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      Combined Protocols for Corneal Collagen Cross-Linking with Photorefractive Surgery for Refractive Management of Keratoconus: Update on Techniques and Review of Literature

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          Abstract

          With the development and gradual dissemination of corneal collagen cross-linking (CXL) in the twenty-first century as an early treatment for keratoconus, the management paradigm has shifted to include a greater focus on complete refractive correction for these patients. Though supplemental hard contact lens therapy remains a mainstay of visual rehabilitation in keratoconus, there has been increasing appeal in a completely surgical approach by combining CXL with adjuvant refractive procedures to both halt the ectatic process and enhance functional visual outcomes. Collectively termed “CXL plus” procedures, several combined protocols have been studied to various degrees in conjunction with CXL, involving photorefractive keratectomy (PRK), transepithelial phototherapeutic keratectomy (PTK), conductive keratoplasty (CK), intrastromal corneal ring segments (ICRS) implantation, phakic intraocular lens (PIOL) implantation, or multiple of these techniques together. The scope of this review aims to encompass a summary of current CXL protocols and present the current status of studies involving adjunctive keratorefractive procedures combined with CXL. By discussing the results to date of these CXL plus protocols, we can assess what further areas of investigation are necessary within this field as the next step to optimizing treatment modalities and outcomes for our keratoconus patients, regardless of disease severity.

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          Most cited references79

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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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              A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results.

              To report the refractive, topographic, and clinical outcomes 3 years after corneal collagen cross-linking (CXL) in eyes with progressive keratoconus. Prospective, randomized controlled trial. One hundred eyes with progressive keratoconus were randomized into the CXL treatment or control groups. Cross-linking was performed by instilling riboflavin 0.1% solution containing 20% dextran for 15 minutes before and during the 30 minutes of ultraviolet A irradiation (3 mW/cm(2)). Follow-up examinations were arranged at 3, 6, 12, 24, and 36 months. The primary outcome measure was the maximum simulated keratometry value (Kmax). Other outcome measures were uncorrected visual acuity (UCVA; measured in logarithm of the minimum angle of resolution [logMAR] units), best spectacle-corrected visual acuity (BSCVA; measured in logMAR units), sphere and cylinder on subjective refraction, spherical equivalent, minimum simulated keratometry value, corneal thickness at the thinnest point, endothelial cell density, and intraocular pressure. The results from 48 control and 46 treated eyes are reported. In control eyes, Kmax increased by a mean of 1.20±0.28 diopters (D), 1.70±0.36 D, and 1.75±0.38 D at 12, 24, and 36 months, respectively (all P <0.001). In treated eyes, Kmax flattened by -0.72±0.15 D, -0.96±0.16 D, and -1.03±0.19 D at 12, 24, and 36 months, respectively (all P <0.001). The mean change in UCVA in the control group was +0.10±0.04 logMAR (P = 0.034) at 36 months. In the treatment group, both UCVA (-0.15±0.06 logMAR; P = 0.009) and BSCVA (-0.09±0.03 logMAR; P = 0.006) improved at 36 months. There was a significant reduction in corneal thickness measured using computerized videokeratography in both groups at 36 months (control group: -17.01±3.63 μm, P <0.001; treatment group: -19.52±5.06 μm, P <0.001) that was not observed in the treatment group using the manual pachymeter (treatment group: +5.86±4.30 μm, P = 0.181). The manifest cylinder increased by 1.17±0.49 D (P = 0.020) in the control group at 36 months. There were 2 eyes with minor complications that did not affect the final visual acuity. At 36 months, there was a sustained improvement in Kmax, UCVA, and BSCVA after CXL, whereas eyes in the control group demonstrated further progression. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                usoiber1@jhmi.edu
                Journal
                Ophthalmol Ther
                Ophthalmol Ther
                Ophthalmology and Therapy
                Springer Healthcare (Cheshire )
                2193-8245
                2193-6528
                11 October 2019
                11 October 2019
                October 2019
                : 8
                : Suppl 1
                : 15-31
                Affiliations
                GRID grid.21107.35, ISNI 0000 0001 2171 9311, Wilmer Eye Institute, , Johns Hopkins Medical Institutions, ; Baltimore, MD USA
                Article
                210
                10.1007/s40123-019-00210-3
                6789054
                31605317
                9c001e66-c2f1-4ba8-85a4-2485fd1f3e21
                © The Author(s) 2019
                History
                : 15 May 2019
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                combined cxl protocol,corneal collagen cross-linking (cxl),cxl plus,keratoconus,photorefractive surgery

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