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Year : 2013  |  Volume : 6  |  Issue : 4  |  Page : 8-11  

Update on corneal cross-linking for keratoconus

Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany

Date of Web Publication30-Nov-2013

Correspondence Address:
Elisabeth M Messmer
Department of Ophthalmology, Ludwig-Maximilians-University, Mathildenstrasse 8, 80336 Munich
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0974-620X.122288

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How to cite this article:
Messmer EM. Update on corneal cross-linking for keratoconus. Oman J Ophthalmol 2013;6, Suppl S1:8-11

How to cite this URL:
Messmer EM. Update on corneal cross-linking for keratoconus. Oman J Ophthalmol [serial online] 2013 [cited 2023 Feb 2];6, Suppl S1:8-11. Available from: https://www.ojoonline.org/text.asp?2013/6/4/8/122288

Keratoconus is a bilateral degeneration of the cornea with cone-shaped corneal bulging and stromal thinning. Changes in the biomechanical properties of the cornea play an important role in pathogenesis. Corneal collagen cross-linking (CXL) has emerged as a promising treatment to slow or even stop the progression of keratoconus and other ectatic diseases such as pellucid marginal degeneration or iatrogenic keratectasia after corneal refractive surgery. Ten years ago, Wollensak et al., described the first 22 patients undergoing this treatment with a regression of maximal keratometry readings and decrease of refractive error in 70% and a slight increase in visual acuity in 65% of patients. [1] Since then our knowledge on patient selection, long-term success, and complications has constantly increased. New treatment protocols and techniques are currently studied in clinical trials.

The standard protocol for collagen cross-linking (CXL) includes epithelial abrasion, the administration of a photosensitizer, riboflavin (vitamin B2, 402.7 mOsm/L) for 30 min combined with ultraviolet A (UVA) irradiation (3 mW/cm 2 ; 5.4 J/cm 2 ; and 370 nm) for 30 min, while riboflavin instillation continues. This technique induces free radicals which catalyze a reaction resulting in additional covalent bonds between collagen molecules with subsequent biomechanical stiffening of the cornea of over 300%. [2] Published evidence suggests that CXL is localized to the anterior stroma with minimal to no effects of UVA irradiation on the corneal endothelium and the posterior parts of the eye as long as the treated cornea has a minimum thickness of the recommended 400 μm. [3],[4]

Keratocytes of the anterior stroma undergo apoptosis as observed by in vivo confocal microscopy after treatment, but recover over time. However, we have observed longstanding keratocyte loss in human corneal specimens after CXL. [5] Recent investigations in postmortem porcine eyes suggest that CXL mainly stabilizes inter- and intrafibrillar, but not interlamellar cohesion of the cornea. [6] CXL has a major impact on corneal nerve morphology and sensitivity, but by 90 days, regenerating nerves can be observed throughout the anterior stroma. [7],[8] Clinically, corneal sensitivity progressively recovers up to 6 months postoperatively. [7] Corneal haze with a demarcation line in the corneal stroma is typically noted on clinical examination after CXL. It is greatest at 1 month, plateaus at 3 months, and is significantly decreased between 3 and 12 months without correlation to postoperative clinical outcome. [9] An increase in intraocular pressure (IOP) measured by Goldmann applanation tonometry is present after CXL probably caused by an increase in corneal rigidity. [10],[11] Pascal dynamic contour tonometry could provide more realistic IOP readings after CXL. [10]

Clinically desired changes after CXL include an improvement in apical keratometry, [12],[13],[14],[15] a reduction in corneal curvature, spherical equivalent refraction, and refractive cylinder [16] as well as reduced corneal and total wavefront aberrations. [15],[17] This is accompanied by an increase in visual function, [12],[14],[15] but also by an improvement in functional visual acuity (driving at night, reading), reduction of diplopia, glare, halo, and starbursts. [18] Corneal thinning and corneal volume loss is typically observed following CXL. [14],[19] The cause and implications of these corneal thickness changes after CXL remain to be elucidated.

   Clinical Indication, Patient Selection Top

There is currently little evidence that CXL is useful in stable keratoconus. Progressive keratoconus indicated as increase in Kmax at the apex of keratoconus of 1 diopter (D) in 1 year, deterioration of visual acuity, or the need for new contact lens fittings more than once in 2 years is an indication for CXL treatment. [20] Vinciguerra defined keratoconus progression as a change in either myopia and/or astigmatism of ≥3 D over 6 months, a mean central change in K-readings of ≥1.5 D in three consecutive topographies during the previous 6 months, or a mean central corneal thickness decrease of ≥5% in three consecutive tomographies performed over 6 months. [15] In US studies, CXL was performed when an increase of ≥1 D in the steepest K-reading and/or the manifest cylinder, or an increase of ≥0.5 D in refraction spherical equivalent was evident over 24 months. [21]

Patients with worse preoperative corrected distance visual acuity (CDVA) and higher K-values, particularly with a CDVA of 20/40 or worse or a maximum K of 55.0 D or more, were most likely to have improvement after CXL. [22] Age older than 35 years and a preoperative CDVA > 0/25 were identified as significant risk factors for complications. [23] A high preoperative maximum keratometry reading >58.0 D was a significant risk factor for CXL failure. [23] Moreover, pregnant and lactating women are typically excluded from treatment. In pediatric patients, keratoconus may present more aggressive with high rates of progression to keratoplasty. [24],[25] CXL should be considered earlier in these young patients.

   Long-Term Clinical Studies Top

Recent publications on CXL-studies performed in Europe and the USA provide clinical evidence to support the efficacy and the safety of the CXL procedure for keratoconus. Raiskup-Wolf et al., reported their long-term results of 241 eyes from 130 patients with a follow-up for up to 6 years after CXL. This retrospective study confirmed earlier findings of the same group with statistically significant improvement in astigmatism, best corrected visual acuity, and K max. [20] Vinciguerra reported on a prospective, nonrandomized, single-center clinical trial in Milan that showed an improved uncorrected and best corrected visual acuity and improved corneal and total wavefront aberrations 1 year after CXL. [15] The Siena Eye Cross Study, a prospective, non-randomized, open trial analyzing 44 eyes confirmed safety of the procedure and stability of keratoconus at least 48 months postoperatively. [26] One-year results of the multicenter prospective randomized controlled clinical trial performed according to the US Food and Drug Administration (FDA) guidelines were published by Hersh et al., in 2011. In this study, eyes randomized to the control group crossed over to the treatment group after only 3 months. A second control group included the fellow eye of participants. Significant improvement in uncorrected and best corrected visual acuity, Kmax (2.0 ± 4.4 D) and average keratometry (1.5 D) were evident after 1 year follow-up. [21]

Recent data suggest that also patients with advanced keratoconus with a maximum K of 58.0 D or more can stabilize following CXL. [27] Especially in children and teenagers with accelerated progression of keratoconus, CXL has proven safe and efficacious and should most probably be performed earlier rather than later. [28],[29]

Only few studies compared CXL to controls or sham treatment. Wittig-Silva et al., reported on 66 eyes of 49 patients where significant flattening of steepest simulated keratometry values of 1.45 D was observed in the treatment group compared to untreated controls after 1 year. [30] No long-term data are available. Coskunseven et al., performed a study in 38 eyes (19 patients) where the worse keratoconus eye was cross-linked and the fellow eye served as control. They demonstrated a mean decrease in spherical equivalent refraction and cylinder (P < 0.01), and an increase in uncorrected visual acuity (UCVA) and best spectacle-corrected visual acuity (BSCVA) (P < 0.01) compared to controls. The maximal curvature decreased by 1.57 ± 1.14 D (range: 0.00-3.90 D), and intraocular pressure increased by 2 ± 2 mmHg, which was statistically significant. [16]

In our study, where CXL was compared to sham treatment without epithelial debridement, fluorescein eye drops and blue light irradiation in 30 patients, CXL was effective in significantly decreasing corneal refractive power compared to controls. However, some treated patients still progressed; whereas, some untreated controls improved (Lang et al., submitted)

   Complications Top

Complications in CXL treatment are reported to occur in 2.9-3.5% of patients. [12],[23] They include loss of BCVA, sterile infiltrates, stromal melting and scarring, bacterial keratitis, and reactivation of herpes simplex virus (HSV)-keratitis. [12],[23],[31],[32],[33] The failure rate of CXL (percentage of eyes with continued progression) was 7.6% in a study by Koller, et al. [23]

   Transepithelial CXL (TE CXL) Top

TE CXL has been propagated to avoid epithelial debridement, but in vitro studies showed only low concentrations of riboflavin into the corneal stroma without epithelial removal. [34] In vivo confocal analysis demonstrated a limited apoptotic effect of TE CXL of approximately one-third of classic epi-off CXL. [35] Functional results after TE CXL showed keratoconus instability and regression of the primarily obtained result. Fifty percent of pediatric patients had to be retreated with epi-off CXL due to significant deterioration 12 months after TE-CXL. [36] TE CXL was also less effective than standard CXL when using proparacaine drops 0.5% preserved with benzalkonium chloride (BAC) 0.005%. [37] TE-CXL may be reserved for pediatric cases, uncooperative patients, and thin corneas. [38],[39] Published evidence suggests to use riboflavin combined with ethylenediaminetetraacetic acid 0.01% and trometamol to enhance epithelial penetration. [39]

   CXL with Hypoosmolar Riboflavin Top

Swelling of thin corneas to at least 400 μm stromal thickness using hypoosmolar riboflavin solution (310 mOsm/L) without dextran has been reported by Hafezi et al., [40] The promptness of the swelling response and the amount of swelling showed a distinct interindividual variation (3-20 min; 36-105 μm). CXL with hypoosmolar riboflavin in advanced keratoconus with mean K-values at the apex of 65.6 ± 11.2 D showed stability of topometry and mean BCVA 1 year after treatment. [41] Greenstein reported similar changes in pupil-center pachymetry and pachymetry at the corneal apex from baseline to 1 year in the isotonic riboflavin group compared to patients requiring hypotonic riboflavin CXL. [19]

   CXL with Improved Intensity Profile Top

The intended depth of CXL using current light sources is achieved only within the central area of the cornea. To provide CXL to the peripheral cornea, the UV beam should either have an improved intensity profile or may have to be decentered. [42] New CXL devices with an optimized beam profile to increase the CXL depth in the periphery, and thus the volume which is cross-linked, are now available and are evaluated in clinical trials.

   CXL with Reduced Irradiation Time Top

In an attempt to decrease the total time for the CXL procedure, increasing the irradiance of the UVA light from 3 to 9 mW/cm 2 and decreasing the time of UVA exposure from 30 to 10 min maintaining the same total irradiance was evaluated. The CXL effect of stiffening rabbit corneas was similar with no statistically significant differences to control corneas. [28]

Rocha and colleagues introduced the concept of "flash-linking" whereby polyvinyl pyrrolidone as a new cross-linking agent is used instead of riboflavin and the UVA irradiation stage only takes 30 s at 4.2 mW/cm 2 , rather than the conventional 30 min at 3 mW/cm 2 . Experiments in porcine eyes suggest a comparable crosslinking effect as conventional CXL. [43] Clinical studies using these new irradiation protocols are currently under way.

   Combination with other Procedures Top

Combinations of CXL with implantation of intrastromal corneal ring segments ± transepithelial phototherapeutic keratectomy, has been reported in small case series with promising results. [44],[45],[46],[47] It seems that intrastromal corneal ring segments (ICRS) implantation followed by CXL results in greater improvement of keratoconus than CXL followed by ICRS placement. [44] Moreover, laser power must be modified following CXL suggesting channel dissection and ICRS implantation before or concurrent with CXL. [45] A clinical trial comparing CXL alone to CXL combined with Intacs in patients with keratoconus and post-LASIK ectasia is currently underway in the USA. [28]

In conclusion, CXL represents currently the only etiopathogenetic approach in ectatic corneas and may postpone the need for corneal transplantation. Long-term studies are available to prove safety and efficacy of this new treatment. New technical modalities and surgical combinations are evolving and are currently studied in clinical trials.

   References Top

1.Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620-7.  Back to cited text no. 1
2.Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg 2003;29:1780-5.  Back to cited text no. 2
3.Beshtawi IM, O'Donnell C, Radhakrishnan H. Biomechanical properties of corneal tissue after ultraviolet-A-riboflavin crosslinking. J Cataract Refract Surg 2013;39:451-62.  Back to cited text no. 3
4.Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using riboflavin/UVA treatment. Cornea 2004;23:43-9.  Back to cited text no. 4
5.Messmer EM, Meyer P, Herwig MC, Loeffler KU, Schirra F, Seitz B, et al. Morphological and immunohistochemical changes after corneal cross-linking. Cornea 2013;32:111-7.  Back to cited text no. 5
6.Wollensak G, Sporl E, Mazzotta C, Kalinski T, Sel S. Interlamellar cohesion after corneal crosslinking using riboflavin and ultraviolet A light. Br J Ophthalmol 2011;95:876-80.  Back to cited text no. 6
7.Wasilewski D, Mello GH, Moreira H. Impact of collagen crosslinking on corneal sensitivity in keratoconus patients. Cornea 2013;32:899-902.  Back to cited text no. 7
8.Xia Y, Chai X, Zhou C, Ren Q. Corneal nerve morphology and sensitivity changes after ultraviolet A/riboflavin treatment. Exp Eye Res 2011;93:541-7.  Back to cited text no. 8
9.Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010;36:2105-14.  Back to cited text no. 9
10.Gkika MG, Labiris G, Kozobolis VP. Tonometry in keratoconic eyes before and after riboflavin/UVA corneal collagen crosslinking using three different tonometers. Eur J Ophthalmol 2012;22:142-52.  Back to cited text no. 10
11.Kymionis GD, Grentzelos MA, Kounis GA, Portaliou DM, Detorakis ET, Magarakis M, et al. Intraocular pressure measurements after corneal collagen crosslinking with riboflavin and ultraviolet A in eyes with keratoconus. J Cataract Refract Surg 2010;36:1724-7.  Back to cited text no. 11
12.Asri D, Touboul D, Fournie P, Malet F, Garra C, Gallois A, et al. Corneal collagen crosslinking in progressive keratoconus: Multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 2011;37:2137-43.  Back to cited text no. 12
13.Koller T, Pajic B, Vinciguerra P, Seiler T. Flattening of the cornea after collagen crosslinking for keratoconus. J Cataract Refract Surg 2011;37:1488-92.  Back to cited text no. 13
14.Toprak I, Yildirim C. Scheimpflug parameters after corneal collagen crosslinking for keratoconus. Eur J Ophthalmol 2013;23:793-8.  Back to cited text no. 14
15.Vinciguerra P, Albe E, Trazza S, Rosetta P, Vinciguerra R, Seiler T, et al. Refractive, topographic, tomographic, and aberrometric analysis of keratoconic eyes undergoing corneal cross-linking. Ophthalmology 2009;116:369-78.  Back to cited text no. 15
16.Coskunseven E, Jankov MR 2 nd , Hafezi F. Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus. J Refract Surg 2009;25:371-6.  Back to cited text no. 16
17.Greenstein SA, Fry KL, Hersh MJ, Hersh PS. Higher-order aberrations after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg 2012;38:292-302.  Back to cited text no. 17
18.Brooks NO, Greenstein S, Fry K, Hersh PS. Patient subjective visual function after corneal collagen crosslinking for keratoconus and corneal ectasia. J Cataract Refract Surg 2012;38:615-9.  Back to cited text no. 18
19.Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg 2011;37:691-700.  Back to cited text no. 19
20.Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: Long-term results. J Cataract Refract Surg 2008;34:796-801.  Back to cited text no. 20
21.Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: One-year results. J Cataract Refract Surg 2011;37:149-60.  Back to cited text no. 21
22.Greenstein SA, Hersh PS. Characteristics influencing outcomes of corneal collagen crosslinking for keratoconus and ectasia: Implications for patient selection. J Cataract Refract Surg 2013;39:1133-40.  Back to cited text no. 22
23.Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 2009;35:1358-62.  Back to cited text no. 23
24.Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R, Balestrazzi A. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea 2012;31:227-31.  Back to cited text no. 24
25.Reeves SW, Stinnett S, Adelman RA, Afshari NA. Risk factors for progression to penetrating keratoplasty in patients with keratoconus. Am J Ophthalmol 2005;140:607-11.  Back to cited text no. 25
26.Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: The Siena eye cross study. Am J Ophthalmol 2010;149:585-93.  Back to cited text no. 26
27.Sloot F, Soeters N, van der Valk R, Tahzib NG. Effective corneal collagen crosslinking in advanced cases of progressive keratoconus. J Cataract Refract Surg 2013;39:1141-5.  Back to cited text no. 27
28.Gaster RN, Caiado Canedo AL, Rabinowitz YS. Corneal collagen cross-linking for keratoconus and post-LASIK ectasia. Int Ophthalmol Clin 2013;53:79-90.  Back to cited text no. 28
29.Kankariya VP, Kymionis GD, Diakonis VF, Yoo SH. Management of pediatric keratoconus-Evolving role of corneal collagen cross-linking: An update. Indian J Ophthalmol 2013;61:435-40.  Back to cited text no. 29
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30.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:S720-5.  Back to cited text no. 30
31.Angunawela RI, Arnalich-Montiel F, Allan BD. Peripheral sterile corneal infiltrates and melting after collagen crosslinking for keratoconus. J Cataract Refract Surg 2009;35:606-7.  Back to cited text no. 31
32.Kymionis GD, Portaliou DM, Bouzoukis DI, Suh LH, Pallikaris AI, Markomanolakis M, et al. Herpetic keratitis with iritis after corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract Surg 2007;33:1982-4.  Back to cited text no. 32
33.Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with riboflavin and ultraviolet-A. J Cataract Refract Surg 2009;35:588-9.  Back to cited text no. 33
34.Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: Riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg 2009;35:893-9.  Back to cited text no. 34
35.Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Paradiso AL. Transepithelial corneal collagen crosslinking for keratoconus: Qualitative investigation by in vivo HRT II confocal analysis. Eur J Ophthalmol 2012;22 Suppl 7:S81-8.  Back to cited text no. 35
36.Caporossi A, Mazzotta C, Paradiso AL, Baiocchi S, Marigliani D, Caporossi T. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg 2013;39:1157-63.  Back to cited text no. 36
37.Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon MJ. Refractive and topographic results of benzalkonium chloride-assisted transepithelial crosslinking. J Cataract Refract Surg 2012;38:1000-5.  Back to cited text no. 37
38.Filippello M, Stagni E, O'Brart D. Transepithelial corneal collagen crosslinking: Bilateral study. J Cataract Refract Surg 2012;38:283-91.  Back to cited text no. 38
39.Spadea L, Mencucci R. Transepithelial corneal collagen cross-linking in ultrathin keratoconic corneas. Clin Ophthalmol 2012;6:1785-92.  Back to cited text no. 39
40.Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg 2009;35:621-4.  Back to cited text no. 40
41.Raiskup F, Spoerl E. Corneal cross-linking with hypo-osmolar riboflavin solution in thin keratoconic corneas. Am J Ophthalmol 2011;152:28-32 e21.  Back to cited text no. 41
42.Koller T, Schumacher S, Fankhauser F 2 nd , Seiler T. Riboflavin/ultraviolet a crosslinking of the paracentral cornea. Cornea 2013;32:165-8.  Back to cited text no. 42
43.Rocha KM, Ramos-Esteban JC, Qian Y, Herekar S, Krueger RR. Comparative study of riboflavin-UVA cross-linking and "flash-linking" using surface wave elastometry. J Refract Surg 2008;24:S748-51.  Back to cited text no. 43
44.Coskunseven E, Jankov MR 2 nd , Hafezi F, Atun S, Arslan E, Kymionis GD. Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus. J Cataract Refract Surg 2009;35:2084-91.  Back to cited text no. 44
45.El-Raggal TM. Effect of corneal collagen crosslinking on femtosecond laser channel creation for intrastromal corneal ring segment implantation in keratoconus. J Cataract Refract Surg 2011;37:701-5.  Back to cited text no. 45
46.Kilic A, Kamburoglu G, Akinci A. Riboflavin injection into the corneal channel for combined collagen crosslinking and intrastromal corneal ring segment implantation. J Cataract Refract Surg 2012;38:878-83.  Back to cited text no. 46
47.Yeung SN, Low SA, Ku JY, Lichtinger A, Kim P, Teichman J, et al. Transepithelial phototherapeutic keratectomy combined with implantation of a single inferior intrastromal corneal ring segment and collagen crosslinking in keratoconus. J Cataract Refract Surg 2013;39:1152-6.  Back to cited text no. 47

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