Cross-linking del collagene corneale per il trattamento del cheratocono e delle ectasie corneali: i risultati a 1 anno

ARTICLE

Corneal collagen crosslinking for keratoconus
and corneal ectasia: One-year results
Peter S. Hersh, MD, Steven A. Greenstein, Kristen L. Fry, OD, MS

PURPOSE: To evaluate 1-year outcomes of corneal collagen crosslinking (CXL) for treatment of ker-
atoconus and corneal ectasia.
SETTING: Cornea and refractive surgery subspecialty practice.
DESIGN: Prospective randomized controlled clinical trial.
METHODS: Collagen crosslinking was performed in eyes with keratoconus or ectasia. The treatment
group received standard CXL and the sham control group received riboflavin alone. Principal out-
comes included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction,
astigmatism, and topography-derived outcomes of maximum and average keratometry (K) value.
RESULTS: The UDVA improved significantly from 0.84 logMAR G 0.34 (SD) (20/137) to
0.77 G 0.37 logMAR (20/117) (P Z .04) and the CDVA, from 0.35 G 0.24 logMAR (20/45) to
0.23 G 0.21 logMAR (20/34) (P<.001). Fifteen patients (21.1%) gained and 1 patient lost
(1.4%) 2 or more Snellen lines of CDVA. The maximum K value decreased from baseline by 1.7 G
3.9 diopters (D) (P<.001), 2.0 G 4.4 D (P Z .002), and 1.0 G 2.5 D (P Z .08) in the entire cohort,
keratoconus subgroup, and ectasia subgroup, respectively. The maximum K value decreased by
2.0 D or more in 22 patients (31.0%) and increased by 2.0 D or more in 3 patients (4.2%).
CONCLUSIONS: Collagen crosslinking was effective in improving UDVA, CDVA, the maximum
K value, and the average K value. Keratoconus patients had more improvement in topographic
measurements than patients with ectasia. Both CDVA and maximum K value worsened between
baseline and 1 month, followed by improvement between 1, 3, and 6 months and stabilization
thereafter.
Financial Disclosure: No author has a financial or proprietary interest in any material or method
mentioned. Additional disclosure is found in the footnotes.
J Cataract Refract Surg 2011; 37:149–160 Q 2011 ASCRS and ESCRS

Keratoconus and corneal ectasia occurring after laser and, ultimately, the need for corneal transplantation
in situ keratomileusis (LASIK) are noninflammatory in 10% to 20% of cases.7 New treatments available
processes in which the cornea deforms in association to patients with keratoconus and ectasia include
with thinning and biomechanical weakening.1 The in- intrastromal corneal ring segment implantation,8–10
cidence of keratoconus is approximately 1 in 2000,2 conductive keratoplasty,11 and corneal collagen cross-
and the literature contains hundreds of cases of post- linking (CXL).
LASIK ectasia.3 Both diseases can result in irregular Collagen crosslinking has emerged as a promising
astigmatism, progressive myopia, or visual impair- technique to slow or stop the progression of keratoco-
ment secondary to stromal scarring.2 Because of nus12 as well as post-LASIK ectasia.13 In this proce-
optical aberrations4,5 caused by this progressive dis- dure, riboflavin (vitamin B2) is administered in
tortion and bowing of the cornea in keratoconus and conjunction with ultraviolet A (UVA, 365 nm). The in-
ectasia, patients usually require rigid or complex teraction of riboflavin and UVA causes the formation
curvature contact lenses to achieve good functional of reactive oxygen species, leading to the formation
vision6; spectacle correction frequently does not result of additional covalent bonds between collagen mole-
in acceptable quality of vision. Furthermore, keratoco- cules, with consequent biomechanical stiffening of
nus tends to progress over the second to fifth decades the cornea.14 In this study, we analyzed primary visual
of life2 and can lead to intolerance of contact lenses acuity, refractive, and topographic outcomes in

Q 2011 ASCRS and ESCRS 0886-3350/$ - see front matter 149
Published by Elsevier Inc. doi:10.1016/j.jcrs.2010.07.030

150 CORNEAL COLLAGEN CROSSLINKING IN KERATOCONUS AND ECTASIA

patients with keratoconus and post-LASIK ectasia 2 weeks before the preoperative eye examination. Contact
over a 1-year postoperative period. In addition, we lens wearers required confirmation of a stable refraction at
2 examinations that were at least 7 days apart. A stable
compared the treatment groups to sham and fellow-
refraction was determined as one in which the MRSE and
eye control groups. keratometry measurements at the first visit did not differ
by more than 0.75 D from the respective measurements at
the second visit.
PATIENTS AND METHODS Patients were initially randomized into a treatment or
control group. The treatment group received standard
Patients were enrolled as part of multicenter prospective ran-
UVA–riboflavin 0.1% CXL treatment. Corneal CXL was per-
domized controlled clinical trials performed under guide-
formed according to the methodology described by
lines of the U.S. Food and Drug AdministrationA,B and
Wollensak et al.12 Initially, a topical anesthetic agent was ad-
approved and monitored by an investigational review
ministered and the central 9.0 mm epithelium removed by
board. This study was compliant with the U.S. Health Insur-
mechanical debridement. Riboflavin (0.1% in 20% dextran
ance Portability and Accountability Act. All patients pro-
T500 solution) was then administered topically every 2 min-
vided informed consent. Randomization was computer
utes for 30 minutes. Riboflavin absorption throughout the
generated and, on the procedure day, a sealed envelope
corneal stroma and anterior chamber was confirmed by
was opened revealing whether the eye would be in the
slitlamp examination. Ultrasound (US) pachymetry was
sham or treatment group. Patients were aware of their ran-
performed and if the cornea was thinner than 400 mm,
domly assigned group.
hypotonic riboflavin (0.1% in sterile water) was adminis-
The inclusion criteria included patients 14 years of age or
tered, 1 drop every 10 seconds for 2-minute sessions, after
older, axial topography pattern consistent with keratoconus
which US pachymetry was performed to ascertain that the
or corneal ectasia, an inferior–superior ratio greater than 1.5
stroma had swollen to more than 400 mm. This was repeated
on topography mapping, a corrected distance visual acuity
until adequate corneal thickness was obtained. The cornea
(CDVA) worse than 20/20, and a diagnosis of progressive
was aligned and exposed to UVA 365 nm light for 30 minutes
keratoconus or LASIK-induced or photorefractive keratec-
at an irradiance of 3.0 mW/cm2 (UV-X system, IROC AG).
tomy (PRK)-induced ectasia. Progressive keratoconus or
During UVA exposure, isotonic riboflavin administration
ectasia was defined as 1 or more of the following changes
was continued every 2 minutes. Postoperatively, antibiotic
over a period of 24 months: an increase of 1.00 diopter (D)
and corticosteroid drops were administered, a soft contact
or more in the steepest keratometry (K) measurement, an
lens bandage was placed, and the eye was reexamined at
increase of 1.00 D or more in manifest cylinder, an increase
the slitlamp. The contact lens was removed after the epithe-
of 0.50 D or more in manifest refraction spherical equivalent
lial defect had closed. Antibiotics and corticosteroid drops
(MRSE). Exclusion criteria included patients with a history
were continued 4 times daily for 1 week and 2 weeks, respec-
of corneal surgery, corneal pachymetry less than 300 mm,
tively. Patients were followed for 12 months postoperatively
history of chemical injury or delayed epithelial healing,
and had complete examinations at 1, 3, 6, and 12 months.
and pregnancy or lactation during the course of the study.

Sham Control Group
Treatment Group
The sham control group received riboflavin 0.1% ophthal-
Contact lens wearers were instructed to discontinue mic solution alone. In this group, the epithelium was not
spherical soft lenses for a minimum of 3 days and soft toric removed. Riboflavin was administered topically every
rigid-gas permeable and hard lenses for a minimum of 2 minutes for 30 minutes. Next, the cornea was exposed to
a sham treatment in which the UVA light was not turned
on, during which time riboflavin was administered topically
every 2 minutes for an additional 30 minutes. The sham con-
Submitted: March 2, 2010.
trol patients were followed for 3 months postoperatively, at
Final revision submitted: July 30, 2010. which point the study eye crossed over to the treatment
Accepted: July 30, 2010. group and received full CXL treatment.
From the Cornea and Laser Eye Institute–Hersh Vision Group, CLEI
Center for Keratoconus (Hersh, Greenstein, Fry), Teaneck, and the Fellow-Eye Control Group
Department of Ophthalmology, UMDNJ–New Jersey Medical In addition to the sham control group, a fellow-eye control
School (Hersh), Newark, New Jersey, USA. group was analyzed. The fellow eyes of patients who did not
have CXL treatment bilaterally were included in this group.
Additional financial disclosure: Dr. Hersh is a paid medical consul- This group consisted of eyes with frank keratoconus or ecta-
tant to Avedro, Inc. sia that did not have CXL, eyes with evidence of disease that
did not meet the inclusion criteria of this study, and eyes
Supported in part by Peschke Meditrade GmbH, Zurich, Switzerland, with no evidence of disease. Visual acuity and topography
and an unrestricted grant to the Department of Ophthalmology, measurements were analyzed at baseline and 12 months
UMDNJ–New Jersey Medical School from Research to Prevent and compared with the postoperative measurements in the
Blindness, Inc., New York, New York, USA. treatment group at the same time points.
Corresponding author: Peter S. Hersh, MD, Cornea and Laser Eye
Institute–Hersh Vision Group, CLEI Center for Keratoconus, 300 Outcome Measures
Frank W. Burr Boulevard, Suite 71, Teaneck, New Jersey 07666, Visual Acuity and Refraction The uncorrected distance
USA. E-mail: phersh@vision-institute.com. visual acuity (UDVA) and CDVA were measured

J CATARACT REFRACT SURG - VOL 37, JANUARY 2011

CORNEAL COLLAGEN CROSSLINKING IN KERATOCONUS AND ECTASIA 151

preoperatively and postoperatively at 1, 3, 6, and 12 months. Visual Acuity Changes after Corneal Collagen
Visual acuity measurements were obtained under controlled Crosslinking
lighting conditions using a modified Lighthouse Early Treat-
ment of Diabetic Retinopathy Study visual acuity test (2nd Uncorrected Distance Table 1 and Figure 1, top, show
edition) with Sloan letters. Patients were tested 4 m from the UDVA over time. The changes in UDVA compared
the visual acuity chart. If patients could not read any letters with baseline failed to reach statistical significance at
at 4 m, they were tested at 2 m. Visual acuity was recorded 1 month, 3 months, or 6 months (P Z .21, P Z .47,
and analyzed as the logMAR value.15 Manifest refraction
was performed preoperatively and 1, 3, 6, and 12 months and P Z .35, respectively). At 12 months, the change
postoperatively, and the MRSE and manifest astigmatism in UDVA compared with baseline was statistically sig-
were analyzed. In the astigmatism analysis, vector analysis nificant (P Z .04). However, when the keratoconus
was performed as described by Holladay et al.16 In this and ectasia subgroups were analyzed individually,
study, the mean surgically induced astigmatism (SIA) and changes in UDVA compared with baseline were not
the vectorial magnitude of the SIA were analyzed using
methodology similar to that in a previous analysis of PRK statistically significant at any time point.
and LASIK.17 For a graphic representation of these results, The UDVA improved by 2 or more Snellen lines in
data points were converted to Cartesian coordinates and 18 eyes (25.4%); 6 eyes (8.5%) lost 2 or more Snellen
the axis of cylinder values were doubled to give a doubled- lines of UDVA (Figure 1, bottom).
angle plot.16 Thus, when plotted on an x–y graph, steepening
toward 90 degrees (induced with the rule) is represented by Corrected Distance Table 1 and Figure 2, top, show the
points on the negative x-axis and steepening toward 180 de- CDVA over time. The mean CDVA remained un-
grees (induced against the rule) is represented by points on changed at month 1 (mean change 0.02 G 0.18 logMAR;
the positive x-axis. To better ascertain the directionality of
the induced astigmatism change, right eyes and left eyes P Z .33). The mean CDVA improved significantly be-
were assessed separately because the astigmatism axis between 1 month and 3 months (mean change À0.07 G
tween eyes in keratoconus may exhibit mirror-image 0.15 logMAR; P!.001) and between 3 months and
symmetry. 6 months (mean change À0.05 G 0.12 logMAR;
P!.001). There was no statistically significant change
Topography Topography measurements were obtained us- between 6 months and 12 months (mean change
ing a rotating Scheimpflug camera (Pentacam, Oculus, Inc.). À0.02 G 0.13, P Z .27). At 12 months, the change in
The Scheimpflug system generates a 3-dimensional model of CDVA compared to baseline was statistically significant
the cornea and anterior segment. Topographic data were ob- (P ! .001).
tained preoperatively and 1, 3, 6, and 12 months postopera-
tively. Maximum K values, average K values, flat K values, Similar to the entire cohort, the mean CDVA im-
and steep K values as well as corneal astigmatism (simulated proved significantly in the keratoconus subgroup
K) were recorded from the topography data generated by the (mean change À0.13 G 0.21 logMAR; P!.001) and
Scheimpflug system. in the ectasia subgroup (mean change À0.07 G 0.11
logMAR; P Z .02) over 1 year. The mean CDVA in
the keratoconus subgroup remained unchanged
Statistical Analysis at 1 month (mean change 0.006 G 0.18 logMAR;
Statistical analysis was performed using PASW Statistics P Z .81), improved between 1 month and 3 months
software (version 18, SPSS, Inc.). Three groups were ana- (mean change À0.07 G 0.14 logMAR; P Z .001) and
lyzed: the entire cohort, the individual keratoconus sub- between 3 months and 6 months (mean change
group, and the ectasia subgroup. A paired 2-tailed Student
t test was performed to analyze the postoperative outcome À0.06 G 0.12 logMAR; P!.001), and plateaued bet-
changes compared with baseline values and to analyze the ween 6 months and 12 months postoperatively
postoperative outcome changes over time. An independent (mean change À0.01 G 0.11 logMAR; P Z .70). In con-
t test was performed to compare outcome data 12 months trast, in the ectasia subgroup, interval changes in
postoperatively between the keratoconus subgroup and ec- CDVA failed to reach statistical significance (0 to
tasia subgroup and between the treatment group and control
group. A P value less than 0.05 was used to determine statis- 1 month, P Z .20; 1 to 3 months, P Z .08; 3 to 6 months,
tical significance. P Z .32; 6 to 12 months, P Z .21).
The CDVA improved by 2 or more Snellen lines in
15 eyes (21.1%); 1 eye (1.4%) in a patient with ectasia
RESULTS lost 2 Snellen lines of CDVA (Figure 2, bottom).
Seventy-one eyes of 58 patients had CXL and were fol-
lowed for 1 year. Of the eyes, 49 were in the keratoco- Refractive Changes after Corneal Collagen
nus subgroup and 22 in the post-LASIK ectasia Crosslinking
subgroup. The sham control group comprised 41 Refraction There was a mean improvement of 0.86 D
eyes (28 keratoconus, 13 ectasia), and the fellow-eye in the MRSE from preoperatively to 12 months postop-
control group comprised 30 eyes (21 keratoconus, 9 eratively; however, the improvement was not statisti-
ectasia). cally significant (P Z .07). There was a statistically



Table 1. Postoperative visual acuity in all eyes, the keratoconus subgroup, and the ectasia subgroup.

Mean LogMAR (Snellen Equivalent)

P Value
Postop (Keratoconus Vs Ectasia)

Change from Baseline
Acuity/Group Preop 1 Month 3 Months 6 Months 12 Months Preop to 12 Months

UDVA .15 .45
All eyes 0.84 G 0.34 0.87 G 0.31 0.82 G 0.37† 0.81 G 0.37 0.77 G 0.37*
(20/137) (20/148) (20/131) (20/129) (20/117)
Keratoconus 0.87 G 0.35 0.91 G 0.31 0.85 G 0.37 0.86 G 0.40 0.82 G 0.39
(20/150) (20/162) (20/143) (20/144) (20/133)
Ectasia 0.75 G 0.30 0.78 G 0.30 0.74 G 0.36† 0.70 G 0.29 0.65 G 0.31
(20/112) (20/120) (20/109) (20/101) (20/89)
CDVA .02 .26
All eyes 0.35 G 0.24 0.37 G 0.29 0.30 G 0.22†,* 0.25 G 0.21†,* 0.23 G 0.21*
(20/45) (20/47) (20/40) (20/35) (20/34)
Keratoconus 0.39 G 0.27 0.39 G 0.30 0.32 G 0.24†,* 0.26 G 0.23*,† 0.25 G 0.23*
(20/49) (20/50) (20/42) (20/36) (20/36)
Ectasia 0.26 G 0.16 0.32 G 0.25 0.25 G 0.17 0.22 G 0.17 0.19 G 0.14*
(20/37) (20/42) (20/35) (20/33) (20/31)

CDVA Z corrected distance visual acuity; UDVA Z uncorrected distance visual acuity
*Significant change compared with baseline measurements
†
Significant change compared with previous visit measurement

significant improvement in MRSE between preopera- P Z .25), between 3 months and 6 months (mean change
tively and 1 month postoperatively (mean change À0.26 G 1.58; P Z .18), or between 6 months and
C0.76 G 2.13 D; P Z .004) but not between 1 month 12 months (mean change À0.03 G 2.58; P Z .92)
and 3 months (mean change C0.38 G 2.73 D; (Table 2 and Figure 3).

Figure 1. Top: Change in UDVA over time. Numbers reported Figure 2. Top: Change in CDVA over time. Numbers reported are
are Snellen visual acuity (20/Â). Bottom: Change in UDVA Snellen Snellen visual acuity (20/Â). Bottom: Change in CDVA Snellen lines
lines between baseline and 12 months postoperatively (KC Z between baseline and 12 months postoperatively.
keratoconus).



Table 2. Postoperative refractive measurements by group.

Mean (D) G SD

P Value

Parameter/Group Preop 1 Month 3 Months 6 Months 12 Months Preop to 12 Months

MRSE .10 .42
All eyes À8.63 G 5.30 À7.86 G 4.61†,* À7.48 G 4.73* À7.74 G 4.74* À7.77 G 5.40
Keratoconus À9.32 G 5.65 À8.34 G 4.95†,* À8.05 G 5.08* À8.20 G 5.04* À8.47 G 5.50
Ectasia À7.08 G 4.10 À6.80 G 3.62 À6.23 G 3.63 À6.73 G 3.91 À6.22 G 4.93
Manifest astigmatism .10 .99
All eyes 4.76 G 2.52 4.62 G 2.30 4.51 G 2.78 4.76 G 2.50 4.81 G 2.51
Keratoconus 5.09 G 2.54 4.95 G 2.21 5.01 G 2.53 5.08 G 2.53 5.01 G 2.43
Ectasia 4.05 G 2.36 3.90 G 2.39 3.41 G 3.05 4.05 G 2.34 4.39 G 2.69

MRSE Z manifest refraction spherical equivalent
†

Manifest Astigmatism entire cohort, the mean induced astigmatism was
Absolute In the entire study cohort, all changes in the 0.99 D Â 88.8 degrees and 0.65 D Â 44.7 degrees in
mean absolute manifest astigmatism between preop- right eyes and left eyes, respectively (Figure 4).
eratively and each postoperative visit failed to reach In the keratoconus subgroup, the mean induced
statistical significance (1 month, P Z .39; 3 months, astigmatism was 1.75 D Â 87.9 degrees and 1.01 D Â
P Z .24; 6 months, P Z .97; 12 months, P Z .84). 49.8 degrees in the right eyes and left eyes, respec-
Similarly, absolute astigmatism in the keratoconus tively. In the ectasia subgroup, the mean induced
and ectasia subgroups remained unchanged at 1 year astigmatism was 0.65 Â 83.3 degrees and 0.42 Â
(Table 2). The manifest astigmatism improved by 79.0 degrees in the right eyes and left eyes, respec-
1.00 D or more in 24 eyes (33.8%) (17 keratoconus, 7 ec- tively. Regarding the induced magnitude of astigma-
tasia), changed between À1.00 D and 1.00 D in 29 eyes tism, the mean vectorial magnitude of SIA at
(34.7%) (19 keratoconus, 10 ectasia), and worsened by 12 months was 2.99 G 2.55 D, 3.16 G 2.72 D, and
1.00 D or more in 18 eyes (25.4%) (13 keratoconus, 2.61 G 2.15 D, in the entire cohort, the keratoconus sub-
5 ectasia). group, and the ectasia subgroup, respectively.

The
Vector Analysis of Surgically Induced Astigmatism Postoperative Topography
mean SIA at 12 months was 0.61 D Â 73.4 degrees, Table 3 shows the postoperative topographic
1.12 D Â 75.2 degrees, and 0.53 D Â 81.7 degrees measurements.
in the entire cohort, the keratoconus subgroup,
and the ectasia subgroup, respectively. In the Maximum Keratometry There was a significant decrease
in the mean maximum K value (À1.7 G 3.9 D) between
preoperatively and 12 months postoperatively
(P!.001). There was a significant increase between
baseline and 1 month (mean 1.39 G 2.80 D; P!.001)
and then a significant decrease between 1 month and
3 months (mean À1.69 G 2.55 D; P!.001) and between
3 months and 6 months (mean À0.93 G 3.02; P Z .01).
There was no significant change in maximum K
between 6 months and 12 months (mean À0.48 G 3.20;
P Z .21) (Figure 5, A).
In the keratoconus subgroup, there was a 2.00 D de-
Figure 3. Postoperative MRSE measurements. Box-and-whisker crease in the mean maximum K value between preop-
plots (upper bar Z 4th quartile; lower bar Z 1st quartile). eratively and 12 months postoperatively (P Z .002).



Figure 4. Double-angle plot of vector change in astigmatism 1 year after CXL. Left: Right eyes. Right: Left eyes.

Table 3. Postoperative topographic measurements by Scheimpflug imaging.

Mean (D) G SD

P Value

Parameter/Group Preop 1 Month 3 Months 6 Months 12 Months Preop to 12 Months

Maximum K .02 .22
All eyes 58.6 G 9.62 60.0 G 9.80*,† 58.3 G 9.09† 57.4 G 8.54*,† 56.9 G 8.62*
Keratoconus 60.4 G 9.99 61.7 G 10.2*,† 60.0 G 9.87† 59.1 G 8.96*,† 58.4 G 8.41*
Ectasia 54.7 G 7.52 56.2 G 7.78*,† 54.54 G 7.91† 53.6 G 6.18* 53.7 G 6.86
Average K
All eyes 48.2 G 6.97 48.8 G 7.11*,† 47.7 G 6.78*,† 47.5 G 6.38* 47.1 G 5.56*,† .001 .07
Keratoconus 50.4 G 7.06 50.8 G 7.34 49.7 G 6.95*,† 49.6 G 6.45* 48.9 G 5.48*,†
Ectasia 43.4 G 3.54 44.3 G 3.90*,† 43.1 G 3.37† 43.0 G 3.00 43.1 G 3.09
Flat K
All eyes 45.8 G 6.42 46.3 G 6.79 45.2 G 6.36*,† 45.2 G6.32* 44.9 G 5.40* .001 .18
Keratoconus 47.9 G 6.35 48.2 G 7.09 47.2 G 6.49*,† 47.3 G 6.32 46.7 G 5.29*,†
Ectasia 41.1 G 3.32 42.0 G 3.22 40.8 G 2.92† 40.5 G 2.82 40.7 G 2.63
Steep K
All eyes 50.9 G 7.33 51.7 G 7.73*,† 50.5 G 7.53*,† 50.2 G6.70 * 49.7 G 6.08* .001 .37
Keratoconus 52.9 G 7.45 53.8 G 7.86*,† 50.5 G 7.53† 52.1 G 6.81* 51.5 G 5.94*,†
Ectasia 46.51 G 4.73 47.0 G 4.98 45.82 G 4.28*,† 45.9 G 3.96 45.7 G 4.33*
Astigmatism
All eyes 4.94 G 2.45 5.46 G 2.82 5.37 G 2.76 4.99 G 2.46 4.76 G 2.59 .50 .34
Keratoconus 4.80 G 2.42 5.64 G 2.95*,† 5.50 G 2.87* 4.87 G 2.26† 4.76 G 2.26
Ectasia 5.24 G 2.55 5.06 G 2.54 5.06 G 2.53 5.28 G 2.89 4.76 G 3.28

K Z keratometry
†



Figure 5. A: Change in maximum K
over time. B: Change in maximum
K between baseline and 12 months
postoperatively. C: Change in
average K over time (KC Z
keratoconus).

There was a significant increase between baseline and was a significant increase between baseline and
1 month (mean change 1.33 G 3.03 D; P Z .003) and 1 month (mean change 1.51 G 2.27 D; P Z .005) and
a significant decrease between 1 month and 3 months a significant decrease between 1 month and 3 months
(mean change À1.70 G 2.66 D; P!.001) and 3 months (mean change À1.66 G 2.35 D; P Z .003). There were
and 6 months (mean change À0.94 G 3.22 D; no significant changes between 3 months and 6 months
P Z .046). There was no significant change between (mean change À0.91 G 2.60 D; P Z .12) or between
6 months and 12 months (mean change À0.72 G 3.58 D; 6 months and 12 months (mean change 0.05 G 2.08 D;
P Z .17). P Z .91).
In the ectasia subgroup, there was a 1.00 D decrease The maximum K value decreased by 2.00 D or more
in the mean maximum K value between preopera- in 22 eyes (31.0%) patients and remained unchanged in
tively and 12 months postoperatively; however, this 28 eyes (39.4%) patients. It increased by 2.00 D or more
failed to reach statistical significance (P Z .08). There in 3 eyes (4.2%) (Figure 5, B).



Average Keratometry In the entire cohort, there was differences between the keratoconus subgroup and ec-
a significant decrease in the mean average K value tasia subgroup in changes in visual acuity (UDVA,
(À1.10 G 2.39 D) between preoperatively and 12 CDVA), refraction (MRSE, manifest astigmatism), or
months postoperatively (P!.001). There was a signifi- topography (maximum K, average K, flat K, steep K,
cant increase between baseline and 1 month (mean astigmatism) 12 months after CXL (Tables 1 to 3).
change 0.56 G 1.87 D; P Z .01) and significant decreases
between 1 month and 3 months (mean change À1.11 G Control Groups
1.26 D; P!.001) and between 6 months and 12 months
Sham In the sham control group, there were no statis-
(mean change À0.41 G 1.60 D; P Z .03). There was no
tically significant changes in CDVA, manifest astigma-
significant change between 3 months and 6 months
tism, MRSE, maximum K value, average K value,
mean change (À0.14 G 1.99 D; P Z .56) (Figure 5, C).
steep K, or corneal astigmatism at the 1-month or
In the keratoconus subgroup, there was a 1.50 D de-
3-month follow-up visits. There was a statistically sig-
crease in the mean average K value between preoper-
nificant improvement in UDVA at 1 month (mean
atively and 12 months postoperatively (P!.001).
change À0.09 G 0.26 logMAR; P Z .03) and 3 months
There was a significant decrease between 1 month
(mean change À0.08 G 0.23 logMAR; P Z .03)
and 3 months (mean change À1.07 G 1.38 D;
compared with baseline. There was also a statistically
P!.001) and between 6 months and 12 months
significant increase in flat K value from baseline to
(mean change À0.64 G 1.79 D; P Z .02). There were
3 months (mean change 0.54 G 1.65 D; P Z .04).
no significant changes in between baseline and
1 month (mean change 0.40 G 2.07 D; P Z .19) or Fellow-Eye In the fellow-eye control group, there were
between 3 months and 6 months (mean change no changes in UDVA, CDVA, maximum K, average K,
À0.15 G 2.27 D; P Z .65). flat K, steep K, MRSE, or corneal astigmatism over
In the ectasia subgroup, there was a 0.3 D decrease the 12-month study The mean change in UDVA
in the mean average K value between preoperatively was À0.04 G 0.18 logMAR (P Z .19); in CDVA,
and 12 months postoperatively; however, this failed À0.04 G 0.14 logMAR (P Z .17), in the maximum K
to reach statistical significance (P Z .22). There was value, C0.29 G 1.19 D (P Z .19); and in the average
a significant increase between baseline and 1 month K value, C0.20 G 0.79 D (P Z .18). There was a statis-
(mean change 0.91 G 1.28 D; P Z .003) followed by tically significant increase in manifest astigmatism
a significant decrease between 1 month and 3 months (mean change 0.34 G 0.82 D; P Z .03) at 1 year.
(mean change À1.21 G 0.99 D; P!.001). There were no
significant changes between 3 months and 6 months Treatment Versus Control Groups
(mean change À0.12 G 1.16 D; P Z .64) or between
6 months and 12 months (mean change 0.09 G 0.92 D; At 3 months, there were no significant differences
P Z .65). between the treatment and sham control group in
changes from baseline in UDVA, CDVA, maximum
Corneal Astigmatism (Simulated Keratometry) In the en- K, or average K value (P Z .13, P Z .44, P Z .25,
tire cohort and the ectasia subgroup, all changes in cor- and P Z .89, respectively). At 1 year, all of the out-
neal astigmatism, measured by Scheimpflug comes were significantly better in the treatment group
simulated K, failed to reach significance at all time than in the fellow-eye control group (P Z .02, P!.001,
points. In the keratoconus subgroup, there were signifi- P !.001, and P!.001, respectively) (Figure 6).
cant increases in corneal astigmatism compared with
baseline at 1 month (P Z .01) and 3 months (P Z .02). DISCUSSION
However, the simulated K value returned to baseline Corneal collagen crosslinking is a promising new
at 6 months; there were no significant changes in cor- treatment for keratoconus12 and corneal ectasia.13
neal astigmatism compared with baseline at 6 months Crosslinking is thought to biomechanically strengthen
(P Z .76) or 12 months (P Z .87). the corneal stroma and, consequently, slow the pro-
gression of keratoconus and ectasia. In many cases,
Comparison Between Groups moreover, CXL improves the patient’s visual, refrac-
Keratoconus Versus Ectasia The baseline CDVA, maxi- tive, and topographic outcomes18 with few reported
mum K value, average K value , flat K value, and steep complications.19 In this controlled clinical trial, visual
K value in the keratoconus subgroup were signifi- acuity, refraction, and topography outcomes were an-
cantly different from the same baseline measurements alyzed in patients diagnosed with keratoconus and in
in the ectasia subgroup (CDVA, P Z .02; maximum K, those with post-LASIK corneal ectasia. This study rep-
P Z .02; average K, P!.001; flat K value, P!.001; resents one of the largest prospectively analyzed treat-
steep K, P!.001). However, there were no significant ment groups to date. Unique to this investigation are



Figure 6. A: Change in CDVA between baseline and 3 months. On the left is a comparison of the treatment group and sham control group and on
the right, between the treatment group and fellow-eye control group. B: Change in maximum K value between baseline and 3 months. On the left
is a comparison of the treatment group and sham control group and on the right, between the treatment group and fellow-eye control group
(CDVA Z corrected distance visual acuity; K Z keratometry; KC Z keratoconus; Tx Z treatment).

the comparisons of the treatment group with a sham Raiskup-Wolf et al.22 found significant improvements
control group and a fellow-eye control group, an anal- in CDVA (0.08 logMAR and 1.34 Snellen lines, respec-
ysis of the postoperative time course of CXL-mediated tively), with continued improvement after 1 year. Ha-
clinical changes, as well as an analysis of these patients fezi et al.13 report that CDVA improved in 4 of 10 eyes
as an entire cohort and individually within their re- with post-LASIK ectasia.
spective keratoconus or ectasia subgroup. In our study, there was also a significant improve-
In our study, the mean UDVA was approximately 1 ment of more than 1 line of mean CDVA 1 year post-
Snellen line better 12 months postoperatively. This im- operatively (mean change 0.12 G 0.19 logMAR). This
provement is somewhat less than previously reported. was in contrast to the fellow-eye control group, in
Vinciguerra et al.18 report a significant improvement which CDVA did not change significantly. In the en-
in mean UDVA, from 0.77 logMAR preoperatively to tire study cohort, 15 eyes (21.1%) gained 2 or more
0.57 logMAR 12 months postoperatively. Caporossi Snellen lines of CDVA and only 1 (1.4%) lost 2 lines
et al.20 reported a significant improvement in mean of CDVA. The latter case had post-LASIK ectasia,
UDVA of 2.41 Snellen lines. and both the CDVA and UDVA decreased from
In clinical practice, it is valuable to give the patient 20/100 to 20/160 at 1 year; the cause was unclear.
an idea of his or her possible outcomes as an individ- We are currently performing further analysis to deter-
ual, rather than as a population mean, to afford them mine preoperative predictors of patients in whom out-
proper expectations. Thus, it is helpful to look at the comes significantly improve or worsen after CXL
likelihood that an individual patient will improve or treatment.
decline substantially. In this type of analysis, 18 eyes Looking at the time course of CDVA change in the
(25.4%) gained 2 or more lines of UDVA, and 6 eyes entire study cohort, the significant changes in CDVA
(8.5%) lost 2 or more lines of UDVA. The cause of appeared to occur between 1 month and 3 months
UDVA loss in these patients is unclear and did not ap- and between 3 months and 6 months, with a plateau
pear directly related to refractive error or change in
corneal topography. Of the 6 eyes, 3 were in the kera-
toconus subgroup and 3 in the ectasia subgroup. The 3 Table 4. Visual acuity in the 6 eyes that lost 2 or more Snellen
keratoconus cases were stage I, stage III, and stage IV. lines of UDVA 1 year after CXL.
The range of baseline UDVA in the 6 eyes was 20/40 to UDVA (Snellen)
20/100, and they lost between 2 lines and 4 lines of
UDVA by 1 year postoperatively (Table 4). Eye Subgroup Stage of KC Baseline 12 Mo Postop
Like UDVA, a significant improvement in postoper- 1 Keratoconus Stage I 20/80 20/160
ative CDVA has been reported in studies of CXL. In 2 Keratoconus Stage III 20/80 20/125
a study by Vinciguerra et al.,18,21 in patients with stage 3 Keratoconus Stage IV 20/40 20/100
III keratoconus, the mean CDVA improved from 0.28 4 Ectasia d 20/100 20/200
logMAR to 0.14 logMAR 12 months postoperatively, 5 Ectasia d 20/100 20/160
and in patients with ectasia, the CDVA improved 6 Ectasia d 20/80 20/160
significantly, from 0.16 logMAR to 0.06 logMAR. Sim- UDVA Z uncorrected distance visual acuity
ilarly, at 1-year follow-up, Caporossi et al.20 and



in improvement thereafter. In the keratoconus sub- Individually, the maximum K value decreased by
group, the change in CDVA over time followed a pat- 2.0 D or more in 22 eyes (31.0%) (17 keratoconus, 5 ec-
tern similar to that in the entire cohort. The ectasia tasia) and increased by 2.0 D or more in 3 eyes (4.2%)
subgroup did not have any significant changes be- (1 keratoconus, 2 ectasia). These latter 3 eyes would be
tween time points; however, there was a significant considered treatment failures because cone progres-
change in CDVA from baseline to 12 months sion was not stabilized. Similar to the results of Koller
postoperatively. et al.,25 the maximum K value increased by 1.00 D or
Previous studies report changes in the MRSE of more in 7 eyes (9.8%) (5 keratoconus, 2 ectasia). Curi-
0.40 D,18 1.43 D,23 and 2.20 D.24 In our study, the ously, none of the 7 eyes were among those that lost
mean improvement in the MRSE at 12 months was 2 or more lines of UDVA and CDVA.
0.86 D. However, this change failed to reach statistical Similar to maximum K value, the decrease in the
significance. Similarly, there were no significant average K value in the entire cohort at 12 months com-
changes in the MRSE in the keratoconus and ectasia pared with baseline was significant. In the keratoco-
subgroups. Poor reproducibility of subjective refrac- nus subgroup, the average K value was significantly
tion in these patients with irregular corneal topogra- decreased at 12 months as well. However, in the ecta-
phies might account for the lack of a significant sia subgroup, the average K value did not significantly
difference in postoperative refraction after CXL. change. Analogous to the maximum K value, all
Previous studies reported significant changes in groups had the largest significant decrease in the aver-
manifest astigmatism of 0.93 D22 and 0.26 D18 respec- age K value between 1 month and 3 months.
tively. In our study, the mean manifest astigmatism es- The flat K and steep K values showed improve-
sentially remained unchanged after CXL. Similarly, in ments similar to those in the maximum K and average
the keratoconus and ectasia subgroups, there were no K values. It remains unclear whether the achieved flat-
significant changes in the mean manifest astigmatism. tening of the flat K value at 1 year is, in fact, a desirable
Vector analysis of SIA showed wide variation in mag- outcome from the clinical viewpoint because it may
nitude and directionality. Again here, difficulty of re- militate irregularity of the corneal topography. Fur-
fraction in these patients could account for our ther study of corneal topography after CXL is needed
inability to identify a consistent change in SIA after to determine whether it is this general topographic
CXL. flattening, or perhaps, more complex changes in the
The maximum K value is a key topographic indica- corneal optical contour, that result in the significant
tor of the success of CXL because it measures, to some improvements in CDVA after CXL treatment.
extent, the severity of the keratoconic cone. Previous In this study, there were significant differences bet-
studies report decreases in maximum the K value of ween the baseline topographic measurements and
2.01 D,12 1.90 D,24 1.46 D,22 and 1.42 D23 in keratoconic CDVA in the keratoconus and ectasia subgroups.
patients. Hafezi et al.13 report a decrease in maximum Therefore, it is difficult to accurately assess the differ-
K value in patients with ectasia after LASIK. Our cur- ences in the changes in postoperative outcome mea-
rent study corroborates findings in these previous surements in these 2 groups. However, the data here
studies; we found a significant decrease in maximum and in previous studies21 suggest that there may be
K value of 1.70 D at 1 year, compared with no signifi- differences between the postoperative CXL outcomes
cant change in the fellow-eye control group. The larg- in keratoconus patients and ectasia patients.
est change was in the keratoconus subgroup, which In the ectasia group, the only significant change in
showed a 2.0 D flattening effect, whereas a smaller CDVA was when 1-year postoperative measurements
change of 1.0 D, which failed to reach statistical signifi- were compared with baseline. In contrast to the kera-
cance, was found in the ectasia subgroup. toconus subgroup, the ectasia subgroup had no signifi-
In all groups, there was a significant increase in cant change in CDVA at any time interval between
maximum K value at 1 month, followed by the largest baseline and 12 months. This may suggest increased
decrease in maximum K value between 1 month and variability in the time course of CDVA changes in ecta-
3 months. In all groups, there was no significant sia patients compared with changes in keratoconus
change in the maximum K value between 6 months patients.
and 12 months. This contrasts with the findings of Furthermore, although there was a trend toward im-
Caporossi et al.20 and Raiskup-Wolf et al.,22 who re- provement, there were no significant changes in maxi-
port a continued decrease in maximum K values after mum K, average K, or flat K in the ectasia subgroup;
the 1-year follow-up. Further follow-up is required to only steep K showed a statistically significant improve-
determine whether the maximum K value will con- ment at the 1-year follow-up. At baseline, the ectatic cor-
tinue to decrease after 12 months in patients with ker- neas in this study were flatter than those in the
atoconus or ectasia. keratoconus subgroup and, therefore, the topographic



changes caused by CXL in these corneas may be subtler. As seen, the basic clinical outcomes of CXL seem to
Notwithstanding, our data suggest that ectatic corneas follow a reproducible time course after treatment. In
may not have as robust a response to CXL as keratoconus general, visual acuity and corneal steepness worsen
corneas. Similar to our findings, Vinciguerra et al.21 somewhat at the 1-month time point. Resolution to
found no significant topographic changes (average K, baseline occurs by approximately 3 months, with im-
flat K, steep K) in patients with post-LASIK ectasia. provement thereafter. This is similar to the clinical
The cause of a potential difference between kerato- time course of CXL-associated corneal haze, which
conic corneas and ectatic corneas is, as yet, unclear. we reported elsewhere.26 In these cases, the haze is
Biomechanical differences caused by the LASIK flap; greatest at 1 month, plateaus at 3 months, and de-
possible differences in the riboflavin diffusion rate in creases significantly between 3 months and 12 months
post-LASIK corneas, especially at the flap interface; postoperatively. Thus, stromal and epithelial healing
and intrinsic pathophysiologic differences between responses to CXL appear to continue over months,
keratoconus and ectasia may all contribute to the dif- concomitant with the changes in clinical outcomes,
ferent responses to CXL between the 2 groups. Cer- which we report here.
tainly, further study with a greater number of ectatic
eyes is necessary to further elucidate differences in
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