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Additional applications of corneal cross linking.
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PMID:  21448300     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Corneal collagen cross-linking (CxL) is a prevalent surgical method for the management of keratoconus. However, literature suggests that, further to keratoconus, CxL has a beneficial impact on a series of corneal related diseases and states. This article attempts to provide a contemporary review for all additional applications of CxL. Specifically, it outlines the most recent studies that demonstrate the beneficial impact of CxL for iatrogenic ectasias, pellucid marginal degeneration, infectious keratitis, bullous keratitopathy, and for ulcerative keratitis. The outcome of this review indicates that CxL could serve as a primary or adjuvant therapeutic modality for all aforementioned corneal-related pathologic states.
Vassilios Kozobolis; Georgios Labiris; Maria Gkika; Haris Sideroudi
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Type:  Journal Article     Date:  2011-02-11
Journal Detail:
Title:  The open ophthalmology journal     Volume:  5     ISSN:  1874-3641     ISO Abbreviation:  Open Ophthalmol J     Publication Date:  2011  
Date Detail:
Created Date:  2011-03-30     Completed Date:  2011-07-14     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  101480505     Medline TA:  Open Ophthalmol J     Country:  Netherlands    
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Languages:  eng     Pagination:  17-8     Citation Subset:  -    
Eye Institute of Thrace (EIT), Democritus University, Alexandroupolis, Greece.
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Journal ID (nlm-ta): Open Ophthalmol J
Journal ID (publisher-id): TOOPHTJ
ISSN: 1874-3641
Publisher: Bentham Open
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© Kozobolis et al.; Licensee Bentham Open
Received Day: 11 Month: 8 Year: 2010
Revision Received Day: 15 Month: 10 Year: 2010
Accepted Day: 3 Month: 11 Year: 2010
Electronic publication date: Day: 11 Month: 2 Year: 2011
collection publication date: Year: 2011
Volume: 5First Page: 17 Last Page: 18
ID: 3065117
PubMed Id: 21448300
Publisher Id: TOOPHTJ-5-17
DOI: 10.2174/1874364101105010017

Additional Applications of Corneal Cross Linking
Vassilios Kozobolis*
Georgios Labiris
Maria Gkika
Haris Sideroudi
Eye Institute of Thrace (EIT), Democritus University, Alexandroupolis, Greece
*Address correspondence to this author at the Eye Institute of Thrace, Democritus University, Department of Medicine, Alexandroupolis, Greece; Tel: +302551030990; Fax: 302551039891; E-mail:


Corneal collagen cross linking is a minimally invasive technique that with the use of riboflavin and Ultraviolet – A irradiation can ensure the production of a stiffening effect capable of augmenting the rigidity of the corneal tissue. The interaction between riboflavin and UVA irradiation results in the formation of bonds between collagen fibrils in the corneal stroma, quasi “freezing” the cornea. The most common use of CXL is the management of ectatic disorders by halting their progression. Nevertheless, a continuous line of new applications is under investigation with promising results.


It is known that both LASIK and PRK modify corneal stability and overall tissue strength. Researchers suggested that regression after refractive surgery might be reduced by means of CXL. This treatment appears to be particularly applicable to patients who are suspected of having forme fruste keratoconus or those with a correction that exceeds -8 D. These patients may benefit from stiffening of the cornea because keratectasia might not develop.

Early treatments of iatrogenic keratectasia after LASIK performed at the University of Dresden seem to be effective in preventing further progression of the post – refractive surgery ectasia. Hafezi et al. reported that CXL arrested and/or partially reversed keratectasia of 10 patients over a postoperative follow-up of up to 25 months as demonstrated by preoperative and postoperative corneal topography showing a reduction in maximum Keratometry readings [1].


Kymionis et al. performed simultaneous photorefractive keratectomy and CXL in a 34-year-old woman with progressive pellucid marginal corneal degeneration in both eyes. 12 months postoperatively, BCVA improved from 20/50 and 20/63 to 20/25 and 20/32 in the right and left eye, respectively. Corneal topography revealed significant improvement in both eyes [2].


CXL has been shown to have an antiedematous effect on the cornea. Wollensak et al. examined if this effect can be used for the treatment of bullous keratopathy [3]. This clinical interventional case series included 3 patients with bullous keratopathy due to pseudophakia, corneal transplant rejection and Fuchs’ endothelial dystrophy. Corneal thickness was reduced. The bullous changes of the epithelium were markedly improved, resulting in loss of pain and discomfort. Visual acuity was significantly improved in the case that did not present prior stromal scarring. In similar results concluded Krueger et al. who performed staged intrastromal delivery of riboflavin with UVA cross-linking in a case of advanced bullous keratopathy [4]. Despite the encouraging results, longer follow-up is necessary to confirm the long-term impact of CXL in bullous keratopathy.


In 2008, Martins et al. [5] demonstrated the antimicrobial properties of CXL against common pathogens. A group of bacteria was tested: Pseudomonas aeruginosa (PA), Staphylococcus aureus (SA), Staphylococcus epidermidis (SE), methicillin-resistant S. aureus (MRSA), multidrug-resistant P. aeruginosa (MDRPA), drug-resistant Streptococcus pneumoniae (DRSP), and Candida albicans (CA). Riboflavin/UVA was effective against SA, SE, PA, MRSA, MDRPA, and DRSP, but was ineffective on CA.

Iseli et al. [6] evaluated the efficacy of CXL for treating infectious melting keratitis. Five patients with infectious keratitis associated with corneal melting were treated with CXL. CXL was performed when the infection did not respond to systemic and topical antibiotic therapy. Follow-up after cross-linking ranged from 1 to 9 months. In all cases, the progression of corneal melting was halted after CXL treatment. Emergency keratoplasty was not necessary in any of the 5 cases presented.

Moreover, Micelli-Ferrari et al. [7] described a case of keratitis caused by the Gram-negative E. Coli treated with CXL with outstanding outcomes.


CXL’s antimicrobial and anti-edematous properties were demonstrated by Kozobolis et al. [8] in their report of two patients with combined bullous keratopathy and ulcerative keratitis, resistant to conventional treatments. Both patients presented significant improvement of their vision-threatening corneal ulcer, corneal edema and BCVA for a follow-up period of two months.


CXL is a promising therapeutic intervention for corneal tissue stabilization in diseases that manifest with progressive keratectasia like keratoconus. Moreover, CXL anti-edematous and antimicrobial properties were demonstrated in a series of studies suggesting its therapeutic indications in bullous keratopathy and in infectious keratitis as an adjuvant treatment to conventional therapeutic modalities.

1. Hafezi F,Kanellopoulos J,Wiltfang R,Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after LASIKJ Cataract Refract SurgYear: 20073312 20354018053900
2. Kymionis GD,Karavitaki AE,Kounis GA,et al. Management of pellucid marginal corneal degeneration with simultaneous customized photorefractive keratectomy and collagen crosslinkingJ Cataract Refract SurgYear: 2009357129830119545822
3. Wollensak G,Aurich H,Wirbelauer C,Pham DT. Potential use of Riboflavin/ UVA crosslinking in bullous keratopathyOphthalmic ResYear: 2009412114719122475
4. Krueger RR,Ramos-Esteban JC,Kanellopoulos AJ. Staged intrastromal delivery of riboflavin with UVA cross-linking in advanced bullous keratopathy: laboratory investigation and first clinical caseJ Refract SurgYear: 2008247 S730618811120
5. Martins SAR,Combs JC,Noguera G,et al. Antimicrobial efficacy of riboflavin/UVA combination (365 n). In vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitisInvest Ophthalmol Vis SciYear: 2008493402818408193
6. Iseli HP,Thiel AM,Hafezi F,et al. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal meltsCorneaYear: 2008275590418520510
7. Micelli Ferrari T,Leozappa M,Lorusso M. Escherichia coli keratitis treated with ultraviolet A/riboflavin corneal cross-linking: a case reportEur J OphthalmolYear: 2009192295719253251
8. Kozobolis V,Labiris G,Gkika M,et al. UVA collagen cross linking treatment of bullous keratopathy combined with corneal ulcerCorneaYear: 2010292 235820023590

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Keywords: Keywords Corneal collagen cross-linking, review, iatrogenic ectasias, pellucid marginal degeneration, bullous keratopathy, infectious keratitis..

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