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ARTICLE

Lid-Parallel Conjunctival Folds and Their Ability to Predict Dry Eye


Heiko Pult, Ph.D. and Stefan Bandlitz, Ph.D.

evidence suggests that practitioners are incorporating LIPCOF as


Purpose: The observation of lid-parallel conjunctival folds (LIPCOF) is
reported to be useful in dry eye diagnoses. Around 70% of the European
part of their dry eye evaluation. For example, around 70% of
clinicians use this test in a dry eye clinic. This study investigated the practitioners in Germany, Switzerland, and Austria use this test,14
sensitivity and specificity of LIPCOF to predict dry eye. although only 40% do so in Australia.15
Methods: Ocular Surface Disease Index (OSDI) outcome, noninvasive Lid-parallel conjunctival folds (Fig. 1) are folds in the lateral,
break-up time (NIKBUT) using the Keratograph (Oculus, Wetzlar, lower quadrant of the bulbar conjunctiva, parallel to the lower lid
Germany), and LIPCOF of 148 randomized selected patient reports (88 margin. Lid-parallel conjunctival folds are significantly related to
females; mean age¼37.0612.9 years) from 3 different sites were analyzed. dry eye.11,13,16–18 Bulbar conjunctival folds may have been first
Subjects were divided into dry eye and non-dry eye groups by OSDI only, described by Middlemore in 1835,19 having used the term “con-
named symptomatic dry eye (OSDI scores $15) and by a composite score junctival fold” to describe bulbar conjunctival folds visible with the
(OSDI scores $15 and NIKBUTaverage of #9 sec).
naked eye. It was Hughes20 in 1942 who named these severe
Results: Lid-parallel conjunctival folds (temporal, nasal, Sum [¼temporal
+nasal]) were significantly correlated to OSDI and to NIKBUTaverage
bulbar conjunctival folds, which are treatable by surgery, “conjunc-
(Spearman; r.20.185, P,0.013). NIKBUTaverage (r¼20.322; P,0.001) tivochalasis” (Fig. 2); however, the term “chalasis” may implicate
was significantly correlated to OSDI scores. Based on the OSDI question- a potential relationship between age and these conjunctival folds.
naire, 37.2% of the subjects were symptomatic and 14.7% were positive for For small conjunctival folds, age does not seem to be correlated
dry eye based on the composite score. Lid-parallel conjunctival folds were with the degree of their formation.13 Consequently, Höh et al.13
a significant discriminator between healthy and dry eye subjects (P#0.001). described this latter type as LIPCOF. This group published the first
The areas under the receiver operating characteristic curve for temporal LIPCOF grading scale in which these folds were compared with
LIPCOF, nasal LIPCOF, and LIPCOF Sum were 0.716, 0.737, and normal tear meniscus height. Pult et al.12,21 then introduced an
0.771, respectively, for the symptomatic dry eye group and 0.771, 0.719, optimized, and for the first time validated, a LIPCOF grading scale
and 0.798, respectively, for the composite dry eye group.
with which the number of folds are counted instead of comparing
Conclusions: As LIPCOF demonstrated high predictive ability of dry eye;
it appears to be a promising test in the diagnoses of dry eye.
fold height to tear meniscus height. In addition, Pult et al.12,17,22
reported the importance of observing not only temporal but also
Key Words: Dry eye—Lid-parallel conjunctival folds—LIPCOF— nasal LIPCOF.
Conjunctivochalasis—Tear film—NIBUT—NIKBUT—OSDI. Lid-parallel conjunctival folds occurs behind the temporal and
(Eye & Contact Lens 2017;0: 1–7)
nasal tear meniscus. Consequently, two-third of the total length of
the inferior tear meniscus is influenced by LIPCOF.23 Interestingly,
although LIPCOF does not occur centrally, it causes central tear
meniscus height measurements to be underestimated24 and disrupts

M illions of patients have ocular-related symptoms, such as


stinging, burning, itching, light sensitivity, and blurry vi-
sion1–4 that limit the quality of life, as well as occupational pro-
ductivity.5,6 Correlations between these symptoms and individual
clinical dry eye tests are frequently poor.7–10
However, other tests such as lid-parallel conjunctival folds
(LIPCOF) have been reported to be promising tests in dry eye
patients.11–13 A multiple regression analysis including common dry
eye tests showed that noninvasive tear film stability and LIPCOF
were the most effective tests in dry eye diagnoses.12 Recent

From the Optometry and Vision Research (H.P.), Weinheim, Germany;


School of Optometry and Vision Sciences (H.P.), Cardiff University, Cardiff,
United Kingdom; Ophthalmic Research Group (H.P., S.B.), Life and Health
Sciences, Aston University, Birmingham, United Kingdom; and Höhere
Fachschule für Augenoptik Köln (HFAK) (S.B.), Cologne, Germany.
The authors have no funding or conflicts of interest to disclose.
Address correspondence to Heiko Pult, Ph.D., Optometry and Vision
Research, Steingasse 15, 69469 Weinheim, Germany; e-mail: ovr@
heiko-pult.de
Accepted August 14, 2017. FIG. 1. Lid-parallel conjunctival folds (LIPCOF degree 2) at the
DOI: 10.1097/ICL.0000000000000435 temporal area of observation.

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only.12 It may be of interest to investigate predictive ability of nasal


and temporal LIPCOF in a larger cohort of patients and using
a combination of symptoms and objective signs as outcome
measurements.
The aim of this study was to evaluate the predictive ability of dry
eye (defined by symptoms and objective signs) of nasal LIPCOF,
temporal LIPCOF, and LIPCOF Sum (nasal+temporal LIPCOF) in
a multicenter study.

METHODS
Ocular Surface Disease Index (OSDI) outcome, noninvasive
break-up time (NIBUT), and LIPCOF of 148 patient reports (88
females; mean age¼37.0612.9 years) were analyzed in this pro-
spective study (Table 1). Volunteers (irrespective of dry eye status,
but meeting the observation and inclusion and exclusion criteria) of
three different sites (Höhere Fachschule für Augenoptik Köln
[HFAK], Cologne, Germany and Horst Riede GmbH, Weinheim,
FIG. 2. Conjunctivochalasis. Germany and Augenoptik/Optometrie Etzler Arnsberg, Germany)
were observed. All procedures were conducted in accordance with
the tear film along the peripheral portions of the lower lid.23,24 the Declaration of Helsinki (1983) and approval for the study was
Decreased mucin production is associated with the severity of given by the Cardiff School of Optometry and Vision Sciences
LIPCOF,22 and LIPCOF are significantly correlated with lid- Human Ethics Committee. All subjects provided written informed
wiper epitheliopathy.12,17,22 Furthermore, LIPCOF are related to consent before participating in the study, and patient data were
blinking (complete and incomplete),25,26 blink speed, and tear film anonymized.
viscosity.27 Lid-parallel conjunctival folds were evaluated, without fluores-
Lid-parallel conjunctival folds are reversible. They can, for cein, on the bulbar conjunctiva in the area perpendicular to the
example, be treated using a liposomal eye spray28 or a carbomer temporal and nasal limbus, above the lower lid (temporal and nasal
eye gel (Bausch and Lomb, Berlin, Germany).29 Experienced con- LIPCOF, respectively). Observations were performed with a slit-
tact lens wearers with an increased LIPCOF score showed signif- lamp microscope using ·25 magnification.16,17,22
icantly lower LIPCOF degrees after 3 months, having been re-fitted Lid-parallel conjunctival folds were classified by counting the
with senofilcon A contact lenses (Johnson & Johnson, Vision Care, number of folds according the Pult scale (Table 2).16,17,22 Care was
Jacksonville, FL).30 taken to differentiate between parallel, permanent, conjunctival
Nemeth et al. evaluated a medium predictive ability of dry eye folds, (LIPCOF) and disrupted microfolds.16,17,22,31–33 This was
(outcome measurement: symptoms plus signs; sensitivity: 0.52, done based on the height of the fold; the height of a single LIPCOF
specificity: 0.64) of temporal LIPCOF. However, this group used is approximately 0.08 mm, whereas that of a microfold is
the former nonvalidated LIPCOF scale of Höh et al.13 and only 0.01 mm.21
observed temporal LIPCOF. NIKBUT was observed using Keratograph 4 (Oculus, Wetzlar,
By contrast, Pult et al.12,16,17,22 demonstrated that the evaluation Germany), and the median of three consecutive measurements was
of both nasal and temporal LIPCOF improves the predictive ability noted. The Keratograph measurement results in two outcomes, the
of dry eye. However, the outcome measurement in the study of very first break-up (NIKBUTfirst) and the average time of all break-
a small group of noncontact lens wearers (n¼47) was symptoms up incidents (NIKBUTaverage).34 The latter seems to be closer to the

TABLE 1. Mean and Standard Deviation (SD) of Sex, Age OSDI Scores, and NIKBUT Average Grouped by the Different Sites and Median and
Interquartile of Lid-Parallel Conjunctival Folds (LIPCOF) Values of the Different Sites
Site 1 Site 2 Site 3

Female Male Female Male Female Male

Sex 29 21 32 17 27 22
Mean SD Mean SD Mean SD
Age 38.69 13.23 38.41 12.43 33.98 12.69
OSDI 15.29 13.02 14.83 12.57 12.43 12.62
NIKBUTaverage 17.69 24.01 15.78 14.25 16.08 14.88

Site 1 Site 2 Site 3

25% Median 75% 25% Median 75% 25% Median 75%

LIPCOF temp 0 1 2 0 1 2 0 1 2
LIPCOF nasal 0 0 1 0 0.5 1 0 0 1
LIPCOF Sum 0 2 3 0 2 3 0 2 3

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Eye & Contact Lens  Volume 0, Number 0, Month 2017 LIPCOF and Dry Eye

TABLE 2. Optimized Lid-Parallel Conjunctival Folds Grading Scale12 Inclusion and Exclusion Criteria
Subjects were excluded if they had abnormal lid margins,
Grade
were younger than 18 years, had any history of ocular surgery,
No conjunctival folds 0 used any medication or eye drops known to affect the ocular
One permanent and clear parallel fold 1
Two permanent and clear parallel folds (normally ,0.2 mm) 2 surface, wore contact lenses, were pregnant, had conjunctivo-
More than two permanent and clear parallel folds 3 chalasis (defined as conjunctival folds increased by forceful
(normally .0.2 mm) blinks or digital pressure toward the lid margin, or at least one
central conjunctival fold47,48). Furthermore, only those reports
in which OSDI and NIKBUT evaluation was masked against
NIBUT measurements when using the Tearscopeplus (Keeler Ltd, LIPCOF evaluation; simply having used two different observers
Windsor, United Kingdom).35 were considered to be included in this study.
Subjects were categorized as dry-eyed in two ways. First, on the
basis of the OSDI only, those with a score of greater than 142 were
RESULTS
assigned to the symptomatic dry eye group. The second method
involved a composite score in which those having an OSDI score Lid-parallel conjunctival folds scores and NIKBUT measure-
of $15 and NIKBUTaverage of #9 sec36 were assigned to the dry ments were not significantly different between right and left
eye group. The reported cutoff value of noninvasive break-up time eyes (Wilcoxon test, P.0.229). In the further analyzes, LIPCOF
is reported to be 10 sec,36 when using a tearscope. However, the and NIKBUT were either taken from the right or left eye (ran-
cut-off value for NIKBUTaverage is reported to be 9 sec,35 and was domized by lottery). Lid-parallel conjunctival folds were not
the value used for this study. different between females and males (U test, P¼0.848,
There are many different tear film tests and ocular signs in dry P¼0.113, and P¼0.220, temporal, nasal, and LIPCOF Sum,
eye diagnosis. However, some of the tests are useful to detect dry respectively). Temporal LIPCOF were significantly negatively
eye generally, known as global tests. Those are, for example, correlated with age, while nasal LIPCOF and LIPCOF Sum
ocular surface staining, tear film stability, LIPCOF, lid-wiper were not. Lid-parallel conjunctival folds were significantly
epitheliopathy, and osmolarity. Other tests are subset tests as, for correlated with OSDI and to NIKBUTaverage (Table 3).
example, the evaluation of the meibomian glands or the evaluation NIKBUTaverage (r¼20.322; P,0.001) was significantly corre-
of the tear volume.37,38 lated to OSDI scores.
Of the listed global tests, only those that are suitable and easily Based on the OSDI questionnaire, 37.2% of the subjects were
available should be considered. For example, conjunctival staining symptomatic and 31.1% showed a NIKBUTfirst #6 sec,35 39.9%
is criticized being rather a test of dry eye severity and limited in the showed a NIKBUTaverage #9 sec.35 Based on the composite score,
diagnoses of mild to moderate dry eye.39 Lid-wiper epitheliopathy 14.7% were positive for dry eye.
is likely to be a frictional sign as LIPCOF is too.27 Therefore, lid- Lid-parallel conjunctival folds score was a significant discrim-
wiper epitheliopathy and staining were not considered as potential inator between healthy and dry dye subjects (Tables 4 and 5, Figs.
objective tests in this study analyzing predictive ability of LIPCOF. 3 and 4) using the published12 cutoff values (temporal LIPCOF 2,
The evaluation of tear film osmolarity is reported to be an nasal LIPCOF 1, LIPCOF Sum 2).
effective dry eye test.39–41 However, this test was not available at Based on the published cutoff values, the sensitivity and
all sites. As NIBUT was found to be one of the most valuable dry specificity of LIPCOF Sum was 83.6% and 54.8%, respectively,
eye test,12,42–44 this study used NIKBUT as the objective dry eye in symptomatic dry eye, and 85.7% and 46.7%, respectively, in the
test. composite dry eye score. However, a different cutoff value of
LIPCOF Sum 3 was derived from this study. This was done by
a trade-off between the detection rate and false positive rate
Statistical Analyzes depending on the distribution of test values between these two
Data were analyzed for normal distribution by
groups.49 The new cutoff value resulted in a better true-negative
Kolmogorov–Smirnov test, and correlations between variables
rate (but a worse true-positive rate) with a sensitivity and specific-
were analyzed by Pearson correlation for parametric data or
ity of 61.8% and 82.8%, respectively, in the symptomatic dry eye
Spearman rank for nonparametric variables. Differences
group and 61.9% and 75.9%, respectively (Table 6), in the com-
between eyes were analyzed by paired t test or Wilcoxon test.
posite dry eye group.
The ability of LIPCOF to predict subjective dry eye and the
composite dry eye was evaluated using the receiver operative
characteristic curve. Sensitivity and specificity values were TABLE 3. Correlations Between Lid-Parallel Conjunctival Folds
calculated based on published cutoff values.12 For any analyzes, (LIPCOF) and Age, OSDI Scores and NIKBUTaverage (Spearman’s Rho)
SPSS version 20 (SPSS, Inc., Chicago, IL) was applied. The Temporal LIPCOF Nasal LIPCOF LIPCOF Sum
sample size was evaluated before the study by power calcula-
Age
tion45 based on a power of 1-b¼0.80 (symptomatic dry eye: r 20.193 20.053 20.146
OSDI differences of 7,46 standard deviation [SD] non-dry eye P 0.019 0.525 0.078
group: 6.90 and dry eye group: 15.1134; NIKBUTaverage: dif- OSDI score
r 0.569 0.584 0.654
ferences of 2.3 sec, SD non-dry eye group: 4.22 sec and dry eye P ,0.001 ,0.001 ,0.001
group: 4.08 sec34). To our knowledge, indicative values for the NIKBUTaverage
composite score are unknown; hence, power calculation was r 20.400 20.185 20.362
P ,0.001 0.013 ,0.001
based on OSDI and NIKBUTaverage.

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TABLE 4. Area Under the Receiver Operating Characteristic (ROC) similar to the current study, but the specificity figures of the current
Curve of the Different Lid-Parallel Conjunctival Folds (LIPCOF) Scores to study were 10% less than those observed in our previous study. In
Discriminate Between Healthy and Dry Eye in the Symptomatic Dry Eye
our previous study12 the number of subjects was smaller, with 64%
Score (OSDI Only)
being women, a median age of 35 years, and a median OSDI score
Asymptomatic 95% of 8.33 (median OSDI scores of the non-dry eye and dry eye
Confidence Interval
groups were 4.2 and 18.8, respectively; only median values and
Area P Lower Bound Upper Bound not mean values are stated in that article). In the current study, 59%
Temporal LIPCOF 0.716 ,0.001 0.632 0.801
of the subjects were women, the median age was 37, and median
Nasal LIPCOF 0.737 ,0.001 0.651 0.822 OSDI scores were 12.0 (OSDI scores of the non-dry eye and dry
LIPCOF Sum 0.771 ,0.001 0.690 0.851 eye groups were 6.25 and 22.9, respectively [symptomatic score]),
and are, therefore, a very similar population to the previous one.
Consequently, those differences may be an effect of the multicenter
DISCUSSION study design. However, using a cutoff value of three for LIPCOF
This was a multicenter retrospective analysis of data to Sum may result in more balanced outcomes of sensitivity and
determine sensitivity and specificity values of LIPCOF in dry specificity and are remarkably closer to those of the previous study.
eye diagnoses. This study confirmed LIPCOF as being a potential However, it is valuable to discuss whether true negatives are more
diagnostic dry eye test. Lid-parallel conjunctival folds values were important than true positives. It may likely be the other way around
significantly correlated to dry eye symptoms. Furthermore, LIP- such that the former cutoff value may be the preferable one. On the
COF Sum seemed to be a good discriminator between dry eye and other hand, the evaluation of the new cutoff value was according to
healthy subjects. The poor correlation between LIPCOF and age, the recommendations of the Dry Eye Workshop Report 2007.49
albeit being negative, may highlight the difference of conjuncti- Another group11 also evaluated predictive ability of LIPCOF
vochalasis, confirming the observations of Höh et al.13 using a composite score. In that multicenter study, the subjects
Previous investigation evaluated predictive ability of dry eye of were grouped based on a self-composed questionnaire, corneal
different common dry eye tests (LIPCOF, tear meniscus height, and conjunctival fluorescein staining, and break-up time measure-
noninvasive break-up time, phenol red thread test, bulbar and limbal ment using fluorescein and Schirmer I. Only sensitivity and spec-
hyperaemia, corneal and conjunctival staining, and lid-wiper epitheli- ificity values of temporal LIPCOF were analyzed in this study
opathy). LIPCOF and NIBUT showed promising predictive ability (sensitivity of 52% and specificity of 64%, cutoff value 2), and
values of dry eye. Furthermore, based on a multiple regression they were remarkably lower than those of the current study. This
analyzes, this study reported that NIBUT and nasal LIPCOF is best can be for many reasons, as we may have observed this in a youn-
test combination to diagnose dry eye symptoms.12 In addition to that ger patient cohort (mean age in this study was 37.0612.9 years
study, our work aimed to analyze sensitivity and specificity values of compared to 52.7616.211) and sex distribution being relatively
LIPCOF to predict symptomatic dry eye and dry eye defined by balanced, while Németh et al.11 analyzed LIPCOF in females
objective evaluation (NIKBUT) and symptoms (OSDI). mainly (75 male, 197 female). Another reason may be the different
However, sensitivity and specificity values in this study were approach of grouping subjects, using a self-composed question-
different from previous published values.11,12 In a previous inves- naire and invasive tests (corneal and bulbar conjunctival fluores-
tigation by our group,12 LIPCOF were evaluated in symptomatic cein staining followed by fluorescein tear film break-up time and
and asymptomatic groups, based on OSDI scores only. Such direct Schirmer I). Furthermore, the only global dry eye tests are the
comparison to the composite dry eye score’s outcome cannot be corneal and bulbar conjunctival fluorescein staining and fluorescein
drawn; however, even the symptomatic grouping showed some tear film break-up time, while Schirmer I is a subset test to detect
differences here. aqueous deficient dry eye.36 Conjunctival staining is criticized
In our previous study, the sensitivity and specificity of LIPCOF when being used in the diagnoses of mild to moderate dry eye.39
Sum (nasal+temporal LIPCOF; cutoff value 2) to discriminate Finally, although fluorescein break-up time is widely used instead
between asymptomatics and symptomatics was 70% and 91%, of the noninvasive measurement of the tear film stability,14 limi-
respectively. The sensitivity and specificity of temporal LIPCOF tations of this test without controlling volume and concentration
were 60% (cutoff value 2) and 81%, respectively, and those of are known.50,51 Therefore, we observed the tear film stability non-
nasal LIPCOF were 70% and 81%, respectively (cutoff value 1). invasively and objectively using the Keratograph. In this study,
Such sensitivity values for temporal and nasal LIPCOF were grouping criteria of subjects in terms of dry eye were based on
symptoms or combined by symptoms and tear–film instability.
This approach meets the dry eye definition of the DEWs Report
TABLE 5. Area Under Receiver Operating Characteristic (ROC) Curve 200736: “Dry eye is a multifactorial disease of the tears and ocular
of the Different Lid-Parallel Conjunctival Folds (LIPCOF) Scores to
Discriminate Between Healthy and Dry Eye in the Composite Dry Eye surface that results in symptoms of discomfort, visual disturbance,
Score (OSDI and NIKBUT Combination) and tear film instability with potential damage to the ocular sur-
face.” It is accompanied by increased osmolarity of the tear film
Asymptomatic 95%
Confidence Interval and inflammation of the ocular surface.52 Although the DEWs
Report 200736 does not state a recommended algorithm for diag-
Area P Lower Bound Upper Bound
nosing dry eye, the three factors symptoms, visual disturbance, and
Temporal LIPCOF 0.771 ,0.001 0.665 0.877 tear film instability are highlighted in the definition of this report.
Nasal LIPCOF 0.719 0.001 0.578 0.859 The other factors are potential factors or accompanying factors.
LIPCOF Sum 0.798 ,0.001 0.682 0.914
Symptoms and visual disturbance were evaluated in this study

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Eye & Contact Lens  Volume 0, Number 0, Month 2017 LIPCOF and Dry Eye

FIG. 3. Discrimination of symptomatic


dry eye by lid-parallel conjunctival folds
(LIPCOF) (temporal, nasal, and Sum).

using the OSDI questionnaire, tear film instability was observed use of the Schirmer I test as a dry eye criterion. However, in
fully objectively using a video topographer. future, it may be interesting to investigate whether the predic-
Nevertheless, differences between both studies may be due to tive ability of LIPCOF differs between aqueous deficient dry
Nemeth et al.11 having observed more severe dry eyes than that eye or evaporation dry eye. This could be done by additionally
observed in this study. In addition, there may be a higher num- grouping patients into groups using appropriate subset tests as
ber of aqueous deficient dry eye patients in their study due to the the evaluation of the tear film volume, lipid layer, meibomian

FIG. 4. Discrimination of composite dry


eye by lid-parallel conjunctival folds
(LIPCOF) (temporal, nasal, and Sum).

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TABLE 6. Sensitivity and Specificity (%) Values of Nasal and Temporal Lid-Parallel Conjunctival Folds (LIPCOF) and LIPCOF Sum
Symptomatic Dry Eye Composite Dry Eye

Cutoff Sensitivity Specificity Sensitivity Specificity

Temporal LIPCOF 2 60.0 71.0 81.0 69.0


Nasal LIPCOF 1 72.7 71.0 66.7 60.7
LIPCOF Sum 2 83.6 54.8 85.7 46.7
LIPCOF Sum 3a 61.8 82.8 61.9 75.9

Symptomatic dry eye derived from OSDI outcome only, composite dry eye is based on OSDI and NIKBUTaverage.
a
New cutoff value.

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Eye & Contact Lens  Volume 0, Number 0, Month 2017 LIPCOF and Dry Eye

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