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Original Article

Prospective longitudinal study of corneal collagencross-linking in progressive keratoconusDeepa Viswanathan FRCS1 and John Males FRANZCO1,2,3

1Australian School of Advanced Medicine, Macquarie University, 2Sydney Eye Hospital, University of Sydney and 3Save Sight Institute,

Sydney, New South Wales, Australia

ABSTRACT

Background: Collagen cross-linking has beenreported to be effective in treating progressive kera-toconus, and this study aims to evaluate the long-term efficacy of this procedure.

Design: Prospective longitudinal interventional studyof patients with progressive keratoconus who under-went cross-linking in a tertiary referral hospital.

Participants: Thirty-five patients (51 eyes) whounderwent cross-linking with a mean follow-up of14.38 � 9.36 months (range 6–48) were comparedwith a control group of 25 fellow eyes that did notundergo the procedure.

Methods: Cross-linking was performed using 0.1%riboflavin (in 20% dextran T500) and ultraviolet Airradiation (370 nm, 3 mW/cm2, 30 min).

Main Outcome Measures: Maximum keratometryin dioptres, logMAR best spectacle-corrected visualacuity, cylindrical power, manifest refraction spheri-cal equivalent and central corneal thickness.

Results: Analysis of the treated group demonstrated asignificant flattening of maximum keratometry by0.96 � 2.33 dioptres (P = 0.005) and a significantimprovement in visual acuity by 0.05 � 0.13 logMAR(P = 0.04). In the control group, maximum keratom-etry increased significantly by 0.43 � 0.85 dioptres(P = 0.05), and visual acuity decreased by mean0.05 � 0.14 (P = 0.2). No statistical differences were

noted regarding cylindrical power, spherical equiva-lent or corneal thickness in both groups.

Conclusions: Results indicate that corneal collagencross-linking using riboflavin and ultraviolet Ais effective as a therapeutic option in cases of pro-gressive keratoconus by reducing the corneal curva-ture and by improving the visual acuity in thesepatients.

Key words: collagen cross-linking, keratoconus, maxi-mum keratometry.

INTRODUCTION

Keratoconus is a bilateral, asymmetric and progres-sive ectasia of the cornea characterized by steepen-ing, distortion and thinning of the apical cornea,resulting in irregular astigmatism and deteriorationof vision.1,2 The approximate incidence of kera-toconus is 1 per 2000 in the general population.3

Keratoconus begins at puberty and progresses inapproximately 20% of patients to such an extent thateither lamellar or full-thickness corneal transplanta-tion becomes necessary to preserve vision.3,4,3 Inmany countries, keratoconus remains the most fre-quent indication for corneal transplantation inpatients aged less than 60 years and therefore has asignificant impact on quality of life over the durationof the affected subject’s life.5–7

Keratoconus is characterized by alteration in thenormal corneal collagen structure and organization,and decreased stromal thickness resulting in corneal

� Correspondence: Dr Deepa Viswanathan, Hub 1, 2 Technology Place, Australian School of Advanced Medicine, Macquarie University, Sydney,

NSW 2109, Australia. Email: [email protected]

Received 19 June 2012; accepted 31 October 2012.

Competing/conflicts of interest: No stated conflict of interest.

Funding sources: No stated funding sources.

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Clinical and Experimental Ophthalmology 2013; 41: 531–536 doi: 10.1111/ceo.12035

© 2012 The AuthorsClinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists

biomechanical weakening.8–12 Biochemical studies ofthe corneal matrix in keratoconic corneas revealed anincreased expression of proteolytic enzymes anddecreased concentration of protease inhibitors ascompared with normal corneas.13–17

Collagen cross-linking (CXL), a method intro-duced for the treatment of progressive keratoconus,employs the photosensitizer riboflavin (vitaminB2), which when exposed to longer wavelengthultraviolet light (370 nm ultraviolet A [UVA])induces chemical reactions in the corneal stroma andultimately results in the formation of covalent bondsbetween the collagen molecules, fibres and microfi-brils, and effectively strengthens the cornea.18 In vitrolaboratory studies on porcine, rabbit and humancorneas have demonstrated that CXL caused anincrease in corneal stiffening by more than 300%and an increase in the collagen fibre diameter by12.2%, thus increasing the corneal biomechanicalrigidity.19–21

Subsequent clinical studies have reported thatCXL is associated with visual improvement andreduction in corneal steepening, and it is safe andeffective in treating progressive keratoconus;22–28

however, there are few studies with a maximumfollow-up of over 12 months.29–31 CXL was intro-duced for the first time in Australia in 2006 as atreatment option for progressive keratoconus, andthe aim of this study is to study the long-term visualand refractive outcome of these cases.

METHODS

Fifty-one eyes of 35 patients with progressivekeratoconus who underwent CXL treatment wereincluded in this long-term prospective study. Theywere compared with a control group of 25 felloweyes with keratoconus, which did not undergo CXL.The institutional ethics committee approved thestudy, and all patients provided informed consentafter receiving a detailed description of the nature ofthe treatment. The mean age of patients was24.25 � 8.08 years (range 15–39); there were 34males and 17 females. The mean follow-up periodfor treated eyes was 14.38 � 9.36 months (range6–48). For each patient, initially the worse eye wastreated, the fellow eye served as a control and insome patients, the fellow eye progressed as well andwas treated on compassionate grounds. The meanfollow-up period for control eyes was 13.88 � 8.86months; it was not statistically different (unpairedt-test, P = 0.82) from the follow-up period for treatedeyes.

The inclusion criteria for CXL were patients withprogressive early to moderate keratoconus (gradeI–III according to the Amsler–Krumeich classifica-tion)32 with a corneal thickness of at least 400

microns. The indication for CXL included an increasein maximum keratometry (Kmax) of 1.00 dioptre (D)in 1 year, deterioration in visual acuity (VA) (exclud-ing other possible non-cornea-related reasons) andthe need for new contact lens fitting more than oncein two years. The exclusion criteria for this studywere advanced keratoconus with stromal scarringrequiring corneal grafting, corneal hydrops, herpetickeratitis, autoimmune and other systemic diseases,pregnancy and breast-feeding. The inclusion criteriafor control eyes were fellow eyes with keratoconuswithout apical scarring or having undergone cornealgrafting or insertion of intracorneal ring segments.

Contact lens wearers were instructed to discon-tinue usage of soft lenses for a minimum of 3 daysand rigid-gas permeable and hard lenses for aminimum of two weeks before the preoperative eyeexamination. All subjects underwent examinationof VA, manifest refraction, corneal topography andcorneal pachymetry measurements preoperativelyand postoperatively at 1, 6, 12, 18 and 24 months.

VA measurement included the best spectacle-corrected VA (BSCVA), which was obtained usingthe Early Treatment of Diabetic Retinopathy Study(ETDRS) VA test and analysed as the logMAR value.Manifest refraction was performed, and the mani-fest refraction spherical equivalent and cylindricalastigmatism were obtained and analysed. Cornealtopography and corneal thickness measurements(pachymetry) were peformed using a non-contactrotating Scheimpflug camera (Pentacam, Oculus Inc.,Wetzlar, Germany) by an experienced orthoptist.Only scans that the Pentacam’s ‘quality specification’function determined as ‘OK’ were included foranalysis. The Pentacam takes 50 pictures of the ante-rior segment within 2 s, and prior clinical studieshave demonstrated that the device provides excellentrepeatable and reproducible corneal curvature andthickness measurements.33,34

For the purpose of analysis, the Kmax values werecompared between eyes at follow-up periods of 6–9months, 12–18 months and at 24 months and beyondfollowing CXL.

Surgical technique

CXL was performed using 0.1% riboflavin (in20% dextran T 500) and UVA irradiation (370 nm,3 mW/cm2, 30 min) under sterile conditions. TheInnocross-R riboflavin isotonic solution (Riboflavin5-phosphate [0.1%] plus 20% dextran T500 in 2 mlsyringes) (IROC Innocross AG, Zurich, Switzerland)was used for the corneal CXL procedure. The UVAmachine used was the UV-X 1000 (IROC InnocrossAG, Zurich, Switzerland). After topical anaesthesia,a lid speculum was inserted, and the epithelial tissuewas removed in a 9.0 mm diameter area to allow

532 Viswanathan and Males


penetration of riboflavin into the corneal stroma. Thephotosensitizer 0.1% riboflavin solution was thenapplied (2–3 drops every 3 min) to the cornea for30 min before the irradiation to allow sufficient satu-ration of the stroma. The central cornea (8.0 mmdiameter) was then exposed to UVA light with awavelength of 370 nm and an irradiance of 3 mW/cm2 for 30 min. Riboflavin solution was instilled(2–3 drops every 3 min) during the UVA exposure.After treatment, the eye was washed with 20 mLof a balanced salt solution, and antibiotic eye drops(ofloxacin 0.3%) and steroid eye drops (dexa-methasone 0.1%) were applied, and a bandagecontact lens was placed in the eye until completere-epithelialization. Subsequent examinations wereperformed at 1 week and thereafter at 1, 6, 12, 18and 24 months, and annually afterwards. At eachfollow-up examination, the refraction, BSCVA,corneal topography and central corneal thicknesswere recorded.

Statistical analysis

To quantify the effect of cross-linking treatment, thechanges in Kmax value, astigmatism (based onrefraction), spherical equivalent and BSCVA wereanalysed by subtracting each parameter at therespective follow-up examination minus the preop-erative value. Statistical evaluation was performedby SPSS software version 19 (SPSS Inc., Chicago, IL,USA). The paired t-test was used to evaluate thedifferences in the different parameters between thetwo groups, a P-value of �0.05 was considered tobe statistically significant.

RESULTS

Fifty-one eyes of 35 patients with progressive kera-toconus who underwent CXL were compared with acontrol group of 25 fellow eyes with keratoconusthat did not undergo CXL. At mean follow-up of14.38 � 9.36 months, the CXL-treated eyes showed asignificant reduction (P = 0.005) in the maximumKmax value by 0.96 � 2.33 D and a significantimprovement (P = 0.04) by 0.05 � 0.13 in logMARBSCVA.

There was a mean reduction in spherical equiva-lent of 0.19 � 1.73 D (P = 0.56) and a mean reductionin cylindrical power of 0.24 � 1.86 D (P = 0.49)in the CXL-treated group; however, these werenot statistically significant. The change in centralcorneal thickness was compared, and there wasno significant difference (P = 0.60) in the valuesbetween preprocedure and final follow-up. Theearlier findings are shown in Table 1. A comparisonof the difference between pre-CXL and post-CXLKmax values for all treated eyes has been illustratedin Figure 1. Although the treated group had a greaterpre-CXL Kmax (49.65 � 4.91 D) and a greater pre-CXL spherical equivalent (-4.56 � 3.73 D) as com-pared with the control group (48.09 � 4.81D and-4.32 � 3.11 D, respectively), there were no statisti-cally significant differences (unpaired t-test, P = 0.20and P = 0.88, respectively) between the treated andcontrol groups.

Analysis of the fellow eye control group re-vealed a significant increase (P = 0.05) in Kmax by0.46 � 1.1 D and a worsening in logMAR BSCVA by0.05 � 0.14, which was not statistically significant(P = 0.2) at mean follow-up of 13.88 � 8.86 months.No statistically significant difference was observed inspherical equivalent, cylindrical power or centralcorneal thickness (Table 2).

Analysis of the CXL-treated group revealed areduction in Kmax by an average of 1.1 � 2.08 D

Table 1. Preoperative and postoperative data for the CXL-treated group at mean 14.38 � 9.36 months follow-up

BSCVA(logMAR)

Spherical equivalent(dioptres)

Cylindrical power(dioptres)

Maximum keratometry(dioptres)

CCT(microns)

Pre-CXL 0.21 � 0.13 -4.56 � 3.73 -3.99 � 2.11 49.65 � 4.91 470.35 � 39.26Post-CXL 0.16 � 0.15 -4.36 � 3.25 -3.75 � 2.13 48.69 � 4.56 467.64 � 43.54P value 0.04 0.56 0.49 0.005 0.60

BSCVA, best spectacle-corrected visual acuity; CCT, central corneal thickness; CXL, collagen cross-linking.

0

5

10

15

20

25

30

Decreaseabove 4D

Decreasebetween 2D

and 4D

Decreaseup to 2D

Pre - Post Kmax in D

Nu

mb

er

of eye

sNo change Increase

up to 2DIncrease

between 2Dand 4D

Figure 1. Difference between pre- and post-collagen cross-linking (CXL) keratometry (Kmax) for treated eyes at mean14.38 � 9.36 months follow-up.

Outcome of cross-linking in keratoconus 533


(P = 0.009) at 6–9 months, 1.18 � 1.83 D (P = 0.005)at 12–18 months and 2.4 � 4.41 D (P = 0.14) beyond24 months. The Kmax increased in the controlgroup by 0.43 � 0.85 D (P = 0.17) in 6-9 months,0.37 � 1.05 D (P = 0.17) in 12–18 months and0.19 � 1.34 D (P = 0.5) beyond 24 months; thiscomparison (difference in Kmax = D Kmax) is shownin Figure 2. Corneal topography demonstrating areduction in Kmax after CXL by 2 D at 10 monthsfollow-up is shown in Figure 3; there was an asso-ciated improvement in logMAR BSCVA from 0.47 to0.18. In comparison, corneal topography of a fellowcontrol eye demonstrating an increase in Kmax by2 D at 11 months follow-up is shown in Figure 4;there was worsening of logMAR BSCVA from 0.12 to0.78.

DISCUSSION

Corneal CXL is an emerging modality of treatmentwith encouraging results for the management of pro-gressive keratoconus. CXL often results in visualimprovement and reduction in corneal steepening inprogressive keratoconus by clinical studies.24–30 CXLchanges the intrinsic biomechanical properties of thecornea, strengthens and stiffens the cornea, andarrests the progression of keratoconus. The aim ofthis study was to report the long-term visual andrefractive outcome of CXL.

Earlier studies have reported a significantimprovement in postoperative BSCVA followingCXL.24–30 Among recent studies with 12 monthsfollow-up, Hersh et al.35 reported an improvement inpostoperative BSCVA (mean change -0.13 � 0.21logMAR), whereas the French multicentre study36

reported stabilization of BSCVA in 47.6% eyes andimprovement of BSCVA in 40 % eyes following CXL.In our study, there was a small improvement inlogMAR BSCVA from 0.21 to 0.16 at mean 14months follow-up. In contrast, there was a worsen-ing of logMAR BSCVA in the fellow control groupfrom 0.14 to 0.19, which did not assume statisticalsignificance. Some of the previous studies havereported a significant reduction in the manifestrefraction spherical equivalent and cylindrical astig-matism following CXL.25,29 In our study, there was areduction in both manifest refraction sphericalequivalent and cylindrical astigmatism in the CXL-treated eyes; however, this was not statisticallysignificant.

The success of CXL as a therapeutic option is dueto a reduction of the corneal curvature, and themaximal Kmax value is the primary indictor of thiseffect. Majority of earlier studies have demonstrateda decrease in Kmax after CXL.24–30 In our study,there was a significant reduction in the Kmax valuein the treated group at mean 14 months follow-upand a continued decrease after 12 and 24 monthsfollow-up; this is in good agreement with the otherlong-term studies by Caporossi et al.29 and Raiskup-Wolf et al.30 In comparison, there was a significantworsening of Kmax in the fellow eye control groupof eyes; this is similar to the findings of the rand-omized controlled study by Wittig-Silva et al.24 Thisis interesting because two other studies that com-pared treated eyes with fellow keratoconus eyes ascontrols did not demonstrate any significant changein Kmax on follow-up in the control eyes.25,35 Thefindings of our study emphasize the fact that kera-toconus, when left untreated, can progress andresult in corneal steepening and deterioration of VA.A comparison of corneal thickness measurementsrevealed no statistically significant change betweenbaseline values and follow-up in both the treatedeyes and the control eyes; this corroborates the find-ings of earlier studies.29,30

Table 2. Preoperative and postoperative data for the fellow eye control group at mean 13.88 � 8.86 months follow up

BSCVA(logMAR)

Spherical equivalent(dioptres)

Cylindrical power(dioptres)

Maximum keratometry(dioptres)

CCT(microns)

Baseline 0.14 � 0.26 -4.32 � 3.11 -0.07 � 3.22 48.09 � 4.81 481.38 � 43.8Follow up 0.19 � 0.19 -4.14 � 3.09 -0.11 � 3.09 48.69 � 5.24 479.13 � 44.93P-value 0.2 0.54 0.84 0.05 0.38

BSCVA, best spectacle-corrected visual acuity; CCT, central corneal thickness; CXL, collagen cross-linking.

0.5

6–9 12–18

Time (months)Δ Kmax controlsΔ Kmax treated

>240

–0.5

–1

–1.5

–2

–2.5

Figure 2. Comparison of difference in maximum keratometry(Kmax) between the collagen cross-linking (CXL) treated andfellow control eyes during follow-up.



One limitation of our study is that there was norandomization protocol; the worse eye of eachpatient underwent CXL and the fellow eye served ascontrol. However, one strength of our study is thelong duration of follow-up, each patient having hada minimum of six months follow-up and at least 40%patients having more than one year of follow-up.Although a number of conservative and surgicalmethods of visual rehabilitation exist for kerato-conus, none other than CXL address progressivenature of this condition. Results from our study indi-cate that corneal CXL is an effective modality for thetreatment of progressive keratoconus by reducing thecorneal curvature and improving VA. Further long-term follow-up of CXL is warranted given the typi-cally young age at treatment.

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Figure 4. Corneal topography showing an increase in maximum keratometry (Kmax) in a control eye on follow-up.

Outcome of cross-linking in keratoconus 535


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