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Original Article
Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: One-year results Maria Clara Arbelaez, Maria Bernardita Sekito, Camila Vidal, Sanak Roy Choudhury Muscat Eye Laser Center, Muscat, Oman Background: The aim of this study is to evaluate the pachymetry, posterior and anterior elevations from safety and effectiveness of riboflavin-ultraviolet type Pentacam and corneal aberrations at 6 months and 1 A (UV-A) light rays induced cross-linking of corneal collagen in improving visual acuity and in stabilizing the progression of keratoconic eyes. The method of Results: Comparative analysis of the pre-operative and corneal cross-linking using riboflavin and UV-A light 1 year post-operative evaluation showed a mean gain of is technically simple and less invasive than all other 4.15 lines of UCVA (P = 0.001) and 1.65 lines of BCVA therapies proposed for keratoconus. It is the only (P = 0.002). The reduction in the average keratometry treatment that treats not only the refractive effects of reading was 1.36 D (P = 0.0004) and 1.4 D (P = 0.001) the condition but the underlying pathophysiology.
at the apex. Manifest refraction sphere showed a mean reduction of 1.26 D (P = 0.033) and 1.25 D (0.0003) for Materials and Methods: In this prospective, manifest cylinder. Topo-aberrometric analysis showed nonrandomized clinical study, 20 eyes of 19 patients improvement in corneal symmetry.
with keratoconus were treated by combined riboflavin Conclusion: Cross-linking was safe and an effective UV-A collagen cross linking. The eyes were saturated therapeutical option for progressive keratoconus. with riboflavin solution and were subjected for 30 min under UV-A light with a dose parameter of 3 mW/cm2. Keywords: Corneal scarring, cross-linking, irregular Safety and effectiveness of the treatment was assessed by measuring the uncorrected visual acuity, best corrected visual acuity, manifest cylinder/sphere, keratometry, Oman Journal of Ophthalmology, 2009; 2(1):33-38 intermarriage with a second- or third-degree relative is a common practice. Keratoconus is a progressive, noninflammatory, bilateral (but usually asymmetrical) disease of the cornea, Spectacles and contact lenses are the usual treatment characterized by paraxial stromal thinning that leads modalities in the early stages of keratoconus. As the to corneal surface distortion.[1] The thinning and the disease advances, severe corneal astigmatism and stromal protrusion in keratoconus induces irregular astigmatism, opacities develop to the point where contact lenses can no myopia and scarring resulting in visual loss and mild to longer provide useful vision and penetrating keratoplasty marked impairment in the quality of vision. Among the risk (PKP) becomes necessary to restore visual function. factors of this condition is genetics, usually inherited in an Penetrating keratoplasty is the most commonly performed autosomal dominant fashion.[2] This could partly explain surgical procedure for keratoconus, but is associated with why keratoconus is a relatively common corneal disease complications including graft rejection.[3] It is estimated entity in the gulf countries particularly in Oman where that eventually 21% of the keratoconus patients require Copyright:  2009 Soliman Mahdy MAE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Correspondence:
Maria Clara Arbelaez, Muscat Eye Laser Center, P.O. Box 938 PC 117 Muscat, Oman. E-mail: drmaria@omantel.net.com, DOI: 10.4103/0974-620X.48420.
Oman Journal of Ophthalmology, Vol. 2, No. 1, 2009 [Downloaded free from http://www.ojoonline.org on Saturday, February 28, 2009]
Arbelaez et al.: Collagen cross-linking in keratoconus surgical intervention (PKP) to restore corneal anatomy and The surgical procedure consisted of topical anesthesia (instillation of oxybuprocaine 0.4% eye drops) and then In selected cases wherein the cornea is still transparent and manual epithelial abrasion of 6–8 mm using 17% ETOH for in relatively young patients who are reluctant to pursue PKP, 20–40 s. This was done to ensure penetration of riboflavin less invasive surgical interventions may be resorted to and in the stroma and that a high level of UV-A absorption these are lamellar keratoplasty (LKP)[5-7] and intrastromal was achieved. Riboflavin solution was repeatedly placed corneal ring segments (Intacs). LKP has the advantages of every 3 min for 30 min to allow sufficient saturation in being extraocular, reversible if tissue complications occur the stroma. This was inspected by slit lamp examination and has the ability to replace only selected areas of diseased as fluorescence within the anterior chamber. Then the corneal tissue with healthy donor tissue.[8] Intacs, which cornea was irradiated with UV-A light at 365 nm with a were initially used to correct low myopia, have been shown dose parameter of 3 mW/cm2 for 30 min (UV-X device). to improve vision in keratoconus[9,10] and post-LASIK During the treatment, riboflavin solution was applied every 5 min to saturate the cornea and drops of BSS every 2 min to moisten the cornea. After the treatment, the cornea was Results of the currently available treatments for keratoconus irrigated with 20-ml BSS solution and an antibiotic drop (rigid contact lens, LKP and Intacs) are viable and are was instilled. Contact lens was placed after the treatment.
considered logical addition to the stepwise treatment of keratoconus for the improvement of vision. However, there is a new procedure that addresses primarily the Antibiotic eye drops (ofloxacin) and Pranoprofen pathophysiology of keratoconus and this is riboflavin UV-A 0.1% E/D were applied for one week until complete rays induced cross-linking. Cross-linking of the cornea is re-epithelializationwas achieved. After the cornea has a procedure that can increase the ties or chemical bonds completely healed, the contact lens is removed. Efemoline between the fibers of the corneal collagen by means of a eye drops and artificial tears were applied for approximately highly localized photo-polymerization using UV-A light and a photosensitizer riboflavin drops. [13,14] Riboflavin (Vitamin B2) has a dual function of acting as a photosensitizer for Outcome measures and statistical analysis the production of oxygen free radicals, which induce Follow-up examination was done at 3, 6, and 12 months physical cross linking of collagen, and it gives a "shielding post-treatment. At each examination, uncorrected visual effect" by absorbing the UV-A irradiation (90%), thereby acuity, best corrected visual acuity, refraction, keratometry, preventing damage to deeper ocular structures. UV-A light corneal topography, pachymetry and corneal aberrations of 370 nm wavelength at 3 mW/cm2 allows approximately were recorded. SPSS statistical software was used for 95% of the UV light to be absorbed into the cornea; thus statistical analysis. there is no risk for damage to the lens and retina. Collagen cross-linking is the only treatment that deals with not only the refractive effects of the condition but the underlying pathophysiology. The aim of this study is to evaluate the Twenty keratoconic eyes of 19 patients were included in safety and effectiveness of riboflavin UV-A light-induced the study. All patients completed 1 year and presented with cross-linking of corneal collagen in improving visual acuity moderate to severe keratoconus. Fourteen patients were and in stabilizing the progression of keratoconic eyes.
men and 5 were women. The mean age was 24.4 years (range: 18–44 years). Materials and Methods
Table 1 shows the pre-operative and postoperative findings This prospective longitudinal study comprised patients with in all patients. The surgery and the postoperative period signs of progressive keratoconus defined as an increase in were unremarkable in all patients. The epithelium re- maximum K readings in several consecutive measurements epithelialized one week after the treatment. In the early over a period of 3 to 6 months, changes in refraction, patient post-operative period, all eyes had minimal anterior stromal reports of deteriorating visual acuity and contact lens corneal haze which resolved approximately 3 months post- intolerance. All of the patients had bilateral keratoconus operatively. After 6 months from the treatment, patients without sub-epithelial scarring, were older than 18 years were given the option to wear contact lenses or to undergo old, with a corneal thickness of at least 400 µm. The eye intrastromal corneal ring surgery if necessary. with the more advanced stage of keratoconus was treated. The institutional ethics committee approved the study, and Visual acuity all patients were asked to sign an informed consent.
Visual acuity was measured using the decimal equivalent Oman Journal of Ophthalmology, Vol. 2, No. 1, 2009 [Downloaded free from http://www.ojoonline.org on Saturday, February 28, 2009]
Arbelaez et al.: Collagen cross-linking in keratoconus Table 1: Comparison between mean preoperative, six months and one year postoperative data
Parameter
Pre-operative Mean ± SD Post-op 6 months Mean ± SD Post-op 1 year Mean ± SD 1.18 (20/320) ± 0.69 0.63 (20/80) ± 0.32 0.55 (20/70) ± 0.32 0.40 (20/50) ± 0.43 0.24 (20/30) ± 0.19 0.22 (20/30) ± 0.17 Manifest refraction sphere (D) Manifest refraction cylinder (D) UCVA-uncorrected visual acuity; BCVA- best corrected visual acuity; D = diopters; In logMAR values (Snellen acuity). SD = standard deviation and transformed into logarithm of the minimum angle manifest refraction sphere at 1 year as compared with the of resolution (logMAR) for further statistical analysis pre-operative evaluation. The mean value of the manifest as recommended by Holladay.[15] Visual acuity data is refraction cylinder was utilized as a measure of the change expressed as logMAR ± standard deviation (Snellen value). in the refractive astigmatism. The cylinder values at 1-year Table 1 provides the uncorrected visual acuity (UCVA) for examination were statistically significantly less than the all patients at the pre-operative, 3 months and 6 months pre-operative measurements (P = 0.0003).One year after examination and Figure 1 shows the change in UCVA the cross-linking treatment, manifest sphere decreased by between the postoperative and one-year examinations. Two a mean of –2.75 D in 13 eyes (65%), and no improvement eyes maintained the preoperative UCVA; seven eyes gained in 7 eyes (35%). Manifest cylinder decreased by a mean of one to two lines, and five eyes gained three to five lines and –1.68 D in 15 eyes (75%) and no change in 5 eyes (25%).
six eyes gained more than five lines. There was a mean gain of 4.15 lines of UCVA from preoperative to the last follow- The K value at the apex decreased by a mean of 1.40 D from pre-operative to 1-year evaluation, P = 0.01.The K average The best corrected visual acuity (BCVA) data from the decreased by a mean of 1.36 D from pre-operative to 1-year study eyes at the pre-operative and 3 and 6 months post- evaluation, P=0.004. Table 1 and Figure 3 describes the operative examinations are shown in Table 1. There was a change in K average and K value at the apex from pre- statistically significant (P = 0.002) improvement in BCVA operative value to 1 year.
between the pre-operative and 1-year evaluations. The change in BCVA lines gained or lost at 1 year compared with the pre-operative baseline is presented in Figure 2. Pachymetry measurements (measured by the Pentacam) Of the 20 eyes evaluated at 1 year, 12 of 20 eyes (60%) at the thinnest location and at the apex were measured experienced at least a gained of 1–5 lines of BCVA. Eight of pre-operatively, 3-months, 6-months and 1-year post- the 20 eyes (40%) experienced no change in BCVA. operatively. At 3-months post-operative examination, there was a significant reduction in pachymetry both at the thinnest location (P = 0.0007) and at the apex (P = 0.0002). Table 1 shows the improvement in manifest refraction Pachymetry at the thinnest location reduced from 452.25 ±
sphere at the pre-operative, 6-month and 1-year evaluations. 29.58 µm pre-operatively to 430.4 ± 44.38 µm at 3 months
There was a statistically significant (P = 0.033) change in (4.83% reduction). At the apex, there was also a significant 1-2 lines gained n = 7 3-5 lines gained n = 5 >5 lines gained n = 6 1-2 lines gained n = 7 3-5 lines gained n = 5 >5 lines gained n = 6 UCVA = uncorrected visual acuity BCVA = Best corrected visual acuity Figure 1: Change in UCVA from preoperative status to status 1 year following cross-
Figure 2: Change in BCVA from preoperative status to status 1 year following cross-
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Arbelaez et al.: Collagen cross-linking in keratoconus Pachymetry (thinnest location, um) Pachymetry (apex, um) Figure 4: Changes in pachymetry measurements (µm) at the thinnest location and at
the apex
Figure 3: Corneal topography of a patient who had cross-linking in the right eye. A:
Preoperative UCVA: –0.70 (20/100), BCVA: –0.10 (20/25), K max at the apex = 47.78.
B: 1 year after cross-linking, UCVA: –0.20 (20/30), BCVA: –0.10 (20/25), K max at the
apex = 45.86, K average = 44.64. C: Pentacam pre-operative, anterior elevation = +17
were measured pre-operatively, 6-months and at 1-year post- µm, posterior elevation = +27 µm. D: 1 year after cross-linking, reduction in anterior treatment by the Oculus Pentacam. There was a significant elevation = +4 µm and posterior elevation = +17 µm.
reduction in anterior elevation both at the thinnest location and at the apex at 6 months post-treatment. At the thinnest location, the anterior elevation decreased significantly, P = 0.015, from 31.25 ±17.06 D pre-operatively to 26.35 ±
16.63 D at 6 months post-treatment. No significant change was noted at 1 year post-treatment. At the apex, the anterior elevation decreased significantly, P = 0.025, from 21.05 ±
15.55 pre-operatively to 17.0 ± 15.37 D at 6 months post-
treatment. No significant change was noted at 1 year post- SPHERICAL ABERRATION Student's t test for paired data did not find any significant difference in the posterior eleavation at the thinnest location and at the apex from pre-operative value, at 6 months and at 1 year post-treatment. Table 2 and Figure 3 present the changes in anterior and posterior elevation at the thinnest location and at the apex over time.
Figure 5: Corneal wavefront analysis with 4-mm pupil; blue arrows indicate (paired t
tests) signifi cant difference with preoperative data
decline from 463.96 ± 27.28 µm pre-operatively to 439.25
± 42.80 µm at 3 months (5.32% reduction). One-year
The goal for the corneal collagen cross-linking treatment evaluation showed the pachymetry to increase gradually to is to delay or halt the progression of keratoconus and to 455 ± 37.98 at the thinnest location and 463.95 ± 37.36
defer the need for a corneal transplant. The results of this at the apex. Figure 4 shows the changes in pachymetry study were encouraging as far as safety and effectiveness measurement at the thinnest location and at the apex in are concerned. No side effects were noted except for the subjective complaints of patients, namely, visual symptoms like fluctuating vision and double images. Although no Corneal wavefront surface aberrometry survey was used in the study, patients anecdotally reported Corneal wavefront surface aberommetry showed a significant improvement in visual symptoms over time. reduction in absolute RMS (P = 0.041) and absolute coma (P = 0.026) at 1 year with respect to the pre-operative value Refractive results in this study were approximately similar to [Figure 5]. Spherical and other high-order aberrations did other studies published.[16,17,18] There was a 1.25-D reduction not show any significant change. in the manifest sphere and cylinder as confirmed by the reduction in the keratometry readings. This reduction in Anterior and posterior elevation refractive error is also associated with a significant increase Anterior elevation at the thinnest location and at the apex in UCVA (4 Snellen lines). Oman Journal of Ophthalmology, Vol. 2, No. 1, 2009 [Downloaded free from http://www.ojoonline.org on Saturday, February 28, 2009]
Arbelaez et al.: Collagen cross-linking in keratoconus Table 2: Anterior surface and posterior surface elevation change at the thinnest location and at
the apex from pre-operative, 6 months and one year post evaluation as measured by the 0cuius
Pentacam

Anterior elevation, thinnest location (D) Anterior elevation, apex (D) Posterior elevation, thinnest location (D) Posterior elevation, apex (D) Corneal wavefront surface aberrometric analysis reflected a corneal collagen cross linking has the potential to become a significant reduction in RMS and comatic aberrations. This standard therapy for progressive keratoconus in the future. could partly explain the improvement in the BCVA in 60% Particularly in Oman, this treatment could benefit a lot of the patients.
of people due to the fact that there are very few centers that are capable of performing corneal transplant and the In a study made by Wollensak et al,[19] it was shown that environment is not suitable for contact lens wear. However, apoptotic cell death occurs after exposure to UV-A light. as with all new treatment modalities, controversies and The massive, transient cellular damage or keratocyte questions remain unanswered. Long-term results are apoptosis is assumed to be an initiator of the corneal wound necessary to evaluate the duration of the stiffening effect, healing response and the start of the complex wound indications and contraindications must be investigated, healing cascade.[20] In the present study, a 5% reduction in hence, the need for long term longitudinal studies.
pachymetry was observed in all patients at 3 months. After which, a steady increase was noted. This finding could correspond to the apoptosis that occurs after the treatment (2 to 3 months) and the repopulation that occurs thereafter Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42:297-319.
(6 months). Based on this finding, the authors strongly Rabinowittz YS. The genetics of keratoconus. Opthalmol Clin North Am suggest that when the cross-linking treatment is combined Thompson RW Jr, Price MO, Bowers PJ, Price FW Jr. Long term graft with an additional treatment such as Intacs or LASEK, a survival after penetrating keratoplasty. Ophthalmology 2003;110:1396- healing interval of approximately 2 to 3 months should be respected to avoid complications caused by the additional Waller SG, Steinert RF, Wagoner MD. Long-term results of epikeratoplasty damage of the added procedure.
for keratoplasty for keratoconus. Cornea 1995;14:84-8 Tan BU, Purcell TL, Torres LF, Schanzlin DJ. New surgical approaches In the present study, a significant reduction in the anterior to the management of keratoconus and post-lasik ectasia Trans Am Ophthalmol Soc 2006;104:212-20.
elevation was noted but the reduction in posterior Bilgihan K, Ozdek SC, Sari A, Hasanreisoglu B. Microkeratome-assisted elevation was not statistically significant. The studies in lamellar keratoplasty for keratoconus: Stromal sandwich. J Cataract animal experiments[21,22] and in humans[23,24] may provide Refract Surg 2003;29:1267-72.
an insight to this finding. These studies have shown Shimazaki J, Shimmura S, Ishioka M, Tsubota K. Randomized clinical trial that treatment of the cornea with riboflavin and UV-A of deep lamellar keratoplasty vs penetrating keratoplasty. Am J Ophthalmol 2002;134:159-65.
significantly stiffened the cornea only in the anterior 300 8. Alio JL, Shah S, Barraquer C, Bilgihan K, Anwar M, Melles GR. µm. This depth dependent stiffening effect may explain New techniques in lamellar keratoplasty. Curr Opin Ophthalmol significant flattening in the anterior cornea as revealed by the reduction in the anterior elevation.
Kanellopoulos AJ, Pe LH, Perry HD, Donnenfeld ED. ModiÞ ed intracorneal ring segment implantations (INTACS) for the management of moderate to advanced keratoconus: EfÞ cacy and complications. Cornea 2006;25:29- It has been shown that collagen cross-linking increases the biomechanical rigidity of the cornea by 4.5 times.[21] By 10. Joseph Colin, MD, European clinical evaluation: Use of intacs for the increasing the biomechanical stability of the cornea using treatment of keratoconus, J Cataract Refract Surg 2006;32:747-55.
the riboflavin and UV-A-induced collagen cross-linking, 11. Pokroy R, Levinger S, Hirsh A. Single Intacs segment for post-LASIK it is possible to stop the progression of keratoconus. The keratectasia. J Cataract Refract Surg 2004;30:1685-95.
12. Boxer Wachler BS, Christie JP, Chandra NS, Chou B, Korn T, Nepomuceno improvement in vision, reduction in the refractive effect, R. Intacs for keratoconus. Ophthalmology 2003;110:1031-40.
reduction in keratometry readings, improvement in the 13. Wollensak G. Crosslinking treatment of progressive keratoconus: New topographic and surface aberrometric analysis are all hope. Curr Opin Ophthalmol 2006;17:357-60 evidences that the treatment can arrest the progression of 14. Wollensak G, Spoerl E, Seiler T. Riboß avin/ultraviolet-A-induced keratoconus. No analysis of the fellow eye was done in this collagen crosslinking for the treatment of keratoconus. Am J Ophthamol study; such analysis is indicated in the future. 15. Holladay JT. Visual acuity measurements. J Cataract Refract Surg Given the effectiveness, simplicity, safety and cost 16. Caporossi A, Baiocchi S, Mazzotta C, Traversi C, Caporossi T. Parasurgical effectiveness (this is a one-time treatment) of this modality, therapy for keratoconus by riboß avin-ultraviolet type A rays induced cross- Oman Journal of Ophthalmology, Vol. 2, No. 1, 2009 [Downloaded free from http://www.ojoonline.org on Saturday, February 28, 2009]
Arbelaez et al.: Collagen cross-linking in keratoconus linking of corneal collagen: Preliminary refractive results in an Italian study. and porcine corneas after riboß avin-ultraviolet-A-induced cross-linking. J J Cataract Refract Surg 2006;32:837-45. Cataract Refract Surg 2003;29:1780-5.
17. Mazzotta C, Traversi C, Baiocchi S, Sergio P, Caporossi T, Caporossi A. 22. Wollensak G, Spoerl E. Collagen crosslinking of humanand porcine sclera. Conservative treatment of keratoconus by riboß avin-UV-A-induced cross- J Cataract Refract Surg 2004;30:689-95.
linking of corneal collagen: Qualitative investigation. Eur J Ophthalmol 23. Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S, Caporossi T, Tommasi C, et al. Treatment of progressive keratoconus by riboß avin-UV-Ainduced 18. Chan CCK, Charma M, Boxler Wachler BS. Effect of inferior-segment cross-linking of corneal collagen: Ultrastructural analysis by Heidelberg Intacs with and without C3R on keratoconus. J Cataract Refract Surg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea 19. Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte cytotoxicity of 24. Seiler T, Hafezi F. Corneal cross-linking-inducedstromal demarcation line. riboß avin/UV-A treatment in vitro. Eye 2004;18:718-22.
20. Wollensak G, Iomdina E, Herbst H, Wound healing in the rabbit after corneal collagen cross linking with riboß avin and UV-A. Cornea 2007;26:600-5.
Source of Support: Nil, Conflict of Interest: None
21. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human Accreditation of Oman Journal of Ophthalmology
CME Credits
The Directorate General of Education and Training, Ministry of Health, Muscat, Oman has announced the award of Category 2 CME credits to local authors and reviewers of the Oman Journal of Ophthalmology. 3 credits per publication 2 credits per publication Third Author and beyond 1 credit per publication 1 credit per paper Oman Journal of Ophthalmology, Vol. 2, No. 1, 2009

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