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TFOS DEWS II Tear Film Report
Willcox, Mark D. P.
2017-07
Willcox , M D P , Argueso , P , Georgiev , G A , Holopainen , J M , Laurie , G W , Millar , T J
, Papas , E B , Rolland , J P , Schmidt , T A , Stahl , U , Suarez , T , Subbaraman , L N ,
Ucakhan , O O & Jones , L 2017 , ' TFOS DEWS II Tear Film Report ' , Ocular Surface , vol.
15 , no. 3 , pp. 366-403 . https://doi.org/10.1016/j.jtos.2017.03.006
http://hdl.handle.net/10138/297896
https://doi.org/10.1016/j.jtos.2017.03.006
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TFOS DEWS II Tear Film Report
Mark D.P. Willcox, PhD, DSc
a
,
1
,
*
, Pablo Argüeso, PhD
b
, Georgi A. Georgiev, PhD
c
,
Juha M. Holopainen, MD, PhD
d
, Gordon W. Laurie, PhD
e
, Tom J. Millar, PhD
f
,
Eric B. Papas, BScOptom, PhD
a
, Jannick P. Rolland, PhD
g
, Tannin A. Schmidt, PhD
h
,
Ulrike Stahl, BScOptom, PhD
i
, Tatiana Suarez, PhD
j
,
Lakshman N. Subbaraman, BS Optom, PhD
i
, Omür
€
O. Uçakhan, MD
k
,
Lyndon Jones, FCOptom, PhD
i
a
School of Optometry and Vision Science, University of New South Wales, Sydney, Australia
b
Schepens Eye Research Institute, Harvard Medical School, Boston, USA
c
Biointerfaces and Biomaterials Laboratory, Department of Optics and Spectroscopy, School of Optometry, Faculty of Physics, St. Kliment Ohridski University
of Sofia, Sofia, Bulgaria
d
Helsinki University Eye Hospital, University of Helsinki, Finland
e
Departments of Cell Biology, Ophthalmology and Biomedical Engineering, University of Virginia, Charlottesville, VA, USA
f
School of Science and Health, Western Sydney University, Australia
g
Institute of Optics, University of Rochester, New York, USA
h
Faculty of Kinesiology and Schulich School of Engineering, University of Calgary, Canada
i
Centre for Contact Lens Research, School of Optometry and Vision Science, University of Waterloo, Canada
j
Bioftalmik Applied Research, Bizkaia, Spain
k
Department of Ophthalmology, Ankara University Faculty of Medicine, Ankara, Turkey
article info
Article history:
Received 25 March 2017
Accepted 27 March 2017
Keywords:
Dry eye disease
Evaporation
Lipidome
Mucin
Osmolarity
Proteome
Tear film
Tear film stability
Tears
abstract
The members of the Tear Film Subcommittee reviewed the role of the tear film in dry eye disease (DED).
The Subcommittee reviewed biophysical and biochemical aspects of tears and how these change in DED.
Clinically, DED is characterized by loss of tear volume, more rapid breakup of the tear film and increased
evaporation of tears from the ocular surface. The tear film is composed of many substances including
lipids, proteins, mucins and electrolytes. All of these contribute to the integrity of the tear film but exactly
how they interact is still an area of active research. Tear film osmolarity increases in DED. Changes to
other components such as proteins and mucins can be used as biomarkers for DED. The Subcomm ittee
recommended areas for future research to advance our understanding of the tear film and how this
changes with DED. The final report was written after review by all Subcommittee members and the
entire TFOS DEWS II membership.
© 2017 Elsevier Inc. All rights reserved.
1. Overview of the tear film in health
A stable preocular tear film is a hallmark of ocular health, largely
because it forms the primary refracting surface for light entering
the visual system and it protects and moisturizes the cornea. The
three layered model of the tear film proposed by Wolff [1,2] has had
an overwhelming allure because it is simple and logical: a mucin
layer covering the ocular surface and lowering the supposed hy-
drophobicity of the epithelial cells; an aqueous layer to nurse the
exposed ocular epithelium by providing lubricity, some nutrients,
antimicrobial proteins and appropriate osmolarity; and a lipid layer
to prevent loss of the aqueous layer through overspill and evapo-
ration. There is a continual return to this three layered model,
despite Doane stating over 20 years ago that the three layered
structure “is a considerable simplification of reality” [3]. This has
generally limited novel perspectives that might lead to a clearer
understanding of the dynamics, structure and function of the tear
* Corresponding author.
E-mail address: m.willcox@unsw.edu.au (M.D.P. Willcox).
1
Subcommittee Chair
Contents lists available at ScienceDirect
The Ocular Surface
journal homepage: www.theocularsurface.com
http://dx.doi.org/10.1016/j.jtos.2017.03.006
1542-0124/© 2017 Elsevier Inc. All rights reserved.
The Ocular Surface 15 (2017) 366e403
film and the changes that occur to cause dry eye. The precorneal
tear film behaves as a single dynamic functional unit [4] with
different compartments.
Laxity of terminology means that there is ready acceptance of
information that may not be entirely correct. For instance, “tear
osmolarity is approximately 302 mOsm/L” is often accepted ter-
minology, but in reali ty such a value is for tears sampled from
within the lower tear meniscus. While it may represent the os-
molarity of the tear film spread over the ocul ar surface, there is
no evidence of this. A consequence of being aware of where the
samples being measured are coming from and how they are
collected may lead to a more cauti ous approach to extrapolating
data to the tear film that covers the ocular surface and, ultimately,
a better understanding of its composition, structure and spatial
distribution. Optical coherence tomography (OCT) has allowed
non-invasive me asurement s of both the upper and lower menisci
in ter ms of height, area, and curvature of the surface and while
the upper and lower meniscus in an individual appear to be
identical in these parameters, none of these parameters corre-
spond to central tear film thickness [5], but lower men iscus
heigh t seems to correspond to the volume of mucoaqueous tears
[6,7].
When the eyes are open the tears are distributed in three
compartments, which are the fornical compartment (which oc-
cupies the fornix and retrotarsal space), the tear menisci and the
preocular tear film. The fornical compartment is assumed to be
narrowest in the region of the lid wiper of the lid margin, which is
directly apposed to the globe. The preocular tear film overlies the
exposed conjunctiva and cornea [8]. The precorneal tear film fol-
lows the contours of the cornea, and is usually highly stable [9]. The
pre-bulbar film follows the varying contours of the bulbar con-
junctiva. The preocular tear film is the whole tear component that is
spread over the exposed surface of the eye. Results from studies
using ultrahigh resolution OCT has resolved the debate over the
thickness of the tear film. It is extraordinarily thin, 2e5.5
m
m thick
over the corneal region (precorneal tear film), and these data
concur with estimates of tear film thickness using interferometry
techniques [8e10]. The tear film is so thin that the roughness of the
corneal surface (~0.5
m
m) cannot be ignored [11]. Neither the tear
film thickness over the conjunctival region, nor the roughness of
the conjunctival surface has been measured. Water has a high
surface tension and therefore to form such a thin film of water
without it collapsing onto the surface or forming lenses, the surface
on which it spreads has to have similar properties to water and the
surface tension of the water at the air interface has to be lowered
[12,13].
The apical surfaces of the corneal and conjunctival epithelia
have transmembrane mucins [14], which increase the adhesion
tension for water, facilitating the spread of the tears across the
ocular surface. Transmembrane mucins attached to the microplicae
of the epithelial cells extend up to 500 nm (0.5
m
m) into the tear
film [15,16]. They also constitute a line of defense for the epithelial
cells against infection and injury [17,18].
Much remains to be learned about the mucoaqueous compo-
nent of the preocular tear film and whether it is the same within all
compartments. In addition to oxygen, metabolites and electrolytes,
the tear film contains antimicrobial peptides, proteins and soluble
immunoglobulins that protect the ocular surface from infection.
The sensitivity of modern proteomics techniques has allowed the
identification of more than 1500 proteins [19], and more than 200
peptides originating from several of those proteins [20]. The nature
of the vast majority of these proteins and peptides reflects that
tears are also a mechanism for removal of cellular debris that occurs
due to the turnover of ocular epithelial cells. In addition, sensitive
lipid studies also show that tears contain a lipid profile similar in
ratio to meibomian lipids, but with a relative abundance of phos-
pholipids [21].
Shortly after a blink, the mucoaqueous component of the pre-
ocular tear film is believed to become physically isolated from the
upper and lower menisci, such that diffusion between these com-
partments does not occur [22,23]. This isolation has been observed
as a black line at the ocular margins in fluorescein-labeled tears.
The tear film lipid layer is approximately 40 nm thick [24],
lowers the surface tension at the air interface of the preocular tear
film and results in spreading of the tear film over the ocular surface.
A feature of the preocular tear film is that it resists evaporation, and
it is purported that the tear film lipid layer is responsible for this
[25e27,67]. The complete nature of the tear film lipid layer is un-
known, but it is likely it has surfactant molecules at the mucoa-
queous interface and lipophilic molecules at the air interface.
Unlike the aqueous component of the preocular tear film, which
appears to be isolated shortly after a blink, the lipid layer of the tear
film appears to be continuous over the menisci and indeed con-
tinues to move upwards over the ocular surface following a blink.
Observations using various interference techniques at different
magnifications show that the lipid layer is variable in thickness
across the ocular surface. This movement and continuum from the
meibomian gland orifices, and direct observation of secretions from
the meibomian glands onto the ocular surface, indicate that the tear
film lipid layer is almost entirely derived from meibomian gland
secretions. It is unknown if lipids from the tear film lipid layer move
into the mucoaqueous compartment of the preocular tear film, or if
lipids from other ocular tissues (origin unknown) transverse the
mucoaqueous compartment and adsorb to the tear film lipid layer.
By examining the shear rheology of
films of meibomian lipids
in vitro and comparing them with other lipids, there is evidence
that meibomian lipid films spread over a mucoaqueous subphase,
causing the subphase to resist collapse as it thins [28]. Dilatational
rheology studies also confirmed that the viscoelastic films of tear
lipids, meibum and contact lens lipid extracts are predominantly
elastic, which may enhance their capability to stabilize the air/tear
surface [29e31].
2. Biophysical measurements of the tear film
2.1. Tear film structure and dynamics
There is evidence that, in the above described three layer
structure of the tear film, the mucin layer has a decreasing gradient
of concentration from the epithelium towards the aqueous layer
[32]. It is also commonly considered that the aqueous and mucin
layers are a single layer of mucoaqueous gel (referred to hereafter
as the mucoaqueous layer) [33].
The tear film lipid layer is derived from meibum secreted from
the lid margins and is spread onto the tear film with each blink,
driven by surface tension forces. It plays an important role in sta-
bilizing the tear film and in the past has been thought to play a key
role in retarding tear evaporation [25e27,67]. The lipid layer can be
investigated with interferometry techniques. The color and
brightness of the interference images are analyzed to yield lipid
layer thickness [24,34e37]. The thickness of the lipid layer has been
reported to be from 15 to 157 nm, with a mean of 42 nm [24].
Evidence from reflection spectra of the precorneal tear film
suggested the tear film has a thickness of approximately 2
m
m [9].
OCT techniques find the thickness of the tear film to range from 2 to
5.5
m
m [10,38e42].
To elucidate the structure of the tear film, studies have made use
of multiple methods. These include combining a wavefront sensor
with OCT [43], using fluorescein tear breakup time (TBUT) and
Schirmer test [43], applying fluorescein and assessing using a
M.D.P. Willcox et al. / The Ocular Surface 15 (2017) 366e403 367
rotating Scheimpflug camera (Pentacam, Oculus, Germany) [44],
simultaneously recording videos of fluorescence and imaging tear
film lipid layer [45], and using dual thermal-fluorescent imaging
[46].
The bulk of the tear volume and flow is via secretion from the
lacrimal gland [47,48], with a smaller portion secreted by the
conjunctiva [49]. In animal studies, tears can be produced by the
accessory lacrimal glands in the conjunctiva even after removal of
the main gland [50]. Both parasympathetic and sympathetic nerves
innervate the main lacrimal glands [51,52] and a few sensory nerves
have also been identified [51]. The nerves are located in close
proximity to acinar, ductal, and myoepithelial cells as well as being
close to blood vessels [51,52]. Stimulation of the lacrimal gland and
secretion occur via the cornea etrigeminal nerveebrain-
stemefacial nerveelacrimal gland reflex arc. Afferent sensory
nerves of the cornea and conjunctiva are activated by stimulation of
the ocular surface. Efferent parasympathetic and sympathetic
nerves are then activated to stimulate secretion from acinar and
tubular cells in the lacrimal gland [53].
Tears have been classified into four broad types - basal, reflex,
emotional and closed-eye. (see review by Craig et al.) [54]. Basal
tears (sometimes referred to as open-eye tears) are tears that
constitutively coat the eye and are deficient in dry eye. Reflex tears
are produced upon stimulation of the ocular surface (for example
by onion vapor) or stimulation of the reflex arc (for example by
nasal stimulation of the sneeze reflex). Emotional tears are also
produced upon stimulation, but in this case via emotions such as
sadness. Closed-eye tears are those that can be collected from the
ocular surface immediately after a period of sleep. Basal, reflex and
emotional tears are produced mainly from the lacrimal glands via
the neural arc [55], but differ in their constitution, for example, the
concentration of various proteins change [54]. Secretion from the
lacrimal gland is greatly reduced during sleep, and so the consti-
tution of closed-eye tears is somewhat different to that of other
types with, for example, an increased amount of serum-derived
proteins leaking from the conjunctival blood vessels [54].
A two-step process of tear film deposition through a blink has
been proposed [56]. In the first step, the upper lid pulls a layer of
tears over the cornea by capillary action; in the second step, the
lipid layer drifts upward, which may drag up aqueous tears along
with it. The upward drift of the lipid layer can be observed using
interferometry imaging approaches [57]. After the blink , tear film
redistribution occurs due to the negative hydrostatic pressure
within the nascent menisci. This draws liquid from the forming tear
film and eventually causes the precorneal portion to separate from
the menisci. The boundary can be observed as a black line of
reduced fluorescence in the fluorescein-stained tear film, indicating
where the aqueous layer is thin but the lipid layer remains intact
[58,59].
Tears flow from the supply region towards the puncta, located
on the lids near the nasal canthi, to facilitate their turnover and
removal [60,61]. Tear turnover rate has been estimated to be
16 ± 5%/min [62e64]. Between blinks, thinning of the tear film
occurs, which can be observed using several different approaches
[40,57,65,66]. Most of the observed tear thinning between blinks is
due to evaporation [25e27,57,65,67,68].
Tear production, turnover and volume can be estimated by
several methods, but there is limited correlation between different
tests [69]. Accordingly, a combination of tests should provide a
more reliable diagnosis and increase the specificity and sensitivity
of dry eye diagnosis [70]. The phenol red thread test (Hamano test)
[71] is a measurement of tear volume or change in tear volume with
time, by observation of the amount of wetting of a phenol red dye
impregnated cotton thread placed over the inferior eyelid. The
Schirmer test [72] is a measure of tear production and is
undertaken by observing the wetting of a standardized paper strip.
Historically, the Schirmer I test is performed without anesthesia
and thus measures predominantly reflex tearing. A variation on the
Schirmer I test involves use of topical anesthesia and claims to
reflect the basal secretion of tears, although a contribution from
reflex tearing cannot be discounted [626]. Tear volume can also be
measured by fluorophotometric assessment, and demonstrates an
apparent normal human volume of approximately 8 ± 3
m
l [47,62].
Tear meniscus height (TMH) is linearly proportional to the lacrimal
secretory rate [47]. Differences in TMH and radius of curvature can
be used to aid diagnosis of dry eye [7,73,74]. Tear clearance rate is
the rate at which the preocular tear fi lm or an instilled marker of
the tears is removed from the tear film by dilution or drainage from
the tear volume [75]. Tear clearance rate measurement is seldom
performed in the clinical setting. Tear dynamics can be estimated
by dividing the value of the Schirmer test with anesthesia by the
tear clearance rate, giving the Tear Function Index [76]. This value
has been shown to have greater sensitivity for detecting dry eye
than either one of these tests alone [76].
2.2. Tear film stability on eye and ocular surface wettability
A stable precorneal tear film has long been viewed as one of the
hallmarks of ocular health, largely because it provides the primary
refracting surface for light entering the visual system as well as
creating a protective and lubricated environment for the tissues of
the palpebral and bulbar surfaces. Unlike some other species,
whose tears can remain stable for many minutes [77], the human
tear film tends to collapse or “break up” in under half a minute or
so, unless it is re-established by the act of blinking. While all in-
dividuals will manifest this behavior if blinking is prevented for
long enough, rapid appearance of regions of localized drying is
viewed as evidence for tear film disorder, particularly in dry eye,
and so observations of stability are commonly and frequently per-
formed as a diagnostic aid.
Experiments have shown that tear film thinning and breakup
occur mainly as a result of evaporation from the tear film, rather
than due to fluid flow, whether that be tangentially within the film
itself, or radially across the ocular surface [78,79]. Using reflectivity
and tear fluorescein as respective indicators for lipid and mucoa-
queous layer thickness, King-Smith et al. suggested a lack of cor-
respondence between dry eye and both lipid layer thickness and
thinning rate [45]. Further, thinning rate was not affected by
apparent thickening of the lipid layer with lipid emulsion-based
eye drops [24], suggesting that the lipid was a poor barrier to
evaporation [45]. Perhaps it is the whole healthy preocular tear film
that resists evaporation from the ocular surface, and hence thin-
ning? Measurement of TBUT may provide a better indicator of the
ability of the preocular tear film to prevent evaporative losses.
Acquiring a TBUT is a relatively simple task, but interpreting the
result is not straightforward because of its inherent variability
[80,81]. A number of approaches to improving repeatability have
been suggested, including taking multiple readings and averaging
or selecting a subset of values [82,83], minimizing the amount of
fluorescein instilled [84e 86] and, most significantly, eliminating
the use of fl uorescein altogether. This last approach, via a number of
different methods, provides a non-invasive breakup time (NIBUT)
value. Tear film additives are avoided, the examination environ-
ment should ideally introduce no additional sources of heat, air
movement, humidity etc., and head posture and blinking behavior
are standardized. Inevitably however, the extent to which these
conditions are achieved varies somewhat between methods.
Early efforts in acquiring a NIBUT projected a grid pattern
[87,88] or keratometry mires [89,90] onto the surface of the tear
film and viewed their distortion in time after a blink. While it is still
M.D.P. Willcox et al. / The Ocular Surface 15 (2017) 366e403368
possible to use keratometer-based methods in clinical situations, a
degree of subjectivity is involved in judging when the image
distortion first occurs. Increasing sophistication in both image
capture and computational capability has led to a refinement of the
technique, using both automated detection and more detailed
targets. In most cases, these targets are identical to those originally
developed and used for measuring corneal shape (keratoscopes)
and consist of multiple concentric rings whose angular subtense is
sufficient to cover more or less all of the visible cornea. The image of
this target is reflected from the anterior surface of the tear film and
captured for subsequent analysis [91e98]. Typically, multiple,
sequential images are acquired during the inter-blink period and
image analysis software utilized to automatically detect the onset
of areas of breakup.
Although repeatability has not been reported for all the devices
using this approach, the available data are in reasonable agreement
that they operate with a coefficient of variation of around 10%
[92,94], which is roughly three times better than traditional TBUT
measurement [92]. Despite this improvement, the range of values
reported for normal individuals is broad, being from about 4 to 19 s
(Table 1 ). It may be that this reflects the different algorithms being
used to extract breakup data among the various instruments, a
suspicion that is strengthened by the observation that the corre-
sponding dry eye breakup times are consistently about half those
given for normal eyes. Thus, while inter-instrument comparisons
are likely to be difficult to interpret, data derived from a given in-
strument type appear reasonably reliable and offer quite good
sensitivity and specificity in distinguishing dry-eyed individuals
from normals (Table 1). Further details may be obtained from the
Tear Film and Ocular Surface Society's Dry Eye Workshop II (TFOS
DEWS II) Diagnostic Methodology report [99].
Ocular surface thermography has been used to measure NIBUT,
on the principle that breakup is associated with evaporative cooling
and therefore thinning areas in the tear film show up as cool spots
in the thermograph [46]. The technique is suggested to be reliable
[100], although test-retest confidence intervals have not been made
available so far. While data are limited to a single study, NIBUT
derived from this method appear similar to those from the lower
end of the videokeratoscopy range. Again, dry-eyed subjects yield
breakup times that are about half those of normals, with levels of
sensitivity and specificity being similar to those from video-
keratoscopy (Table 1).
All the systems discussed so far are commercially available and
so could feasibly be used in routine clinical practice. The following
discussion deals with instruments that are more complex and/or
unlikely to be applicable outside a research setting. Recently, lateral
shearing interferometry has been used to monitor changes in tear
film stability. This instrument uses an optical wedge to laterally
shift the wavefront reflected from the tear film surface and rotate it
so that it can be made to interfere with itself [101,102]. Information
about the shape of the refl
ecting surface is contained in this
wavefront and can be extracted from the resulting interference
pattern. Note that this differs from colored fringe methods, such
those of Guillon [103], or the interferometer developed by Doane
[104], both of which rely on interference between light reflected
from different surfaces within the tear film, such as the front and
back of the lipid layer. Using fast Fourier transformation, images
derived with the shearing technique can be processed to generate a
surface stability index parameter (M2). Sequential image acquisi-
tion allows M2 to be followed over the blink cycle, in real time, at a
resolution determined by the video frame rate. It is claimed that
this method is relatively insensitive to eye movements and the
degree of dryness of the surface being measured [105] and is better
able to discriminate dry eyed subjects from normal than either
dynamic area high speed videokeratoscopy or wavefront sensing
[106].
Another technique that may be developed for clinical applica-
tion is the use of double pass methods. The basis for double pass
methods is that the view of the retina obtained using a double pass
optical system, in which the image forming light traverses all the
optical surfaces of the eye twice (once on entry and again on exit),
will be affected by scattering from all these surfaces, including the
tear film. Thus, analysis of double-pass retinal images on the time
scale of the blink cycle may provide an indirect measure of tear film
stability. Deteriorations in image quality metrics such as intensity
distribution index [107], Strehl ratio, modulation transfer function
cut-off frequency and objective scattering index [108] are observed
in dry eye. More data are needed to establish the diagnostic ability
of this approach for discriminating dry eye.
2.3. Vision quality
An association between dry eye and compromised visual acuity
postulated by Rieger [110] is poorly documented using high
contrast letter acuity [111]. However, based on the measurement of
“functional visual acuity”, whereby acuity is measured after sus-
pension of blinking for several seconds, dry eyed subjects do
significantly worse than normals [111]. Delayed blinking generates
subtle wavefront aberrations that more rapidly give rise to higher
order aberrations after the blink in dry eye individuals [112].Inan
effort to directly link tear film changes to visual loss, a three
channel optical system that allowed concurrent measurement of
letter contrast acuity, TBUT and refractive aberrations was con-
structed. Although the data reported were for contact lens wearing
eyes only, progression of TBUT was clearly associated with both
visual performance reduction and declining optical quality [113].
Table 1
Summary of non-invasive breakup time (NIBUT) measurements in normal and dry-eyed subjects, together with discrimination diagnostic metrics. NIBUT ¼ non-invasive
breakup time; AUC ¼ area under the curve of a receiver operating characteristic graph plotting sensitivity vs. 1-specificity.
Author (Reference) NIBUT Normal (sec) NIBUT Dry Eye (sec) AUC Sensitivity Specificity Instrument Principle
Hong et al. 2013[94] 4.3 ± 0.3 2.0 ± 0.2 0.83 84.1 75.6 Oculus keratograph Videokeratoscopy
n ¼ 41 n ¼ 44
Gumus et al. 2011[97] 4.9 ± 1.6 2.4 ± 2.5; Mild n ¼ 23 82.2 88.0 Tomey RT7000 Videokeratoscopy
n ¼ 25 1.2 ± 1.8; Moderate n ¼ 11
0.4 ± 0.5; Severe n ¼ 11
Downie 2015 [92] 19.4 ± 5.3 7.9 ± 4.9 0.92 81.5 94.4 Medmont E300 Videokeratoscopy
n ¼ 17 n ¼ 28
Koh et al. 2016[95] 9.7 ± 6.7 4.6 ± 1.3 Keratograph M5 Videokeratoscopy
n ¼ 31 n ¼ 49
Su et al. 2016[109] 4.5 ± 0.9 2.1 ± 1.1 0.88 80.0 89.0 IT-85, United Integrated Services Co Thermography
n ¼ 31 n ¼ 42
M.D.P. Willcox et al. / The Ocular Surface 15 (2017) 366e403 369
![Fig. 2. Tear film lipid layer interferometry grading patterns. From Yokoi et al., Correlation o Ophthalmol. 1996; 122: 818-24 [35]. A ¼ Grade 1 (gray uniform), B ¼ Grade 2 (gray non-uni E ¼ Grade 5 (partly exposed corneal surface).](/figures/fig-2-tear-film-lipid-layer-interferometry-grading-patterns-1aj48htf.webp)
![Table 6 Human ‘extracellular’ tear proteins reported to decrease or increase with ocular surface pathology. Right column: # articles detecting a significant change from normal by: unbiased mass spectrometric screening (‘US’) and/or a candidate immuno-detection or activity detection approach [CA]; NP, not performed. ‘Extracellular’, in whole or part by Gene Ontology.](/figures/table-6-human-extracellular-tear-proteins-reported-to-2z9glzhu.webp)