Corneal cross‐linking – a review

Purpose

To review cross‐linking the cornea using riboflavin and ultraviolet A light, which has been widely adopted, refined and applied in a range of corneal surgeries and pathologies where the strength of the cornea might be compromised.

Recent findings

A large number of clinical trials have been carried out, most of which have demonstrated that standard cross‐linking is a successful method to halt the progression of keratoconus or even aid regression.

Summary

This review describes our current understanding of the technique, focussing on how cross‐linking works, how the treatment is being optimised, the clinical results that have been reported to date and the potential use of the therapy in the treatment of other corneal disorders.     

Transepithelial corneal collagen cross‐linking by iontophoresis of riboflavin

Purpose: To evaluate the effectiveness of transepithelial cornea impregnation with riboflavin 0.1% by iontophoresis for collagen cross‐linking. Material and methods:  Transepithelial collagen cross‐linking by iontophoresis of riboflavin was performed in a series of 22 eyes of 19 patients with progressive keratoconus I–II of Amsler classification. The riboflavin solution was administered by iontophoresis for 10 min in total, after which standard surface UVA irradiation (370 nm, 3 mW/cm²) was performed at a 5‐cm distance for 30 min. Results:  The riboflavin/UVA treatment resulted in a decrease in the average keratometry level from 46.47 ± 1.03 to 44.12 ± 1.12 D 1 year after the procedure. Corneal astigmatism decreased from 3.44 ± 0.48 to 2.95 ± 0.23 D. Uncorrected distance visual acuity improved from 0.61 ± 0.44 up to 0.48 ± 0.41 (LogMAR). Preoperative and postoperative endothelial cell density remained unchanged at 2765 ± 21.15 cells/mm². Conclusion:  Transepithelial collagen cross‐linking by iontophoresis might become an effective method for riboflavin impregnation of the corneal stroma reducing the duration of the procedure and being more comfortable for the patients. Further long‐term studies are necessary to complete the evaluation of the efficacy and risk spectrum of the modified cross‐linking technique.     

Effects of riboflavin/UVA corneal cross‐linking on keratocytes and collagen fibres in human cornea

Purpose: To evaluate the effects of corneal cross‐linking on keratocytes and collagen fibres in human corneas. Methods: Fifteen corneal buttons were examined. Ten were from patients with keratoconus submitted to penetrating keratoplasty and five of them were treated with cross‐linking 6 months before penetrating keratoplasty. Five normal corneal buttons from healthy donors were used as controls. All samples were prepared for TUNEL assay and Western blot analysis for the detection of keratocyte apoptosis and immunohistochemical analysis for the morphological evaluation of keratocytes and collagen fibre diameter. Results: Normal corneas exhibited no TUNEL‐positive keratocytes and keratoconic and cross‐linked corneas showed moderate apoptotic cells mainly in the anterior part of the stroma. This apoptotic trend was confirmed by the cleavage of poly (ADP‐ribose) polymerase assessed using Western blot. The Ki‐67 staining showed a significant increase in the keratocyte proliferation in cross‐linked corneas compared with normal and keratoconus. In cross‐linked corneas CD34‐positive keratocytes were regularly distributed throughout the whole corneal stroma as in the control, and keratoconus was associated with patchy loss of immunoreactivity. The immunohistochemical analysis of collagen type I showed a significant increase in fibre diameter of cross‐linked corneas compared with control and keratoconus. Conclusion: Corneal cross‐linking leads to keratocyte damage; after 6 months a repopulation by proliferating cells, a distribution of CD34‐positive keratocytes as in control and an increase in collagen fibre diameter were observed. These modifications are the morphological correlate of the process leading to an increase in biomechanical stability.     

Corneal collagen cross‐linking for infectious keratitis: an update of clinical studies

Collagen cross‐linking (CXL) with ultraviolet light‐activated riboflavin is a corneal surface procedure developed for the treatment of keratoconus and corneal ectasia. With the known microbicidal and corneal stiffening effects of ultraviolet irradiation and photoactivated riboflavin, it has recently been introduced for the management of infectious keratitis, especially for ulcers resistant to antimicrobial therapy or associated with corneal melting. Various authors have attempted to use CXL as an adjunctive, salvage or even as the sole treatment for infectious corneal ulcers. The aim of this review was to provide a summary of the clinical studies in the literature. It is worth noting that there is still no consensus on the treatment protocol of CXL against infectious keratitis. The disparities in outcome measures, treatment protocol and study design can confound the interpretation and hamper the generalization of the study results. Based on current evidence, the role of CXL in infectious keratitis remained unclear despite the reported success in some clinical cases. Further investigations are warranted concerning the efficacy and safety of treating infectious keratitis with CXL.     

角膜胶原交联术研究进展

目的角膜胶原交联术(corneal collagen cross linking,CXL)是第一种能有效控制圆锥角膜进展的治疗方法,通过核黄素/紫外光介导的角膜胶原交联,增加角膜的机械强度,阻止了圆锥角膜的进展。经过近年来的研究,CXL的安全性得到了广泛的认可,随着技术方法不断改进,治疗范围也有所扩大。本文就近年来对于CXL原理、适应证、并发症、禁忌证的研究进展进行了综述。     

Corneal refractive surgery combined with simultaneous corneal cross‐linking: Indications,protocols and clinical outcomes—A review

Corneal refractive surgery is one of the most common approaches for correction of refractive errors. Combined corneal refractive surgery and corneal cross‐linking (CXL) has been proposed as a method to achieve better refractive stability and to prevent iatrogenic corneal ectasia. However, there are concerns regarding its indications, surgical safety, standardization of protocols and long‐term effect on corneal tissue. This review article aims to discuss the current knowledge and recent updates on combination of CXL and refractive surgery.     

Silicone hydrogel mini‐scleral contact lenses in early stage after corneal collagen cross‐linking for keratoconus: a retrospective case series

Background : The aim was to the evaluate performance of a novel silicone hydrogel mini‐scleral contact lens (SHmS) for optical correction of keratoconus in the early stages after the corneal collagen cross‐linking procedure (CXL). Methods : We retrospectively analysed the visual acuity improvement and corneal adaptation in the first 10 eyes of nine patients fitted with SHmS lenses one to 3.5 months after corneal collagen cross‐linking. The lenses were designed to rest over the patients’ sclera and peri‐limbal cornea and vault the central cornea with minimal support over it. Visual acuities with manifest refraction and contact lenses, refractive and topographical values (Kmin and Kmax) were evaluated on lens dispensing and after six month of lens wearing. Ocular physiological responses were evaluated using the Institute of Eye Research (IER) grading scales. Results : SHmS fitting was performed 2.1 ± 0.97 (SD) months after collagen cross‐linking. Mean follow up was 10.9 ± 4.41 months (range six to 18 months). Mean decimal visual acuity with SHmS was 0.66 ± 0.22 (approximately 6/9 Snellen fraction, range 0.3 to 0.1) or 0.75 ± 0.14 (approximately 6/8.1, range 0.5 to 1.0), when omitting two amblyopic eyes. Nine (90 per cent) eyes were successfully fitted, that is, able to wear the lenses for 10 hours per day or longer. Mean wearing time was 11.7 hours (range six to 14) per day. No corneal neovascularisation or papillary reaction was found in all fitted eyes. Conclusions : SHmS contact lenses provide successful visual rehabilitation shortly after corneal collagen cross‐linking. This new soft contact lens design with scleral fixation and minimal apical touch was demonstrated to be safe shortly after collagen cross‐linking, as the avoidance of contact with the treated zone minimises contact lens influence on corneal recovery.     

Riboflavin‐ultraviolet light induced cross‐linking in endothelial decompensation

Purpose: To evaluate the potential of collagen cross‐linking in the treatment of corneal oedema caused by endothelial decompensation. Methods: Riboflavin‐ultraviolet (UV) treatment induces cross‐linking and reduces stromal swelling. Eleven patients with corneal oedema were treated. The technique comprised: epithelial abrasion; instillation of 0.1% riboflavin in saline, and 5.4 J/cm² illumination with 365 nm UV‐A light over approximately 30 mins (3 mW/cm²). Results: A reduction in corneal thickness was observed in 10 patients. The majority also experienced improvement in vision. The effect occurred over weeks and lasted for months. Conclusions: The study shows a potential application of collagen cross‐linking in the management of patients with corneal oedema. Experimental and additional clinical studies are necessary in order to define the precise indications for this type of treatment.     

角膜胶原交联术治疗圆锥角膜的研究进展

角膜胶原交联术(corneal collagen cross-linking,CXL)是一种治疗原发或继发性圆锥角膜、感染性角膜炎及大泡性角膜病变等角膜疾病的新疗法。它利用光化学原理来增加角膜强度,阻止角膜病变进展,现已被广泛应用于临床。目前临床上普遍采用的方法多为经典去上皮角膜交联(dresden protocol),但经典方法耗时较长,可能存在角膜上皮愈合不良、感染等术后并发症。近年来多项研究对经典方式进行了改良,例如核黄素液浸入角膜的多种方式选择,增加紫外光照射能量以缩短照射时间的加速交联以及跨上皮角膜交联等。本文就非经典角膜胶原交联术在治疗圆锥角膜的研究作一综述。