Citation:
Elhusseiny
AM, Khalil AA, El Sheikh RH, Bakr MA, Eissa MG, El Sayed YM. New approaches for diagnosis of dry eye disease. Int J
Ophthalmol 2019;12(10):1618-1628.
DOI:10.18240/ijo.2019.10.15
·Review Article·
New approaches
for diagnosis of dry eye disease
Abdelrahman M. Elhusseiny1,2, Ali A. Khalil3,
Reem H. El Sheikh1, Mohammad A. Bakr1, Mohamed Gaber
Eissa1, Yasmine M. El Sayed1
1Department of Ophthalmology, Kasr Al
Ainy School of medicine, Cairo University, Dokki 12611, Egypt
2Department of Ophthalmology, Bascom
Palmer Eye Institute, University of Miami Miller School of Medicine, 900 NW 17
Street, Miami, FL 33136, USA
3Faculty of Medicine, American
University of Beirut, Beirut 2341, Lebanon
Correspondence to: Abdelrahman M. Elhusseiny.
Department of Ophthalmology, Kasr Al Ainy School of medicine, Cairo University,
Dokki 12611, Egypt. aelhusseiny@postgrad.kasralainy.edu.eg
Received:
Abstract
We reviewed the literature for
different diagnostic approaches for dry eye disease (DED) including the most
recent advances, contradictions and promising diagnostic tools and technique.
We performed a broad literature search for articles discussing different
methods for diagnosis of DED including assessment of tear osmolarity, tear film
stability, ocular biomarkers and others. Articles indexed in PubMed and google
scholar were included. With the growing cosmetic industry, environmental pollution,
and booming of digital screens, DED is becoming more prevalent. Its
multifactorial etiology renders the diagnosis challenging and invites the
emergence of new diagnostic tools and tests. Diagnostic tools can be
classified, based on the parameter they measure, into tear film osmolarity,
functional visual acuity, tear volume, tear turnover, tear film stability, tear
film composition, ocular biomarkers and others. Although numerous methods
exist, the most accurate diagnosis can be reached through combining the results
of more than one test. Many reported tests have shown potential as
diagnostic/screening tools, however, require more research to prove their
diagnostic power, alone or in combination. Future research should focus on
identifying and measuring parameters that are the most specific to DED
diagnosis.
KEYWORDS: dry eye
disease; tear film stability; tear osmolarity; ocular biomarkers
DOI:10.18240/ijo.2019.10.15
Citation: Elhusseiny AM, Khalil AA, El
Sheikh RH, Bakr MA, Eissa MG, El Sayed YM. New approaches for diagnosis of dry eye disease. Int J
Ophthalmol 2019;12(10):1618-1628
INTRODUCTION
Dry eye disease (DED), also known as
keratoconjunctivitis sicca, is one of the most common ophthalmic conditions,
affecting hundreds of millions of people worldwide[1]. Recent technological advances
and research targeting DED have led to the emergence of new definitions and new
approaches for DED diagnosis and management. The two main subtypes of DED,
which form an overlapping spectrum, include evaporative and aqueous-deficient
DED[2]. Based
on the Tear Film and Ocular Surface Society Dry Eye WorkShop II (TFOS DEWS II)
definition for DED, multiple factors are involved that would ultimately lead to
loss of tear film homeostasis together with abnormalities involving the ocular
surface[3].
The main pathophysiology of the DED is based on evaporation-induced tear
hyperosmolarity which leads to direct and indirect inflammatory damage and associated
ocular symptoms Evaporative dry eye may be due to intrinsic factors, such as
low blink rate, or extrinsic factors, such as contact lens wear[4]. Ocular symptoms may
include discomfort symptoms and/or symptoms of visual disturbance[3]. However, chronic
ocular pain is the most commonly reported symptom by DED patients. The
long-term damage to the corneal nerves has been found to induce sensitization
accounting for ocular pain[5].
DED symptoms can significantly impact patients’ work productivity and quality
of life with various effects on different life activities including, a delayed
reaction time while driving, a decline in sustained reading performance, and a
slowing of out-loud reading but to a lesser extent than silent reading[6]. DED has even been
associated with depression and anxiety, especially in DED associated with
Sjögren syndrome[1].
FACTORS RELATED TO DRY EYE DISEASE DEVELOPMENT
Role of Blinking
Blinking plays a major role in
maintaining the precorneal tear film and promotes the release of meibomian lipids
that lubricate the ocular surface and delay tear film evaporation[7]. Many in vitro
studies that have challenged the conventionally attributed function of the tear
film lipid layer (TFLL) and demonstrated that the lipid layer may not inhibit
the rate of evaporation[8],
but serve other functions such as to allow the spread of the tear film and to
prevent collapse[9].
Forceful blinking has been shown to make the lipid layer of the precorneal tear
film thicker[10]
and has been reported to reduce dry eye symptoms[11]. However, a recent study, like
multiple previous studies, demonstrated no correlation between TFLL thickness
and non-invasive tear break up time (TBUT)[11]. Infants have a significantly
lower spontaneous blink rate (1-6/min)[12-13]
than adults (15-30/min)[13-14], attributed to a
thicker lipid layer and higher tear film stability, and associated with a
higher TBUT[15-16]. Decreased spontaneous
blinking rate during visual tasks has been shown to be associated with
increased tear film instability and subsequent symptoms of DED[17]. However, a
recent study has shown no significant correlation between the frequency of
blinking and any of the ocular surface parameters, including the Ocular Surface
Disease Index (OSDI) questionnaire score[7]. Incomplete blinking, on the
other hand, has been associated with greater meibomian gland dropout, poorer
meibum quality and decreased tear film thickness, all of which accounting for
about two-fold increase in the risk of developing DED[7]. As a result, more partial blinks
were found in DED patients with shorter inter-blink periods compared to healthy
subjects, and the number of partial blinks was positively associated with OSDI
scores[18].
Environmental Factors Environmental pollution also exacerbates the
manifestations of DED. Exposure to nitrogen dioxide was found to increase the
frequency of eye irritation, and the OSDI score was found to be positively
associated with the duration of exposure to environmental pollutants[19-20]. Other studies demonstrated that
exposure to ozone gas and low humidity also carries a risk of developing DED
symptoms[21].
Isotretinoin, used in dermatology creams, was found to cause the ductal
epithelium of meibomian gland in animal models to thicken and the mature acini
number to decrease; the ocular discomfort complaint is increasing because of
the growing use of cosmetic products and associated accidental eye exposure[22]. Staring at digital
screens for long time is another factor that contributes to the exacerbation of
DED, as prolonged use was associated with higher OSDI scores and shorter TBUT;
possibly due to the reduced spontaneous blinking rate during reading tasks,
thus promoting tear fluid evaporation[23]. Higher OSDI Scores were noted in the smartphone users
given the smaller screens which are usually held at a closer distance than
other screens, and the large amount of blue light emitted increase oxidative
stress relative to using computer displays[23]. Cessation of digital screens
use in children decreased the punctate erosion, OSDI scores and increased TBUT[24].
Ambient temperature can also affect
the rate of tear film evaporation. It was demonstrated that as the temperature
of the air increases to
Ocular Surgeries
Ocular procedures can result in
or exacerbate a preexisting DED[27].
Cataract surgery
Phacoemulsification can result in
reduction of the tear film secretion with subsequent DED development through
its effect on the neurogenic response of the eye[27]. Although
cataract-surgery-induced DED was reported to be improve after only one month
postoperatively, others demonstrated that it may persist for up to 6mo[27-28]. Hence, the importance of ocular
surface evaluation in prospective cataract surgery patients[28].
Refractive surgery
Although commonly transient,
lasting 6-9mo; post-LASIK dry eye may last more than a year in some patients
due to the reduction of corneal innervation with subsequent reduction of tear
secretion and alteration in tear film quality; and to the compromise of the
corneal and conjunctival epithelium integrity including goblet cells; all
resulting in reduced tear film stability[29]. Patients with prolonged dry eye
after refractive surgery showed signs of lipid layer deficiency which improved
with lid warming, suggesting the presence of meibomian gland dysfunction (MGD)
as an underlying cause, that is possibly due to reduced corneal sensation
causing reduced blink rate as well as incomplete blinking[29]. Induced flattening was found to
generate incongruity between the corneal surface and the posterior surface of
the eye lids[29].
Strabismus surgery
DED symptoms were experienced by
some patients after strabismus surgery due to changes in corneal sensitivity, tear
film instability and goblet cell loss. However, some patients reported symptoms
prior to surgery which was attributed to the larger area of bulbar conjunctiva
opposite to the side of deviation and distortion of the normal relation between
the lids and the globe, leading to microtrauma with increased friction between
the lids and the globe[30].
Diseases and Treatments
Sjögren’s syndrome
Sjögren’s syndrome is an
autoimmune disorder characterized by exocrine gland dysfunction and
predominantly associated with aqueous-deficient DED. Although the exact
pathogenesis is unclear there is evidence of a concurrent evaporative
mechanism, due to MGD, along with its principle etiology of autoimmune mediated
lacrimal gland dysfunction[31].
Parkinson’s disease
Parkinson’s disease (PD) has also
been associated with a myriad of ocular manifestations and conditions including
an increased risk of DED. The principal feature of DED in PD is decreased
aqueous tear production, attributed to the autonomic dysfunction[32].
Hemopoietic stem cell transplant Graft versus host disease (GVHD) is a grave complication
associated with allogeneic hematopoietic stem cell transplant. DED is the most
common manifestation of ocular GVHD (oGVHD)[33]. The underlying mechanism is a
combination of lacrimal gland destruction, severe meibomian gland damage and
other factors, resulting in severe ocular surface abnormalities and symptoms[34].
Diabetes Diabetes has been recognized as one of the leading
systemic risk factors for DED[35], however DED prevalence in this population may be
underestimated due decreased symptom reporting associated with diminished
corneal sensitivity in diabetic patients[1]. DED frequency was found to be
positively associated with longer duration of the disease and significantly
higher in diabetic retinopathy patients[36]. Furthermore, DED severity has
been positively correlated with the severity of diabetic retinopathy[37]. The pathogenesis
is multifactorial and stems from the vast complications of systemic hyperglycemia,
ultimately leading to lacrimal dysfunction and associated deficiency in tear
production, changes in tear film parameters and blinking abnormalities[35].
Other Factors
Contact lenses
The mechanical and hypoxic stress
caused by wearing contact lens, and the associated increased risk of microbial
contamination, contribute to the development of subtle epithelial injury and
severe infiltration and microbial keratitis[38]. The inflammation subsequently
creates a vicious cycle of ocular damage making contact lens wear an additional
factor related to the precipitation or exacerbation of DED[38].
Age Tear film stability decreases with advancing age[39] and major decline
has been shown to occur between birth to age 25y; with infants having the most
stable tears[40].
Signs of DED, such as decreased breakup time and increased blink rate, are the
same changes observed with aging[39]. Age-related derangements affecting the lacrimal
glands, meibomian glands, eyelids, conjunctiva, ocular surface and other ocular
elements[41]
including tear film compositional and structural changes[39] have all been associated with
increased DED manifestations. Furthermore, the increased prevalence of certain
ocular diseases with age, such as glaucoma[42] and systemic co-morbidities, such
as hypertension and diabetes, and their treatments can all exacerbate dry eye
with advancing age[41].
Occupation and others Occupation is another risk factor for DED especially
among patients with indoor and sedentary jobs. Office workers with heavy
digital screen usage have been shown to exhibit the highest risk[43]. In addition to
the drying effects of the office environment, the underlying mechanism has been
attributed to various effects of digital screen use including, incomplete
blinking, diminished blink frequency and inappropriate gaze angle[44]. On the other
hand, outdoor and active occupations, such as agriculture and fishing, were
found to be protective against DED[43]. Other risk factors for DED include female sex, Asian
race, medication use, allergies, estrogen replacement therapy, vitamin A
deficiency, essential fatty acid (EFA) deficiency and hormonal imbalance such
as androgen deficiency[1].
DRY EYE DISEASE AND HIGH ORDER ABERRATIONS
Tear film instability causes
irregularity of the corneal surface resulting in development of higher order
aberrations (HOA)[45].
Hartmann-Shack or double-pass aberrometers, can be used to evaluate the dynamic
changes in image quality in DED patients[45]. Functional visual acuity
assesses vision periodically. It can demonstrate reduction of visual acuity in DED
patients with eye opening due to tear film irregularity and visual impairment
experienced in daily tasks[46].
Studies using aberrometers have demonstrated higher HOA only in eyes having
superficial punctate keratitis[47]. However, regardless of presence of superficial
punctate keratitis, eyes with DED had higher straylight which is responsible
for glare[47].
When compared to controls, patients with DED had lower contrast sensitivity[47].
APPROACHES FOR DRY EYE DISEASE DIAGNOSIS
According to the TFOS DEWS II
report, DED is a self-perpetuating cyclic disease whose pathogenesis begins
along the continuum of evaporative and aqueous-deficient DED, ultimately
leading to the disruption of tear film homeostasis and a vicious cycle of
events[3]. DED
creates a diagnostic challenge which undermines attempts at its definition due
to the various diagnostic criteria available[48]. Relying on symptoms alone for
DED diagnosis was found to be inadequate, because symptoms, although
reproducible, are similar to those found in a range of other ocular conditions,
with objective signs of DED present only in 57% of symptomatic patients[49-50]. The discordance between signs
and symptoms may be because the symptoms precede the signs or due to a
different underlying etiology within the pathophysiology of dry eye[50]. Neurosensory
abnormalities have also been newly identified to play a key role in the
multifactorial etiology of DED. Dysfunctional sensation, for example, may lead
to ocular surface signs without any symptoms, hence, diagnosis based on
presenting symptoms or signs alone may lead to misdiagnosis[3]. A variety of diagnostic tests
for DED diagnosis are available, however, their sensitivity and specificity
vary significantly according to patient specific characteristics, disease
severity and other factors[51].
Questionnaires are valuable tools
for symptom screening that can capture the patient’s experience and be easily
implemented in everyday practice[44]. Furthermore, they can detect subclinical and
unrecognizable cases of dry eye, which is especially important in patients who
are planned to undergo high visual expectation ophthalmic surgeries[52]. Many different
questionnaires are available to assess and quantify DED symptom severity and
effect on quality of life, however, a standardized questionnaire for diagnosis
has not yet been developed. A comparative listing of DED questionnaires is
included in the Epidemiology section of the International DEWS 2017 Report[1].
According to the TFOS DEWS II
Report, diagnosis should begin with excluding other possible conditions that
can mimic DED through triaging questions. Then, questionnaires, such as the
OSDI, can be used for screening and grading of DED symptoms. A positive symptom
score (≥13 points OSDI score) would then warrant minimally invasive tests for
homeostatic markers including ocular surface staining, tear osmolarity and
non-invasive tear breakup time. It is sufficient to confirm the diagnosis if
any one of the homeostatic markers was found to be positive in either eye. Once
diagnosis is confirmed additional more invasive tests, such as meibography and
tear volume (TV) assessment, are instigated to assess DED severity and allow
sub-classification of DED based on its etiological origin, hence leading to
appropriate treatment[51].
A comprehensive listing of DED differential diagnosis is included in the DEWS 2017
diagnostic methodology report[51].
SLIT-LAMP EXAMINATION
After careful history taking and
symptom screening, examination should begin with a thorough slit-lamp
examination, with and without staining, to identify signs of DED. Ocular
surface examination using vital stains, including fluorescein and lissamine
green, have been used to assess dry eye. These tests are cheap and easy to
perform; however, they assess surface damage so they can’t be utilized as
diagnostic tools for early DED[33]. Fluorescein staining can identify superficial
punctate epithelial erosions and can be helpful in diagnosis, especially when
present in specific patterns that reflect certain DED etiologies, such as
inferior corneal erosions in lagophthalmos[52]. Low tear film meniscus height
is another important marker for DED that can be measured by slit-lamp
biomicroscopy without staining, however, measurements were found to be more
stable with Tearscope-plus device[53]. Unlike other causes of conjunctival injection, DED
associated conjunctival hyperaemia is usually subtle and involves the fine,
horizontal vessels in the bulbar conjunctiva, where the ocular surface is
exposed[54].
In addition to investigator grading scales, computer-automated redness grading
scales have been developed to objectively assess dry eye-associated redness for
potential diagnostic and treatment follow up purposes[54]. Slit-lamp examination of the
eyelid margin, eyelashes and meibomian gland orifices is important to reveal
possible meibomian gland impaction, gland dropout, telangiectasias,
collarettes, and chalazia[52].
However, diagnosis and classification of MGD is limited by examiner variability
and poor repeatability of the different MGD grading scales[52]. Although previously reported to
have poor diagnostic value[55],
Lid-parallel conjunctival folds (LIPCOFs), have been shown to be a promising
diagnostic sign[56]
and a potential screening tool[57] for DED. LIPCOFs can be easily detected and graded by
slit-lamp examination, however, more objective methods such as optical
coherence tomography (OCT) have been developed for its classification[58-59].
TEAR FILM OSMOLARITY
Tear film osmolarity reflects the
balance between tear production, evaporation, drainage and absorption[60]. Quantitative
measurements of these variables can identify any imbalance and thus the cause
of DED due to associated derangement in the normal physiological parameters[60]. A single
osmolarity reading maybe normal in DED patients and thus an average tear film
osmolarity, rather than a static value, should be utilized for improved
diagnosis[61].
Moreover, variability of tear film osmolarity has been shown to be directly
correlated with DED severity[62].
Three main methods are used to
measure the tear osmolarity: freezing point depression (the gold standard), vapor
pressure method and electrical impedance of tear film[63-65].
Devices Using Electrical Impedance to Measure Tear
Osmolarity Electrical conductivity of tear film can be easily utilized
in clinical practice as it requires a small tear film volume and a short test
time (30s). TearLab osmometer is a new device that measures tear film
osmolarity based on the number of the charged particles in the tear film sample[66-67]. Without using anesthetic or
manipulation of the eyelids, the device can collect a small, but sufficient,
tear sample using a small chip touching the tear film[67]. It measures the electrical
impedance in a 50-nL tear film sample[67]. The I-Pen® is a new device that measures
the electrical impedance using flexible sensor touching the conjunctiva.
However, it has been suggested to be deficient in differentiating between
normal eyes and DED[68].
Vapor Pressure Concept Vapor pressure osmometry is a highly accurate technique
utilized to measure tear osmolarity. The main disadvantages were previously
related to the impracticality of the test due to tear evaporation and reflex
tearing and the need of large TV (5 mL)[66]. Wescor 5520 model is a new
device that depends on the concept of vapor pressure to measure the tear film
osmolarity, however, it can process smaller sample volumes (up to 0.2 microns)
using a specialized sample holder, allowing better clinical feasibility and
decreased error[64].
Freezing Pressure Osmometers Freezing pressure osmometers have been the gold standard
to measure tear film osmolarity[63]. They can work accurately on a very small sample size
up to 0.2 µL, allowing basal tears to be obtained rapidly minimizing the risk
of contamination which may lead to falsely low osmolarity readings[63]. One limitation
for its use includes being operator-dependent with resultant operator-bias. It
also requires an extensive apparatus and is time consuming, requiring up to
fifteen minutes per measurement[64].
TEAR FILM STABILITY
Tear film break up time (TBUT) is a
commonly used technique to measure tear film stability. TBUT using fluorescein
is more liable, repeatable and minimally invasive. Performing the test without using
fluorescein can better asses the tear stability but still lacks the information
on tear evaporation[69].
Fluorescein can destabilize the tear film affecting the results[69]. Non-invasive
methods for evaluating the TBUT by capturing images of rings reflected by the
tear film include the TFLL interferometry, the xeroscope and the Keeler
tearscope and are superior to traditional methods in that the tear film is
undisturbed by fluorescein; however, their results are not standardized[52,70-71]. Topographic analysis, which uses the corneal contour
to provide data about regularity of the corneal surface and measures tear
stability in patients with tear dysfunction, can give only one result at a time[72]. To overcome this
limitation, a software was made to allow corneal topography instruments to take
multiple measures and give dynamic results[70]. The system takes 10
consecutives corneal topograms over 10s period; and uses the intensity of the
light reflected from each point to make a wave pattern that can be used to
measure tear stability[70].
Instruments such as the Oculus Keratograph
FUNCTIONAL VISUAL ACUITY
Another attempt to monitoring and
reaching DED diagnosis was made by creating a device that relies on visual
acuity[75].
Patients usually notice transient blurring of vision that is influenced by
environmental factors, time of day, job requirements, and rate of blinking and
visual demands[75].
FVA was defined as functional vision for daily activities[75].
The proposed method for measuring
visual acuity with the eyes kept open without blinking (for 10 to 20s) after
the instillation of 30 mL of 0.4% oxybuprocaine chloride into the eye[76]. However, the
accuracy of measurements, inter-test variations and the timing of measurements
all represented significant drawbacks to this method[77].
The Functional Visual Acuity
Measurement System (SSC-350) may be used in patients who should refrain from
blinking for 30s after a topical anesthetic instillation for the process[76]. DED patients
were found to have a decreased FVA that can improve with treatment[78]. Accordingly, the
device is thought to be useful in the diagnosis of DED and following up
treatment.
MEIBOGRAPHY
Meibography is a valuable imagining
tool that allows for direct clinical evaluation of MGD, which is at the root of
evaporative DED. MGD can be broadly classified according to secretion rate into
Low delivery (obstructive or hyposecretion) and high delivery (hypersecretory)
states both having either primary or secondary underlying etiological origins[79]. MGD is more
commonly associated with evaporative DED than aqueous-deficient dry eye[80]. The two
principle meibography techniques are contact transillumination and the most
recent non-contact meibography (NCT) which allows for non-invasive evaluation
morphological abnormalities and quantification of MG loss (MGL)[81]. Infrared
meibography is the most common meibographic technology utilized in both contact
and non-contact techniques, however more recent technologies including laser
confocal meibography and optical coherence tomographic meibography are
available[82].
Recent advances have led to more compact and mobile devices that can be easily
be used in common clinical practice[80]. Meibography alone cannot be used to diagnosis of DED
however it is a useful clinical tool that can reinforce the diagnosis of
evaporative DED[79].
TEAR VOLUME
The Schirmer test is one of the most
commonly used tests for measuring tear production and diagnosis of dry eye
given that it is simple, cheap and readily available, however, it has many
limitations; and its results are non-reproducible and inaccurate due to the
reflex tear component[83].
Furthermore, the test lacks standardization and can only quantify tear
production in terms of volume without considering other etiologies that may
contribute to the pathophysiology of DED, such as evaporative aspects and the actual
tear constituents[83-84]. Although phenol
red test, which measures TV production, is more difficult to perform compared
to Schirmer test; it is less irritating and needs less testing time[69].
Tear film meniscus height reflects
the overall TV, which in turns indicates the secretion and drainage rates of
the lacrimal system[85].
The tear film meniscus can be measured quantitatively in a minimally invasive
manner[86].
Classically, TV was measured using slit lamp, photography, video recording, or
a tearscope. Recently, anterior segment optical coherence tomography (AS-OCT),
is used as an accurate non-invasive method to measure the height of tear
meniscus, which in turn reflects TV[61]. It has been proven that tear meniscus measurements
correlate with fluorescein staining and TBUT in DED patients[61]. AS-OCT captures and analyzes
the tear meniscus image according to tear meniscus area, depth, and height. It
can be used to differentiate between normal and DED patients based on the tear
meniscus area and height[85].
AS-OCT can also measure epithelial thickness which is affected by tear film
dysfunction[87].
AS-OCT ensures good repeatability and can be used to follow up changes of tear
meniscus morphology after fluid instillation[88]. Thus, AS-OCT can be used as a
rapid, qualitative and quantitative method of determining tear clearance rate.
It has been suggested that changes in tear meniscus morphology and tear
clearance measured by AS-OCT is a function of age[88]. Advanced AS-OCT technology can
acquire 3D images of Meibomian glands which appear to be parallel to each other
like clusters of grapes with clearly visible saccular acini in healthy
individuals[89].
Analysis of tear film dynamics during blinking in DED patients using AS-OCT
revealed reduced tear meniscus volume and height in DED patients compared to
healthy individuals except for volume of the upper tear film meniscus[90]. Epithelial
integrity factor has been proposed as an objective quantitative measure for
corneal surface irregularities using high resolution AS-OCT with scores ranging
from 0 to 4[91].
TEAR TURNOVER
Reduced tear turnover (TT) results
in the ocular surface inflammation and positively correlated with DED symptoms[92].
Adequate physiological tear
clearance depends on the integrity of the lacrimal system, and the rate of
clearance is the summation of tear secretion by the lacrimal glands and ocular
surface epithelia, fluid transudation through the conjunctiva, tear
evaporation, tear drainage through the nasolacrimal system, and corneal and
conjunctival permeability[49].
Tear clearance is used to reflect ocular surface irritation, severity of the
ocular surface disease[49],
MGD[93], and
decreased ocular surface sensitivity[94].
Tear function index (TFI) and fluorescein
clearance test (FCT) measure tear clearance by fluorescein instillation and a
testing strip in the lower conjunctival fornix. Length of the wetted part is
measured through serial measurements, and intensity of dye staining is compared
to standard strip colors[78].
Fluorophotometery is the gold
standard for measuring TT and TV; however, it is expensive and requires a lab
and special expertise which makes it not practical clinically and limits its
use to research purposes[73].
The International DEWS report presents assessment of TT rate with
fluorophotometery as one of the additional measures of tear film that can be
used to diagnose and monitor DED and addressed the need to develop cheaper,
shorter and more simple methodologies[1].
TEAR FILM COMPOSITION
Meibum Lipid Composition, Structure and Function The TFLL constitute 0.3% of the thickness of the tear
film and is mostly derived from meibomian glands, with minor contribution from
sebaceous glands[95].
In conjunction with other tear film components, the TFLL has a multitude of
equally important functions, including suppressing evaporation, stabilizing the
air/tear surface and serving as a first line of defense against bacterial
invasion[96].
Multiple analytical tools, including infrared spectroscopy and H1-NMR
spectroscopy can be used to uncover the compositional and structural details of
human meibum. Human meibum’s contribution to the tear film stability has been
shown to decline with advancing age[39-40],
MGD[97] and
hematopoietic stem cell (HSCT) transplant patients[98]. This decline has been
correlated to changes in the meibum composition and structure. Meibum lipid
order (viscous structure), positively associated with lipid saturation and
phase transition temperature, has been shown to increase in MGD patients[99] and HSCT
transplant patients[98],
however, contrasting studies have reported an increasing[40] vs a decreasing[39,99] lipid order with advancing age
and in both cases attributed to the decreased tear film stability. Increased
unsaturation, associated with decrease in lipid order, could contribute to
decreased tear film stability with age[39]. Lipid order in infants is higher than adults and
associated with enhanced tear film (TF) stability[39], whereas, an even higher lipid
in MGD patients is associated with diminished stability[99]. The changes in meibomian lipid
order can be used as a discriminatory marker for MGD with an accuracy of 93%,
thus a promising diagnostic marker for DED[99]. Heating eye lids, associated
with increased lipid disorder, has been shown to ameliorate symptoms in DED
patients[100].
Furthermore, treatment with azithromycin, in addition to ameliorating symptoms,
was associated with reduction of the meibum lipid order, which further stresses
the relationship between lipid order and tear film stability[101]. Meibum should
be balanced, such that it is fluid enough to exit the meibomian glands while at
the same time rigid enough to form a continuous layer that can withstand shear
stress and resist TF breakup[8].
Meibum compositional changes, such as lower cholesteryl esters in MGD patients,
can also serve as diagnostic markers that can discriminate between normal and
DED patients and can potentially be used to follow up efficacy of treatment[102].
Tear Film Biomarkers
A biomarker is defined as a
certain parameter that can be objectively measured and quantified to reflect a biological
process whether physiological or pathological[103]. Biomarkers can be classified
according to what they reflect for example predictive, diagnostic or for
monitoring[103].
For a biomarker to be approved for clinical practice certain criteria should be
met, such as sensitivity, specificity, reproducibility and cost effectiveness[104]. However, the
same diagnostic challenge of DED still stands regarding finding it suitable
biomarkers and the multifactorial etiology of the disease creates an obstacle
to look for a single parameter[104].
There is very strong and valid
evidence that inflammation constitutes an important pillar in the pathophysiology
of DED. Increased inflammatory cells, increased expression of immune activation
and adhesion molecules, T-helper type 1 (Th-1) and Th-17 attracting immune
pathways, cytokines, and chemokines are all evidence supporting the
inflammatory pathology of dry eye[105].
Thus, in the ongoing attempts to
diagnose this multifactorial disease, several studies attempted to tackle these
specific proteins and inflammatory cells and compare their values between DED patients
and healthy controls to serve as biomarkers for diagnosing and monitoring the
disease[106].
Several studies have analyzed the
protein profile in tears of dry eye patients and difference in certain proteins
were found between DED patients and those of controls such as (S
In one study, tear samples from 24
patients with DED were compared to that of 18 control subjects[107]. The panel of
proteins in each group was comparatively studied. The ratio of proteins from
each of the 24 patients was calculated relative to that collected from the 18
healthy controls, using isobaric tagging for relative and absolute
quantification (iTRAQ) technology[107]. The study showed increasing tear levels of S
S
A large study compared patients with
dry eye to controls and found increased levels of IL-1b, IL-6, IL-8, TNF-α, and
IFN-γ and increased expression of lipocalin, cystatin SN, and a-1 antitrypsin
in tears of dry eye patients as compared to the control subjects[110]. Protein
amounts were 2 to 2.5 times greater in dry eye patients as compared to
controls. Cystatin SN and IL-6 showed the greatest differences when comparing
values of DED patients to controls[110]. Subjects in the study were further subdivided into
controls (CTRL), patients with aqueous-deficient dry eye (DRYaq), patients with
changes of the lipid layer (DRYlip), and patients with a combination of both
(DRYaqlip).Variation in protein profiles was most noticeable when comparing DED
patients and controls in case of DRYaq or a DRYaqlip. On the other hand,
minimal differences were observed in protein profiles when comparing of lipid
layer deficiency patients with controls[110].
In aqueous deficient DED patients,
cystatin SN was elevated up to 3-fold compared with controls, other proteins
were increased between 2-folds to 3-folds. The cytokine with the most
pronounced difference between DRYaq group and controls was TNF-α with a 2.5fold
difference[110].
The significance of these findings is that proinflammatory cytokines are
involved in the promotion of the differentiation of naive CD4 cells to Th17 T
cells, which are important cells in autoimmune processes, thus fortifying the
hypothesis of the inflammatory nature of DED[111].
Matrix metalloproteinases (MMPs) are
enzymes found in high levels in cases of ocular inflammation, which contributes
to the pathophysiology of DED[112]. It has been found that MMP-9 level is positively
associated with decreased low-contrast visual acuity, scores of corneal and
conjunctival fluorescein staining among other parameters. Also, it is
negatively associated with fluorescein TBUT[113]. The InflammaDry test detects
MMP
Another study was preformed to study
C-C chemokine receptor type 5 (CCR5) and its ligands on the ocular surface and
how they correlate with the severity of symptoms in DED patients. They studied
the expression of the MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/ CCL5, and CCR
CCL5/RANTES levels is significantly
and positively correlated with each of the following parameters TBUT, basal
tear secretion, tear clearance rate, keratoepitheliopathy score and goblet cell
density[114].
CCR5 is a receptor for the chemokine
ligands CCL3, -4, and -5, it was found to be expressed on a number of different
cells including activated (memory) Th-1 lymphocytes[115]. Thus, documented
overexpression of CCR
In the study CCL5 level showed
significant correlation with different tear film and ocular surface parameters
when compared to both CCL3 and CCL4[114]. Accordingly, CCL5 can be considered the most
important cytokine for T cells involved in the pathophysiology of DED[114].
CONCLUSION
The prevalence of DED is increasing
with the increasing number and extent of DED risk factors, however its
diagnosis remains challenging given its multifactorial etiology and frequent
discordance between signs and symptoms. Various diagnostic tools and techniques
are available, however, combining results from more than one test, in addition
to signs and symptoms, can lead to a more dependable diagnosis, especially that
no single test can measure all the factors involved in the pathophysiology of
DED. With that, DED diagnosis continues to be a challenge that invites for the
development of new tools and technologies and conduction of further research in
the field.
ACKNOWLEDGEMENTS
The authors thank Hazar M. Kanj for
her insightful suggestions.
Conflicts of Interest: Elhusseiny
AM, None; Khalil
AA, None; El Sheikh RH, None; Bakr MA, None; Eissa MG, None;
El Sayed YM, None.
REFERENCES