Journal of Eye Diseases and Disorders

Corneal Cross-Linking in Progressive Keratoconus: Mechanisms, Outcomes, and Long-Term Safety

Rebekah Tseng^* Department of Corneal Surgery, National Taiwan University, Taipei, Taiwan
^*Correspondence: Rebekah Tseng, Department of Corneal Surgery, National Taiwan University, Taipei, Taiwan, Email:

Received: 03-Mar-2025, Manuscript No. JEDD-25-29175; Editor assigned: 05-Mar-2025, Pre QC No. JEDD-25-29175 (PQ); Reviewed: 19-Mar-2025, QC No. JEDD-25-29175; Revised: 26-Mar-2025, Manuscript No. JEDD-25-29175 (R); Published: 02-Apr-2025, DOI: 10.35248/2684-1622.25.10.276

Description

Keratoconus is a progressive, non-inflammatory ectatic disorder of the cornea characterized by thinning and anterior protrusion, resulting in irregular astigmatism and decreased visual acuity. Although the exact etiology remains multifactorial and not fully understood, genetic predisposition, enzymatic imbalances, mechanical trauma such as eye rubbing, and environmental influences are believed to contribute to its development. The disease typically manifests in adolescence and progresses over the next two decades, posing a major threat to vision and quality of life if left untreated. Corneal Cross-Linking (CXL), a relatively recent innovation, has transformed the therapeutic landscape by offering a minimally invasive approach to halt disease progression and preserve corneal structure.

The principle of corneal cross-linking involves the photochemical strengthening of the corneal stroma by inducing new covalent bonds between collagen fibrils. This is achieved through the combined application of riboflavin (vitamin B2) as a photosensitizer and Ultraviolet-A (UVA) light at a wavelength of 365-370 nm. Riboflavin penetrates the corneal stroma and, upon UVA exposure, generates reactive oxygen species that catalyze the formation of cross-links between collagen molecules. This enhances biomechanical rigidity, increases resistance to enzymatic degradation, and stabilizes the corneal architecture.

The standard “Dresden protocol,” developed in the early 2000s, remains the most widely used technique for CXL. It involves epithelial removal (epithelium-off or “epi-off”) to facilitate stromal absorption of riboflavin, followed by 30 minutes of UVA irradiation at 3 mW/cm². Numerous studies have validated the efficacy of this method in halting keratoconus progression, improving uncorrected and best-corrected visual acuity, and inducing mild flattening of the corneal curvature as measured by keratometry. Long-term data spanning over 10 years demonstrate sustained stability and low rates of adverse events.

Despite its success, the epithelium-off technique is associated with transient discomfort, risk of infection, corneal haze, and delayed epithelial healing. To address these limitations, alternative protocols such as transepithelial (epi-on) CXL and accelerated CXL have been developed. Transepithelial techniques preserve the epithelium and reduce patient discomfort and recovery time, though penetration of riboflavin is often suboptimal, potentially compromising efficacy. Various enhancers and iontophoresis techniques have been explored to improve riboflavin delivery without removing the epithelium.

Accelerated CXL shortens treatment duration by increasing UVA intensity while reducing exposure time, based on the Bunsen-Roscoe law of reciprocity. Protocols such as 9 mW/cm² for 10 minutes or 18 mW/cm² for 5 minutes have shown comparable outcomes in some studies, though debate continues regarding the depth of cross-linking and long-term results. Customization of CXL parameters, including pulsed light protocols and personalized irradiation patterns, is an evolving area of research aimed at optimizing treatment for various stages and morphologies of keratoconus.

Indications for CXL extend beyond classic keratoconus to include pellucid marginal degeneration, post-LASIK ectasia, and iatrogenic or traumatic corneal weakening. Pediatric patients, who typically experience more rapid disease progression, particularly benefit from early CXL intervention. Studies in younger populations show high success rates in halting keratoconus progression, with improved functional vision and minimal complications when appropriately performed.

Combining CXL with refractive or therapeutic procedures has also gained traction. Simultaneous or sequential CXL with topography-guided Photorefractive Keratectomy (PRK), intracorneal ring segment implantation, or phakic intraocular lens insertion can enhance visual outcomes and reduce dependence on corrective lenses. Such combination therapies aim not only to stabilize the disease but also to rehabilitate vision and improve corneal regularity. However, careful patient selection and timing are crucial to minimize complications.

Safety is a key consideration in CXL. While the procedure is generally well-tolerated, potential complications include persistent epithelial defects, corneal haze, endothelial cell damage, and rarely, infectious keratitis. Corneal thickness plays a vital role in procedural planning, with a minimum of 400 μm typically required to protect the endothelium from UVA toxicity. Newer protocols, such as hypoosmolar riboflavin solutions or contact lens-assisted CXL, have expanded eligibility for patients with thinner corneas.