Refractive Surgery | May 2010

BONUS FEATURE: Crosslinking for Keratoconus

Studies suggest this procedure halts progression of ectasia and may reverse the process.

Keratoconus is a clinical diagnosis characterized by progressive corneal thinning, apical corneal scarring, and irregular corneal astigmatism.1 This condition is typically bilateral, but it can be unilateral. The reported prevalence of keratoconus varies from 50 to 230 per 100,000 people.2,3 Typically, patients present in early adulthood complaining of poor vision, and, on examination, vision is often less than 20/20. Myopia and irregular astigmatism are commonly found in eyes with keratoconus.1 A family history of keratoconus correlates with the condition, as does a history of atopic disease, Down syndrome, connective tissue disorders, or eye rubbing.4

Stimulated by the advent of corneal refractive surgery imaging, computerized analysis of corneal Placido-disc images have revealed abnormal topographies in eyes with no slit-lamp findings. A continuum of topographies exists, from normal to irregular (forme fruste keratoconus) to abnormal (keratoconus with slit-lamp findings).

Traditional management of keratoconus has included spectacles for mild cases, contact lenses for moderately severe cases, and penetrating keratoplasty for severe cases. More recently, additional treatment modalities have been introduced, such as corneal collagen crosslinking (CXL), intrastromal corneal ring segments (ICRS), and deep anterior lamellar keratoplasty. CXL creates chemical bonds between collagen molecules, stiffening the cornea and preventing progression of ectatic corneal diseases (Figure 1). Currently, CXL is used to treat keratoconus and postoperative ectasia in Europe and is under evaluation in clinical trials in Australia and the United States.

The current method of CXL uses riboflavin as a photosensitizer to generate reactive oxygen species that create covalent bonds between collagen molecules by photopolymerization on exposure to ultraviolet-A (UV-A) light (Figure 2).5 In biomechanical studies, corneal rigidity increased by greater than 300% in human corneas after CXL.6 Using gel electrophoretic analysis, researchers showed that the area of CXL and larger diameter collagen fibers correlates with a band of highmolecular– weight collagen polymers.7 For CXL treatment, the epithelium must be removed because an intact epithelium prevents adequate absorption of riboflavin.8-10

ECTASIA
CXL can halt and potentially reverse the ectatic process in keratoconus and ectasia after LASIK (Figure 3). Wollensak and colleagues11 found, and other studies confirmed, that CXL halted the progression of keratoconus, decreased keratometry (K) values in 70% of patients (P =.001), and stabilized or decreased refractive error. Another study reported initial reduction in mean corneal curvature and improved mean spherical equivalent.12

Most of the CXL effect occurs in the anterior 200 to 300 μm of the corneal stroma.5 In cases of corneal ectasia after LASIK, the anterior cornea is functionally decoupled from the posterior stroma after the LASIK flap is created; the corneal flap contributes minimally to the tensile strength of the cornea. CXL procedures may prove to be effective for postoperative ectasia by strengthening the remaining central and posterior cornea.5 However, the full extent of clinical applications of CXL for postoperative ectasia remain to be determined.

COMPLICATIONS AND TOXICITY
In a prospective study, Wollensak et al11 found that there were no side effects of CXL, the cornea and lens remained transparent, and endothelial cell density was stable. Although UV-A light can damage the lens and the retina, there has not been evidence of damage with the current safety protocols.8 Caporossi et al12 found no change in macular and perimacular thickness on optical coherence tomography analysis 3 months after CXL treatment. In a prospective study of 117 eyes of 99 patients, Koller et al13 reported a complication rate (loss of 2 Snellen lines) of 2.9%. Sterile infiltrates were seen in 7.6% of eyes and central stromal scars in 2.8%. Significant risk factors for complications included preoperative age greater than 35 years and preoperative visual acuity of 20/25 or better. The failure rate of CXL (ie, eyes with continued progression) was 7.6%, and a high preoperative maximum K reading (58.00 D) was a significant risk factor for failure.

Wollensak and collegues14 established that damage and apoptosis of keratocytes occurs after CXL treatment and increases relative to the levels of UV-A irradiance. Despite keratocyte damage, the cornea maintains its transparency. Spoerl and colleagues8 found that in a 400-µm thick cornea saturated with riboflavin, endothelial toxicity was well below damage threshold levels. As a result, the threshold corneal thickness for CXL treatment is 400 µm, based upon studies of riboflavin penetration levels and endothelial toxicity.5,15 Clinical studies have shown no evidence of damage to the corneal endothelium on confocal microscopy with a minimum corneal thickness of 400 µm.12 In some borderline circumstances, hypotonic riboflavin solution can be applied to thicken corneas sufficiently to allow treatment. Some patients with severe ectasia and thinning do not meet current safety criteria for CXL, and other treatment protocols are being evaluated.

RESULTS
Numerous studies have shown that CXL halts the progression of keratoconus, slightly decreases corneal curvature, and stabilizes or decreases refractive error (Figure 3).11,12,16 In a prospective, randomized clinical trial, researchers in Australia observed statistically significant flattening of the steepest simulated K value over 12 months.16

Treatment with CXL is becoming widespread in Europe. Clinicians can now recommend CXL upon evidence of progression of keratoconus. Given the higher risk of complications in patients with visual acuity of 20/25 or better, it is unclear if clinicians will recommend CXL for forme fruste keratoconus or early keratoconus; however, there will be a low threshold for treatment if a patient shows evidence of progression. CXL treatment in combination with ICRS or refractive surgery may be a future option for refractive correction in eyes with keratoconus. 17 Kanellopoulos et al18 reported that a patient with keratoconus underwent CXL treatment but remained intolerant to rigid gas permeable lenses. Topography-guided PRK was performed, and 18 months later the patient had UCVA of 20/20 and no evidence of progressive keratectasia. Dr. Kanellopoulos reported continued success with same-day simultaneous topographyguided PRK and CXL on more patients at the American Society of Cataract and Refractive Surgery (ASCRS) meeting in Boston in April 2010.19 (See Combining Topography- Guided PRK With CXL: The Athens Protocol, page 18, for more information.)

CONCLUSION
Patients with keratoconus comprise a significant portion of the cornea specialist's practice. New diagnostic procedures such as topography allow early identification of these patients. CXL is a promising method to prevent keratectasia progression. Perhaps, as the technique is perfected, CXL will be recommended for all patients with keratoconus. Many clinicians predict that keratoconus patients who undergo CXL may avoid corneal transplantation surgery. Additionally, CXL treatment may indeed expand eligibility for refractive surgery to include patients with keratoconus.

Maria A. Woodward, MD, is an Assistant Professor of Ophthalmology, Section of Cornea and External Diseases, Emory Eye Center, Atlanta. She states that she has no financial interest in the products or companies mentioned. Dr. Woodward may be reached at e-mail: mwoodwa@emory.edu.

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