ARTICLE
Safety of high-intensity corneal collagen crosslinking George D. Kymionis, MD, PhD, Michael A. Grentzelos, MD, Vardhaman P. Kankariya, MD, Dimitrios A. Liakopoulos, MD, MSc, Dimitra M. Portaliou, MD, Konstantinos I. Tsoulnaras, MD, Alexandra E. Karavitaki, MD, Aristophanis I. Pallikaris, MSc
PURPOSE: To evaluate the safety of a new high-intensity corneal collagen crosslinking (CXL) treatment protocol for keratoconus. SETTING: Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece. DESIGN: Prospective interventional case series. METHODS: Patients with progressive keratoconus had CXL using a new treatment protocol with 9 mW/cm2 irradiance for duration of 10 minutes. The rate of reepithelialization, endothelial cell density (ECD), corrected distance visual acuity (CDVA), and steep and flat keratometry (K) values were evaluated preoperatively and 3 months postoperatively. RESULTS: Nine patients (10 eyes) were enrolled. No intraoperative or early postoperative complications were observed in any patient. The ECD did not change significantly 3 months postoperatively (PZ.169). The CDVA improved from 0.19 logMAR G 0.20 (SD) preoperatively to 0.10 G 0.16 logMAR 3 months postoperatively; however, the improvement did not attain significance (PZ.141). No eye lost lines of CDVA. The mean steep K readings decreased significantly from 48.04 G 2.57 diopters (D) preoperatively to 46.51 G 2.81 D 3 months postoperatively (PZ.047); the mean flat K readings did not change significantly postoperatively (PZ.285). CONCLUSIONS: Corneal collagen crosslinking at 9 mW/cm2 irradiance for 10 minutes did not cause significant changes in ECD or intraoperative or early postoperative complications. None patient lost a line of CDVA 3 months after the procedure. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1337–1340 Q 2014 ASCRS and ESCRS
The introduction of corneal collagen crosslinking (CXL) in routine clinical practice has changed the management of keratoconus. Corneal collagen crosslinking is a technique that uses riboflavin (photosensitizer, vitamin B2) and ultraviolet-A (UVA) irradiation. The photochemical reaction between the 2 in the corneal stroma leads to the development of chemical bonds between collagen fibrils. Thereby, CXL strengthens the cornea and slows or even stops the progression of keratoconus and corneal ectasia.1–6 The efficacy and safety of the standard CXL procedure for stabilizing keratoconus has been reported in several studies.4–6 In the Dresden protocol, after epithelial debridement and riboflavin stromal saturation for 30 minutes, UVA light (365 nm) is used for illumination
Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
at the intensity of 3 mW/cm2 for 30 minutes.1 This delivers 5.4 J/cm2 total energy to the cornea. To shorten the treatment span of the CXL procedure for improving patient cooperation and comfort, an increase in illumination intensity has been used. By increasing intensity, it is hypothesized that a fundamental photochemical law, the Bunsen-Roscoe law of reciprocity, can be applied in CXL. According to this law, the effects of the photochemical reaction are similar if the intensity and time is changed while the total energy is maintained. Thus, the total energy delivered and amount of crosslinks induced in standard CXL (3 mW/cm2 for 30 minutes) should be similar to irradiation at 9 mW/cm2 for 10 minutes and 18 mW/cm2 for 5 minutes, all delivering 5.4 J/cm2.
0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.11.041
1337
1338
SAFETY OF HIGH-INTENSITY CXL
The purpose of this study was to evaluate safety of a new high-intensity CXL (9 mW/cm2 for 10 minutes) treatment protocol for keratoconus. PATIENTS AND METHODS This prospective interventional case series comprised eyes with progressive keratoconus. Patients were thoroughly informed about the nature of the procedure, the possible risks, and the current clinical experience. Institutional review board approval was obtained, and all patients gave written informed consent in accordance with institutional guidelines of the Declaration of Helsinki. Inclusion criteria comprised progressive keratoconus (progression of the ectatic disorder indicating necessity of treatment based on an increase in cone apex keratometry [K] of 0.75 diopter (D) or on alteration of 0.75 D in spherical equivalent refraction during the past 6 months), corneal thickness more than 400 mm, no central or paracentral subepithelial or stromal corneal scarring, no pregnancy or lactation, absence of previous anterior segment ocular surgery, absence of autoimmune or collagen disease, active ocular infection, and severe dry eye. Preoperative and 3-month postoperative data obtained from the patient records included ocular and general health history assessment, age, sex, corrected distance visual acuity (CDVA), corneal topography (iTrace, Tracey Technologies), slitlamp examination, rate of reepithelialization, and endothelial cell density (ECD) using corneal confocal microscopy with a modified confocal scanning laser ophthalmoscope (HRT II, Heidelberg Engineering GmbH).
Surgical Technique The same surgeon (G.D.K.) performed all procedures under sterile conditions. After topical anesthesia with proxymetacaine hydrochloride 0.5% eyedrops (Alcaine) was applied, the corneal epithelium was removed using transepithelial phototherapeutic keratectomy (Cretan protocol).4 After epithelial removal, riboflavin (0.1% solution of 10 mg riboflavin-5-phosphate in 10 mL dextran-T-500 20% solution, Medicross, Medio Haus Medizinprodukte GmbH) was instilled on the center of the cornea every 3 minutes for approximately 30 minutes. Ultraviolet-A irradiation was performed using a UVA optical system (CCL-365, Peschke
Submitted: October 1, 2013. Final revision submitted: November 13, 2013. Accepted: November 13, 2013. From Vardinoyiannion Eye Institute of Crete (Kymionis, Grentzelos, Kankariya, Liakopoulos, Portaliou, Tsoulnaras, Karavitaki, Pallikaris), Faculty of Medicine, University of Crete, Heraklion, Crete, Greece; the Department of Ophthalmology (Kymionis, Kankariya, Portaliou), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA. Supported in part by the special research account of the University of Crete. Corresponding author: George D. Kymionis, MD, PhD, University of Crete, Faculty of Medicine Vardinoyiannion Eye Institute of Crete, 71003 Heraklion, Crete, Greece. E-mail: [email protected].
Meditrade GmbH). Before treatment, an intended irradiance of 9.0 mW/cm2 was calibrated using a UVA light meter (YK-35UV, Lutron Electronics Co., Inc.), which is supplied with the UVA optical system. Irradiance was performed for 10 minutes in an intended irradiance of 9.0 mW/cm2, corresponding to a total surface dose of 5.4 J/cm2. During UVA irradiation, riboflavin solution was applied every 1 to 2 minutes to maintain corneal saturation with riboflavin. At the end of the procedure, a silicone–hydrogel bandage contact lens (lotrafilcon B, Air Optix, Ciba Vision; 14.0 mm diameter, 8.6 base curvature, oxygen permeability 140 barrers) was applied until full reepithelialization. Postoperative medication included ofloxacin (Exocin) 4 times daily and chloramphenicol–dexamethasone drops (Dispersadron) 4 times daily until the epithelium healed completely. After full reepithelialization, the bandage contact lens was removed and patients received fluorometholone 0.1% drops (FML), which were tapered over the next 2 weeks. Patients were encouraged to use artificial tears at least 6 times a day for 3 months postoperatively.
Confocal Microscopy Confocal microscopy was performed using the modified confocal scanning laser ophthalmoscope in all patients as previously described.4
Statistical Analysis All data were analyzed for normality. Because normality was not valid for all data, the Wilcoxon signed-rank test (SPSS software, version 20, SPSS, Inc.) was used. All values are expressed as mean values G standard deviation. A P value less than 0.05 was considered significant. Visual acuity is expressed in logMAR notation.
RESULTS The study evaluated 10 eyes of 9 patients. The mean age of the 5 men and 4 women was 24.90 G 5.24 years (range 16 to 33 years). The follow-up was 3 months in all cases. No intraoperative or early postoperative complications were observed. The mean time of reepithelialization was 4.2 G 0.79 days (range 3 to 5 days). Table 1 shows the parameters evaluated preoperatively and at the 3-month postoperative visit. There was no statistically significant change in the ECD between preoperatively and 3 months postoperatively (PZ.169). The logMAR CDVA improved, although the improvement was not statistically significant (PZ.141). No eyes lost lines of CDVA (Figure 1). The decrease in the mean steep K readings from preoperatively to 3 months postoperatively was statistically significant (PZ.047), although the decrease in the mean flat K readings was not statistically significant (PZ.285). DISCUSSION Several studies have established the safety and efficacy of standard CXL for the stabilization of corneal ectatic disorders.4–6 Nevertheless, the Dresden protocol
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Table 1. Preoperative and postoperative patient data. Mean G SD Parameter
Preoperative
Postoperative
P Value
LogMAR CDVA Mean steep K (D) Mean flat K (D) ECD (cells/mm2)
0.19 G 0.20 48.04 G 2.57 43.88 G 1.67 2688 G 130
0.10 G 0.16 46.51 G 2.81 43.55 G 1.88 2640 G 127
.141 .047 .285 .169
CDVA Z corrected distance visual acuity; ECD Z endothelial cell density; K Z keratometry
requires up to 1 hour of surgical time (up to 30 minutes for riboflavin saturation and 30 minutes for UVA irradiation at 3 mW/cm2), which may be inconvenient to the patient as well as the surgeon.1 In an attempt to shorten the duration of treatment, 2 approaches have been proposed. One is riboflavin application by iontophoresis technique for a rapid stromal saturation and the other, use of high-intensity UVA irradiation.7,8 In accordance with the photochemical law of reciprocity (Bunsen-Roscoe law), it is possible to achieve the same photochemical effect (induced crosslinking) with a reduced irradiation time and correspondingly increased irradiation intensity so the total energy dose remains the same. Recently, Wernli et al.8 showed that the Bunsen-Roscoe reciprocity law is only valid for illumination intensities up to 40 to 50 mW/cm2 and illumination times more than 2 minutes. However, UVA irradiation may cause damage in keratocytes, corneal endothelial cells, the crystalline lens, and the retina.9 Riboflavin works as a photosensitizer and functions as a protective barrier against the harmful influence of UVA irradiation on the underlying tissues. The cell-damage threshold of UVA irradiation combined with riboflavin is 10 times lower than UVA irradiation alone in standard CXL.10 Although the total energy applied in high-intensity CXL is similar to that with the standard protocol, the intensity of irradiation is higher and may have acute side effects (eg, on the corneal endothelium). Two recent studies11,12 report transient corneal endothelial changes after accelerated CXL for the treatment of progressive keratoconus. In both studies, there was a significant decrease in ECD on corneal specular microscopy at the 1-month and 3-month postoperative intervals; the ECD returned to preoperative values by 6 months postoperatively.11,12 In contrast, using confocal microscopy, Touboul et al.13 found no significant changes in ECD after accelerated CXL. In our case series of high-intensity CXL (9 mW/cm2 for 10 minutes), there was no significant change in
Figure 1. Change in CDVA (safety) 3 months postoperatively (CDVA Z corrected distance visual acuity).
ECD; Touboul et al.13 report similar results but for a different irradiation time and irradiation intensity (30 mW/cm2 for 3 minutes). The results in the 2 recent studies that showed transient decrease in ECD at the 1-month and 3-month postoperative intervals11,12 may be attributed to the use of specular microscopy because in the presence of typical post-CXL corneal haze, increased scattering and limited visualization of the corneal endothelium may result. In contrast, confocal microscopy (used in our and the Touboul et al. study13) allows the examination of corneal endothelium in the presence of edema and haze; the composite nature of the images obtained ensures that confocal biomicroscopy is not affected by the scattering usually present in the third postoperative month after CXL.13,14 In addition, in our study there were no intraoperative or early postoperative complications and no eye had delayed reepithelialization. The CDVA remained stable postoperatively, and no patient lost a line of CDVA. The mean steep K readings decreased significantly postoperatively, while mean flat K readings did not change significantly. Limitations of our case series are the small number of patients and the short follow-up; thus, no sufficient conclusions can be made. Another limitation is the lack of a control group of standard CXL, which could facilitate the comparison between standard CXL (3 mW/cm2 for 30 minutes) and high-intensity CXL (9 mW/cm2 for 10 minutes). In conclusion, in our preliminary study of a highintensity CXL treatment protocol, CXL at 9 mW/cm2 irradiance for 10 minutes did not affect the ECD while the CDVA remained stable postoperatively. Even though preliminary results are not sufficient for an evaluation of the safety profile, CXL at 9 mW/cm2 irradiance for 10 minutes did not result in significant changes in ECD and or in intraoperative or early postoperative complications. In addition, no patient lost a line of CDVA 3 months after the procedure. Larger case series with a longer follow-up are required to confirm these encouraging results.
J CATARACT REFRACT SURG - VOL 40, AUGUST 2014
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SAFETY OF HIGH-INTENSITY CXL
WHAT WAS KNOWN Standard CXL (30 minutes UVA irradiation at intended irradiance of 3.0 mW/cm2 with total surface dose of 5.4 J/cm2) is a safe and efficient surgical procedure for stabilizing keratoconus. According to the BunsenRoscoe law of reciprocity, a 10-minute illumination at 9.0 mW/cm2 should provide the same effect with a 30-minute illumination at 3.0 mW/cm2. WHAT THIS PAPER ADDS Corneal collagen crosslinking at 9 mW/cm2 irradiance for 10 minutes did not result in significant changes in ECD and no intraoperative or early postoperative complications occurred. No patient lost a line of CDVA 3 months after the procedure.
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. Available at: http:// grmc.ca/assets/files/collagen_crosslinking_2003_wollensak.pdf. Accessed March 22, 2014 2. Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg 2007; 33:2035–2040 3. Kymionis GD, Karavitaki AE, Kounis GA, Portaliou DM, Yoo SH, Pallikaris IG. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinking. J Cataract Refract Surg 2009; 35:1298–1301 4. Kymionis GD, Grentzelos MA, Kounis GA, Diakonis VF, Limnopoulou AN, Panagopoulou SI. Combined transepithelial phototherapeutic keratectomy and corneal collagen crosslinking for progressive keratoconus. Ophthalmology 2012; 119:1777–1784 5. 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
6. Caporossi A, Mazzotta 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 7. Vinciguerra P, Rechichi M, Rosetta P, Romano MR, Mastropasqua L, Scorcia V, Azzolini C, Vinciguerra R. High fluence iontophoretic corneal collagen cross-linking: in vivo OCT imaging of riboflavin penetration [letter]. J Refract Surg 2013; 29:376–377; reply by H Nagaraj, R Shetty, RS Kumar, H Veluri, C Malhotra, KB Shetty, 377 8. Wernli J, Schumacher S, Spoerl E, Mrochen M. The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Inv Ophthalmol Vis Sci 2013; 54:1176–1180. Available at: http://www.iovs.org/ content/54/2/1176.full.pdf. Accessed March 22, 2014 9. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA–riboflavin cross-linking of the cornea. Cornea 2007; 26:385–389 €rl E, Reber F, Pillunat L, Funk R. Corneal 10. Wollensak G, Spo endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 2003; 35:324–328 € AK, Sogutlu-Sari E, C‚ınar Y, S‚ahin M, Tu €rkc‚u € FM, 11. Cingu _ Transient corneal endothelial € ksel H, S‚ahin A, C‚ac‚a I. Yu changes following accelerated collagen cross-linking for the treatment of progressive keratoconus. Cutan Ocul Toxicol 2013 Jul 17 [Epub ahead of print] € € AK, Tu €rkcu € FM, C‚ınar T, Yu € ksel H, Ozkurt 12. C‚ınar Y, Cingu ZG, C‚ac‚a I. Accelerated corneal collagen cross-linking for progressive keratoconus. Cutan Ocul Toxicol 2013 Oct 22 [Epub ahead of print] 13. Touboul D, Efron N, Smadja D, Praud D, Malet F, Colin J. Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. J Refract Surg 2012; 28:769–776 14. Hara M, Morishige N, Chikama T, Nishida T. Comparison of confocal biomicroscopy and noncontact specular microscopy for evaluation of the corneal endothelium. Cornea 2003; 22:512–515
J CATARACT REFRACT SURG - VOL 40, AUGUST 2014
First author: George D. Kymionis, MD, PhD Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
Safety of high-intensity corneal collagen crosslinking George D. Kymionis, MD, PhD, Michael A. Grentzelos, MD, Vardhaman P. Kankariya, MD, Dimitrios A. Liakopoulos, MD, MSc, Dimitra M. Portaliou, MD, Konstantinos I. Tsoulnaras, MD, Alexandra E. Karavitaki, MD, Aristophanis I. Pallikaris, MSc
PURPOSE: To evaluate the safety of a new high-intensity corneal collagen crosslinking (CXL) treatment protocol for keratoconus. SETTING: Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece. DESIGN: Prospective interventional case series. METHODS: Patients with progressive keratoconus had CXL using a new treatment protocol with 9 mW/cm2 irradiance for duration of 10 minutes. The rate of reepithelialization, endothelial cell density (ECD), corrected distance visual acuity (CDVA), and steep and flat keratometry (K) values were evaluated preoperatively and 3 months postoperatively. RESULTS: Nine patients (10 eyes) were enrolled. No intraoperative or early postoperative complications were observed in any patient. The ECD did not change significantly 3 months postoperatively (PZ.169). The CDVA improved from 0.19 logMAR G 0.20 (SD) preoperatively to 0.10 G 0.16 logMAR 3 months postoperatively; however, the improvement did not attain significance (PZ.141). No eye lost lines of CDVA. The mean steep K readings decreased significantly from 48.04 G 2.57 diopters (D) preoperatively to 46.51 G 2.81 D 3 months postoperatively (PZ.047); the mean flat K readings did not change significantly postoperatively (PZ.285). CONCLUSIONS: Corneal collagen crosslinking at 9 mW/cm2 irradiance for 10 minutes did not cause significant changes in ECD or intraoperative or early postoperative complications. None patient lost a line of CDVA 3 months after the procedure. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1337–1340 Q 2014 ASCRS and ESCRS
The introduction of corneal collagen crosslinking (CXL) in routine clinical practice has changed the management of keratoconus. Corneal collagen crosslinking is a technique that uses riboflavin (photosensitizer, vitamin B2) and ultraviolet-A (UVA) irradiation. The photochemical reaction between the 2 in the corneal stroma leads to the development of chemical bonds between collagen fibrils. Thereby, CXL strengthens the cornea and slows or even stops the progression of keratoconus and corneal ectasia.1–6 The efficacy and safety of the standard CXL procedure for stabilizing keratoconus has been reported in several studies.4–6 In the Dresden protocol, after epithelial debridement and riboflavin stromal saturation for 30 minutes, UVA light (365 nm) is used for illumination
Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
at the intensity of 3 mW/cm2 for 30 minutes.1 This delivers 5.4 J/cm2 total energy to the cornea. To shorten the treatment span of the CXL procedure for improving patient cooperation and comfort, an increase in illumination intensity has been used. By increasing intensity, it is hypothesized that a fundamental photochemical law, the Bunsen-Roscoe law of reciprocity, can be applied in CXL. According to this law, the effects of the photochemical reaction are similar if the intensity and time is changed while the total energy is maintained. Thus, the total energy delivered and amount of crosslinks induced in standard CXL (3 mW/cm2 for 30 minutes) should be similar to irradiation at 9 mW/cm2 for 10 minutes and 18 mW/cm2 for 5 minutes, all delivering 5.4 J/cm2.
0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.11.041
1337
1338
SAFETY OF HIGH-INTENSITY CXL
The purpose of this study was to evaluate safety of a new high-intensity CXL (9 mW/cm2 for 10 minutes) treatment protocol for keratoconus. PATIENTS AND METHODS This prospective interventional case series comprised eyes with progressive keratoconus. Patients were thoroughly informed about the nature of the procedure, the possible risks, and the current clinical experience. Institutional review board approval was obtained, and all patients gave written informed consent in accordance with institutional guidelines of the Declaration of Helsinki. Inclusion criteria comprised progressive keratoconus (progression of the ectatic disorder indicating necessity of treatment based on an increase in cone apex keratometry [K] of 0.75 diopter (D) or on alteration of 0.75 D in spherical equivalent refraction during the past 6 months), corneal thickness more than 400 mm, no central or paracentral subepithelial or stromal corneal scarring, no pregnancy or lactation, absence of previous anterior segment ocular surgery, absence of autoimmune or collagen disease, active ocular infection, and severe dry eye. Preoperative and 3-month postoperative data obtained from the patient records included ocular and general health history assessment, age, sex, corrected distance visual acuity (CDVA), corneal topography (iTrace, Tracey Technologies), slitlamp examination, rate of reepithelialization, and endothelial cell density (ECD) using corneal confocal microscopy with a modified confocal scanning laser ophthalmoscope (HRT II, Heidelberg Engineering GmbH).
Surgical Technique The same surgeon (G.D.K.) performed all procedures under sterile conditions. After topical anesthesia with proxymetacaine hydrochloride 0.5% eyedrops (Alcaine) was applied, the corneal epithelium was removed using transepithelial phototherapeutic keratectomy (Cretan protocol).4 After epithelial removal, riboflavin (0.1% solution of 10 mg riboflavin-5-phosphate in 10 mL dextran-T-500 20% solution, Medicross, Medio Haus Medizinprodukte GmbH) was instilled on the center of the cornea every 3 minutes for approximately 30 minutes. Ultraviolet-A irradiation was performed using a UVA optical system (CCL-365, Peschke
Submitted: October 1, 2013. Final revision submitted: November 13, 2013. Accepted: November 13, 2013. From Vardinoyiannion Eye Institute of Crete (Kymionis, Grentzelos, Kankariya, Liakopoulos, Portaliou, Tsoulnaras, Karavitaki, Pallikaris), Faculty of Medicine, University of Crete, Heraklion, Crete, Greece; the Department of Ophthalmology (Kymionis, Kankariya, Portaliou), Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA. Supported in part by the special research account of the University of Crete. Corresponding author: George D. Kymionis, MD, PhD, University of Crete, Faculty of Medicine Vardinoyiannion Eye Institute of Crete, 71003 Heraklion, Crete, Greece. E-mail: [email protected].
Meditrade GmbH). Before treatment, an intended irradiance of 9.0 mW/cm2 was calibrated using a UVA light meter (YK-35UV, Lutron Electronics Co., Inc.), which is supplied with the UVA optical system. Irradiance was performed for 10 minutes in an intended irradiance of 9.0 mW/cm2, corresponding to a total surface dose of 5.4 J/cm2. During UVA irradiation, riboflavin solution was applied every 1 to 2 minutes to maintain corneal saturation with riboflavin. At the end of the procedure, a silicone–hydrogel bandage contact lens (lotrafilcon B, Air Optix, Ciba Vision; 14.0 mm diameter, 8.6 base curvature, oxygen permeability 140 barrers) was applied until full reepithelialization. Postoperative medication included ofloxacin (Exocin) 4 times daily and chloramphenicol–dexamethasone drops (Dispersadron) 4 times daily until the epithelium healed completely. After full reepithelialization, the bandage contact lens was removed and patients received fluorometholone 0.1% drops (FML), which were tapered over the next 2 weeks. Patients were encouraged to use artificial tears at least 6 times a day for 3 months postoperatively.
Confocal Microscopy Confocal microscopy was performed using the modified confocal scanning laser ophthalmoscope in all patients as previously described.4
Statistical Analysis All data were analyzed for normality. Because normality was not valid for all data, the Wilcoxon signed-rank test (SPSS software, version 20, SPSS, Inc.) was used. All values are expressed as mean values G standard deviation. A P value less than 0.05 was considered significant. Visual acuity is expressed in logMAR notation.
RESULTS The study evaluated 10 eyes of 9 patients. The mean age of the 5 men and 4 women was 24.90 G 5.24 years (range 16 to 33 years). The follow-up was 3 months in all cases. No intraoperative or early postoperative complications were observed. The mean time of reepithelialization was 4.2 G 0.79 days (range 3 to 5 days). Table 1 shows the parameters evaluated preoperatively and at the 3-month postoperative visit. There was no statistically significant change in the ECD between preoperatively and 3 months postoperatively (PZ.169). The logMAR CDVA improved, although the improvement was not statistically significant (PZ.141). No eyes lost lines of CDVA (Figure 1). The decrease in the mean steep K readings from preoperatively to 3 months postoperatively was statistically significant (PZ.047), although the decrease in the mean flat K readings was not statistically significant (PZ.285). DISCUSSION Several studies have established the safety and efficacy of standard CXL for the stabilization of corneal ectatic disorders.4–6 Nevertheless, the Dresden protocol
J CATARACT REFRACT SURG - VOL 40, AUGUST 2014
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Table 1. Preoperative and postoperative patient data. Mean G SD Parameter
Preoperative
Postoperative
P Value
LogMAR CDVA Mean steep K (D) Mean flat K (D) ECD (cells/mm2)
0.19 G 0.20 48.04 G 2.57 43.88 G 1.67 2688 G 130
0.10 G 0.16 46.51 G 2.81 43.55 G 1.88 2640 G 127
.141 .047 .285 .169
CDVA Z corrected distance visual acuity; ECD Z endothelial cell density; K Z keratometry
requires up to 1 hour of surgical time (up to 30 minutes for riboflavin saturation and 30 minutes for UVA irradiation at 3 mW/cm2), which may be inconvenient to the patient as well as the surgeon.1 In an attempt to shorten the duration of treatment, 2 approaches have been proposed. One is riboflavin application by iontophoresis technique for a rapid stromal saturation and the other, use of high-intensity UVA irradiation.7,8 In accordance with the photochemical law of reciprocity (Bunsen-Roscoe law), it is possible to achieve the same photochemical effect (induced crosslinking) with a reduced irradiation time and correspondingly increased irradiation intensity so the total energy dose remains the same. Recently, Wernli et al.8 showed that the Bunsen-Roscoe reciprocity law is only valid for illumination intensities up to 40 to 50 mW/cm2 and illumination times more than 2 minutes. However, UVA irradiation may cause damage in keratocytes, corneal endothelial cells, the crystalline lens, and the retina.9 Riboflavin works as a photosensitizer and functions as a protective barrier against the harmful influence of UVA irradiation on the underlying tissues. The cell-damage threshold of UVA irradiation combined with riboflavin is 10 times lower than UVA irradiation alone in standard CXL.10 Although the total energy applied in high-intensity CXL is similar to that with the standard protocol, the intensity of irradiation is higher and may have acute side effects (eg, on the corneal endothelium). Two recent studies11,12 report transient corneal endothelial changes after accelerated CXL for the treatment of progressive keratoconus. In both studies, there was a significant decrease in ECD on corneal specular microscopy at the 1-month and 3-month postoperative intervals; the ECD returned to preoperative values by 6 months postoperatively.11,12 In contrast, using confocal microscopy, Touboul et al.13 found no significant changes in ECD after accelerated CXL. In our case series of high-intensity CXL (9 mW/cm2 for 10 minutes), there was no significant change in
Figure 1. Change in CDVA (safety) 3 months postoperatively (CDVA Z corrected distance visual acuity).
ECD; Touboul et al.13 report similar results but for a different irradiation time and irradiation intensity (30 mW/cm2 for 3 minutes). The results in the 2 recent studies that showed transient decrease in ECD at the 1-month and 3-month postoperative intervals11,12 may be attributed to the use of specular microscopy because in the presence of typical post-CXL corneal haze, increased scattering and limited visualization of the corneal endothelium may result. In contrast, confocal microscopy (used in our and the Touboul et al. study13) allows the examination of corneal endothelium in the presence of edema and haze; the composite nature of the images obtained ensures that confocal biomicroscopy is not affected by the scattering usually present in the third postoperative month after CXL.13,14 In addition, in our study there were no intraoperative or early postoperative complications and no eye had delayed reepithelialization. The CDVA remained stable postoperatively, and no patient lost a line of CDVA. The mean steep K readings decreased significantly postoperatively, while mean flat K readings did not change significantly. Limitations of our case series are the small number of patients and the short follow-up; thus, no sufficient conclusions can be made. Another limitation is the lack of a control group of standard CXL, which could facilitate the comparison between standard CXL (3 mW/cm2 for 30 minutes) and high-intensity CXL (9 mW/cm2 for 10 minutes). In conclusion, in our preliminary study of a highintensity CXL treatment protocol, CXL at 9 mW/cm2 irradiance for 10 minutes did not affect the ECD while the CDVA remained stable postoperatively. Even though preliminary results are not sufficient for an evaluation of the safety profile, CXL at 9 mW/cm2 irradiance for 10 minutes did not result in significant changes in ECD and or in intraoperative or early postoperative complications. In addition, no patient lost a line of CDVA 3 months after the procedure. Larger case series with a longer follow-up are required to confirm these encouraging results.
J CATARACT REFRACT SURG - VOL 40, AUGUST 2014
1340
SAFETY OF HIGH-INTENSITY CXL
WHAT WAS KNOWN Standard CXL (30 minutes UVA irradiation at intended irradiance of 3.0 mW/cm2 with total surface dose of 5.4 J/cm2) is a safe and efficient surgical procedure for stabilizing keratoconus. According to the BunsenRoscoe law of reciprocity, a 10-minute illumination at 9.0 mW/cm2 should provide the same effect with a 30-minute illumination at 3.0 mW/cm2. WHAT THIS PAPER ADDS Corneal collagen crosslinking at 9 mW/cm2 irradiance for 10 minutes did not result in significant changes in ECD and no intraoperative or early postoperative complications occurred. No patient lost a line of CDVA 3 months after the procedure.
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J CATARACT REFRACT SURG - VOL 40, AUGUST 2014
First author: George D. Kymionis, MD, PhD Vardinoyiannion Eye Institute of Crete, Faculty of Medicine, University of Crete, Heraklion, Crete, Greece
![[Corneal collagen crosslinking in keratoconus].](/assets/img/hold.png)
