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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 107  |  Issue : 3  |  Page : 187-190

Evaluation of the therapeutic effect of corneal collagen cross-linking in the treatment of resistant corneal ulcer


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

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

Correspondence Address:
Mohammed I Hafez
Sohag University, 82524 Sohag
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2090-0686.148168

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  Abstract 

Purpose
The aim of this study was to evaluate the therapeutic results of corneal collagen cross-linking (CXL) in terms of safety and efficacy in the treatment of resistant corneal ulcer.
Design
This study was designed as a noncomparative prospective clinical trial.
Patients and methods
Five eyes of five patients with resistant corneal ulcers that failed to heal after maximal topical treatment underwent CXL using UVA rays and transepithelial riboflavin. Preoperative and postoperative evaluation included slit-lamp examination of the cornea, corneal pachymetry, and visual acuity. Postoperative outcome included the degree of improvement of epithelization, relief of pain, disappearance of the corneal stromal edema, and improvement in visual acuity. Exclusion criteria were corneal thickness less than 400 μm, topical treatment less than 1 month, and impending corneal perforation or melting.
Results
Three eyes of the five eyes showed improvement in re-epithelization up to complete healing of the ulcer and development of corneal opacification with relief of ciliary injection, photophobia, pain, foreign body sensation, and lacrimation. Also, there was an improvement in corneal edema, but visual acuity showed no remarkable improvement. Most of these results were observed within 14 days after CXL. The remaining two eyes showed similar results, but after more than 1 month of CXL.
Conclusion
This study proved that CXL is a beneficial therapeutic procedure for healing of resistant corneal ulcers. Also, CXL seems to be a safe and effective method for healing of resistant corneal ulcers. Further studies on a large proportion of patients with a longer follow-up period are recommended.

Keywords: anterior OCT, corneal healing, cross-linking, fungal keratitis, resistant ulcer


How to cite this article:
Hafez MI. Evaluation of the therapeutic effect of corneal collagen cross-linking in the treatment of resistant corneal ulcer. J Egypt Ophthalmol Soc 2014;107:187-90

How to cite this URL:
Hafez MI. Evaluation of the therapeutic effect of corneal collagen cross-linking in the treatment of resistant corneal ulcer. J Egypt Ophthalmol Soc [serial online] 2014 [cited 2019 Aug 19];107:187-90. Available from: http://www.jeos.eg.net/text.asp?2014/107/3/187/148168


  Introduction Top


Corneal collagen cross-linking (CXL) might have a beneficial impact against resistant corneal ulcers and corneal melting from bacterial and fungal enzymes because of the antimicrobial effect of Ultraviolet Light A (UVA) radiation per se [1].

There is evidence that post-CXL corneal stabilization might prevent the outflow of aqueous humor to the intracorneal space in diseases that manifest endothelial decompensation [2].

Advanced cases of infectious keratitis, including melting of the cornea, are encountered at regular intervals in an ophthalmological practice and can be difficult to control, with a risk of several sight-threatening complications. The possible risk posed by the spread of antibiotic multiresistant and panresistant bacterial strains further indicates the need for new therapeutics in infectious keratitis and, as will be explained later, it is possible that photo-oxidative therapy for corneal infections by UVA-riboflavin photoactivation could be a future tool in keratitis management [3].

The data published on photochemical UVA-riboflavin interaction in infectious keratitis and melting of the cornea indicate that an implementation of the method could prove to be a means to reduce complications, the need for emergency keratoplasty, and increase healing rates. Presently, the collective information rather point toward considering utilization of the CXL procedure in the treatment of nonresponsive infections and more advanced cases of corneal necrosis. A more standardized practice of CXL in infections is still premature and ongoing and future research will have to determine whether it will be integrated as a photodynamic infection therapeutic [3].

This study focused on five patients who presented with resistant corneal ulcers that failed to heal with maximal topical treatment that lasted more than 1 month.


  Patients and methods Top


The study protocol, patients' consent details, and explanation of the aim of surgery to the patient were approved by the Ethics Committee of Sohag University Hospital. This study focused on five eyes of five patients with resistant corneal ulcers that failed to heal after maximal topical treatment that included topical antibiotic eye drops (gatifloxacin 0.3%), topical antifungal eye drops (natamycin 5%), cyclopentolate eye drops, and autologus serum eye drops.

Corneal scrapings and laboratory investigations proved that all cases were fungal ulcers (filamentous Aspergillus keratitis). These eyes were subjected to CXL using UVA rays and transepithelial riboflavin (Ricrolin TE; Sooft, Australia, Scotland, United Kingdom). Preoperative and postoperative evaluation included visual acuity, slit-lamp examination of the cornea, and corneal pachymetry.

Surgical procedure

Topical anesthesia was administered in the form of benoxinate hydrochloride as one drop every 5 min for 30 min before surgery. The device used in this study was XLink Opto (Australia, Optos plc, Scotland, United Kingdom) [Figure 1]. Parameters were T (time): 30 min, D (dose): 5.371 J/ccm, P (power): 1.50 mW, and I (intensity): 2.984 mW/ccm [Figure 1]a.
Figure 1: The device and material used: (a) XLink Opto, (b) transepithelial riboflavin phosphate 0.127 g (Ricrolin TE; Sooft).

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The riboflavin used was transepithelial riboflavin phosphate 0.127 g (Ricrolin TE; Sooft), which was equivalent to 0.1% basic riboflavin with enhancers, which were sodium edetate and tromethamine [Figure 2]b.
Figure 2: The surgical steps: (a) dropping of riboflavin for 30 min, (b) exposure of the cornea to UVA for 30 min, (c) irrigation of the eye to wash out the remnants of riboflavin, (d) application of soft contact lens.

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The lights were turned off so that the composition and efficacy of riboflavin was not affected by room light. The riboflavin was instilled every 2 min for 30 min till the corneal stroma saturated with riboflavin [Figure 3]a. The working area of the device was adjusted to 6 mm and limited to the ulcer area. Corneal irradiation with UVA was performed for 30 min [Figure 3]b), with dropping of the riboflavin every 2 min. Irrigation of the eye with saline was performed [Figure 3c). A soft contact lens was applied onto the cornea [Figure 3]d. Eye drops were instilled at the end of surgery in the form of antifungal eye drops (natamycin 5%), antibiotic eye drops (gatifloxacin 0.3%), steroids eye drops (flurometholone), and cyclopentolate. Finally, the eye was covered by an eye patch.

Postoperative antifungal eye drops (natamycin 5%) were used hourly during the first 24 h and then four times daily; antibiotic eye drops (gatifloxacin 0.3%) were used hourly during the first 24 h and then four times daily and steroid eye drops (flurometholone) were used three times a day and cyclopentolate was used four times daily. Systemic vitamin A and vitamin C were used twice daily. The treatment period ranged between 2 and 4 weeks postoperatively.

The patient was followed up daily during the first week. During this follow-up, the patient was examined by the slit-lamp to detect corneal re-epithelization, haziness, corneal edema, and/or opacification. Then, the patient was followed up weekly for 1 month postoperatively and then monthly for 3 months.
Figure 3: Postoperative results of one eye: (a) preoperative view showing the ulcer, (b) postoperative view on the fourth postoperative day, (c) postoperative view on the 10th postoperative day, (d) postoperative view on the 14th postoperative day.

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  Results Top


The preoperative and postoperative clinical data of the five eyes are presented in [Table 1].
Table 1 Preoperative and postoperative data of the five eyes


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Postoperatively, three eyes showed improvement in re-epithelization up to total closure of the ulcer and development of corneal opacification with relief by ciliary injection, photophobia, and lacrimation. In addition, there was improvement in corneal edema, but visual acuity showed no remarkable improvement. Most of these results were obtained within 14 days after CXL.

[Figure 3]a shows the preoperative state of one eye with a large corneal ulcer that did not heal. [Figure 3]b shows the 4-day postoperative view, with a decrease in the size of the ulcer and a slight improvement in the corneal edema. [Figure 3]c shows the 10-day postoperative view, with more improvement. [Figure 3]d shows the 14-day view, with complete healing of the ulcer with corneal pacification and resolution of the corneal edema. The remaining two eyes showed similar results, but after more than 1 month of CXL.

Furthermore, [Figure 4]a shows the preoperative anterior segment Optical Coherence Tomography (OCT) of the same eye in which a corneal ulcer appeared clearly with a marked epithelial and stromal defect. [Figure 4]b shows the postoperative anterior segment OCT two weeks after CXL that showed healing of the ulcer with obvious stromal opacification and re-epithelization.
Figure 4: OCT images: (a) preoperative anterior segment OCT, (b) postoperative anterior segment OCT.

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  Discussion Top


This study proved the curing effect of the CXL in healing of resistant corneal ulcers and relief of symptoms.

Similar results were reported by Schnitzler et al. [4], who reported four cases of non infectious corneal ulcers that were treated successfully with CXL.

Furthermore, Iseli et al. [5] reported five cases of infectious keratitis that were treated with CXL. In all cases, the progression of corneal melting was interrupted after CXL treatment, preventing emergency keratoplasty.

Both Schnitzler et al. [4] and Iseli et al. [5] supported the results of our study.

In addition, the results of this study clearly showed the excellent effect of the CXL in resolving corneal edema. This main outcome in our study is supported by Wollensak et al. [6] as they reported that the riboflavin-UVA irradiation-induced cross-linking seems to lead to stromal deswelling and increased transparency. This effect can be attributed to a decreased stromal imbibition pressure and hence reduced transendothelial inflow.

Moreover, Ehlers and Hjortdal [7] reported that the effect of riboflavin-UVA can be attributed to a reduction in stromal imbibition pressure. Alternative mechanisms may be interfibrillar or intrafibrillar cross-linking, implying an increase in internal cohesion.

Anwar et al. [8] reported that cross-linking is a promising new technique for the management of infective keratitis not responding to antimicrobial therapy. Further elucidation of its safety and role in the management of infectious keratitis is needed by way of future studies.

Alio et al. [9] reported that the expected complications of CXL in infectious keratitis are endothelial cell loss related to fungal deep infiltration and reactivation of previous herpes simplex. With the intention of avoiding these complications, they proposed the following: first, to exclude all patients with a history of herpes keratitis, and second, to use hyposmolarity riboflavin when a deep infiltration is observed. At present, CXL should be considered in cases of severe unresponsive infectious keratitis before performing emergency keratoplasty. A study comparing CXL with standard topical antibiotic treatment in which the severity of keratitis and the infecting organism are homogeneous is required to clarify and prove its application.

Cross-linking corneal rebuild hypothesis

This study led the author to put forward the cross-linking rebuild hypothesis as follows:

Some studies proved that CXL affects mainly the anterior 200-300 μm of the cornea [10-12]. Other studies proved that CXL is effective in clearing corneal edema by preventing influx of aqueous through the endothelium [7].

In this study, it was observed that the maximal topical treatment succeeded in abolishing many signs, for example hypopyon, aqueous flare in most cases. However, it failed to make the defect close and totally heal. Thus, we believe that this failure may be because of the fact that the defect is actually an epitheliostromal defect and not just a simple epithelial ulcer.

Therefore, the hypothesis is simply that CXL actually plays no direct role in re-epithelization of the ulcer; meanwhile, its real action is to stimulate the growth of the anterior stromal collagen tissue haphazardly, thus filling the stromal defect, creating an opacity. This indirectly allows the epithelium to regrow over the newly formed stromal tissue filling the defect.

In summary, we believe that the CXL corneal rebuild hypothesis needs to be investigated thoroughly to be proved or rejected by further studies.


  Conclusion Top


This study proved that CXL is a beneficial therapeutic procedure for healing of resistant corneal ulcers. Also, CXL seems to be a safe and effective method for healing of resistant corneal ulcers. Further studies on a large proportion of patients with a longer follow-up period are recommended.


  Acknowledgements Top


 
  References Top

1.
Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 2004; 29 :35-40.  Back to cited text no. 1
    
2.
Wollensak G, Spoerl E, Wilsch M, et al. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004; 23 :43-49.  Back to cited text no. 2
    
3.
Hafezi F, Randleman JB. Corneal collagen cross-linking. USA, SLACK Incorporated; 2013; 14 :99-103.  Back to cited text no. 3
    
4.
Schnitzler E, Sporl E, Seiler T. Irradiation of cornea with ultraviolet light and riboflavin administration as a new treatment for erosive corneal processes, preliminary results in four patients. Klin Monatsbl Augenheilkd 2000; 217 :190-193.  Back to cited text no. 4
    
5.
Iseli HP, Thiel MA, Hafezi F, et al. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea 2008; 27 :590-594.  Back to cited text no. 5
    
6.
Wollensak G, Aurich H, Pham DT, et al. Hydration behavior of porcine cornea crosslinked with riboflavin and ultraviolet A. J Cataract Refract Surg 2007; 33 :516-521.  Back to cited text no. 6
    
7.
Ehlers N, Hjortdal J. Riboflavin-ultraviolet light induced cross-linking in endothelial decompensation. Acta Ophthalmol 2008; 86 :549-551.  Back to cited text no. 7
    
8.
Anwar H, El-Danasoury A, Hashem A. Corneal collagen crosslinking in the treatment of infectious keratitis. Clin Ophthalmol 2011; 5 :1277-1280.  Back to cited text no. 8
    
9.
Alio J, Abbouda A, Valle D, et al. Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthalmic Inflamm Infect 2013; 3 :47.  Back to cited text no. 9
    
10.
Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998; 66 :97-103.  Back to cited text no. 10
    
11.
Kasper M, Sporl E, Huhle M, et al. Artificial stiffening of the cornea by induction of intrastromal cross-links. Ophthalmologe 1997; 94 :902-906.  Back to cited text no. 11
    
12.
Kohlhaas M, Spoerl E, Schilde T, et al. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 2006;32:279-283.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1]



 

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Abstract
Introduction
Patients and methods
Results
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Acknowledgements
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