Corneal Collagen Crosslinking for Post-LASIK Ectasia: An Australian Study. 18 rigid gas permeable contact lenses, and intrastromal corneal

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1 original clinical study Corneal Collagen Crosslinking for ost-lasik Ectasia: An Australian Study Jessica Y. Tong, BMed, MD,* Deepa Viswanathan, hd, FRCS,* Christopher Hodge, hd, BAppSc(Orth), Gerard Sutton, FRANZCO, FRACS, Colin Chan, FRANZCO, and John J. Males, FRANZCO* urpose: ost laser-assisted in situ keratomileusis (LASIK) ectasia is a rare and unpredictable complication after LASIK. Corneal collagen crosslinking (CXL) has emerged as a promising technique to address this complication. Our study evaluates the long-term efficacy of CXL for post-lasik ectasia in an Australian setting. Design: Retrospective review of post-lasik ectasia patients referred to and treated at 3 corneal refractive surgery institutions in Sydney, Australia. Methods: Eleven patients (14 eyes; mean age, 39.7 ± 12.6 years) underwent epithelium-off CXL with follow-up ranging from months. Best spectacle-corrected visual acuity (BSCVA), simulated keratometry, corneal topography indices, and higher-order aberrations (HOAs) [mean ± standard error of the mean (SEM)] were measured with a rotating Scheimpflug camera (entacam, Oculus). Comparisons between baseline measurements and postoperative outcomes were performed using paired t test analysis. Results: At last follow-up, BSCVA improved significantly by 0.2 ± 0.06 logmar ( = 0.01), and 12 of 14 eyes showed no keratometric deterioration. Of the corneal topography indices, index of height asymmetry showed a trend toward a significant improvement ( = 0.05). There was no progression of corneal HOAs. Central corneal thickness was not significantly altered ( = 0.6). No major postoperative complications were observed. Conclusions: In the Australian setting, CXL has proven effective at stabilizing the progression of post-lasik ectasia, inducing corneal regularity, and improving visual acuity. Key Words: crosslinking, ectasia, LASIK, refractive surgery (Asia-ac J Ophthalmol 2017;6: ) ost laser-assisted in situ keratomileusis (LASIK) ectasia is a corneal disorder characterized by progressive stromal thinning and central or asymmetric inferior corneal steepening. 1 It has been suggested that central ectasia is associated with low residual stromal bed thickness, whereas inferotemporal ectasia is a sign of pre-existing forme fruste keratoconus (FFK) or pellucid marginal degeneration (MD). 2 ost-lasik ectasia can be histologically similar to keratoconus, sharing features such as microstriae in the stromal bed and thinning of the stromal collagen lamellae. From the *Sydney Cornea Clinic, Sydney; Faculty of Medicine and Health Sciences, Macquarie University, Sydney; Vision Eye Institute, Chatswood; Save Sight Institute, Sydney Medical School, University of Sydney, Sydney; and South West Vision Institute, Liverpool, New South Wales, Australia. Received for publication November 2, 2016; accepted February 7, The authors have no funding or conflicts of interest to declare. Reprints: Jessica Y. Tong, BMed, MD, Concord Repatriation General Hospital, Hospital Road, Concord NSW 2139, Australia. E mail: jtong_90@hotmail. com. Copyright 2017 by Asia acific Academy of Ophthalmology ISSN: DOI: /AO However, there is typically no disruption to the Bowman layer or endothelium. 3,4 ost-lasik ectasia was first described in 1998, which prompted concerns of an impending ectasia epidemic that fortunately never transpired. 5 Currently, its reported incidence ranges from %, although the true incidence is likely unknown due to a substantial number of patients being lost to follow-up. 3,6 10 atients can develop complications from 1 week to several years after LASIK, often presenting with an increase in myopia and astigmatism. 1,3,4 The exact pathophysiology of post-lasik ectasia remains unknown. It is thought that alteration of the anterior corneal biomechanics can precipitate thinning and compression of collagen fibrils, resulting in loss of global structural integrity. 1,4,11,12 Most cases are likely manifestations of occult ectatic disorders, such as FFK, MD, or keratoconus. 13 Other contributory factors are low residual stromal bed thickness less than 250 µm, young age, thin preoperative pachymetry, and high myopia. 4,12 15 Between-eye topographic asymmetry and atypical astigmatic patterns in young patients are additional risk factors recognized from clinical experience. The percent tissue altered (TA) metric is a depth-based marker to predict likelihood of post-lasik ectasia. A higher TA value has been associated with greater ectasia risk, regardless of preoperative topography patterns. 16,17 Therapeutic options traditionally include spectacle correction, 18 rigid gas permeable contact lenses, and intrastromal corneal ring segments. 4 In recent years, corneal collagen crosslinking (CXL) has emerged as a promising technique to address post- LASIK ectasia. It combines the use of ultraviolet A (UVA) irradiation and riboflavin as a photosensitizer to produce reactive oxygen species, which induce intra- and interfibrillar covalent bonds to biomechanically stabilize the cornea. 19,20 Several clinical studies have demonstrated that it effectively halts or even reverses progression of ectasia The current study aims to evaluate an Australian experience with CXL for the treatment of post-lasik ectasia and its long-term efficacy. The primary outcome measures are visual and refractive outcomes, corneal topographic changes, and higher-order aberrations (HOAs). MATERIALS AND METHODS Fourteen eyes of 11 patients with post-lasik ectasia who underwent CXL treatment were included in this retrospective study. atients were referred from multiple ophthalmic surgeons and treated at 1 of 3 different institutions between 2006 and The study was approved by the institutional ethics committee and conducted according to the principles of the Declaration of Helsinki. All patients provided informed consent. Inclusion Criteria atients 18 years of age or older with progressive post-lasik Asia-acific Journal of Ophthalmology Volume 6, Number 3, May/June 2017

2 Asia-acific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 Crosslinking for ost-lasik Ectasia ectasia were included. The indications for CXL included an increase in Kmax of 1.00 diopter (D) or more in 1 year, deterioration in best spectacle-corrected visual acuity (BSCVA), and the need for new contact lens fittings more than once in 2 years. Exclusion criteria were patients with corneal pachymetry less than 400 µm, corneal infections, autoimmune diseases, and pregnant or lactating women. Tests and Evaluation Contact lens wearers were instructed to discontinue wearing soft contact lenses for a minimum of 3 days and rigid gas permeable and hard lenses for a minimum of 2 weeks before the preoperative eye examination. All patients received preoperative and postoperative evaluation of BSCVA, corneal pachymetry, and corneal topography. Higher-order aberrations were measured in a subset of 16 eyes. The logarithm of the minimum angle of resolution (logmar) BSCVA was obtained using the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Manifest refraction spherical equivalent (MRSE) and cylindrical astigmatism were obtained. Corneal topography indices, pachymetry, and HOAs were measured with a noncontact rotating Scheimpflug camera (entacam, Oculus Inc, Germany). Crosslinking Technique The Dresden protocol involved removal of the corneal epithelium in a diameter of 9 mm, followed by saturation of the corneal stroma using Innocross-R riboflavin isotonic solution [riboflavin 5-phosphate (0.1%) plus 20% dextran T 500 in 2 ml syringes; IROC Innocross AG, Zurich, Switzerland] and UVA irradiation (370 nm, 3 mw/cm 2 for 30 min) under sterile conditions. The UVA machine used was the UV-X 1000 (IROC Innocross AG, Zurich, Switzerland). One eye received accelerated CXL, which was performed with 0.1% riboflavin in 20% dextran and accelerated UVA irradiation (370 nm, 9 mw/cm 2 for 10 min) under sterile conditions. After topical anesthesia, a lid speculum was inserted, and the epithelial tissue was removed in a 9.0-mm diameter area to allow penetration of riboflavin into the corneal stroma. The photosensitizer 0.1% riboflavin solution was then applied (2 3 drops every 3 minutes) to the cornea for 30 minutes before the irradiation to allow sufficient saturation of the stroma. The central cornea (8.0 mm diameter) was then exposed to UVA light with a wavelength of 370 nm and an irradiance of 3 mw/cm 2 for 30 minutes or 9 mw/cm 2 for 10 minutes. Riboflavin solution was instilled (2 3 drops every 3 minutes) during the UVA exposure. After treatment, the eye was washed with 20 ml of a balanced salt solution. Antibiotic eye drops (ofloxacin 0.3%) and steroid eye drops (dexamethasone 0.1%) were applied, and a bandage contact lens was placed on the eye until complete re-epithelialization. After contact lens removal, the postoperative treatment regimen consisted of a tapering schedule of topical dexamethasone 0.1% over a period of 2 months. Corneal Topography Seven corneal topography indices were evaluated: index of surface variance (ISV), index of vertical asymmetry (IVA), keratoconus index (KI), central keratoconus index (CKI), minimum radius of curvature (Rmin), index of height asymmetry (IHA), and index of height decentration (IHD). Higher-order aberrations were measured with the entacam and quantified as the root mean square (RMS) value for primary horizontal coma, primary vertical coma, and total spherical aberration. Statistical Analysis Changes in BSCVA, MRSE, refractive astigmatism, simulated keratometry values in the flattest meridian (K1) and steepest meridian (K2), topometric astigmatism, and other corneal topography indices from baseline were analyzed to evaluate the effect of CXL treatment. Comparisons between preoperative and postoperative outcomes at last follow-up were made using paired t tests. Statistical evaluation was performed using IBM SSS Statistics Software A value of less than 0.05 was considered statistically significant. RESULTS Of 11 patients (14 eyes), there were 5 males and 6 females (mean age, 39.7 ± 12.6 years). The refractive and topographic outcomes post-cxl at 1 year and last follow-up (range, months) are demonstrated in Tables 1 3. Visual Acuity and Refractive Outcomes In patients who were followed up beyond 1 year, the difference in visual outcome between baseline and 12 months was not significant ( = 0.07). However, at last follow-up, logmar BSCVA had improved significantly by 0.2 ± 0.06 standard error of the mean (SEM) ( = 0.01). Compared with baseline measurements, mean keratometry values had progressed at 12 months, then recovered at last follow-up. The greatest response was observed in K2, with a mean reduction of 0.4 ± 0.4 D at last followup ( = 0.3) (Fig. 1). Ultimately, 12 of 14 eyes showed no keratometric deterioration. Central corneal thickness was not significantly altered by crosslinking ( = 0.6). Topographic Results All pre-cxl corneal topography indices were in the pathological range (Table 2). After treatment, there was a general trend toward correction across all indices. Improvements Table 1. Refractive and Keratometric Changes in Treated Eyes re- and arameter re-cxl (Reference) 1-Year Follow-Up BSCVA (logmar) K1 (D) K2 (D) Kmax (D) 0.3 ± 0.06 SEM 42.7 ± ± ± ± 0.04 SEM 44.1 ± ± ± ± 0.03 SEM 42.6 ± ± ± Asia-acific Academy of Ophthalmology 229

3 Tong et al Asia-acific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 Table 2. Corneal Topography Indices in Treated Eyes re- and arameter Abnormal athological re-cxl (Reference) 1-Year Follow-Up ISV IVA KI CKI Rmin (mm) IHA IHD < <6.71 > ± 15.7 SEM 1.1 ± ± ± ± ± ± ± ± ± ± ± ± ± ± 16.8 SEM 1.1 ± ± ± ± ± ± Abnormal and pathological values derived from J Cataract Refract Surg 2011;37: and Clin Ophthalmol 2013;7: observed after 12 months became more marked with longer duration of follow-up time. Index of height asymmetry showed the greatest trend toward significant improvement at last follow-up ( = 0.05). Corneal topography maps derived from 1 eye provide a clinical demonstration of a reduction in Kmax of 1.0 D and an associated improvement in logmar BSCVA from 0.48 to 0.1 (Fig. 2). There was no significant difference in primary horizontal coma, primary vertical coma, or total spherical aberration at any stage after CXL treatment (Table 3). Early postoperative complications were limited to mild corneal edema and stromal haze, and had resolved in all patients within 6 months. There were no serious complications such as scarring or infections in this retrospective series. DISCUSSION Corneal CXL was first introduced to Australia in 2006 as a treatment modality for progressive keratoconus. 26 Our results confirm its efficacy as a minimally invasive technique for the treatment of post-lasik ectasia. The total number of LASIK procedures across all author institutions exceeded 30,000 over the past decade. Although the number of post-lasik ectasia patients is likely to be higher than the current cohort, we believe that the number of patients included in this study remains a relatively accurate portrayal of the Australian experience with post-lasik ectasia referrals. Although post-lasik ectasia does not appear to have reached epidemic proportions, it remains an essential concern for refractive surgeons. Crosslinking combines UVA irradiation with riboflavin, which acts as a photosensitizer to create free radicals and induce new covalent bonds between stromal collagen fibrils to increase corneal biomechanical stability. 18 The stiffening effect is heterogeneous and more pronounced in the anterior cornea. In recent years, accelerated CXL has been demonstrated to be safe and effective in pediatric and adult patients. 27,28 The reduced exposure time to UVA is thought to be cytoprotective. Badawi et al 29 reported significant endothelial cell loss and polymegathism 3 months after treatment and recovery within 1 year. 29 However, the authors did not compare the magnitude of endothelial damage with conventional CXL-treated eyes, which limits conclusions about the precedence of either method. In our cohort, 1 eye was treated using accelerated CXL and achieved improvements in keratometry and topographic values at last follow-up. Although we are limited in our ability to make meaningful comparisons between the 2 protocols, we consider the accelerated and Dresden CXL treatment methods to be comparable. revious studies have reported a significant improvement in BSCVA and refractive spherical equivalent after CXL. Yildirim et al 25 demonstrated a significant improvement in BSCVA from logmar 0.27 to 0.19 and cylindrical power from 2.28 to 1.96 D after a mean follow-up of 42 months. Salgado et al 24 reported BSCVA regression in the first postoperative month due to an increase in myopia and MRSE. This soon recovered within 3 months and subsequently remained stable over 12 months. Unlike keratoconus, ectatic eyes do not gain significant improvements in BSCVA until 12 months after CXL. 22 In our cohort, there were no lines lost on the logmar chart. A significant improvement in BSCVA was masked at 12 months, only becoming apparent at last follow-up. Iatrogenic alterations of the anterior stromal collagen Table 3. Zernike Analysis of Higher-Order Aberrations in Treated Eyes re- and ost- CXL arameter re-cxl figure 1. Difference in K2 (diopters) between baseline and last follow-up. RMS HOA Vertical coma Horizontal coma Total spherical aberration 2.5 ± 0.6 SEM 2.1 ± ± ± ± 0.5 SEM 1.9 ± ± ± Asia-acific Academy of Ophthalmology

4 Asia-acific Journal of Ophthalmology Volume 6, Number 3, May/June 2017 Crosslinking for ost-lasik Ectasia figure 2. Corneal topography maps provide a clinical demonstration of the long-term improvement in keratometry values after CXL. fibrils may predispose to a delayed healing response. Changes in BSCVA do not always correlate with magnitude of improvement, which suggests that topographic measurements are important considerations. The earliest manifestation of corneal irregularity is vertical asymmetry due to inferotemporal thinning. 30,31 Index of surface variance and index of height asymmetry are therefore useful indices for early diagnosis and monitoring of progressive keratoconus and perhaps corneal ectasia. 32 Vinciguerra et al 33 described stabilization and flattening of the central corneal curvature 6 months post-cxl for iatrogenic ectasia, but these changes were not significant after 1 year. In our study, IHA showed a trend toward normalization after CXL, whereas the other indices remained unchanged. This suggests possible regularization of the cornea despite the lack of reported changes to the overall curvature. ost-lasik ectasia has been described as a region of abnormal steepening and increased curvature within a centrally flattened optical zone. 33 rominence of vertical coma is the most sensitive parameter to distinguish between a normal cornea and a keratoconus suspect. 31,34,35 This may be extrapolated to post- LASIK ectasia eyes. Spherical aberration tends toward negative values in keratoconic eyes due to steepening of the anterior corneal surface. 35 Vinciguerra et al 33 reported a nonsignificant decrease in corneal coma and spherical aberration coefficients 1 year after CXL. Similarly, we demonstrated a decrease in primary horizontal coma, vertical coma, and total spherical aberration. Although these changes did not reach statistical significance, our results demonstrate that CXL is effective in halting the progression of aberrations in corneal curvature. The impact of HOA as a significant marker of postsurgical corneal regularization is, however, yet to be fully elucidated. Our study demonstrates that CXL is an appropriate and effective intervention for post-lasik ectasia. Benefits include improved visual acuity, reduced vertical asymmetry, and corneal topographic indices and HOAs did not progress further. Although 2 out of 14 eyes (from the same patient) had increased K2 readings of up to 2 D, there was an associated improvement of logmar 0.1 at last follow-up. Although an improvement in visual acuity does not exclude the possibility of ectatic progression, it may also show that post-lasik ectasia eyes inherently undergo a slower recovery process. One limitation of our study is the lack of a control eye for comparison, as 3 patients were treated in both 2017 Asia-acific Academy of Ophthalmology eyes. However, our results are strengthened by a long duration of postoperative follow-up: the date of the last examination ranged from months after CXL, and 11 out of 14 eyes had a minimum follow-up of 2 years. In the Australian setting, CXL is a safe and effective method for treating post-lasik ectasia, as patients benefit from long-term improvements in visual acuity and vertical asymmetry with overall stabilization of corneal curvature REFERENCES Twa M, Nichols J, Joslin C, et al. Characteristics of corneal ectasia after LASIK for myopia. Cornea. 2004;23: Kerautret J, Colin J, Touboul D, et al. Biomechanical characteristics of the ectatic cornea. J Cataract Refract Surg. 2008;34: Meghpara B, Nakamura H, Macsai M, et al. Keratectasia after laser in situ keratomileusis: a histopathologic and immunohistochemical study. 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