Novel Technique of Transepithelial Corneal Cross-Linking Using Iontophoresis in Progressive Keratoconus

In this work, the authors presented the techniques and the preliminary results at 6 months of a randomized controlled trial (NCT02117999) comparing a novel transepithelial corneal cross-linking protocol using iontophoresis with the Dresden protocol for the treatment of progressive keratoconus. At 6months, there was a significant average improvement with an average flattening of themaximum simulated keratometry reading of 0.72\ub11.20D(P = 0.01); in addition, corrected distance visual acuity improved significantly (P = 0.08) and spherical equivalent refraction was significantly lessmyopic (P = 0.02) 6months a\u17fter transepithelial corneal cross-linkingwith iontophoresis. The novel protocol using iontophoresis showed comparable resultswith standard corneal cross-linking to halt progression of keratoconus during 6-month follow-up. Investigation of the long-term RCT outcomes are ongoing to verify the efficacy of this transepithelial corneal cross-linking protocol and to determine if it may be comparable with standard corneal cross-linking in themanagement of progressive keratoconus

Epithelium-off corneal cross-linking surgery compared with standard care in 10- to 16-year-olds with progressive keratoconus: the KERALINK RCT

Background: Keratoconus is a disease of the cornea affecting vision that is usually first diagnosed in the first three decades. The abnormality of corneal shape and thickness tends to progress until the patient reaches approximately 30 years of age. Epithelium-off corneal cross-linking is a procedure that has been demonstrated to be effective in randomised trials in adults and observational studies in young patients. // Objectives: The KERALINK trial examined the efficacy and safety of epithelium-off corneal cross-linking, compared with standard care by spectacle or contact lens correction, for stabilisation of progressive keratoconus. // Design: In this observer-masked, randomised, controlled, parallel-group superiority trial, 60 participants aged 10–16 years with progressive keratoconus were randomised; 58 participants completed the study. Progression was defined as a 1.5 D increase in corneal power measured by maximum or mean power (K2) in the steepest corneal meridian in the study eye, measured by corneal tomography. // Setting: Referral clinics in four UK hospitals. // Interventions: Participants were randomised to corneal cross-linking plus standard care or standard care alone, with spectacle or contact lens correction as necessary for vision, and were monitored for 18 months. // Main outcome measures: The primary outcome was K2 in the study eye as a measure of the steepness of the cornea at 18 months post randomisation. Secondary outcomes included keratoconus progression, visual acuity, keratoconus apex corneal thickness and quality of life. // Results: Of 60 participants, 30 were randomised to the corneal cross-linking and standard-care groups. Of these, 30 patients in the corneal cross-linking group and 28 patients in the standard-care group were analysed. The mean (standard deviation) K2 in the study eye at 18 months post randomisation was 49.7 D (3.8 D) in the corneal cross-linking group and 53.4 D (5.8 D) in the standard-care group. The adjusted mean difference in K2 in the study eye was –3.0 D (95% confidence interval –4.93 D to –1.08 D; p = 0.002), favouring corneal cross-linking. Uncorrected and corrected differences in logMAR vision at 18 months were better in eyes receiving corneal cross-linking: –0.31 (95% confidence interval –0.50 to –0.11; p = 0.002) and –0.30 (95% confidence interval –0.48 to –0.11; p = 0.002). Keratoconus progression in the study eye occurred in two patients (7%) randomised to corneal cross-linking compared with 12 (43%) patients randomised to standard care. The unadjusted odds ratio suggests that, on average, patients in the corneal cross-linking group had 90% (odds ratio 0.1, 95% confidence interval 0.02 to 0.48; p = 0.004) lower odds of experiencing progression than those receiving standard care. Quality-of-life outcomes were similar in both groups. No adverse events were attributable to corneal cross-linking. // Limitations: Measurements of K2 in those eyes with the most significant progression were in some cases indicated as suspect by corneal topography device software. // Conclusions: Corneal cross-linking arrests progression of keratoconus in the great majority of young patients. These data support a consideration of a change in practice, such that corneal cross-linking could be considered as first-line treatment in progressive disease. If the arrest of keratoconus progression induced by corneal cross-linking is sustained in longer follow-up, there may be particular benefit in avoiding the later requirement for contact lens wear or corneal transplantation. However, keratoconus does not continue to progress in all patients receiving standard care. For future work, the most important questions to be answered are whether or not (1) the arrest of keratoconus progression induced by corneal cross-linking is maintained in the long term and (2) the proportion of those receiving standard care who show significant progression increases with time

The Use of Corneal Cross-linking in Treatment of Progressive Keratoconus: a Review

AbstractKeratoconus is a common corneal ectatic disorder which affects approximately 1 in 2,000 people. The traditional treatments for keratoconus are the use of inserts, deep anterior lamellar keratoplasty (DALK) and anterior lamellar keratoplasty (ALKP). Corneal cross-linking is a relatively new minimally invasive therapeutic approach for treatment of progressive keratoconus, which increases the structural integrity of the cornea. In corneal cross-linking the production of oxygen free radicals by ultraviolet A (UVA) light increases the biomechanical strength of cornea while riboflavin acts as a photo synthesizer for production of oxygen free radicals by UVA. Treatment of progressive keratoconus is the most widespread use of cross-linking technique. In the present manuscript we will summarize different aspects of the utilization of cross-linking in treatment of corneal keratoconus. Keywords: Corneal Cross-linking; Treatment; Progressive; Keratoconu

Macular phototoxicity after corneal cross-linking

Purpose: To assess potential vascular, structural, and functional changes to the macula in patients with keratoconus that underwent ultraviolet A (UVA)-riboflavin-mediated corneal collagen cross-linking (CXL) therapy. Patients and methods: Seventeen eyes from 17 patients of age 16 years or older with keratoconus undergoing CXL treatment were studied. The same eye served as its own control (before CXL vs after CXL). Eyes were evaluated in terms of best-corrected visual acuity (BCVA), refractive error, intraocular pressure, Amsler grid, retinography, fluorescein angiography, autofluorescence, and spectral domain optical coherence tomography (SD-OCT) prior to CXL and 7 and 30 days after treatment. Multifocal electroretinography (mfERG) was recorded prior to and 7 days after CXL. Results: Mean (SD) BCVA by logMAR chart was 0.47 (+/-0.12) pre-CXL, 0.55 (+/-0.15) 7 days post-CXL (P=0.57), and 0.46 (+/-0.10) 30 days post-CXL (P=0.87). Mean (SD) SD-OCT central macular thickness (microm) was 253.62 (+/-20.9) pre-CXL, 260.5 (+/-18.7) 7 days post-CXL (P=0.48), and 256.44 (+/-21.6) 30 days post-CXL (P=0.69). In 12 eyes, mfERG revealed a statistically significant increase (P=0.0353) in P1 latency (ms) of ring four from the pre-CXL period (39.45+/-2.05) to 7 days post-CXL (41.04+/-1.28) period. Regression analysis showed that the increase in P1 latency was correlated with the increase in central macular thickness (P=0.027). Furthermore, nine patients experienced a significant decrease in P1 amplitudes of rings 1 (P=0.0014), 2 (P=0.0029), 3 (P=0.0037), 4 (P=0.0014), and 5 (P=0.0012) from pre-CXL to 7 days post-CXL. Conclusion: In this pilot study, most of the patients exhibited slight changes in their mfERG parameters and OCT thickness, despite a lack of vascular abnormalities observed on fluorescein angiography/autofluorescence imaging, no alteration in BCVA, and no reports of symptoms. These changes could, therefore, be categorized as a mild subclinical effect of the corneal cross-linking procedure

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/cm2 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/cm2 for corneas of thickness 540 [mu]m down to 1.2 mW/cm2 for corneas of thickness 350 [mu]m. 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

Additional Applications of Corneal Cross Linking

Corneal collagen cross-linking (CxL) is a prevalent surgical method for the management of keratoconus. However, literature suggests that, further to keratoconus, CxL has a beneficial impact on a series of corneal related diseases and states

Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus

Background: Corneal cross-linking is widely used to treat keratoconus. However, to date, only limited data from randomized trials support its efficacy. Methods: The efficacy and safety of corneal cross-linking for halting progression of keratoconus were investigated in a prospective, randomized, blinded, placebo controlled, multicentre trial. Twenty-nine keratoconus patients were randomized in three trial centres. The mean age at inclusion was 28 years. Longitudinal changes in corneal refraction were assessed by linear regression. The best corrected visual acuity, surface defects and corneal inflammation were also assessed. These data were analysed with a multifactorial linear regression model. Results: A total of 15 eyes were randomized to the treatment and 14 to the control group. Follow-up averaged 1098 days. Corneal refractive power decreased on average (+/-standard deviation) by 0.35 +/- 0.58 dioptres/year in the treatment group. The controls showed an increase of 0.11 +/- 0.61 dioptres/year. This difference was statistically significant (p = 0.02). Conclusions: Our data suggest that corneal cross-linking is an effective treatment for some patients to halt the progression of keratoconus. However, some of the treated patients still progressed, whereas some untreated controls improved. Therefore, further investigations are necessary to decide which patients require treatment and which do not

Corneal stromal demarcation line after collagen cross-linking in corneal ectatic diseases: a review of the literature

Collagen cross-linking (CXL) is a relatively new conservative approach for progressive corneal ectasia, which is able to strengthen corneal tissue reforming new covalent bonds. Subjective and objective results following this method seem to be promising. In recent years, newer CXL protocols have been developed to perform more effective and less invasive procedures. The increasing diffusion of CXL in the corneal ectatic disease has increased the need to have actual indices regarding the efficacy of the treatment. Evaluation of demarcation line (DL), a transition zone between the cross-linked anterior corneal stroma and the untreated posterior corneal stroma, is considered a measurement of the depth of CXL treatment into the stroma. Some evidence in the literature emphasize that DL could be a measure of effectiveness of the CXL. On the contrary, some authors believe that the "the deeper, the better" principle is rather a simplistic approach for interpreting the clinical importance of the corneal stromal DL

Morphological and Immunohistochemical Changes After Corneal Cross-Linking

Purpose: To present light and electron microscopic as well as immunohistochemical findings after corneal cross-linking (CXL). Methods: Six keratoconus corneas after CXL, 12 keratoconus corneas without CXL, and 7 normal corneas were examined by light microscopy, indirect immunohistochemistry using antibodies against proapoptotic BAX, antiapoptotic survivin, and BCL-2, and anti-smooth muscle actin and, in part, by transmission electron microscopy. Direct immunofluorescence with 4'6-diamidino-2-phenylindole was performed to analyze keratocytes/area in the anterior, middle, posterior, peripheral, and central corneal stroma. Results: The period between CXL and keratoplasty ranged from 5 to 30 months. All keratoconus corneas showed the typical histological changes. Increased proapoptotic BAX expression and/or antiapoptotic survivin expression were noticed in keratocytes and endothelium in 2 keratoconus specimens after CXL. Smooth muscle actin was only observed in subepithelial scar tissue of 2 keratoconus corneas without CXL. Keratoconus corneas after CXL revealed a significant reduction in keratocyte counts in the entire cornea (P = 0.003) compared with keratoconus corneas without CXL and normal corneas. This difference was because of a loss of keratocytes in the anterior (P = 0.014) and middle (P = 0.024) corneal stroma. Keratocytes in CXL corneas were reduced in the center (P = 0.028) and the periphery (P = 0.047). Conclusions: CXL in human keratoconus can cause considerable morphologic corneal changes up to 30 months postoperatively. Especially noteworthy is a long-lasting, maybe permanent, keratocyte loss in the anterior and middle corneal stroma involving the central and peripheral cornea. As long-term corneal damage after CXL is of genuine concern, particular care should be taken to perform this procedure only in accordance with investigational protocols