Collagen Cross Linking For Keratoconus

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Continuing Education Activity

Keratoconus (KC) is one of the most prevalent corneal ectatic disorders characterized by progressive, non-inflammatory changes in stromal collagen structure and usually results in protrusion and alteration of the central and paracentral cornea. This activity describes the role of collagen crosslinking procedure in the management of keratoconus. It highlights a multitude of clinical factors that require consideration in patients who undergo collagen crosslinking.


  • Describe the common clinical and topographic features of keratoconus.
  • Summarize the mechanism of action of collagen crosslinking.
  • Outline the indications for the collagen crosslinking procedure.
  • Review potential outcomes of the procedure in available literature.


Keratoconus (KC) is one of the most prevalent corneal ectatic disorders characterized by progressive, non-inflammatory changes in stromal collagen structure and usually results in protrusion and alteration of the central and paracentral cornea.[1] The etiology of this condition remains unknown; however, several ocular and systemic associations exist like Leber’s congenital amaurosis, atopy, Down syndrome, and the connective tissue disorders of Ehlers-Danlos and Marfan syndromes. Presentation is typically in the second or third decade of life with features of progressive myopia and astigmatism. The initial presentation is unilateral; however, both eyes eventually become involved.[2] On examination, several eponymous clinical signs may present that increase the suspicion for KC. Munson’s sign is a V shape bulging of the lower eyelid on downgaze. Slit-lamp examination may reveal Vogt striae: fine, vertical, stromal stress lines, and a Fleischer ring: a ring-like configuration of epithelial iron deposits. Distant direct ophthalmoscopy reveals a characteristic “oil-droplet” reflex, and retinoscopy can demonstrate a characteristic scissoring reflex.

Placido-disc topography, Scheimpflug imaging, and Optical Coherence Tomography allow for the detection of subtle changes in corneal topography, tomography, and epithelium changes associated with KC. A well-known classification system is the Amsler-Krumeich system that uses the patient’s refractive error, central keratometry readings, central corneal thickness and, the presence or absence of scarring. Notably, the Amsler-Krumeich system does not utilize corneal topographic values. Various topographic indices have been proposed for the diagnosis of preclinical KC (forme fruste keratoconus), and clinical KC. Rabinowitz suggests the following topographical characteristics of KC: increased areas of keratometric readings surrounded by areas of reduced corneal power, inferior-superior symmetry, and skewed radial axes. [3]The newer Scheimpflug imaging-based Pentacam system (Oculus GmbH, Wetzlar, Germany) utilizes the Belin/Ambrósio Enhanced Ectasia Display (BAD) to screen for KC using maximal keratometry, anterior and posterior elevation and, tomographic thickness data.[4]

Treatment of early keratoconus involves prescribing spectacles to improve vision, but as the disease progresses, rigid gas permeable contact lenses are required. In a small but significant proportion of patients, disease progression may require eventual corneal transplantation. Several new therapeutic options have emerged, including refractive, optical, and lamellar surgery, which slow the progression of the disease and/or delay more intensive treatment. Collagen cross­linking (CXL) with ultraviolet A (UV-A) light and riboflavin (vitamin B2) is a relatively new treatment that reportedly slows the advancement of the disease in its early stages.[5]

CXL was introduced to clinical practice in the late 1990s and has since then completely modified conservative management of progressive corneal ectasia. CXL utilizes riboflavin as a photosensitizer, which, when exposed to longer wavelength UV-A, induces chemical reactions in the corneal stroma and ultimately results in the formation of covalent bonds between the collagen molecules. This collagen crosslinking increases the tensile strength and rigidity of the cornea, preventing further thinning and ectasia.[5]


Keratoconus, with evidence of progression, is the most common indication for CXL. Other indications include pellucid marginal degeneration, Terrien marginal degeneration, and post-refractive surgery (such as LASIK, PRK, or radial keratotomy) ectasia. The Global Delphi Panel of Keratoconus and Ectatic Diseases recognized the lack of set criteria for documenting disease progression and suggested that two out of the following three parameters should be taken into account when considering progression: steepening of either the anterior or posterior corneal surfaces or, corneal thinning.[6] 

Many studies have based their criteria based on an increase in Kmax value, myopia and/or astigmatism, mean central K-readings, and a decrease in mean central corneal thickness.[7] 

Not every cornea with keratoconus needs to undergo CXL; simple spectacle correction and rigid contact lens form the basis of conservative therapy. CXL is not indicated for KC that is stable, as might be the case in older eyes that naturally have stiffer corneas due to age-related changes.


Contraindications to standard CXL treatment primarily include a corneal thickness of fewer than 400 microns and prior herpetic ocular infection. Other contraindications are concurrent ocular infection, presence of severe scarring, severe dry eye, history of poor epithelial wound healing, autoimmune disorders, and pregnancy.[7]


The Dresden protocol, as described by Wollensak et al., is considered the “conventional” CXL treatment protocol. Also known as the ‘epi-off’ protocol, this involves removal of central epithelium followed by the application of 0.1% riboflavin solution followed by 30 minutes of UVA radiation of wavelength 370nm and power 3mW/cm.[5] Although clinical outcomes of this technique have been reported in mostly prospective or retrospective case series, the medium-term results are very favorable.[5][8] The Dresden group have published their 10-year follow-up results of 34 eyes, demonstrating long-term stability and a good safety profile.[8][9]

Thinner corneas are more susceptible to radiation damage to the endothelium and hence are not suitable for epi-off CXL. Additional protection can be provided to the endothelium by either retaining the epithelium or using hypo-osmolar riboflavin to increase stromal thickness during the radiation exposure stage. Riboflavin penetration through epithelial tight junctions can increase by using chemical enhancers like benzalkonium chloride or EDTA. This “epi-on” protocol reduces the risk of complications associated with the “epi-off” protocol. There are conflicting reports about the efficacy of this procedure. [7]

Accelerated CXL protocols were introduced to clinical practice to shorten the procedure length and reduce the exposure time of the cornea to sources of infection. This concept works on the Bunsen-Roscoe law of photochemical reciprocity: the same photochemical effect is achieved with a shorter irradiation time by a corresponding increase in irradiation intensity. The irradiation time is shortened from 30 minutes down to 3 minutes with comparable results to the standard protocol and may be safe to use in thin corneas.[7][10]

A technique currently under investigation is iontophoresis CXL, which facilitates the penetration of riboflavin through the cornea through the use of a low-intensity electrical current. Iontophoresis shortens riboflavin penetration time and duration of irradiation and does not require epithelium removal.[11] There are yet no long term published studies comparing this to conventional CXL, and the results of short-term follow-up show that it may also be inferior to conventional CXL.[12]

Combining CXL with other modalities was initially suggested by Kymionis et al. in 2011, known as ‘CXL Plus.’[10] The technique involved doing PRK in KC patients to regularise the astigmatic corneal surface that subsequently was followed by CXL to strengthen the corneal biomechanically, thus giving the additional benefit of improvement in visual acuity, which CXL alone cannot offer. Intracorneal ring segments (ICRS) have proven to be useful in KC or post-LASIK ectasia patients for regularising corneal astigmatism, but they cannot halt the progression of the disease. According to few studies combining CXL with ICRS does offer the combined benefit improved visual acuity and strengthening cornea biomechanically.[10]


Common complications related to include temporary corneal haze (10 to 90%), delayed epithelial closure, sterile infiltrates, and central stromal scars. The literature describes postoperative microbial keratitis from bacterial, herpetic, protozoal, and fungal sources.[13] The stromal haze is usually temporary and appears to be likely due to increased edema and keratocyte activation and occurs three to six months post-operatively.[13][14] Rarer but more serious side effects include corneal melts and endothelial failure. Treatment failure is also a noted complication, defined as progression of the condition with an increase in Kmax values of 1.0 D over the pre-operative value or greater than a 10% decrease in pachymetry readings six months post-operatively; this may occur in up to 10% of patients.[1]

Clinical Significance

More than 15 years since its introduction, conventional CXL has proven to be a safe and effective means of halting the progression of corneal ectasias, reducing the need for more invasive treatment options. Modified CXL techniques have had mixed results in regards to efficacy when compared to conventional CXL, and long-term follow-up results are still needed. In addition to treating ectasias, CXL has increasing utilization as a treatment for microbial keratitis and reduction of low myopia, and further research into these domains is still underway.[15][16]

Enhancing Healthcare Team Outcomes

An interdisciplinary team approach involving subspecialty trained physicians and ophthalmic trained nurses provide patient support and follow-up care will lead to the best outcomes. With early detection of keratoconus by healthcare members, corneal crosslinking is an effective way of slowing down and potentially halting progression (Level 3 evidence).[17]

Article Details

Article Author

Vishal Vohra

Article Author

Sahib Tuteja

Article Editor:

Harshika Chawla


5/5/2022 4:49:16 PM



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