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Clinical and Experimental Ophthalmology 2013; 41: 531536 doi: 10.1111/ceo.12035

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
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532

Viswanathan and Males

biomechanical weakening.812 Biochemical studies of

the corneal matrix in keratoconic corneas revealed an
increased expression of proteolytic enzymes and
decreased concentration of protease inhibitors as
compared with normal corneas.1317
Collagen cross-linking (CXL), a method introduced for the treatment of progressive keratoconus,
employs the photosensitizer riboflavin (vitamin
B2), which when exposed to longer wavelength
ultraviolet light (370 nm ultraviolet A [UVA])
induces chemical reactions in the corneal stroma and
ultimately results in the formation of covalent bonds
between the collagen molecules, fibres and microfibrils, and effectively strengthens the cornea.18 In vitro
laboratory studies on porcine, rabbit and human
corneas have demonstrated that CXL caused an
increase in corneal stiffening by more than 300%
and an increase in the collagen fibre diameter by
12.2%, thus increasing the corneal biomechanical
rigidity.1921
Subsequent clinical studies have reported that
CXL is associated with visual improvement and
reduction in corneal steepening, and it is safe and
effective in treating progressive keratoconus;2228
however, there are few studies with a maximum
follow-up of over 12 months.2931 CXL was introduced for the first time in Australia in 2006 as a
treatment option for progressive keratoconus, and
the aim of this study is to study the long-term visual
and refractive outcome of these cases.

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

microns. The indication for CXL included an increase

in maximum keratometry (Kmax) of 1.00 dioptre (D)
in 1 year, deterioration in visual acuity (VA) (excluding other possible non-cornea-related reasons) and
the need for new contact lens fitting more than once
in two years. The exclusion criteria for this study
were advanced keratoconus with stromal scarring
requiring corneal grafting, corneal hydrops, herpetic
keratitis, autoimmune and other systemic diseases,
pregnancy and breast-feeding. The inclusion criteria
for control eyes were fellow eyes with keratoconus
without apical scarring or having undergone corneal
grafting or insertion of intracorneal ring segments.
Contact lens wearers were instructed to discontinue usage of soft lenses for a minimum of 3 days
and rigid-gas permeable and hard lenses for a
minimum of two weeks before the preoperative eye
examination. All subjects underwent examination
of VA, manifest refraction, corneal topography and
corneal pachymetry measurements preoperatively
and postoperatively at 1, 6, 12, 18 and 24 months.
VA measurement included the best spectaclecorrected VA (BSCVA), which was obtained using
the Early Treatment of Diabetic Retinopathy Study
(ETDRS) VA test and analysed as the logMAR value.
Manifest refraction was performed, and the manifest refraction spherical equivalent and cylindrical
astigmatism were obtained and analysed. Corneal
topography and corneal thickness measurements
(pachymetry) were peformed using a non-contact
rotating Scheimpflug camera (Pentacam, Oculus Inc.,
Wetzlar, Germany) by an experienced orthoptist.
Only scans that the Pentacams quality specification
function determined as OK were included for
analysis. The Pentacam takes 50 pictures of the anterior segment within 2 s, and prior clinical studies
have demonstrated that the device provides excellent
repeatable and reproducible corneal curvature and
thickness measurements.33,34
For the purpose of analysis, the Kmax values were
compared between eyes at follow-up periods of 69
months, 1218 months and at 24 months and beyond
following CXL.

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

2012 The Authors

Clinical and Experimental Ophthalmology 2012 Royal Australian and New Zealand College of Ophthalmologists

Outcome of cross-linking in keratoconus

Table 1.

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

penetration of riboflavin into the corneal stroma. The

photosensitizer 0.1% riboflavin solution was then
applied (23 drops every 3 min) to the cornea for
30 min before the irradiation to allow sufficient saturation of the stroma. The central cornea (8.0 mm
diameter) was then exposed to UVA light with a
wavelength of 370 nm and an irradiance of 3 mW/
cm2 for 30 min. Riboflavin solution was instilled
(23 drops every 3 min) during the UVA exposure.
After treatment, the eye was washed with 20 mL
of a balanced salt solution, and antibiotic eye drops
(ofloxacin 0.3%) and steroid eye drops (dexamethasone 0.1%) were applied, and a bandage
contact lens was placed in the eye until complete
re-epithelialization. Subsequent examinations were
performed at 1 week and thereafter at 1, 6, 12, 18
and 24 months, and annually afterwards. At each
follow-up examination, the refraction, BSCVA,
corneal topography and central corneal thickness
were recorded.

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

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Clinical and Experimental Ophthalmology 2012 Royal Australian and New Zealand College of Ophthalmologists

534

Viswanathan and Males

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

Figure 2. Comparison of difference in maximum keratometry

(Kmax) between the collagen cross-linking (CXL) treated and
fellow control eyes during follow-up.

(P = 0.009) at 69 months, 1.18 1.83 D (P = 0.005)

at 1218 months and 2.4 4.41 D (P = 0.14) beyond
24 months. The Kmax increased in the control
group by 0.43 0.85 D (P = 0.17) in 6-9 months,
0.37 1.05 D (P = 0.17) in 1218 months and
0.19 1.34 D (P = 0.5) beyond 24 months; this
comparison (difference in Kmax = D Kmax) is shown
in Figure 2. Corneal topography demonstrating a
reduction in Kmax after CXL by 2 D at 10 months
follow-up is shown in Figure 3; there was an associated improvement in logMAR BSCVA from 0.47 to
0.18. In comparison, corneal topography of a fellow
control eye demonstrating an increase in Kmax by
2 D at 11 months follow-up is shown in Figure 4;
there was worsening of logMAR BSCVA from 0.12 to
0.78.

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.

Earlier studies have reported a significant

improvement in postoperative BSCVA following
CXL.2430 Among recent studies with 12 months
follow-up, Hersh et al.35 reported an improvement in
postoperative BSCVA (mean change -0.13 0.21
logMAR), whereas the French multicentre study36
reported stabilization of BSCVA in 47.6% eyes and
improvement of BSCVA in 40 % eyes following CXL.
In our study, there was a small improvement in
logMAR BSCVA from 0.21 to 0.16 at mean 14
months follow-up. In contrast, there was a worsening of logMAR BSCVA in the fellow control group
from 0.14 to 0.19, which did not assume statistical
significance. Some of the previous studies have
reported a significant reduction in the manifest
refraction spherical equivalent and cylindrical astigmatism following CXL.25,29 In our study, there was a
reduction in both manifest refraction spherical
equivalent and cylindrical astigmatism in the CXLtreated eyes; however, this was not statistically
significant.
The success of CXL as a therapeutic option is due
to a reduction of the corneal curvature, and the
maximal Kmax value is the primary indictor of this
effect. Majority of earlier studies have demonstrated
a decrease in Kmax after CXL.2430 In our study,
there was a significant reduction in the Kmax value
in the treated group at mean 14 months follow-up
and a continued decrease after 12 and 24 months
follow-up; this is in good agreement with the other
long-term studies by Caporossi et al.29 and RaiskupWolf et al.30 In comparison, there was a significant
worsening of Kmax in the fellow eye control group
of eyes; this is similar to the findings of the randomized controlled study by Wittig-Silva et al.24 This
is interesting because two other studies that compared treated eyes with fellow keratoconus eyes as
controls did not demonstrate any significant change
in Kmax on follow-up in the control eyes.25,35 The
findings of our study emphasize the fact that keratoconus, when left untreated, can progress and
result in corneal steepening and deterioration of VA.
A comparison of corneal thickness measurements
revealed no statistically significant change between
baseline values and follow-up in both the treated
eyes and the control eyes; this corroborates the findings of earlier studies.29,30

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Clinical and Experimental Ophthalmology 2012 Royal Australian and New Zealand College of Ophthalmologists

Outcome of cross-linking in keratoconus

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.

One limitation of our study is that there was no

randomization protocol; the worse eye of each
patient underwent CXL and the fellow eye served as
control. However, one strength of our study is the
long duration of follow-up, each patient having had
a 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 surgical
methods of visual rehabilitation exist for keratoconus, none other than CXL address progressive
nature of this condition. Results from our study indicate that corneal CXL is an effective modality for the
treatment of progressive keratoconus by reducing the
corneal curvature and improving VA. Further longterm follow-up of CXL is warranted given the typically young age at treatment.

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