Meeting Highlights: Cross-Linking Congress

Below is a sampling of research underway in dry eye and ocular surface disease, reported in presentations at the International Congress on Surface Ablation, Femto-Lasers and Cross-Linking, on July 31 and August 1, 2011, in Deer Valley, Utah.

Physicians and scientists from around the world met to discuss corneal collagen cross-linking (CXL) in an informal, interactive setting. Developed in the late 1990s for treating keratoconus and ectasia, CXL involves placing riboflavin on the cornea and then exposing it to ultraviolet light, which creates bonds between collagen molecules, stiffening the cornea. The procedure is currently being offered in Europe and Asia and is in clinical trials in the United States.

In addition to the presentations described in more detail below, conference highlights included a discussion by David Muller, MD, of a technique under development that would deliver more intense UVA light during a shorter period of time to achieve corneal stiffening during a 3-minute treatment. Muller indicated that data obtained by Avedro from Peschke Meditrade, following 98 eyes for 1 year after CXL would be ready to present to the FDA in the near future.

Stephen Slade, MD, president of the American College of Ophthalmic Surgeons (ACOS), announced plans to offer ACOS members an opportunity to participate in uncontrolled phase III clinical trials of CXL under observational protocols developed by Topcon or Avedro, significantly expanding treatment opportunities for U.S. citizens who might otherwise travel to undergo CXL. U.S. studies would also add to the current literature regarding the safety and efficacy of the procedure.

I presented an interim analysis of the Topcon FDA clinical trial of CXL using riboflavin (Ricrolin) and the Vega UVA illumination system (CSO) to cross-link corneas of patients with keratoconus or ectasia after LASIK. This study is a prospective, block-randomized trial of CXL in which 162 eyes were randomized to receive treatment or a sham procedure. At 6 months, a significant difference was evident in the maximum and average K values, compared with baseline, in the treatment group versus the control group in eyes with keratoconus. A similar trend was seen in the ectasia group, but the number of eyes that could be evaluated at 6 months was too small to reach significance. These changes were consistent with published reports from outside the United States.

We predict eventual approval of this procedure by the FDA, and the trial will be expanded in the future to evaluate transepithelial CXL using Ricrolin TE. Transepithelial CXL uses chemical enhancers to allow riboflavin to enter the corneal stroma, avoiding potential complications of epithelial removal, such as infectious keratitis, sterile infiltrate and corneal scarring from delayed epithelial healing.

Other discussion of CXL highlighted not only its application to ectatic disease, but also its potential for the treatment of infectious keratitis that is resistant to traditional antibiotics, autoimmune corneal melts and corneal edema. Simon Holland, MD, also reported promising outcomes with topography-guided PRK in association with CXL at the same sitting, which can provide stability and improved refractive performance of the keratoconic cornea.

Many ophthalmologists believe that CXL will become the procedure of choice that will be offered to patients as soon as a diagnosis of keratoconus or corneal ectasia is made. The procedure has the potential to replace 20% to 50% of the corneal transplants performed in this country. CXL will eventually be coupled with topography-guided PRK, intracorneal rings, thermal keratoplasty or other refractive procedures to not only arrest the progression of ectatic diseases, but also to improve visual acuity. The enthusiasm evident at the ACOS meeting was reflective of that felt by numerous corneal surgeons around the country, who eagerly await FDA approval of this significant advance in our field.

R. Doyle Stulting, MD, PhD

IVIS Topo-Guided Treatment with Simultaneous CXL for Keratoconus and Ectasia

At the Pacific Laser Eye Centre, Simon Holland, MD, and I treated 45 keratoconus eyes using simultaneous topography-guided surface PRK and corneal cross-linking.Topography maps were obtained using an iVIS Precisio high-definition tomographer, which takes 50 Scheimpflug cross-sections per second, allowing us to image highly aberrated corneas, even for patients with extreme keratometries greater
than 60 D. All-laser, one-step
(epithelial debridement included) PRK treatments were performed with the iVIS, a 1,000-Hz topography-guided laser that also includes a 1,000-Hz tracker and active cyclotorsion, allowing for more precise centering of treatments.

Using very small optical zones of 1.5 to 3 mm and a larger transition zone, a smoother ablation can be achieved with minimal tissue removal and a large refractive change. Corneal cross-linking was followed according to the Dresden protocol.¹

Using a topography neutralization technique² (CUSTOM-TNT) refractive algorithm with the iVIS laser treatment, uncorrected visual acuity at 1 month was as follows: 63% of eyes achieved 20/40 or better, and 13% of eyes achieved 20/20 or better. Best spectacle-corrected visual acuity was unchanged or better in 87% of eyes.

In summary, even though cross-linking stabilizes eyes with keratoconus, the procedure by itself does not always improve the refractive error, resulting in dissatisfied patients. Topography-guided iVIS PRK with cross-linking using CUSTOM-TNT algorithms is an all-laser treatment for keratoconus that both stabilizes the cornea and improves the residual refractive error. With improved predictability, patient satisfaction also increases.

David T. C. Lin, MD, FRCS(C)

References

Wollensak G, Spoerl E, Seilter T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620-627.
Lin DTC, Holland SP, Rocha K, Krueger R. Method for optimizing topography-guided ablation of highly aberrated eyes with the ALLEGRETTO WAVE Excimer laser. J Refract Surg. 2008; 24(4):439-445 Suppl.

Epi-On vs. Epi-Off CXL: Which Direction to Go?

Collagen cross-linking with UVA and riboflavin has become a popular and valuable treatment worldwide.When it was introduced in the late 1990s, the technique involved removing the corneal epithelium to load the corneal stroma with riboflavin. More recently, international investigators have been performing epithelium-on cross-linking, without removing the epithelium.

Over the past 2 years, we have been conducting prospective, multicenter trials involving more than 1,000 eyes to evaluate the efficacy of epithelium-on cross-linking. A significant amount of data should be collected by December 2011. Subjects must be age 10 or older and have keratoconus, pellucid marginal degeneration, forme fruste keratoconus, ectasia following LASIK, or unstable refraction after PRK. Exclusion criteria include severe scarring, pregnancy and known sensitivity to any of the study medications. The surgical technique involves topical anesthetics and riboflavin loading of the cornea via topical application followed by UVA application. The primary outcome measures include best corrected visual acuity, uncorrected visual acuity and change in corneal curvature.

Preliminary data in a subset of patients show improved best corrected visual acuity in eyes undergoing the epi-on procedure compared with epi-off. At 3 months, 50% of the 128 epi-on eyes had improved vision versus 31.1% for the epi-off group (n=45). At 6 months, 51.7% of the 45 epi-on eyes had improved vision compared with 24% of the epi-off group (n=25).

Future research should be directed toward improving riboflavin penetration through relatively intact epithelium and reducing disruption of the ocular surface as much as possible. Find additional information about our ongoing clinical trials at www.cxlusa.com and www.clinicaltrials.gov, identifiers NCT01189864, NCT01024322 and NCT01097447.

Roy S. Rubinfeld, MD, MS

Risk Factors for Post-LASIK Ectasia

Collagen cross-linking is a promising treatment for corneal ectasia after refractive surgery. In order to predict which patients might develop ongoing ectasia after surgery, we examined a large cohort of consecutive LASIK procedures treated in 2008 and 2009, comprising 64,695 eyes of 33,561 patients. All patients had preoperative myopia, and surgery was performed with either femtosecond laser or mechanical flaps. With 2 to 3 years of follow-up, ectasia was observed in 11 patients.

We compared preoperative parameters in the ectasia cases and the primary cohort. Mean preoperative and postoperative corneal thicknesses were 549 µ (SD 31 µ) and 365 µ (SD 43 µ), respectively, in the entire cohort and 531 µ and 337 µ, respectively, in the ectasia group. The mean preoperative sphere was -2.92 D (SD 1.81 D) for the entire cohort, and -3.59 D for the ectasia group. Mean preoperative cylinder for the entire cohort was -0.74 D (SD 0.71 D) and -0.66 D for the ectasia group. The mean age was 35.6 years (SD 10.3 years) for the entire cohort and 26.3 years for the ectasia group. The oldest member of the ectasia group was 32 years.

Based on these preliminary data and analysis, corneal shape and patient age appear to have the strongest association with ectasia after LASIK. However, since these results are preliminary, much more work is needed to fully analyze this dataset.

Steven Schallhorn, MD