Keratoconus: cross-linking the window of the eye

Abstract

Keratoconus is a condition in which the cornea progressively thins and weakens, leading to severe, irregular astigmatism and a significant reduction in quality of life. Although the precise cause of keratoconus is still not known, biochemical and structural studies indicate that overactive enzymes within the cornea break down the constituent proteins (collagen and proteoglycans) and cause the tissue to weaken. As the disease develops, collagen fibres slip past each other and are redistributed across the cornea, causing it to change shape. In recent years, it was discovered that the photochemical induction of cross-links within the corneal extracellular matrix, through the use of riboflavin and ultraviolet (UVA) light, could increase the strength and enzymatic resistance of the tissue and thereby halt keratoconus progression. Worldwide acceptance and use of riboflavin/UVA corneal cross-linking therapy for halting keratoconus progression has increased rapidly, in accordance with the growing body of evidence supporting its long-term effectiveness. This review focusses on the inception of riboflavin/UVA corneal cross-linking therapy for keratoconus, its clinical effectiveness and the latest scientific advances aimed at reducing patient treatment time, improving patient comfort and increasing patient eligibility for treatment.

Plain language summary: Review of current treatments using cross-linking to halt the progress of keratoconus Keratoconus is a disease in which the curved cornea, the transparent window at the front of the eye, weakens, bulges forward into a cone-shape and becomes thinner. This change of curvature means that light is not focussed onto the retina correctly and vision is progressively impaired. Traditionally, the effects of early keratoconus were alleviated by using glasses, specialist contact lenses, rings inserted into the cornea and in severe cases, by performing a corneal transplant. However, it was discovered that by inducing chemical bonds called cross-links within the cornea, the tissue could be strengthened and further thinning and shape changes prevented. The standard cross-linking procedure takes over an hour to perform and involves the removal of the cells at the front of the cornea, followed by the application of Vitamin B2 eye drops and low energy ultraviolet light (UVA) to create new cross-links within the tissue. Clinical trials have shown this standard procedure to be safe and effective at halting keratoconus progression. However, there are many treatment modifications currently under investigation that aim to reduce patient treatment time and increase comfort, such as accelerated cross-linking procedures and protocols that do not require removal of the surface cells. This review describes the different techniques being developed to carry out corneal cross-linking efficiently and painlessly, to halt keratoconus progression and avoid the need for expensive surgery.

Keywords: UVA; collagen; cornea; cross-linking; keratoconus; riboflavin.

Figure 1.

Laboratory set-up (authors own) for riboflavin/UVA corneal cross-linking of an enucleated porcine eye. Note the bright yellow fluorescence of the stromal riboflavin as the cornea is exposed to UVA light from above. UVA, ultraviolet.

Figure 2.

CCT of ex vivo porcine eyes (n = 40) measured with their epithelium intact (CCT with epi), after epithelium removal (CCT epi-off) and again, after a 20-min application of a 0.1% riboflavin solution in a carrier solution of 20% dextran or 1.1% HPMC (CCT after ribo). CCT, Central corneal thickness; HPMC, hydroxypropyl methylcellulose.

Figure 3.

(a–d) Corneal iontophoresis involves the creation of a low intensity electric field to help transport negatively charged riboflavin solution across the intact epithelium. The corneal applicator is attached to the surface of the cornea by a vacuum suction system (a). The negative electrode is a steel grid (housed within the applicator) that is fully submerged within a reservoir of riboflavin (b). In our ex vivo system, a steel needle is inserted into the anterior chamber (c) and connected to the positive electrode (d), which returns to the power supply to complete the circuit. In the clinical situation, the positive electrode is attached to the patient’s forehead by means of a patch.