Corneal collagen cross-linking (CXL) is used to increase

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1 REVIEW ARTICLE Corneal Collagen Cross-linking: A Review of Clinical Applications Kunyong Xu, MD, MHSc,*Þ Tommy C.Y. Chan, FRCS,þ Rasik B. Vajpayee, MS, FRCSEd, FRANZCO, and Vishal Jhanji, MDþ ** Corneal collagen cross-linking (CXL) has been shown to slow down or stop the progression of keratoconus. In addition, CXL has been applied in cases of corneal ectasia. Recent reports of the use of CXL in cases of infectious keratitis have generated further interest in this treatment modality. This review discusses the principle, clinical uses, and complications associated with CXL. Key Words: corneal collagen cross-linking, ectasia, keratitis, keratoconus (Asia Pac J Ophthalmol 2015;4: 300Y306) Corneal collagen cross-linking (CXL) is used to increase the rigidity of the cornea and its structural integrity by a photopolymerization process that induces intrafibrillar and interfibrillar collagen cross-links. It has been used for the management of corneal ectasias, such as keratoconus and postylaser-assisted in situ keratomileusis (LASIK) ectasia. In this review, we discuss the principle and procedure of CXL, physiochemical changes in the cornea induced by CXL, clinical uses of CXL, and complications and contraindications of CXL. Principle of Corneal Collagen Cross-linking The current technique for CXL involves the use of riboflavin (vitamin B 2 ), which is exposed to a source of UV-A light with a wavelength of 370 nm. In the process of CXL, riboflavin acts as a photosensitizer and absorbs ultraviolet (UV) radiation. Free radicals are produced in the photosensitizing process, which catalyze a reaction that leads to the formation of covalent bonds between the collagen molecules and microfibrils. 1,2 With the standard irradiance of 3 mw/cm 2, apoptosis of keratocytes was present up to a depth of 300 Km. 3 Surgical Procedure of Corneal Collagen Cross-linking The treatment protocol for CXL is based on previous laboratory work to maximize the CXL effect while minimizing the From the *Department of Ophthalmology, Queen s University, Kingston, Canada; Department of Ophthalmology, Hotel Dieu and Kingston General Hospitals, Kingston, Canada; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong; Hong Kong Eye Hospital, Hong Kong; Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia; Vision Eye Institute, Royal Victorian Eye and Ear Hospital, North West Academic Centre University of Melbourne, Melbourne, Australia; and **Department of Ophthalmology, Prince of Wales Hospital, Hong Kong. Received for publication April 21, 2015; accepted August 10, The authors have no funding or conflicts of interest to declare. Reprints: Vishal Jhanji, MD, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Mongkok, Kowloon, Hong Kong. vishaljhanji@cuhk.edu.hk. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO damage to ocular tissue. 1,4,5 Nine millimeters of the central corneal epithelium is scraped off under topical anesthesia. Ultrasound-based pachymetry is often used to measure the baseline corneal thickness. Iso-osmolar riboflavin solution 0.1% in 20% dextran is applied on the corneal surface every 2 to 3 minutes for 30 minutes. The corneal pachymetry is then measured at various points to ensure that the thinnest point ofthestromaisnotlessthan400km. The limbus of the cornea can be protected by placing a sponge ring to prevent UV light from passing beyond the outer periphery of the cornea, which thereby prevents any potential damage to the limbal stem cells. The photoactivation of riboflavin within the cornea starts with the UV-A light illumination, which is calibrated at 365 nm to provide an irradiance of 3 mw/cm 2. This equals to a total dose of 5.4 J/cm 2. The light is usually located at a distance of 5 cm from the cornea. The light is kept in position for 30 minutes, and riboflavin solution is instilled every 3 minutes. Intraoperative corneal thickness can be measured with ultrasound pachymetry or optical coherence tomography. 6 At the end of the irradiation process, a broad-spectrum antibiotic drop is instilled on the cornea, followed by the placement of a bandage contact lens. Topical corticosteroids can be used to reduce postoperative inflammation or corneal haze. 7 The patient should be closely monitored in the postoperative period to ensure epithelial healing, after which the contact lens is removed. Based on the Bunsen-Roscoe law of reciprocity, having a constant radiant exposure of 5.4 J/cm 2, accelerated CXL has been developed as an alternative treatment protocol with higher illumination intensity but shorter duration. The development of accelerated CXL has shortened the treatment duration tremendously. Biomechanical strength between the human corneas cross-linked with low-intensity (370 nm, 3 mw/cm 2 CXL for 30 minutes) and high-intensity (370 nm, 9 mw/cm 2 CXL for 10 minutes) protocols was found to be similar in in vitro experiments. 8 There are several accelerated cross-linking systems available including the UV-X (IROC Innocross, Zurich, Switzerland), CCL-HE (Peschke Meditrade GmbH, Huenenberg, Switzerland), and KXL (Avedro Inc, Waltham, Mass). The Avedro KXL accelerated CXL system provides the shortest treatment time as it requires only a shorter riboflavin soaking time and UV-A illumination, typically up to 3 minutes. A few clinical studies also demonstrated the treatment efficacy and safety of these accelerated protocols, 9Y12 although no general consensus on this form of treatment has been made. 13,14 Variations in Treatment Protocols of Corneal Collagen Cross-linking Thin Cornea It is not safe to perform the above standard procedure if the residual corneal thickness is less than 400 Km. In such cases, the de-epithelialized cornea can be swelled with hypoosmolar 0.1% riboflavin for 30 minutes to increase the corneal Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October 2015

2 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October 2015 Corneal Collagen Cross-linking: A Review of Clinical Applications thickness. Subsequently, the cornea is photoactivated using identical treatment parameters as described previously. Transepithelial Corneal Collagen Cross-linking Riboflavin does not readily penetrate the intact epithelium. Different techniques have been developed to increase the absorption of riboflavin into the stroma, including the use of eye drops containing preservatives, such as benzalkonium chloride preoperatively, to break the epithelial tight junctions or the creation of superficial epithelial trauma without complete epithelial debridement. 15 Animal eye studies have not supported the use of incomplete manual epithelial removal. 16 Wollensak and Iomdina 17 showed that transepithelial CXL had one fifth of the CXL effect compared with conventional CXL with complete epithelial removal. Chan and colleagues 18 reported the first study describing CXL without epithelial debridement. In this study, the authors used intracorneal ring segments with or without CXL to treat keratoconus. After the placement of an inferior intracorneal ring, the cornea was soaked with riboflavin with diluted carboxymethylcellulose for 5 minutes followed by UV-A for 30 minutes. Improvements in manifest cylinder, average keratometry, and the steepest keratometry in the group with CXL were found. Filippello et al 19 used a 0.1% aqueous riboflavin involving trometamol and sodium ethylenediaminetetraacetic acid (EDTA) to break down epithelial intercellular junctions. In this study, anterior segment optical coherence tomography showed a dense line at 100 Km, whereas the demarcation line was seen at a depth of 320 to 340 Km in conventional CXL. This may suggest a more superficial effect of transepithelial CXL. Mastropasqua et al 20 investigated the differences in riboflavin concentration in the anterior, intermediate, and posterior stroma after 3 different CXL imbibition techniques of 0.1% riboflavin, including the standard epithelium-off, epithelium-on, and iontophoresis-assisted administration. In this study, the authors found that CXL transepithelial iontophoresis imbibition produced greater and deeper riboflavin saturation with respect to conventional epithelium-on CXL while maintaining the advantages of avoiding epithelial removal, but did not reach concentrations obtained with standard epithelium-off CXL. Physiochemical Changes of Cornea Induced by Corneal Collagen Cross-linking Corneal collagen cross-linking has been shown to increase the Young modulus, resistance to bending, and shape retention. 21 It also increased collagen fiber diameter and resistance to enzymatic digestion. 22,23 In addition, it was observed that CXL increased corneal surface temperature and shrinking temperature. 24,25 Clinical Uses of Corneal Collagen Cross-linking Keratoconus Keratoconus is a progressive, ectatic corneal disease that leads to irregular astigmatism due to weakening of the stromal collagen layers and subsequent stromal thinning. 26 Irregular astigmatism is the primary cause of vision loss in early and intermediate stages of the disease, whereas corneal scarring may compromise visual acuity in advanced stages. 27 The biomechanical strength of the cornea is reduced in cases of keratoconus. This may be due to the reduction of the number of intralamellar and interlamellar cross-links compared with normal controls. 28,29 Keratoconus spares corneas with an increased number of natural cross-links, such as in the elderly, 30 smokers, 31,32 and patients with diabetes. 33,34 Corneal collagen cross-linking was proposed as a treatment modality to stabilize weak corneas and prevent the progression of keratoconus, thereby preventing visual loss and significantly reducing the number of patients requiring surgical treatment. In a previous study, 23 eyes of 22 patients with moderate to severe progressive keratoconus were treated with CXL. 1 The length of follow-up was between 4 months and 3 years. The authors reported that 70% of cases had a reduction in maximal keratometry by 2.01 diopters (D) and in refractive error by 1.14 D. There was no change in corneal transparency, intraocular pressure, lens transparency, or corneal endothelial cell count. The progression of keratoconus was halted in all cases. The same author published a long-term review with a 5-year follow-up period. 4 This study included 60 eyes of 48 patients with progressive keratoconus and showed an average reduction of maximum keratometry of 2.87 D and an improvement of visual acuity by 1.14 Snellen lines. Wittig-Silva and colleagues 35 reported the results of CXL in 66 eyes of 49 patients with documented progression of keratoconus. Interim analysis of treated eyes showed a flattening of the steepest simulated keratometry value by 0.74 D at 3 months, 0.92 D at 6 months, and 1.45 D at 12 months. A trend toward an improvement in the best spectacle-corrected visual acuity was observed. In the control eyes, the mean maximum keratometry steepened by 0.60 D after 3 months, by 0.60 D after 6 months, and by 1.28 D after 12 months. Best spectaclecorrected visual acuity decreased by logmar over 3 months, over 6 months, and 0.12 over 12 months. Goldich and colleagues 36 reported their results among patients with progressive keratoconus who underwent CXL. After 2 years of follow-up, the authors found that these patients had stable uncorrected visual acuity, improved best-corrected visual acuity, and reduced keratometry. In this study, the corneal pachymetry, endothelial cell density, and foveal thickness were unchanged. O Brart and colleagues 37 published a randomized, felloweye controlled trial assessing the effect of CXL on the progression of keratoconus. In this study, compared with untreated eyes, there was an improvement in simulated keratometry, simulated astigmatism, cone apex power, and wavefront measurements (root mean square, coma, and pentafoil) after an 18-month followup period. The authors reported that none of the treated eyes progressed, whereas 3 of 22 untreated eyes showed progression. Vinciguerra et al 38 published their 12-month data from a prospective nonrandomized clinical study on CXL in advanced keratoconus. The authors assessed 28 eyes that underwent CXL at 1-year follow-up. The study found an improvement in visual acuity and a decrease in minimal and maximal keratometry readings in the treated group compared with deterioration in the contralateral untreated eye. There was also a reduction of total and corneal higher-order aberrations in the eyes treated with CXL. No significant change in endothelial cell count after CXL was found in this study. Caporossi et al 39 reported a 3.6-line increase in uncorrected visual acuity, a 1.66-line improvement in best spectacle-corrected visual acuity, a mean reduction in maximum keratometry of 2.1 D, and a 2.5-D reduction in manifest refraction spherical equivalent at 3 months after CXL in a series of 10 eyes in 10 patients with progressive keratoconus after CXL treatment. Later, the same authors published the results of an open, prospective, nonrandomized, phase 2 clinical trial of CXL on keratoconus. 40 In this study, 363 eyes with progressive keratoconus were treated with a standard CXL protocol. Of these, 48 eyes were followed up between 48 and 60 months. The authors reported stability or improvement of keratoconus in 44 cases (92%), with a mean * 2015 Asia Pacific Academy of Ophthalmology 301

3 Xu et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October 2015 reduction of average keratometry readings of 2 D and a significant improvement in visual acuity and higher-order aberrations. It was found that the mean best spectacle-corrected visual acuity improved by 1.9 Snellen lines, and the mean uncorrected visual acuity improved by 2.7 Snellen lines in the treated group. In contrast, the fellow untreated eye showed progression of keratoconus in more than 65% of the cases within 24 months. No significant change in endothelial cell counts and no adverse events were recorded. Hafezi and colleagues 41 published their study of CXL in patients with progressive keratoconus, where the corneas in question were thinner than the required 400 Km after epithelial removal. In this study, 20 patients with progressive keratoconus and keratectasia after refractive laser treatment were treated with a modified version of the standard protocol, where hypoosmolar riboflavin was used to swell thin corneal stroma to greater than 400 Km before the application of UV-A light. The corneal thickness of all the patients after epithelial removal was at least 320 Km and was swollen to greater than 400 Km in each case before UV-A light application. All patients were followed up at 6 months, and the progression of ectasia was halted in all patients. Stabilization of keratometry was noted in 12 patients, whereas regression was noted in 8 patients. There were no changes in corneal endothelium or corneal clarity or adverse effects noted. The authors concluded that this modified CXL treatment for thin corneas appeared to be safe and effective up to 6 months. However, a longer follow-up is required to determine if the behavior of these thin corneas is comparable to corneas with normal thickness undergoing CXL. Raiskup-Wolf et al 42 reported the 7-year results of CXL in keratoconus. In this study, the authors found a decrease in maximum keratometry of 2.7 D at 1 year, 2.2 D at 2 years, and 4.8 D at 3 years. It was reported that visual acuity improved by 1 line per year in 54% of patients in the first 3 years. In addition, 2 patients had continued progression and had to undergo subsequent CXL procedures. Corneal collagen cross-linking has also been performed in pediatric populations (up to 18 years of age) with progressive keratoconus. 43,44 Caporossi et al 43 reported a statistically significant improvement in uncorrected visual acuity and best spectacle-corrected visual acuity 48 months after CXL in patients (e18 years) with progressive keratoconus. Vinciguerra and colleagues 44 also reported significant improvements in spherical equivalent (1.57 D), simulated keratometry in the flat meridian (from to D), and mean average corneal power (from to D) for patients younger than 18 years who had CXL for documented progressive keratoconus with a 2-year follow-up. Corneal Collagen Cross-linking in Refractive SurgeryYInduced Keratectasia Several studies have assessed the use of CXL in postyrefractive surgery corneal ectasia. Hafezi et al 45 performed CXL in 10 patients (1 eye per patient) with post-lasik keratectasia. In this study, the authors found that CXL was able to arrest and partially reverse the progression of LASIK-induced iatrogenic keratectasia over a postoperative follow-up of up to 25 months. In a retrospective, interventional case series, Yildirim et al 46 reported the long-term results of combined same-day intrastromal corneal ring segment (ICRS) placement and CXL for postoperative LASIK ectasia. In this study, 16 eyes of 14 patients with postoperative ectasia after LASIK were treated with femtosecond laser-assisted ICRS implantation followed by same-day CXL. The patients were followed up between 36 and 62 months. The uncorrected distance visual acuity improved from logmar 1.18 T 0.42 to 0.44 T 0.22 (P G 0.001), and the corrected distance visual acuity improved from logmar 0.46 T 0.26 to 0.21 T 0.14 (P G 0.001). No serious complications were found in this study. Vinciguerra et al 47 studied the outcomes of CXL in 13 eyes after refractive surgery. An improvement in best spectaclecorrected visual acuity by logmar 0.1 and stabilization of keratometry after CXL were found. It was reported that corneal response was less marked compared with keratoconus. Combined Corneal Collagen Cross-linking and Refractive Surgery Combined CXL and photorefractive keratectomy (PRK) is performed to offer functional vision for patients with keratoconus. Kymionis and colleagues 48 performed customized topographyguided PRK immediately followed by CXL on 14 eyes of 12 patients with progressive keratoconus. In this study, the range of follow-up was between 3 and 16 months. The mean steepest keratometry was reduced from T 3.40 D preoperatively to T 1.80 D at last follow-up. Preoperatively, the mean spherical equivalent refraction was j3.03 T 3.23 D, and defocus was 4.67 T 3.29 D. At the last follow-up, the mean spherical equivalent refraction and defocus were statistically significantly reduced to j1.29 T 2.05 D and 3.04 T 2.53 D, respectively. Preoperative mean uncorrected visual acuity was logmar 0.99 T 0.81, and best spectacle-corrected visual acuity was 0.21 T 0.19, which improved postoperatively to 0.16 T 0.15 and 0.11 T 0.15, respectively. Kanellopoulos 49 reported the efficacy of combined PRK and CXL among 325 eyes with keratoconus. In this study, the mean uncorrected visual acuity and mean best-corrected visual acuity were improved. However, the authors suggested caution because the long-term effects and safety of removing the Bowman layer with laser ablation in this group of patients have not been established. Coskunseven and colleagues 50 performed a randomized trial over a 6-month period comparing CXL followed by intracorneal ring segment implantation and CXL performed after ring segment implantation. In this study, the mean duration between treatments was 7 months. The authors reported that while uncorrected vision, visual acuity, mean spherical equivalent, cylinder, and mean keratometry values improved in both groups, the overall effect was greater when CXL was performed after ring segment implantation. Corneal collagen cross-linking has been combined with both PRK and ICRS insertion as a 3-step procedure. 51 In a prospective case series of 16 eyes with progressive keratoconus, all patients underwent topography-guided transepithelial PRK after intracorneal ring segment implantation, followed by CXL treatment. This study showed significant improvement in visual acuity, refraction, and keratometry within 6 months after completion of the 3-step procedure. Apart from treating post-lasik ectasia, CXL has been used prophylactically to prevent this rare complication. 52 The additional cross-linking has been proposed to induce early stabilization of the cornea after LASIK and improve the refractive and keratometric predictability in highly myopic eyes. 53,54 However, the long-term needs and efficacy of ectasia prophylaxis with CXL are still lacking. Corneal Collagen Cross-linking and Pellucid Marginal Degeneration A few studies have evaluated the use of CXL in patients with pellucid marginal degeneration (PMD). Spadea 55 performed CXL in a patient with an inferiorly decentered treatment zone and found * 2015 Asia Pacific Academy of Ophthalmology

4 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October 2015 Corneal Collagen Cross-linking: A Review of Clinical Applications improvement in corrected distance visual acuity at 3 months and stabilization thereafter up to 12 months. Stojanovic et al 56 reported improvement in visual, refractive, and topographic outcomes in 5 eyes with PMD that underwent topography-guided surface ablation followed by CXL after 1 year. In addition, Kymionis et al 57 published a case report describing the successful outcome of intrastromal rings followed 12 months later by combined PRK and CXL in 1 patient with PMD. Corneal Collagen Cross-linking and Infectious Keratitis Photoactivation of riboflavin may be used to treat corneal infections because of its antimicrobial effects. Riboflavin has an affinity for nucleic acid, and its absorption of UV-A light can lead to the oxidation of guanine bases, which prevents the replication of the viral and bacterial genome. 58 The antimicrobial efficacy of the combination of riboflavin and UV-A light against common bacterial pathogens that cause infectious keratitis has been reported in vitro. 59Y61 In a prospective study by Price et al, patients with infectious keratitis were treated with topical antimicrobial agents together with CXL. The authors concluded that CXL worked best in keratitis cases without deep corneal involvement as its effects diminished with increasing depth of the corneal infiltrates. Makdoumi et al 63 excluded patients who had received antibiotics before presentation and investigated the use of CXL as the primary and sole treatment for patients with bacterial keratitis. Sixteen patients were recruited in total. After CXL, 15 patients had complete re-epithelialization of the infective corneal ulcer without additional intervention. Fourteen of the 16 patients did not require antibiotics at all throughout the course of their disease. The mean time from CXL to complete corneal healing was 7.1 days. None of these 16 patients experienced major complications, and keratoplasty was not required in any of them. A prospective randomized controlled trial comparing standard antimicrobial treatment with standard antimicrobial treatment with corneal CXL was reported in 40 patients. 64 The mean duration to complete epithelialization of the corneal ulcer was T days in the CXL group and T days in the control group, although this difference did not reach a level of statistical significance. In a retrospective comparative study analyzing the effectiveness of adjuvant CXL in 20 patients with fungal keratitis, resolution of infection was seen in 90% of the cases, although the addition of CXL did not affect the time to resolution or final visual outcome compared with eyes receiving medical therapy only. 65 Li et al 66 also applied CXL to 8 cases of keratomycosis resistant to topical antifungal treatment. Complete healing was noted in all cases within 3 to 8 days, and 6 cases had improved vision with no corneal transplantation required. It is important to know that there is still no consensus on the treatment protocol of CXL in cases of infectious keratitis. The role of CXL in infectious keratitis remains unclear despite the encouraging results in some case reports and series. 67 Corneal Collagen Cross-linking and Cornea Edema Corneal collagen cross-linking has been used for the treatment of corneal edema. This may be supported by changes in the hydration behavior of the porcine cornea after CXL 68 and stromal compaction after CXL. 69 Ehlers and Hjortdal 70 found a reduction in corneal thickness in 10 of 11 eyes treated with CXL, with the majority experiencing some improvement in vision. In addition, Wollensak and colleagues 71 found thinning in 3 eyes with corneal edema after CXL. Because of lack of evidence, more studies to assess CXL for corneal edema are indicated. Complications of Corneal Collagen Cross-linking With a surge in the number of CXL procedures performed, there is an increase in the number of adverse events reported. The complications include stromal edema, 40,72Y75 corneal haze, 40,76,77 sterile infiltrates, 78Y82 endothelial irregularity or damage, 45,72,75 microbial keratitis, 83Y85 corneal melting and perforation, 86,87 recurrent corneal erosion syndrome, 88 herpes simplex virus keratouveitis, 89 and endothelial damage. 45,75 Sterile corneal infiltrates are one of the most commonly seen complications. 78Y81 The pathogenesis of sterile infiltrates is not known but may be the result of an altered immune response to antigens or due to phototoxic effects from CXL itself. 90 These infiltrates can be seen in up to 7.6% of cases. Resolution with an increase in topical steroid therapy has been reported. 82 Microbial keratitis has been reported with different organisms, including Pseudomonas, 83 microsporidia, 91 Acanthamoeba, 84 and Fusarium. 85 The presence of an epithelial defect, contact lens use, and the instillation of topical steroids may predispose to the development of microbial keratitis. In addition, CXL may also change the response of the cornea to injury and infection. 92 Treatment failure with a loss of 2 Snellen lines was reported in up to 3.5% of cases. 73,82 Koller and colleagues 82 followed 117 eyes during the first postoperative year in a prospective trial. In this study, the risk factors for complications included age older than 35 years and corrected visual acuity better than 20/25. It was reported that 7.6% of eyes continued to have an increase in maximum keratometry reading of 1 D or more during the study period, which indicated the failure of CXL. It was reported that there was a significant effect of preoperative maximum keratometry of 58 D or more and female sex on increased failure rate. 73 Greenstein and colleagues 7 studied the natural history of corneal haze after CXL. In this study, the authors measured the corneal densitometry and its correlation with slit lampydetected haze. Maximum haze was reported at 1 month, which plateaued for 3 months, followed by a decrease until 1 year. Haze returned to baseline in the ectasia subgroup compared with the keratoconus subgroup, in which haze remained at 1 year but was not a predictor of clinical outcomes. Raiskup et al 77 reported that permanent stromal haze was found in 8.6% of eyes after CXL. Advanced keratoconus was associated with risk of haze with decreased postoperative visual acuity. In another study, it was reported that posterior stromal haze was found in 46.4% of eyes treated with combined PRK and CXL. 93 However, this was not associated with a decrease in corrected distance visual acuity. Contraindications of Corneal Collagen Cross-linking Corneal collagen cross-linking requires a minimum corneal thickness of 400 Km after the removal of the epithelium. Individuals with thin corneas (G400 Km) may not be appropriate candidates for the CXL procedure because of possible endothelial cell damage. 1,5,94,95 Corneal collagen cross-linking seems to be a safe treatment with a complication rate of approximately 1% if the patient is younger than 35 years of age and the best-corrected visual acuity is worse than 20/ Also, the efficacy of CXL would likely increase if the treatment was limited to eyes with a maximum keratometry of less than 58.0 D. The goal of CXL is to stabilize or halt the progression of keratoconus with a small chance of visual improvement. Patients who have poor bestcorrected visual acuity associated with extensive corneal scarring * 2015 Asia Pacific Academy of Ophthalmology 303

5 Xu et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October 2015 should not undergo CXL. Patients with prior incisional refractive surgery (radial keratotomy or astigmatic keratotomy) might not be suitable for CXL. It was reported that alterations within the corneal stroma after CXL, particularly the contraction of the collagen lamellae, can cause the keratotomy incisions to rupture. 96 Other contraindications include pregnancy, nursing, or systemic collagen vascular diseases because the safety and effects of CXL procedures in these populations have not been sufficiently assessed. CONCLUSIONS In the past decade, CXL has been investigated for its applications in ophthalmology. The results reported in most of the studies investigating its safety and efficacy in the management of keratoconus are promising. Although CXL is being used for other indications such as keratitis and corneal edema, proper clinical trials are awaited to support its efficacy for these indications. REFERENCES 1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620Y Sung HW, Chang WH, Ma CY, et al. Crosslinking of biological tissues using genipin and/or carbodiimide. J Biomed Mater Res A. 2003;64:427Y Wollensak G, Spoerl E, Wilsch M, et al. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/uva treatment. Cornea. 2004;23:43Y Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356Y Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA-riboflavin cross-linking of the cornea. Cornea. 2007;26:385Y Chow VW, Biswas S, Yu M, et al. Intraoperative pachymetry using spectral-domain optical coherence tomography during accelerated corneal collagen crosslinking. Biomed Res Int. 2013;2013: Greenstein SA, Fry KL, Bhatt J, et al. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg. 2010;36:2105Y Beshtawi IM, Akhtar R, Hillarby MC, et al. Biomechanical properties of human corneas following low- and high-intensity collagen cross-linking determined with scanning acoustic microscopy. Invest Ophthalmol Vis Sci. 2013;54:5273Y Chan TC, Chow VW, Jhanji V, et al. Different topographic response between mild to moderate and advanced keratoconus after accelerated collagen cross-linking. Cornea. 2015;34:922Y Tomita M, Mita M, Huseynova T. Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg. 2014;40: 1013Y Hashemi H, Fotouhi A, Miraftab M, et al. Short-term comparison of accelerated and standard methods of corneal collagen crosslinking. J Cataract Refract Surg. 2015;41:533Y Ng AL, Chan TC, Cheng AC. Conventional versus accelerated corneal collagen cross-linking in the treatment of keratoconus [published online ahead of print July 3, 2015]. Clin Experiment Ophthalmol Tsatsos M, MacGregor C, Kopsachilis N, et al. Is accelerated corneal collagen cross-linking for keratoconus the way forward? Yes. Eye (Lond). 2014;28:784Y MacGregor C, Tsatsos M, Hossain P. Is accelerated corneal collagen cross-linking for keratoconus the way forward? No. Eye (Lond). 2014;28:786Y Hayes S, O Brart DP, Lamdin LS, et al. Effect of complete epithelial debridement before riboflavin-ultraviolet-a corneal collagen crosslinking therapy. J Cataract Refract Surg. 2008;34:657Y Samaras K, O Brart DP, Doutch J, et al. Effect of epithelial retention and removal on riboflavin absorption in porcine corneas. J Refract Surg. 2009;25:771Y Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg. 2009;35:540Y Chan CC, Sharma M, Wachler BS. Effect of inferior-segment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg. 2007;33:75Y Filippello M, Stagni E, O Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg. 2012;38:283Y Mastropasqua L, Nubile M, Calienno R, et al. Corneal cross-linking: intrastromal riboflavin concentration in iontophoresis-assisted imbibition versus traditional and transepithelial techniques. Am J Ophthalmol. 2014;157:623.e1Y630.e Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-ayinduced cross-linking. J Cataract Refract Surg. 2003;29:1780Y Wollensak G, Wilsch M, Spoerl E, et al. Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/uva. Cornea. 2004;23:503Y Wollensak G, Redl B. Gel electrophoretic analysis of corneal collagen after photodynamic cross-linking treatment. Cornea. 2008;27:353Y Mencucci R, Mazzotta C, Rossi F, et al. Riboflavin and ultraviolet A collagen crosslinking: in vivo thermographic analysis of the corneal surface. J Cataract Refract Surg. 2007;33:1005Y Spoerl E, Wollensak G, Dittert DD, et al. Thermomechanical behavior of collagen-cross-linked porcine cornea. Ophthalmologica. 2004;218:136Y Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol. 2011;95:1044Y Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42:297Y Cannon DJ, Foster CS. Collagen crosslinking in keratoconus. Invest Ophthalmol Vis Sci. 1978;17:63Y Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res. 1980;31:435Y Elsheikh A, Brown M, Alhasso D, et al. Experimental assessment of corneal anisotropy. J Refract Surg. 2008;24:178Y Spoerl E, Raiskup-Wolf F, Kuhlisch E, et al. Cigarette smoking is negatively associated with keratoconus. J Refract Surg. 2008;24:S737YS Hafezi F. Smoking and corneal biomechanics. Ophthalmology. 2009;116:2259e Hadley JC, Meek KM, Malik NS. Glycation changes the charge distribution of type I collagen fibrils. Glycoconj J. 1998;15:835Y Seiler T, Huhle S, Spoerl E, et al. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol. 2000;238:822Y Wittig-Silva C, Whiting M, Lamoureux E, et al. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24:S720YS Goldich Y, Marcovich AL, Barkana Y, et al. Clinical and corneal biomechanical changes after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up. Cornea. 2012;31:609Y O Brart DP, Chan E, Samaras K, et al. A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal * 2015 Asia Pacific Academy of Ophthalmology

6 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October 2015 Corneal Collagen Cross-linking: A Review of Clinical Applications collagen cross-linkage to halt the progression of keratoconus. Br J Ophthalmol. 2011;95:1519Y Vinciguerra P, Albe E, Trazza S, et al. Intraoperative and postoperative effects of corneal collagen cross-linking on progressive keratoconus. Arch Ophthalmol. 2009;127:1258Y Caporossi A, Baiocchi S, Mazzotta C, et al. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg. 2006;32:837Y Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: the Siena Eye Cross Study. Am J Ophthalmol. 2010;149:585Y Hafezi F, Mrochen M, Iseli HP, et al. Collagen crosslinking with ultraviolet-a and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg. 2009;35:621Y Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-a light in keratoconus: long-term results. J Cataract Refract Surg. 2008;34:796Y Caporossi A, Mazzotta C, Baiocchi S, et al. Age-related long-term functional results after riboflavin UV A corneal cross-linking. J Ophthalmol. 2011;2011: Vinciguerra P, Albe E, Frueh BE, et al. Two-year corneal cross-linking results in patients younger than 18 years with documented progressive keratoconus. Am J Ophthalmol. 2012;154:520Y Hafezi F, Kanellopoulos J, Wiltfang R, et al. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg. 2007;33:2035Y Yildirim A, Uslu H, Kara N, et al. Same-day intrastromal corneal ring segment and collagen cross-linking for ectasia after laser in situ keratomileusis: long-term results. Am J Ophthalmol. 2014;157: 1070Y Vinciguerra P, Camesasca FI, Albe E, et al. Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg. 2010;26:486Y Kymionis GD, Portaliou DM, Kounis GA, et al. Simultaneous topography-guided photorefractive keratectomy followed by corneal collagen cross-linking for keratoconus. Am J Ophthalmol. 2011;152:748Y Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg. 2009;25:S812YS Coskunseven E, Jankov MR 2nd, Hafezi F, et al. Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus. J Cataract Refract Surg. 2009;35:2084Y Coskunseven E, Jankov MR 2nd, Grentzelos MA, et al. Topographyguided transepithelial PRK after intracorneal ring segments implantation and corneal collagen CXL in a three-step procedure for keratoconus. J Refract Surg. 2013;29:54Y Kanellopoulos AJ. Long-term safety and efficacy follow-up of prophylactic higher fluence collagen cross-linking in high myopic laser-assisted in situ keratomileusis. Clin Ophthalmol. 2012;6:1125Y Kanellopoulos AJ, Asimellis G, Karabatsas C. Comparison of prophylactic higher fluence corneal cross-linking to control, in myopic LASIK, one year results. Clin Ophthalmol. 2014;8:2373Y Tan J, Lytle GE, Marshall J. Consecutive laser in situ keratomileusis and accelerated corneal crosslinking in highly myopic patients: preliminary results [published online ahead of print December 5, 2014]. Eur J Ophthalmol Spadea L. Corneal collagen cross-linking with riboflavin and UVA irradiation in pellucid marginal degeneration. J Refract Surg. 2010;26:375Y Stojanovic A, Zhang J, Chen X, et al. Topography-guided transepithelial surface ablation followed by corneal collagen cross-linking performed in a single combined procedure for the treatment of keratoconus and pellucid marginal degeneration. J Refract Surg. 2010;26:145Y Kymionis GD, Grentzelos MA, Portaliou DM, et al. Photorefractive keratectomy followed by same-day corneal collagen crosslinking after intrastromal corneal ring segment implantation for pellucid marginal degeneration. J Cataract Refract Surg. 2010;36:1783Y Corbin F 3rd. Pathogen inactivation of blood components: current status and introduction of an approach using riboflavin as a photosensitizer. Int J Hematol. 2002;76 suppl 2:253Y Martins SA, Combs JC, Noguera G, et al. Antimicrobial efficacy of riboflavin/uva combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci. 2008;49:3402Y Makdoumi K, Backman A, Mortensen J, et al. Evaluation of antibacterial efficacy of photo-activated riboflavin using ultraviolet light (UVA). Graefes Arch Clin Exp Ophthalmol. 2010;248:207Y Schrier A, Greebel G, Attia H, et al. In vitro antimicrobial efficacy of riboflavin and ultraviolet light on Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Pseudomonas aeruginosa. J Refract Surg. 2009;25:S799YS Price MO, Tenkman LR, Schrier A, et al. Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg. 2012;28:706Y Makdoumi K, Mortensen J, Sorkhabi O, et al. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012;250:95Y Said DG, Elalfy MS, Gatzioufas Z, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology. 2014;121:1377Y Vajpayee RB, Shafi SN, Maharana PK, et al. Evaluation of corneal collagen cross-linking as an additional therapy in mycotic keratitis. Clin Experiment Ophthalmol. 2015;43:103Y Li Z, Jhanji V, Tao X, et al. Riboflavin/ultraviolet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol. 2013;97:669Y Chan TC, Lau TW, Lee JW, et al. Corneal collagen cross-linking for infectious keratitis: an update of clinical studies [published online ahead of print May 19, 2015]. Acta Ophthalmol Wollensak G, Aurich H, Pham DT, et al. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg. 2007;33:516Y Bottos KM, Dreyfuss JL, Regatieri CV, et al. Immunofluorescence confocal microscopy of porcine corneas following collagen cross-linking treatment with riboflavin and ultraviolet A. J Refract Surg. 2008;24:S715YS Ehlers N, Hjortdal J. Riboflavin-ultraviolet light induced cross-linking in endothelial decompensation. Acta Ophthalmol. 2008;86:549Y Wollensak G, Aurich H, Wirbelauer C, et al. Potential use of riboflavin/uva cross-linking in bullous keratopathy. Ophthalmic Res. 2009;41:114Y Doors M, Tahzib NG, Eggink FA, et al. Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. Am J Ophthalmol. 2009;148:844Y851 e Asri D, Touboul D, Fournie P, et al. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg. 2011;37:2137Y2143. * 2015 Asia Pacific Academy of Ophthalmology 305

7 Xu et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 5, September/October Henriquez MA, Izquierdo L Jr, Bernilla C, et al. Riboflavin/ultraviolet A corneal collagen cross-linking for the treatment of keratoconus: visual outcomes and Scheimpflug analysis. Cornea. 2011;30:281Y Gokhale NS. Corneal endothelial damage after collagen cross-linking treatment. Cornea. 2011;30:1495Y Mazzotta C, Balestrazzi A, Baiocchi S, et al. Stromal haze after combined riboflavin-uva corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Experiment Ophthalmol. 2007;35:580Y Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-uvayinduced cross-linking in keratoconus. J Refract Surg. 2009;25:S824YS Angunawela RI, Arnalich-Montiel F, Allan BD. Peripheral sterile corneal infiltrates and melting after collagen crosslinking for keratoconus. J Cataract Refract Surg. 2009;35:606Y Rodriguez-Ausin P, Gutierrez-Ortega R, Arance-Gil A, et al. Keratopathy after cross-linking for keratoconus. Cornea. 2011;30:1051Y Koppen C, Vryghem JC, Gobin L, et al. Keratitis and corneal scarring after UVA/riboflavin cross-linking for keratoconus. J Refract Surg. 2009;25:S819YS Mangioris GF, Papadopoulou DN, Balidis MO, et al. Corneal infiltrates after corneal collagen cross-linking. J Refract Surg. 2010;26:609Y Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35:1358Y Sharma N, Maharana P, Singh G, et al. Pseudomonas keratitis after collagen crosslinking for keratoconus: case report and review of literature. J Cataract Refract Surg. 2010;36:517Y Rama P, Di Matteo F, Matuska S, et al. Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use. J Cataract Refract Surg. 2009;35:788Y Garcia-Delpech S, Diaz-Llopis M, Udaondo P, et al. Fusarium keratitis 3 weeks after healed corneal cross-linking. J Refract Surg. 2010;26:994Y Labiris G, Kaloghianni E, Koukoula S, et al. Corneal melting after collagen cross-linking for keratoconus: a case report. J Med Case Rep. 2011;5: Gokhale NS, Vemuganti GK. Diclofenac-induced acute corneal melt after collagen crosslinking for keratoconus. Cornea. 2010;29:117Y Romppainen T, Bachmann LM, Kaufmann C, et al. Effect of riboflavin-uvayinduced collagen cross-linking on intraocular pressure measurement. Invest Ophthalmol Vis Sci. 2007;48:5494Y Kymionis GD, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg. 2007;33:1982Y Ghanem RC, Netto MV, Ghanem VC, et al. Peripheral sterile corneal ring infiltrate after riboflavin-uva collagen cross-linking in keratoconus. Cornea. 2012;31:702Y Gautam, Jhanji V, Satpathy G, et al. Microsporidial keratitis after collagen cross-linking. Ocul Immunol Inflamm. 2013;21:495Y Kymionis G, Portaliou D. Corneal crosslinking with riboflavin and UVA for the treatment of keratoconus. J Cataract Refract Surg. 2007;33: 1143Y1144; author reply Kymionis GD, Portaliou DM, Diakonis VF, et al. Posterior linear stromal haze formation after simultaneous photorefractive keratectomy followed by corneal collagen cross-linking. Invest Ophthalmol Vis Sci. 2010;51:5030Y Wollensak G, Spoerl E, Wilsch M, et al. Endothelial cell damage after riboflavinyultraviolet-a treatment in the rabbit. J Cataract Refract Surg. 2003;29:1786Y Goldich Y, Marcovich AL, Barkana Y, et al. Safety of corneal collagen cross-linking with UV-A and riboflavin in progressive keratoconus. Cornea. 2010;29:409Y Abad JC, Vargas A. Gaping of radial and transverse corneal incisions occurring early after CXL. J Cataract Refract Surg. 2011;37:2214Y2217. Change your thoughts and you change your world. V Norman Vincent Peale * 2015 Asia Pacific Academy of Ophthalmology