Effect of lubricating eye drops on posterior-lid-margin sign in patients with dysfunctional-tear syndrome
John Alfred H. Lim, MD, Ruben Lim Bon Siong, MD
DRY-EYE syndrome (DES) or dysfunctional-tear
syndrome (DTS) is a multifactorial disease involving the
tears and ocular surface, resulting in subjective symptoms
of ocular discomfort and visual disturbance and tear-film
It is associated with objective findings of tear
hyperosmolarity and ocular-surface inflammation.
DES affects a person’s quality of life. According to the
Women’s Health Study,
patients with DES are three times
more likely to have ocular complaints with common
activities such as reading and watching television
compared with those without the disease.
Patients, seen at the Dry Eye Clinic of the Department
of Ophthalmology and Visual Sciences of the University
of the Philippines–Philippine General Hospital (UP–
PGH), generally presented with the following symptoms
(in descending order of frequency): irritation/discomfort,
foreign-body sensation, mild itchiness, tearing, dryness,
burning/stinging, and eye strain/fatigue (Lim Bon Siong
R, Sy E. Profile of patients in a tertiary hospital dry-eye
specialty clinic in the Philippines, unpublished, 2007).
Because the symptoms are largely subjective, dry-eye
disease is difficult to evaluate and manage. Although there
are several clinical objective tests, including tear-filmbreakup time, Schirmer tear test, and corneal and
conjunctival vital staining to determine its presence and
quantify severity, their correlation with the symptoms is
A recently recognized and very promising, albeit not
widely popular, objective clinical assessment of dry-eye
patients is the concept of lid-wiper epitheliopathy
described by Korb
in 2003. Independent of this study,
the UP–PGH Dry Eye Clinic has been monitoring this
clinical finding prior to 2003 and has been using the term
posterior-lid-margin (PLM) sign. In a recent unpublished
study by Sy and Lim Bon Siong evaluating the profile of
dry-eye patients at the UP–PGH Dry Eye Clinic, 255
(79.69%) of the 320 subjects evaluated for lid-margin
lissamine green staining had the PLM sign.
The lid wiper is located at the marginal conjunctiva of
the upper eyelid beginning posterior to the meibomian
gland orifices and extending superiorly to the subtarsal
fold. This is the region where there is a transition between
keratinized and nonkeratinized stratified squamous
epithelium and is in direct contact with the ocular surface.
As implied by the term, the lid wiper wipes the ocular
surface during blinking.
In dry-eye patients, there is boundary lubrication in
which the thickness of the tear film between the opposing
tissues, particularly the lid wiper and the ocular surface,
is inadequate to separate the two surfaces. With
inadequate lubrication, there is a concomitant increase
in frictional coefficient and an increase in the ocularsurface damage.
Korb and colleagues
demonstrated the direct correlation between dry-eye symptoms and the physical finding
and severity of lid-wiper epitheliopathy or PLM sign. The
UP–PGH Dry Eye Clinic has consistently seen relief of
dry-eye symptoms with the disappearance of the PLM sign
after instituting topical lubricants. However, we have not
done any formal study to document the effect of topical
lubricants on the severity grading of PLM sign and how
soon these lubricants help resolve the sign.
Demonstrating the effect of these eye drops on PLM
sign will aid the clinician in the management of dry-eye
syndrome by providing a more objective surrogate
measure of symptom resolution. More importantly, it may
help the clinician choose the most effective topical
lubricant to relieve the patients of dry-eye symptoms as
quickly as possible.
As mentioned, the subjectivity of symptoms poses a
dilemma in the management of dry-eye patients.
Nonetheless, its documentation is crucial since the goal
of treatment is patient comfort and improvement in the
quality of life. To evaluate patient perception of symptoms,
a subjective-grading-of-ocular-discomfort questionnaire
was adapted from the Dry Eye Workshop in 2007 based
on the most common symptoms documented by Sy and
Lim Bon Siong. The questionnaire was translated into
This study correlated the PLM sign with dry-eye symptoms
among patients with DTS and compared the effect of
lubricating eye drops on the PLM sign in terms of its
Thirty eyes of patients diagnosed with DTS were
enrolled in this double-masked, randomized, clinical trial
at a hospital-based dry-eye specialty clinic from March 2008
to September 2008. Eligible patients had a primary
diagnosis of DTS (either aqueous-tear deficiency, tear-film
instability, or both), with PLM sign. They were at least 18
years old, with best-corrected or pinhole visual acuity of
at least 20/40 in both eyes. Excluded were patients who
had any ocular condition that will mimic dry-eye
symptoms, used any form of eye drops within the previous
3 months, had any eyelid or eyelash abnormalities that
will mimic the PLM sign (entropion, trichiasis, lid
imbrication syndrome, floppy eyelid syndrome), had
severe meibomian-gland disease or severe blepharitis, had
severe ocular-surface disease (chemical burn, StevensJohnson Syndrome), had active ocular allergy or infection,
used contact lenses, were pregnant and nursing, had
hypersensitivity to any components of the eye drops.
The subjective-grading-of-ocular-discomfort questionnaire was administered by the investigator to the qualified
participants after obtaining informed consent. The questionnaire used a five-point scale (none at all = 0;
seldom = 1; sometimes = 2; most of the time = 3; all the
time = 4) to grade the following symptoms: discomfort/
irritation; dry sensation; burning/stinging sensation;
itching; sandiness/foreign-body sensation; tearing or
moist sensation; eye strain or fatigue. The sum of the scores
was classified into mild (14 and below), moderate (15 to
21), or severe (22 to 28). The symptoms and grading key
were translated into Filipino and a standard script for the
interviewer as well as visual aid for the key were presented
to the subject.
Participants were assigned a study number from 1 to
30, given in ascending order, for documentation. They
were then randomly assigned by an independent research
assistant based on a predetermined list of random
numbers to receive one of the following: PEG 400
propylene glycol (Systane, Alcon Laboratories, Fort Worth,
TX, USA), hydroxypropylmethylcellulose (Genteal,
Novartis, Annonay, France), or carboxymethylcellulose
(Cellufresh, Allergan, Waco, TX, USA). The research
assistant was masked as to the type of eye drops assigned
to the patients.
Patients were instructed to use their assigned eye drops
only, applying 1 drop of the medication at specified hours
4 times a day. Each subject was given a compliance
monitoring sheet to mark each time the eye drop was
instilled. Subjects were followed up everyday for the first
2 days then every other day thereafter up to a maximum
of 2 weeks until the PLM sign disappeared. At every visit,
the subjective-grading-of-ocular-discomfort questionnaire
was administered and lissamine green staining with
measurement and grading of the PLM sign were
The resolution time—the number of days needed for
complete disappearance of PLM sign—was recorded. A
sterile dye-impregnated strip of lissamine green was
moistened with 2 drops of sterile balanced saline solution
and agitated for 15 seconds. The dissolved dye was
dropped into the inferior fornix of each eye. After letting
the patient blink for approximately 5 seconds, the upper
eyelid was everted by grasping the eyelashes. The area of
the posterior-lid margin was examined under diffused
light using the white light of the slitlamp biomicroscope
with 10X magnification. The horizontal length of the
posterior lid margin, which extends from the upper
punctum to the lateral canthus, and its sagittal width,
which extends from just proximal to the line of Marx to
the subtarsal fold, were examined. Staining of the
horizontal length and sagittal width was measured using
the slitlamp caliper and was graded adopting the scheme
used by Korb and colleagues for fluorescein and rose
bengal staining (Table 1). Individual grades for these two
categories were averaged to get the final grade.
Grading of PLM sign and classification was based on
the final grades obtained: 0.25 to 1.0, grade 1, mild; 1.25
to 2.0, grade 2, moderate; 2.25 to 3.0, grade 3, severe.
The eye with the worse (higher grade) PLM sign was
assigned as the study eye. For subjects with the same
PLM-sign grading in both eyes, the right eye was assigned
as the study eye.
For secondary outcome measure, the correlation
between ocular-discomfort grading and PLM-sign severity
grading before and after treatment was determined.
Symptom grading and PLM-sign grading were as described
All statistics were computed using Statistical Package
for the Social Sciences (SPSS version 10). Assuming a
standard deviation of four, a sample size of 13 eyes/group
was calculated using a 95% significance level and a 10%
risk of a false negative finding.
All numerical continuous data were summarized using
descriptive statistics (percentage, measures of central
tendency, and frequency distribution). Analysis of variance
(ANOVA) was used to test for homogeneity among subjects
in terms of age and to compare the resolution time of the
PLM sign for the 3 eye drops. Chi-square test was used to
test for homogeneity in terms of sex and diagnosis.
Pearson’s correlation coefficient was used to compute
for the correlation between subjective grading of ocular
discomfort and PLM-sign grading. Descriptive analysis was
used to demonstrate the incidence and grading of PLM
sign among patients diagnosed with dysfunctional-tear
The study conformed with the guidelines set by the
Declaration of Helsinki. Informed consent was obtained
from all the subjects after thorough explanation of the
nature and possible risks and benefits of the study. The
hospital Ethics Review Board approved the protocol.
A total of 30 subjects completed the study. There were
no dropouts. The baseline characteristics and tests of
homogeneity of samples are summarized in Table 2.
The youngest patient was 45 years old and the oldest
was 77, with a mean age of 58.2 ± 7.6 years. Females
outnumbered males 5 to 1. Twenty-six (87%) had the PLM
sign in both eyes, 3 in the left eye only, and 1 in the right
eye. Of the 26, 11 had equal grading, 8 had a worse grading
in the left eye, and 7 had a worse grading in the right eye.
In terms of laterality, 19 (63%) involved the right eye and
11 (37%) the left eye. The patients were not characterized
under DTS subtypes since there is currently no universally
accepted categorization of DTS.
Comparing between groups, there was no statistically
significant difference in terms of age (p = 0.06), sex
distribution (p = 0.79), and diagnosis (p = 0.30). The
difference in baseline PLM sign between groups (p = 0.58)
was also not statistically significant.
There was no significant difference (p = 0.35) in the
mean resolution time (1.1 ± 0.3 days ) of the PLM sign for
the 3 eye drops (Figure 1). The corresponding PLM
resolution times for each of the three eye drops were as
follows: Systane: 1.0 ± 0 days; Genteal: 1.1 ± 0.32 days; and
Cellufresh: 1.2 ± 0.42 days.
The baseline PLM sign had a positive, moderate
correlation with baseline subjective grading of ocular
discomfort, with a correlation coefficient of 0.74 (Figure
2). However, there was no correlation between symptom
grading and PLM-sign grading after treatment on day 1
with a correlation coefficient of 0.50 (Figure 3).
The baseline ranges of the PLM sign for the different
groups were similar.
The use of lubricants is central in the management of
DES. Aside from their lubricating effect, ocular lubricants
are also theorized to replace missing tear constituents, reduce elevated tear osmolarity, reduce or wash out
This study mainly evaluated the effect of these eye drops
on the PLM sign (Figure 4), which is a newly documented
sign associated with dry eyes. The results showed no
significant difference among the 3 in terms of the
resolution time of the PLM sign.
This study found a positive moderate correlation
between the symptoms as perceived by the patients and
severity grading of the PLM sign at baseline. However,
there was no correlation statistically between the PLM sign
and the symptoms after 1 day of treatment. This was
probabl y bec ause a l l pa t ient s but 3 had complete
resolution of the PLM sign on day 1. Although there was
a corresponding decrease in the grading of symptoms in
all subjects, the correlation between the above parameters
The study was limited to the complet ion of the
investigation defined as the time when the PLM sign has
completely resolved. Upon completion of the study, the
patients were asked to discontinue the eye drop and were
sent back to the UP–PGH Dry Eye Clinic for follow-up. It
was not the objective of the study to compare the effects
of the eye drops on the symptoms of the patients once
the PLM sign had resolved. Moreover, the patients were not classified into different subtypes of DTS. Only the
severity of symptoms was correlated with the PLM sign.
In conclusion, Systane, Genteal, and Cellufresh were
equally effective in resolving the PLM sign, which was
moderately correlated with dry-eye symptoms. A larger
study sample taking into consideration the different
subtypes of DTS and a longer study period to obtain the
prevalence of the PLM sign are recommended for better
under s t anding of the PLM s ign in di agnos ing and
monitoring the treatment of DTS.
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