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Collagen corneal cross-linking for keratoconus


The recently approved procedure will help many with this progressive disease

Corneal collagen cross-linking is a treatment for keratoconus that was approved in the United States in April 2016. The procedure has long been available in Europe, and Avedro’s approval of Photrexa brings it to many more patients in need.

Let’s first understand the condition of keratoconus.

Understanding keratoconus

Keratoconus is a progressive, degeneration of the cornea which often begins in teenagers and slowly progresses at a variable rate for the rest of the patient’s life. It is estimated that the incidence of keratoconus in the United States is about one in 2000 patients, but that number may be much higher when using modern screening strategies. In some countries, keratoconus is much more common, affecting as many as one patient in 500.

Because the cornea is the primary focusing lens of the eye, even mild cases of keratoconus have an effect on the quality of the patient’s vision. The most common early symptom of keratoconus is blurred vision caused by astigmatism Keratoconus is almost always bilateral, but it can be more advanced in one eye than the other.

At first, glasses can adequately correct the vision; however, the amount and axis of the astigmatism in keratoconus changes frequently and in many patients glasses no longer provide clear vision and contact lenses are often required. Because the astigmatism is asymmetrical, rigid gas permeable contact lenses usually provide the best vision.


Most patients can function for years with contact lenses, and in fewer than 10 percent of patients the degeneration becomes severe requiring corneal transplantation. Figure 1 shows a side view of a cornea with a cone-shaped protrusion indicating advanced keratoconus.

Diagnosing and treating keratoconus

Frequent changes in a patient’s prescription for glasses may be an early sign of keratoconus. The definitive diagnosis is made with corneal topography.

The corneal topographic map shows the shape of the cornea, much like a topographic map of the earth in which red and yellow colors indicate a steep curve (mountains), and blue and green colors indicate a flat curve (oceans and plains). Typically, the inferior part of the cornea in keratoconus becomes steeper, so the map shows a red spot in the lower portion of the cornea (Figure 2 top). As the cone progresses, the steep area becomes steeper and larger, and the astigmatism increases (Figure 2 bottom right). The area of the cone also becomes thinner than the surrounding area.

The pathology of keratoconus is due to an often inherited weakness of a portion of the millions of collagen fibers that make up the structure of the cornea. Until recently, keratoconus was treated with glasses, contact lenses, and, in a small percentage of patients, with corneal transplant (penetrating keratoplasty) surgery when the keratoconus progressed to the point that contact lenses were no longer adequate.

Now, a procedure called corneal cross-linking, can halt progression in most patients and even cause some regression of keratoconus. This procedure will dramatically reduce the number of patients who will require corneal transplants during their lifetime and provide patients with many alternatives for vision improvement.


Corneal collagen cross-linking therapy

 A focal weakening of the collagen fibers leads to a bulging of the cornea (ectasia). More than 15 years ago, Prof. Theo Seiler learned about collagen cross-linking during a visit to his dentist. The dentist was performing a procedure to strengthen Dr. Seiler’s gums. The gums were painted with riboflavin, and the collagen fibers were strengthened when they were exposed to ultraviolet light for several minutes.


Intrigued by this process, Professor Seiler performed experiments on rabbit corneas and found that the treated corneas were more rigid after cross-linking than the control corneas. He then began a study on patients with keratoconus and published the preliminary results in 2003.1

Corneal collagen fibers span the cornea in the horizontal plane, and the new crosslinks bond the fibers together by attaching the elements attached to individual fibers, acting like struts between groups of collagen fibers (Figure 3). Corneal collagen fibers are then stronger, and the number of crosslinks increase following cross-linking.

Cross-linking is indicated when it can be demonstrated that the corneal ectasia is progressing over time. This can be shown either with increasing astigmatism and/or an increase in the keratometry (K) readings by manual K readings or through the topography map.

The usual criteria are an increase in the subjective amount of astigmatism of 1.00 D or more through refraction, or more commonly, objectively with manual K readings or on the map, with exams one year apart. Corneal thickness should be at least 400 µm in the thinnest portion of the cornea.

In younger patients (≤ 18 years of age), many physicians are advocating for treatment at the time of initial diagnosis because these patients are likely to progress over their lifetimes.


The most common method of corneal cross-linking is to first manually remove the corneal epithelium in the epi-off procedure (Figure 4), then soak the cornea with riboflavin drops for about 30 minutes.

Once the riboflavin can be observed inside the anterior chamber, visible as greenish flare in the aqueous, the collagen fibers are loaded with the riboflavin (Figure 5).

Next, the cornea is exposed to a special ultraviolet light (Figure 6) for 15 to 30 minutes, depending on the particular protocol being followed.

Investigations are underway with cross-linking without removing the epithelium, the epi-on procedure.1

In general, this is not as effective as epi-off cross-linking, but the technique is still evolving and may one day become as effective as the standard technique.

Currently, the only FDA-approved cross-linking protocol is the epi-off technique using the Avedro system.

Cross-linking results and complications

The first study of cross-linking for keratoconus was published in 2003 by Drs. Wollensak, Spoerl, and Seiler2 in 23 eyes of 22 patients with follow-up from three months to four years. In all treated eyes, the progression of keratoconus was halted.

In 16 eyes (70 percent), regression with a reduction of the maximal keratometry readings by 2.01 D and of the refractive error by 1.14 D was found.


Since that initial report, other studies have confirmed that corneal collagen cross-linking is effective in stabilizing most corneas with keratoconus and in many cases reducing the magnitude of the cone as evidenced by a decrease in the steepest K reading and a reduction of myopia and/or astigmatism.

Wollensak3 provided a long-term follow-up review of cross-linking using the Dresden protocol.

The three- and five-year results of the Dresden clinical study have shown that in 60 treated eyes, the progression of keratoconus was halted in all 60 eyes.

In 31 of the eyes, there also was a slight reversal and flattening of the steep K reading by up to 2.87 D.

In another long-term study of 40 eyes in 32 patients, Haehemi4 concluded: “Based on our five-year results, treatment of progressive keratoconus with corneal cross-linking can stop disease progression, without raising any concern for safety, and can eliminate the need for keratoplasty.”

Because cross-linking usually involves removal of the epithelium and four to five days of healing with a bandage contact lens, complications are always possible, just like those that might be expected from a photorefractive keratectomy (PRK) or prolonged wearing of soft contact lenses.



Dr. Seiler’s group performed a PubMed search of reported complications of corneal crosslinking.5

They reported the published complication rates ranged from 1 percent to 10 percent, depending on the stage of keratoconus.

Early postoperative complications were transient stromal haze, sterile infiltrates, endothelium decompensation, delayed epithelial healing, and infectious keratitis.

Stromal opacity (Figure 7) can be a delayed postoperative event. In analyzing the risk-benefit ratio, cross-linking appears to have a very high benefit and a low risk of complications.

Wrapping up

Corneal collagen cross-linking is a major advance in medicine and for the first time allows patients an opportunity to stabilize and at times partially reverse the progressive changes usually observed over their lifetime.

Because keratoconus is a worldwide problem affecting thousands of patients, the necessity of corneal transplants and frequent changes in the prescription for glasses and contact lenses will be dramatically reduced.

For further reading, Randleman et al have published an extensive review article with 170 references on corneal cross-linking.6


1. Rush SW, Rush RB. Epithelium-off versus transepithelial corneal collagen crosslinking for progressive corneal ectasia: a randomized and controlled trial. Br J Ophthalmol. 2016 Jul 7. pii: bjophthalmol-2016-308914. doi: 10.1136/bjophthalmol-2016-308914. [Epub ahead of print]

2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003 May;135(5):620-7.

3. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006 Aug;17(4):356-60.

4. Hashemi H, Seyedian MA, Miraftab M, Fotouhi A, Asgari S. Corneal collagen cross-linking with riboflavin and ultraviolet a irradiation for keratoconus: long-term results. Ophthalmology. 2013 Aug;120(8):1515-20.

5. Seiler TG, Schmidinger G, Fischinger I, Koller T, Seiler T. Complications of corneal cross-linking. Ophthalmologe. 2013 Jul;110(7):639-44.

6. Randleman JB, Khandelwal SS, Hafezi F. Corneal cross-linking. Surv Ophthalmol. 2015 Nov-Dec;60(6):509-23.

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