OD News Articles

6th January 2016

Corneal Crosslinking

by Kimberly Rueb, OD Great Falls, Montana

Crosslinking of our body’s collagen fibers is a natural part of the aging process. This normal mechanism increases rigidity and decreases elasticity of connective tissue and is thought to contribute to skin wrinkling—something most of us would rather avoid.

However, the natural crosslinking that occurs within the cornea can be extremely beneficial for those with corneal ectatic diseases. In fact, eye surgeons are now reproducing and amplifying the normal crosslinking process to increase corneal strength and slow or halt the progression of ectasias. The minor surgical procedure is known as corneal crosslinking (CXL). A number of private practitioners in the US, including several PCLI surgeons, are performing CXL on an off-label basis, with the understanding that it is not FDA approved.

Troubling Scenario

I’m sure most of us can relate to this disturbing scenario:

  • During consecutive annual eye exams, a 20-something patient shows increasing amounts of astigmatism.
  • Their prescription has been updated annually. But this year, the refractive astigmatism has increased by 1 diopter and there is a decrease in best corrected visual acuity (BCVA).
  • The likely suspect is keratoconus (KCN), or some other corneal ectasia.

As the young patient’s corneas continue to change and steepen, their BCVA can be affected in both glasses and soft contact lenses.

What can you do for an early KCN patient with progressing disease? Fit RGP or scleral lenses? Hope their BCVA doesn’t change and wait to see what happens next year? How can you manage this patient to prevent progression to severe disease?

CXL may be an option to consider.

What is CXL?

CXL is a minimally-invasive corneal treatment that strengthens stromal tissue. It is used to stabilize the stroma in many degenerative corneal diseases, including KCN and pellucid marginal degeneration. It can also benefit laser vision correction patients with post-surgical ectasias, and possibly radial keratotomy patients who experience fluctuating vision. Studies have found CXL treatment to increase the rigidity of the cornea by over 300%, a change which halts the progression of keratoconus more than 90% of the time.

The Procedure

CXL involves 4 steps:

  • The epithelium is either loosened or removed.
  • Riboflavin (vitamin B2) drops are applied and allowed to saturate the cornea for 15 to 20 minutes.
  • Low dose ultraviolet A light is applied for 5-30 minutes.
  • A bandage contact lens is placed to aid initial healing.

Riboflavin, a photosensitizer, penetrates the corneal tissue to be treated. UVA light at a wavelength of 360nm activates the riboflavin and forms free radicals that create chemical bonds (cross links) between collagen fibers within stromal tissue. The end result is increased corneal rigidity and stabilization.


The foundation for current CXL was developed in the late 1990s at the University of Dresden in Germany by Professors Theo Seiler and Eberhard Spöerl. While CXL is widely used in Canada, Europe and Asia, FDA clinical trials have been ongoing in the US since 2008.


The goal of CXL is to halt ectasia rather than reverse its course. So pre-existing corneal distortion is expected to remain. But treatment will usually prevent further deterioration in vision, and patients who do not need RGP contact lenses prior to CXL will likely never need them. Those requiring RGP contact lenses will continue to need them after CXL. However, they will likely avoid going on to need corneal transplantation.

In addition to slowing disease progression, CXL can also benefit contact lens wearers. By creating a mild flattening of the corneal curvature, contact lens fitting can become easier and patients may notice improvement in contact lens comfort and stability. Although the primary goal and only current indication of CXL is to halt progressive ectasia, several studies have shown average Kmax reductions of 1.5-2D within 12 to 24 months. And some studies have found 1 to 2 lines of improvement in BCVA a year after treatment.

Candidates and Complications

Good candidates for treatment:

  • Have progressing mild-moderate keratoconus or corneal ectasias
    ~ Increase in either the spherical or cylindrical component of refraction
    ~ Change in corneal topographies
    ~ Good visual potential with glasses or contact lenses
  • Are between 15 and 35 years old
    ~ Patients over 35 have increased risk of complications
  • Generally have central pachymetry of 400+ microns, although this can be reviewed case by case
    ~ Thinner corneas have increased risk of endothelial damage

Contraindications include:

  • Advanced corneal disease with significant corneal scarring and/or RGPs no longer provide reasonable vision
  • Prior herpetic infection or current infection
  • History of poor epithelial wound healing
  • Severe ocular surface disease
  • Autoimmune disorders

Potential complications include:

  • Delayed re-epithelialization
  • Corneal haze
  • Inflammation
  • Infection
  • Increased IOP
  • Endothelial damage
  • Treatment failure
    ~ Studies have found that 3% of patients have clinically significant progression (>1D increase in Kmax) at 12 months post-op, in which case retreatment is indicated
The Healing Process

After CXL treatment, the signs and symptoms are similar to photorefractive keratectomy (PRK) with slightly greater possibility of discomfort.

Patients wear a bandage contact lens for 3 or 4 days until re-epithelialization occurs. They are given oral pain medication and instructed to use a topical antibiotic and anti-inflammatory. The frequent use of preservative free artificial tears is strongly recommended. Patients are instructed to avoid sunlight for 24 hours and wear sun protection outdoors for 1 to 2 days due to lingering riboflavin in the corneal stroma.

Maximum keratometry and visual acuity is typically worsened at 1 month, followed by improvement and stabilization after 6 months. There is initial epithelium thinning, stromal edema and keratocyte apoptosis on confocal microscopy that explains the initial worsening at 4 to 6 weeks. Improvement after 3 months is demonstrated by epithelial thickening, decreased edema and collagen compaction.

What the Future Holds

CXL advancements are continually emerging, including transepithelial protocols and rapid crosslinking. Rapid crosslinking is something our surgeons are starting to use. It delivers the same total UVA energy level, but over a shorter period of time. Similar results have been achieved with the possible added benefit of reduced damage to endothelial cells.

With transepithelial crosslinking, the corneal epithelium is left intact. However, current formulations of riboflavin do not sufficiently penetrate corneal epithelium and underlying tissue. Various methods and techniques of increasing permeability are being trialed with the hope of improving post-op comfort and reducing complications—without compromising efficacy.

Corneal Crosslinking at PCLI

Several of our surgeons are offering CXL for patients with progressive corneal ectatic disease. If you have questions or are interested in referring a patient for possible treatment, contact our office nearest you. 


Bethke, W. (2015). When Corneal Cross-linking Goes Bad. Review of Ophthalmology.

Gore, D. E. (2013). New clinical pathways for keratoconus. Eye, 329-339.

Greenstein, S. e. (2011 Apr:37(4)). Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one year results. Journal of Catract Refractive Surgery, 691-700.

Greenstein, S. e. (2011 Jul:37(7)). Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one year results. Journal of Cataract and Refractive Surgery, 1282-90.

Hersh, P. e. (2011). Corneal Collagen Crosslinking for Keratoconus and corneal ectasia: one year results. Journal of Cataract and Refractive Surgery, 149-160.

Kent, C. (2015). Cross-linking: Finding the Right parameters. Review of Ophthalmology.