1 Faculty of Medicine, Mutah University, Al-Karak, Jordan
2 Saraya Eye Centre, Amman, Jordan
The progression of keratoconus is stabilized with the help of corneal collagen cross-linking (CXL) supported through photosynthesized riboflavin.
This study aims to compare the effectiveness of the transepithelial procedure and epithelium off procedure of corneal collagen crosslinking among keratoconus patients in Jordan.
The study recruited 80 patients suffering from progressive keratoconus, from a tertiary care setting in Jordan. These participants were randomly divided into two groups; group 1 with 40 participants subjected to transepithelial (Corneal collagen cross-linking) CXL; and 40 participants in group 2 received conventional epithelium off CXL.
Improvement was observed in the mean contact lens, which corrected distance visual acuity (CDVA) from logMAR 0.332 ± 0.09 (group 1), 0.35 ± 0.09 (group 2) to 0.241 ± 0.07 (group 1), 0.21 ± 0.07 (group 2), respectively at the end of follow-up (12 months). The mean pachymetry improved from 429.81 ± 18.96 μm (group 1), 430.08 ± 17.05 μm (group 2) to 436.5 ± 15.49 μm (group 1), 436.44 ± 12.53 μm (group 2), respectively, after twelve months. Additionally, the mean Sim K astigmatism declined from 7.0 ± 2.0 (group 1), 6.73 ± 1.98 (group 2) to 5.97 ± 1.88 (group 1), 5.53 ± 0.08 (group 2) respectively at twelve months post-treatment. Majority of the patients in group 2 experienced more pain as compared to group 1 participants.
The effectiveness of a cross-linking procedure related to keratometry readings and corneal thickness showed that conventional (epithelium off) CXL method is more effective than transepithelial CXL.
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* Address correspondence to this author at the Faculty of Medicine, Mutah University, Al-Karak, Postal Address: P. O. Box 1342
Aljubaiha, Amman 11941, Jordan; Tel: 00962797950830; E-mail: email@example.com
Keratoconus is an eye condition characterized by a progressive paracentral and central thinning and protrusion of cornea, which leads to visual function impairment and irregular astigmatism [1Espandar L, Meyer J. Keratoconus: Overview and update on treatment. Middle East Afr J Ophthalmol 2010; 17(1): 15-20.[PMID: 20543932] ]. A recent investigation has suggested that keratoconus is associated with inflammatory etiology [2Balasubramanian SA, Pye DC, Willcox MD. Are proteinases the reason for keratoconus? Curr Eye Res 2010; 35(3): 185-91.[http://dx.doi.org/10.3109/02713680903477824] [PMID: 20373876] ]. The initial histopathologic characteristics include corneal stromal ectasia and thinning, breaks in Bowman’s layer, and deposition of iron in the epithelial basement membrane [3Fernandes BF, Logan P, Zajdenweber ME, Santos LN, Cheema DP, Burnier MN Jr. Histopathological study of 49 cases of keratoconus. Pathology 2008; 40(6): 623-6.[http://dx.doi.org/10.1080/00313020802320648] [PMID: 18752131] ]. Its association has been established with Leber’s congenital amaurosis, Down syndrome, and Turner’s syndrome [4Ozcan AA, Ersoz TR. Severe acute corneal hydrops in a patient with Down syndrome and persistent eye rubbing. Ann Ophthalmol (Skokie) 2007; 39(2): 158-60.[http://dx.doi.org/10.1007/s12009-007-0009-6] [PMID: 17984507] , 5Vazirani J, Basu S. Keratoconus: Current perspectives. Clin Ophthalmol 2013; 7: 2019-30.[PMID: 24143069] ]. Its treatment includes wearing contact lenses, glasses, intrastromal corneal rings, and penetrating keratoplasty [6Abu Ameerh MA, Al Refai RM, Al Bdour MD. Keratoconus patients at Jordan University Hospital: A descriptive study. Clin Ophthalmol 2012; 6: 1895-9.[PMID: 23204831] ].
Keratoconus mostly begins during puberty age, and its progression stops in the third or fourth decade, ranging from 5-20 per 10,000 populations. This prevalence rate identified that keratoconus is considered one of the leading corneal ectasia [7Romero-Jiménez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: A review. Cont Lens Anterior Eye 2010; 33(4): 157-66.[http://dx.doi.org/10.1016/j.clae.2010.04.006] [PMID: 20537579] ]. Considering the population of Jordan, a study has found that 5% of bilateral or unilateral blindness existed due to keratoconus [8Al-Bdour MD, Al-Till MI, Abu-Khader IB. Causes of blindness among adult Jordanians: A hospital-based study. Eur J Ophthalmol 2002; 12(1): 5-10.[http://dx.doi.org/10.1177/112067210201200102] [PMID: 11936445] ]. Another study stated that keratoconus was the most common cause behind penetrating keratoplasty among Jordanians, constituting 65.6%, related to visual result after penetrating keratoplasty [9Al-Till M. Visual Outcome in Penetrating keratoplasty at Jordan University Hospital (1979-1998). Al-Magallat al-Tibbiyyat al-Urdunniyyat 2004; 38: 33-6.]. On the other hand, it has been suggested that keratoconus is more prevalent among females than males across the world [7Romero-Jiménez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: A review. Cont Lens Anterior Eye 2010; 33(4): 157-66.[http://dx.doi.org/10.1016/j.clae.2010.04.006] [PMID: 20537579] , 10McMonnies CW. Abnormal rubbing and keratectasia. Eye Contact Lens 2007; 33(6 Pt 1): 265-71.[http://dx.doi.org/10.1097/ICL.0b013e31814fb64b] [PMID: 179938 19] , 11Weed KH, MacEwen CJ, Giles T, Low J, McGhee CN. The Dundee University Scottish Keratoconus study: Demographics, corneal signs, associated diseases, and eye rubbing. Eye (Lond) 2008; 22(4): 534-41.[http://dx.doi.org/10.1038/sj.eye.6702692] [PMID: 17237755] ]. Crosslinking is a common technology used in several industries for different medical processes [12Snibson GR. Collagen cross-linking: A new treatment paradigm in corneal disease - A review. Clin Experiment Ophthalmol 2010; 38(2): 141-53.[http://dx.doi.org/10.1111/j.1442-9071.2010.02228.x] [PMID: 203981 04] ]. Introduced in 1997, cross-linking was induced in corneal collagens which constructed an optimistic perspective of all kinds of corneal ectasia, particularly keratoconus [13Farjadnia M, Naderan M. Corneal cross-linking treatment of keratoconus. Oman J Ophthalmol 2015; 8(2): 86-91.[http://dx.doi.org/10.4103/0974-620X.159105] [PMID: 26622134] ] (Table 1).
Table 1 Studies on Effectiveness of collagen crosslinking procedure.
Several studies have been conducted previously to find the effectiveness of the collagen crosslinking procedure. Wittig-Silva et al., illustrated the progression of keratoconus after a year in the treated eyes. Though, only one-third of the participants completed the whole 12-month follow-up [14Wittig-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(7): S720-5.[http://dx.doi.org/10.1016/j.ophtha.2013.10.028] [PMID: 18811118] ]. Complex study design was implemented by Hersh et al., [15Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg 2011; 37(1): 149-60.[http://dx.doi.org/10.1016/j.jcrs.2010.07.030] [PMID: 21183110] ] to find the effectiveness of crosslinking. 1.5 D reduction in average keratometry and 2 D decline was observed in maximum keratometry among the patients treated for keratoconus. Remarkably, no changes were observed in refraction, keratometry, and visual acuity at 1 year, presenting a halt in the disease's progression [15Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg 2011; 37(1): 149-60.[http://dx.doi.org/10.1016/j.jcrs.2010.07.030] [PMID: 21183110] ]. Similarly, O’Brart et al., [16O’Brart DP, Chan E, Samaras K, Patel P, Shah SP. A randomised, prospective study to investigate the efficacy of riboflavin/ultraviolet A (370 nm) corneal collagen cross-linkage to halt the progression of keratoconus. Br J Ophthalmol 2011; 95(11): 1519-24.[http://dx.doi.org/10.1136/bjo.2010.196493] [PMID: 21349938] ] conducted a study with 18 months follow-up period after the procedure. None of the eyes presented the progression of keratoconus. However, another study proposed certain limitations for the treatment including the absence of calculation of sample size, the age of the patients, and the difference in progression rate of the two groups [17Jain R, Basu S, Garg P. Corneal collagen cross-linkage in keratoconus. Br J Ophthalmol 2013; 97(1): 108-9.[http://dx.doi.org/10.1136/bjophthalmol-2012-302322] [PMID: 2308 7421] ].
Some studies have reported adverse effects of collagen crosslinking namely, sterile keratitis, Acanthamoeba, fungal, and bacterial keratitis [18Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 2009; 35(3): 588-9.[http://dx.doi.org/10.1016/j.jcrs.2008.09.029] [PMID: 19251154] -20Arora R, Jain P, Gupta D, Goyal JL. Sterile keratitis after corneal collagen crosslinking in a child. Cont Lens Anterior Eye 2012; 35(5): 233-5.[http://dx.doi.org/10.1016/j.clae.2012.06.002] [PMID: 22784969] ]. Spoerl et al., [21Spoerl E, Hoyer A, Pillunat LE, Raiskup F. Corneal cross-linking and safety issues. Open Ophthalmol J 2011; 5: 14-6.[http://dx.doi.org/10.2174/1874364101105010014] [PMID: 21399770] ] presented safety guidelines and recommended it to be followed during the crosslinking technique. Nevertheless, epithelium debriding imposes the potential risk of infection in the cornea, herpetic activation, endothelial damage, corneal scarring, sterile corneal infiltrates, and subepithelial haze [22Hovakimyan M, Guthoff RF, Stachs O. Collagen cross-linking: Current status and future directions. J Ophthalmol 2012; 2012[http://dx.doi.org/10.1155/2012/406850] -25Kymionis GD, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007; 33(11): 1982-4.[http://dx.doi.org/10.1016/j.jcrs.2007.06.036] [PMID: 17964410] ]. Therefore, transepithelial procedure was introduced by combining the benefits of epithelium off technique with higher safety [26Stojanovic A, Chen X, Jin N, Zhang T, Stojanovic F, Raeder S, et al. Safety and efficacy of epithelium-on corneal collagen cross-linking using a multifactorial approach to achieve proper stromal riboflavin saturation. J Ophthalmol 2012; 2012[http://dx.doi.org/10.1155/2012/498435] ].
2. MATERIALS AND METHODS
2.1. Study Participants
The study has recruited participants (n = 80), from a Jordan tertiary care setting, who were presented with progressive keratoconus on topography with a 1-year follow-up period. After the selection of participants, the keratoconus patients were allocated to one of the two groups in a random fashion in accordance with the odd-even number allocation method, known as a randomized control trial.
2.2. Inclusion Criteria
The individuals with keratoconus aged 18 years or above with documented progression of keratoconus (greater than 0.5 D rise in six months or greater than 1 D rise in steep K/12 months), keratometry (between 46 D and 56 D along with the corneal thickness being ≥400 μm) from the thinnest point, and no corneal scarring on presentation were included in this study.
2.3. Evaluating Parameters
The participants were evaluated to obtain certain parameters with the help of corneal topography (on pentacam) before the process of crosslinking. These parameters included contact lens Corrected Distance Visual Acuity (CDVA); Uncorrected Distance Visual Acuity (UCDVA); and Central Corneal Thickness (CCT) by utilizing ultrasonic pachymetry. A computerized test chart was used to measure CDVA using MiQ 720 that is controlled remotely using Apple iPad. An HD LED screen or monitor is used as a mirror for displaying. The entire procedure takes around 10 – 15 minutes. Values for keratometric astigmatism, flattest keratometry (Kmin), and steepest keratometry (Kmax) were gathered from pentacam. The procedure on the participants was carried out in appropriate and strict aseptic surroundings of the operation theater.
2.4. Clinical Procedure
In group 1 (trans-epithelial method); 0.5% of Proparacaine anesthetic drops were administered three times with an interval of 5 minutes before introducing 0.1% riboflavin’s isotonic solution in 20% dextran. Post cleaning and covering of the eye, riboflavin drops were administered after every 3 to 5 minutes for about half an hour, in addition to recurrent eye drops of proparacaine. The biomicroscopy end result was established through monitoring anterior chamber fluorescence on the slit lamp at the end of half hour. UVA radiation was then provided to the patients with the help of 2 ultraviolet diodes. The intensity of desired radiation was 3 mW/cm2, along with a UVA meter placed at a centimeter distance. This radiation of 370 nm wavelengths was provided to the patients for about half an hour. During this period, proparacaine and riboflavin eye drops were administered after every 3 to 5 minutes.
The loosening of epithelium in the epithelium-off group was performed by administrating proparacaine eye drops in every 5 minutes. A disposable corneal trephine was used to label or mark the corneal epithelium center. This marked corneal epithelium of 7 mm was scraped off by using a merosel sponge. Later, the analogous to the above-mentioned protocol for CXL was followed. For participants in group 2, a soft dressing contact lens was recommended, which was then removed after three to five days. This assured that the epithelium has been healed completely. It was recommended to the patients that moxifloxacin 0.3% topical drops should be instilled four times a day. Similarly, 0.1% fluorometholone QID was administered to Group 2 after healing of epithelium and since 1st day to group 1 participant (lessen slowly and stopped after a month). Moreover, artificial eye drops were used at least four times daily.
Daily follow-up was performed among the group 2 participants until complete formation of the epithelium was reported. However, group 1 participants were assessed on day 1 and day 7. Consequently, participants of both the groups were followed-up at 3, 6, and 12 months after the procedure of crosslinking. Pachymetry, topography, CDVA, and UCDVA were recorded at every follow-up visit. Moreover, subjective pain analysis was performed to document the experience of each participant.
2.5. Data Analysis
Visual acuity was measured with the help of Snellen’s chart to analyze the results of procedures. The obtained measurements were converted to logarithm of the minimum angle of resolution (logMAR) to calculate the means. All the obtained variables were tailored into a normal distribution that enables the utilization of parametric analysis (mean and standard deviation) to evaluate quantitative data. Chi-square test for nonparametric variables and Student’s t-test for paired values was used to evaluate the significance between parameters or variables. The difference between the observations of the two groups was established at baselines and after therapy, with the help of t-test. The significance was considered to be P < 0.05 for this study.
In group 1 (transepithelial), the mean age of the participants was 23.55 ± 4.01 years (age range: 18 to 27 years). In group 2 (epithelium-off), the mean age was 22.89 ± 3.99 years (age range: 18 to 29 years). Considering the age of the participants, there was no significant difference between group 1 and group 2 (P = 0.19). Seventy-five percent of the patients were male, and the remaining 25% were female. In group 1, there were 31 males (77.5%) and nine females (11.25%); whereas, in group 2, there were 29 males (72.5%) and 11females (27.5%). Therefore, it can be argued that gender distribution was comparable (P = 0.8). The CDVA presented in the units of logMAR showed that there was a statistically significant improvement (P < 0.001) in both the groups when acuity at baseline was compared with acuity after CXL at all points.
In group 1, the vision was 0.332 ± 0.09 logMAR at preoperative stage or baseline, which was improved to 0.324 ± 0.08 after 3 months and then further improved to 0.241 ± 0.07 after 12 months (P < 0.001). Likewise, in group 2 CDVA improved from 0.35 ± 0.09 logMAR at preoperative phase to 0.21 ± 0.07 at 12 months (P < 0.001). Markedly, with regard to visual acuity among group 1 and group 2, there was no remarkable difference between the groups at baseline (P = 0.26) and at any follow-up period till 12 months (P = 0.80) (Table 2).
In group 1, mean Km at baseline was 51.05 ± 0.08 D, with a range of 47.01 D to 51.89 D. However, mean Km was 49.97 D ± 1.98 D, with a range of 47.04 D to 51.01 D in group 2. At baseline, the difference between groups 1 and 2 was not significant (P = 0.46). At the preoperative stage, the mean Sim K astigmatism was 7.0 ± 2.0 D in group 1, with a range of 4.8 D to 11.0 D. While, mean Sim K astigmatism was 6.73 ± 1.98 D in group 2 (range 4.3 D to 11.1 D). There was a significant difference between the two groups (P = 0.02). In group 1, the mean Spherical Equivalent (SE) refraction was found to be −6.75 ± 1.82 DS (range – 3.01 DS to – 7.95 DS) and −5.98 ± 2.01 DS (range − 3.05 DS to − 9.05 DS) in group 2 (P = 0.2). At the baseline, no difference existed in the calculated topographic indices of both the groups (Table 3).
In group 1, the mean baseline keratometric astigmatism, flattest keratometry, and steepest keratometry were 6.01 ± 2.37 D, 48.11 ± 5.13 D, and 54.04 ± 3.99 D, respectively. Conversely, in group 2, the mean baseline keratometric astigmatism, flattest keratometry, and steepest keratometry were 6.56 ± 3.02 D, 46.96 ± 4.71 D, and 54.88 ± 4.06 D respectively. Considering the calculated topographic indices, no significant difference between the two groups was found in any of the values at the baseline. A slight decrease was observed in the flattest and steepest values of K-readings at 3, 6, and 12 months, after cross-linking in group 1 (P < 0.05). However, in group 2, no statistically significant difference was observed after 3 and 6 months, but moderate difference was observed in contrast to baseline values after twelve months.
In group 1 participants, keratometric astigmatism decreased from 6.01 ± 2.37 D at baseline to 5.11 ± 2.19 D after 12 months. Moreover, flattest K declined from 48.11 ± 5.13 D to 47.51 ± 4.76 D and steepest K changed from 54.04 ± 3.99 D to 53.07 ± 4.48 D at the end of 12 months follow-up. Correspondingly, participant in epithelium-off group (group 2) also showed decrease in keratometric astigmatism from 6.56 ± 3.02 D at baseline to 5.29 ± 2.94 D at the end of twelve months. Lowest K declined from 46.96 ± 4.71 D to 45.84 ± 4.66 D and steepest K changed from 54.88 ± 4.06 D to 53.48 ± 4.58 D at the end of 12 months.
In group 1, the mean CCT at baseline was 429.81 ± 18.96 μm, and after 6 and 12 months, the values were 432.6 ± 15.89 μm and 436.5 ± 15.49 μm, respectively. Statistically, significant difference was found between baseline and 12 months (P < 0.001) after crosslinking. Likewise, in the epithelium off group, the mean CCT at baseline was 430.08 ± 17.05 μm, at six months 433.27 ± 19.54 μm and 435.44 ± 12.53 μm after twelve months. This group depicted increase in corneal thickness while comparing between baseline and last follow-up of 12 months (P = 0.002). Moreover, no significant change in corneal thickness was observed at 6 months when paralleled with baseline values (P = 0.2). At baseline, there was no significant difference between group 1 and 2 at baseline, six months, or at twelve months follow-up.
No complication was observed among the patients of group 1 or trans-epithelial group. On the other hand, in group 2 (epithelium off) participants, stromal haze was present in the posterior stroma of four eyes that was detected in the initial post-operative period and persevered till three to four months. Majority of the participants in group 2 reported to have experienced photophobia and pain on the first two days; however, this was not the case among the patients of group 1. Among both the groups, none of the participants complained of edema or considerable increase in intraocular tension. Moreover, none of the eyes were presented with sterile infiltrates or infection after cross-linking. No other adverse effects or incidents were documented among all the participants.
Corneal collagen cross-linking enhances the ability of cornea through the development of a covalent cross-linkage between the collagen fibers, which in turn, contributes up to 300% of the corneal rigidity. It minimizes the chances of morbidity related to the progression of the disease that eventually reduces the demand of corneal transplantation [22Hovakimyan M, Guthoff RF, Stachs O. Collagen cross-linking: Current status and future directions. J Ophthalmol 2012; 2012[http://dx.doi.org/10.1155/2012/406850] ]. On the other hand, the performance of CXL through trans-epithelial method has emerged as a current technique and is introduced in the area of health care for the purpose of reducing the potential risks posed by complications related to the conventional method of debridement [22Hovakimyan M, Guthoff RF, Stachs O. Collagen cross-linking: Current status and future directions. J Ophthalmol 2012; 2012[http://dx.doi.org/10.1155/2012/406850] -24Dhawan S, Rao K, Natrajan S. Complications of corneal collagen cross-linking. J Ophthalmol 2011; 2011: 869015.[http://dx.doi.org/10.1155/2011/869015] [PMID: 22254130] ].
Transepithelial cross-linking also provides an opportunity to subject thinner cornea to CXL, which projects range of CCT less than 400 μm [27Filippello M, Stagni E, Buccoliero D, Bonfiglio V, Avitabile T. Transepithelial cross-linking in keratoconus patients: Confocal analysis. Optom Vis Sci 2012; 89(10): e1-7.[http://dx.doi.org/10.1097/OPX.0b013e318269c8e5] [PMID: 22940 781] ]. It has been observed that the subbasal nerve plexus in epithelium-on technique patients can be preserved, as compared to the patients treated with a conventional method [28Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Paradiso AL. Transepithelial corneal collagen crosslinking for keratoconus: Qualitative investigation by in vivo HRT II confocal analysis. Eur J Ophthalmol 2012; 22(Suppl. 7): S81-8.[http://dx.doi.org/10.5301/ejo.5000125] [PMID: 22344471] ]. Baiocchi et al., claimed that CXL
Table 2 CDVA, and mean keratometric indices between the two groups.
Table 3 Keratometric indices between group 1 and 2.
provides effective and safe concentration of riboflavin when epithelium removal has been performed and not in the case of the intact epithelium [29Baiocchi S, Mazzotta 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(5): 893-9.[http://dx.doi.org/10.1016/j.jcrs.2009.01.009] [PMID: 19393890] ]. Wachler et al., utilized concentration of critical micelle and tetracaine in their alteration of transepithelial procedure and claimed that this technique was efficacious with a very low retreatment rate of four years [30Boxer Wachler BS, Pinelli R, Ertan A, Chan CC. Safety and efficacy of transepithelial crosslinking (C3-R/CXL). J Cataract Refract Surg 2010; 36(1): 186-8.[http://dx.doi.org/10.1016/j.jcrs.2009.08.019] [PMID: 20117737] ]. Drops of proparacaine were conserved with benzalkonium chloride 0.01% to enhance the penetration of riboflavin through chemical disruption of epithelium tight junctions [31Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon MJ. Refractive and topographic results of benzalkonium chloride-assisted transepithelial crosslinking. J Cataract Refract Surg 2012; 38(6): 1000-5.[http://dx.doi.org/10.1016/j.jcrs.2012.01.024] [PMID: 22624899] ].
Stojanovic et al., [26Stojanovic A, Chen X, Jin N, Zhang T, Stojanovic F, Raeder S, et al. Safety and efficacy of epithelium-on corneal collagen cross-linking using a multifactorial approach to achieve proper stromal riboflavin saturation. J Ophthalmol 2012; 2012[http://dx.doi.org/10.1155/2012/498435] ] used more than one method to improve the permeability of riboflavin in epithelium. These methods included protracted riboflavin-induction usage, superficial epithelium’s mechanical disruption, and epithelial tight junctions’ disruption [26Stojanovic A, Chen X, Jin N, Zhang T, Stojanovic F, Raeder S, et al. Safety and efficacy of epithelium-on corneal collagen cross-linking using a multifactorial approach to achieve proper stromal riboflavin saturation. J Ophthalmol 2012; 2012[http://dx.doi.org/10.1155/2012/498435] ]. They showed that transepithelial technique was effective in decreasing Kmax, cylindrical equivalent, SE, and enhanced CDVA without any considerable harmful effects. Raiskup et al., [32Raiskup F, Pinelli R, Spoerl E. Riboflavin osmolar modification for transepithelial corneal cross-linking. Curr Eye Res 2012; 37(3): 234-8.[http://dx.doi.org/10.3109/02713683.2011.637656] [PMID: 22335811] ] suggested that the concentration of alcohol content in blood whether low or high obtain a similar level of riboflavin absorption through the epithelium of cornea. On the other hand, Kocak et al., [33Kocak I, Aydin A, Kaya F, Koc H. Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus. J Fr Ophtalmol 2014; 37(5): 371-6.[http://dx.doi.org/10.1016/j.jfo.2013.11.012] [PMID: 24679451] ] compared the effectiveness of both the procedures and proposed that epithelium-off technique was effective in halting the progression of keratoconus; while transepithelial technique was ineffective in stopping keratoconus progression.
In this study, riboflavin 0.1% was used in 20% dextran in addition to continuous administration of anesthetic drops, which aid in the penetration of riboflavin through corneal stroma. Utilization of this technique clinically has shown beneficial effects among some groups [34Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in keratoconus. J Refract Surg 2010; 26(12): 942-8.[http://dx.doi.org/10.3928/1081597X-20100212-09] [PMID: 20166 621] -36Saffarian L, Khakshoor H, Zarei-Ghanavati M, Esmaily H. Corneal Crosslinking for Keratoconus in Iranian Patients: Outcomes at 1 year following treatment. Middle East Afr J Ophthalmol 2010; 17(4): 365-8.[http://dx.doi.org/10.4103/0974-9233.71600] [PMID: 21180440] ]. Both the groups showed an increase in the values of central pachymetry at 6 and 12-months post-treatment in contrast to the pre-operative values. Few studies have proposed that decline in CCT at one month after the treatment is caused by CXL, which improved to normal thickness at 3 and 6 months of follow-up [37Alió JL, Toffaha BT, Piñero DP, Klonowski P, Javaloy J. Cross-linking in progressive keratoconus using an epithelial debridement or intrastromal pocket technique after previous corneal ring segment implantation. J Refract Surg 2011; 27(10): 737-43.[http://dx.doi.org/10.3928/1081597X-20110705-01] [PMID: 217517 66] , 38Mencucci R, Paladini I, Virgili G, Giacomelli G, Menchini U. Corneal thickness measurements using time-domain anterior segment OCT, ultrasound, and Scheimpflug tomographer pachymetry before and after corneal cross-linking for keratoconus. J Refract Surg 2012; 28(8): 562-6.[http://dx.doi.org/10.3928/1081597X-20120703-02] [PMID: 227850 60] ]. Other studies have reported that no change occurred in the corneal thickness over a long follow-up period [39Çınar Y, Cingü AK, Turkcu FM, et al. Accelerated corneal collagen cross-linking for progressive keratoconus. Cutan Ocul Toxicol 2014; 33(2): 168-71.[http://dx.doi.org/10.3109/15569527.2013.816724] [PMID: 23879803] , 40Goldich Y, Barkana Y, Lior OW, Marcovich AL, Hirsh A, Avni I, et al. Corneal collagen cross-linking for the treatment of progressive keratoconus: 3-year prospective outcome. Canadian Journal of Ophthalmology 2014; 49: 54-9.]. Nevertheless, the ultimate corneal thickness increase has been claimed by some authors [39Çınar Y, Cingü AK, Turkcu FM, et al. Accelerated corneal collagen cross-linking for progressive keratoconus. Cutan Ocul Toxicol 2014; 33(2): 168-71.[http://dx.doi.org/10.3109/15569527.2013.816724] [PMID: 23879803] , 41He X, Spoerl E, Tang J, Liu J. Measurement of corneal changes after collagen crosslinking using a noninvasive ultrasound system. J Cataract Refract Surg 2010; 36(7): 1207-12.[http://dx.doi.org/10.1016/j.jcrs.2009.12.047] [PMID: 20610102] ].
A study conducted by Choi et al., [42Choi S, Lee SC, Lee HJ, et al. Structural response of human corneal and scleral tissues to collagen cross-linking treatment with riboflavin and ultraviolet A light. Lasers Med Sci 2013; 28(5): 1289-96.[http://dx.doi.org/10.1007/s10103-012-1237-6] [PMID: 23179311] ] illustrated an increase of 107% in corneal thickness after administration of CXL in ex vivo models. The study has provided evidence that epithelial debridement has no effect on the absolute pachymetry reading. These findings are similar to the outcomes, depicted by few of the previous studies [27Filippello M, Stagni E, Buccoliero D, Bonfiglio V, Avitabile T. Transepithelial cross-linking in keratoconus patients: Confocal analysis. Optom Vis Sci 2012; 89(10): e1-7.[http://dx.doi.org/10.1097/OPX.0b013e318269c8e5] [PMID: 22940 781] , 43Vinciguerra P, Albè E, Trazza S, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology 2009; 116(3): 369-78.[http://dx.doi.org/10.1016/j.ophtha.2008.09.048] [PMID: 19167087] , 44Vinciguerra P, Camesasca FI, Albè E, Trazza S. Corneal collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg 2010; 26(7): 486-97.[http://dx.doi.org/10.3928/1081597X-20090910-02] [PMID: 19772 221] ]. The posterior stromal haze was observed in the epithelium off group, which was recognized to be secondary to myofibroblast generation, among four of the participating eyes [45Salomão MQ, Chaurasia SS, Sinha-Roy A, et al. Corneal wound healing after ultraviolet-A/riboflavin collagen cross-linking: A rabbit study. J Refract Surg 2011; 27(6): 401-7.[http://dx.doi.org/10.3928/1081597X-20101201-02] [PMID: 21162 471] , 46Kymionis GD, Portaliou DM, Diakonis VF, et al. Posterior linear stromal haze formation after simultaneous photorefractive keratectomy followed by corneal collagen cross-linking. Invest Ophthalmol Vis Sci 2010; 51(10): 5030-3.[http://dx.doi.org/10.1167/iovs.09-5105] [PMID: 20463316] ]. The absence or presence of haze was not found to be correlated with clinical findings [45Salomão MQ, Chaurasia SS, Sinha-Roy A, et al. Corneal wound healing after ultraviolet-A/riboflavin collagen cross-linking: A rabbit study. J Refract Surg 2011; 27(6): 401-7.[http://dx.doi.org/10.3928/1081597X-20101201-02] [PMID: 21162 471] ]. The potential risk of development of haze is higher in advanced keratoconus cases [47Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25(9): S824-8.[http://dx.doi.org/10.3928/1081597X-20090813-12] [PMID: 19772 259] ].
The study has identified that the effectiveness of transepithelial treatment of CXL by utilizing isotonic riboflavin in dextran along with frequent anesthetic drops, is slightly lower than the conventional technique in halting keratoconus progression (BAC 0.05%). The two procedures were equivalent with regard to postoperative complications and clinical results, with the exception of stromal haze in 10% of participating eyes among the epithelium-off group. Moreover, higher ocular comfort was observed among Jordanian patients in the transepithelial group. However, the effectiveness of epithelium-off procedure related to keratometry readings and corneal thickness showed that conventional CXL method is more effective; therefore, further research is needed to establish the effectiveness of transepithelial treatment. Previously, no research has provided evidence that one method of corneal crosslinking is more effective than another with regard to prevention of corneal haze formation. However, large sample size is needed to prove this relationship statistically. This study has certain limitation including short follow-up period and a small number of participants in each group.
ETHICS APPROVAL AND CONSENT TO PARTICIPATE
The study was ethically approved from the Ethics Committee in Faculty of Medicine-Mutah University.
HUMAN AND ANIMAL RIGHTS
No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.
CONSENT FOR PUBLICATION
Informed consent was obtained from the participants to ensure the confidentiality and anonymity of the study.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.
The author is very thankful to all the associated personnel in any reference that contributed in/for the purpose of this research.
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