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ORIGINAL ARTICLE
Year : 2014  |  Volume : 107  |  Issue : 3  |  Page : 181-186

Comparison of epithelium-off and transepithelial corneal collagen cross-linking for treatment of keratoconus


Department of Ophthalmology, Sohag University Hospital, Sohag University, Egypt

Date of Submission07-May-2014
Date of Acceptance30-Jun-2014
Date of Web Publication30-Dec-2014

Correspondence Address:
Mohammed I Hafez
El Mahata Street, El Rowad Tower, First Flour, Iqbal Eye Center, 82524, Sohag Governate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.148163

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  Abstract 

Purpose
The aim of the study was to assess the safety and efficacy of epithelium-off corneal cross-linking (conventional cross-linking) versus epithelium-on cross-linking (epithelium-on cross-linking) in the treatment of keratoconus.
Patients and Methods
This study was a nonrandomized comparative trial. Forty-three eyes of 35 patients were included in this study. All eyes were subjected to the preoperative and postoperative measures including uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA), pachymetry, simulated keratometry, and corneal topography. The preoperative and postoperative data were analyzed at baseline and at 3, 6, and 12 months in all eyes. The epithelium-off cross-linking group (the CXL group) included 25 eyes of 20 patients, whereas the epithelium-on cross-linking group (the transepithelial CXL group) included 18 eyes of 15 patients. The thinnest corneal thickness was at least 400 μm in all eyes.
Results
In the epithelium-off CXL group, there was a remarkable improvement regarding postoperative UCVA and BCVA (one line or more). Average K showed a marked reduction reaching more than 2 diopters. The mean astigmatism showed unremarkable changes. The main central corneal thickness showed very marked corneal thinning with reduction in the corneal thickness reaching more than 50 um in many cases. In the epithelium-on CXL group, there was unremarkable improvement regarding postoperative UCVA and BCVA. Average K showed almost no changes during the 12-month follow-up period. The mean astigmatism showed minimal changes. In addition, the main central corneal thickness showed considerable corneal thinning with reduction in the corneal thickness reaching up to 30 μm.
Conclusion
This study has proved that epithelium-on CXL is superior to epithelium-off CXL regarding pain, complications, and early patient convalescence. However, epithelium-off CXL is superior to epithelium-on CXL regarding the efficacy in visual stabilization and improvement. In short, this study concluded that conventional epithelium-off CXL is better than epithelium-on CXL.

Keywords: cross-linking, epithelium-off, epithelium-on, keratoconus, visual stabilization


How to cite this article:
Hafez MI. Comparison of epithelium-off and transepithelial corneal collagen cross-linking for treatment of keratoconus. J Egypt Ophthalmol Soc 2014;107:181-6

How to cite this URL:
Hafez MI. Comparison of epithelium-off and transepithelial corneal collagen cross-linking for treatment of keratoconus. J Egypt Ophthalmol Soc [serial online] 2014 [cited 2018 Aug 21];107:181-6. Available from: http://www.jeos.eg.net/text.asp?2014/107/3/181/148163


  Introduction Top


Corneal collagen cross-linking (CXL) with epithelial debridement (epithelium-off method) has clearly demonstrated its efficacy in preventing the progression of keratoconus [1]. CXL initiates photopolymerization of the corneal collagen, causing additional covalent bonds within collagen fibrils and the quaternary structure of the collagen, and consequent corneal stiffening while maintaining structural integrity and corneal transparency and preserving corneal and ocular anatomical and histological structures [2].

It strengthens the stromal collagen fibrillae of the cornea, healing and stabilizing the evolution of keratoconus with a long-term increase in corneal biomechanical rigidity. CXL stiffens the human cornea by ~300%, increases the collagen fiber diameter by 12.2%, and induces the formation of high molecular weight collagen polymers, with a remarkable chemical stability [3].

The intact corneal epithelium, with its tight junctions, is considered to be the most important barrier to permeability, and the inefficacy or penetration of riboflavin solutions with dextran into the corneal stroma in epithelium-on application was confirmed again and again in the past years [4-8]. Therefore, mechanical removal of the corneal epithelium (epithelium-off method) is an indispensable point of the standard protocol for CXL before application of riboflavin [1].

The epithelium-on CXL with intact epithelium and standard riboflavin solution with dextran is not possible. However, the combination of modified permeability of epithelium and modified riboflavin solution (without dextran, hyo-osmolar, and 0.2% riboflavin) also gives good results in epithelium-on CXL. An inadequate intrastromal concentration of riboflavin impairs the CXL effect. CXL should be performed either without the epithelium or using an efficient method to deliver riboflavin into the corneal stroma [1,4].


  Patients and methods Top


This study was performed in Sohag University Hospital. Forty-three eyes of 35 patients were divided into two groups. The first group was the epithelium-off CXL group that included 25 eyes of 20 patients with mean age 17.7 ± 2.9 years, whereas the second group was the epithelium-on cross-linking group (the TE-CXL group) that included 18 eyes of 15 patients with mean age 16 ± 3.2 years.

In this study, the inclusion criteria were age above 12 years, confirmed keratoconus, central corneal thickness at least 400 μm, progressive cases, clear cornea, and increased corneal astigmatism.

Furthermore, the exclusion criteria were patients below 12 years, dry eye disease, corneal opacities or infections, previous ocular surgery, and any abnormalities in lens or retina.

All patients were subjected to the following preoperatively and postoperatively:

(1) Visual acuity testing [uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA)].

(2) Slit lamp examination.

(3) Simulated keratometry, corneal topography, and pachymetry (Sirius; CSO, Florence, Italy).

Epithelium-off collagen cross-linking procedure

Pilocarpine 2% was given (one drop every 10 min 0.5 h before surgery) to minimize the lens and retina exposure to UV rays. Topical anesthesia was given as benoxinate hydrochloride (one drop every 5 min half an hour before surgery). Skin disinfection was performed by povodine iodine 10%.

The device used was Xlink Opto (Optos plc, Scotland, United Kingdom) [Figure 1]a. The parameters used were T (time) 30 min, D (dose) 5.371 J/cm 3 , P (power) 1.50 mW, and I (intensity) 2.984 mW/cm 3 . The type of riboflavin was riboflavin phosphate 0.127 g (Ricrolin; Sooft, Scotland, United Kingdom), which is equivalent to 0.1% basic riboflavin [Figure 1]b. Riboflavin was kept in the refrigerator at +4 to +8°C and discarded immediately after surgery.
Figure 1: The preoperative preparation: (a) the device Xlink, Opto, (b) riboflavin phosphate 0.127 g (Ricrolin; Sooft).

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An 8 mm zone marker was used to mark corneal area to be de-epithelized [Figure 2]a). The epithelium was removed with a blunt-tipped spatula [Figure 2]b. Sodium hyaluronate (Provisc; Alcon, Fort Worth, Texas, USA) was applied on the limbus all around to keep riboflavin on the cornea. The room lights were turned off in order not to affect the composition and efficacy of riboflavin. The riboflavin was instilled every 3 min for 30 min [Figure 2]c. Corneal irradiation with UVA was performed for 30 min while dropping of the riboflavin every 3 min [Figure 2]d. Irrigation of the eye by saline was performed. A bandage soft contact lens was applied onto the cornea [Figure 2]e. At the end of surgery, eye drops were applied including topical antibiotic (gatifloxacin 0.3%), topical steroid (prednisolone acetate 1%), and cyclopentolate followed by eye patching.
Figure 2: The operative procedure: (a) 8 mm zone marker to mark corneal area to be de-epithelized, (b) epithelial removal with a blunt-tipped spatula, (c) dropping of riboflavin every 3 min, (d) corneal irradiation by UVA, (e) contact lens application, and (f) the 8 mm marker and the blunt-tipped spatula.

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The surgical instruments used in this procedure were the 8-mm zone marker and blunt-tipped spatula [Figure 2]f.

Postoperative treatment usually lasted for 2-4 weeks and included the following:

(1) Antibiotic eye drops: gatifloxacin 0.3% hourly during first 24 h then four times daily.

(2) Steroid eye drops: prednisolone acetate 1% twice daily from the first postoperative day.

(3) Topical gel: twice daily.

(4) Systemic vitamin A and vitamin C twice daily.

(5) Systemic analgesic and anti-inflammatory.

The patient was followed up daily in the first week until re-epithelization of the cornea took place. During this follow-up, the patient was examined by the slit lamp to detect corneal re-epithelization and haziness. Thereafter, the patient was followed up at 1, 3, 6, and 12 months postoperatively.

In most cases, re-epithelization took place in the first 48 h, then the contact lens was removed and eye patching was stopped. The patient was instructed to wear sunglasses for 2 weeks.

Epithelium-on collagen cross-linking procedure

The preoperative preparation was the same as in conventional CXL. The same device used in conventional CXL was used in TE-CXL, but the type of riboflavin was riboflavin phosphate 0.127 g (Ricrolin TE; Sooft), which is equivalent to 0.1% basic riboflavin in which enhancers (sodium edetate and tromethamine) were added to facilitate absorption of riboflavin into the corneal stroma [Figure 3]a.
Figure 3: The operative procedure: (a) transepithelial riboflavin phosphate 0.127 g (Ricrolin TE; Sooft), (b) silicon ring application to preserve the dropped riboflavin, and (c) riboflavin dropping with turned off lights.

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The first step in this procedure was application of the silicon ring onto the cornea [Figure 3]b. Transepithelial riboflavin phosphate 0.127 g (Ricrolin TE; Sooft) was instilled every 2 min for 30 min until the anterior corneal stroma was saturated by riboflavin [Figure 3]c. Corneal irradiation was performed with the use of UVA source (Xlink, Opto) for 30 min while riboflavin was still instilled every 2 min. Irrigation of the eye was performed to wash the remnants of riboflavin. At the end of surgery, eye drops were applied including topical antibiotic (gatifloxacin 0.3%), topical steroid (prednisolone acetate 1%), and cyclopentolate. The patient was instructed to wear sunglasses for 2 weeks.

Postoperative treatment usually lasted from 1 to 2 weeks and included topical antibiotic, topical steroid, systemic vitamin A and C, and systemic analgesic and anti-inflammatory.

The patient was followed up daily in the first week. During this follow-up, the patient was examined by the slit lamp to detect corneal haziness. Thereafter, the patient was followed up at 1, 3, 6, and 12 months postoperatively.

All eyes were subjected to the preoperative and postoperative measures including UCVA and BCVA, pachymetry, simulated keratometry, and corneal topography (Sirius; CSO). The preoperative and postoperative data were analyzed at baseline and at 3, 6, and 12 months in all eyes.


  Results Top


Forty-three eyes of 35 patients were included in the study. The mean age was 16.35 ± 3.5 years with an overall male-to-female ratio of 1 : 2.5. The preoperative data of patients and the postoperative data at 6 and 12 postoperative months are summarized in [Table 1] and [Table 2].
Table 1 Summary of the preoperative and postoperative data of the epithelium-off CXL group


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Table 2 Summary of the preoperative and postoperative data of the epithelium-on CXL group


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In the epithelium-off CXL group, there was a remarkable improvement regarding postoperative UCVA and BCVA (one line or more). Furthermore, average K showed a marked reduction reaching more than 2 diopters in some cases. In contrast, the mean astigmatism showed unremarkable changes.

Surprisingly enough, the main central corneal thickness showed very marked corneal thinning with reduction in the corneal thickness reaching more than 50 μm in many cases. These results proved that the epithelium-off CXL was effective in visual stabilization and improvement.

In the epithelium-on CXL group, there was unremarkable improvement regarding postoperative UCVA and BCVA. Furthermore, average K showed almost no changes during the 12-month follow-up period. In addition, the mean astigmatism showed minimal changes.

In addition, the main central corneal thickness showed considerable corneal thinning with reduction in the corneal thickness reaching up to 30 μm in many cases. These results proved that the epithelium-on CXL was effective only in visual stabilization with no visual improvement.

In order to understand the difference in the results between both groups, examples of the preoperative and postoperative data of both groups are shown in [Table 3] and [Table 4].
Table 3 Example of epithelium-off CXL, the preoperative and postoperative data of the right eye of one patient


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Table 4 Example of transepithilial CXL, the preoperative and postoperative data of the right eye of another patient


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In clinical practice, there were marked differences between both groups regarding the surgical technique, simplicity, patient comfortability, and final visual outcome. These differences are summarized in [Table 5].
Table 5 Final clinical comparison between the both types of corneal collagen cross-linking


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  Discussion Top


This study revealed that both procedures succeeded to halt the progression of keratoconus in all studied eyes over the 12-month follow-up period. In this study, the male-to-female ratio was 1: 2.5. In contrast, other studies reported different ratio such as the 4: 1 ratio reported by Caporossi et al. [9] and the 2: 1 ratio reported by Rabinowitz [10].

In the CXL group, UCVA and BCVA improved significantly at 3, 6, and 12 months. The central corneal thickness showed a remarkable progressive thinning during the 12-month follow-up period. However, the corneal topographic indices showed a significant improvement indicating the good effect of the epithelium-off CXL regarding visual stabilization and improvement.

In the TE-CXL group, UCVA and BCVA seemed to be stable at 3, 6, and 12 months. The central corneal thickness showed a less remarkable thinning during the 12-month follow-up period. However, the corneal topographic indices showed unremarkable changes indicating the good effect of the epithelium-on CXL regarding visual stabilization.

Regarding the safety of the procedure, this study proved that TE-CXL was less painful and more comfortable than epithelium-off CXL. Furthermore, TE-CXL was more accepted by the patients because of the early postoperative convalescence and shorter postoperative medication period, which was not more than 2 weeks in most eyes. In addition, postoperative sunglasses were described for all patients in the TE-CXL group from the first postoperative day, whereas eye patching was required for all patients in the epithelium-off CXL group.

Regarding complications, TE-CXL had lower rate of complications in this study. Most complications were the postoperative patients' discomfort, burning and FB sensations, pain, glare, halos of light, corneal edema, and haze that was noticed mainly in the epithelium-off CXL group.

In contrast, temporary corneal haze, corneal melting, permanent scars, endothelial damage, treatment failure, sterile infiltrates, and herpes reactivation are the other reported complications of epithelium-off CXL [11-14]. Furthermore, corneal edema is more frequent after epithelium-off CXL than after TE-CXL, presumably because of a greater exposure of corneal endothelium to UV damage after removal of epithelium [15,16].

Ghanem et al. [17] reported close results for our study regarding postoperative pain after epithelium-off CXL that had been shown to be intense, especially on the first 3 days, even with an aggressive pain control regimen. Furthermore, Ghanem et al. [17] showed that postoperative pain after epithelium-off CXL seems inversely related to patient's age. The results in this study agree with the degree of postoperative pain rating scale observed by Ghanem et al. [17] in patients younger than 20 years.

Actually, in this study, it was found that TE-CXL was the procedure of choice for the patient comfortability, safety, and convalescence. However, the results of study confirmed that epithelium-off CXL was the procedure of choice for the patient benefit and guaranteed visual stabilization and additional visual improvement.

Spoerl et al. [1] summarized the advantages of epithelium-off CXL, which were the fast penetration of riboflavin into the stroma and a high concentration of riboflavin in the stroma, therefore a strong and deep CXL effect, and the high absorption of the UC light, a strong protection of the endothelium, lens, and retina. Disadvantages are pain, discomfort in the form of burning and tearing for many days, delay in contact lens wear, and the risk for infections.

In addition, Spoerl et al. [1] reported the advantages of the epithelium-on CXL, which were less pain, more comfort during the early postoperative period, faster visual recovery, lower risk for infection, and faster return to contact lens wear.

Murphy et al. [18] showed an inverse correlation between corneal sensitivity and age, as they suggested that the number of functional nerves in the peripheral sensory nervous system decreases with age, and those remaining become less efficient at transmitting signals to the central nervous system.

One of the remarkable features of this study was that there was zero case of postoperative infection. This might be attributed to the strict sterilization measures included in this study. However, this complication after epithelium-off CXL has been described [19].


  Conclusion Top


This study has proved that epithelium-on CXL is superior to epithelium-off CXL regarding pain, complications, and early patient convalescence. However, epithelium-off CXL is superior to epithelium-on CXL regarding the efficacy in visual stabilization and improvement. In short, this study concluded that conventional epithelium-off CXL is better than epithelium-on CXL.


  Acknowledgements Top


 
  References Top

1.
Spoerl E, Hafezi F, Bradley J. Corneal collagens cross-linking. USA, SLACK incorporated 2013; 20 :139-142.  Back to cited text no. 1
    
2.
Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol 2010; 149 :585-593.  Back to cited text no. 2
    
3.
Wollensak G, Iomdina E. Long-term biomechanical properties of rabbit cornea after photodynamic collagen crosslinking. Acta Ophthalmol 2009; 87 :48-51.  Back to cited text no. 3
    
4.
Spoerl E, Mrochen M, Sliney D, et al. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26 :385-389.  Back to cited text no. 4
    
5.
Hayes S, O'Brart DP Lamdin LS, et al. Effect of complete epithelial debridement before riboflavin-ultraviolet-A corneal collagen crosslinking therapy. J Cataract Refract Surg 2008; 34 :657-661.  Back to cited text no. 5
    
6.
Baiocchi S, Mazzotta C, Cerretani D, et al. Corneal crosslinking: riboflavin concentration in corneal storma exposed with and without epithelium. J Cataract Refract Surg 2009; 35 :893-899.  Back to cited text no. 6
    
7.
Bottos K, Schor P, Dreyfuss J, et al. Effect of corneal epithelium on ultraviolet-A and riboflavin absorption. Arq Bras Oftalmol 2011; 74 :348-351.  Back to cited text no. 7
    
8.
Cui L, Huxlin KR, Xu L, et al. High-resolution, noninvasive, two-photon fluorescence measurement of molecular concentrations in corneal tissue. Invest Ophthalmol Vis Sci 2011; 5 :2556-2564.   Back to cited text no. 8
    
9.
Caporossi A, Mazzotta C, Baiocchi S, et al. Age-related long-term functional results after riboflavin UV a corneal cross-linking. J Ophthalmol 2011; 2011 :608041.  Back to cited text no. 9
    
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Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42 :297-319.  Back to cited text no. 10
    
11.
Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009; 35 :1358-1362.  Back to cited text no. 11
    
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Dhawan S, Rao K, Natrajan S. Complications of corneal collagen crosslinking. J Ophthalmol 2011; 2011 :869015.  Back to cited text no. 12
    
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Angunawela RI, Arnalich-Montiel F, Allan BD. Peripheral sterile corneal infiltrates and melting after collagen crosslinking for keratoconus. J Cataract Refract Surg 2009; 35 :606-607.  Back to cited text no. 13
    
14.
Mazzotta C, Balestrazzi A, Baiocchi S, et al. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation. Clin Experiment Ophthalmol 2007; 35 :580-582.  Back to cited text no. 14
[PUBMED]    
15.
Caporossi A, Baiocchi S, Mazzotta C, et al. Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: preliminary refractive results in an Italian study. J Cataract Refract Surg 2006; 32 :837-845.  Back to cited text no. 15
    
16.
Raiskup-Wolf F, Hoyer A, Spoerl E, et al. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34 :796-801.  Back to cited text no. 16
    
17.
Ghanem VC, Ghanem RC, de Oliveira R. Postoperative pain after corneal collagen cross-linking. Cornea 2013; 32 :20-24.  Back to cited text no. 17
    
18.
Murphy PJ, Patel S, Kong N, et al. Noninvasive assessment of corneal sensitivity in young and elderly diabetic and nondiabetic subjects. Invest Ophthalmol Vis Sci 2004; 45 :1737-1742.  Back to cited text no. 18
    
19.
Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 2009; 35:588-589.  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


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