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Post Info TOPIC: Cross-Linking: Frequently Asked Question & Answers

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Date: Mon Aug 6 3:47 AM, 2007
Cross-Linking: Frequently Asked Question & Answers
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Corneal collagen (X Linking) Cross-Linking (C3R or UVX) FAQs
Produced Exclusively for KC Global Freedom


What is cross-linking?

Cross-linking is a medical procedure that combines the use of ultra-violet light and riboflavin eye drops.

What is the purpose of cross-linking?

The last two of years has seen a marked increase in the prominence of corneal collagen cross-linking as a treatment strategy for progressive Keratoconus. This interest has arisen from a body of evidence documenting the biomechanical and cellular changes induced by cross-linking. The findings of this research provide a rationale for its use in Keratoconus to retard the progression of this common disease. A rapidly growing number of clinical reports suggest a consistent stabilizing effect of cross-linking along with a variable improvement in corneal shape and visual function in some patients. As a first-line treatment the greatest aim of cross-linking is to reduce and stop Keratoconus in the early phase of the condition, and to treat the progressive vision loss that occurs which can lead to corneal transplantation.

How does cross-linking work?

Riboflavin (vitamin B2) is dripped onto the cornea and then exposed to ultra violet light. The light causes the riboflavin to fluoresce, which leads to the formation of bonds between collagen molecules or simply stated, collagen cross-linking.

How effective is crosslinking?

In 2008, Raiskup-Wolf et al. described what remains the largest published series comprising 241 eyes followed in Dresden for up to 6 years after crosslinking. This uncontrolled, retrospective study confirmed earlier findings with statistically significant improvements in astigmatism, best-corrected visual acuity (BCVA) and maximum simulated keratometry values (Kmax) at 12 months. Flattening was observed in 54% of eyes with a mean change in Kmax of -1.91 D (P 0.01). The effects of cross-linking were maintained over the duration of follow up with progression of the disease documented in only two patients (which responded to re-treatment). Subsequent published reports from several other centers have described similar results.


What is the safety profile regarding the use of ultra-violet light and of riboflavin in the eye?
The ultraviolet light exposure during a crosslinking procedure is comparable to, or even less than, the exposure of the eye to the ultraviolet light in skylight for a full day outdoors in summer.

The riboflavin drops are simply vitamin B2, commonly used in foods such as your breakfast cereal.

How long ago was the first one done?

The first human eyes were treated in 1998.

How safe is it in treating Keratoconus ?

Very. There are no cuts in the body of the cornea. It is much safer than a corneal graft which has been very successful in the past, and even than a gas permeable contact lens, and also there is no chance of rejection (some grafts tend to last around 10 -15 years).

The transplant carries risks such as infection, rejection, glaucoma and astigmatism. At 15 years, there is no difference in the survival rate between penetrating corneal transplants performed for Keratoconus and those performed for all other indications. Young Keratoconus patients are likely to need one or more repeated grafts during their lifetime. Crosslinking avoids the removal of any corneal structural tissue (only the surface epithelial cells are removed and these grow back mostly within 2 days).

Who is suitable and who is not?

With today’s improved technology, the vast majority of people suffering from Keratoconus and other corneal ectasia may safely undergo cross-linking. However, there are exclusion criteria, so consult your ophthalmologist to determine if you are a candidate.

Are there any age limits?

Not usually but consult your ophthalmologist.

How is cross-linking performed?

Anesthetic eye drops are applied and the surface cells of the cornea (the epithelium) are gently removed so the riboflavin eye drops can penetrate into the cornea. The riboflavin eye drops are applied and allowed to soak into the cornea. The cornea is then irradiated with ultra-violet light. The amount of time the riboflavin soaks into the eye and the amount of time the cornea is irradiated with ultra-violet light vary significantly depending on the ultra violet light source used by the ophthalmologist. Advances in ultra violet light sources have reduced total procedure time from one-hour to as little as 12 minutes. At the completion of the procedure, a bandage contact lens is inserted and the eye is patched overnight.

Are there newer riboflavin formulations that do not require the epithelium to be removed?

Studies are ongoing with riboflavin formulations that may allow the epithelium to remain intact during cross-linking. Check with your ophthalmologist regarding this option.    

What are the possible complications and side effects of cross-linking?

Often transient and treatable and a part of the healing process: Pain in the first 1-2 days, sensitivity to light for several days, haze within the cornea that may cause blurring for up to a few weeks. There are other, less common, possible complications and side effects that your ophthalmologist can discuss with you.

Can cross-linking be combined with other treatments?

Cross-linking can be combined with Corneal Rings, Phakic Lens Implants, Refractive Lens Exchange, ARK, PRK and LASEK.

Can cross-linking be redone if needed?

Yes, but during the past 13 years a one-time treatment has been shown generally to be enough to treat progression.

Can I wear soft contact lenses after cross-linking?

One of the goals of cross-linking is to make the cornea more regular, allowing for soft contact lenses to replace the need for rigid gas permeable lenses. Rigid gas permeable lenses are good for vision in Keratoconus, but without warning can cause central scarring and/or can aggravate the condition. Your ophthalmologist will tell you if soft contact lenses are possible after cross-linking and how soon after treatment you may begin wearing them.

Are there any limitations or restrictions as to what I can do after cross-linking?

The blurring mentioned earlier may affect some people, especially in the first few days, and could limit work and driving during that time. However, consult your ophthalmologist.

Can anyone tell by my appearance that I have had cross-linking?

No. There is no change in the appearance of your eyes following cross-linking.

How many people have undergone a cross-linking procedure?

Tens-of-thousands of people have had their corneas cross-linked during the past 13 years. Due to the universal acceptance of the benefits of cross-linking among ophthalmologists, and recent advances in technology, the annual number of cross-linking procedures is expected to increase substantially.

Is cross-linking approved for general use in treating keratoconus?

Cross-linking was fully approved for use in the EU in January 2007 and almost all other countries have now approved its general use to treat Keratoconus. Cross-linking began FDA clinical trials in the United States in 2008 and at least one company has completed those trials and is expected to submit its results during 2011.


Can both eyes be cross-linked at the same time?

Technically yes, but the short term blurring due to the current procedure makes this impractical.

Will other eye treatments be a problem to perform after cross-linking?

No. It has no effect on any future surgery as far has been determined until now.

What other eye conditions can be treated with cross-linking?

Although most research to date has related to the treatment of Keratoconus, a role for CXL has also been suggested for other forms of corneal ectasia and a number of unrelated corneal conditions (Table 1). Although cross-linking has been used in all these circumstances, other than for progressive Keratoconus, there is currently little published evidence to support these applications.


  Table 1. Potential applications of corneal collagen cross-linking


The Indications Include:


Pellucid marginal degeneration

Iatrogenic keratectasia

(post laser in situ keratomileusis)

Prevention of keratectasia

(prior to refractive surgery)

Bullous keratopathy

Microbial keratitis

Corneal (stromal) ulceration

Donor tissue modification prior to keratoplasty

As an adjunct to orthokeratology


What companies offer ultra violet light sources and what are their differences?

See Table 2.(click to enlarge)

 Table 2. Ultra Violet Light Sources by Company

Table 2. Ultra Violet Light Sources by Company


Has it become a common treatment?

Yes, hugely and rapidly in various locations all over the world. Corneal collagen cross-linking has so many potential uses and so few side effects and complications that it is being taken up at a very rapid rate by doctors. If it fulfills its promise of saving many patients from corneal transplants then it will be a very great advance.


Complied for KC Global with thanks to Mellisa.


eBook on the current state of the art in cross-linking published by Prof. Farhad Hafezi.

This book is available for download on your iPad with iBooks or on your computer with iTunes here.


Dr. David Jory MBBS FRCOphth
Consultant Ophthalmologist

The London Centre for Refractive Surgery
15 Harley Street
United Kingdom

Tel: +44 (0)207 580 - 9010
Fax: +44 (0)207 580 - 9020
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Farhad Hafezi, MD PhD
Associate Professor of Ophthalmology

University of Zurich, Institute for Refractive and Ophthalmic Surgery (IROC)
Stockerstrasse 37
CH – 8002 Zürich

Tel: +41 (0)43 - 488 38 00
Fax: +41 (0)43 - 488 38 09
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Last review made on the 23rd of May 2011 for this first ever published FAQs on corneal collagen cross-linking, originally produced by Dr David Jory on the 31st of July 2007 and updated by Dr Farhad Hafezi on the 23rd of January 2009.
[1] Grant R Snibson FRANZCO; Collagen cross-linking: a new treatment paradigm in corneal disease – a review; Clinical and Experimental Ophthalmology 2010; 38: 141–153 doi: 10.1111/j.1442-9071.2010.02228.x

[1] Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34: 796–801.

[1] Optical Radiation Safety of the Avedro KXL System and Accelerated Cross-Linking Procedure; DAVID H. SLINEY, Ph.D.

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