CLINICAL SCIENCE
Long-Term Density Changes in Corneal Layers After
Primary Pterygium Excision With Topical Mitomycin-C
Ka Wai Kam, MRCSEd (Ophth), MBBS,* Rachel P. W. Kwok, FRCOphthHK,*
Michael W. Belin, MD, FRANZCO,† and Alvin L. Young, FRCSI, MMedSc (Hons)*‡
Purpose: To evaluate the long-term change in average corneal
densities at 18 months after primary pterygium excision with topical
adjuvant mitomycin-C application, particularly the relationship
between anterior and posterior corneal layer densities.
Methods: Prospective observational case series. Patients were imaged
with the Pentacam at 18 months after their surgery. Average corneal
densities were the primary outcome and were compared with
postoperative weeks 1, 4, and 12 data using paired
t test.
Results: In all, 31 eyes of 31 patients were recruited. Mean age at
time of operation was 62.0 6 9.4 years. Mean best-corrected logarithm
of the minimal angle of resolution visual acuity at 18 months was 0.14.
The mean total anterior, central, and posterior average corneal densities
were 30.6, 25.9, and 20.5 respectively. Compared with postoperative
week 1 data, the anterior layer was reduced by 12.7% (P = 0.0144);
however, there was no significant change in the central and posterior
layers (P = 0.5353 and 0.0858, respectively). Subgroup analyses did not
support the use of a 10- to 12-mm annulus as opposed to total-diameter
data, and density reduction effect at 18 months from week 12 and week
1 seemed to be stronger in males (P = 0.0074 and 0.0042, respectively).
Conclusions: Anterior corneal scars continued to diminish in density
with time. Previous finding of a significant increase in posterior layer
density at postoperative week 12 is likely not a result of optical
phenomenon caused by a less dense anterior layer. Sex difference in
terms of scar remodeling may be present.
Key Words: corneal scar, pterygium, densitometry, Scheimpflug
image
(Cornea 2016;35:1093–1096)
Received for publication January 2, 2016; revision received March 12, 2016;
accepted March 25, 2016. Published online ahead of print May 18, 2016.
From the *Department of Ophthalmology and Visual Sciences, Prince of Wales
Hospital, Hong Kong; †Department of Ophthalmology and Vision Science,
University of Arizona, Tucson, AZ; and ‡Department of Ophthalmology and
Visual Sciences, The Chinese University of Hong Kong, Hong Kong.
The authors have no funding or conflicts of interest to disclose.
Reprints: Alvin L. Young, FRCSI, MMedSc (Hons), Department of
Ophthalmology and Visual Sciences, Prince of Wales Hospital, The
Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
(e-mail: youngla@ha.org.hk).
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Cornea Volume 35, Number 8, August 2016
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C orneal scars are often the final sequel of many corneal
disorders, such as infective keratitis, pterygium, corneal
inflammation, trauma, and complications of ectasia. Not only do
these corneal opacities impede or alter the pathway of light,
they frequently result in surface irregularities leading to
irregular astigmatism that is often difficult to treat. Clinically
significant corneal scars can be treated with either surgical
removal or replacement with an optically clear donor graft, 1 or
in selected cases, laser ablation (eg, phototherapeutic
keratectomy).2,3 Studies on the medical treatment of corneal
scars have been scarce. The Steroid for Corneal Ulcer Trial
evaluated corneal scars by depth and size after episodes of acute
infective keratitis. The authors found a potential role for topical
corticosteroid in improving visual acuities in selected cases of
corneal ulcers.4 Modern imaging techniques allow for the
observation of the evolution of corneal scars with time in a
more objective manner. Densitometry is an inherent feature of
the Pentacam (OCULUS GmbH, Wetzlar, Germany), which
uses the Scheimpflug principle in capturing high-quality
images of the cornea and the anterior segment. The software
automatically segmentalizes the cornea into 3 layers of depth
(anterior 120 mm, central layer, and posterior 60 mm) and 4
annuli (0–2, 2–6, 6–10, and 10–12 mm). Because most
pterygium scars are located in the anterior stroma, the anterior
120-mm density is the primary outcome of interest in our study.
This study follows our previous observation that anterior
corneal densities significantly decreased at week 12 after
primary pterygium excision with adjuvant topical mitomycin-
C5,6 as compared with week 1 after surgical excision.7 The
majority reduction in densities corresponded to the pterygium
scar region. We observed that even chronic corneal scars would
become less dense with time. We additionally noted a
significant increase in mean densities of the posterior corneal
layer, which we hypothesized could be either the result of an
optical effect from a less dense anterior stroma or represent a
genuine change in the tissue density. Therefore, we set out to
reassess the corneal densities and observe the trend in densities
in different layers of the cornea with time.
MATERIALS AND METHODS
The recruitment, operative procedure, postoperative
management, and data collection at postoperative weeks 1
and 12 were described in our earlier study.7 The same
31 participants were invited to participate in this follow-up
study. Subjects with a history of corneal scars from any cause
including trauma, infection, or inflammatory condition were
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Kam et al
excluded. Written informed consent was obtained from all
participants, and the study was approved by the Joint
Chinese University of Hong Kong—New Territories East
Cluster Clinical Research Ethics Committee.
The primary outcome of interest was the average
densities of the anterior 120-mm layer and posterior 60-mm
layer at 1.5 years postoperatively. Secondary outcomes included
clinical data such as visual acuity, intraocular pressures, and
recurrence status of pterygium. Any visible corneal scar that
corresponded to the site of pterygium was measured by the
longest dimension followed by the longest perpendicular to the
first measurement, a protocol adapted from the Herpetic Eye
Disease Study.8 The depth of the scar was documented as
epithelial, anterior, mid, posterior stromal, and Descemetic
level. The presence or absence of visible scars was also
documented as a binary variable. We further measured the
anterior, central, and posterior mean densities of the 10- to 12-
mm annulus, because all pterygia excised measured at least 2
mm from the limbus at the time of operation. Graphical
representation and comparison maps were used to assist
interpretation of change in density values because the numerical
values represented a summary value but the color-coded maps
indicate more clearly the location where densities changed the
most and the magnitude of the change.
Statistical Analysis
Statistical tests were computed using StataCorp 2013.
Univariate statistics including mean, SD, and 95% confidence
intervals (CIs) where appropriate were reported. Distribution
was assessed with a histogram for normality. Paired t tests were
performed to calculate statistical significance and 2-sided P
values for the change in mean densities at 1.5 years post-
operatively versus weeks 4 and 12 postoperatively. Mean
corneal density values were further stratified by sex using
Wilcoxon signed-rank tests and by annulus using paired t tests.
P values less than 0.05 were considered statistically significant.
RESULTS
In all, 31 eyes of 31 subjects participated in this study,
of whom 15 were female and 19 were left eyes. Mean age
the at time of operation was 62.0 6 9.4 years. Mean best-
corrected logarithm of the minimal angle of resolution visual
acuity at 18 months was 0.14. The mean intraocular pressure
was 11.7 mm Hg. Recurrence was noted in 6 eyes, of which
2 exceeded 2 mm in size. Scars visible at the slit-lamp were
documented in 80.6% (N = 25) participants. All these scars
were either located in the epithelium or the anterior stroma.
Of those with significant scars, the geo-metric mean of the
scars was 2.7 mm (N = 17, interquartile range, 1.9–3.4 mm).
None of the patients displayed significant peripheral corneal
degeneration on slit-lamp examination such as arcus senilis
or thinning.
Total Anterior Layer Density
At year 1.5, the mean total anterior density was 30.6
(95% CI, 28.4–32.9, SE = 1.10). The mean total anterior
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Cornea Volume 35, Number 8, August 2016
densities were 31.7 (95% CI, 29.7–33.7, SE = 1.00) and 35.1
(95% CI, 31.2–39.0, SE = 1.92), respectively, at weeks 1
and 12. The reductions of total anterior densities from weeks
1 and 12 to 1.5 years were both significant at 23.5% (P =
0.0483) and 212.7% (P = 0.0144), respectively (Fig. 1).
After stratification by sex, only male subjects dis-
played statistically significant reduction of mean total
anterior densities at 1.5 years postoperatively when
compared with weeks 1 and 12 (P = 0.0074 and 0.0042,
respectively). Statistical significance could not be achieved
among female subjects (P = 0.6072 and
1. 0000, respectively).
Total Central Layer Density
At year 1.5, the mean total central density was 25.9
(95% CI, 23.8–28.1, SE = 1.06). This was not significantly
different from the mean total central densities at weeks 1 and
12, which were 26.4 (95% CI, 24.3–28.5, SE = 1.02) and
26.2 (95% CI, 24.0–28.4, SE = 1.08), respectively (P =
0.2237 and 0.5353).
Total Posterior Layer Density
At year 1.5, the mean total posterior density was 20.5
(95% CI, 18.9–22.1, SE = 0.78). The mean total posterior
densities were 21.3 (95% CI, 19.4–23.1, SE = 0.89) and 19.9
(95% CI, 18.3–21.4, SE = 0.74), respectively, at weeks 1 and
12. The percentage changes in total posterior densities from
weeks 1 and 12 to 1.5 years were both insignificant (P =
0.1651 and 0.0858, respectively). As previously noted, there
was a statistically significant increase in mean total posterior
densities from week 1 to week 12, with a P value of 0.0089.
Subgroup Analyses 10- to 12-mm
Annulus Anterior Layer
At year 1.5, the mean 10- to 12-mm anterior density
was 44.1 (95% CI, 39.7–48.4, SE = 2.13). The mean 10- to
12-mm anterior densities were 47.4 (95% CI, 42.3–52.4, SE
= 2.47) and 46.6 (95% CI, 40.7–52.5, SE = 2.89),
FIGURE 1. Plot showing changes in anterior, central, and
posterior total-diameter mean average densities at post-
operative weeks 1 and 12 and month 18.
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Cornea Volume 35, Number 8, August 2016
respectively, at weeks 1 and 12. The reduction of mean 10-to
12-mm anterior densities from week 12 to 1.5 years was
significant at P = 0.0411. However, the reduction from week
1 to 1.5 years did not achieve statistical significance (P =
0.1225).
10- to 12-mm Annulus Central Layer
At year 1.5, the mean 10- to 12-mm central density was
35.5 (95% CI, 32.1–39.0, SE = 1.68). The mean 10- to 12-mm
central densities were 37.6 (95% CI, 33.9–41.3, SE = 1.81) and
36.3 (95% CI, 32.0–40.6, SE = 2.10), respectively, at weeks 1
and 12. The reduction of mean 10- to 12-mm central densities
from week 12 to 1.5 years was significant at P = 0.0188.
However, the reduction from week 1 to 1.5 years did not
achieve statistical significance (P = 0.4014).
10- to 12-mm Annulus Posterior Layer
At year 1.5, the mean 10- to 12-mm posterior density
was 28.0 (95% CI, 26.0–30.1, SE = 1.02). The mean 10- to
12-mm posterior densities were 28.9 (95% CI, 26.5–31.3,
SE = 1.17) and 26.7 (95% CI, 24.2–29.2, SE = 1.22),
respectively, at weeks 1 and 12. The percentage change of
mean 10- to 12-mm posterior densities from weeks 1 and 12
FIGURE 2. Missing data and blinking artifact despite good quality specification on a large average densitometry map on the
Pentacam.
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Corneal Scar Densities After Pterygium Surgery
to 1.5 years was both insignificant with P = 0.2398 and 0.,
respectively. There was a significant increase in mean 10- to
12-mm posterior density from week 1 to week 12 with P =
0.0008.
DISCUSSION
Our extended observation revealed that the average
total-diameter anterior corneal densities decreased by a total
of 12.7% at postoperative month 18 from week 1, which was
an increment from the previous value of 3% at week 12. One
must also note that this 12.7% represented the change in the
total-diameter average, and therefore, it was subjected to a
dilutional effect from the larger overall area of cornea with a
presumed constant density over time. The graphical
representation often showed that the changes took place
mostly over the scarred region, and the percentage
reductions from assessing difference maps were often
greater than the averaged numerical values. Hence, we
believe that this 12.7% remained a diluted value owing to
the inherent design of the Pentacam software.
The total-diameter average posterior corneal densities
approximately returned to the week 1 value at postoperative
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Kam et al
month 18. Combining with an almost constant average
central layer density value, this rejected our hypothesis that
the significant rise of the average posterior corneal density at
postoperative week 12 was because of an optical effect of a
less dense anterior layer. The change detected at week 12
was therefore likely to represent a genuine change in tissue
properties. However, the cause and significance of such an
increase remains to be elucidated.
This is the first report to quantify such a change, and this
knowledge serves as a reference for future studies to compare
the treatment effects for corneal scars. Unlike in the past when
slit-lamp photographs were the only tool to evaluate change in
scar densities, modern imaging like the Pentacam allows us to
quantify such change more objectively.
Stratification by sex revealed a significant reduction in
male patients but not among females. However, from our
current study, no correlation between sex and the rate of
corneal modification can be drawn. The lack of significance
among female subjects may be explained by our small
sample hence limiting our study power to detect a genuine
change. Further larger scale studies are needed to validate
the change among female subjects.
Subgroup analyses using the 10- to 12-mm annulus did
not always achieve statistical significance when comparing
month 18 and week 1 data. This may be explained with the
graphical assistance of color-coded density maps, in which
there were areas of missing data and blinking artifacts even
though the images were given a satisfactory quality specifi-
cation score (Fig. 2). The SEs were also generally greater in
the 10- to 12-mm annulus data when compared with the
average total-diameter data. This may be related to a smaller
sampling area concentrating the effect of the missing data
and/or artifacts, hence giving results inconsistent with the
total-diameter values.
Besides, the extent of scars beyond 2 mm from the
limbus may have been missed from a 10- to 12-mm annulus
analysis. The geometric mean of the longest diameter of the
scars and the longest perpendicular to that diameter was 2.7
mm. Hence, the choice of 10- to 12-mm annulus for analysis
may not be superior to using the total-diameter approach in
analyzing pterygium scars.
Nonetheless, in either mode of analysis, the
assumption that densities of the unoperated cornea remain
the same with time must be held and that effect of dilution
was unavoidable in either settings. This idea was supported
by simple inspection of the difference maps in comparing 2
densitom-etry readings over time.
Limitations of our study were similar to those of our
previous report. The relatively small sample size, nature of
observation, and nonrandomized selection of subjects subjects
the results to random errors. The inherent lack of tracking
feature of the Pentacam may introduce numerical errors during
comparison; however, low variability has been reported in a
recent study that tried to establish normative data for cornea
densities.9 Unlike in measuring postoperative haze after
refractive surgery of the cornea, the presence of a pterygium
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Cornea Volume 35, Number 8, August 2016
might negatively influence the value of a preoperative densi-
tometry. Hence, we decided to adopt week 1 values as the
baseline. Limitations of the analysis were majorly contributed
by the inherent nature of the Pentacam software, where it either
generates a total-diameter average or a predetermined annulus
average; hence, an ideal comparison of what is actually
happening in a specific region of the cornea affected cannot be
accurately determined. Neither of the 2 available modes is
specific to the location of the anterior stromal scars after
pterygium removal, and hence, the effect of dilution or
contamination by artifacts and missing data may affect the
results. Newer methods to resample the areas that approximate
the pterygium scars and reanalyze the data may yield more
accurate and clinically significant values.
This study evaluated the changes in scars at the
periphery of the cornea, and therefore, minimal effect on the
visual acuity was detected upon subsequent follow-up. In
future studies, we hope to evaluate centrally located corneal
scars and correlate the change in density of the scars with the
visual acuity and refractive errors.
Total-diameter average anterior corneal densities contin-ued
to decrease up to 1.5 years after excision of primary pterygia and
by 12.7% when compared with week 1. Whereas the total-diameter
average posterior densities at 1.5 years returned to approximately
the values at week 1, which rejected our prior hypothesis of an
optical effect of a lesser dense anterior layer. Despite good quality
specifications, the 10- to 12-mm annulus method may not be the
best method to analyze corneal scars after pterygium excision
owing to the influence of artifacts and missing data. Such
knowledge serves as a reference for future studies that compare
treatment effects on corneal densities.
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