Corneal collagen crosslinking in the management of ectatic diseases

Corneal crosslinking (CXL) is recognized as a major therapeutic advance in the management of ectatic diseases. CXL is an effective means of halting progressive corneal thinning and steepening in patients with keratoconus, pellucid marginal degeneration, and ectasia after laser-assisted in situ keratomileusis (LASIK) or small incision lenticule extraction (SMILE). Other potential applications include treatment of corneal edema in bullous keratopathy, infectious corneal ulcers, enhancing corneal flattening after the insertion of intrastromal corneal rings, strengthening the cornea before photorefractive keratectomy (PRK) treatment in high myopia or mild or forme fruste patients with keratoconus, and reducing the fluctuation in vision and hyperopic shift following radial keratotomy. More than 500 peer reviewed articles support its efficacy in halting the progression of keratoconus and numerous reports support its use for other potential indications.

CXL treatment involves the use of riboflavin drops (vitamin B 2 ) and ultraviolet A (UVA) light. The main goal of CXL in ectatic diseases is to stabilize the corneal curvature and prevent the need for corneal transplantation. Treatment at an early stage in the disease process can prevent loss of best-corrected acuity and allow patients to function without hard contact lenses. The treatment has been adopted by ophthalmologists around the globe as the standard of care for progressive ectasia.


Keratoconus is a degenerative disorder of the cornea with an incidence of approximately one in 1000. Structural changes of the cornea cause it to thin and become conical. The disease usually presents in adolescence and tends to peak in severity in patients aged in their 20 s or 30 s; 10% to 25% of patients with keratoconus may require a corneal transplant. CXL has been shown to decrease the need for a transplant.

Clinical signs of keratoconus

The diagnosis of keratoconus is made based on a number of clinical signs and topographic imaging ( Fig. 37.1 ). One of the earliest signs on routine examination is an irregular scissors reflex on retinoscopy. With further ectatic disease, Vogt’s striae or stress lines appear as vertical lines in the deep stroma. The striae temporarily disappear if slight pressure is applied to the cornea. A ring of yellow-brown pigmentation known as a Fleischer ring can be observed in around half of keratoconic eyes. This ring is caused by deposition of the iron oxide hemosiderin within the corneal epithelium. Further progression can lead to breaks in Bowman’s membrane, resulting in apical scarring. A break in Descemet’s membrane results in rapid stromal and often epithelial edema, referred to as corneal hydrops. An advanced cone can create a V-shaped indentation in the lower eyelid when the patient’s gaze is directed downward, known as Munson’s sign. This finding, though a classic sign of the disease, tends not to be of primary diagnostic importance because it occurs late in the disease process.

Fig. 37.1

Clinical signs of keratoconus may be early or late in the disease process.

Computerized topography and tomography

Sophisticated corneal imaging today allows for an early diagnosis of keratoconus. Computerized corneal topography can take the form of curvature analysis or with computerized tomography both curvature and elevation detection. Asymmetric astigmatism with inferior steepening is a typical topographic pattern ( Fig. 37.2 ). Elevation imaging allows for the comparison of the anterior surface or posterior surface with a best-fit sphere. Changes to the posterior corneal curvature may represent the earliest clinical sign of keratoconus ( Fig. 37.3 ). Corneas are typically thinner in keratoconus, and the finding of the thinnest spot on the cornea in the steepest region associated with posterior corneal elevation is characteristic for keratoconus. Clinical studies on the measurement of the thickness of the epithelium indicate that eyes with keratoconus typically have thinner epithelium overlying the cone and thicker at the base of the cone.

Fig. 37.2

Computerized videokeratography of keratoconus with inferior steepening.

Fig. 37.3

(A) Computerized topography shows a relatively normal bowtie pattern of astigmatism. (B) However, posterior corneal elevation shows a focal area of bulging, characteristic of keratoconus.

Etiology of keratoconus

The etiology of keratoconus remains unknown. Kerato-conus likely arises from a number of factors: genetic, environmental, or cellular, any of which may form the trigger for the onset of the disease. A genetic predisposition to keratoconus has been observed, with the disease running in certain families, and incidences reported of concordance in identical twins. Most genetic studies agree on an autosomal dominant mode of inheritance. The condition is seen at a higher frequency in those with Down syndrome. Keratoconus also has been associated with atopic diseases, which include asthma, allergies, and eczema. There is support for the finding that excess eye rubbing contributes to the progression of keratoconus.

Pellucid marginal degeneration

Pellucid marginal degeneration (PMD) is a degenerative corneal ectatic disease that is often confused with keratoconus. It is characterized by thinning in the periphery of the cornea. The corneas typically have a normal thickness in the center. The inferior cornea exhibits a peripheral band of thinning. There is usually high against-the-rule astigmatism. Computerized topography shows a classic butterfly appearance. No known cause for the disease has been found. Like keratoconus, PMD represents a contraindication to LASIK and SMILE.

Corneal ectasia following laser-assisted in situ keratomileusis or small incision lenticule extraction

Corneal ectasia is a rare, potentially devastating complication following LASIK or SMILE. Ectatic changes may occur as early as 1 week, but are usually delayed by many years. The actual incidence of ectasia is undetermined, although incidence rates of 0.04%, 0.2%, and 0.6% have been reported.

Risk factors for corneal ectasia include:

  • 1.

    Abnormal preoperative topography as seen with keratoconus, pellucid marginal degeneration, or forme fruste keratoconus.

  • 2.

    Low residual stromal bed (RSB) thickness is an important factor after LASIK or SMILE because tensile strength analysis indicates greater strength in the anterior 40% relative to the posterior 60% of stroma. LASIK or SMILE reduces corneal structural integrity; it is clear that a cutoff of 250 μm of the corneal bed does not absolutely discriminate development of ectasia; however, the risk of ectasia increases reciprocally relative to RSB thickness.

  • 3.

    Young age may be a significant risk factor for ectasia in patients without other risk factors. One hypothesis is that some of these individuals would have developed delayed-onset forme fruste or keratoconus even without the LASIK or SMILE procedure.

  • 4.

    Low preoperative corneal thickness is a factor along with the degree of myopia and RSB. RSB thickness is the most significant predictor of ectasia among them.

  • 5.

    High myopia, especially greater than 10.00 diopters, is associated with a higher risk of ectasia. Despite this finding, post-LASIK and SMILE ectasia has been reported in patients with low refractive errors.

Other risk factors include eye rubbing, family history of keratoconus, refractive instability, and best corrected visual acuity (BCVA) of less than 20/20 preoperatively.

Development of corneal crosslinking

The derivation of the concept of CXL came from the recognition that diabetic individuals tend not to develop keratoconus because of natural crosslinking from high blood glucose levels and exposure to UV light. The basic research on CXL was conducted from 1993 to 1997 by Doctors Theo Seiler and Eberhard Spoerl in Germany. Research has shown that CXL increases corneal rigidity by 328%. New bonds are formed across adjacent collagen fibers to enhance the cornea’s mechanical strength. The procedure has been effective in treating keratoconus, pellucid marginal degeneration, and ectasia following laser vision correction.

The idea of crosslinking is not new. The practice has been used since around 1940 in the field of material science in the conversion of silicone oil to rubber. Dentists have been using crosslinking for more than 25 years ( Fig. 37.4 ). Natural crosslinking occurs as a normal aging change in connective tissues of the body. This may explain why the progression of keratoconus tends to slow down with age.

Fig. 37.4

Crosslinking has been used in the field of dentistry for more than 25 years.

Basic research on safety of corneal crosslinking

CXL with riboflavin solution and UVA light at 370 nm has been shown to be safe when using an irradiance of 3 mW/cm 2 with a minimum corneal thickness of 400 μm. With a thickness of 400 μm or greater, minimal energy gets delivered to the corneal endothelium, and this level is below the threshold for any damage. The damage thresholds for keratocytes and endothelial cells are 0.45 and 0.35 mW/cm 2 , respectively. In a 400-mm thick cornea saturated with riboflavin, the irradiance at the endothelial level was 0.18 mW/cm 2 ( Fig. 37.5 ), which is a factor of 2 smaller than the damage threshold. Studies have looked at the amount of radiant energy that gets into the eye that could affect the iris, the lens, and the retina, and this also has been shown to be below the damage threshold ( Fig. 37.6 ). For the development of cataract, various dose values have been discussed in the literature with wavelengths between 290 and 365 nm. The retina is damaged by thermal or blue light-induced photochemical damage in the wavelength range of 400 to 1400 nm. Studies with confocal microscopy have shown that keratocytes are depleted to a depth of 300 μm, with repopulation of new keratocytes taking up to 6 months ( Fig. 37.7 ).

Fig. 37.5

Radiant energy exposure from ultraviolet A (UVA) light versus damage threshold of structures in the eye.

Jun 26, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Corneal collagen crosslinking in the management of ectatic diseases
Premium Wordpress Themes by UFO Themes