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ORIGINAL ARTICLE
Year : 2017  |  Volume : 110  |  Issue : 1  |  Page : 8-13

Corneal collagen cross-linking in patients with keratoconus associated with dry eye


Lecturer of Ophthalmology, October 6 University Giza, Egypt

Date of Submission07-Dec-2016
Date of Acceptance30-Nov-2016
Date of Web Publication17-May-2017

Correspondence Address:
Tamer H El-Sersy
11 Montaza St., Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.206315

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  Abstract 

Purpose The aim of this study was to assess the safety and efficacy of corneal collagen cross-linking in keratoconus associated with dry eye.
Patients and methods This study included 35 eyes of 29 patients diagnosed as having keratoconus associated with moderate dry eye manifestations (as measured by Schirmer 1 test result of 8-4 mm after 5 min). Moreover, 12 keratoconic eyes were also included in this study without any manifestations of dry eye as a control group (as measured by Schirmer 1 test result of ≥15 mm after 5 min). All eyes were subjected to preoperative and postoperative assessments including uncorrected visual acuity, best-corrected visual acuity, pachymetry, simulated keratometry, and corneal topography. The thinnest corneal thickness was at least 400 μm in all eyes. As mentioned before, the degree of preoperative dry eye was assessed using Schirmer 1 test. Epithelium-on cross-linking technique was used. All data were analyzed and recorded.
Results The results of ‘epithelium-on’ collagen cross-linking are variable, but its noninvasive nature makes it potentially useful in cases when epithelium debridement is better to be avoided, such as in patients with dry eyes.
In our study, there was a remarkable improvement regarding postoperative uncorrected visual acuity and best-corrected visual acuity (one line or more). There was no statistical significant difference between the results among dry eyes and nondry eyes. Average K readings showed a marked reduction reaching more than 2 D. The mean astigmatism showed unremarkable changes. The main central corneal thickness showed marked corneal thinning with reduction in the corneal thickness of ∼50 μm or more in many eyes.
Conclusion This study showed no significant difference in efficacy and safety of corneal collagen cross-linking among eyes with keratoconus either associated with dry eye or not.

Keywords: collagen, corneal, cross-linking, dry eye, keratoconus


How to cite this article:
El-Sersy TH. Corneal collagen cross-linking in patients with keratoconus associated with dry eye. J Egypt Ophthalmol Soc 2017;110:8-13

How to cite this URL:
El-Sersy TH. Corneal collagen cross-linking in patients with keratoconus associated with dry eye. J Egypt Ophthalmol Soc [serial online] 2017 [cited 2017 Sep 22];110:8-13. Available from: http://www.jeos.eg.net/text.asp?2017/110/1/8/206315


  Introduction Top


Keratoconus is a bilateral, asymmetric condition characterized by progressive corneal protrusion and thinning, leading to irregular astigmatism and impairment of visual function. It may take years after the initial diagnosis of keratoconus in one eye for the condition to become apparent in the fellow eye. The term ‘forme fruste keratoconus’ is used for such less-affected fellow eyes that display no clinical findings except certain topographic changes. In contrast, the term ‘keratoconus suspect’ should be reserved for eyes with suspicious topographic patterns, wherein the fellow eye of the individual does not have keratoconus.

Corneal collagen cross-linking with riboflavin and ultraviolet A (UVA) light (CXL) is the only method used to stop the progression of keratoconus. Spoerl et al. [1] were the first to report the use of cross-linking for stabilizing the cornea decreasing the need for keratoplasty.

Cross-linking is a natural phenomenon that normally occurs in cornea with aging in either an enzymatic or nonenzymatic pattern, which will be accelerated in diabetes in a nonenzymatic pattern [2].

Riboflavin/UVA corneal cross-linking is a photo-oxidation process between UVA (370 nm) and riboflavin (vitamin B2). In detail, UVA activates riboflavin into triplet, which in turn produces reactive oxygen species. Reactive oxygen species react with the stromal collagen fibril molecules and enhance the formation of new chemical bonds between the amino groups of these collagen fibrils, thus increasing the mechanical strength of the cornea [3].

Corneal cross-linking leads to apoptosis of corneal stromal cells in the anterior stroma at the early stage after CXL as evident by a stromal demarcation line appearing at a depth of ∼300 μm of cornea (epithelium-debrided) when viewed under confocal microscopy, which may represent a boundary between cross-linked and non-cross-linked areas [4].

However, cross-linked region is limited to a depth of 90-110 μm in epithelium-intact corneas [5].

There is a temporary visual reduction seen in the early postoperative phase. This is owing to stromal edema evident in 100% of eyes with confocal microscopy. Visual improvement generally starts 3 months after treatment [6].

The aim of this work was to evaluate the safety and efficacy of corneal collagen cross-linking in keratoconus associated with dry eyes.


  Patients and methods Top


This study included 35 eyes diagnosed as keratoconus of 29 patients manifested with signs of mild to moderate dry eye syndrome. Moreover, 12 keratoconic eyes without dry eye manifestations were also included in this study as a control group.

All cases were subjected to full preoperative and postoperative opthalmological assessment including uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), pachymetry, simulated keratometry, and corneal topography (CT). The degree of preoperative and postoperative dry eye was assessed using Schirmer 1 test. All assessments were done preoperatively and at 3, 6, and 9 months, postoperatively.

In this study, the inclusion criteria were patients older than 12 years, with confirmed keratoconus, central corneal thickness at least 400 μm, clear cornea, and increased corneal astigmatism.

Furthermore, the exclusion criteria were patients younger 12 years, corneal opacities or infections, previous ocular surgery, and any associated other ocular pathology.

Operative details

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 povidine-iodine 10%.

The device used was Xlink Opto (Optos Plc, Scotland, UK). The parameters used were time (30 min), dose (5.371 J/cm3), power (1.50 mW), and intensity (2.984 mW/cm3). The type of riboflavin was riboflavin phosphate 0.127 g (Ricrolin TE., Sooft, Italy), which is equivalent to 0.1% basic riboflavin in which enhancers (sodium edentate and tromethamine) were added to facilitate absorption of riboflavin into the corneal stroma. Riboflavin was kept in the refrigerator at +4–8°C and discarded immediately after surgery.

The first step in this procedure was application of the silicon ring onto the cornea. Transepithelial riboflavin phosphate 0.127 g (Ricrolin TE) was instilled every 2 min for 30 min until the anterior corneal stroma was saturated by riboflavin. Corneal irradiation was performed with the use of UVA source (Xlink; Opto; Rua Joaquim Augusto Ribeiro de Souza, 1071 – Jardim Santa FelíciaCEP 13563-330 – São Carlos – SP – Brasil) for 30 min whereas 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 vitamins 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 9 months postoperatively.


  Results Top


A total of 35 eyes of 29 patients were included in this study. The mean age was 18.32±2.5 years with 1 : 2 male to female ratio.

There was a remarkable improvement regarding postoperative UCVA and BCVA (one line or more). Furthermore, average K-reading showed a marked reduction reaching more than 2 D in some cases. The mean astigmatism showed unremarkable changes. There was no alteration in the degree of dry eye as measured using Schirmer 1 test. There was no statistical significant difference among the result of patients manifested with dry eye manifestation and those without dry eye ([Table 1] and [Figure 1],[Figure 2],[Figure 3],[Figure 4]).
Table 1 Results of preoperative and postoperative data concerning the uncorrected visual acuity

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Figure 1 Preoperative corneal topography in one case

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Figure 2 Postoperative corneal topography

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Figure 3 Preoperative corneal topography

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Figure 4 After 9 months postoperative

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  Discussion Top


This study included 35 eyes of 29 patients with keratoconus presented with dry eye manifestations (mild to moderate degrees). A comparative study was done with a control group contained 12 patients with keratoconus without dry eye manifestations. Both groups underwent corneal collagen cross-linking procedure.

All our cases were evaluated preoperatively and postoperatively by full ophthalmological assessment included UCVA, BCVA, keratometry, pachymetry, CT, and Schirmer 1 test. Postoperative follow-up was on 3, 6, and 9 month.

In this study, the male to female ratio was 1 : 2 owing to the availability of cases. In contrast, other studies reported different ratios, such as the 4 : 1 ratio reported by Caporossi et al. [7] and 2 : 1 ratio reported by Rabinowitz [8].

In our study, UCVA and BCVA improved significantly at 3, 6, and 9 months postoperatively in both groups. CT indices showed a significant improvement regarding visual stabilization and improvement.

Another study stated that the average visual improvement was between 1 and 2 Snellen lines from 1 to 4 years after treatment [9].

The improved UCVA can be partially explained by reduction in the sphere causes spherical equivalent reduction. Postoperative reduction in coma seen on aberrometry is also responsible for the improvement in visual acuity [10].

This reduction in values was maintained for up to 36–48 months [9].

In a study by Wollensak et al. [11], 22 eyes of 22 patients with progressive keratoconus underwent CXL and were followed up for 2–4 years. They demonstrated no progression of keratoconus in all eyes, improved UCVA and BCVA in 15 of 22 eyes and flattening of Kmax by 2 D in 16 of 22 eyes.

Caporossi et al. [12] reported a 3.6 line increase in UCVA, a 1.66 line improvement in BCVA, a mean reduction in maximum keratometric readings (Kmax) of 2.1±0.13 D, and a 2.5 D reduction in manifest refraction spherical equivalent at 3 months of follow up after CXL in a series of 10 eyes in 10 patients with progressive keratoconus. There were no changes in endothelial cell density.

Raiskup-Wolf et al. [13] reported on 7-year results at the University of Dresden. They noted a decrease in Kmax of 2.7 D at 1 year; 2.2 D at 2 years, and 4.8 D at 3 years. Visual acuity improved by one line per year in 54% of patients in the first 3 years. In their study, two patients had continued progression and had to undergo repeat CXL procedures.

Sondergaard et al. [14] postulated that the stiffening of cornea is depth dependent, which is being confined to approximately the anterior 200 μm of the cornea.

Some authors believed that 70% of UVA is absorbed within the anterior 200 urn of the corneal stroma and 90% within the anterior 400 urn [15].

Transmission electron microscope studies in another study showed a 12.2% (3.96 nm) increase in collagen fibril diameters within this anterior 200 urn region, demonstrating that collagen fibrils thickness also participate in the cross-linking process [16].

In-vivo confocal microscopy shows immediate loss of keratocytes in the anterior and midstroma shortly after treatment followed by an increase in number at 3 months; the process of keratocytes repopulation is finalized at 6 months after collagen cross-linking process, though the damage of corneal endothelium usually does not occur during the process [17].

The first step in this procedure was application of the silicon ring onto the cornea. Transepithelial riboflavin phosphate 0.127 g (Ricrolin TE) was instilled every 2 min for 30 min until the anterior corneal stroma was saturated by riboflavin. Corneal irradiation was performed with the use of UVA source (Xlink; Opto) for 30 min whereas 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 vitamins 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 9 months postoperatively.

‘Dresden protocol’ is the most commonly used protocol of corneal collagen cross-linking. After the application of topical anesthesia, the central epithelium with a diameter of 8–9 mm is removed with blade, alcohol, or laser [18].

Then 0.1% riboflavin solution containing 20% dextran is dropped every 5 min for 30 min on the corneal surface until the stroma is saturated with riboflavin, as evident by the chartreuse flare in the anterior chamber observed with blue light with slit-lamp examination.

Then the cornea is exposed to UVA (370 nm) for ∼30 min (energy density 3 mW/cm2).

Riboflavin administration is then continued during UVA illumination at the same 5-min intervals. Topical anesthesia is applied if needed to relieve the mild discomfort during the procedure.

After illumination, antibiotic eye drops, topical steroids, and soft bandage contact lens are applied on cornea to reduce pain and promote the growth of epithelium.

The soft lens is removed 5–7 days later when the healing of epithelium is observed [19].

However, in many patients with advanced keratoconus, CT is less than 400 μm. Kymionis et al. [20] applied corneal collagen cross-linking with ‘Dresden protocol’ to thin cornea (range: 340±399 urn), and a significant endothelial cell count loss occurred, but no other signs of intraocular toxicity (lens and retina) were noted during the follow up.

‘Epithelium-on’ CXL was performed by applying an enhanced riboflavin solution with benzalkonium chloride [21], EDTA [22], and gentamicin which can help riboflavin corneal stromal penetration through epithelium [23].

However, the effect of ‘epithelium-on’ collagen cross-linking varies from ‘less effective than standard collagen cross-linking protocol’ to ‘moderately effective’ to an effective procedure appearing to halt keratoconus progression, with a statistically significant improvement in visual and topographic parameters.

Though the result of ‘epithelium-on’ collagen cross-linking is variable, its noninvasive nature makes it potentially useful in cases when epithelial debridement is better to be avoided, such as in patients with dry eyes, uncooperative patients, patients with low pain threshold, and patients with very thin corneas [5].In our study, most complications were the postoperative patients’ discomfort, burning and foreign body (FB) sensations, pain, glare, halos of light, corneal edema, and haze.

In a published retrospective study of 163 eyes with grades I–III keratoconus, ∼9% of the 127 patients developed clinically significant haze after 1-year follow-up. The subset of patients developing severe steroid-resistant haze appeared to have more advanced keratoconus, as reflected in a lower mean central corneal thickness and higher K-reading value of the apex compared with the control group [24].

Sterile infiltration after CXL may be caused by staphylococcal antigen deposition in areas of static tear pooling beneath the bandage contact lens [10].

CXL failure occurs by keratoconic progression following treatment. One study of 117 eyes from 99 patients who underwent CXL showed a failure rate of 7.6% at 1-year follow up. The results also showed that 2.9% of eyes lost two or more lines of Snellen visual acuity [25].


  Conclusion Top


This study revealed that corneal collagen cross-linking is a safe and beneficial procedure in cases with keratoconus. There was no statistical significant difference among the results in eyes with dry eye manifestations and those without.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007; 26:385–389.  Back to cited text no. 1
    
2.
Elsheikh A, Wang D, Brown M, Rama P, Campanelli M, Pye D. Assessment of corneal biomechanical properties and their variation with age. Curr Eye Res 2007; 32:11–19.  Back to cited text no. 2
    
3.
Raiskup F, Spoerl E. Corneal cross-linking with riboflavin and ultraviolet A. I. principles. Ocul Surf 2013; 11:65–74.  Back to cited text no. 3
    
4.
Seiler T, Koufala K, Richter G. Iatrogenic keratectasia after laster in situ keratomileusis. J Refract Surg 2006; 14:312–317.  Back to cited text no. 4
    
5.
Filippello M, Stagni E, O’Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012; 38:283–291.  Back to cited text no. 5
    
6.
Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano MC et al. Corneal healing after riboflavin ultraviolet-a collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol 2008; 146:527–533.  Back to cited text no. 6
    
7.
Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R. Age-related long-term functional results after riboflavin UV a corneal cross-linking. J Ophthalmol 2011; 211:608041.  Back to cited text no. 7
    
8.
Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42:297–319  Back to cited text no. 8
    
9.
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.  Back to cited text no. 9
    
10.
Angunawela RI, Arnalich-Montiel F, Allan BDS. Peripheral sterile corneal infiltrates and melting after collagen cross-linking for keratoconus. J Cataract Refract Surg 2009; 35:606–607.  Back to cited text no. 10
    
11.
Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine cornea after riboflavin − ultraviolet A-induced cross-linking. J Cataract Refract Surg 2003; 29:1780–1785.  Back to cited text no. 11
    
12.
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. 12
    
13.
Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet. A lit in keratoconus: long-term results. J Cataract Refract Surg 2008; 34:796–801.  Back to cited text no. 13
    
14.
Sondergaard AP, Hjortdal J, Breitenbach T, Ivarsen A. Corneal distribution of riboflavin prior to collagen cross-linking. Curr Eye Res 2010; 35:116–121.  Back to cited text no. 14
    
15.
Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE. Biomechanical evidence of the distribution of cross-links in corneastreated with riboflavin and ultraviolet a light. J Cataract Refract Surg 2006; 32:279–283.  Back to cited text no. 15
    
16.
Wollensak G, Wilsch M, Spoerl E, Seiler T. Collagen fiber diameter in the rabbit cornea after collagen crosslinking by riboflavin/UVA. Cornea 2004; 23:503–507.  Back to cited text no. 16
    
17.
Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S, Caporossi T, Tommasi C, Caporossi A. Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg retinal tomography II in vivo confocal microscopy in humans. Cornea 2007; 26:390–397.  Back to cited text no. 17
    
18.
Kymionis GD, Mikropoulos DG, Portaliou DM, Voudouragkaki IC, Kozobolis VP, Konstas AGP. An overview of corneal collagen cross-linking (CXL) advances in therapy. Adv Ther 2013; 30:858–869.  Back to cited text no. 18
    
19.
Gu S, Fan Z, Wang L, Tao X, Zhang Y, Mu G. Corneal collagen cross-linking with hypoosmolar riboflavin solution in keratoconic corneas. BioMed Res Int 2014; 2014:754182.  Back to cited text no. 19
    
20.
Kymionis GD, Portaliou DM, Diakonis VF, Kounis GA, Panagopoulou SI, Grentzelos MA. Corneal collagen cross-linking with riboflavin and ultraviolet-A irradiation in patients with thin corneas. Am J Ophthalmol 2012; 153:24–28.  Back to cited text no. 20
    
21.
Kissner A, Spoerl E, Jung R, Spekl K, Pillunat LE, Raiskup F. Pharmacological modification of the epithelial permeability by benzalkonium chloride in UVA/Riboflavin corneal collagen cross-linking. Curr Eye Res 2010; 35:715–721.  Back to cited text no. 21
    
22.
Nakamura T, Yamada M, Teshima M, Nakashima M, To H, Ichikawa N, Sasaki H. Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients. Biol Pharm Bull 2007; 30:2360–2364.  Back to cited text no. 22
    
23.
Chang SW, Chi RF, Wu CC, Su MJ. Benzalkonium chloride and gentamicin cause a leak in corneal epithelial cell membrane. Exp Eye Res 2000; 71:3–10.  Back to cited text no. 23
    
24.
Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25:S824–S828.  Back to cited text no. 24
    
25.
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. 25
    


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