUSIONS: Custom fast cross-linking, epi-on, rapid, narrowed beam apex-centered treatment of keratoconus with riboflavin-vitamin E TPGS produced a significant, rapid, and lasting cone progression stoppage, astigmatism reduction, and visual acuity improvement.

Customized Corneal Cross-Linking-A Mathematical Model.

PURPOSE: To improve the safety, reproducibility, and depth of effect of corneal cross-linking with the ultraviolet A (UV-A) exposure time and fluence customized according to the corneal thickness. METHODS: Twelve human corneas were used for the experimental protocol. They were soaked using a transepithelial (EPI-ON) technique using riboflavin with the permeation enhancer vitamin E-tocopheryl polyethylene glycol succinate. The corneas were then placed on microscope slides and irradiated at 3 mW/cm for 30 minutes. The UV-A output parameters were measured to build a new equation describing the time-dependent loss of endothelial protection induced by riboflavin during cross-linking, as well as a pachymetry-dependent and exposure time-dependent prescription for input UV-A fluence. The proposed equation was used to establish graphs prescribing the maximum UV-A fluence input versus exposure time that always maintains corneal endothelium exposure below toxicity limits. RESULTS: Analysis modifying the Lambert-Beer law for riboflavin oxidation leads to graphs of the maximum safe level of UV-A radiation fluence versus the time applied and thickness of the treated cornea. These graphs prescribe UV-A fluence levels below 1.8 mW/cm for corneas of thickness 540 µm down to 1.2 mW/cm for corneas of thickness 350 µm. Irradiation times are typically below 15 minutes. CONCLUSIONS: The experimental and mathematical analyses establish the basis for graphs that prescribe maximum safe fluence and UV-A exposure time for corneas of different thicknesses. Because this clinically tested protocol specifies a corneal surface clear of shielding riboflavin on the corneal surface during UV-A irradiation, it allows for shorter UV-A irradiation time and lower fluence than in the Dresden protocol.

Corneal Cross-Linking: Evaluating the Potential for a Lower Power, Shorter Duration Treatment.

PURPOSE: To determine the cross-linking effect of a riboflavin ultraviolet-A (UV-A) corneal cross-linking treatment that is both shorter and has lower energy than the Dresden protocol. METHODS: In a first experiment, 12 human corneas were presoaked with riboflavin and then irradiated with UV-A at 3 mW/cm after clearing the surface of riboflavin, with no added riboflavin during irradiation. Percent UV-A transmission through the corneas was measured at intervals up to 30 minutes. A second experiment involved 24 porcine corneas. Eight were de-epithelialized, presoaked in riboflavin for 30 minutes, and irradiated at 1.5 mW/cm for 10 minutes. An additional 8 were riboflavin treated and similarly irradiated, but with epithelium intact and a final 8 corneas were not treated. Young modulus was measured in all 24 corneas at the end of the experiment. RESULTS: The first experiment showed essentially complete riboflavin oxidation after only 10 minutes. Based on these results, a shortened UV-A exposure cross-linking experiment was designed using a reduced UV-A fluence of 1.5 mW/cm, an endothelial exposure within safety limits in humans. With this protocol Young modulus was the same in the irradiated porcine corneas but with epithelium intact as in the untreated corneas. In contrast, Young modulus increased by a factor of 1.99 in the UV-A cross-linked corneas at 1.5 mW/cm for 10 minutes with the epithelium removed. CONCLUSIONS: A shorter, lower energy protocol than the Dresden protocol seems to provide a significant increase in Young modulus, similar to published results with higher energy, longer exposure protocols.

Transepithelial Corneal Cross-Linking With Vitamin E-Enhanced Riboflavin Solution and Abbreviated, Low-Dose UV-A: 24-Month Clinical Outcomes.

PURPOSE: To report the clinical outcomes with 24-month follow-up of transepithelial cross-linking using a combination of a D-alpha-tocopheryl polyethylene-glycol 1000 succinate (vitamin E-TPGS)-enhanced riboflavin solution and abbreviated low fluence UV-A treatment. METHODS: In a nonrandomized clinical trial, 25 corneas of 19 patients with topographically proven, progressive, mild to moderate keratoconus over the previous 6 months were cross-linked, and all patients were examined at 1, 3, 6, 12, and 24 months. The treatments were performed using a patented solution of riboflavin and vitamin E-TPGS, topically applied for 15 minutes, followed by two 5-minute UV-A treatments with separate doses both at fluence below 3 mW/cm(2) that were based on preoperative central pachymetry. RESULTS: During the 6-month pretreatment observation, the average Kmax increased by +1.99 ± 0.29 D (diopter). Postoperatively, the average Kmax decreased, changing by -0.55 ± 0.94 D, by -0.88 ± 1.02 D and by -1.01 ± 1.22 D at 6, 12, and 24 months. Postoperatively, Kmax decreased in 19, 20, and 20 of the 25 eyes at 6 months, 12 months, and 24 months, respectively. Refractive cylinder was decreased by 3 months postoperatively and afterward, changing by -1.35 ± 0.69 D at 24 months. Best spectacle-corrected visual acuity (BSCVA) improved at 6, 12, and 24 months, including an improvement of -0.19 ± 0.13 logarithm of the minimum angle of resolution units at 24 months. There was no reduction in endothelial cell count. No corneal abrasions occurred, and no bandage contact lenses or prescription analgesics were used during postoperative recovery. CONCLUSIONS: Transepithelial cross-linking using the riboflavin-vitamin E solution and brief, low-dose, pachymetry-dependent UV-A treatment safely stopped keratoconus progression.

Pentacam HR criteria for curvature change in keratoconus and postoperative LASIK ectasia.

PURPOSE: To determine criteria for keratoconus or postoperative LASIK ectasia progression or improvement based on Pentacam HR (Oculus Optikgeräte GmbH) measured steepest corneal curvature. METHODS: Sixty-one eyes from 41 patients with keratoconus or postoperative LASIK ectasia were evaluated. Each eye was measured 5 times with the Pentacam HR during the same clinic visit and the random measurement variations of Rmin(back) and maximal keratometry (Kmax; mathematically linked to Rmin[front]) were statistically analyzed. Confidence levels for diagnosing true curvature change were determined for 3 typical clinical situations differing by the number of available Pentacam measurements. RESULTS: With a single past and single present Pentacam HR measurement available (situation 1+1), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 1.51 diopters (D), 0.162 mm, and 0.290 mm, respectively. With one prior and the average of five present Pentacam measurements (situation 5+1), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 1.17 D, 0.126 mm, and 0.225 mm, respectively. With the average of five past and five present measurements (situation 5+5), the 95% confidence levels of true change for ΔKmax, ΔRmin(front), and ΔRmin(back) were 0.68 D, 0.072 mm, and 0.130 mm, respectively. CONCLUSIONS: Steepest corneal curvature changed with 95% confidence if the difference between single past and present Kmax exceeded 1.51 D. With the advantage of five past and five present measurements, 95% confidence of real Kmax change occurs at a 0.68-D difference.