Accepted Manuscript

Influence of Nasal Tear Osmolarity on Ocular Symptoms Related to Dry Eye Disease

Ho Chul Yi, Yoon Pyo Lee, Young Joo Shin

PII: S0002-9394(18)30066-7
DOI: 10.1016/j.ajo.2018.02.008
Reference: AJOPHT 10419

To appear in: American Journal of Ophthalmology

Received Date: 28 October 2017

Revised Date: 9 February 2018
Accepted Date: 11 February 2018

Please cite this article as: Yi HC, Lee YP, Shin YJ, Influence of Nasal Tear Osmolarity on Ocular
Symptoms Related to Dry Eye Disease, American Journal of Ophthalmology (2018), doi: 10.1016/
j.ajo.2018.02.008.

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ABSTRACT

Purpose: To investigate relationships between local tear osmolarity and tear film

characteristics and dry eye disease (DED) symptoms.

Design: Prospective, cross-sectional, observational study.

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Methods: Nasal and temporal tear osmolarity were measured in subjects with DED. The

difference between nasal and temporal tears (OSM difference) was then calculated. Ocular

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symptoms were evaluated and tear break-up time (TBUT), corneal fluorescein staining score

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(CFSS), eyelid hyperemia, and tear production were measured. Correlations between DED

symptoms and nasal tear osmolarity, temporal tear osmolarity, OSM difference, and tear film

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characteristics were evaluated using Pearson’s correlation analyses. Subjects were divided
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into three groups based on OSM difference: the temporal group had a temporal osmolarity >

nasal osmolarity, the nasal group had a temporal osmolarity < nasal osmolarity and the equal
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group had an OSM difference < 10 mOsm/L.

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Results: Forty-eight eyes of 48 subjects were included. Eleven eyes were in the temporal

group, 17 eyes were in the equal group, and 20 eyes were in the nasal group. Temporal
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osmolarity, nasal osmolarity, and OSM difference were not correlated with TBUT, CFSS, lid
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hyperemia, or tear production. Nasal tear osmolarity was correlated with cold sensitivity

frequency (r = 0.298, p = 0.040), foreign body sensation severity (r = 0.293, p = 0.043), and
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light sensitivity severity (r = 0.293, p = 0.043). Additionally, OSM difference was correlated
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with daily symptom frequency (r = 0.339, p = 0.019).

Conclusions: Nasal tear osmolarity and OSM difference play an important role in DED

symptoms. Lid hyperemia, TBUT, CFSS, and tear secretion volume are not significantly

affected by tear osmolarity. It is important to measure both nasal and temporal tear osmolarity

when evaluating patients with DED.

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Influence of Nasal Tear Osmolarity on Ocular Symptoms Related to Dry Eye Disease

Ho Chul Yi, Yoon Pyo Lee, Young Joo Shin

Department of Ophthalmology, Hallym University Medical Center, Hallym University

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College of Medicine, Seoul, Korea

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Short title: Nasal Tear Osmolarity on Symptoms Related to Dry Eye Disease

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Corresponding Author:

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*Young Joo Shin, MD,
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Department of Ophthalmology, Hallym University Medical Center, Hallym University
College of Medicine, 1 Shingil-ro, Youngdeungpo-gu, Seoul 07441, Korea
Phone: 82-2-829-5193 Fax: 82-2-848-4638
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e-mail: schinn@hanmail.net
The authors have no financial interest regarding the subject matter of this manuscript.
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This study was supported by the National Research Foundation (NRF) grant (NRF-
2015R1D1A1A09058505) funded by the Korea government.
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INTRODUCTION

Dry eye disease (DED) is characterized by ocular symptoms and tear film instability.1 Tear

film evaluation methods include tear break-up time (TBUT), tear osmolarity, and tear

secretion measurement.2 Tear osmolarity is an important parameter in eyes with DED, has

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diagnostic value,3 and is involved in the pathogenesis of dry eye syndrome. In fact, an

increase in tear osmolarity is thought to be a hallmark of DED.3 Many studies have reported

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that no clinical sign correlates with symptoms in patients with DED,4-7 but that tear

osmolarity is reflective of ocular surface health.8 Therefore, tear osmolarity is useful for

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diagnosing DED.8

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Ocular surface pain is caused by tear hyperosmolarity via corneal cold
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thermoreceptors.9 Impairment of the lacrimal functional unit compromises tear film integrity

and function.10,11 The lacrimal functional unit consists of the lacrimal glands, cornea,
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conjunctiva, meibomian glands, and lacrimal puncta.11 Tears are secreted by the lacrimal
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glands on the temporal side of the eye and move nasally, across the ocular surface, to the

punctum, where they drain out of the eye.10 Blinking causes secreted tears to mix with
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meibum, evaporate into the air, and spread across the entire ocular surface.10 Therefore,
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composition of initially secreted tears can change and widely varies across the ocular surface.

Since tears are secreted on the temporal side of the ocular surface,12 temporal tear osmolarity
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reflects osmolarity of initial tears secreted from lacrimal glands. Nasal osmolarity may reflect
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the final, altered tear product after initial tears are modified as they pass over the ocular

surface and cause corneal symptoms. Exposure of the cornea to altered tear is important

because symptoms are closely linked to corneal cold thermoreceptors. Therefore, nasal tear

osmolarity is thought to represent the overall tear film. Nevertheless, most studies have only

examined temporal osmolarity and did not consider tear composition changes across the tear

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film. This study evaluates the relationship between the tear film, including local tear film

differences, and ocular surface symptoms of DED.

METHODS

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This prospective, observational study protocol was reviewed and approved by the

Institutional Review Board of Hallym University Medical Center, Seoul, Korea (IRB No:

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2016-06-73) and registered at ClinicalTrials.gov: NCT03364322. All study conduct adhered

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to the tenets of the Declaration of Helsinki and all subjects provided written informed consent

to participate in the study.

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Study subjects

Patients with ocular discomfort related to DED who visited the Hallym University Kangnam
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Sacred Heart Hospital between June 2016 and June 2017 were considered for enrollment.
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Subjects who were elderly (≥80 years old) or had an autoimmune disease (e.g., Sjögren’s

syndrome and systemic lupus erythematosus) were excluded from participation. Patients
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without clinical dry eye signs were excluded from our study to discriminate between DED
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pain and neuropathic pain. Patients with chronic pain syndrome, fibromyalgia, chronic

headache, depression, and history of herpes zoster ophthalmicus with possible neuropathic
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pain were also excluded.

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Study examinations and measurements

All subjects underwent measurement of nasal and temporal tear osmolarity using the TearLab

system (TearLab Co., San Diego, CA). One eye from each patient was randomly selected for

inclusion in the study. Tear samples were obtained from the nasal and temporal conjunctiva in

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the same eye. Differences between nasal and temporal tear osmolarity (OSM difference) were

calculated by subtracting temporal from nasal tear osmolarity. Tear break-up time (TBUT),

corneal fluorescein staining score (CFSS), eyelid hyperemia, and tear production (Schirmer’s

test without anesthesia) were also measured. Ocular symptoms were evaluated using the

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Ocular Surface Disease Index (OSDI), the visual analogue pain score (VAS), and a modified

Standardized Patient Evaluation of Eye Dryness (SPEED). A higher OSDI (0–100 points),

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VAS (0–10 points), or SPEED score indicates a higher level of discomfort. The impact of

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ocular symptoms on daily life and frequency of ocular symptoms were evaluated for the

following symptoms: cold sensitivity, foreign body sensation, light sensitivity, and eye

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fatigue. The SPEED questionnaire was scored for both frequency of symptoms (0 = no
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symptoms, 1 = sometimes, 2 = often, and 3 = constant) and severity of symptom/impact on

daily life (0 = no symptoms, 1 = tolerable but not uncomfortable, 2 = uncomfortable but does
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not interfere with my day, 3 = bothersome and interferes with my day, and 4 = intolerable and
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unable to perform my daily tasks).

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Data Analyses
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Subjects were divided into three groups based on OSM difference. The temporal group had a

temporal tear osmolarity that was at least 10 mOsm/L higher than nasal tear osmolarity. The
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nasal group had a nasal tear osmolarity that was at least 10 mOsm/L higher than temporal
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osmolarity. The equal group had an OSM difference that was less than 10 mOsm/L.

Tear film measurements and ocular symptom scores were evaluated in and compared

between the three study groups. Correlations between DED symptoms and tear osmolarity

measurements and OSM differences were examined using Pearson’s correlation analyses.

Mann-Whitney U-tests were used to examine differences in parameters among groups. All

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statistical analyses were performed using Statistical Package for Social Sciences

(SPSS)software (version 24, PSS, Inc, Chicago, IL, USA). Statistical significance was

defined as P < 0.05.

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RESULTS

A total of 116 eyes of 116 patients were considered for enrollment, but only 48 eyes of 48

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patients met all study inclusion criteria. Mean subject age was 53.96 ± 13.17 years and 38

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subjects (79.16%) were men. Mean TBUT was 4.58 ± 2.49 s, mean tear secretion was 8.29 ±

8.90 mm, CFSS was 0.26 ± 0.59, and eyelid hyperemia was 1.87 ± 0.82. The mean OSDI

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score was 33.78 ± 22.68 and mean VAS was 2.13 ± 2.31. Additionally, temporal tear
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osmolarity was 305.96 ± 16.11 mOsm/L (range: 285–360 mOsm/L), nasal tear osmolarity

was 308.69 ± 15.91 mOsm/L (range: 285–360 mOsm/L), and OSM difference was 2.73 ±
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22.301 mOsm/L (range: -50–51 mOsm/L).

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Nasal and temporal tear osmolarities were not correlated with TBUT, CFSS, eyelid

hyperemia, or tear secretion volume (Figures 1 and 2, Table 1). They were also not correlated
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with OSDI score, VAS score, symptom daily frequency, or daily life impact. However, nasal
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tear osmolarity was correlated with daily frequency of cold sensitivity (r = 0.298, p = 0.040),

severity of foreign body sensation (r = 0.293, p = 0.043), and severity of light sensitivity (r =
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0.293, p = 0.043). Temporal tear osmolarity was not correlated with any of these symptom
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measures. Similarly, the OSM difference was not correlated with TBUT, CFSS, eyelid

hyperemia, or tear secretion volume (Figure 3). It was also not correlated with OSDI score,

VAS score, or the impact on daily life. However, the OSM difference was significantly

correlated with the daily frequency of symptoms (r = 0.339, p = 0.019).

Subjects were divided into nasal, temporal, and equal OSM difference subgroups as

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described above. Eleven eyes (22.9%) classified into the temporal group, 17 eyes (35.4%)

were classified into the equal group, and 20 eyes (41.7%) were classified into the nasal group

(Table 1). The TBUT, CFSS, eyelid hyperemia, and tear secretion volume were not different

among groups (Figure 4). Additionally, OSDI score, VAS score, symptom daily frequency,

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and impact on daily life were not significantly different among groups. However, severity of

fatigue (p = 0.045) and pain (p = 0.017) were higher in the nasal group than in the equal

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group.

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DISCUSSION

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Tear osmolarity has been reported to be a hallmark of DED and is thought to be useful in
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diagnosing the condition.13 Tear osmolarity variability has been shown to be larger in DED

patients than in normal controls.14 However, previous studies measured tear osmolarity at the
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temporal conjunctiva and did not consider possible tear osmolarity variations across the
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ocular surface. The current study evaluated both local tear osmolarity and showed that only

35.4% of subjects had equal (<10 mOsm/L difference) temporal and nasal tear osmolarity.
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Therefore, the relatively large difference between temporal and nasal tear osmolarity should
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not be ignored. In a previous study, it has been reported that TearLab osmolarity

measurements are highly variable in healthy patients and in those with blepharitis and
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Sjögren’s syndrome; this makes the clinical interpretation of measurements unclear.15

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However, that study was limited in that systemic medication use, which can influence

osmolarity, was not controlled.15 In contrast, other studies have reported that tear osmolarity

is very stable in healthy people16 and very useful for DED diagnosis in patients with or

without Sjögren syndrome.8,17,18 A large portion of the variability has been attributed to blink-

to-blink tear film instability in eyes with DED.19

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The current study showed that nasal tear osmolarity is significantly correlated with

ocular symptoms, including cold sensitivity, foreign body sensation, and light sensitivity.

Cold sensitivity bas been reported to be enhanced in response to hyperosmolar tears and to

result in ocular discomforts in DED.20,21 Additionally, tear hyperosmolarity can result in tear

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film instability, which results in foreign body sensation and ocular irritation.22 Light

sensitivity associated with DED is caused by trigeminal nerve ending stimulation on the V1

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branch.23

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Tear osmolarity is usually measured in the temporal conjunctiva. However, tears

secreted from lacrimal glands pass over the ocular surface and are modified by conjunctival

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and Meibomian gland secretions.10 Conjunctival goblet cells secrete mucin and conjunctival
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accessory lacrimal glands constantly produce the aqueous component of tears.24 Additionally,

eyelid meibomian glands secrete neutral sterols and wax esters into tears.24 As a result, tear
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composition can differ between the initial tear secreted onto the temporal ocular surface and
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the ultimate tear film present on the nasal ocular surface. Therefore, nasal tear osmolarity is

likely a better representation of overall tear quality and evaporation resistance because it
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reflects conjunctival and meibomian gland tear film modifications.

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In conclusion, TBUT, CFSS, eyelid hyperemia, and tear secretion volume were not

significantly influenced by tear osmolarity. However, nasal tear osmolarity was significantly
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correlated with DED symptoms. Therefore, both nasal and temporal tear osmolarity should be
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measured when evaluating DED patients.

Acknowledgments/Disclosure

a. Funding/Support: This study was supported by the National Research Foundation (NRF)

grant (NRF-2015R1D1A1A09058505) funded by the Korea government.

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b. Financial Disclosures: the following authors have no financial disclosures: Ho Chul Yi,

Yoon Pyo Lee, Young Joo Shin. All authors attest that they meet the current ICMJE criteria

for authorship.

c. Other Acknowledgements: None

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on human tear fluid osmolarity. Curr Eye Res 2013;38(4):428-436.
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associated with Sjogren disease. Ocul Surf 2015;13(2):118-132.

18. Mathews PM, Karakus S, Agrawal D, Hindman HB, Ramulu PY, Akpek EK. Tear Osmolarity
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22. Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: dry eye disease and
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Table 1. Demographic data according to tear osmolarity difference.

Temporal group Equal group Nasal group

N 11 17 20

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Age (y) 51.82 ± 16.28 55.82 ± 14.58 53.55 ± 10.23

M:F 8:3 14:3 16:4

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Nasal tear osmolarity 298.36 ± 11.33 300.29 ± 10.19 321.50 ± 13.17

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(mOsm/L)

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Temporal tear osmolarity 326.18 ± 18.24
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(mOsm/L)

OSM difference -27.82 ± 14.93 0.59 ± 4.69 21.35 ± 13.63

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(mOsm/L)
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OSDI 27.49 ± 18.12 35.79 ± 19.79 35.54 ± 27.21

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Figure legends

Figure 1. Correlation of nasal tear osmolarity and tear film or ocular discomforts.

*statistically significant

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Figure 2. Correlation of temporal tear osmolarity and tear film or ocular discomforts.

*statistically significant

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Figure 3. Correlation of difference of tear osmolarity (OSM difference) and tear film or

ocular discomforts. *statistically significant

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Figure 4. Tear film and ocular discomforts between groups. *statistically significant
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Highlights

Tear osmolarity is an important parameter in eyes with DED, has diagnostic value, and
is involved in the pathogenesis of dry eye syndrome. This study showed that nasal tear
osmolarity and OSM difference play an important role in DED symptoms. Nasal tear

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osmolarity may be a better representation of overall tear quality and evaporation
resistance. It is important to measure both nasal and temporal tear osmolarity when
evaluating patients with DED.

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