Corneal collagen cross-linking

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 cross-linking 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 criss-crossing support ropes across the cornea. Collagen is a normal and important part of the structure of many tissues in the body, especially skin.  Corneal collagen cross-linking (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 collagen cross-linking 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 was 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 is 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 receives no treatment. These 2 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 and has only been following patients for a little over a year and a half 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), has 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 are due to commence in 2009 and will run at several hospitals across the USA.

It is important to understand that collagen cross-linking treatment 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 transplantation.

The active ingredient of the eye drops used for the cross-linking treatment 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, 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 cross-linking treatments other than UVA and riboflavin will be used.

Who is suitable to have corneal collagen cross-linking (Inclusion Criteria)?

  1. 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 corneal collagen cross-linking (Exclusion Criteria)?

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