CET CONTINUING EDUCATION & TRAINING 1 FREE CET POINT Approved for: Optometrists 4 OT CET content supports Optometry Giving Sight Dispensing Opticians 4 Having trouble signing in to take an exam? View CET FAQ Go to www.optometry.co.uk Corneal Collagen Crosslinking for Keratoconus C-18113 O/D 45 Preeti Singla, MSc, MCOptom Keratoconus is a non-inflammatory disease of the cornea also known as primary corneal ectasia. It is characterised by biomechanical instability and thinning 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 It is interesting that young patients (CXL). This article describes the treatment, results, and contraindications, so with diabetes have never been reported that patients with keratoconus can be educated about this new development. to develop keratoconus unless its onset was before the onset of diabetes, whilst a look to slow the progression of the disease those patients already diagnosed with stiffness of only 60% of that of a normal too. Intra-corneal ring segments (Intacs) keratoconus are not noted to have cornea,1 which often leads to progressive are one example, which involve the progression of the disease following the myopia, irregular astigmatism, higher insertion of PMMA ring segments into the onset of diabetes. It is the natural cross- order aberrations and corneal scarring, corneal stroma in order to delay the need linking effect of glucose in the corneae thus resulting in a potential decrease for corneal transplant surgery (Figure 1). of such patients that increases corneal in visual acuity (VA). It affects 1 in Less invasive than this is the cross-linking resistance to deformation of shape.9 2000 of the general population and of collagen fibres in the cornea, to provide is added strength, which is known as CXL. A cornea with generally first keratoconus diagnosed has in the Cross-linking a well-established technique used in synthetic polymer chemistry second and third decades of life.2 It is is and the manufacture of generally bilateral but often asymmetric The principles of CXL plastics and is progressive in 20% of cases. The cornea is made up of a regular matrix orthopaedics.11 It works by increasing the of collagen fibres of which the primary mechanical strength of a material. Its use in function mechanical the cornea was discovered at the Dresden support. These are called the stromal Technical University in 199812 and its largely lamellae. The individual collagen fibrils use for keratoconus was first reported disease are strengthened by inter-molecular cross- by Wollensak and colleagues in 2003.5 progression. Until recently, treatment of links that develop as a natural part of Corneal cross-linking has also been used the condition centred on providing an their maturation process. In conditions successfully in the treatment of iatrogenic improvement in VA, initially by spectacles where the cornea is weak, such as in ectasia after excimer laser ablation and and then contact lenses, and finally, keratoconus, there is an abnormality in for when refractive correction can no longer the types and numbers of these links and provide adequate levels of vision or when as a result the corneal shape begins to Technique there is intolerance to contact lenses, by bulge into a conic shape. CXL works by CXL involves the use of riboflavin penetrating and lamellar keratoplasty. increasing these collagen cross-links and (vitamin B2) and ultraviolet-A (UVA) However, all of these techniques only thereby strengthening the human cornea light irradiation. Riboflavin has a two- correct the refractive error associated by up to 328.9%4 (Figure 2). A beneficial fold role in the procedure. It acts as both with keratoconus and do not address the side effect of CXL in many patients is a photo-sensitizer for the induction of underlying ectasia. Recently-introduced flattening and regularisation of the conic cross-links between collagen fibrils, as treatments however, no longer aim to corneal shape, which in turn can cause a well as shielding the underlying tissue simply maintain good vision but actually reduction in myopia and astigmatism. from the effects of UVA (Figure 3).12 Traditional management methods Management of depends the on keratoconus extent of is to provide 10 as well as in dentistry and pellucid marginal degeneration. 3 5-8 For the latest CET visit www.optometry.co.uk/cet 24/02/12 CET Figure 1 Intra-corneal ring segments (Intacs) as a treatment for keratoconus of the corneal stroma as a result of weakened collagen fibres. Recent years CET CONTINUING EDUCATION & TRAINING 1 FREE CET POINT Approved for: Optometrists 4 OT CET content supports Optometry Giving Sight Dispensing Opticians Having trouble signing in to take an exam? View CET FAQ Go to www.optometry.co.uk 4 Contraindications Corneal opacities,17 ocular pathologies,17 corneal scarring,14 Vogt striae,14 dry eye,8 corneal infections,8 and previous surgery8 were all listed as contraindications for CXL in the studies carried out to date. It is not clearly indicated whether corneal 46 scarring or pathology causes an adverse effect following treatment or whether the 24/02/12 CET Figure 2 CXL works by increasing collagen cross-links thereby strengthening the human cornea treatment would just be less effective. The interaction of riboflavin and UVA whilst improvement in best-corrected produces a reactive oxygen species, VA (BCVA) was on average 1-2 lines which causes the formation of additional of acuity.5-9,14 A reduction in myopia of covalent collagen between 0.40D to 1.14D5-7 was noted molecules, consequently producing a and a reduction in astigmatism of biomechanical stiffening of the cornea. 0.93D was also reported.8 The average bonds between sterile flattening of the corneal keratometry conditions and is therefore generally readings was by 1.42D to 2.00D.7,14,15 carried out in an operating theatre Post-operative regression of keratoconus (Figure 4). There are some variations to has been noted in 70% of cases.5 The treatment requires the treatment procedure but generally Patient suitability anaesthetic drops and then removal of the Age central 7mm diameter area of the corneal Studies have included patients as young epithelium. The exposed corneal surface as 10 years of age,14 up to the age of 60 is then treated with the application of years6 and as of yet, the National Institute riboflavin 0.1% solution for a total of for 30 minutes; 5 minutes into this process, (NICE) the cornea is irradiated with UVA of there will be any age limitations on 370nm wavelength and irradiance of the availability of the CXL treatment.16 has and not Although no difference in pre- and postoperative corneal thickness has been reported with CXL treatment,14 CXL in corneas with thickness less than 400µm 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 it involves the instillation of topical Health Corneal thickness 400 µm.5,6,8,9,14,15 However a recent study Clinical Excellence indicated whether 3mW/cm2 at a distance of 1cm from the has shown that the thickness of thinner corneas can be increased by application of hypo-osmolar 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 1-year follow-up.20 Complications cornea. This too is applied for a period Progression of 30 minutes, delivering a total dose of NICE the Failure of a treatment can be described in 5.4Jcm-1. Antibiotic eye drops are then procedure should only be carried out on a number of ways. Failure and retreatment instilled, as a prophylaxis following patients with progressive keratoconus.16 levels have been found to be low, with less treatment, as well as a bandage contact However, how this should be decided than 2% of patients experiencing acute lens, until the epithelium has healed.13 and over what time scale is not exacerbation of neurodermatitis, which in indicated. Studies to date have used turn can cause progression of keratoconus varying methods of analysis to establish and Studies on the outcome of CXL have progression. These include (i) increase Another indication of failure is an increase only been conducted for approximately in keratometry reading of greater than rather than decrease in maximum corneal a decade. These initial results, some 1.00D,7,8,15,17 (ii) increase in spherical keratometry reading; an increase of more of refractive error by 0.50D,7 (iii) increase than 1.00D was noted in 7.6% of patients.21 Results which have conducted long- guidelines Failure indicate that may require repeat treatment.8 8 in astigmatism by 1.00D, (iv) the need in for a new contact lens fitting in the space Haze uncorrected VA (UCVA) was found to of 2 years,8,15 and (v) patient report of Temporary haze is a very common be between 1 to 3.6 lines of acuity6-8,14 decrease in VA over the past 2 years.8 occurrence after CXL treatment but this term are analysis very of positive. up to 6 years, Improvement 7 Find out when CET points will be uploaded to Vantage at www.optometry.co.uk/cet/vantage-dates Figure 3 Appearance of the cornea after absorption of riboflavin during CXL. Courtesy of Mr Mohammed Muhtaseb, Consultant Ophthalmic Surgeon 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 a grade of 0.06 noted at 12 months (grade 1 being total corneal haze),21 or with use of topical preservative-free follow-up to include the use of topical 47 antibiotic agents, and for informed consent to be obtained from patients who elect to have this procedure for keratoconus. Figure 4 Set-up of the CXL surgical technique steroid therapy.14 Permanent The future corneal haze is more likely The ability to achieve predictable cross- progression. The weaker biomechanical in patients with thinner corneas and linking without epithelial removal would effect is presumably due to insufficient steeper corneal curvature.19 Persistent be a desirable modification in order to trans-epithelial haze was found to reduce the BCVA by lessen and into the stroma. Translated to a human 2 lines of acuity in 2.9% of patients. shorten recovery time. However, it is likely cornea, this will produce an increase in A scar developed in 2.9% of eyes. that complete removal of the epithelium is Young’s modulus of only 64% with the necessary to permit adequate and uniform epithelium intact compared to 320% saturation of the stroma with riboflavin. found with standard CXL. Early studies Removal of the corneal epithelium during In 2004 Boxer Wachler proposed a on human eyes have shown a limited the process of CXL treatment will cause slight modification of the existing CXL but favourable effect of trans-epithelial post-operative pain, often severe, for 24-72 treatment. He suggested the use of pre- CXL hours, as is noted with similar procedures operative anaesthetic eye drops containing However, based on these predictions involving excimer surface ablation such as benzalkonium chloride to loosen the perhaps this method would best be LASEK. It has been found that removing tight junctions of corneal epithelial cells. reserved for patients with thin corneas.24 the superficial epithelium by excimer The use of benzalkonium chloride is It would be reasonable to postulate laser is significantly more painful than thought to allow trans-epithelial cross- that the risk for infection might be full-thickness removal of the epithelium linking treatment without removal of the lower in trans-epithelial CXL where the using the Amolis brush. Only removing epithelium. epithelium the superficial epithelium also requires the epithelium intact are absence of post- almost 40% longer for full saturation of the operative pain and better patient comfort.11 stroma with riboflavin.22 New treatments This modification of the technique is developed 21 21 Pain post-operative 24 discomfort The advantages of keeping on riboflavin keratoconus remains diffusion progression.25 intact. However further research is needed to confirm this. Another new technique that has been is called ‘flash-linking’, cross-linking still in the early stages of human trials. which uses a customised photoactive however have been designed to reduce However, the biomechanical effect of cross-linking agent requiring only 30 levels of pain experienced (see later). the trans-epithelial CXL procedure has seconds of UVA exposure. In porcine been successfully assessed in rabbit eyes. eyes it has so far shown a similar Young’s modulus measures the increase efficacy in increasing the stiffness of Microbial keratitis following CXL has been in biomechanical rigidity and is the the cornea as standard CXL. However, observed infrequently with the majority most reliable parameter for assessment this is only through measurement with of incidence reported as anecdotal case of biomechanical properties. Studies on surface wave elastometry and further reports. The possibility of a secondary rabbits have shown that standard cross- studies are still awaited on human eyes.26 infection following CXL exists due to linking increases Young’s modulus by epithelial debridement as well as the 102.4%, whereas in trans-epithelial CXL Summary application of a soft contact lens. By 2010 there is only an increase of 21.3%. This At present keratoconus is not curable. a total of 5 incidents of keratitis following is one-fifth of that found in CXL and However, it has been shown that cross- CXL had been reported with BCVA ranging may not be adequate to increase corneal linking can stop the progression of from 6/6 to 6/60. strength enough to prevent keratoconus keratoconus. Taking into account both such as trans-epithelial Microbial Infection 23 Even if an infection For the latest CET visit www.optometry.co.uk/cet 24/02/12 CET disappears over time, with CET CONTINUING EDUCATION & TRAINING 1 FREE CET POINT Approved for: Optometrists 4 OT CET content supports Optometry Giving Sight Dispensing Opticians Having trouble signing in to take an exam? View CET FAQ Go to www.optometry.co.uk 4 rate of corneal flattening and failure rate, the patient’s PCT. It is not known how research shows that overall success rate many of these requests will be funded is best in corneas with a curvature of 54- but hopefully an NHS referral pathway 58D. will be established in the near future. 17 Where progression can be reliably documented it is important to cross-link corneas with progressive keratoconus as 24/02/12 CET 48 early as possible. Frequently patients are Acknowledgements The author would like to thank only referred to the Hospital Eye Service Consultant Ophthalmologists Mr Bruce once spectacles and contact lenses can Allan (Moorfields Eye Hospital) and Mr no longer provide adequate levels of Andrew Coombes (Barts and The Royal vision or the patient becomes intolerant to London) for their help and support. contact lenses. Often by this stage there is Thanks to Consultant Ophthalmologists evidence of significant disease progression Mr Chad Rostron and Mr Mohammed and they may have passed the stage where Muhtaseb for use of the images. CXL is a suitable management option, for example where the cornea has become About the author too thin or is no longer transparent. Preeti Singla is a Specialist Optometrist Cross-linking is mainly indicated with a keen interest in Paediatrics, in young patients with clinical and Contact Lenses and Low Vision. She holds instrumental documented evidence of keratoconus progression, a minimum thickness of 400µm and biomicroscopic evidence of a clear cornea. It can also be suitable for older patients with progression a Masters Degree in Clinical Optometry 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 and works at Barts and The London NHS Trust and Moorfields Eye Hospital. References 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 www. nkcf.org accessed on 28th October 2011 3.Cannon DJ and Foster CS (1978) 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-ultravioletA-induced cross-linking. Journal of Cataract and Refractive Surgery. 29:1780-1785. 5.Wollensak G, Spoerl E, Seiler T (2003) Riboflavin/Ultraviolet-Ainduced Collagen Crosslinking for the Treatment of Keratoconus. American Journal of Ophthalmology. 135:620-627. 6.Vinciguerra P, Albè E, Trazza s, Rosetta P, Vinciguerra R, Seiler T, Epstein D (2009) Refractive, Topographic, Tomographic, and Aberrometric Analysis of Keratoconic Eyes Undergoing Corneal CrossLinking. 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 riboflavinultraviolet 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 crosslinking: 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: http://www.oteurope. com/ophthalmologytimeseurope/Cornea/C3R-the-present-and-the-future/ArticleStandard/ Article/detail/556880 21st October 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 The Siena Journal of for Eye Keratoconus Cross in Study. Ophthalmology. Italy: American 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 corneal guidance collagen on Photochemical cross-linkage using riboflavin and ultraviolet A for keratoconus. Issued at November 2009. www.nice.org.uk, 27th Accessed October online 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 Find out when CET points will be uploaded to Vantage at www.optometry.co.uk/cet/vantage-dates 20. Raiskup F, Spoerl E (2011) Corneal CrossLinking 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 Surgery 24 (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 www.optometry.co.uk. 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 www.optometry.co.uk/cet/vantage-dates 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 1-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% For the latest CET visit www.optometry.co.uk/cet 49 24/02/12 CET 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: http://www.sciencedirect.com/ science?_ob=MiamiImageURL&_cid=271967&_ user=7153203&_pii=S0002939411004636&_ check=y&_origin=&_coverDate=08-Sep2011&view=c&wchp=dGLbVlV-zSkzV&md 5=4a9f8e82c42953d8bcbdb6f2be263731/1s2.0-S0002939411004636-main.pdf 19. Raiskup F, Hoyer A, Spoerl E (2009) Permanent corneal haze after riboflavin-UVAinduced cross-linking in keratoconus. Journal of Refractive Surgery 25 (Supplement): S824-828.
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