The Use of Corneal Cross-linking in Treatment of Progressive Keratoconus: a Review
Journal of Ophthalmic and Optometric Sciences,
Vol. 1 No. 4 (2017),
24 June 2017
,
Page 15-21
https://doi.org/10.22037/joos.v1i4.22804
Abstract
Abstract
Keratoconus is a common corneal ectatic disorder which affects approximately 1 in 2,000 people. The traditional treatments for keratoconus are the use of inserts, deep anterior lamellar keratoplasty (DALK) and anterior lamellar keratoplasty (ALKP). Corneal cross-linking is a relatively new minimally invasive therapeutic approach for treatment of progressive keratoconus, which increases the structural integrity of the cornea. In corneal cross-linking the production of oxygen free radicals by ultraviolet A (UVA) light increases the biomechanical strength of cornea while riboflavin acts as a photo synthesizer for production of oxygen free radicals by UVA. Treatment of progressive keratoconus is the most widespread use of cross-linking technique. In the present manuscript we will summarize different aspects of the utilization of cross-linking in treatment of corneal keratoconus.
Keywords: Corneal Cross-linking; Treatment; Progressive; Keratoconus
How to Cite
References
It was believed that corneal cross-linking should be avoided in corneas with corneal thickness of less than 400 µm 8. Efforts have been made to modify the cross-linking procedure to be applicable in thin corneas; however the evidence of safety and efficacy in the use of modified cross-linking protocols for thinner corneas is still limited to few studies 8. Relative contraindications are maximum K reading of more than 58.00 D 8, IOP over 21mmhg, a history of glaucoma, corneal guttata or other endothelial irregularities, a history of recurrent erosions, ocular surface disorders, and connective tissue diseases 4. Treatment during pregnancy should be deferred as the safety of the procedure and its impact to the fetus has not been established 9. Another relative contraindication is extensive corneal scarring 9.
Concurrent ocular infection, neurotrophic keratopathy, past history of poor epithelial wound healing, severe dry eye, are also considered contraindication for cross-linking 9.
Complications
Permanent loss of 2 or more Snellen lines might happen in about 1 to 3 % of patients 27. Age older than 35 years and a preoperative CDVA of better than 20/25 have been indicated as significant risk factors for complications 27. Haze might increase immediately after cross-linking but completely subsides in most cases 28. The presence of hypo-reflective stromal microstriae or activated keratocytes in the anterior stroma preoperatively and Langerhans cells after contact lens removal are the main risk factors are the risk factors for haze after cross-linking 29. Temporary corneal edema and persistent corneal edema necessitating further treatment
has also been reported in patients undergoing corneal cross linking 29. During the epithelial healing, the cornea is vulnerable to infection and melting and infectious keratitis has been reported 30, 31. Also endothelial damage might occur if the cross linking procedure is used in thin corneas (340–399 μm) 32.
Outcome of CCL in some recent studies
In a study by Tiveron at al., in 2017 on topographic outcomes after performing corneal cross-linking the authors found that After 3 months, steepest keratometry reading (K2) and maximum keratometry (Kmax) were significantly decreased with no statistically significant difference between male and female patients 33. In a prospective, randomized, double-blind trial with average follow-up of 1098 days by Lang et al., conducted in 2015, the efficacy and safety of corneal cross-linking for halting the progression of keratoconus were investigated. In this study, refractive power on average decreased by 0.35 ± 0.58 diopters/year in treatment group 34. The controls showed an increase of 0.11 ± 0.61 diopters/year 34. The difference between the case and control group was statistically significant 34. In a study by Recalde et al., on variations in tear quantity and quality after corneal collagen cross-linking in patients with keratoconus the authors found that during the first postoperative year, corneal cross-linking does not modify the parameters used to evaluate tear film function 35. Plat et al., in their study on influence of corneal collagen cross-linking on anterior chamber in keratoconus found that improvement of corneal parameters by corneal cross-linking in keratoconus patients can have a positive effect on anterior chamber parameters at the 6-month postoperative evaluation 36. Kosekahya et al., evaluated changes in the coordinates of the line of sight and higher order aberrations of eyes with keratoconus, following corneal crosslinking and found that line of sight significantly shifts to the nasal region after corneal corneal cross-linking in both right and left eyes and the improvements in HOAs are significant at postoperative 6th month compared to the baseline measurements 37. Ameen et al., in a study to evaluate the efficacy and safety of transepithelial collagen cross-linking in patients with progressive keratoconus found statistically significant changes from baseline in astigmatism, Maximum simulated Keratometry value (Kmax) and Spherical equivalent (SE) 38. They concluded that transepithelial collagen cross-linking is a safe and effective procedure with statistically significant reduction in corneal astigmatism, Kmax and SE, with reasonable gain in Snellen's visual acuity 38. Wittig-Silva et al., in analysis of 66 progressive keratoconus patients treated with collagen cross-linking reported a flattening (K-max) by an average of 0.74 diopters at 3 months, 0.92 D at 6 months and 1.45 D at 12 months 38. In the control eyes, mean K-max steepened by 0.60 D after 3 months, 0.60 D after 6 months, and 1.28 D after 12 months. No statistically significant changes were found for spherical equivalent or endothelial cell density 39. In a study performed on Iranian patients by Saffarian et al. in 2010 the mean baseline simulated keratometry (SIM K) was 46.94 ± 2.37 D which decreased to 46.0 ± 2.33 D one year postoperatively 40.
The use of corneal cross-linking in combination with other treatment methods
Corneal cross-linking might be used in combination with other treatment modalities to optimize visual outcomes in eyes with keratoconus 41. Combined use of cross-linking and photorefractive keratectomy (PRK) has been suggested. Al-Amiri et al., evaluated the visual outcomes of simultaneous non-topography guided (PRK) and corneal collagen cross-linking, 5 years post-operatively, in eyes with keratoconus 42. In their non-randomized case series study sixty eyes of 30 patients with mild, non-progressive of keratoconus were enrolled 42. Patients’ uncorrected distance visual acuity (UDVA) and corrected distance visual acuity CDVA significantly increased 42. Also a significant decrease in the mean SE refraction, manifest sphere, manifest cylinder and mean steepest keratometry (Kmax) was observed 42. Fadlallah et al., evaluated the safety and clinical outcome of combined photorefractive keratectomy (PRK) and corneal collagen cross-linking in treatment of mild refractive errors in patients with early stage keratoconus 43. They reported that UDVA significantly improved and CDVA remained stable. Also the mean spherical equivalent and the mean cylinder and mean central corneal thickness significantly decreased with no intraoperative complications 43. Another suggested combination therapy is combined cross-linking and corneal ICRS insertion 44. Saleem et al.’ analyzed three-year outcomes of combined cross-linking with femto second laser ICRS implantation for keratoconus management 45. They reported that this combination therapy had a synergistic action correcting and maintaining the correction of both myopic and astigmatic components of keratoconus and was successful in halting the progression keratoconus 45. Abdelmassih evaluated the safety and visual outcomes of ICRS implantation followed by cross-linking in pediatric keratoconus patients 46. They found that ICRS implantation is a safe and effective procedure for visual rehabilitation in children with keratoconus and poor CDVA with no intraoperative or postoperative complications 46. In this study at the 6-month follow-up, mean CDVA and UDVA showed significant improvement in comparison to preoperative levels and a significant decrease in both keratometry readings and spherical equivalent was also observed 46.
Conclusion
A strong body of literature suggests that corneal cross-linking is an effective and safe treatment method for halting the progression of keratoconus. Future studies should focus on the long term results and improvements in methodology of this technique.
References
- Subasinghe SK, Ogbuehi KC, Dias GJ. Current perspectives on corneal collagen crosslinking (CXL). Graefes Arch Clin Exp Ophthalmol. 2018;256(8):1363-84.
- Liskova P, Dudakova L, Krepelova A, Klema J, Hysi PG. Replication of SNP associations with keratoconus in a Czech cohort. PLoS One. 2017;12(2):e0172365.
- Gordon-Shaag A, Millodot M, Shneor E, Liu Y. The genetic and environmental factors for keratoconus. Biomed Res Int. 2015;2015:795738.
- Samaras KE, Lake DB. Corneal collagen cross linking (CXL): a review. Int Ophthalmol Clin. 2010 Summer;50(3):89-100.
- Subasinghe SK, Ogbuehi KC, Dias GJ. Current perspectives on corneal collagen crosslinking (CXL). Graefes Arch Clin Exp Ophthalmol. 2018;256(8):1363-84.
- Spörl E, Huhle M, Kasper M, Seiler T. Increased rigidity of the cornea caused by intrastromal cross-linking. Ophthalmologe. 1997;94:902-6. (Article in German)
- Wollensak G, Spörl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen cross-linking for the treatment of keratoconus. Am. J. Ophthalmol. 2003;135:620-7.
- Chen X, Stojanovic A, Eidet JR, Utheim TP. Corneal collagen cross-linking (CXL) in thin corneas. Eye Vis (Lond). 2015;2:15.
- Galvis V, Tello A, Ortiz AI, Escaf LC. Patient selection for corneal collagen cross-linking: an updated review. Clin Ophthalmol. 2017;11:657-68.
- Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17(4):356-60.
- Tomkins O, Garzozi HJ. Collagen cross-linking: Strengthening the unstable cornea. Clin Ophthalmol. 2008;2(4):863-7.
- McCall AS, Kraft S, Edelhauser HF, Kidder GW, Lundquist RR, Bradshaw HE, et al. Mechanisms of Corneal Tissue Cross-linking in Response to Treatment with Topical Riboflavin and Long-Wavelength Ultraviolet Radiation (UVA). Invest Ophthalmol Vis Sci. 2010; 51(1): 129-38.
- Tamer M. El-Raggal. Riboflavin-Ultraviolet A Corneal Cross-linking for Keratoconus. Middle East Afr J Ophthalmol. 2009; 16(4): 256-9.
- Ruyter IE. Composite-characterization of composite filling materials: reactor response. J Adv Dent Res 1988;2:122-9.
- El Rami H, Chelala E, Dirani A, Fadlallah A, Fakhoury H, Cherfan C, et al. An Update on the Safety and Efficacy of Corneal Collagen Cross-Linking in PediatricKeratoconus. Biomed Res Int. 2015;2015:257927.
- Hafezi F. Tobacco smoking and its impact on corneal biomechanics. Invest Ophthalmol Vis Sci. 2010;51(12):6892.
- Seiler T, Huhle S, Spoerl E, Kunath H. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol. 2000;238(10):822-5.
- Kobashi H, Rong SS. Corneal Collagen Cross-Linking for Keratoconus: Systematic Review. Biomed Res Int. 2017;2017:8145651.
- Lim L, Lim EWL. A Review of Corneal Collagen Cross-linking - Current Trends in Practice Applications. Open Ophthalmol J. 2018;12:181-213.
- Bellini LP. New uses for collagen crosslinking. J Cataract Refract Surg. 2008;34(6):879-80.
- Khan MS, Basit I, Ishaq M, Shakoor T, Yaqub A, Intisar R. Corneal Collagen Cross Linking (CXL) in treatment of Pseudophakic Bullous Keratopathy. Pak J Med Sci. 2016;32(4):965-8.
- Salgado JP, Khoramnia R, Lohmann CP, Winkler von Mohrenfels C. Corneal collagen crosslinking in post-LASIK keratectasia. Br J Ophthalmol. 2011;95(4):493-7.
- Subasinghe SK, Ogbuehi KC, Dias GJ. Current perspectives on corneal collagen crosslinking (CXL). Graefes Arch Clin Exp Ophthalmol. 2018;256(8):1363-84.
- Bozkurt Oflaz A, Bozkurt B, Kamış Ü, Ekinci Köktekir B. Corneal Collagen Crosslinking Treatment in a Case with Pneumococcal Keratitis. Turk J Ophthalmol. 2017;47(3):161-4.
- Morén H, Malmsjö M, Mortensen J, Ohrström A. Riboflavin and ultraviolet a collagen crosslinking of the cornea for the treatment of keratitis. Cornea. 2010;29(1):102-4.
- Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T. Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea. 2008;27(5):590-4.
- Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35(8):1358-62.
- Omary R, Shehadeh-Mashor R. Late onset of persistent, deep stromal haze after corneal cross-linking in a patient with keratoconus. Can J Ophthalmol. 2017;52(2):e81-e83.
- Evangelista CB, Hatch KM. Corneal Collagen Cross-Linking Complications. Semin Ophthalmol. 2018;33(1):29-35.
- Zamora KV1, Males JJ. Polymicrobial keratitis after a collagen cross-linking procedure with postoperative use of a contact lens: a case report. Cornea. 2009;28(4):474-6.
- Koppen C, Vryghem JC, Gobin L, Tassignon MJ.Keratitis and corneal scarring after UVA/riboflavin cross-linking for keratoconus. J Refract Surg. 2009;25(9):S819-23.
- Panagopoulou SI, Grentzelos MA. Corneal collagen cross-linking with riboflavin and ultraviolet-A irradiation in patients with thin corneas. Am J Ophthalmol. 2012;153:24–28.
- Tiveron MC Jr, Pena CRK, Hida RY, Moreira LB, Branco FRE, Kara-Junior N. Topographic outcomes after corneal collagen crosslinking in progressive keratoconus: 1-yearfollow-up. Arq Bras Oftalmol. 2017;80(2):93-6.
- Lang SJ, Messmer EM, Geerling G, Mackert MJ, Brunner T, Dollak S, et al. Prospective, randomized, double-blind trial to investigate the efficacy and safety of corneal cross-linking to halt the progression of keratoconus. BMC Ophthalmol. 2015l 21;15:78.
- Recalde JI, Acera A, Rodríguez-Agirretxe I, Sánchez-Tena MA, San-Cristóbal J, Durán JA. Ocular Surface Disease Parameters After Collagen Cross-Linking for Keratoconus. Cornea. 2017;36(2):148-52.
- Polat N, Gunduz A, Colak C. The influence of corneal collagen cross-linking on anterior chamber in keratoconus. Indian J Ophthalmol. 2017;65(4):271-5.
- Kosekahya P, Koc M, Tekin K, Uzel M, Atilgan CU, Caglayan M, et al. Evaluation of the shifting of the line of sight and higher order aberrations of eyes with keratoconus after corneal cross-linking. Cont Lens Anterior Eye. 2017;40(5):311-17.
- Ameen SS, Mehboob MA, Ali K. Efficacy and safety of transepithelial collagen cross linking for progressive keratoconus. Pak J Med Sci. 2016;32(5):1111-5.
- Wittig-Silva C, Whiting M, Lamoureux E, Lindsay RG, Sullivan LJ, Snibson GR. A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg. 2008;24(7):S720-5.
- Saffarian L, Khakshoor H, Zarei-Ghanavati M, Esmaily H. Corneal Crosslinking for Keratoconus in Iranian Patients: Outcomes at 1 year following treatment. Middle East Afr J Ophthalmol. 2010;17(4):365-8.
- O’Brart DP. Corneal collagen cross-linking: A review. J Optom. 2014 Jul; 7(3): 113-24.
- Al-Amri AM. 5-year follow-up of combined non-topography guided photorefractive keratectomy and cornealcollagen cross linking for keratoconus. Int J Ophthalmol. 2018;11(1):48-52.
- Fadlallah A, Dirani A, Chelala E, Antonios R, Cherfan G, Jarade E. Non-topography-guided PRK combined with CXL for the correction of refractive errors in patients with early stage keratoconus. J Refract Surg. 2014;30(10):688-93.
- Avni-Zauberman N, Rootman DS. Cross-linking and intracorneal ring segments--review of the literature. Eye Contact Lens. 2014;40(6):365-70.
- Saleem MIH, Ibrahim Elzembely HA, AboZaid MA, Elagouz M, Saeed AM, et al. Mohammed OA1, Three-Year Outcomes of Cross-Linking PLUS (Combined Cross-Linking with Femtosecond Laser Intracorneal Ring Segments Implantation) for Management of Keratoconus. J Ophthalmol. 2018;2018:6907573.
- Abdelmassih Y, El-Khoury S, Dirani A, Antonios R, Fadlallah A, Cherfan CG3 Safety and Efficacy of Sequential Intracorneal Ring Segment Implantation and Cross-linking in Pediatric Keratoconus. Am J Ophthalmol. 2017;178:51-7.
- Abstract Viewed: 225 times
- PDF Downloaded: 84 times