What is corneal collagen cross-linking?
Although current treatments for keratoconus (such as contact lenses and corneal ring implants) can improve vision, they do not treat the underlying cause; corneal weakness. As such, they do not prevent the keratoconus from progressing. Corneal collagen crosslinking (CXL) aims to address this problem.

The cornea is made up of many overlapping long strands, termed lamellae, of multiple collagen molecules. These act like multiple cross-crossing support ropes across the cornea. Collagen is a normal and important part of the structure of many tissues in the body, especially skin. CXL uses chemicals to form connections, or cross-links, between adjoining strands of collagen. This is currently performed using riboflavin (vitamin B2) and ultraviolet light (UVA). Natural occurring collagen cross-linking has been observed in many different tissues within the body including the cornea, teeth and bones.

In extensive experimental studies in animal and human eyes researchers have demonstrated a significant increase in corneal rigidity or stiffness after CXL using the riboflavin/UVA cross-linking treatment. The hope is this stiffening of the cornea can prevent the keratoconus from getting worse, and possibly even lead to some improvement with flattening down of the cone.

CXL has been used in parts of Europe and the USA since the late 1990’s to treat patients with keratoconus. A clinical trial commenced in 2007 at the Melbourne University Department of Ophthalmology based at the Royal Victorian Eye and Ear Hospital Melbourne, Australia. The aim of the study was to assess both the safety and benefit of CXL for people with progressive keratoconus, that is, keratoconus that is still getting worse. The type of study being performed is what is referred to as a randomized, controlled trial. This
means that half the people with keratoconus that participate in the trial are randomly assigned to be treated with CXL and the other half received no treatment. These two groups of people are then followed over several years to see if the group that had the treatment had any complications, and very importantly whether their keratoconus progressed at a different rate from the group of people who didn’t have the treatment. This type of trial is one of the most powerful ways of assessing the effectiveness of a new treatment.

The results of this trial to date have shown the CXL treatment to be both safe and effective in halting progression of keratoconus. In fact, it has found that the group of people with keratoconus who were treated with CXL actually had an improvement in the cornea with it becoming less steep and out of shape. Very importantly, this resulted in an improvement in their vision. This effect was variable being
quite marked in some people who were treated and only marginal in others. Interestingly, the effect of the treatment seems to lead to continued improvement over a long time, perhaps even years. This study is still underway so the long-term effectiveness of the treatment is still under investigation. It is not known if patients will require a second treatment at any stage although it is possible that only one treatment ever will be required.

The main national regulator for medical treatments in the USA, the Food and Drug Agency (FDA), announced that they will sponsor a similar trial to assess the safety and effectiveness of CXL for both people with progressive keratoconus and people with progressive corneal thinning and distortion following LASIK, termed “iatrogenic keratoectasia”. These studies commenced in 2009 and ran at several hospitals across the USA.

It is important to understand that CXL is not a cure for keratoconus in that significant corneal distortion is expected to remain even after the treatment. Rather, it aims to slow or even halt the progression of the condition. After the treatment, it is expected that it will continue to be necessary for individual people to wear spectacles or contact lenses (although a change in the prescription, probably to a lower powered script, may be required). As such it is felt likely that the treatment will prevent further deterioration in vision and the need for corneal graft transplant.

The active ingredient of the eye drops used for CXL is riboflavin (vitamin B2). Riboflavin is a vitamin that can be found in many foods and is a common ingredient in a number of multi-vitamin preparations in Australia. The pure pharmaceutical grade solution form of riboflavin that is required for this trial is currently not available in Australia or registered with the Therapeutic Goods Administration (TGA). It is imported from Switzerland where it is registered for this use.

There are several other ways of chemically cross-linking the collagen strands within the cornea and some of these have already been used experimentally on human corneas from eye banks. As yet, none are available for treating people with keratoconus, however, it is quite possible that over time different CXL treatments other than UVA and riboflavin will be used.

Who is suitable to have CXL (Inclusion Criteria)?
People with progressive keratoconus or post laser keratoectasia.

All patients must sign a written informed consent form (provided after the consultation), and be available for follow-up examinations as required.

Who cannot be treated with CXL (Exclusion Criteria)?

  • If the cornea is too thin (usually thickness less than 400 μm at the thinnest point);
  • If there is an active ocular disease other than keratoectasia;
  • People with Herpes Simplex Keratitis (a corneal infection caused by the cold sore virus herpes simplex);
  • Women who are pregnant;
  • People who have active, uncontrolled eye allergies or an autoimmune disease such as rheumatoid arthritis;
  • People with central corneal scars that significantly affect their vision.

Normally only one eye is treated at a time with the worst eye performed on first. You will usually be at the facility where you have the procedure performed for around two hours. Prior to the CXL being performed you will be asked to lie down on a firm operating bed. Usually, you will not need to change out of your normal clothes. Several drops of anaesthetic are put in your eye throughout the procedure (you do not have any injections). The anaesthetic eye drops numb the eye so you won’t have any pain during the procedure.

The central skin (termed the epithelium) on the cornea, is removed and drops of riboflavin are instilled every thre minutes for 15 minutes to totally saturate the cornea. This is then checked and the UVA light, a moderate strength blue light, is shone on the eye for a total of 30 minutes. More riboflavin drops are placed on the eye every three minutes. You will need to lie still during this stage. If you like, you can usually bring an MP3 music player, such as an iPod to listen to, to help you to relax and lie still.

At the end of the procedure several drops of antibiotic and anti-inflammatory medicine are instilled and a soft contact lens is usually put on the eye. This contact lens is used to decrease postoperative pain and is usually removed several days after the procedure.

After the procedure

  • Allergy to medications leading to a red swollen eye (this usually does not cause any long-term problems);
  • Postoperative corneal haze (generally temporary and not enough to affect vision);
  • Fluctuating and/or decreased vision (generally reported to improve after the first three to four months);
  • Discomfort wearing contact lenses in the treated eye for up to eight weeks;
  • UV damage to the internal structures of the eye (not yet seen in the Melbourne trials but reported overseas and if severe could lead to corneal swelling requiring a corneal graft transplant);
  • An increase in eye pressure due to post-treatment drops (this usually resolves spontaneously with discontinuation of the eye drops);
  • An infection of the cornea is very unlikely but could occur in the first several days to a week after the procedure. This can usually be successfully treated but could lead to scarring of the cornea and permanently lead to blurred vision.

It is not possible to state every possible complication that may occur following any treatment and this list may be incomplete. Unknown or unforeseen side effects may also occur.

Although new and as yet not fully assessed, (CXL) is a very exciting development in the treatment of keratoconus. It holds the promise of effectively stopping further deterioration in the corneal shape and as such of vision. Many questions remain, but with the further development of the treatment, and results from clinical trials under way, it is likely that CXL will become an extremely useful addition to our range of treatments for keratoconus. Ultimately, it is hoped it will reduce the number of people requiring a corneal graft transplant for advanced keratoconus.