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Seminars in Ophthalmology
ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: https://www.tandfonline.com/loi/isio20
Correlation of Non-invasive Tear Break-Up Time
with Tear Osmolarity and Other Invasive Tear
Function Tests
Kemal Ozulken, Gozde Aksoy Aydemir, Kemal Tekin & Tarkan Mumcuoğlu
To cite this article: Kemal Ozulken, Gozde Aksoy Aydemir, Kemal Tekin & Tarkan
Mumcuoğlu (2020) Correlation of Non-invasive Tear Break-Up Time with Tear Osmolarity
and Other Invasive Tear Function Tests, Seminars in Ophthalmology, 35:1, 78-85, DOI:
10.1080/08820538.2020.1730916
To link to this article: https://doi.org/10.1080/08820538.2020.1730916
Published online: 16 Mar 2020.
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Correlation of Non-invasive Tear Break-Up Time
with Tear Osmolarity and Other Invasive Tear
Function Tests
Kemal Ozulken
1
, Gozde Aksoy Aydemir
2
, Kemal Tekin
3
, and Tarkan Mumcuoğlu
1
1
Ophthalmology Department, TOBB ETU Medical School, Ankara, Turkey,
2
Ophthalmology Department,
Adıyaman University Training and Research Hospital, Adıyaman, Turkey, and
3
Ophthalmology Department,
Van ErcişState Hospital, Van, Turkey
ABSTRACT
Aim: To compare the outcomes of non-invasive break-up time (NI-BUT) test and the other conventional dry
eye tests.
Methods: The right eyes of 170 subjects were included in the study. In order to evaluate the tear quality of the
patients, NI-BUT levels were measured by the Scheimplug-Placido disk system (Sirius topography). Tear
osmolarity test was performed with TearLab Osmolarity System. Topical anesthesia-assisted type I Schirmer
test and topical anesthesia-assisted BUT were lastly applied to all patients in order not to affect other
measurements.
Results: The mean NI-BUT value was 9.59 ± 4.37 sec, tear osmolarity was 292.93 ± 9.30 mOsm/L, Schirmer test
was 15.32 ± 6.05 mm/5 min, and biomicroscopic BUT value was 8.98 ± 3.79 sec. The Schirmer test results were
statistically significantly correlated with biomicroscopic BUT and NI-BUT values (p= .019, r = 0.180 and
p= .030, r = 0.166; respectively). It was also found that tear osmolarity was strongly and inversely correlated
with biomicroscopic BUT and topographic NI-BUT values (p< .001, r = −0.554 and p< .001, r = −0.528;
respectively). There was no significant correlation between Schirmer test and tear osmolarity.
Conclusion: It is important to use a sensitive, reproducible and non-invasive method in the evaluation of tear
functions. We think that the objective and noninvasive topographic NI-BUT measurements and the minimally
invasive osmolarity measurements should be used more frequently in practice because they are correlated with
the measurements obtained by invasive methods and should be widespread in clinics.
Keywords: Dry eye, break-up time, non-invasive break-up time, osmolarity test, Schirmer test
INTRODUCTION
The tear film layer is defined as a bilayer structure in
the form of muco-aqueous gel, in which mucus and
aqueous structure are combined.
1
The muco-aqueous
layer plays an antimicrobial role with IgA antibo-
dies, lysozyme, lactoferrin, and betalysins. In addi-
tion, growth factor ratios that play a role in
conjunctival and corneal epithelial repair are high
in this layer.
2
The optical role of the muco-aqueous layer by flat-
tening the tear film surface is very important.
3
Because of the effect of the tear film on visual quality
and contrast sensitivity, it causes early symptoms in
any condition affecting the tear (atopic conjunctivitis,
blepharitis, dry eye syndrome, etc.).
1
Accurate assessment of tear function is very impor-
tant in diagnosis and in evaluating the treatment.
Numerous tests have been developed to better under-
stand and evaluate the tear film and its optical role.
Tear assessment by corneal topography, interferome-
try, evaluation of tear meniscus, measurement of tear
osmolarity and aberrometry are among the tests that
are included in our clinical practice with technology.
Of these tests, easy to apply, non-invasive, fast and
inexpensive methods are more preferred.
4
Received 17 September 2019; accepted 12 February 2020; published online 18 March 2020.
Correspondence: Kemal Ozulken, TOBB ETU Medical School Hospital, Ankara, Turkey. E-mail: kemalozulken@hotmail.com
Seminars in Ophthalmology, 2020; 35(1): 78–85
© Taylor & Francis
ISSN: 0882-0538 print / 1744-5205 online
DOI: https://doi.org/10.1080/08820538.2020.1730916
78
This study focuses on the tear film, which plays
a vital role in maintaining healthy visual function and
protecting the corneal surface. In our study, we aimed
to compare the recently developed non-invasive tear
function test [noninvasive break-up time (NI-BUT)]
with the other conventional tear function tests and
to investigate the correlation between them.
METHODS
This study was performed at the ophthalmology
department of TOBB ETU Hospital with approval
granted by the local research ethics committee
(KAEK-118/065). All procedures were performed in
accordance with the ethical standards of the Helsinki
Declaration for human subjects and written informed
consent was obtained from each patient before the
examination. In this study, the right eyes of 170 sub-
jects who presented to the ophthalmology clinic with
dry eye complaints such as burning, stinging and
foreign body sensation were included. To evaluate
the tear quality of the patients, firstly NI-BUT mea-
surements were performed using the improved tear
analysis program of Sirius topography (Costruzione
Strumenti Ophthalmici, Florence, Italy), which works
with Scheimplug-Placido disc system. Then, tear
osmolarities of the patients were measured with the
TearLab Osmolarity System (TearLab Corporation,
California, USA). Topical anesthesia (proparacaine
HCl, Alcaine 0.5%, Alcon) assisted type I Schirmer
test (TearFlo, HUB Pharmaceuticals LLC, USA) and
topical anesthesia-assisted fluorescein break-up time
(BUT) were last applied to all patients to avoid other
measurements being affected. All measurements were
performed at the same time of day (between 10 a.m.
and 12 p.m.) as corneal hydration shows diurnal
variation.
Patients with ocular surface diseases and irregula-
rities, previous ocular trauma, acute corneal or con-
junctival infection, glaucoma, ocular surgery within
one-year, systemic disease or medications that would
affect the ocular surface and inadequate cooperation
during the examination were excluded from the
study.
Measurements
NI-BUT with Sirius Topography
The purpose of the analysis of the tear film is to
evaluate the integrity of the tear film over the anterior
corneal surface over time. The tear layer tends to thin
and break between each eye opening and closing.
This break-up is examined by video recording by the
projection of the Placido disc. Any deformation of the
tear film causes the breakage of the disc rings. The
system evaluates the received video image in real
time and takes measurements without user interven-
tion. With this method, the NI-BUT value, which
represents the average time to break-up of the tear
film, is measured. The map is colored according to the
time obtained. The yellow color indicates a slight
separation that is not visible or difficult to see with
the naked eye, while the red tones indicate a more
severe separation.
Tear Osmolarity Measurement
Tear osmolarity was recorded using the TearLab
Osmolarity System (TearLab Corporation, California,
USA). The gently placed osmolarity test pen removes
50 nL of tears from the tear meniscus in the lateral
canthus. The tear sample is then placed in the device
where the osmolarity is measured in mOsm/L. In
normal subjects, the average tear film osmolarity
values range from 270 to 315 mOsm/L, with an aver-
age of 300 mOsm/L in general.
5
Based on this informa-
tion, we divided the subjects into two groups as tear
osmolarity values above and below 315 mOsm/L.
Schirmer Test
Type I Schirmer test with topical anesthesia was
applied to all participants. Standardized strips of filter
paper were inserted at the lower-lid margin at the
junction of the middle and temporal third of both
eyes during Schirmer tests after topical anesthesia
with proparacaine and drying of the lower fornix.
After Schirmer paper was inserted, the patient was
asked to look straight ahead and blink normally. After
five minutes, the paper was taken and the measure-
ment was recorded.
Fluorescein Break-up Time (BUT) by Biomicroscopy
One drop of topical anesthesia and fluorescein mix-
ture (proparacaine 0.375% and sodium fluorescein
0.25% mixture) were instilled into the eye of all parti-
cipants. The patient was then asked to blink several
times to spread the fluorescein over the entire corneal
surface. Under the biomicroscope, the tear layer was
evaluated with the help of cobalt blue filter and wide
base light. The first black spot or break-up time after
the last eyelid opening was calculated. A fluorescein
BUT of above 10 seconds is considered normal,
between 5 and 9 seconds indicates light dry eye,
and less than 5 seconds indicates a severe dry eye.
6
Statistical Analysis
Descriptive data were presented as the mean ± stan-
dard deviations, frequency distributions, and percen-
tages. The Shapiro–Wilk test was used to assess the
conformity of the data to normal distribution. The
Wilcoxon test was used for the analysis of data not
Seminars in Ophthalmology 79
© 2020 Taylor & Francis
showing normal distribution and the Mann–Whitney
U test was used for data with normal distribution.
Data were analyzed using SPSS Windows 20.0 soft-
ware (IBM, Armonk, New York, USA). A value of
p< .05 was considered statistically significant.
Spearman correlation was used to compare methods.
RESULTS
One hundred and seventy eyes of 170 subjects were
examined. Thirty-eight (22.4%) of the cases were male
and 132 (77.6%) were female. The mean age was
37.85 ± 8.86 years (18–55 years). The mean refractive
error of the participants was spheric: −0.67 ± 1.81 (−10
to +3) diopter (dpt), cylindrical: −0.35 ± 0.44 (−2.00 to
+2.00) dpt, mean k1 value 42.42 ± 1.57 dpt (37.01–-
45.98 dpt), the mean k2 value was calculated as
44.06 ± 1.48 dpt (40.42–48.35 dpt).
When the tear analysis values of all participants were
examined, the mean Schirmer test was 15.32 ± 6.05 mm/
5min(3–30 mm/5 min), the mean tear osmolarity was
292.93 ± 9.30 mOsm/L (270 to 322 mOsm/L), the mean
NI-BUT value was 9.59 ± 4.37 sec (1.40–17.10 sec), and
the mean biomicroscopic BUT was 8.98 ± 3.79 sec (2.-
00–15.00 sec) (Table 1).
No correlations were observed between spherical
and cylindrical refractive errors and any tear para-
meters (p> .05). There was no statistically significant
correlation between k1 and k2 values and any tear
parameters (p> .05).
When the correlations between Schirmer test and
BUT and NI-BUT values were examined, it was found
that Schirmer test was statistically correlated with
biomicroscopic BUT and topographic NI-BUT values
(p= .019, r = 0.180 and p= .030, r = 0.166; respectively)
(Figures 1 and 2). On the other hand, there was no
significant correlation between Schirmer test and tear
osmolarity (p= .969, r = 0.03).
When the correlations between tear osmolarity and
BUT and NI-BUT values were examined, it was found
that tear osmolarity was strongly and inversely corre-
lated with biomicroscopic BUT and topographic NI-
BUT values (p< .001, r = −0.554 and p< .001, r = −0.528;
respectively) (Figures 3 and 4). When the correlations of
tear osmolarity values below and above 315 mOsm/L
with topographic NI-BUT measurements were exam-
ined, tear osmolarity values were correlated with topo-
graphic NI-BUT measurements in both groups (p< .001,
r=−0.467 and p= .010, r = −0.377; respectively)
(Figure 5a,b). BUT and NI-BUT measurements were
quite consistent with each other (p< .001, r = 0.947).
Figure 6 shows the Bland–Altman graph of BUT mea-
sured by biomicroscopy and NI-BUT measured by Sirius
topography.
TABLE 1. Characteristics of the study subjects.
Mean ± SD Min-Max
Age (years) 37,85 ± 8,86 18-55
Schirmer’s Test (mm/5 mn) 15.32 ± 6.05 3-30
Tear Osmolarity (mOsm/L) 292.93 ± 9.30 270-322
Sirius Topography NI-BUT (second) 9.59 ± 4.37 1.40–17.10
Biomicroscopy BUT (second) 8.98 ± 3.79 2-15
SD: Standart Deviation, Min: minimum, Max: maximum,
mm: milimeter, mn: minute, mOsm/L: miliosmol/liter, NI-
BUT: Non-Invazive Break-Up Time.
FIGURE 1. Correlation of Schirmer test with topographic NI-
BUT values.
FIGURE 2. Correlation of Schirmer test with biomicroscopic
BUT values.
80 K. Ozulken et al.
Seminars in Ophthalmology
All participants were divided into four groups
according to Schirmer test results (<5 mm,
6–10 mm, 11–20 mm, >21 mm) (Table 2). In all
groups, three measurement methods were compared
with each other. Positive correlations between bio-
microscopic BUT and topographic NI-BUT were
found to be significant in all groups except
Schirmer test less than 5 mm.
DISCUSSION
The optical quality of the retinal image is the result of
light passing through the ocular structures. Since the
tear film is the first system to affect the transmission
of light, the optical quality of the eye depends on the
homogeneity of the tear.
7
As changes in the tear layer
give early clinical findings, cases with dry eye and
FIGURE 3. Correlation of tear osmolarity test with biomicroscopic BUT values.
FIGURE 4. Correlation of tear osmolarity test with topographic NI-BUT values in all participants.
Seminars in Ophthalmology 81
© 2020 Taylor & Francis
ocular surface problems constitute the most common
patient population in the outpatient clinics.
4
Tear tests are the most commonly used tests during
a routine examination. Therefore, it is important to use
a sensitive, reproducible and non-invasive method in
the evaluation of tear functions.
5
Diagnostic tests used
to assess tear stability, ocular staining, and reflex tear
production rate should be prioritized according to
patients’symptoms.
8
The recommended test order
according to the International Dry Eye Workshop
(DEWS) is; clinical history, symptom questionnaire,
BUT with fluorescein, degree of ocular surface stain-
ing, Schirmer tests, tests evaluating meibomian gland
pathology, and subsequent transition to other available
tests (DEWS 2007).
8
In this study, we aimed to com-
pare the most frequently used tests with advanced tear
analysis performed by the Sirius topography device.
There are many studies comparing the most fre-
quently used Schirmer test and osmolarity test in the
literature to evaluate the severity of dry eye disease.
Szalai et al.
9
reported that there was no correlation
between tear osmolarity measurement and other clas-
sical dry eye tests and this was not distinguishing
between healthy and dry eye subjects. Aktas et al.
10
reported that tear osmolarity was higher and corneal
sensitivity was lower in the smoker population, but
they did not observe a significant change in the
Schirmer test. Contrary to these studies, Suzuki et al.
11
found a negative and statistically significant correlation
between Schirmer test and tear osmolarity in their
study in which they evaluated tear osmolarity in deter-
mining the severity of dry eye disease. Utine et al.
12
also found a statistically significant negative correla-
tion between Schirmer test and tear osmolarity in
patients with primary Sjögren syndrome. In our
study, no significant correlation was observed between
FIGURE 5. Correlation of tear osmolarity test with topographic NI-BUT values in subjects who had tear osmolarity value below 315
mOsm/L (Figure 5a) and above 315 mOsm/L (Figure 5b).
FIGURE 6. Bland–Altman graph of BUT measured by biomi-
croscopy and NI-BUT measured by Sirius topography.
TABLE 2. Comparison of the other three methods in participants grouped according to Schirmer test.
Schirmer’s Test
(The number of participants)
<5 mm (22) 6–10 mm (31) 11–20 mm (107) >21 mm (10)
Tear Osmolarity/Biomicroscopy BUT p < .001 p < .001 p < .001 p < .001
Tear Osmolarity/Sirius Topography
NI-BUT
p < .001 p < .001 p < .001 p < .001
Biomicroscopy BUT/Sirius Topography NI-BUT p = .294* p = .031 p < .001 p = .030
NI-BUT: Non-Invazive Break-Up Time, *Statistically nonsignificant change, mm: millimeter.
82 K. Ozulken et al.
Seminars in Ophthalmology
tear osmolarity and Schirmer test. Therefore, we
recommend combining with the most possible mea-
surement methods in the diagnosis and treatment of
dry eye.
As it is known, the fact that tear osmolarity is very
valuable for the diagnosis and treatment of dry eye.
9
The advantages of Tearlab, which measures osmolar-
ity with electrical impedance technique; it can mea-
sure with low tear volume (0.05 L), no transfer of the
sample is required and results in a short time of
30 seconds for both eyes. Its disadvantages are mini-
mally invasive and costly due to the need for consum-
ables per measurement.
4
Lemp et al.
13
reported that
osmolarity was higher in dry eye patients than in the
normal population. In another study with osmolarity,
it was stated that the decrease in osmolarity is a good
predictor of dry eye treatment efficacy.
14
Tomlinson
et al.
15
reported that tear osmolarity was superior to
Schirmer’s test and Rose Bengal staining for the diag-
nosis of dry eye. In addition, different studies have
shown that unlike Schirmer test, tear osmolarity is not
affected by age, race, sex, menstrual cycle or oral
contraceptive use.
16–18
Derakhshan et al.
19
showed
that tear osmolarity measurement was better corre-
lated with dry eye symptoms and glycemic control
than Schirmer test and biomicroscopic BUT measure-
ment in diabetic patients. Erdur et al.
20
examined dry
eye symptoms in patients with vitiligo and showed
that tear osmolarity measurement was more consis-
tent with the symptoms of the patients than the
Schirmer test. In the light of these results, the tear
osmolarity test is more correlated with the other
tests we evaluated in our study than the Schirmer
test and we think that tear osmolarity test is more
valuable than classical Schirmer test.
When all participants were classified according to
Schirmer test and osmolarity, we observed that NI-
BUT and BUT values were not correlated with
Schirmer test in the group with Schirmer test less
than 5 mm. In the light of these results, as suggested
by Tomlinson et al.
15
, we think that the Schirmer test
should be supported by combined tests for precise
accuracy in the diagnosis and treatment of dry eye.
When we compared tear osmolarity with topo-
graphic NI-BUT, we found a statistically significant
negative correlation. According to the DEWS 1
report
7
, tear osmolarity was defined as one of the
two core mechanisms of dry eye disease, regardless
of etiology. Based on the information in the DEWS 2
report
5
, the average tear film osmolarity values in
normal subjects ranged from 270 to 315 mOsm/L,
we considered patients with tear osmolarity above
315 mOsm/L as having dry eye disease. When we
investigated the correlations between NI-BUT mea-
surements of subjects with tear osmolarity values
below and above 315 mOsm/L, we found correlations
between NI-BUT measurements and tear osmolarity
values of subjects in both groups. In the light of this
result, it can be said that NI-BUT measurement is
a valuable test in diagnosing dry eye disease. In addi-
tion, for the NI-BUT test measurements, we believe
that cut-off values should be determined in larger
studies in order to detect dry eye disease as in the
tear osmolarity test. Tear osmolarity and Sirius topo-
graphy tear analysis results are compatible with each
other, indicating that they can be used interchange-
ably because they are fast and reproducible in out-
patient conditions. We also think that they are more
advantageous because they are fast and reproducible
in polyclinic conditions. However, because the tearlab
device is minimally invasive, costly and only used in
the diagnosis and treatment of dry eye disease, we
think that the osmolarity measurements obtained by
this device are not superior to the NI-BUT measure-
ment obtained with the topography device used in
the diagnosis and treatment of many eye diseases.
In our study, it was observed that the biomicro-
scopic BUT and topographic NI-BUT values were
very close to each other and the measurements were
very consistent with each other. Biomicroscopic BUT
does not require precision to identify extreme cases
but is subject to operator error since the amount of
fluorescein introduced each time should be standard.
There have been studies evaluating and comparing
NI-BUT measurements with devices other than the
Sirius topography device. Hong et al.
21
observed
that NI-BUT values obtained in Keratograph 5M®
(Oculus, Wetzlar, Germany) were significantly lower
in both healthy subjects and dry eye patients com-
pared to biomicroscopic BUT (3.2 ± 2.3 seconds and
5.2 ± 3.4 seconds; P< .001). In a study by Gulati
et al.
22
, NI-BUT values obtained in Keratograph
5M® (Oculus, Wetzlar, Germany) were more objec-
tive than classical BUT with fluorescein and empha-
sized the advantage of taking measurements without
fluorescein. Downie et al.
23
reported that measure-
ments taken with Placido disc videokeratography
(E300 corneal topography, Medmont International
Pty Ltd., Victoria, Australia) were a valuable marker
in dry eye patients and showed high sensitivity (82%)
and specificity (94%) compared to biomicroscopic
BUT. In the light of these results, we can say that NI-
BUT measurements obtained with topography device
are more advantageous than classical biomicroscopic
BUT measurements because it is more practical and
does not require fluorescein paper and topical
anesthesia.
When the correlations between keratometric values
and tear parameters analysis of the patients were
examined, no statistically significant relationships
were found between k1 and k2 values and tear tests.
In contrast to our study, Saraç et al.
24
reported that the
biomicroscopic BUT value was significantly lower in
the group with high keratometric value in keratoconus
Seminars in Ophthalmology 83
© 2020 Taylor & Francis
patients. Therefore, we can conclude that NI-BUT mea-
surements are not affected in patients with low or high
keratometry values.
One of the limitations of our study is the lack of
repeatability of the measurement methods used in
our study. Other limitations of our study are that
the tear meniscus measurement was not included in
the study, the dry eye symptom questionnaire was
not administered to the participants and the results
of this survey were not compared with the measure-
ments. In the following studies, the evaluation of all
the methods used in clinical practice will give more
objective results in terms of their advantages and
disadvantages.
In conclusion, we believe that objective methods
such as Sirius topography tear analysis should be
used more frequently in practice because it is corre-
lated with invasive methods. We anticipate that objec-
tive methods, which provide more qualified data that
we can standardize both in the follow-up and com-
parison of patients, will be in the forefront in the
future. In addition, we think that corneal tear map-
ping according to the etiology may be beneficial to the
literature in the following studies.
DECLARATION OF CONFLICTING
INTERESTS
The authors declared no potential conflicts of interest
with respect to the research, authorship, and/or pub-
lication of this article.
FUNDING
The author(s) received no financial support for the
research, authorship, and/or publication of this
article.
ORCID
Kemal Ozulken http://orcid.org/0000-0001-9963-
7607
Kemal Tekin http://orcid.org/0000-0002-7461-6129
Tarkan Mumcuoğlu http://orcid.org/0000-0002-
1079-1964
REFERENCES
1. Cher I. A new look at lubrication of the ocular surface:
fluid mechanics behind the blinking eyelids. Ocul Surf.
2008;6:79–86. doi:10.1016/S1542-0124(12)70271-9.
2. Gachon A, Lacazette E. Tear lipocalin and the eye’s front
line of defence. Br J Ophthalmol.1998;82:453–455.
doi:10.1136/bjo.82.4.453.
3. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The
international workshop on meibomian gland dysfunction:
report of the subcommittee on anatomy, physiology, and
pathophysiology of the meibomian gland. Invest
Ophthalmol Vis Sci.2011;52:1938–1978. doi:10.1167/
iovs.10-6997c.
4. Sullivan BD, Whitmer D, Nichols KK, et al. An objective
approach to dry eye disease severity. Invest Ophthalmol Vis
Sci.2010;51:6125–6130. doi:10.1167/iovs.10-5390.
5. Willcox MDP, Argüeso P, Georgiev GA, et al. TFOS DEWS
II tear film report. Ocul Surf.2017;15:366–403. doi:10.1016/j.
jtos.2017.03.006.
6. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocu-
lar surface disease in glaucoma patients. J Glaucoma.
2008;17:350–355. doi:10.1097/IJG.0b013e31815c5f4f.
7. Hamam H. A new measure for optical performance. Optom
Vis Sci.2003;80:175–184. doi:10.1097/00006324-200302000-
00014.
8. International Dry Eye Workshop (DEWS) Definition and
Classification. The definition and classification of dry eye
disease: report of the definition and classification subcom-
mittee of the international dry eye workshop. Ocul Surf.
2007;5:75–92. doi:10.1016/S1542-0124(12)70081-2.
9. Szalai E, Berta A, Szekanecz Z, Szucs G, Modis L Jr. Evaluation
of tear osmolarity in non-Sjögren and Sjögren syndrome dry
eye patients with the TearLab system. Cornea.2012;31:867–871.
doi:10.1097/ICO.0b013e3182532047.
10. AktaşS, Tetikoğlu M, Koçak A, et al. Impact of smoking
on the ocular surface, tear function, and tear osmolarity.
Curr Eye Res.2017;42:1585–1589. doi:10.1080/027
13683.2017.1362005.
11. Suzuki M, Massingale ML, Ye F, et al. Tear osmolarity as
a biomarker for dry eye disease severity. Invest Ophthalmol
Vis Sci.2010;51:4557–4561. doi:10.1167/iovs.09-4596.
12. Utine CA, Bıçakçıgil M, Yavuz S, Çiftçi F. Tear osmolarity
measurement in dry eye related to primary Sjögren’s syn-
drome. Curr Eye Res.2011;36:683–690. doi:10.3109/
02713683.2011.571357.
13. Lemp MA, Bron AJ, Baudouin C, et al. Tear osmolarity in
the diagnosis and management of dry eye disease. Am
J Ophthalmol.2011;151:792–798. doi:10.1016/j.ajo.2010.
10.032.
14. Baudouin C, Cochener B, Pisella P-J, et al. Randomized,
phase III study comparing osmo-protective carboxy-
methylcellulose with sodium hyaluronate in dry eye
disease. Eur J Ophthalmol.2012;22:751–761. doi:10.5301/
ejo.5000117.
15. Tomlinson A, Khanal S, Ramaesh K, Diaper C,
McFadyen A. Tear film osmolarity: determination of
a referent for dry eye diagnosis. Invest Ophthalmol Vis Sci.
2006;47:4309–4315. doi:10.1167/iovs.05-1504.
16. Caffery B, Chalmers RL, Marsden H, et al. Correlation of
tear osmolarity and dry eye symptoms in convention
attendees. Optom Vis Sci.2014;91:142–149. doi:10.1097/
OPX.0000000000000130.
17. Yeh TN, Graham AD, Lin MC. Relationships among tear
film stability, osmolarity, and dryness symptoms. Optom Vis
Sci.2015;92:264–272. doi:10.1097/OPX.0000000000000649.
18. Chen SP, Massaro-Giordano G, Pistilli M, Schreiber CA,
Bunya VY. Tear osmolarity and dry eye symptoms in
women using oral contraception and contact lenses.
Cornea.2013;32:423–428. doi:10.1097/
ICO.0b013e3182662390.
19. Derakhshan A, Abrishami M, Khajedaluee M,
Omidtabrizi A, Moghaddam SG. Comparison between
tear film osmolar concentration and other tear film
function parameters in patients with diabetes mellitus.
Korean J Ophthalmol.2019;33:326–332. doi:10.3341/
kjo.2013.0146.
84 K. Ozulken et al.
Seminars in Ophthalmology
20. Erdur Karaman S, AydınR,BaleviA,OzsutcuM,
Kocabora MS. Dry eye assessment in patients with vitiligo.
Cornea.2018;37:412–415. doi:10.1097/ICO.0000000000001469.
21. Hong J, Sun X, Wei A, et al. Assessment of tear film stability in
dry eye with a newly developed keratograph. Cornea.
2013;32:716–721. doi:10.1097/ICO.0b013e3182714425.
22. Gulati S, Jain S. Ocular pharmacology of tear film, dry eye,
and allergic conjunctivitis. Handb Exp Pharmacol.
2017;242:97–118.
23. Downie LE. Automated tear film surface quality
breakup time as a novel clinical marker for tear hyper-
osmolarity in dry eye disease. Invest Ophthalmol Vis Sci.
2015;
56:7260–7268. doi:10.1167/iovs.15-17772.
24. Saraç Ö, Uysal S, Gürdal C. Keratokonus Hastalarında
GözyaşıFonksiyon Testleri ve Alt GözyaşıMenisküs
Yüksekliğinin Değerlendirilmesi. Turk J Ophthalmol.
2012;42:249–252.
Seminars in Ophthalmology 85
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