Traversing the CXL pathway: Where do we go from here?

The impact of oxygen on crosslinking procedures was not appreciated until recently. New understanding of the effect of oxygen on crosslinking may allow clinicians to compensate for the lack of oxygen. 

This article was reviewed by Theo Seiler, MD, PhD

A new understanding of the effect of oxygen on corneal collagen crosslinking (CXL) may allow clinicians to compensate for the lack of oxygen, said Theo Seiler, MD, PhD.

“The oxygen level was not a consideration in the early evolution of the technique,” explained Dr. Seiler, professor of ophthalmology, Institute for Refractive and Ophthalmic Surgery, Zurich, Switzerland.

Related: When to consider corneal cross-linking treatment 

In the beginning, the standard for the procedure initially was a riboflavin concentration of 0.1%, irradiance of 3 mW/cm² for 30 minutes with application of 5.4 Joules/cm², and use of 20% oxygen.

The results showed, according to Dr. Seiler, that the normal corneal architecture was disrupted to about 250 μm deep and the keratocytes were killed. At the depth of 293 μm, the keratocytes appeared normal.

Irradiance levels exceeding 9 mW/cm² resulted in significantly reduced efficacy of the technique, and efficacy did not increase with riboflavin concentrations over 0.1%. The real bottleneck was found to be the level of interstitial oxygen.

Related: Facing challenges of corneal infection management in operated eyes Step 1
​Early in the evolution of CXL, John Kanellopoulous, MD, suggested that the lengthy treatment process comprising 30 minutes each of drops and irradiation be altered to an increased irradiance of 9 mW/cm2 to become more practice-friendly.

However, shorter was not better, and actually proved to be less efficient. Other studies also showed that the higher irradiance rates (30 mW/cm²) resulted in a much flatter demarcation line compared with irradiance of 3 mW/cm², Dr. Seiler explained.

A look at the other end of the treatment spectrum, i.e., 1.5 mW/cm² for 60 minutes, found no difference between that lower level and the standard level of 3 mW/cm² and the lower level required twice the time. 

The first conclusion that investigators drew was that irradiances higher than 9 mW/cm² cause a significant reduction in the efficacy of CXL.

Related: CXL combination therapies may encompass variety of surgical goals 

Step 2
Investigators then moved on to evaluate the riboflavin dose. The result was similar to that of the irradiance level-more is not necessarily better. The standard dose of 0.1% produced desirable CXL effects to a depth of about 300 μm; increasing the dose to 0.5% resulted in complete absorption within the first 100 μm and there was no volume effect in diseased corneas, according to Dr. Seiler.

The finding that higher concentrations of riboflavin do not increase the efficacy of CXL has been corroborated by other groups of investigators.

Step 3
The uninvestigated component that remained was the oxygen level. Though it was determined early on that oxygen is a mandatory component of corneal CXL, the precise amount remained in question.

Investigations carried out by Avedro found immediately after the ultraviolet application, the oxygen in the cornea was consumed; with the 30 mW/cm² protocol, that happened in one second and within about five seconds with the 3 mW/cm² protocol, Dr. Seiler noted. These results begged the question regarding why the irradiance is performed for 30 minutes.

Related: CXL adoption involves planning, training professional rewards 

In addition, it also forced investigators to evaluate what happens if more oxygen is added. When Dr. Seiler and colleagues added more than 90% oxygen over the cornea and then turned the ultraviolet light on, the oxygen was also consumed rapidly, but 2% to 3% remained. 

“This made us hope that there was still oxygen-mediated CXL going on,” Dr. Seiler explained. 

They found that with use of supplemental oxygen, sufficient oxygen was present even at a corneal depth of 300 μm to initiate CXL.

Related: Determining best time for crosslinking

“Because of this, we believe that supplemental oxygen is the ‘new kid in town’ and likely the most successful factor in improving the efficiency of crosslinking,” Dr. Seiler said. “Interstitial oxygen is the real bottleneck of crosslinking. Adding supplemental oxygen is a simple way to increase the efficiency of the procedure.”

With epi-on procedures, there is far less activity in the cornea because of the lack of oxygen. 

Dr. Seiler also noted the “dramatic” corneal flattening of 6 D to 8 D in customized CXL procedures in epi-off cases at one month postoperatively.

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Theo Seiler, MD, PhD
E: theo.seiler@iroc.ch
This article is based on Dr. Seiler's presentation at the American Academy of Ophthalmology's 2019 annual meeting. Dr. Seiler is a scientific consultant for Avedro.