The FDA recently approved corneal collagen cross-linking in the United States for the treatment of progressive keratoconus. This procedure now offers patients a treatment option aimed at targeting the underlying disease process and halting its progression, rather than just treating the symptoms commonly associated with keratoconus.

It is important for optometrists to understand how this treatment works, who would be considered candidates, what the procedure entails, and potential side effects of cross-linking, so that you can educate your patients on this exciting new technology. 

Review of Keratoconus

Keratoconus is classically described as a bilateral, asymmetric, non-inflammatory, progressive disorder in which the cornea assumes a conical shape secondary to the loss of structural integrity, continued thinning, and protrusion of the corneal tissue. Keratoconus is the most common primary corneal degeneration with a reported prevalence ranging from approximately 1:500 to 1:2000. Presentation normally occurs during pubescent years and advances throughout adolescence until about the third or fourth decades of life when it typically arrests.

The diagnosis of keratoconus is usually confirmed by the presence of several observable clinical features, in addition to typical corneal topography characteristics. The hallmark signs of keratoconus are central or paracentral corneal stromal thinning, apical corneal protrusion, and the presence of irregular astigmatism. Clinical evaluation will often reveal an irregular “scissors” reflex on retinoscopy, and an “oil droplet” reflex using a direct ophthalmoscope. Slit-lamp examination of the anterior segment may show fine, vertical, deep striae within the corneal stroma (known as Vogt lines), which disappear when external pressure is applied the globe. Additionally, iron deposits may be observed surrounding the base of the cone at the level of the corneal epithelium (Fleisher ring). In advanced cases of keratoconus, bulging of the lower lid can be observed in downgaze (Munson’s sign), and ruptures in Descemet’s membrane can occur, leading to an acute influx of aqueous into the cornea resulting in hydrops.

Corneal topography data in patients with keratoconus will show progressive inferior axial steepening and irregular astigmatism, with steep keratometry values that are usually greater than 48D in mild cases, and can be greater than 54D in both meridians in severe cases. Corneal pachymetry data will also show progressive corneal thinning corresponding to the area of the conical protrusion. 

Etiology of Keratoconus

The etiology of keratoconus remains uncertain, although environmental influences and genetic factors have been proposed, and both may play a role in the development of this disease. Biomechanical studies have demonstrated that these eyes exhibit structural weakness and lower than average stiffness as compared to normal corneas.

It is believed that the number of covalent bonds between adjacent collagen microfibrils, and bonding between neighboring molecules of the extracellular matrix is reduced in these diseases, resulting in diminished biomechanical strength and stability of the corneal tissue. Furthermore, studies have reported that elevated expression of proteolytic enzymes, decreased concentrations of protease inhibitors, and increased keratocyte apoptosis are also among the proposed pathophysiologic mechanisms associated with keratoconus.

Without the appropriate tensile strength, stability, and organization, thinning of the central or paracentral cornea will occur, producing irregular astigmatism, progressive myopia, reduction of visual acuity, and topographic and pachymetric abnormalities.

What is Cross-linking?

Corneal collagen cross-linking (CXL) is a procedure that has been recently utilized in an attempt to biomechanically strengthen a weak cornea in order to prevent progressive keratectasia. The term cross-linking is used to describe the creation of bonds between large molecules following chemical reactions that are often initiated by heat, pressure, or radiation.

The process of cross-linking is used in dentistry to harden filling materials. It is also performed in the polymerization process during the production of contacts and intraocular lens materials. Natural cross-linking due to aging causes hardening of the arteries and stiffens joints, and cross-linking has also been shown to occur throughout the body in patients with diabetes.

Cross-linking Procedure

Though different techniques and technologies have been developed over the years for corneal collagen cross-linking procedures, the standard protocol described by Wollensak and colleagues in 2003 is the most widely utilized method. CXL involves the process of applying ultraviolet (UVA) light of 370nm wavelength to a cornea that has been infused with the photosensitizer riboflavin (vitamin B₂).

Typically, the corneal epithelium is removed (or weakened) and riboflavin drops are applied to the cornea every 2-5 minutes until it can be detected in the anterior chamber (usually over a period of about 30 minutes). Cross-linking bonds occur when riboflavin absorbs the UVA energy applied to the cornea, becomes excited, and produces reactive oxygen species.

These reactive oxygen species then interact further with the collagen molecules within the corneal stroma, inducing chemical covalent bonds between collagen molecules and the interspersed proteoglycans. This process is essentially analogous to idea of adding steps to a ladder, thus strengthening it and reinforcing it against external forces. 

Ideal Candidates for CXL

As with any surgical procedure, critical attention to patient selection is important in maximizing success and minimizing failure rates and potential post-operative complications. Because the principal purpose and most well-documented goal of CXL treatment is to halt the progression of corneal ectasia, it should be reserved for patients with progressive ectatic disease.

However, CXL is indicated in children and adolescents at the time of their diagnosis, without the need of documented progression. Additionally, the maximum corneal power that should be considered for CXL is 65D, as higher keratometric values are associated with increased failure rates. Furthermore, patients over the age of 35, and those with distance visual acuity of 20/25 or better, have a greater risk of visual acuity loss after CXL treatment. In order to reduce the chance of UVA-induced corneal endothelial damage, corneal thickness less than 400 microns was an exclusion criterion for CXL using the standard protocol.

Therefore, the best candidates for CXL include those patients who are 35 years of age or younger, with eyes that show progression in adults or at the time of diagnosis in children, with moderate keratoconus (max K value less than 65D), a corneal thickness greater than 400 microns, and with visual acuities of 20/30 or worse. Exclusion criteria for CXL include prior history of herpetic infections (to avoid potential viral reactivation), concurrent infection, severe corneal scarring or opacification, a history of poor wound healing, severe ocular surface disease, and a history of autoimmune disorders. 

Results of CXL Studies

Results of many clinical trials completed on this procedure have concluded that cross-linking is effective in halting the progression of ectasia, without causing significant side-effects or complications. Additional corneal changes that have been observed following CXL include stiffening of the corneal tissue, flattening of the corneal curvature, and improvement in visual acuity.

Specifically, studies focused on biomechanical stress-strain measurements showed a remarkable increase in corneal strength by over 300% in human corneas treated with CXL. Histological investigations revealed a significant increase in the collagen fiber diameter in the anterior and posterior stroma of rabbit corneas exposed to riboflavin and UVA light. Additionally, an increase in tissue compaction of the anterior collagen fibers was demonstrated in porcine eyes after CXL treatment.

CXL has also been shown to increase biomechanical resistance to collagenase activity, while also increasing corneal thermostability, decreasing corneal permeability, and reducing the potential for corneal stromal hydration. 

Potential Complications of CXL

Potential complications associated with corneal collagen cross-linking are uncommon, and when reported are often noted to be mild and transient. UV light in general represents a potential danger to the human eye; however, the riboflavin molecule absorbs the majority of the UVA light during CXL, shielding most of the ocular structures from the detrimental effects of exposure.

CXL complications typically include temporary stromal edema, temporary or permanent corneal stromal haze, corneal scarring, sterile corneal infiltrates, and infectious keratitis.

Other Potenital Applications of CXL

A lot of effort is currently going into researching cross-linking procedures and other potential clinical applications of this treatment. One of the most promising additional uses of CXL is in the treatment of microbial keratitis and corneal melts. Studies have proven that several bacterial strains that are commonly associated with microbial keratitis were eliminated by the application of riboflavin and UVA light to the corneal tissue. It is believed that it is the excitation of riboflavin and successive oxidative damage that produces the antibacterial action. 

CXL of the cornea has also been shown to have an anti-edematous effect on the cornea and has lead to improvement in clinical signs and symptoms in patients with bullous keratopathy. Other experiments involve the combination of CXL with refractive surgery procedures in patients with irregular astigmatism. For example, some researchers have proposed a procedure in which a surgeon performs topography-guided PRK to correct the patient’s refractive error, immediately followed by CXL to strengthen the cornea.

Additionally, there have also been studies in which CXL was combined with intracorneal ring segments (Intacs), with the idea that the Intacs would flatten and regularize the corneal shape, followed by CXL that would stabilize the cornea.

-Dr. Dexter