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      A Review of Corneal Collagen Cross-linking – Current Trends in Practice Applications

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          Abstract

          Objective:

          To review the literature on current applications of corneal Collagen Cross-Linking (CXL).

          Methods:

          A review of publications on corneal cross-linking was conducted. This included systemic reviews, randomized controlled clinical trials, cohort studies, case-controlled studies and case series. A summary of the publications is tabulated.

          Results:

          The original indication of riboflavin – Ultraviolet-A (UVA) induced corneal collagen cross-linking is to arrest the progression of keratoconus. Studies show that it is effective in arresting the progression of keratoconus and post-LASIK ectasia with the standard Dresden protocol (epithelium-off). There are also improvements in visual, keratometric and topographic measurements over time. Severe complications of cross-linking are rare. The epithelium-on techniques have less efficacy than the Dresden protocol. Accelerated protocols have variable results, with some studies reporting comparable outcomes to the Dresden protocol while other studies reporting less efficacious outcomes. Cross-linking combined with refractive procedures provide better visual outcome but long term studies are warranted. Cross-linking for the treatment of infective keratitis is a promising new treatment modality. Initial studies show that it is more effective for superficial rather than deep infections and for bacterial rather than fungal infections.

          Conclusions:

          Corneal cross-linking is a procedure with an expanding list of indications from the treatment of corneal ectasias to infective keratitis. While the standard Dresden protocol is established as the gold standard treatment for progressive keratoconus, the more recent protocols may require further refinements, investigative and long-term studies.

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          Most cited references125

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          Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study.

          To report the long-term results of 44 keratoconic eyes treated by combined riboflavin ultraviolet A collagen cross-linking in the first Italian open, nonrandomized phase II clinical trial, the Siena Eye Cross Study. Perspective, nonrandomized, open trial. After Siena University Institutional Review Board approval, from September 2004 through September 2008, 363 eyes with progressive keratoconus were treated with riboflavin ultraviolet A collagen cross-linking. Forty-four eyes with a minimum follow-up of 48 months (mean, 52.4 months; range, 48 to 60 months) were evaluated before and after surgery. Examinations comprised uncorrected visual acuity, best spectacle-corrected visual acuity, spherical spectacle-corrected visual acuity, endothelial cells count (I Konan, Non Con Robo; Konan Medical, Inc., Hyogo, Japan), optical (Visante OCT; Zeiss, Jena, Germany) and ultrasound (DGH; Pachette, Exton, Pennsylvania, USA) pachymetry, corneal topography and surface aberrometry (CSO EyeTop, Florence, Italy), tomography (Orbscan IIz; Bausch & Lomb Inc., Rochester, New York, USA), posterior segment optical coherence tomography (Stratus OCT; Zeiss, Jena, Germany), and in vivo confocal microscopy (HRT II; Heidelberg Engineering, Rostock, Germany). Keratoconus stability was detected in 44 eyes after 48 months of minimum follow-up; fellow eyes showed a mean progression of 1.5 diopters in more than 65% after 24 months, then were treated. The mean K value was reduced by a mean of 2 diopters, and coma aberration reduction with corneal symmetry improvement was observed in more than 85%. The mean best spectacle-corrected visual acuity improved by 1.9 Snellen lines, and the uncorrected visual acuity improved by 2.7 Snellen lines. The results of the Siena Eye Cross Study showed a long-term stability of keratoconus after cross-linking without relevant side effects. The uncorrected visual acuity and best spectacle-corrected visual acuity improvements were supported by clinical, topographic, and wavefront modifications induced by the treatment. Copyright 2010 Elsevier Inc. All rights reserved.
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            Safety of UVA-riboflavin cross-linking of the cornea.

            To study potential damage to ocular tissue during corneal collagen cross-linking (X-linking) by means of the riboflavin/UVA (370 nm) approach. Comparison of the currently used technique with officially accepted guidelines regarding direct UV damage and the damage created by the induced free radicals (photochemical damage). The currently used UVA radiant exposure of 5.4 mJ/cm and the corresponding irradiance of 3 mW/cm2 is below the known damage thresholds of UVA for the corneal endothelium, lens, and retina. Regarding the photochemical damage caused by the free radicals, the damage thresholds for keratocytes and endothelial cells are 0.45 and 0.35 mW/cm, respectively. In a 400-microm-thick cornea saturated with riboflavin, the irradiance at the endothelial level was 0.18 mW/cm, which is a factor of 2 smaller than the damage threshold. After corneal X-linking, the stroma is depopulated of keratocytes approximately 300 microm deep. Repopulation of this area takes up to 6 months. As long as the cornea treated has a minimum thickness of 400 microm (as recommended), the corneal endothelium will not experience damage, nor will deeper structures such as lens and retina. The light source should provide a homogenous irradiance, avoiding hot spots.
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              Increased resistance of crosslinked cornea against enzymatic digestion.

              Collagen-crosslinking using combined riboflavin/ UVA treatment has been developed by us as a new treatment for keratoconus by stiffening the collagenous matrix. Recently, we have started to use the same method for the treatment of corneal ulcers. The aim of the present study was to evaluate the influence of the crosslinking treatment on the resistance of the cornea against enzymatic degradation. 60 enucleated porcine eyes were treated with the photosensitizer riboflavin and UVA-irradiation (370 nm; irradiance of 1, 2 or 3 mW/cm2) for 30 minutes and compared with 20 untreated control eyes. After crosslinking treatment, the corneal buttons were trephined and exposed to pepsin, trypsin and collagenase solutions. The extent of the corneal digestion was monitored daily. Selected cases were examined by light microscopy. The corneal buttons crosslinked with riboflavin/ UVA at 3 mW/cm2 were dissolved only by day 13 following pepsin digestion and by day 14 following collagenase treatment versus 6 days in the untreated control corneas. Digestion by trypsin was observed on day 5 in buttons crosslinked at 3 mW/cm2 compared to day 2 in the control corneas. Microscopically, a prolonged preservation especially of the anterior portion of the crosslinked corneas could be demonstrated. Photochemical crosslinking of the cornea using riboflavin and UVA results in a markedly increased resistance versus collagen digesting enzymes. The findings support the use of the new method in the treatment of corneal ulcers.
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                Author and article information

                Journal
                Open Ophthalmol J
                Open Ophthalmol J
                TOOPHTJ
                The Open Ophthalmology Journal
                Bentham Open
                1874-3641
                23 July 2018
                2018
                : 12
                : 181-213
                Affiliations
                [1 ]MBBS (Singapore), MMed (Ophth), FRCS(Ed), FAMS (S'pore) Senior Consultant, Corneal and External Eye Disease Service, Singapore National Eye Centre, Singapore, Singapore
                [2 ]Undergraduate medical student, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
                Author notes
                [* ]Address correspondence to this author at the Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751, Singapore; Tel: +6562277255; E-mail: lim.li@ 123456singhealth.com.sg lim.li@singhealth.com.sg
                Article
                TOOPHTJ-12-181
                10.2174/1874364101812010181
                6062907
                30123383
                e8c44bdf-0166-45e6-9dc1-d12a236e219f
                © 2018 Lim et al .

                This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: ( https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 07 July 2017
                : 05 December 2017
                : 22 January 2018
                Categories
                Ophthalmology
                Suppl-1, M7

                Ophthalmology & Optometry
                cornea collagen cross-linking,post-lasik ectasia,keratoconus,infective keratitis,uva,dresden protocol

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