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Original Article
Prospective longitudinal study of corneal collagen
cross-linking in progressive keratoconus
Deepa Viswanathan FRCS1 and John Males FRANZCO1,2,3
1
Australian 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
been
reported to be effective in treating progressive keratoconus, and this study aims to evaluate the longterm efficacy of this procedure.
Design: Prospective longitudinal interventional study
of patients with progressive keratoconus who underwent cross-linking in a tertiary referral hospital.
Participants: Thirty-five patients (51 eyes) who
underwent cross-linking with a mean follow-up of
14.38 9.36 months (range 648) were compared
with a control group of 25 fellow eyes that did not
undergo the procedure.
Methods: Cross-linking was performed using 0.1%
riboflavin (in 20% dextran T500) and ultraviolet A
irradiation (370 nm, 3 mW/cm2, 30 min).
Main Outcome Measures: Maximum keratometry
in dioptres, logMAR best spectacle-corrected visual
acuity, cylindrical power, manifest refraction spherical equivalent and central corneal thickness.
Results: Analysis of the treated group demonstrated a
significant flattening of maximum keratometry by
0.96 2.33 dioptres (P = 0.005) and a significant
improvement in visual acuity by 0.05 0.13 logMAR
(P = 0.04). In the control group, maximum keratometry increased significantly by 0.43 0.85 dioptres
(P = 0.05), and visual acuity decreased by mean
0.05 0.14 (P = 0.2). No statistical differences were
noted regarding cylindrical power, spherical equivalent or corneal thickness in both groups.
Conclusions: Results indicate that corneal collagen
cross-linking using riboflavin and ultraviolet A
is effective as a therapeutic option in cases of progressive keratoconus by reducing the corneal curvature and by improving the visual acuity in these
patients.
Key words: collagen cross-linking, keratoconus, maximum keratometry.
INTRODUCTION
Keratoconus is a bilateral, asymmetric and progressive ectasia of the cornea characterized by steepening, distortion and thinning of the apical cornea,
resulting in irregular astigmatism and deterioration
of vision.1,2 The approximate incidence of keratoconus is 1 per 2000 in the general population.3
Keratoconus begins at puberty and progresses in
approximately 20% of patients to such an extent that
either lamellar or full-thickness corneal transplantation becomes necessary to preserve vision.3,4,3 In
many countries, keratoconus remains the most frequent indication for corneal transplantation in
patients aged less than 60 years and therefore has a
significant impact on quality of life over the duration
of the affected subjects life.57
Keratoconus is characterized by alteration in the
normal 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.
2012 The Authors
Clinical and Experimental Ophthalmology 2012 Royal Australian and New Zealand College of Ophthalmologists
532
METHODS
Fifty-one eyes of 35 patients with progressive
keratoconus who underwent CXL treatment were
included in this long-term prospective study. They
were compared with a control group of 25 fellow
eyes with keratoconus, which did not undergo CXL.
The institutional ethics committee approved the
study, and all patients provided informed consent
after receiving a detailed description of the nature of
the treatment. The mean age of patients was
24.25 8.08 years (range 1539); there were 34
males and 17 females. The mean follow-up period
for treated eyes was 14.38 9.36 months (range
648). For each patient, initially the worse eye was
treated, the fellow eye served as a control and in
some patients, the fellow eye progressed as well and
was treated on compassionate grounds. The mean
follow-up period for control eyes was 13.88 8.86
months; it was not statistically different (unpaired
t-test, P = 0.82) from the follow-up period for treated
eyes.
The inclusion criteria for CXL were patients with
progressive early to moderate keratoconus (grade
IIII according to the AmslerKrumeich classification)32 with a corneal thickness of at least 400
Surgical technique
CXL was performed using 0.1% riboflavin (in
20% dextran T 500) and UVA irradiation (370 nm,
3 mW/cm2, 30 min) under sterile conditions. The
Innocross-R riboflavin isotonic solution (Riboflavin
5-phosphate [0.1%] plus 20% dextran T500 in 2 ml
syringes) (IROC Innocross AG, Zurich, Switzerland)
was used for the corneal CXL procedure. The UVA
machine used was the UV-X 1000 (IROC Innocross
AG, Zurich, Switzerland). After topical anaesthesia,
a lid speculum was inserted, and the epithelial tissue
was removed in a 9.0 mm diameter area to allow
533
Preoperative and postoperative data for the CXL-treated group at mean 14.38 9.36 months follow-up
Pre-CXL
Post-CXL
P value
BSCVA
(logMAR)
Spherical equivalent
(dioptres)
Cylindrical power
(dioptres)
Maximum keratometry
(dioptres)
CCT
(microns)
0.21 0.13
0.16 0.15
0.04
-4.56 3.73
-4.36 3.25
0.56
-3.99 2.11
-3.75 2.13
0.49
49.65 4.91
48.69 4.56
0.005
470.35 39.26
467.64 43.54
0.60
BSCVA, best spectacle-corrected visual acuity; CCT, central corneal thickness; CXL, collagen cross-linking.
Statistical analysis
To quantify the effect of cross-linking treatment, the
changes in Kmax value, astigmatism (based on
refraction), spherical equivalent and BSCVA were
analysed by subtracting each parameter at the
respective follow-up examination minus the preoperative value. Statistical evaluation was performed
by SPSS software version 19 (SPSS Inc., Chicago, IL,
USA). The paired t-test was used to evaluate the
differences in the different parameters between the
two groups, a P-value of 0.05 was considered to
be statistically significant.
RESULTS
Fifty-one eyes of 35 patients with progressive keratoconus who underwent CXL were compared with a
control group of 25 fellow eyes with keratoconus
that did not undergo CXL. At mean follow-up of
14.38 9.36 months, the CXL-treated eyes showed a
significant reduction (P = 0.005) in the maximum
Kmax value by 0.96 2.33 D and a significant
improvement (P = 0.04) by 0.05 0.13 in logMAR
BSCVA.
30
25
Number of eyes
20
15
10
5
0
Decrease Decrease Decrease No change Increase Increase
above 4D between 2D up to 2D
up to 2D between 2D
and 4D
and 4D
Pre - Post Kmax in D
Figure 1. Difference between pre- and post-collagen crosslinking (CXL) keratometry (Kmax) for treated eyes at mean
14.38 9.36 months follow-up.
There was a mean reduction in spherical equivalent of 0.19 1.73 D (P = 0.56) and a mean reduction
in cylindrical power of 0.24 1.86 D (P = 0.49)
in the CXL-treated group; however, these were
not statistically significant. The change in central
corneal thickness was compared, and there was
no significant difference (P = 0.60) in the values
between preprocedure and final follow-up. The
earlier findings are shown in Table 1. A comparison
of the difference between pre-CXL and post-CXL
Kmax values for all treated eyes has been illustrated
in Figure 1. Although the treated group had a greater
pre-CXL Kmax (49.65 4.91 D) and a greater preCXL spherical equivalent (-4.56 3.73 D) as compared with the control group (48.09 4.81D and
-4.32 3.11 D, respectively), there were no statistically significant differences (unpaired t-test, P = 0.20
and P = 0.88, respectively) between the treated and
control groups.
Analysis of the fellow eye control group revealed a significant increase (P = 0.05) in Kmax by
0.46 1.1 D and a worsening in logMAR BSCVA by
0.05 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 in
spherical equivalent, cylindrical power or central
corneal thickness (Table 2).
Analysis of the CXL-treated group revealed a
reduction in Kmax by an average of 1.1 2.08 D
534
Table 2. Preoperative and postoperative data for the fellow eye control group at mean 13.88 8.86 months follow up
Baseline
Follow up
P-value
BSCVA
(logMAR)
Spherical equivalent
(dioptres)
Cylindrical power
(dioptres)
Maximum keratometry
(dioptres)
CCT
(microns)
0.14 0.26
0.19 0.19
0.2
-4.32 3.11
-4.14 3.09
0.54
-0.07 3.22
-0.11 3.09
0.84
48.09 4.81
48.69 5.24
0.05
481.38 43.8
479.13 44.93
0.38
BSCVA, best spectacle-corrected visual acuity; CCT, central corneal thickness; CXL, collagen cross-linking.
0.5
0
69
0.5
1
1218
Time (months)
>24
Kmax controls
Kmax treated
1.5
2
2.5
DISCUSSION
Corneal CXL is an emerging modality of treatment
with encouraging results for the management of progressive keratoconus. CXL often results in visual
improvement and reduction in corneal steepening in
progressive keratoconus by clinical studies.2430 CXL
changes the intrinsic biomechanical properties of the
cornea, strengthens and stiffens the cornea, and
arrests the progression of keratoconus. The aim of
this study was to report the long-term visual and
refractive outcome of CXL.
535
Figure 3.
Corneal topography showing a reduction in maximum keratometry (Kmax) after collagen cross-linking (CXL) on follow-up.
Figure 4.
Corneal topography showing an increase in maximum keratometry (Kmax) in a control eye on follow-up.
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