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Year : 2020  |  Volume : 33  |  Issue : 2  |  Page : 569-573

Corneal surface changes after cross-linking in patients of keratoconus

1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Ophthalmology, Qalyub Ophthalmology Hospital, Qalyubia, Egypt

Date of Submission11-Jun-2019
Date of Decision26-Jul-2019
Date of Acceptance03-Aug-2019
Date of Web Publication27-Jun-2020

Correspondence Address:
Ahmed M Abd-Elhamid Akel
15 Elkhalig Elmasry Street, Hadayiq El Kobba, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mmj.mmj_192_19

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To evaluate the outcome of the corneal cross-linking procedure regarding their effect on morphological and optical properties of the cornea.
Cross-linking using ultraviolet A light and riboflavin is a method to stop the progression of keratoconus. The orbscan system has the ability to yield corneal thickness, curvature, and elevation data.
Patients and methods
The study was carried out on 40 eyes of 30 patients, with a mean age 22.55 ± 3.15 years. All underwent corneal cross-linking.Uncorrected visual acuity and best-corrected visual acuity were assessed. Orbscan's Kmax, thickness at thinnest corneal point and at the center of the cornea, irregularity at 3 and at 5 mm optical zone and topographic astigmatism, were all determined before cross-linking and 6 months after.
There was improvement of uncorrected visual acuity from 0.21 ± 0.09 to 0.23 ± 0.08 and best-corrected visual acuity from 0.62 ± 0.13 to 0.72 ± 0.10 after 6 months (P < 0.001). Significant decreases after 6 months were found in Kmaxvalue from 48.81 ± 2.05 to 47.83 ± 1.94 D (P < 0.001). There was decrease in thickness at thinnest corneal point and at the corneal center (P < 0.001). Irregularity at 3 mm optical zone and irregularity at 5 mm optical zone showed stability without significant change (P = 1.000 and 0.888, respectively). Corneal astigmatism also showed stability without significant change (P = 0.88).
Patients with progressive keratoconus appear to have improvements in most of the anterior surface topographic measures.

Keywords: astigmatism, cross-linking, keratoconus, riboflavin, ultraviolet rays

How to cite this article:
El Saadany AE, Marey HM, Ibrahim AM, Abd-Elhamid Akel AM. Corneal surface changes after cross-linking in patients of keratoconus. Menoufia Med J 2020;33:569-73

How to cite this URL:
El Saadany AE, Marey HM, Ibrahim AM, Abd-Elhamid Akel AM. Corneal surface changes after cross-linking in patients of keratoconus. Menoufia Med J [serial online] 2020 [cited 2020 Oct 22];33:569-73. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/569/287756

  Introduction Top

Keratoconus is a condition of the cornea characterized by asymmetric, bilateral, progressive, and noninflammatory ectasia due to progressive stromal thinning and loss of structural integrity resulting in corneal shape change, most typically inferior steepening which results in irregular astigmatism and progressive myopia and this eventually leads to a decrease in visual acuity[1].

Keratoconus stabilizes with age. Diagnosis and most rapid progression generally begin in puberty and continue throughout adolescence, arresting in the third or fourth decade of life[2].

It seems to occur in all populations throughout the world, although it may occur more frequently in certain ethnic groups. The exact cause of keratoconus is unknown. The majority of keratoconus cases are temporally sporadic and some forms are defined by the existence of several clinically affected patients within the same family. Autosomal dominant with reduced penetrance and autosomal recessive transmission modes have been described[3].

Treatment modalities are based on refractive correction with spectacles, contact lenses, and intrastromal corneal rings to correct astigmatism and restore visual acuity. Such modalities do not stop ectatic progression and further visual deterioration, which ultimately necessitate corneal transplantation in 10–20% of patients[4].

Corneal collagen cross-linking (CXL) is a recently introduced treatment for addressing progressive keratoconus. Cross-linking is a low-invasive procedure designed to strengthen the corneal structure and stop the progression of keratoconus[5].

In this procedure on the cornea, additional cross-links can be induced within or between the collagen fibers using ultraviolet A (UVA) light and the photo-mediator riboflavin[6].

The biomechanical stiffening was one of the effects of the CXL procedure. Other effects of CXL were a higher resistance against enzymatic digestion or reduced biodegradation and a reduction of corneal swelling[7].

The Bausch and Lomb Orbscan II anterior segment analysis system (Rochester, New York, USA) performs a complete anatomical analysis of the anterior segment of the eye. The system combines two technologies: a calibrated video and scanning slit-beam system that measures anterior segment geometry and an advanced Placido disk system that measures the curvature of the anterior surface of the cornea[8].

The aim of our study was to evaluate corneal changes after corneal collagen CXL in progressive keratoconus with scanning-slit anterior topography (orbscan II).

  Patients and Methods Top

This study was a prospective case series study. It was conducted between 2015 and 2017 and included 40 eyes of 30 patients with a mean age 22.55 ± 3.15 years (range, 18–30). There were 22 female eyes and 18 male eyes; all underwent corneal CXL using riboflavin and UVA light at Noor Elhyaa Ophthalmology Center, Masr El Gedida. Ten had both eyes performed. This study was performed in accordance with the ethical standards and informed consent was obtained from all patients.

Inclusion criteria were patients above 18 years of age suffering from progressive keratoconus documented in the last 6 months (an increase in astigmatism or myopia by at least 1 D). Patient's corneas should have a clear center with thickness not less than 400 μm.

Patients with central or paracentral corneal scars whether epithelial or stromal. Patients with evidence of active ophthalmic inflammation or severe dry eye were excluded. Also patients with corneal thickness less than 400 μm were also excluded and patients with previous ocular surgeries. Any pregnant or lactating females were not included in the study.

The following was performed to all patients, preoperatively and 6 months postoperatively: detailed medical and ophthalmic history, complete ophthalmic examination and uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) (both in Snellen lines). Orbscan system (Bausch and Lomb) was used to assess patient's corneal topography and pachymetry. The value of Kmax, thickness at thinnest corneal point and at the corneal center, irregularity at 3 mm and 5 mm optical zones, topographic astigmatism, were all determined.

All eyes underwent photo-oxidative corneal collagen CXL using riboflavin and UVA light after epithelial debridement of the central 8–9 mm of the cornea. All cases were conducted under topical anesthesia (Benoxinate HCL drops 0.4%) instilled twice for 2 min before the procedure. After applying the eyelid speculum, epithelium was removed in the central 8–9 mm with a blunt metal spatula. De-epithelialization was followed by instillation of 0.1% isotonic riboflavin (VibeX Rapid; Avedro Inc., Waltham, Massachusetts, USA) every 2 min for 10 min until the stroma was completely saturated and a yellow flare is noted in the anterior chamber. The irradiating source is placed about 5 cm from cornea center. The UVA irradiation was performed using Avedro CXL system (Avedro Inc.) with wavelength 365 nm. This wavelength allows about 93% of UV light to be absorbed into the cornea, thus, there is no risk of damage of lens or retina. The UVA-irradiation was 30 mW/cm2 for 4 min and total dose intensity of 7.2 J/cm2.

At the end of the procedure, a soft contact lens was placed until full corneal re-epithelialization occurred. After UVA irradiation, the cornea was washed with sterile balanced salt solution.

The postoperative treatment was antibiotic drops moxifloxacin were administered in all patients five times daily for 1 week. Lacrimal substitutes (preservative-free artificial tears) were administered four times daily for 4–6 weeks. Patients received fluorometholone acetate 0.1% four times a day, which was tapered over 2 weeks following the removal of the contact lens. If haze appeared, prolonged steroids were used. Four days after the procedure, the contact lens was removed. Three cases had a delayed re-epithelialization and were followed up to full re-epithelialization 2 days later. At 2 weeks follow-up, all cases showed corneal haze, which was expected with the procedure and was resolved at 6 month follow-up visit.

Statistical analysis

All collected data were revised for completeness and accuracy. Precoded data were entered on the computer using the SPSS, version 22 (SPSS Inc., Chicago, Illinois, USA). Data were summarized using mean and SD for quantitative variables and number and percent for qualitative variable. Comparison between quantitative variable was performed using paired samples t test for variables that were normally distributed. Nonparametric Wilcoxon was used for quantitative variables that were not normally distributed. P value greater than 0.05 indicates not significant; P value less than 0.05 means it is significant; and P value less than 0.01 means it is highly significant.

  Results Top

The mean preoperative UCVA was 0.21 ± 0.09 Snellen line, whereas the mean postoperative UCVA at 6 months was 0.23 ± 0.08 Snellen line with a P value less than 0.001 showing a statistically significant improvement from the preoperative value. The mean preoperative BCVA was 0.62 ± 0.13 Snellen line, whereas the mean postoperative BCVA at 6 months was 0.72 ± 0.10 Snellen line. Thus improving by a mean of 1.0 Snellen lines from the preoperative value with a P value less than 0.001 showing a statistically significant improvement. [Table 1] shows the visual acuity changes.
Table 1: Orbscan changes

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The topographic analysis performed by the orbscan revealed a mean preoperative Kmax value of 48.81 ± 2.05 D, whereas the mean postoperative Kmax value at 6 months was 47.83 ± 1.94 D with a P value less than 0.001 showing a statistically significant improvement from before CXL.

Statistically significant decrease in corneal thinnest location and at the corneal center were recorded after 6 months with mean pachymetry of 439.55 ± 49.55 and 461.65 ± 48.06 μm, respectively with a P value less than 0.001.

Orbscan of pachymetry showing central corneal thickness of right eye of patient number 7 before crosslinking and 6 months after [Figure 1].
Figure 1: Orbscan of pachymetry showing central corneal thickness of right eye of patient number 7 before cross-linking and 6 months after.

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The mean corneal astigmatism (cylinder) was 3.94 ± 2.24 D, whereas the mean postoperative cylinder at 6 months was 3.93 ± 2.02 D showing stability without significant change with a P value of 0.880.

Middle box of orbscan showing corneal astigmatism, Kmax, irregularity indices at 3 and 5 mm and corneal thickness at thinnest location values of patient number 19 before cross linking and 6 months after [Figure 2].
Figure 2: Middle box of orbscan showing corneal astigmatism, Kmax, irregularity indices at 3 and 5 mm and corneal thickness at thinnest location values of patient number 19 before cross-linking and 6 months after.

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Corneal irregularity indices showed stability without significant change at 3 mm from 5.40 ± 1.80 to 5.40 ± 2.07 with a P value of 1.000 and at 5 mm from 6.26 ± 2.09 to 6.29 ± 2.28 with a P value of 0.888.

  Discussion Top

The technique of accelerated CXL was recently introduced. The idea behind accelerated CXL is to shorten the illumination time by increasing the illumination intensity, while maintaining a constant radiant exposure of 5.4 J/cm2, according to the Bunsen–Roscoe law of reciprocity[9].

According to this physical principle, 9 mW/cm2 for 10 min, 18 mW/cm2 for 5 min, 30 mW/cm2 for 3 min, or 45 mW/cm2 for 2 min at constant energy dose of 5.4 J/cm2 may have the same photochemical impact of conventional CXL with 3 mW/cm2 for 30 min[10].

In our study, patients showed a statistically significant improvement of UCVA and BCVA postoperatively. Our results are comparable with the results of the study conducted by Sedaghat et al.[11] (97 eyes with average follow up was 6–12 months) using the standard protocol at 3 mW/cm2 for 30 min. This study stated that the UCVA before the operation was 0.31 ± 0.29. And at 6 months UCVA was 0.39 ± 0.27. While the BCVA of the patients before CXL was 0.78 ± 0.23. Postoperatively after 6 months BCVA was 0.81 ± 0.22 (P < 0.001). The differences were statistically significant.

Topographic analysis performed for our patients revealed stability with significant flattening of the values of Kmax after 6 months after CXL. Our results are comparable with the results of the study conducted by Lang et al.[12], on 51 eyes using the standard protocol at 3 mW/cm2 for 30 min. It showed a mean preoperative Kmax is 55.04 ± 5.1 D. After 3, 6, and 12 months post-CXL, the mean Kmax was 54.54 ± 4.5, 53.80 ± 5.1 and 53.12 ± 4.9 D, respectively, with a statistically significant reduction for Kmax at 12 months.

Stability of the corneal astigmatism without significant reduction was noticed. It was comparable with results of the study conducted by Choi et al.[13], using the accelerated protocol 30 mW/cm2 for 3 min with a total of 13 eyes were included in the analysis. The mean topographic astigmatism was 3.49 ± 2.20 D preoperatively and 3.92 ± 2.26 D 6 months postoperatively (P = 0.126) in which the difference did not show a significant change.

Patient's pachymetry was recorded throughout the study revealing that there was a statistically significant corneal thinning at thinnest location and central corneal thickness. These results are similar to the study conducted by Chow et al.[14], using accelerated CXL (18 mW/cm2 for 5 min) for 19 patients showed that the corneal thicknesses (thinnest corneal thickness and central corneal thickness) decreased significantly post operatively after one year from 466.39 ± 11.13 and 482.74 ± 10.81 μm to 444.02 ± 13.82 and 460.10 ± 13.99 μm, respectively.

The topographic analysis done by the orbscan revealed stability without significant reduction of the values of irregularity at 3 mm optical zone and 5 mm optical zone.

If compared with Razmjoo et al.[15], using standard protocol CXL 3 mW/cm2 for 30 min for 66 patientsshowed that the mean preoperative 3 mm irregularity was 3.71 ± 0.22 and after follow up at 12 months was 3.96 ± 0.21 (P = 0.850) and the mean preoperative 5 mm irregularity was3.94 ± 0.21 and after follow up at 12 months was 4.01 ± 0.22 (P = 0.505). The differences were not statistically significant.

  Conclusion Top

We found that CXL was a safe, effective and minimally invasive procedure to halt keratoconus progression. Patients with progressive keratoconus appear to have improvements in most of the anterior surface topography measures, suggesting an overall improvement of the optical contour of the cornea that apparently results in improved visual acuity. Longer follow-up of these patients is necessary to determine the stability of clinical and optical outcomes.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Meek KM, Tuft SJ, Huang Y, Gill PS, Hayes S, Newton RH,et al. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci 2005; 46 :1948–1956.  Back to cited text no. 1
Ertan A, Muftuoglu O. Keratoconus clinical findings according to different age and gender groups. Cornea 2008; 27 :1109–1113.  Back to cited text no. 2
Wang Y, Rabinowitz YS, Rotter JI, Yang H. Genetic epidemiological study of keratoconus: evidence for major gene determination. Am J Med Genet 2000; 93 :403–409.  Back to cited text no. 3
Caporossi A, Baiocchi S, Mazzotta 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.  Back to cited text no. 4
Wollensak G, Aurich H, Wirbelauer C, Pham DT. Potential use of riboflavin/UVA crosslinking in bullous keratopathy. Ophthalmic Res 2009; 41 :114–117.  Back to cited text no. 5
Sharma A, Nottage JM, Mirchia K, Sharma R, Mohan K, Nirankari VS,et al. Persistent corneal edema after collagen cross-linking for keratoconus. Am J Ophthalmol 2012; 154 :922926.  Back to cited text no. 6
Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen cross-linking with ultraviolet A and hypo-osmolar riboflavin solution in thin corneas. J Cataract Refract Surg 2009; 35 :621624.  Back to cited text no. 7
Wang M. Corneal topography: aguide for clinical application in the wavefront era, 2nd ed. Slack Incorporated, Thorofare, New Jersy, United States; 2012;103–166.  Back to cited text no. 8
Mrochen M. Current status of accelerated corneal cross-linking. Indian J Ophthalmol 2013; 61 :428–429.  Back to cited text no. 9
Kamaev P, Friedman MD, Sherr E, Muller D. Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci 2012; 53 :2360–2367.  Back to cited text no. 10
Sedaghat M, Bagheri M, Ghavami S, Bamdad S. Changes in corneal topography and biomechanical properties after collagen cross linking for keratoconus: 1-year results. Middle East Afr J Ophthalmol 2015; 22 :212–219.  Back to cited text no. 11
Lang PZ, Thulasi P, Khandelwal SS, Hafezi F, Randleman JB. Comparing change in anterior curvature after corneal cross-linking using scanning-slit and scheimpflug technology. Am J Ophthalmol 2018; 191 :129–134.  Back to cited text no. 12
Choi M, Kim J, Kim EK, Seo KY, Kim T. Comparison of the conventional Dresden protocol and accelerated protocol with higher ultraviolet intensity in corneal collagen cross-linking for keratoconus. Cornea 2017; 36 :523–529.  Back to cited text no. 13
Chow VWS, Chan TCY, Yu M, Wong VWY, Jhanji V. One-year outcomes of conventional and accelerated collagen crosslinking in progressive keratoconus. Sci Rep 2015; 5 :14425.  Back to cited text no. 14
Razmjoo H, Nasrollahi APK, Salam H, Karbasi N, Najarzadegan MR. Topographic corneal changes after collagen cross linking in patients with corneal keratoconus. J Res Med Sci 2013; 18 :882–886.  Back to cited text no. 15


  [Figure 1], [Figure 2]

  [Table 1]


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