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Refractive and topographic results of benzalkonium chloride–assisted transepithelial crosslinking
ARTICLE
Refractive and topographic results of benzalkonium chloride–assisted transepithelial crosslinking Carina Koppen, MD, Kristien Wouters, MSc, PhD, Danny Mathysen, MSc, Jos Rozema, MSc, PhD, Marie-Jose Tassignon, MD, PhD
PURPOSE: To evaluate the effect of benzalkonium chloride–assisted (BAC) transepithelial collagen crosslinking (CXL) in eyes with progressive keratoconus and a minimum follow-up of 6 months. SETTING: Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium. DESIGN: Cohort study. METHODS: Eyes with progressive keratoconus had CXL treatment without epithelial debridement. The standard CXL irradiation was preceded by instillation of proparacaine drops 0.5% preserved with BAC 0.005% every 5 minutes for 30 minutes. Selected parameters of refraction assessed by Placido disk (Eyesys) and Scheimpflug (Pentacam) examinations were compared before CXL and after CXL at 6, 12, and 18 months. RESULTS: The study enrolled 53 eyes of 38 patients. Sphere, cylinder, as well as maximum keratometry (K max) simulated K values (steep, flat, astigmatism), and refractive power values (steep, flat, astigmatism) measured using the Placido disk device remained stable over the 18-month follow-up. Only corrected distance visual acuity showed a statistically significant improvement at 6 months and 12 months. The Scheimpflug device measurements of maximum K and pachymetry at the thinnest point showed statistically significant progression throughout the study. No patient developed corneal haze or other complications. CONCLUSION: Transepithelial CXL using proparacaine drops 0.5% preserved with BAC 0.005% was less effective than standard CXL in stabilizing progressive keratoconus. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2012; 38:1000–1005 Q 2012 ASCRS and ESCRS
Corneal collagen crosslinking (CXL) by means of riboflavin and ultraviolet-A (UVA) light was introduced by Wollensak et al.1 The technique creates extra crosslinks in the corneal stroma to increase the rigidity of the corneal tissue. Since 2003, several clinical studies2–10 have indicated that standard CXL with epithelial debridement is effective in stopping the progression of keratoconus. The idea of riboflavin–UVA CXL without epithelial removal was first applied in the United State by Boxer WachlerA in 2004. It was introduced in Europe by Pinelli in 2006.B Authors of studies using in vitro testing,11,12 however, point out that the uptake of riboflavin by the cornea is strongly reduced without epithelial removal, thereby impairing the efficacy of the CXL process. Discussions on whether to leave the 1000
Q 2012 ASCRS and ESCRS Published by Elsevier Inc.
epithelium intact or to remove it continue to enliven the yearly International Corneal Cross-Linking Conference. For patient comfort, a CXL technique that does not require removal of the epithelium might be preferable. Safety would also be enhanced with a transepithelial procedure that keeps the epithelial barrier function intact and avoids wound-response reactions in the stroma. Boxer Wachler et al.13 argue that the use of preservative-based anesthetic drops is a decisive feature for the success of transepithelial CXL. Benzalkonium chloride (BAC) can loosen the tight junctions of the corneal epithelial cells, increasing permeability for riboflavin and allowing CXL without removal of the epithelium.14 Peer-reviewed literature on this topic is scarce, comprising 3 limited reports of 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2012.01.024
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transepithelial CXL combined with intrastromal corneal ring implantation.15–17 In 2009, Wollensak and Iomdina18 evaluated the biomechanical efficacy of the transepithelial technique as proposed by Pinelli in vivo in rabbits. They found that transepithelial CXL with BAC-containing proparacaine eyedrops led to a biomechanical stiffening effect that was one fifth that of the standard CXL protocol. They speculate that this technique might have an indication in eyes with a thin cornea (stromal pachymetry !400 mm) when the criteria for safe CXL are otherwise not met. Confronted with 4 cases of complications after CXL (2 cases of sterile keratouveitis, 1 infectious ulcer, 1 late epithelial defect) in a series of 36 eyes in our department, we became interested in the concept of transepithelial CXL. Encouraged by the research of Wollensak and Iomdina,18 we decided to follow their treatment protocol to offer a safer CXL procedure to our patients. In the informed consent process, we explained that the dosage and effect of CXL would be lower but that the necessary dosage of CXL for an individual patient is still under investigation. We report the results of BAC-assisted transepithelial crosslinking over a follow-up ranging from 6 to 18 months. PATIENTS AND METHODS Patients This prospective longitudinal study was performed at the Ophthalmology Department, Antwerp University Hospital, from July 2009 to December 2010. For statistical evaluation of the refractive and topographic outcome, the study included all eyes with progressive keratoconus that had uneventful riboflavin–UVA CXL during this period. All eyes included had a minimum follow-up of 6 months. The study was performed in accordance with the principles of the Declaration of Helsinki and approved by the hospital’s ethics committee (reference 6/5/21). All patients read and signed an informed consent form; for patients younger than 18 years, both parents were required to sign the form.
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As shown in a previous study,19 patients wearing contact lenses should be excluded from the evaluation of CXL outcomes because the use of these lenses affects topographic parameters. No patient in this study had a history of rigid contact lens wear.
Ophthalmologic Examination and Follow-up Progression of keratoconus over a 6-month period was defined as an increase in the maximum keratometry (K) value of at least 1.00 diopter (D) on Placido-disk topography or elevation-based tomography supported by worsening of visual acuity and refraction. In young patients, a history of a recent decrease in visual acuity and diagnosis of keratoconus were considered sufficient evidence of progression. All stages of keratoconus except advanced cones with scarring (stage IV of the Krumeich classification20) were treated. Patients were examined before CXL (ie, baseline); 1, 3, and 6 months after CXL; and at 6-month intervals thereafter. Because the group of eyes was heterogeneous, with only severe cases with corneal scarring excluded, the effect of the CXL treatment was measured by changes from baseline. The following subjective parameters were recorded: corrected distance visual acuity (CDVA), manifest sphere, and cylinder. The following objective parameters were established using Placido-disk topography (Eyesys system, Eyesys Vision, Inc.): maximum K value, inferior–superior (I–S) value, simulated K measurements (simulated K steep, simulated K flat, astigmatism), and refractive power measurements (refractive power steep, refractive power flat, astigmatism). For Scheimpflug tomography (Pentacam, Oculus Optikger€ ate GmbH), the maximum K value and pachymetry at the thinnest point were recorded.
Surgical Technique The CXL was performed without epithelial debridement. In the first 30 minutes, proparacaine 0.5% preserved with BAC 0.005% (Alcaine) was instilled every 5 minutes. In the second 30 minutes, riboflavin 0.1% in dextran 20.0% (Peschke Meditrade GmbH) was added every 3 minutes. Irradiation was performed with the Vega C.B.M. X-linker (OFTA High-Tech) using standard parameters (UVA 365 nm, 3 mW/cm2) while proparacaine and riboflavin instillation was continued every 5 minutes and every 3 minutes, respectively. After completion of the treatment, ofloxacin drops (Trafloxal) were instilled and continued 3 times a day for 5 days.
Statistical Analysis
Submitted: August 26, 2011. Final revision submitted: January 16, 2012. Accepted: January 18, 2012. From the Department of Ophthalmology (Koppen, Mathysen, Rozema, Tassignon) and Department of the Medical Director/ Statistics (Wouters), Antwerp University Hospital, Edegem, and the Faculty of Medicine (Koppen, Mathysen, Rozema, Tassignon), University of Antwerp, Wilrijk, Antwerp, Belgium. Presented at the 6th International Congress of Corneal CrossLinking, Milan, Italy, January 2011. Corresponding author: Carina Koppen, MD, Department of Ophthalmology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: [email protected].
The statistical analysis addressed 2 sources of withinsubject correlation; that is, the correlation between both eyes of the same patient and the correlation due to repeated measurements. Both sources of within-subject correlation were fitted in a mixed-effects model with a nested eyewithin-patient random effect. A separate model was fitted for each parameter. All statistical analyses were performed using SAS software (version 9.2, SAS Institute, Inc.). A P value less than 0.05 was considered statistically significant.
RESULTS Seven eyes of 5 patients were lost to follow-up within 6 months after treatment and were not included. Fifteen eyes of 10 patients were excluded because contact
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Table 1. Mean parameter values at baseline (53 eyes). Parameter
Mean G SEM
Range
CDVA (decimal) Sphere (D) Cylinder (D) I–S value (D) K max Placido disk (D) Sim K steep (D) Sim K flat (D) Sim astigmatism (D) RP steep (D) RP flat (D) RP astigmatism (D) K max Scheimpflug (D) Pachymetry thinnest point (mm)
0.58 G 0.26 1.02 G 1.65 1.83 G 1.63 5.95 G 4.02 54.71 G 8.57 48.69 G 5.39 45.26 G 3.21 3.43 G 3.02 51.24 G 7.77 46.22 G 6.19 5.02 G 2.92 55.21 G 7.91 462.36 G 45.60
0.05, 1.00 C1.75, 6.00 0.00, 6.00 0.27, 16.90 44.16, 87.26 41.97, 71.65 39.89, 58.59 0.06, 13.90 41.93, 79.64 38.48, 68.82 0.13, 11.48 44.50, 83.10 354.00, 573.00
CDVA Z corrected distance visual acuity; I–S Z inferior–superior; K Z keratometry; max Z maximum; RP Z refractive power; SEM Z standard error of the mean; Sim Z simulated
lens correction was initiated after the CXL treatment. The final study group consisted of 53 eyes of 38 patients. The mean age of the 29 men and 9 women was 24.02 years G 7.29 (SD) (range 12 to 46 years). There were more right eyes than left eyes (31 versus 22). Table 1 shows the mean values at baseline. Pre-CXL data were available for all 53 eyes in this study group. Fifty-one eyes were evaluated at 6 months, 37 eyes at 12 months, and 21 eyes at 18 months. Table 2 shows the visual acuity, refraction, and topography results compared with baseline values
and the statistical significance of the changes from baseline. The CDVA improved slightly (!0.1), but significantly, at 6 months and 12 months. The parameters on Placido-disk topography remained stable throughout the study period compared with baseline with the exception of the I–S value, which increased significantly at all time points. On Scheimpflug imaging, there was a highly significant increase in the maximum K value and a significant decrease in pachymetry at the thinnest point throughout the follow-up period. DISCUSSION The advantages of transepithelial CXL for the patient include painless treatment and an early return to contact lens wear and daily activities. Regarding the safety of the CXL procedure, epithelial debridement in and of itself can be complicated by wound infection, epithelial healing problems, and complications related to the activation of wound-healing responses in the stroma. Adding UV irradiation to epithelial debridement causes cytotoxic damage to the keratocytes in the corneal stroma up to a depth of 300 mm in standard CXL and up to 200 mm in transepithelial CXL.18 Most studies of complications report isolated cases of viral reactivation,21 haze,22 melting,23 and infectious ulceration.24 We observed a prevalence of sterile keratitis and scarring in 3.4% of 117 eyes at 2 Belgian treatment centers,25 which is in accordance with the complication rate of 2.9% in a similar series by Koller et al.26 Raiskup et al.27 report permanent corneal haze leading to a loss of 2 lines or more of CDVA in 8.6% of patients after CXL. More advanced cases with higher K values
Table 2. Mean difference from baseline value after false discovery rate correction. 6 Mo Follow-up (N Z 51) Parameter CDVA (decimal) Sphere (D) Cylinder (D) I–S value (D) K max Placido disk (D) Sim K steep (D) Sim K flat (D) Sim astigmatism (D) RP steep (D) RP flat (D) RP astigmatism (D) K max Scheimpflug (D) Pachymetry thinnest point (mm)
Mean G SEM 0.07 G 0.02* 0.33 G 0.17 0.19 G 0.15 0.51 G 0.22* 0.35 G 0.25 0.40 G 0.20 0.03 G 0.09 0.37 G 0.18 0.07 G 0.28 0.49 G 0.25 0.42 G 0.23 0.94 G 0.30* 6.30 G 1.77*
Range 0.20, C0.37 1.50, C5.00 3.00, C4.00 4.16, C5.86 6.59, C4.58 9.54, C4.88 6.62, C1.28 1.65, C6.17 5.98, C5.46 8.95, C6.27 6.64, C2.97 2.60, C7.80 43.00, C14.00
12 Mo Follow-up (N Z 37) Mean G SEM 0.06 G 0.02* 0.23 G 0.18 0.04 G 0.16 0.64 G 0.25* 0.47 G 0.28 0.44 G 0.23 0.20 G 0.10 0.25 G 0.21 0.18 G 0.32 0.50 G 0.28 0.31 G 0.25 1.33 G 0.32* 8.06 G 1.97*
Range 0.22, C0.40 3.75, C2.00 4.00, C6.00 3.99, C5.61 5.69, C6.21 9.66, C11.37 2.95, C1.71 4.06, C10.06 8.20, C7.83 4.64, C8.60 7.66, C4.21 2.40, C8.20 57.00, C19.00
18 Mo Follow-up (N Z 18) Mean G SEM 0.05 G 0.03 0.04 G 0.21 0.08 G 0.19 0.88 G 0.33* 0.65 G 0.35 0.48 G 0.28 0.23 G 0.12 0.26 G 0.26 0.21 G 0.40 0.57 G 0.35 0.35 G 0.31 1.76 G 0.39* 10.31 G 2.47*
Range 0.10, C0.50 5.75, C2.00 1.75, C3.00 2.97, C10.72 5.47, C8.40 9.77, C7.05 2.54, C2.14 1.16, C4.91 7.00, C8.52 1.88, C9.83 7.40, C3.45 3.10, C11.30 58.00, C9.00
CDVA Z corrected distance visual acuity; I–S Z inferior–superior; K Z keratometry; max Z maximum; RP Z refractive power; SEM Z standard error of the mean; Sim Z simulated *Statistically significant
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(71.1 D versus 62.1 D in the control group) and lower pachymetry (420.0 mm versus 478.1 mm) could be considered to be at higher risk for developing permanent haze. Taken together, these reports indicate that the incidence of complications related to CXL could reach 10% in more advanced cases of keratoconus, and this should remind us of the precautionary principle of first, do no harm. Modifications of the standard CXL treatment, however, should not be used in patients without first performing safety and efficiency testing.18 Wollensak and Iomdina’s18 extensive research on biomechanical and histological changes after CXL with and without epithelial debridement in rabbits provided validation for BAC-assisted transepithelial CXL. They used proparacaine 0.5% drops preserved with BAC 0.005% as a pretreatment before CXL and they found a significant increase in corneal rigidity in stress– strain measurements. However, the effect was only one fifth of the effect of standard CXL with epithelial debridement. We believe that we present the first report on the clinical application of Wollensak and Iomdina’s18 protocol of transepithelial CXL using proparacaine 0.5% drops preserved with BAC 0.005%. The results of subjective testing with visual acuity and refraction measurements indicate that transepithelial CXL stabilized refraction and led to a statistically significant improvement in CDVA at 6 months and 12 months. If we then examine the objective measurements, in the first instance of the Placido-based topography (Eyesys) only, we can conclude that there was stabilization of all disease parameters with the exception of the I–S value, which significantly increased at all time points in the study. If we look closer, however, we see nonsignificant worsening of all other parameters with the exception of refractive power astigmatism, which showed a nonsignificant improvement throughout the follow-up. Finally, when we take elevation-based topography (Scheimpflug Pentacam) into account, we see a statistically significant and progressive worsening of maximum K and pachymetry throughout the study. Of note is that the increase in the maximum K value on Scheimpflug topography was approximately 2.5 times higher than that measured with the Placido-disk system at every time point. The only other peer-reviewed study of transepithelial CXL in keratoconus patients was by Leccisotti.28 The study used a modified protocol with a prolonged pretreatment period (4 hours) with various eyedrops containing gentamicin, ethylenediaminetetraacetic acid, and BAC and oxybuprocaine drops preserved with benzoate to enhance epithelial permeability. This paired-eye study showed results similar to ours,
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with the K apex and the index of surface variance on Placido-based topography showing a nonsignificant worsening. No complications occurred in our series. At most, patients experienced some redness and photophobia for 24 to 48 hours. Leccisotti28 reports 2 eyes with transient subepithelial haze in a series of 51 patients. Although our results are less favorable than those of standard CXL, we are convinced that the technique of CXL without epithelial debridement should be pursued further. Kissner et al.29 recently assessed the efficacy of transepithelial CXL in vivo in rabbits with hypoosmolar riboflavin 0.1% solution with BAC 0.02% and BAC 0.04% versus the standard solution of unpreserved riboflavin 0.1% in dextran. Stress– strain measurements showed that treatment with hypoosmolar BAC 0.02% induced a sufficient increase in epithelial permeability for the passage of riboflavin, resulting in increased corneal stiffening that was similar to that with standard CXL. In December 2011, SpoerlC presented promising results on the efficacy of riboflavin 0.1% with BAC 0.01% in sodium chloride 0.44%. He referred to research showing that an osmotic gradient over an epithelial cell layer leads to a change in the ultrastructure of the tight junctions and thereby a modulation of the paracellular transport of molecules through the epithelium.30 The different result regarding the change in maximum K values between Placido-based topography and elevation-based topography in our study is an unexpected finding. It is commonly assumed by clinicians that the sagittal map on the Pentacam Scheimpflug system corresponds to the sagittal topography map on Eyesys and other Placido-based devices. This may be true for recognition of the color-coded pattern; however, the K values have to be correlated and corrected for comparison between Pentacam Scheimpflug corneal analysis and Eyesys Placido-disk corneal analysis. Indeed, studies comparing Pentacam Scheimpflug topography and Placido-based topography found that these systems are not fully interchangeable.31,32 Although most studies of CXL used a Placido-based device,1–5,8 with the increasing popularity of Scheimpflug tomography, more recent publications have used Scheimpflug imaging.6,7,9,10 Until now, no one has reported the use of both systems in the follow-up of CXL patients. In the literature and in clinical practice, authors consider the change in the maximum K value over a specific period of time to be the main marker to define disease progression.1–10 Regardless of the topography technique used, progression of keratoconus is generally defined as an increase in the maximum K value by 1.00 D or more in 6 months,4–8 12 months,3,7,10 or 24 months.9 Koller et al.7 are the
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only ones who studied the variability in Scheimpflug imaging in 10 keratoconus patients within the same session; the change was considered significant if the K value changed by more than 3 maximally measured standard deviations, corresponding to approximately G1.00 D on Pentacam Scheimpflug maps. Based on our findings, we conclude that future study of the reproducibility of anterior curvature measurements is required to define criteria for topographic stability or a significant change with different devices in patients with different stages of keratoconus. In conclusion, transepithelial CXL using riboflavin 0.1% in dextran 20.0% standard solution drops preceded by instillation of proparacaine 0.5% drops preserved with benzalkonium chloride 0.005% seemed to be less efficient than standard CXL; however, there were no side effects. We realize a limitation is that ours was not a prospective comparative trial; however, the results are not unexpected in view of Wollensak and Iomdina’s18 calculations based on in vivo transepithelial CXL of rabbit corneas. Further research is ongoing to refine the transepithelial treatment and improve efficacy. Several preliminary reports of changes in the composition of riboflavin drops or iontophoresis for transepithelial delivery of riboflavin have been presented.D–F The results seem promising and indicate that further modifications of the transepithelial CXL technique could lead to the same stiffening effect as standard CXL. WHAT WAS KNOWN Corneal CXL with epithelial debridement can be associated with corneal haze, sterile infiltrates, and infectious keratitis. In a prior rabbit study of the biomechanical efficacy of a transepithelial CXL technique using BAC-containing proparacaine eyedrops, a stiffening effect was achieved but was limited to one fifth of that produced with an epithelium-off CXL protocol. WHAT THIS PAPER ADDS Transepithelial CXL using riboflavin 0.1% in dextran 20.0% standard solution drops preceded by instillation of proparacaine 0.5% drops preserved with BAC 0.005% may be less effective at stabilizing or improving topographic features of keratoconus than standard CXL but was not associated with corneal haze or keratitis in this series. Measuring the anterior curvature with different devices (Placido versus Scheimpflug) led to different results regarding the effects of CXL.
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18. Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg 2009; 35:540–546 19. Koppen C, Gobin L, Mathysen D, Wouters K, Tassignon M-J. Influence of contact lens wear on the results of ultraviolet A/riboflavin cross-linking for progressive keratoconus. Br J Ophthalmol 2011; 95:1402–1405 € lle A. Live-epikeratophakia for 20. Krumeich JH, Daniel J, Knu keratoconus. J Cataract Refract Surg 1998; 24:456–463 21. Kymionis GD, Portaliou DM, Bouzoukis DI, Suh LH, Pallikaris AI, Markomanolakis M, Yoo SH. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007; 33:1982–1984 22. Herrmann CIA, Hammer T, Duncker GIW. Haze-Bildung nach Vernetzungstherapie bei Keratokonus [Haze formation (corneal scarring) after cross-linking therapy in keratoconus]. Ophthalmologe 2008; 105:485–487 23. Faschinger C, Kleinert R, Wedrich A. Beidseitiges Einschmelzen der Hornhaut nach beidseitigem simultanen KollagenCrosslinking bei Keratokonus und Down-Syndrom [Corneal melting in both eyes after simultaneous corneal crosslinking in a patient with keratoconus and Down syndrome]. Ophthalmologe 2010; 107:951–955 24. Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 2009; 35:588–589 25. Koppen C, Vryghem JC, Gobin L, Tassignon M-J. Keratitis and corneal scarring after UVA/riboflavin cross-linking for keratoconus. J Refract Surg 2009; 25:S819–S823 26. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009; 35:1358–1362 27. Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced crosslinking in keratoconus. J Refract Surg 2009; 25:S824–S828 28. Leccisotti A, Islam T. Transepithelial corneal collagen crosslinking in keratoconus. J Refract Surg 2010; 26:942–948 29. Kissner A, Spoerl E, Jung R, Spekl K, Pillunat L, Raiskup F. Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/riboflavin corneal collagen cross-linking. Curr Eye Res 2010; 35:715–721 30. Tokuda S, Miyazaki H, Nakajima K, Yamada T, Marunaka Y. NaCl flux between apical and basolateral side recruits claudin1 to tight junction strands and regulates paracellular transport. Biochem Biophys Res Commun 2010; 393:390–396 31. De Stefano VS, Soares Melo LA Junior, Mallmann F, Schor P. cido e o sistema Permutabilidade entre o disco de Pla
lise quantitativa e qualitativa [InterchangeabilScheimpflug: ana ity between Placido disc and Scheimpflug system: quantitative and qualitative analysis]. Arq Bras Oftalmol 2010; 73:363–366. Available at: http://www.scielo.br/pdf/abo/v73n4/v73n4a13.pdf. Accessed February 20, 2012 32. Read SA, Collins MJ, Iskander DR, Davis BA. Corneal topography with Scheimpflug imaging and videokeratography: comparative study of normal eyes. J Cataract Refract Surg 2009; 35:1072–1081
OTHER CITED MATERIAL A. Boxer Wachler BS, ‘‘Corneal Collagen Crosslinking with Riboflavin,’’ Cataract & Refract Surg Today, January 2005, pages 73–74. Available at: http://www.crstoday.com/PDF%20Articles/ 0105/PDFs/f12_boxerwaqchler.pdf. Accessed February 20, 2012 B. Pinelli R, “The Italian Refractive Surgery Society (SICR) Results Using C3 R,” presented at the 2nd International Congress of €rich, Switzerland, December, 2006 Corneal Cross-Linking, Zu C. Spoerl E, Raiskup F, “CXL With or Without Epithelial Abrasion: Is There Any Difference in Corneal Biomechanics?” presented at the 6th International Congress of Corneal Cross-Linking, Milan, Italy, January 2011 D. Bikbova G, Bikbov M. “Transepithelial Collagen Crosslinking by Electrophoresis of Riboflavin (TCCER),” presented at the 2nd EuCornea Congress of the ESCRS, Vienna, Austria, September 2011 E. Ziebarth NM, Persaud I, Arrieta E, Dias J, Lee E, Rowaan C, I, Yoo SH, Parel J-M. Efficiency of Coulomb controlled Nose iontophoresis for transcorneal delivery of riboflavin: a pilot study. IOVS 2011; 52: ARVO E-Abstract 2544 F. Waring G IV, Fant B, Stulting R, Roy P, “Iontophoretic Delivery of Riboflavin as a Cross-Linking Agent With UV-A in Patients for the Treatment of Keratoconus,” presented at the XXIX congress of the European Society of Cataract & Refractive Surgeons, Vienna, Austria, September 2011
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First author: Carina Koppen, MD Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium
Refractive and topographic results of benzalkonium chloride–assisted transepithelial crosslinking Carina Koppen, MD, Kristien Wouters, MSc, PhD, Danny Mathysen, MSc, Jos Rozema, MSc, PhD, Marie-Jose Tassignon, MD, PhD
PURPOSE: To evaluate the effect of benzalkonium chloride–assisted (BAC) transepithelial collagen crosslinking (CXL) in eyes with progressive keratoconus and a minimum follow-up of 6 months. SETTING: Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium. DESIGN: Cohort study. METHODS: Eyes with progressive keratoconus had CXL treatment without epithelial debridement. The standard CXL irradiation was preceded by instillation of proparacaine drops 0.5% preserved with BAC 0.005% every 5 minutes for 30 minutes. Selected parameters of refraction assessed by Placido disk (Eyesys) and Scheimpflug (Pentacam) examinations were compared before CXL and after CXL at 6, 12, and 18 months. RESULTS: The study enrolled 53 eyes of 38 patients. Sphere, cylinder, as well as maximum keratometry (K max) simulated K values (steep, flat, astigmatism), and refractive power values (steep, flat, astigmatism) measured using the Placido disk device remained stable over the 18-month follow-up. Only corrected distance visual acuity showed a statistically significant improvement at 6 months and 12 months. The Scheimpflug device measurements of maximum K and pachymetry at the thinnest point showed statistically significant progression throughout the study. No patient developed corneal haze or other complications. CONCLUSION: Transepithelial CXL using proparacaine drops 0.5% preserved with BAC 0.005% was less effective than standard CXL in stabilizing progressive keratoconus. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2012; 38:1000–1005 Q 2012 ASCRS and ESCRS
Corneal collagen crosslinking (CXL) by means of riboflavin and ultraviolet-A (UVA) light was introduced by Wollensak et al.1 The technique creates extra crosslinks in the corneal stroma to increase the rigidity of the corneal tissue. Since 2003, several clinical studies2–10 have indicated that standard CXL with epithelial debridement is effective in stopping the progression of keratoconus. The idea of riboflavin–UVA CXL without epithelial removal was first applied in the United State by Boxer WachlerA in 2004. It was introduced in Europe by Pinelli in 2006.B Authors of studies using in vitro testing,11,12 however, point out that the uptake of riboflavin by the cornea is strongly reduced without epithelial removal, thereby impairing the efficacy of the CXL process. Discussions on whether to leave the 1000
Q 2012 ASCRS and ESCRS Published by Elsevier Inc.
epithelium intact or to remove it continue to enliven the yearly International Corneal Cross-Linking Conference. For patient comfort, a CXL technique that does not require removal of the epithelium might be preferable. Safety would also be enhanced with a transepithelial procedure that keeps the epithelial barrier function intact and avoids wound-response reactions in the stroma. Boxer Wachler et al.13 argue that the use of preservative-based anesthetic drops is a decisive feature for the success of transepithelial CXL. Benzalkonium chloride (BAC) can loosen the tight junctions of the corneal epithelial cells, increasing permeability for riboflavin and allowing CXL without removal of the epithelium.14 Peer-reviewed literature on this topic is scarce, comprising 3 limited reports of 0886-3350/$ - see front matter doi:10.1016/j.jcrs.2012.01.024
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transepithelial CXL combined with intrastromal corneal ring implantation.15–17 In 2009, Wollensak and Iomdina18 evaluated the biomechanical efficacy of the transepithelial technique as proposed by Pinelli in vivo in rabbits. They found that transepithelial CXL with BAC-containing proparacaine eyedrops led to a biomechanical stiffening effect that was one fifth that of the standard CXL protocol. They speculate that this technique might have an indication in eyes with a thin cornea (stromal pachymetry !400 mm) when the criteria for safe CXL are otherwise not met. Confronted with 4 cases of complications after CXL (2 cases of sterile keratouveitis, 1 infectious ulcer, 1 late epithelial defect) in a series of 36 eyes in our department, we became interested in the concept of transepithelial CXL. Encouraged by the research of Wollensak and Iomdina,18 we decided to follow their treatment protocol to offer a safer CXL procedure to our patients. In the informed consent process, we explained that the dosage and effect of CXL would be lower but that the necessary dosage of CXL for an individual patient is still under investigation. We report the results of BAC-assisted transepithelial crosslinking over a follow-up ranging from 6 to 18 months. PATIENTS AND METHODS Patients This prospective longitudinal study was performed at the Ophthalmology Department, Antwerp University Hospital, from July 2009 to December 2010. For statistical evaluation of the refractive and topographic outcome, the study included all eyes with progressive keratoconus that had uneventful riboflavin–UVA CXL during this period. All eyes included had a minimum follow-up of 6 months. The study was performed in accordance with the principles of the Declaration of Helsinki and approved by the hospital’s ethics committee (reference 6/5/21). All patients read and signed an informed consent form; for patients younger than 18 years, both parents were required to sign the form.
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As shown in a previous study,19 patients wearing contact lenses should be excluded from the evaluation of CXL outcomes because the use of these lenses affects topographic parameters. No patient in this study had a history of rigid contact lens wear.
Ophthalmologic Examination and Follow-up Progression of keratoconus over a 6-month period was defined as an increase in the maximum keratometry (K) value of at least 1.00 diopter (D) on Placido-disk topography or elevation-based tomography supported by worsening of visual acuity and refraction. In young patients, a history of a recent decrease in visual acuity and diagnosis of keratoconus were considered sufficient evidence of progression. All stages of keratoconus except advanced cones with scarring (stage IV of the Krumeich classification20) were treated. Patients were examined before CXL (ie, baseline); 1, 3, and 6 months after CXL; and at 6-month intervals thereafter. Because the group of eyes was heterogeneous, with only severe cases with corneal scarring excluded, the effect of the CXL treatment was measured by changes from baseline. The following subjective parameters were recorded: corrected distance visual acuity (CDVA), manifest sphere, and cylinder. The following objective parameters were established using Placido-disk topography (Eyesys system, Eyesys Vision, Inc.): maximum K value, inferior–superior (I–S) value, simulated K measurements (simulated K steep, simulated K flat, astigmatism), and refractive power measurements (refractive power steep, refractive power flat, astigmatism). For Scheimpflug tomography (Pentacam, Oculus Optikger€ ate GmbH), the maximum K value and pachymetry at the thinnest point were recorded.
Surgical Technique The CXL was performed without epithelial debridement. In the first 30 minutes, proparacaine 0.5% preserved with BAC 0.005% (Alcaine) was instilled every 5 minutes. In the second 30 minutes, riboflavin 0.1% in dextran 20.0% (Peschke Meditrade GmbH) was added every 3 minutes. Irradiation was performed with the Vega C.B.M. X-linker (OFTA High-Tech) using standard parameters (UVA 365 nm, 3 mW/cm2) while proparacaine and riboflavin instillation was continued every 5 minutes and every 3 minutes, respectively. After completion of the treatment, ofloxacin drops (Trafloxal) were instilled and continued 3 times a day for 5 days.
Statistical Analysis
Submitted: August 26, 2011. Final revision submitted: January 16, 2012. Accepted: January 18, 2012. From the Department of Ophthalmology (Koppen, Mathysen, Rozema, Tassignon) and Department of the Medical Director/ Statistics (Wouters), Antwerp University Hospital, Edegem, and the Faculty of Medicine (Koppen, Mathysen, Rozema, Tassignon), University of Antwerp, Wilrijk, Antwerp, Belgium. Presented at the 6th International Congress of Corneal CrossLinking, Milan, Italy, January 2011. Corresponding author: Carina Koppen, MD, Department of Ophthalmology, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: [email protected].
The statistical analysis addressed 2 sources of withinsubject correlation; that is, the correlation between both eyes of the same patient and the correlation due to repeated measurements. Both sources of within-subject correlation were fitted in a mixed-effects model with a nested eyewithin-patient random effect. A separate model was fitted for each parameter. All statistical analyses were performed using SAS software (version 9.2, SAS Institute, Inc.). A P value less than 0.05 was considered statistically significant.
RESULTS Seven eyes of 5 patients were lost to follow-up within 6 months after treatment and were not included. Fifteen eyes of 10 patients were excluded because contact
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Table 1. Mean parameter values at baseline (53 eyes). Parameter
Mean G SEM
Range
CDVA (decimal) Sphere (D) Cylinder (D) I–S value (D) K max Placido disk (D) Sim K steep (D) Sim K flat (D) Sim astigmatism (D) RP steep (D) RP flat (D) RP astigmatism (D) K max Scheimpflug (D) Pachymetry thinnest point (mm)
0.58 G 0.26 1.02 G 1.65 1.83 G 1.63 5.95 G 4.02 54.71 G 8.57 48.69 G 5.39 45.26 G 3.21 3.43 G 3.02 51.24 G 7.77 46.22 G 6.19 5.02 G 2.92 55.21 G 7.91 462.36 G 45.60
0.05, 1.00 C1.75, 6.00 0.00, 6.00 0.27, 16.90 44.16, 87.26 41.97, 71.65 39.89, 58.59 0.06, 13.90 41.93, 79.64 38.48, 68.82 0.13, 11.48 44.50, 83.10 354.00, 573.00
CDVA Z corrected distance visual acuity; I–S Z inferior–superior; K Z keratometry; max Z maximum; RP Z refractive power; SEM Z standard error of the mean; Sim Z simulated
lens correction was initiated after the CXL treatment. The final study group consisted of 53 eyes of 38 patients. The mean age of the 29 men and 9 women was 24.02 years G 7.29 (SD) (range 12 to 46 years). There were more right eyes than left eyes (31 versus 22). Table 1 shows the mean values at baseline. Pre-CXL data were available for all 53 eyes in this study group. Fifty-one eyes were evaluated at 6 months, 37 eyes at 12 months, and 21 eyes at 18 months. Table 2 shows the visual acuity, refraction, and topography results compared with baseline values
and the statistical significance of the changes from baseline. The CDVA improved slightly (!0.1), but significantly, at 6 months and 12 months. The parameters on Placido-disk topography remained stable throughout the study period compared with baseline with the exception of the I–S value, which increased significantly at all time points. On Scheimpflug imaging, there was a highly significant increase in the maximum K value and a significant decrease in pachymetry at the thinnest point throughout the follow-up period. DISCUSSION The advantages of transepithelial CXL for the patient include painless treatment and an early return to contact lens wear and daily activities. Regarding the safety of the CXL procedure, epithelial debridement in and of itself can be complicated by wound infection, epithelial healing problems, and complications related to the activation of wound-healing responses in the stroma. Adding UV irradiation to epithelial debridement causes cytotoxic damage to the keratocytes in the corneal stroma up to a depth of 300 mm in standard CXL and up to 200 mm in transepithelial CXL.18 Most studies of complications report isolated cases of viral reactivation,21 haze,22 melting,23 and infectious ulceration.24 We observed a prevalence of sterile keratitis and scarring in 3.4% of 117 eyes at 2 Belgian treatment centers,25 which is in accordance with the complication rate of 2.9% in a similar series by Koller et al.26 Raiskup et al.27 report permanent corneal haze leading to a loss of 2 lines or more of CDVA in 8.6% of patients after CXL. More advanced cases with higher K values
Table 2. Mean difference from baseline value after false discovery rate correction. 6 Mo Follow-up (N Z 51) Parameter CDVA (decimal) Sphere (D) Cylinder (D) I–S value (D) K max Placido disk (D) Sim K steep (D) Sim K flat (D) Sim astigmatism (D) RP steep (D) RP flat (D) RP astigmatism (D) K max Scheimpflug (D) Pachymetry thinnest point (mm)
Mean G SEM 0.07 G 0.02* 0.33 G 0.17 0.19 G 0.15 0.51 G 0.22* 0.35 G 0.25 0.40 G 0.20 0.03 G 0.09 0.37 G 0.18 0.07 G 0.28 0.49 G 0.25 0.42 G 0.23 0.94 G 0.30* 6.30 G 1.77*
Range 0.20, C0.37 1.50, C5.00 3.00, C4.00 4.16, C5.86 6.59, C4.58 9.54, C4.88 6.62, C1.28 1.65, C6.17 5.98, C5.46 8.95, C6.27 6.64, C2.97 2.60, C7.80 43.00, C14.00
12 Mo Follow-up (N Z 37) Mean G SEM 0.06 G 0.02* 0.23 G 0.18 0.04 G 0.16 0.64 G 0.25* 0.47 G 0.28 0.44 G 0.23 0.20 G 0.10 0.25 G 0.21 0.18 G 0.32 0.50 G 0.28 0.31 G 0.25 1.33 G 0.32* 8.06 G 1.97*
Range 0.22, C0.40 3.75, C2.00 4.00, C6.00 3.99, C5.61 5.69, C6.21 9.66, C11.37 2.95, C1.71 4.06, C10.06 8.20, C7.83 4.64, C8.60 7.66, C4.21 2.40, C8.20 57.00, C19.00
18 Mo Follow-up (N Z 18) Mean G SEM 0.05 G 0.03 0.04 G 0.21 0.08 G 0.19 0.88 G 0.33* 0.65 G 0.35 0.48 G 0.28 0.23 G 0.12 0.26 G 0.26 0.21 G 0.40 0.57 G 0.35 0.35 G 0.31 1.76 G 0.39* 10.31 G 2.47*
Range 0.10, C0.50 5.75, C2.00 1.75, C3.00 2.97, C10.72 5.47, C8.40 9.77, C7.05 2.54, C2.14 1.16, C4.91 7.00, C8.52 1.88, C9.83 7.40, C3.45 3.10, C11.30 58.00, C9.00
CDVA Z corrected distance visual acuity; I–S Z inferior–superior; K Z keratometry; max Z maximum; RP Z refractive power; SEM Z standard error of the mean; Sim Z simulated *Statistically significant
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(71.1 D versus 62.1 D in the control group) and lower pachymetry (420.0 mm versus 478.1 mm) could be considered to be at higher risk for developing permanent haze. Taken together, these reports indicate that the incidence of complications related to CXL could reach 10% in more advanced cases of keratoconus, and this should remind us of the precautionary principle of first, do no harm. Modifications of the standard CXL treatment, however, should not be used in patients without first performing safety and efficiency testing.18 Wollensak and Iomdina’s18 extensive research on biomechanical and histological changes after CXL with and without epithelial debridement in rabbits provided validation for BAC-assisted transepithelial CXL. They used proparacaine 0.5% drops preserved with BAC 0.005% as a pretreatment before CXL and they found a significant increase in corneal rigidity in stress– strain measurements. However, the effect was only one fifth of the effect of standard CXL with epithelial debridement. We believe that we present the first report on the clinical application of Wollensak and Iomdina’s18 protocol of transepithelial CXL using proparacaine 0.5% drops preserved with BAC 0.005%. The results of subjective testing with visual acuity and refraction measurements indicate that transepithelial CXL stabilized refraction and led to a statistically significant improvement in CDVA at 6 months and 12 months. If we then examine the objective measurements, in the first instance of the Placido-based topography (Eyesys) only, we can conclude that there was stabilization of all disease parameters with the exception of the I–S value, which significantly increased at all time points in the study. If we look closer, however, we see nonsignificant worsening of all other parameters with the exception of refractive power astigmatism, which showed a nonsignificant improvement throughout the follow-up. Finally, when we take elevation-based topography (Scheimpflug Pentacam) into account, we see a statistically significant and progressive worsening of maximum K and pachymetry throughout the study. Of note is that the increase in the maximum K value on Scheimpflug topography was approximately 2.5 times higher than that measured with the Placido-disk system at every time point. The only other peer-reviewed study of transepithelial CXL in keratoconus patients was by Leccisotti.28 The study used a modified protocol with a prolonged pretreatment period (4 hours) with various eyedrops containing gentamicin, ethylenediaminetetraacetic acid, and BAC and oxybuprocaine drops preserved with benzoate to enhance epithelial permeability. This paired-eye study showed results similar to ours,
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with the K apex and the index of surface variance on Placido-based topography showing a nonsignificant worsening. No complications occurred in our series. At most, patients experienced some redness and photophobia for 24 to 48 hours. Leccisotti28 reports 2 eyes with transient subepithelial haze in a series of 51 patients. Although our results are less favorable than those of standard CXL, we are convinced that the technique of CXL without epithelial debridement should be pursued further. Kissner et al.29 recently assessed the efficacy of transepithelial CXL in vivo in rabbits with hypoosmolar riboflavin 0.1% solution with BAC 0.02% and BAC 0.04% versus the standard solution of unpreserved riboflavin 0.1% in dextran. Stress– strain measurements showed that treatment with hypoosmolar BAC 0.02% induced a sufficient increase in epithelial permeability for the passage of riboflavin, resulting in increased corneal stiffening that was similar to that with standard CXL. In December 2011, SpoerlC presented promising results on the efficacy of riboflavin 0.1% with BAC 0.01% in sodium chloride 0.44%. He referred to research showing that an osmotic gradient over an epithelial cell layer leads to a change in the ultrastructure of the tight junctions and thereby a modulation of the paracellular transport of molecules through the epithelium.30 The different result regarding the change in maximum K values between Placido-based topography and elevation-based topography in our study is an unexpected finding. It is commonly assumed by clinicians that the sagittal map on the Pentacam Scheimpflug system corresponds to the sagittal topography map on Eyesys and other Placido-based devices. This may be true for recognition of the color-coded pattern; however, the K values have to be correlated and corrected for comparison between Pentacam Scheimpflug corneal analysis and Eyesys Placido-disk corneal analysis. Indeed, studies comparing Pentacam Scheimpflug topography and Placido-based topography found that these systems are not fully interchangeable.31,32 Although most studies of CXL used a Placido-based device,1–5,8 with the increasing popularity of Scheimpflug tomography, more recent publications have used Scheimpflug imaging.6,7,9,10 Until now, no one has reported the use of both systems in the follow-up of CXL patients. In the literature and in clinical practice, authors consider the change in the maximum K value over a specific period of time to be the main marker to define disease progression.1–10 Regardless of the topography technique used, progression of keratoconus is generally defined as an increase in the maximum K value by 1.00 D or more in 6 months,4–8 12 months,3,7,10 or 24 months.9 Koller et al.7 are the
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only ones who studied the variability in Scheimpflug imaging in 10 keratoconus patients within the same session; the change was considered significant if the K value changed by more than 3 maximally measured standard deviations, corresponding to approximately G1.00 D on Pentacam Scheimpflug maps. Based on our findings, we conclude that future study of the reproducibility of anterior curvature measurements is required to define criteria for topographic stability or a significant change with different devices in patients with different stages of keratoconus. In conclusion, transepithelial CXL using riboflavin 0.1% in dextran 20.0% standard solution drops preceded by instillation of proparacaine 0.5% drops preserved with benzalkonium chloride 0.005% seemed to be less efficient than standard CXL; however, there were no side effects. We realize a limitation is that ours was not a prospective comparative trial; however, the results are not unexpected in view of Wollensak and Iomdina’s18 calculations based on in vivo transepithelial CXL of rabbit corneas. Further research is ongoing to refine the transepithelial treatment and improve efficacy. Several preliminary reports of changes in the composition of riboflavin drops or iontophoresis for transepithelial delivery of riboflavin have been presented.D–F The results seem promising and indicate that further modifications of the transepithelial CXL technique could lead to the same stiffening effect as standard CXL. WHAT WAS KNOWN Corneal CXL with epithelial debridement can be associated with corneal haze, sterile infiltrates, and infectious keratitis. In a prior rabbit study of the biomechanical efficacy of a transepithelial CXL technique using BAC-containing proparacaine eyedrops, a stiffening effect was achieved but was limited to one fifth of that produced with an epithelium-off CXL protocol. WHAT THIS PAPER ADDS Transepithelial CXL using riboflavin 0.1% in dextran 20.0% standard solution drops preceded by instillation of proparacaine 0.5% drops preserved with BAC 0.005% may be less effective at stabilizing or improving topographic features of keratoconus than standard CXL but was not associated with corneal haze or keratitis in this series. Measuring the anterior curvature with different devices (Placido versus Scheimpflug) led to different results regarding the effects of CXL.
REFERENCES 1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A– induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627 2. Caporossi A, Baiocchi S, Mazotta C, Traversi C, Caporossi T. 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; 32:837–845 3. Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34:796–801 4. Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg 2008; 24:S720–S725 E, Trazza S, Rosetta P, Vinciguerra R, 5. Vinciguerra P, Albe Seiler T, Epstein D. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology 2009; 116:369–378 6. Coskunseven E, Jankov MR II, Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg 2009; 25:371–376 7. Koller T, Iseli HP, Hafezi F, Vinciguerra P, Seiler T. Scheimpflug imaging of corneas after collagen cross-linking. Cornea 2009; 28:510–515 8. Caporossi A, Mazotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: the Siena Eye Cross Study. Am J Ophthalmol 2010; 149:585–593 9. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg 2011; 37:149–160. Available at: http:// www.vision-institute.com/UserFiles/File/CXL%20results%20 published2011.pdf. Accessed February 20, 2012 10. Henriquez MA, Izquierdo L Jr, Bernilla C, Zakrzewski PA, Mannis M. Riboflavin/Ultraviolet A corneal collagen crosslinking for the treatment of keratoconus: visual outcomes and Scheimpflug analysis. Cornea 2011; 30:281–286 11. Hayes S, O’Brart DP, Lamdin LS, Doutch J, Samaras K, Marshall J, Meek KM. Effect of complete epithelial debridement before riboflavin-ultraviolet-A corneal collagen crosslinking therapy. J Cataract Refract Surg 2008; 34:657–661 12. Baiocchi S, Mazotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg 2009; 35:893–899 13. Boxer Wachler BS, Pinelli R, Ertan A, Chan CCK. Safety and efficacy of transepithelial crosslinking (C3-R/CXL) [letter]. J Cataract Refract Surg 2010; 36:186–188; reply by S Baiocchi, C Mazzotta, A Caporossi, 188 189 14. Pinelli R. Corneal collagen crosslinking: is it necessary to remove the epithelium? J Intraocular Implant Refract Soc India 2008; 4:28–34 15. Chan CCK, Sharma M, Boxer Wachler BS. Effect of inferiorsegment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007; 33:75–80 16. Kamburoglu G, Ertan A. Intacs implantation with sequential collagen cross-linking treatment in postoperative LASIK ectasia. J Refract Surg 2008; 24:S726–S729 lu G. Refractive and topographic 17. Ertan A, Karacal H, Kamburog results of transepithelial cross-linking treatment in eyes with Intacs. Cornea 2009; 28:719–723
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First author: Carina Koppen, MD Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium