Faculty Bibliography

BACKGROUND:Corneal cross-linking (CXL) using ultraviolet light-A (UV-A) and riboflavin is a technique developed in the 1990's to treat corneal ectatic disorders such as keratoconus. It soon became the new gold standard in multiple countries around the world to halt the progression of this disorder, with good long-term outcomes in keratometry reading and visual acuity. The original Dresden treatment protocol was also later on used to stabilize iatrogenic corneal ectasia appearing after laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK). CXL efficiently strengthened the cornea but was also shown to kill most of the keratocytes within the corneal stroma, later on repopulated by those cells. REVIEW/METHODS:Ultraviolet-light has long been known for its microbicidal effect, and thus CXL postulated to be able to sterilize the cornea from infectious pathogens. This cytotoxic effect led to the first clinical trials using CXL to treat advanced infectious melting corneal keratitis. Patients treated with this technique showed, in the majority of cases, a stabilization of the melting process and were able to avoid emergent à chaud keratoplasty. Following those primary favorable results, CXL was used to treat beginning bacterial keratitis as a first-line treatment without any adjunctive antibiotics with positive results for most patients. In order to distinguish the use of CXL for infectious keratitis treatment from its use for corneal ectatic disorders, a new term was proposed at the 9th CXL congress in Dublin to rename its use in infections as photoactivated chromophore for infectious keratitis -corneal collagen cross-linking (PACK-CXL). CONCLUSION/CONCLUSIONS:PACK-CXL is now more frequently used to treat infections from various infectious origins. The original Dresden protocol is still used for this purpose. Careful modifications of this protocol could improve the efficiency of this technique in specific clinical situations regarding certain types of pathogens.

PURPOSE/OBJECTIVE:To compare the long-term outcomes of accelerated and standard corneal cross-linking protocols in the treatment of progressive keratoconus. DESIGN/METHODS:Prospective randomized clinical trial. METHODS:Thirty-one eyes with keratoconus were treated with an accelerated protocol (18 mW/cm(2), 5 min) and all contralateral eyes were treated with the standard method (3 mW/cm(2), 30 min) using the same overall fluence of 5.4 J/cm(2). RESULTS:At 18 months after the procedure, the standard group showed significant improvement in spherical equivalent (P < .05), K-readings (P < .05), Q value (P < .05), index of surface variance (P < .05), and keratoconus index (P = .008) and decline in central corneal thickness (P < .05), but no significant change in visual acuity, corneal hysteresis, corneal resistance factor, P2 area, or endothelial cell density. In the accelerated group, central corneal thickness was the only parameter with statistically significant change. However, neither of these parameters showed significant differences between the standard and the 18 mW/cm(2) accelerated protocol, except K-reading (P = .059) and index surface variance (P = .034). CONCLUSION/CONCLUSIONS:An accelerated cross-linking protocol, using 18 mW/cm(2) for 5 minutes, shows a comparable outcome and safety profile when compared to the standard protocol, but better corneal flattening is achieved with the standard method than the accelerated method. Overall, both methods stop the disease progression similarly. This study will continue to examine more long-term results.

PURPOSE/OBJECTIVE:To compare the currently available ultraviolet-A (UV-A) corneal cross-linking (CXL) treatment protocols for thin corneas with respect to oxygen, UV fluence, and osmotic pressure. METHODS:Freshly enucleated murine (n = 16) and porcine (n = 16) eyes were used. The dependency on oxygen and the amount of UV absorption were evaluated using different CXL protocols, including standard CXL, contact lens-assisted CXL (caCXL), and CXL after corneal swelling. The CXL protocol was adapted from the treatment parameters of the human cornea to fit the thickness of murine and porcine corneas. Immediately after CXL, the corneas were subjected to biomechanical testing, including preconditioning, stress relaxation at 0.6 MPa, and stress-strain extensiometry. A two-element Prony series was fitted to the relaxation curves for viscoelastic characterization. RESULTS:Standard CXL was most efficient; prior corneal swelling reduced the long-term modulus by 6% and caCXL by 15% to 20%. Oxygen reduction decreased the long-term modulus G∞ by 14% to 15% and the instantaneous modulus G0 by 2% to 5%, and increased the short-term modulus G2 by 22% to 31%. Reducing the amount of absorbed UV energy decreased the long-term modulus G∞ by 5% to 34%, the instantaneous modulus G0 by 7% to 29%, and the short-term modulus G2 by 17% to 20%. The amount of absorbed UV light was more important in porcine than in murine corneas. CONCLUSIONS:The higher oxygen availability in thin corneas potentially increases the overall efficacy of riboflavin UV-A CXL compared to corneas of standard thickness. Clinical protocols for thin corneas should be revised to implement these findings.

OBJECTIVE:The objective of this study was to analyse the failure mode of adhesive interfaces by comparing OCT and scanning electron microscope (SEM) analysis of class V restoration margins located on enamel and dentin. MATERIALS AND METHODS/METHODS:Three groups were tested that differed in the application of a 3-step etch-and-rinse adhesive system (OptiBond FL) prior to cavity filling with restorative composite resin (Clearfil AP-X). After tooth restoration and polishing, the samples were loaded in a fatigue machine, and adhesive interfaces were evaluated with OCT and SEM. RESULTS:Important and complementary information could be obtained with OCT analysis in respect to how marginal defects can propagate inside the cavity, compromising the restoration's long-term performance. A self-etching effect was observed with OptiBond FL due to the presence of an acidic primer (GPDM) within its composition. Our results could show that areas of bonding and gaps coexisted within the same restoration. CONCLUSIONS:When marginal imperfections, or non-continuous margins, were detected by SEM, also imperfections beneath the surface could be observed at the tooth-restoration interface with OCT. Restoration loss occurred above the borderline of 50% of marginal gaps on enamel and dentin. CLINICAL RELEVANCE/CONCLUSIONS:Marginal discrepancies of adhesive restorations can propagate inside the cavity and lead to restoration loss.

In vivo confocal microscopy (IVCM) findings of 84 patients who had undergone conventional epithelium-off corneal collagen crosslinking (CXL) and accelerated CXL (ACXL) were retrospectively reviewed. Analysis confirmed that despite a significant decrease in the mean density of anterior keratocytes in the first 6 postoperative months, cell density after CXL and ACXL returned to baseline values at 12 months. The demarcation lines observed after treatments represent an expression of light-scattering (reflectivity changes) through different tissue densities. Temporary haze of the anterior-mid stroma after conventional CXL represents an indirect sign of CXL-induced stromal collagen compaction and remodeling. IVCM showed that treatment penetration varies to some extent, but that the endothelium is not damaged and is correlated with CXL biomechanical effects. IVCM of limbal structures shows no evidence of pathological changes. Regeneration of subepithelial and stromal nerves was complete 12 months after the operation with fully restored corneal sensitivity and no neurodystrophic occurrences. IVCM allowed detailed high magnification in vivo micromorphological analysis of corneal layers, enabling the assessment of early and late corneal modifications induced by conventional and accelerated CXL. IVCM confirms that CXL is a safe procedure, which is still undergoing development and protocol adjustments.

PURPOSE/OBJECTIVE:To establish corneal cross-linking (CXL) with riboflavin and UV-A in in the mouse cornea in vivo and to develop tools to measure the biomechanical changes observed. METHODS:A total of 55 male C57BL/6 wild-type mice (aged 5 weeks) were divided into 14 groups. Standard CXL parameters were adapted to the anatomy of the mouse cornea, and riboflavin concentration (0.1%-0.5%) and fluence series (0.09-5.4 J/cm²) were performed on the assumption of the endothelial damage thresholds. Untreated and riboflavin only corneas were used as controls. Animals were killed at 30 minutes and at 1 month after CXL. Corneas were harvested. Two-dimensional (2D) biomechanical testing was performed using a customized corneal holder in a commercially available stress-strain extensometer/indenter. Both elastic and viscoelastic analyses were performed. Statistical inference was performed using t-tests and specific mathematical models fitted to the experimental stress-strain and stress-relaxation data. Adjusted P values by the method of Benjamini and Hochberg are reported. RESULTS:For all CXL treatment groups, stress-relaxation showed significant differences (P < 0.0001) after 120 seconds of constant strain application, with cross-linked corneas maintaining a higher stress (441 ± 40 kPa) when compared with controls (337 ± 39 kPa). Stress-strain analysis confirmed these findings but was less sensitive to CXL-induced changes: at 0.5% of strain, cross-linked corneas remained at higher stress (778 ± 111 kPa) when compared with controls (659 ± 121 kPa). CONCLUSIONS:Cross-linking was induced in the mouse cornea in vivo, and its biomechanical effect successfully measured. This could create opportunities to study molecular pathways of CXL in transgenic mice.

PURPOSE/OBJECTIVE:Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. DESIGN/METHODS:The study is a multicenter, single-arm, prospective clinical trial. PARTICIPANTS/METHODS:There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). METHODS:The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES/METHODS:The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. RESULTS:A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. CONCLUSIONS:The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.