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Review Article

A review on recent advances in dry eye: Pathogenesis and

management
Ankita S. Bhavsar, Samir G. Bhavsar1, Sunita M. Jain
Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380 009, 1Department of Ophthalmology,
S. K. Hospital and P. S. Medical College, Karamsad, Anand 388 325, Gujarat, India

Keratoconjunctivitis
sicca,
more
commonly
known as dry eye, is an extremely common and
often unrecognized disease. It is the condition in
ophthalmology that in its mild grade of severity will
affect most of the population at one time or other. Due
to a wide variety of presentations and symptoms, it
often frustrates the ophthalmologists as well as patients.
Due to multifactorial and elusive etiology, it is often
challenging to treat dry eye. Ocular surface disorders
are also clinically important to treat especially in terms
of visual acuity. Xero-dacryology is therefore becoming
a very important branch of ophthalmology. Recent
studies have given insight into the inflammatory
etiology of dry eye. The conventional and main
approach to the treatment of dry eye is providing
lubricating eye drops or tear substitutes. However, the

Introduction
Dry eye is one of the most frequently encountered ocular
morbidities, a growing public health problem and one of the
most common conditions seen by eye care practitioners.[1] In
the light of new knowledge about the roles of ocular surface
inflammation and tear hyperosmolarity in dry eye and the effects
of dry eye on visual function, the International Dry Eye Workshop
(DEWS) defined dry eye as a multifactorial disease of the tears
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DOI:
10.4103/0974-620X.83653

newer treatment approach is to target the underlying

cause of dry eye instead of conventional symptomatic
relief. In light of the above knowledge, the present
article focuses on newer theories on pathogenesis of
dry eye and their impact on dry eye management.
Method of Literature Search: A systematic literature
review was performed using PubMed databases in two
steps. The first step was oriented to articles published
for dry eye. The second step was focused on the role
of inflammation and anti-inflammatory therapy for
dry eye. The search strategy was not limited by year
of publication. A manual literature search was also
undertaken from authentic reference books on ocular
surface disease.
Keywords: Apoptosis, inflammation, pathogenesis

and ocular surface that results in symptoms of discomfort, visual

disturbance, and tear film instability with potential damage to the
ocular surface. It is accompanied by increased osmolarity of the
tear film and inflammation of the ocular surface.[2]
Over the past few years, as a result of numerous studies, new
concepts of pathogenesis have shown that dry eye seems to be caused
by inflammation mediated by T-cell lymphocytes.[3-5] This finding
has also been augmented by the studies investigating the role of
antiinflammatory therapies. Consequently, because of the increasing
importance of the role of inflammation in etiopathogenesis, we
have included recent understanding of pathogenesis and treatment
of dry eye disease (DED) in the present article.

Lacrimal Functional Unit The Newer Concept

DEWS in 2007 recognized dry eye as a disturbance of the

Copyright: 2011 Bhavsar AS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Correspondence:
Dr. Sunita M. Jain, Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India.
E-mail: sunitalmcp@yahoo.com

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Bhavsar, et al.: Dry eye disease

Lacrimal Functional Unit (LFU) whose parts act together and not
in isolation. It is an integrated system comprising the lacrimal
glands, ocular surface (cornea, conjunctiva and meibomian
glands) and lids, and the sensory and motor nerves that connect
them[2] [Figure 1].
Abnormality of any of several subparts of the lacrimal functional
unit can be transferred across the entire system through its
extensive neural connections to result in an unstable and
unrefreshed tear film having altered composition like elevated
tear osmolarity, presence of proinflammatory mediators and
proteases, which no longer supports the normal functioning of
the ocular surface.[6]

Etiology and Risk Factors of Dry Eye Disease

The last decade has brought about significant improvement in
the understanding of the etiology and pathogenesis of DED.[7]
Appreciation of the role of inflammation in DED was one of
the most important factors that aided in the understanding and
treatment of DED. The findings of the association of inflammation
with reduced tear secretion and subsequent damage to the ocular
surface led to the proposal of a unified concept of DED.[8] Older
age and female sex (particularly peri and postmenopausal age)
are wellknown risk factors for DED.[9,10] Hormonal studies suggest
that sex hormones influence ocular surface conditions through
their effects on tear secretion, meibomian gland function, and
conjunctival goblet cell density.[11] Chronic androgen deficiency
is associated with meibomian gland dysfunction. Postmenopausal
women who use hormonal replacement therapy (HRT) especially
estrogen alone, have a higher prevalence of DED compared with
those who have never used HRT.[12,13]

provoke symptoms of dry eye.[17,18]

Dry eye can be worsened by low relative humidity (RH) conditions
like office environment, air-conditioned cars, airplane cabins and
extreme hot or cold weather.[19,20] Certain systemic medications
can cause dry eye.[9] Frequent use (>4-6 times daily) of preserved
eye drops (including glaucoma medications and artificial tears)
may contribute to DED because of the well established toxicity of
preservatives like benzalkonium chloride.[21]

Role of Inflammation in Etiopathogenesis of

Dry Eye
There has been considerable increase in knowledge regarding
pathogenesis of dry eye. Though the term keratoconjunctivitis
sicca (KCS) was used for more than 50 years, it is only recently
recognized that inflammation of the ocular surface is part of
the pathophysiology of dry eye. In KCS patients, ocular surface
inflammation can be evaluated as both the cause and the
consequence of cell damage. A dangerous vicious cycle ensures
between ocular inflammation and dry eye, which in turn may
lead to sight threatening complications [Figure 2]. The role of
inflammatory cytokines and matrix metalloproteinases (MMPs)
in the pathogenesis of dry eye seems to be very important for
both the easier understanding of KCS and for the discovery of new
therapeutic agents.[22-24]

Other factors that precipitate and/or exacerbate DED include

long-term contact lens wear, refractive surgeries such as laserassisted in situ keratomileusis (LASIK) or photorefractive
keratectomy (PRK),[9,14,15] smoking,[16] extended visual tasking
during computer use, television watching and prolonged reading

As mentioned earlier, disease or dysfunction of any component

of lacrimal functional unit disrupts the delicate balance between
secretion and degradation of tear components on the ocular
surface which destabilizes the tear film with delayed tear
clearance that causes ocular irritation and epithelial abnormalities
leading to KCS or DED.[25] Any condition that results in rapid
stimulation of the lacrimal functional unit (e.g. due to dryness)
will induce neurogenic inflammation within the acini of lacrimal
gland resulting in antigen presentation and cytokine production,
ultimately leading to activation of T cells. Normally when there is
no inflammation, these T lymphocytes undergo apoptosis. But in

Figure 1: The lacrimal functional unit

Figure 2: Vicious cycle of ocular surface inflammation

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Bhavsar, et al.: Dry eye disease

the presence of inflammation, they are activated, become resistant
to apoptosis and secrete proinflammatory cytokines which results
in even more Tcell activation.[26,27] One of the causes of lacrimal
dysfunction in Sjogren syndrome is lymphocytic infiltration of
the lacrimal gland with damage to secretory acini. The presence
of focal lymphocytic infiltrates and increased production of
proinflammatory cytokines are characteristic findings of lacrimal
gland inflammation.[28] Release of inflammatory cytokines by
infiltrating inflammatory cells and diseased lacrimal epithelial
cells themselves further causes epithelial cell dysfunction or
apoptosis.[29]

Thus, it can be summarized that the dysfunction of any component

of lacrimal functional unit can result in unstable tear film with
altered tear film composition, ocular discomfort and ocular
surface disease. The end result is ocular surface inflammation
starting a vicious cycle of dryness and more inflammation.

Apoptosis of the ocular surface epithelium which may serve as one

of the initiating events is further exacerbated by the inflammatory
process and the decreasing levels of lacrimal gland derived factors.
This is evident by increased expression of proapoptic markers
(e.g. Fas, Fas ligand, CD40, CD40 ligand) by the conjunctival
epithelium.[30]

Common DED symptoms are dry, scratchy, gritty or sandy feeling,

foreign body sensation, pain or soreness, burning, itching and
increased blinking.[37] Two complaints provide important clues
that patients may be suffering from dry eye: exacerbation of
irritation by environmental stress and exacerbation of irritation
by activities that require prolonged visual attention.[38] A number
of questionnaires are available for evaluation of various aspects of
DED symptomatology, including severity, effect on daily activities
and quality of life. The ocular surface disease index (OSDI)[39]
permits quantification of common symptoms and provides a
reasonably objective approach to the evaluation of symptoms over
time. It is a valuable tool in clinical treatment trials.[40]

Disease or dysfunction of the lacrimal functional unit leads

to changes in tear film composition and stability, which have
adverse consequences for the ocular surface. Common feature of
dysfunctional unit is elevated tear osmolarity.[31] There are several
reports suggesting that hyperosmolarity induces inflammation.[31,32]
The role of inflammation in the etiopathogenesis of DED is briefly
summarized in Figure 3.
Androgens are important for providing trophic support to
the lacrimal functional unit as well as creating a general antiinflammatory environment.[33,34] Decrease in androgen levels
can cause loss of the anti-inflammatory environment within
the lacrimal gland. Meibomian glands are also androgen target
organs. As circulatory androgen level drops (e.g. in menopause),
the lacrimal tissue becomes vulnerable to immunogenic
inflammation.[26] Relative androgen deficiency might explain the
greater prevalence of dry eye in women. Alteration of either mucin
distribution or mucin glycosylation on the surfaces of apical
epithelial cells is also involved in the pathogenesis of dry eye.[35]

Diagnosis of Dry Eye

Currently, there are no uniform criteria for the diagnosis of DED.
Traditionally, combinations of diagnostic tests have been used to
assess symptoms and clinical signs.[36]

Physical examination includes visual acuity measurement,

external examination, and slit-lamp biomicroscopy for grading
the severity of DED.[25] Dry eye is classified according to the
clinical severity into three grades.[41]
Grade 1 or mild: Patients have symptoms of dryness in normal
environmental conditions but no signs on slit-lamp examination.
However, other electrophysiological or invasive tests, such as
hyperosmolarity, hypolysozyme or inflammatory cytokines, may
be positive.
Grade 2 or moderate: In addition to symptoms, patient has
reversible slitlamp signs such as epithelial erosion, punctate
keratopathy, filamentary keratitis, short tear breakup time
(TBUT), etc.
Grade 3 or severe: The patient has, besides the symptoms of
ocular dryness, signs that have evolved to permanent sequelae
such as corneal ulcer, corneal opacity, corneal neovascularization
or squamous epithelial metaplasia. These signs are commonly
seen in untreated patients.
Additional diagnostic tests may be performed to assess tear film
instability, ocular surface damage and aqueous tear flow.

Tear film stability assessment

Figure 3: Etiopathogenesis of dry eye disease

52

It is commonly done by performing TBUT.[38] Values of

<10 seconds have traditionally been considered abnormal.
Noninvasive breakup time (NIBUT) is a test of tear stability that
does not involve the instillation of fluorescein dye. Measurements
are performed with a xeroscope or keratometer.[42]
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Ocular surface integrity

Fluorescein, Rose Bengal and lissamine green are the dyes used
to view any conjunctival and corneal abnormalities.[42,43] The
staining pattern can be photographed and graded using one of
several scoring systems,[36] for example, Van Bijsterveld scoring
system for Rose Bengal dye. Intensity of stain is scored in two
exposed conjunctival zones (nasal and temporal) and cornea.
Score of 03 is given for each zone where 0 is for no stain, +1 for
separate spot, +2 for many separate spots, and +3 for confluent
spots, with a maximum score of 9.[43]

Aqueous tear flow

It is commonly assessed by performing a Schirmer test which is
of two types. Schirmer 1 (without topical anesthesia) to measure
reflex tearing and Schirmer II also known as Jones test (with
anesthesia) to measure basal tearing by minimizing ocular surface
reflex activity. Value of less than 6 mm of strip wetting in 5 minutes
is accepted as diagnostic marker for aqueous tear deficiency.[42]
Other diagnostic tests that may be performed include the
following:
Fluorescein clearance: This test measures tear clearance
or turnover. Delayed clearance has been associated with
increased tear cytokine concentration, which may contribute
to chronic inflammation.[44]
Corneal topography: A number of non-invasive techniques
like videokeratography may be useful as an objective test for
diagnosing and evaluating the severity of DED.[45,46]
Impression cytology: This test serves as a minimally invasive
alternative to ocular surface biopsy. Superficial layers of the
ocular surface epithelium are collected (e.g. by applying filter
paper) and examined microscopically. Impression cytology is
useful for detecting abnormalities such as goblet cell loss and
squamous metaplasia.[47]
Although useful for confirming the diagnosis, the above diagnostic
test results generally correlate poorly with symptoms.[9]
Tear hyperosmolarity is a global mechanism of DED. It is clear
from the comparison of the diagnostic efficiency of various tests
for KCS, used singly or in combination, that osmolarity could
potentially provide a gold standard for DED diagnosis.[48]

Treatment Approaches
As evident from pathophysiology of dry eye, many factors
contribute to or exacerbate dry eye, including: tear deficiency, tear
instability, irritation and inflammation. Over the past few years, as
a result of numerous studies, new concepts of pathogenesis have
shown that DED seems to be inflammatory in origin, mediated by
Tcell lymphocytes.[3,5] This finding has also been augmented by
the studies investigating the role of anti-inflammatory therapies.
So, in the last few years, there has been a paradigm shift in the
strategy to treat DED. However, conventional treatment still has
importance. Therapy of dry eye requires a multipronged approach
Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011

including tear conservation, and tear replacement through

methods such as, punctual plug, novel antiinflammatory drugs
and surgical procedures.

Tear conservation techniques

Patients with a clinical diagnosis of mild dry eyes may benefit
from behavioral and environmental modification which causes
preservation of existing tears by reducing evaporation, such as
learning to take breaks while reading, lowering the computer
monitors to decrease lid aperture, use of protective glasses
with side pieces in outdoor setting and humidification of the
environment.[49,50]
Punctal occlusion is a good tear conserving method and should
be considered for patients with aqueous tear deficiency when
medical means of aqueous enhancement are not useful. It can be
temporary occlusion by punctual plugs or permanent occlusion
by thermocautery, radiofrequency needle[51] or argon laser
canliculoplasty.[52]

Tear substitutes
Still they are the mainstay of treatment for mild to moderate aqueous
tear deficiency. They are aqueous solutions containing polymers
that determine their viscosity, retention time and adhesion to
ocular surface such as cellulose derivatives [e.g. hydroxypropyl
methyl cellulose (HPMC), carboxymethyl cellulose], polyvinyl
derivatives (e.g. polyvinyl alcohol), chondroitin sulfate, and
sodium hyluronate.[53]
Artificial tears provide temporary improvement in symptoms of
eye irritation, blurred vision and visual contrast sensitivity.[54]
Artificial tears containing preservatives, particularly benzylkonium
chloride, are poorly tolerated and harmful in moderate to severe
cases, especially if used frequently.

Antiinflammatory therapy
Due to a newer understanding of the pathogenesis of DED, use of
antiinflammatory medications is a paradigm shift in the treatment
of dry eye. It addresses the root cause of the dry eye instead of
giving symptomatic relief as done by lubricants. Antiinflammatory
therapy is considered to be the first causative therapeutic
approach in the treatment of dry eye, since its objective is to
interrupt the inflammatory cascade.[24,55]
In this section of the review, we present uptodate antiinflammatory
therapy strategies discussing both well-known and newly designed
current novel medications.
1 Cyclosporine A (CsA): Several clinical studies have shown
topical CsA to improve both objective and subjective sign
of KCS.[56-59] It is a fungal derived peptide that prevents Tcell
activation and inflammatory cytokine production.[60] It also
inhibits mitochondrial mediated pathways of apoptosis.
Recently, several large multicentric randomized trials
confirmed the safety and efficacy of topical application of CsA
for the treatment of dry eyes. It marks the first step in shifting
focus of the therapy into the underlying mechanisms that
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Bhavsar, et al.: Dry eye disease

contribute to the development and progression of the disease.
2 Corticosteroids: Numerous studies have concluded that
topical or systemic corticosteroid therapy may have several
benefits in the treatment of moderate to severe dry eyes.[50,62,63]
It is very effective for achieving a quick response by
nonspecifically inhibiting many aspects of the inflammatory
response.[64] However, it has to be emphasized that careful
monitoring is mandatory in these cases because of steroidrelated complications[63] like glaucoma and posterior
subcapsular cataract in addition to increased chance of local
infection.
3 Tetracycline: Though traditionally used as an antibiotic,
tetracyclines have a number of anti-inflammatory properties.
They inhibit the production and action of inflammatory
cytokines and matrix metalloproteinase. Oral doxycycline
can be used in all patients with dry eyes who have significant
component of meibomian gland disease.[25,64]
4 Essential fatty acids: Omega3 and omega6 essential fatty
acids (EFAs) are the precursors of eicosanoids, locally acting
hormones involved in mediating inflammatory processes.[65]
Recent studies have shown significant improvement in ocular
irritation symptoms and decreased ocular surface lissamine
green staining by EFA like linolenic acid and gammalinolenic
acid administered orally.[66,67] Dietary supplementation
of omega-3 EFA has already proven to be effective in
coronary heart disease and arthritis. Evidence suggests that
supplementation with omega-3 EFA may be beneficial in the
treatment and prevention of DED.[68]
5 Autologous serum: Serum and plasma contain many
antiinflammatory factors which include inhibitors of
inflammatory cytokines and inhibitors of MMPs. They
have potential to inhibit mediators of the ocular surface
inflammatory cascade of dry eye.[64] The major limitation is
that it requires special preparation for each patient and also
carries the risk of infection.[25]
6 Novel therapeutic agents with antiinflammatory properties:
Numerous researches continue to establish new therapeutic
agents for cases with dry eye, in addition to the agents
explained above. For instance, one of the promising agents is
the antiCD4 monoclonal antibody.[69] There are several reports
which suggest that hydroxychloroquine, when given orally for
the treatment of Sjogren syndrome, has a beneficial effect on dry
eye, also with an improvement in all diagnostic parameters.[70,71]
There are reports that DA-6034 (7-carboxymethyloxy-3,4,5trimethoxy flavone) has the therapeutic effect in rabbit
lacrimal gland inflammation model of dry eye and might be a
potential treatment option for acute DED.[75]

Secretagogues
They are cholinergic agonists that stimulate endogenous tear
production by the lacrimal glands and/or ocular surface epithelia
(e.g. oral pilocarpine).[73] The main limitation is systemic
cholinergic side effects like sweating, nausea and intestinal
cramping.[25] Recently, a muscarinic acetylcholine receptor agonist,
cevimeline, has been approved for use against symptoms of dry
mouth in patients with Sjogren syndrome. It has been found that
54

cevimeline is safe and effective in improving symptoms of dry eye

in patients with Sjogren syndrome.[74]
Recently, the safety and efficacy of CF101, an A (3) adenosine
receptor agonist, has been explored. The results show a
statistically significant improvement in the corneal staining and
an improvement in the tear film breakup time and tear meniscus
in patients with moderate to severe dry eye syndrome.[75]
Lastly, along with conventional medicine, research in alternative
medicines such as acupuncture and yoga reported beneficial effect
in the treatment of DED.[76]

Surgical treatment
In patients who continue to have significant pathology despite
medical therapy, surgical treatment may be considered in a
stepwise fashion.[25]
1 Punctal occlusion: One of the most useful and practical
therapies for conserving tears. Purpose is to decrease
physiological outflow of the tear film down the nasolacrimal
system.
2 Tarsorrhaphy and botulinum toxin induced ptosis: They
decrease the palpebral aperture height, thus decreasing tear
evaporation.
3 Salivary gland transplantation: Reported to be successful in
patients with severe lacrimal gland dysfunction with intact
salivary function (e.g. Sjogren syndrome), radiation-induced
lacrimal gland atrophy or surgical removal of lacrimal
gland. Though the results appear to be promising, there is
disadvantage of technical complexity and altered tear film
consistency and composition and possibility of tear secretion
during eating (i.e. crocodile tears).
In conclusion, the therapy of dry eye traditionally involved
hydrating and lubricating the ocular surface, which may provide
temporary improvement in symptoms of irritation and blurred
vision, but did not address the inflammation that is the underlying
cause of dry eye. New insights into the inflammatory nature of this
disease have led to a paradigm shift in the therapeutic approach
to KCS. In particular, treatment is now directed more toward
suppressing the inflammatory response on the ocular surface.

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Cite this article as: Bhavsar AS, Bhavsar SG, Jain SM. A review on recent
advances in dry eye: Pathogenesis and management. Oman J Ophthalmol
2011;4:50-6.
Source of Support: Nil, Conflict of Interest: None declared.

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Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011