Original Article

Long-term Outcomes of Collagen Crosslinking for Early
Keratoconus

Akbar Derakhshan, MD1,2; Javad Heravian, MD3,4; Milad Abdolahian, MS4,5; Shahram Bamdad, MD5

1Cornea Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2Khatam-Al-Anbia Hospital, Mashhad University of Medical Sciences, Mashhad, Iran

3Refractive Errors Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
4Department of Optometry, School of Paramedical Science, Mashhad University of Medical Sciences, Mashhad, Iran

5Poostchi Ophthalmology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

ORCID:
Akbar Derakhshan: http://orcid.org/0000-0002-0217-0156
Shahram Bamdad: http://orcid.org/0000-0002-5609-016x

Abstract

Purpose: To evaluate the long-term outcomes of collagen crosslinking in early
keratoconus.
Methods: Thirty eyes of twenty patients with early keratoconus were enrolled.
Uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA),
objective refraction, subjective refraction, corneal topography and pachymetry were
assessed before and 3, 6, 12 months and 9 years after performing collagen
crosslinking surgery.
Results: The patients’ mean age was 31.2 ± 5.59 years at nine-year follow-up
(range, 25–44 years). The means of preoperative UCVA and BSCVA were 0.57 ±
0.34 and 0.15 ± 0.12 logMAR, respectively, and these values remained stable at
the final follow-up (P = 0.990 and P = 0.227, respectively). The mean objective
spherical equivalent decreased considerably from –6.00 ± 4.05 D preoperatively
to –5.22 ± 3.71 D at the final follow-up (P < 0.05). The mean subjective spherical
equivalent was –4.25 ± 2.87 D preoperatively and this value was stable at the last
follow-up (P = 0.92). No considerable difference was found between the post- and
preoperative mean objective cylinder values (P = 0.34). The mean subjective cylinder
value changed significantly from –4.05 ± 1.85 D preoperatively to –3.1 ± 1.42 D at the
final follow-up (P < 0.05). The mean central corneal thickness was 496.97 ± 45.95
µm preoperatively and this value was stable at nine-year follow-up (P = 0.183). No
significant difference was found between the pre- and postoperative mean maximum
and mean minimum corneal curvature values (P = 0.429 and P = 0.248, respectively).
There were no significant postoperative complications.
Conclusion: Corneal crosslinking in early keratoconus seems to be a safe procedure
that can effectively stabilize UCVA, BSCVA, subjective SE and CCT, while improving
objective spherical equivalent.

Keywords: Cornea; Collagen Crosslinking; Keratoconus

J Ophthalmic Vis Res 2021; 16 (2): 151–157

© 2021 DERAKHSHAN ET AL. THIS IS AN OPEN ACCESS ARTICLE DISTRIBUTED UNDER THE CREATIVE COMMONS ATTRIBUTION LICENSE | PUBLISHED BY

KNOWLEDGE E 151

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Longstanding Outcomes of Collagen Crosslinking; Derakhshan et al

INTRODUCTION

Keratoconus is a bilateral, progressive, asymmetric,
noninflammatory corneal ectasia. The cornea
presumes a conical form due to its biomechanical
instability leading to irregular astigmatism and
reduction in visual quality. Treatment options
available for increasing the visual acuity or/and
halting the progression of keratoconus consist of
spectacles, rigid gas permeable contact lenses,[1]
collagen crosslinking,[2] intracorneal rings,[3] and
keratoplasty.[4, 5] Corneal collagen crosslinking
(CXL) has been introduced as a promising method
for keratoconus management. It was frequently
reported that CXL could effectively stabilize the
keratoconus progression, with a good safety
profile.[6–8]

In 2003, Wollensak et al pioneered CXL
treatment post-op progression of keratoconus. In
CXL, the interaction between the riboflavin and
ultraviolet-A (UVA, 365 nm) results in crosslinking
between the intracellular matrix and collagen
of the stroma, overwhelmingly in the anterior
300 µm, leading to enhanced strength of the
cornea.[8] Studies have indicated that collagen
crosslinking leads to an increase of collagen
fiber diameter[10] and improves biomechanical
stiffness[11] by inducing increased covalent bond
formation within or between collagen fibers
in the corneal stroma.[12] Some studies have
demonstrated improvement in visual acuity,[9, 13–15]
apical curvature of the cornea,[9, 16–18] contrast
sensitivity improvement,[19, 20] and a decrease in
refractive error.[9, 16, 17, 21] However, most of the
studies have short follow-up period; therefore, this
study aimed to assess the long-standing outcomes
of CXL for early keratoconus.

METHODS

Our research was approved by Khatam al Anbia
Hospital affiliated to Mashhad University of

Correspondence to:

Shahram Bamdad, MD. Department of Poostchi
Ophthalmology, Zand St., Shiraz, Fars, Iran
E-mail: shahrambamdad@yahoo.com
Received: 12-03-2020 Accepted: 01-01-2021

Access this article online

Website: https://knepublishing.com/index.php/JOVR

DOI: 10.18502/jovr.v16i2.9077

Medical Sciences. All steps of this study were
based on the principles of the Declaration of
Helsinki, and an informed consent was obtained
from each subject after explaining the goals of the
study. In this hospital-based prospective study,
32 eyes of 22 patients with early keratoconus
were initially enrolled but 2 of them missed the
follow-ups; therefore, we removed their data from
this study. The diagnosis was performed based
on video keratographic findings and all patients
demonstrated progression before the surgery by
longitudinal evaluation using corneal topography.
The indications of keratoconus progression
included an increase of 1.00 D or more in the
cylindrical component of the manifest refraction, an
increase of 1.00 D or more in the maximum corneal
curvature, an increase of 0.50 D or more in the
spherical equivalent (SE) manifest refraction in one
year and a decrease of ≥5% in the central corneal
thickness in three consecutive topographies in
six months. Pre- and postoperative evaluation
after 3, 6, and 12 months and then 9 years of
follow-up consisted of uncorrected visual acuity
(UCVA) and best spectacle corrected visual acuity
(BSCVA) measurement, ultrasonic pachymetry
(Tomey, Erlangen, Germany), corneal computerized
topography (Technomed, Baseweile, Germany),
and slit lamp and fundus examinations. Corneal
thickness <400 μm, herpetic keratitis history, and
concurrent infectious or autoimmune disease were
the exclusion criteria. All procedures were carried
out by the same surgeon (AD) in our institute under
sterile conditions. For performing the surgery,
corneal epithelium was removed by mechanical
debridement over 9.0 mm of the central region of
the cornea following administration of the topical
anesthesia. Then, the photosensitizing solution
(0.1% riboflavin within 20% dextran) was instilled
every 3 min for 30 min, after epithelial debridement
following topical anesthesia and inserting a wire lid
speculum. Riboflavin penetrated into the anterior
chamber and corneal stroma completely and the
penetration was checked by slit lamp examination.

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How to cite this article: Derakhshan A, Heravian J, Abdolahian M, Bamdad
S. Long-term Outcomes of Collagen Crosslinking for Early Keratoconus. J
Ophthalmic Vis Res 2021;16:151–157.

152 JOURNAL OF OPHTHALMIC AND VISION RESEARCH VOLUME 16, ISSUE 2, APRIL-JUNE 2021

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Longstanding Outcomes of Collagen Crosslinking; Derakhshan et al

Then, the UVA was irradiated on the cornea for
30 min (radiance of 3 mW/cm2), utilizing a 370 nm
UVA double-diode light source. Over irradiating,
the riboflavin solution was dropped every 5 min,
and balanced salt solution was frequently applied
intraoperatively to prevent dehydration of the
cornea. Topical antibiotics were prescribed for five
days along with tear substitutes for three to four
weeks.

Data were analyzed using the SPSS.21 software
(SPSS Inc., Chicago, Illinois, USA). Normality of the
data was assessed using the Kolmogorov–Smirnov
test. Comparisons were made using paired sample
t-test. In all tests, p-values < 0.05 were considered
significant.

RESULTS

Vision Outcomes

The mean age of patients was 31.2 ± 5.59 years
at the nine-year follow-up period. The mean UCVA
was 0.57 ± 0.34 logMAR preoperatively and it
did not significantly change at the final follow-up
examination (P = 0.990). No significant difference
existed between the post- and preoperative mean
BSCVA (P = 0.227). At the last follow-up, BSCVA
improved at least one Snellen line in 11 eyes
(36.66%) and remained stable in 9 eyes (30%);
10 eyes (33.33%) lost one line or more. The pre-
and postoperative values are represented in Table
1. Figure 1 shows the UCVA and BSCVA stability
following corneal CXL.

Refractive Results

The mean objective SE improved significantly
from –6.00 ± 4.05 D preoperatively to –5.22 ±
3.71 D (P < 0.05) at the nine-year follow-up. No
significant difference was found between the post-
and preoperative mean subjective SE (P = 0.92)
and mean objective cylinder value (P = 0.348).
The mean subjective cylinder value significantly
changed from –4.05 ± 1.85 D preoperatively to
–3.1 ± 1.42 D at the nine-year follow-up (P = 0.002).
Figure 2 shows the changes in objective and
subjective refraction.

Central Corneal Thickness

No significant difference was found between
the preoperative and postoperative mean central

corneal thickness (P = 0.183). Figure 3 shows the
changes in the central corneal thickness.

Topographic Outcomes

No statistically significant difference was detected
in the mean maximum (P = 0.429) and mean
minimum corneal curvature (P = 0.248) at the nine-
year follow-up. During the follow-ups, no macular
and corneal abnormalities were observed.

None of the cases underwent repeated CXL.

DISCUSSION

Collagen crosslinking with riboflavin and UVA
is a surgical technique used in the treatment of
keratoconus. CXL is a surgical method utilized
to improve the corneal rigidity, stabilize the
corneal ectasia, and inhibit the progression of
the keratoconus.[5] Previous studies reported that
collagen crosslinking improved visual, refractive,
topographic and aberrometric values.[15, 16, 21–25]
However, some challenges are associated with
the long-term outcomes of CXL.[18, 21, 23, 26–28]
Vinciguerra et al[26] reported that UCVA and
BSCVA significantly increased two years following
CXL. Raiskup-Wolf et al[23] demonstrated
stabilization and improvement of the cornea during
long-term period following CXL. Keratoconus
stability in 44 eyes after a minimum follow-up of 48
months was reported by Caporossi et al.[21] O’Brart
et al[27] also showed that CXL was a safe and
effective method used to stabilize the progression
of the keratoconus over a long-term period.
Hashemi et al[28] reported halting of keratoconus
progression up to five years of follow-up, while
Wittig-Silva et al[18] indicated improvements in
maximum corneal curvature, UCVA, and BSCVA
over a three-year follow-up period.

In our study, the stability of subjective SE was
demonstrated similar to the reports by Wittig-Silva
et al[29] and Grewal et al.[30] However, Caporossi
et al,[31] Wollensak et al,[9] and Vinciguerra et al[26]
reported a decrease in subjective SE. In this study,
the subjective SE and subjective astigmatism
reduced significantly during the six-month follow-
up and then gradually returned to the preoperative
values. Significant changes in the cylinder values
were reported at the first-year follow-up in some
studies.[32–34] Given the visual outcomes of the
subjects in this study, there was no significant

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Longstanding Outcomes of Collagen Crosslinking; Derakhshan et al

Figure 1. Stability of logMAR UCVA and logMAR BSCVA after corneal CXL.

Figure 2. Changes in objective and subjective refraction (diopter).

difference between pre- and postoperative values
of UCVA (P = 0.990) and BSCVA (P = 0.227).
Our results showed that 40% of patients had
improved UCVA and 40% had improved BSCVA,
whereas only 43.33% lost lines of UCVA and
23.33% lost BCVA at the last follow-up. UCVA
and BSCVA increased significantly in the first six
months due to reduction in refractive error and
corneal steepening. Caporossi et al[31] proposed
that a decrease in the coma aberration following
morphologic symmetry leads to an increase in
BCVA. In our study, UCVA and BSCVA gradually
returned to the preoperative values between the
6th and 12th postoperative months. At the final
follow-up, the UCVA and BSCVA did not change
significantly compared with the preoperative
values. Caporossi et al[35] reported mean increases
of +0.12 and +0.10 Snellen lines in UCVA and BCVA
48 months after CXL, respectively. In our research,
30 of 32 cases were followed-up for nine years,
while only 11 of 286 eyes included in their study
had completed visits during four years. A 96%

drop in the follow-up could lead to different results.
Similarly, a study by Raiskup-Wolf et al[23] revealed
that only 5 out of 241 included eyes stayed in the
study at six-year follow-up. One-year researches
indicated that UCVA tended to increase during
the first year after CXL.[32, 33, 36] However, Asri et al
reported no statistically significant changes.[37] Our
results also showed that BSCVA did not change
significantly at the last follow-up. Some other
researches demonstrated different results ranging
from no change in BCVA at one-year follow-up[37]
to 1.26 Snellen lines[9] and 0.1133 and 0.1832
logMAR increase in BCVA after CXL.

In this study, there were no statistically
significant changes in CCT at any postoperative
intervals. However, corneal thinning was reported
in some studies.[28, 38] Greenstein et al[38] showed
corneal thinning and return to the standard values
during the first three months and the first one year
after treatment, respectively. An early reduction in
CCT was also reported by Hashemi et al[28] at the
first postoperative month after an increment and

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Longstanding Outcomes of Collagen Crosslinking; Derakhshan et al

Figure 3. Changes in CCT (µm).

Table 1. Preoperative and postoperative patient data

Parameters Preoperative 3-months
postoperative

6-months
postoperative

12-months
postoperative

9-years
postoperative

LogMAR UCVA
P

0.57 ± 0.34 0.45 ± 0.34
P < 0.05

0.38 ±0.32
P < 0.05

0.38 ± 0.33
P< 0.001

0.57 ±0.37
P = 0.990

LogMAR BCVA
P

0.15 ± 0.12 0.11 ± 0.10
P < 0.05

0.05 ±0.06
P < 0.05

0.06 ± 0.07
P < 0.05

0.12 ±0.12
P = 0.227

OBJ SE
P

−6.00 ± 4.0 −5.71±3.79
P = 0.09

–5.46 ± 3.44
P < 0.05

−5.40 ± 3.44
P < 0.05

–5.22 ± 3.71
P < 0.05

OBJ AST
P

−4.68±2.28 −4.75 ± 2.36
P = 0.37

–4.85 ± 2.03
P = 0.63

−4.64 ± 2.16
P = 0.42

–4.50 ± 2.06
P = 0.34

SUB SE
P

-4.25 ± 2.87 −3.72 ± 3.01
P = 0.055

–2.88 ± 2.23
P < 0.001

−3.75±2.83
P = 0.001

–3.8 ± 3.06
P = 0.09

SUB AST
P

−4.05 ± 1.85 −3.04 ± 1.38
P < 0.05

–3.01 ± 1.48
P < 0.001

−3.52 ± 1.70
P < 0.05

–3.1 ± 1.42
P < 0.05

CCT
p

496.97 ± 45.95 496 ± 17.10
P = 0.21

508.88 ± 18.44
P = 0.52

504.20 ± 26.18
P = 0.07

491.43 ± 37.98
P = 0.18

K-max
p

51.92 ± 5.47 54.71 ± 6.16
P = 0.23

48.06 ± 1.30
P = 0.45

50.95 ± 4.46
P = 0.23

51.40 ± 4.40
P = 0.42

K-min
p

46.63 ± 4.36 43.55 ± 3.25
P = 0.477

44.91 ± 1.93
P = 0.18

45.71 ± 4.05
P = 0.85

46.34 ± 4.56
P = 0.24

UCVA, uncorrected visual acuity; BCVA, best corrected visual acuity; LogMAR, logarithm of the minimum angle of resolution;
OBJ, objective; SUB, subjective; SE, spherical equivalent; AST, astigmatism; CCT, central corneal thickness

achieving a plateau in this period; no alteration was
reported following one and over five postoperative
years. Caporossi et al[21] and O’Brart et al[27]
reported that CT did not change significantly after
long-term follow-up. Raiskup-Wolf et al[23] showed
an increase in CCT in the second year after CXL.

In our study, the steepest and flattest corneal
curvatures following CXL did not change
significantly at any interval after treatment. Our
topographic results showed a mean decrease of
2.42 D in 56.6% of patients and a mean increase of
1.93 D in 43.33% of patients in the steepest corneal
curvature at the last follow-up. A mean decrease

of 2.01 D was reported by Wollensak et al in the
maximum curvature values after four years.[9] A
mean reduction of 2.10 D in minimum corneal
curvature values after six months were reported by
Caporossi et al.[31] Raiskup-Wolf et al[23] reported
2.68 D, 2.21 D, and 4.84 D reduction of corneal
curvature in the first, second, and third years after
CXL, respectively. Steepest corneal curvature was
reported as a weak parameter for both efficacy of
the CXL and the keratoconus progression.[40] The
reason is that the steepest curvature characterizes
the steepest curvature of the anterior corneal
surface taken from a little region and it is not

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Longstanding Outcomes of Collagen Crosslinking; Derakhshan et al

able to recognize the degree of ectasia; hence,
keratoconus can progress without any change in
the steepest corneal curvature.[41]

In conclusion, we recommend the use of
CXL for patients with early keratoconus. Our
findings indicate that the CXL procedure is an
effective and a safe method for the treatment
of keratoconus within a long-term postoperative
follow-up duration. However, more studies with
larger sample size are required to confirm the
effectiveness of CXL.

Acknowledgements

The authors thank Prof. Shokrpour for English
editing of the paper.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

None declared.

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