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Corneal collagen cross-linking for keratoconus: C-18113 O/D.

Keratoconus is a non-inflammatory disease of the cornea also known as primary corneal ectasia. It is characterised by biomechanical instability and thinning of the corneal stroma as a result of weakened collagen fibres. Recent years have seen the introduction of exciting new treatments that aim to slow the progression of the disease. One such treatment is corneal collagen cross-linking (CXL). This article describes the treatment, results, and contraindications, so that patients with keratoconus can be educated about this new development.

A cornea with keratoconus has a stiffness of only 60% of that of a normal cornea, (1) which often leads to progressive myopia, irregular astigmatism, higher order aberrations and corneal scarring, thus resulting in a potential decrease in visual acuity (VA). It affects one -in-2,000, of the general population and is generally first diagnosed in the second and third decades of life. (2) It is generally bilateral but often asymmetric and is progressive in 20% of cases.

Traditional management methods

Management of keratoconus largely depends on the extent of disease progression. Until recently, treatment of the condition centred on providing an improvement in VA, initially by spectacles and then contact lenses, and finally, when refractive correction can no longer provide adequate levels of vision or when there is intolerance to contact lenses, by penetrating and lamellar keratoplasty. However, all of these techniques only correct the refractive error associated with keratoconus and do not address the underlying ectasia. Recently-introduced treatments however, no longer aim to simply maintain good vision but actually look to slow the progression of the disease too. Intra-corneal ring segments (Intacs) are one example, which involve the insertion of PMMA ring segments into the corneal stroma in order to delay the need for corneal transplant surgery (Figure 1). Less invasive than this is the cross-linking of collagen fibres in the cornea, to provide added strength, which is known as CXL.

The principles of CXL

The cornea is made up of a regular matrix of collagen fibres of which the primary function is to provide mechanical support. These are called the stromal lamellae. The individual collagen fibrils are strengthened by inter-molecular cross-links that develop as a natural part of their maturation process. In conditions where the cornea is weak, such as in keratoconus, there is an abnormality in the types and numbers of these links (3) and, as a result, the corneal shape begins to bulge into a conic shape. CXL works by increasing these collagen cross-links and thereby strengthening the human cornea by up to 328.9% (4) (Figure 2). A beneficial side effect of CXL in many patients is flattening and regularisation of the conic corneal shape, which in turn can cause a reduction in myopia and astigmatism. (5-8)


It is interesting that young patients with diabetes have never been reported to develop keratoconus unless its onset was before the onset of diabetes, whilst those patients already diagnosed with keratoconus are not noted to have progression of the disease following the onset of diabetes. It is the natural cross-linking effect of glucose in the corneae of such patients that increases corneal resistance to deformation of shape. (9)

Cross-linking is a well-established technique used in synthetic polymer chemistry and the manufacture of plastics (10) as well as in dentistry and orthopaedics. (11) It works by increasing the mechanical strength of a material. Its use in the cornea was discovered at the Dresden Technical University in 1998 (12) and its use for keratoconus was first reported by Wollensak and colleagues in 2003. (5) Corneal cross-linking has also been used successfully in the treatment of iatrogenic ectasia after excimer laser ablation and for pellucid marginal degeneration.


CXL involves the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) light irradiation. Riboflavin has a twofold role in the procedure. It acts as both a photo-sensitizer for the induction of cross-links between collagen fibrils, as well as shielding the underlying tissue from the effects of UVA (Figure 3). (12)


The interaction of riboflavin and UVA produces a reactive oxygen species, which causes the formation of additional covalent bonds between collagen molecules, consequently producing a biomechanical stiffening of the cornea.

The treatment requires sterile conditions and is therefore generally carried out in an operating theatre (Figure 4). There are some variations to the treatment procedure but generally it involves the instillation of topical anaesthetic drops and then removal of the central 7mm diameter area of the corneal epithelium. The exposed corneal surface is then treated with the application of riboflavin 0.1% solution for a total of 30 minutes; five minutes into this process, the cornea is irradiated with UVA of 370nm wavelength and irradiance of 3mW/[cm.sup.2] at a distance of 1cm from the cornea. This too is applied for a period of 30 minutes, delivering a total dose of 5.4J[cm.sup.-1]. Antibiotic eye drops are then instilled, as a prophylaxis following treatment, as well as a bandage contact lens, until the epithelium has healed. (13)


Studies on the outcome of CXL have only been conducted for approximately a decade. These initial results, some of which have conducted long-term analysis of up to six years, (8) are very positive. Improvement in uncorrected VA (UCVA) was found to be between 1 to 3.6 lines of acuity (6-8,14) whilst improvement in best-corrected VA (BCVA) was, on average, 1-2 lines of acuity. (5-9,14) A reduction in myopia of between 0.40D to 1.14D (5-7) was noted and a reduction in astigmatism of 0.93D was also reported. (8) The average flattening of the corneal keratometry readings was by 1.42D to 2.00D. (7,14,15) Post-operative regression of keratoconus has been noted in 70% of cases. (5)

Patient suitability


Studies have included patients as young as 10 years of age, (14) up to the age of 60 years (6) and as of yet, the National Institute for Health and Clinical Excellence (NICE) has not indicated whether there will be any age limitations on the availability of the CXL treatment. (16)


NICE guidelines indicate that the procedure should only be carried out on patients with progressive keratoconus. (16) However, how this should be decided and over what timescale is not indicated. Studies to date have used varying methods of analysis to establish progression. These include (i) increase in keratometry reading of greater than 1.00D, (7,8,15,17) (ii) increase in spherical refractive error by 0.50D, (7) (iii) increase in astigmatism by 1.00D, (7) (iv) the need for a new contact lens fitting in the space of two years, (8,15) and (v) patient report of decrease in VA over the past two years. (8)


Corneal opacities, (17) ocular pathologies, (17) corneal scarring, (14) Vogt striae, (14) dry eye, (8) corneal infections8 and previous surgery (8) were all listed as contraindications for CXL in the studies carried out to date. It is not clearly indicated whether corneal scarring or pathology causes an adverse effect following treatment, or whether the treatment would just be less effective.

Corneal thickness

Although no difference in pre- and postoperative corneal thickness has been reported with CXL treatment, (14) CXL in corneas with thickness less than 400pm after epithelial removal has been shown to result in significant endothelial cell density decrease following treatment. (18) More significantly, in patients with thin corneas, a permanent stromal scar tends to develop after CXL. (19) Most traditional studies use a minimum thickness entry requirement of 400 [micro]m. (5,6,8,9,14,15) However, a recent study has shown that the thickness of thinner corneas can be increased by application of hypoosmolar riboflavin solution following epithelium removal. All corneas in this study were found to be transparent without any detectable scarring lesions in the stroma at the one-year follow-up. (20)



Failure of a treatment can be described in a number of ways. Failure and retreatment levels have been found to be low, with less than 2% of patients experiencing acute exacerbation of neurodermatitis, which in turn can cause progression of keratoconus and may require repeat treatment. (8) Another indication of failure is an increase, rather than decrease, in maximum corneal keratometry reading; an increase of more than 1.00D was noted in 7.6% of patients. (21)


Temporary haze is a very common occurrence after CXL treatment but this disappears over time, with a grade of 0.06 noted at 12 months (grade 1 being total corneal haze), (21) or with the use of topical preservative-free steroid therapy. (14) Permanent corneal haze is more likely in patients with thinner corneas and steeper corneal curvature. (19) Persistent haze was found to reduce the BCVA by 2 lines of acuity in 2.9% of patients. (21) A scar developed in 2.9% of eyes. (21)



Removal of the corneal epithelium during the process of CXL treatment will cause post-operative pain, often severe, for 24-72 hours, as is noted with similar procedures involving excimer surface ablation such as LASEK. It has been found that removing the superficial epithelium by excimer laser is significantly more painful than full-thickness removal of the epithelium using the Amolis brush. Only removing the superficial epithelium also requires almost 40% longer for full saturation of the stroma with riboflavin. (22) New treatments such as trans-epithelial cross-linking, however, have been designed to reduce levels of pain experienced (see later).

Microbial infection

Microbial keratitis following CXL has been observed infrequently, with the majority of incidence reported as anecdotal case reports. The possibility of a secondary infection following CXL exists due to epithelial debridement as well as the application of a soft contact lens. By 2010 a total of five incidents of keratitis following CXL had been reported with BCVA ranging from 6/6 to 6/60. (23) Even if an infection is recognised and treated appropriately, it may still cause corneal scarring and decrease the BCVA. Therefore, although rare, these cases emphasise the need for all surgical procedures to be carried out under sterile conditions, for post-operative follow-up to include the use of topical antibiotic agents, and for informed consent to be obtained from patients who elect to have this procedure for keratoconus.

The future

The ability to achieve predictable cross-linking without epithelial removal would be a desirable modification in order to lessen post-operative discomfort and shorten recovery time. However, it is likely that complete removal of the epithelium is necessary to permit adequate and uniform saturation of the stroma with riboflavin.

In 2004 Boxer Wachler proposed a slight modification of the existing CXL treatment. He suggested the use of preoperative anaesthetic eye drops containing benzalkonium chloride to loosen the tight junctions of corneal epithelial cells. The use of benzalkonium chloride is thought to allow trans-epithelial cross-linking treatment without removal of the epithelium. (24) The advantages of keeping the epithelium intact are absence of postoperative pain and better patient comfort. (11) This modification of the technique is still in the early stages of human trials. However, the biomechanical effect of the trans-epithelial CXL procedure has been successfully assessed in rabbit eyes.

Young's modulus measures the increase in biomechanical rigidity and is the most reliable parameter for assessment of biomechanical properties. Studies on rabbits have shown that standard cross-linking increases Young's modulus by 102.4%, whereas in trans-epithelial CXL there is only an increase of 21.3%. This is one-fifth of that found in CXL and may not be adequate to increase corneal strength enough to prevent keratoconus progression. The weaker biomechanical effect is presumably due to insufficient trans-epithelial riboflavin diffusion into the stroma. Translated to a human cornea, this will produce an increase in Young's modulus of only 64% with the epithelium intact compared to 320% found with standard CXL. Early studies on human eyes have shown a limited, but favourable, effect of trans-epithelial CXL on keratoconus progression. (25) However, based on these predictions, perhaps this method would best be reserved for patients with thin corneas. (24)


It would be reasonable to postulate that the risk for infection might be lower in trans-epithelial CXL where the epithelium remains intact. However further research is needed to confirm this.

Another new technique which has been developed is called 'flash-linking', which uses a customised photoactive cross-linking agent requiring only 30 seconds of UVA exposure. In porcine eyes it has, so far, shown a similar efficacy in increasing the stiffness of the cornea as standard CXL. However, this is only through measurement with surface wave elastometry and further studies are still awaited on human eyes. (26)


At present keratoconus is not curable. However, it has been shown that cross-linking can stop the progression of keratoconus. Taking into account both rate of corneal flattening and failure rate, research shows that the overall success rate is best in corneas with a curvature of 54-58D. (17) Where progression can be reliably documented, it is important to cross-link corneas with progressive keratoconus as early as possible. Frequently patients are only referred to the Hospital Eye Service once spectacles and contact lenses can no longer provide adequate levels of vision or the patient becomes intolerant to contact lenses. Often by this stage there is evidence of significant disease progression and they may have passed the stage where CXL is a suitable management option, for example where the cornea has become too thin or is no longer transparent.

Cross-linking is mainly indicated in young patients with clinical and instrumental documented evidence of keratoconus progression, a minimum thickness of 400 [micro]m and biomicroscopic evidence of a clear cornea. It can also be suitable for older patients with progression or to improve VA in those intolerant to rigid gas permeable contact lens wear. (14)

Although the risks of CXL have not yet been fully quantified, the potential for some risk would seem justified in the context of a progressive disease that is otherwise likely to result in further impairment of VA, or even the need for lamellar or penetrating keratoplasty. The decision to undergo surgical treatment, such as lamellar or penetrating keratoplasty, should always be undertaken with careful consideration to both risks and recovery period.

CXL has been shown to be a practical outpatient service, which is minimally invasive and cost-effective with minimal stress for patients. (8) So far it has been used in research studies and is available privately. Its use for keratoconus under the NHS has been approved by NICE, (16) although so far there is no routine funding for CXL under the NHS. For each individual deemed suitable for the treatment, an Individual Funding Request (IFR) must be completed and sent to the patient's PCT. It is not known how many of these requests will be funded but hopefully an NHS referral pathway will be established in the near future.


The author would like to thank consultant ophthalmologists, Bruce Allan (Moorfields Eye Hospital) and Andrew Coombes (Barts and The Royal London) for their help and support. Thanks also to consultant ophthalmologists Chad Rostron and Mohammed Muhtaseb for use of the images.


(1.) Andreassan TT, Simonsen AH, Oxlund H (1980) Biomechanical properties of keratoconus and normal corneas, Experimental Eye Research 31: 435-441.

(2.) National Keratoconus Website accessed on October 28 2011

(3.) Cannon DJ and Foster CS (1978J Collagen crosslinking in keratoconus. Investigative Ophthalmology and Visual Science 17: 63-64.

(4.) Wollensak G, Spoerl E, Seiler T (2003) Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. Journal of Cataract and Refractive Surgery. 29: 1780-1785.

(5.) Wollensak G, Spoerl E, Seiler T (2003) Riboflavin/Ultraviolet-A-induced collagen crosslinking for the treatment of keratoconus. American Journal of Ophthalmology. 135: 620-627.

(6.) Vinciguerra P, Albe E, Trazza s, Rosetta P, Vinciguerra R, Seiler T, Epstein D (2009) Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology 116: 369-378.

(7.) Hersch PS, Greenstein SA; Fry KL (2011) Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. Journal of Cataract and Refractive Surgery. 37: 149-160.

(8.) Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE (2008) Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: Long-term results. Journal of Cataract and Refractive Surgery 34: 796-801.

(9.) Caporossi A, Baiocchi S, Mazzotto C, Traversi C, Caporossi T (2006) Parasurgical therapy for keratoconus by riboflavin-ultraviolet type A rays induced cross-linking of corneal collagen: Preliminary refractive results in an Italian study. Journal of Cataract and Refractive Surgery 32: 837-845.

(10.) Snibson GR (2010) Collagen cross-linking: a new treatment paradigm in corneal disease--a review. Clinical and Experimental Ophthalmology 38: 141-153.

(11.) Pinelli R, El Beltagi T (2008) C3-R: the present and the future. Ophthalmology Times Europe 4(8). Accessed online at: the-future/ArticleStandard/Article/detail/556880 October 21 2011.

(12.) Spoerl E, Huhle M, Seiler T (1998) Induction of cross-links in corneal tissue. Experimental Eye Research. 66: 97-103.

(13.) Ashwin PT and McDonnell PJ (2010) Collagen cross-linkage: a comprehensive review and directions for future research. British Journal of Ophthalmology. 94: 965-970.

(14.) Caporossi A, Mazzotto C, Baiocchi S, Caporossi T (2009) long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: The Siena Eye Cross Study. American Journal of Ophthalmology. 149: 585-592.

(15.) Grewal DS, Brar GS, Jain R, Sood V, Singla M, Grewal SPS (2009) Corneal collagen crosslinking using riboflavin and ultraviolet-A light for keratoconus: One year analysis using Scheimpflug imaging. Journal of Cataract and Refractive Surgery. 35: 425-432.

(16.) NICE guidance on Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus. Issued November 2009. Accessed online at, October 27 2011

(17.) Koller T, Pajic B, Vinciguerra P, Seiler T (2011) Flattening of the cornea after collagen crosslinking for keratoconus. Journal of Cataract and Refractive Surgery. 37: 1488-1492.

(18.) Kymionis GD, Portaliou DM, Diakonis VF, Kounis GA, Panagopoulou SI, Grentzelos MA (2011) Corneal collagen cross-linking With riboflavin and ultraviolet-A irradiation in patients with thin corneas. American Journal of Ophthalmology epub ahead of print accessed at: 7153203&_pii=S0002939411004636&_check=y&_origin=&_coverDate=08- Sep2011&view=c&wchp=dGLbVlV-zSkzV&md5=4a9f8e82c42953d8bcbdb6f2be263731/ 1s2.0-S0002939411004636-main.pdf

(19.) Raiskup F, Hoyer A, Spoerl E (2009) Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. Journal of Refractive Surgery 25 (Supplement): S824-828.

(20.) Raiskup F, Spoerl E (2011) Corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas. American Journal of Ophthalmology 152: 28-32.

(21.) Koller T, Mrochen M, Seiler T (2009) Complications and failure rates after corneal crosslinking. Journal of Cataract and Refractive Surgery. 35: 1358-1362.

(22.) Bakke EF, Stojanovic A, Chen X, Droslum L (2009) Penetration of riboflavin and postoperative pain in corneal collagen crosslinking: Excimer laser superficial versus mechanical full-thickness epithelial removal. J Cataract Refr Surg. 35: 1363-1366.

(23.) Sharma N, Maharana P, Singh G, Titiyal J (2010) Psedomonas keratitis after collagen crosslinking for keratoconus: Case report and review of literature. Journal of Cataract and Refractive Surgery 36: 517-520.

(24.) Wollensak G, Iomdina E (2009) Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. Journal of Cataract and Refractive Surgery. 35: 540-546.

(25.) Leccisotti A, Islam T (2010) Transepithelial corneal collagen cross-linking in keratoconus. Journal of Refractive Surgery 26: 942-948.

(26.) Rocha KM, Ramos-Esteban JC, Qian Y, Herekar S, Kruegar RR (2008) Comparative study of riboflavin-UVA cross-linking and 'flash-linking' using surface wave elastometry. Journal of Refractive Surgery24 (Supplement): S748-S751.

Module questions Course code: C-18113 O/D

PLEASE NOTE There is only one correct answer. All CET is now FREE. Enter online. Please complete online by midnight on March 23, 2012--You will be unable to submit exams after this date--answers to the module will be published on CET points for these exams will be uploaded to Vantage on April 2, 2012. Find out when CET points will be uploaded to Vantage at

1) Keratoconus is a non-inflammatory disease of the cornea which:

a) Affects 1 in 2000 people and is generally unilateral

b) Affects 2 in 1000 people and is generally bilateral

c) Affects 1 in 2000 people and is generally bilateral

d) Affects 2 in 1000 people and is generally unilateral

2) The primary function of corneal collagen fibres is to:

a) Provide nutrition

b) Provide mechanical support

c) Confer refractive power

d) Confer elasticity

3) The technique of CXL involves:

a) Removal of the central 7mm of corneal epithelium

b) Use of a bandage contact lens

c) Application of riboflavin 0.1% solution for 30 minutes

d) All of the above

4) Following CXL, a reduction in myopia has been noted, in the order of:

a) 0.93D

b) 0.40D-1.14D

c) 1.42D-2.00D

d) 1.00D-3.60D

5) At one-year post treatment, corneal haze was found to be of grade:

a) 1.00

b) 0.06

c) 0.60

d) 6.00

6) In standard CXL there is an increase in Young's Modulus, of the human cornea, by:

a) 320%

b) 102.4%

c) 21.3%

d) 64%

Preeti Singla, MSc, MCOptom

Preeti Singla is a specialist optometrist with an interest in paediatrics, contact lenses and low vision. She holds a Masters Degree in Clinical Optometry and works at Barts and The London NHS Trust and Moorfields Eye Hospital.
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Author:Singla, Preeti
Publication:Optometry Today
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Geographic Code:4EUUK
Date:Feb 24, 2012
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