Вы находитесь на странице: 1из 0

50 Oman Journal of Ophthalmology, Vol. 4, No.

2, 2011
Review Article
A review on recent advances in dry eye: Pathogenesis and
management
Ankita S. Bhavsar, Samir G. Bhavsar
1
, Sunita M. Jain
Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380 009,
1
Department of Ophthalmology,
S. K. Hospital and P. S. Medical College, Karamsad, Anand 388 325, Gujarat, India
Correspondence:
Dr. Sunita M. Jain, Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad 380009, Gujarat, India.
E-mail: sunitalmcp@yahoo.com
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
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.
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
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
Access this article online
Quick Response Code:
Website:
www.ojoonline.org
DOI:
10.4103/0974-620X.83653
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal
Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011 51
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]
Other factors that precipitate and/or exacerbate DED include
long-term contact lens wear, refractive surgeries such as laser-
assisted in situ keratomileusis (LASIK) or photorefractive
keratectomy (PRK),
[9,14,15]
smoking,
[16]
extended visual tasking
during computer use, television watching and prolonged reading
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 Infammation 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]
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
Bhavsar, et al.: Dry eye disease
Figure 1: The lacrimal functional unit Figure 2: Vicious cycle of ocular surface infammation
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal
52 Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011
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]
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]
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 anti-
inflammatory 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]
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.
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]
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]
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
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]
Bhavsar, et al.: Dry eye disease
Figure 3: Etiopathogenesis of dry eye disease
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal
Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011 53
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
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
Bhavsar, et al.: Dry eye disease
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal
54 Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011
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 steroid-
related 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-3,4,5-
trimethoxy 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
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.

References
1. OBrien PD, Collum LM. Dry eye: Diagnosis and current treatment
strategies. Curr Allergy Asthma Rep 2004;4:314-9.
2. The defnition and classifcation of dry eye disease: Report of the Defnition
and Classifcation Subcommittee of the International Dry Eye Workshop
(2007). Ocul Surf 2007;5:75-92.
3. Gao J, Schwalb TA, Addeo JV, Ghosn CR, Stern ME. The role of apoptosis
in the pathogenesis of canine keratoconjunctivitis sicca: The effect of
topical cyclosporine A therapy. Cornea 1998;17:654-63.
4. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical
cyclosporine treatment of patients with dry eye syndrome: Effect on
conjunctival lymphocytes. Arch Ophthalmol 2000;118:1489-96.
5. Stern ME, Gao J, Schwalb TA, Ngo M, Tieu DD, Chan CC, et al. Conjunctival
T-cell subpopulations in Sjgrens and non- Sjgrens patients with dry
eye. Invest Ophthalmol Vis Sci 2002;43:2609-14.
Bhavsar, et al.: Dry eye disease
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal
Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011 55
6. Pfugfelder SC. The Lacrimal Functional Unit. In: Pfugfelder SC, Roger
WB, editors. Dry eye and Ocular Surface disorders. New York: Marcel
Dekker; 2004. p. 11-32.
7. Gayton JL. Etiology, prevalence and treatment of dry eye disease. Clin
Ophthalmol 2009;3:405-12.
8. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pfugfelder SC. A
unifed theory of the role of the ocular surface in dry eye. Adv Exp Med
Biol 1998;438:643-51.
9. The epidemiology of dry eye disease: Report of the Epidemiology
Subcommittee of the International Dry Eye Workshop (2007). Ocul Surf
2007;5:93-107.
10. Lambert DW, Foster CS, Perry HD. Schirmer test after topical anesthesia
and the tear meniscus height in normal eyes. Arch Ophthalmol
1979;97:1082-5.
11. Connor CG, Flockencier LL, Hall CW. The infuence of gender on the
ocular surface. J Am Optom Assoc 1999;70:182-6.
12. Krenzer KL, Dana MR, Ullman MD, Cermak JM, Tolls DB, Evans JE, et al.
Effect of androgen defciency on the human meibomian gland and ocular
surface. J Clin Endocrinol Metab 2000;85:4874-82.
13. Schaumberg DA, Buring JE, Sullivan DA. Hormone replacement therapy
and dry eye syndrome. JAMA 2001;286:21149.
14. Ang RT, Dartt DA, Tsubota K. Dry eye after refractive surgery. Curr Opin
Ophthalmol 2001;12:318-22.
15. Donnenfeld ED, Ehrenhaus M, Solomon R, Mazurek J, Rozell JC, Perry
HD. Effect of hinge width on corneal sensation and dry eye after laser
in situ keratomileusis. J Cataract Refract Surg 2004;30:790-7.
16. Lee AJ, Lee J, Saw SM, Gazzard G, Koh D, Widjaja D, et al. Prevalence
and risk factors associated with dry eye symptoms: A population based
study in Indonesia. Br J Ophthalmol 2002;86:1347-51.
17. Schlote T, Kadner G, Frudenthaler N. Marked reduction and distinct
pattern of eye blinking in patients with moderately dry eyes during video
display terminal use. Graefes Arch Clin Exp Ophthalmol 2004;242:306-12.
18. Blehm C, Vishnu S, Khattak A, Mitra S, Yee RW. Computer vision
syndrome: A review. Surv Ophthalmol 2005;50:253-62.
19. Wolkoff P, Njaard JK, Troiano P, Piccoli B. Eye complaints in the offce
environment: Precorneal tear flm integrity infuenced by eye blinking
effciency. Occup Environ Med 2005;62:4-12.
20. Wolkoff P, Njaard JK, Franck C, Skov P. The modern offce environments
desiccate the eye? Indoor Air 2006;16:258-65.
21. Management and therapy of dry eye disease: Report of the Management
and Therapy Subcommittee of the International Dry Eye WorkShop
(2007). Ocul Surf 2007;5:163-78.
22. Corrales RM, Villarreal A, Farley W, Stern ME, Li DQ, Pfugfelder SC.
Strain-related cytokine profles on the murine ocular surface in response
to desiccating stress. Cornea 2007;26:579-84.
23. Li DQ, Pfugfelder SC. Matrix metalloproteinases in corneal infammation.
Ocul Surf 2005;3(4 Suppl):S198-202.
24. Gumus K, Cavanagh DH. The role of infammation and antiinfammation
therapies in keratoconjunctivitis sicca. Clin Ophthalmol 2009;3:57-67.
25. Djalilian AR, Pedram H, Pfugfelder SC. Dry Eye. In: Krachmer, Mannis,
Holland, editors. Cornea, Vol 1, 2
nd
ed. Philadeiphia: Elsevier; 2005. p.
521-38.
26. Dana MR, Hamarah P. Role of immunity and infammation in corneal
and ocular surface disease associated with dry eye. Adv Exp Med Biol
2002;506:729-38.
27. Hamarah P, Haq SO, Gulati A, Dana MR. Mechanism of ocular surface
immune response. In: Pfugfelder SC, Roger W.B, editors. Dry eye and
Ocular Surface disorders. New York: Marcel Dekker; 2004. p. 111-41.
28. Zoukhri D. Effect of infammation on lacrimal gland function. Exp Eye Res
2006;82:885-98.
29. Zhu Z, Stevenson D, Ritter T, Schechter JE, Mircheff AK, Kaslow HR,
et al. Expression of IL-10 and TNF-inhibitor genes in lacrimal gland
epithelial cells suppresses their ability to activate lymphocytes. Cornea
2002;21:210-4.
30. Brignole F, De Saint Jean M, Goldschild M, Becquet F, Goguel A,
Baudouin C. Expression of the fas-fas ligand antigens and appropriate
marker apo2.7 by the human conjunctival epithelium. Positive correlation
with class II HL-DR expression in infammatory ocular surface disorders.
Exp Eye Res 1998;67:687-97.
31. Farris RL. Tear osmolarity- a new gold standard? Adv Exp Med Biol
1994;350:495-503.
32. Schwartz L, Guais A, Pooya M, Abolhassani M. Is infammation a
consequence of extracellular hyperosmolarity? J Infamm (Lond)
2009;23:21.
33. Mircheff AK. Hormonal support of lacrimal function, primary lacrimal
defciency, autoimmunity and peripheral tolerance in the lacrimal gland.
Ocul Immunol Infamm 1996;4:145-52.
34. Azzarolo AM, Mircheff AK, Kaswan RL, Stanczyk FZ, Gentschein E,
Becker L, et al. Androgen support of lacrimal gland function. Endocrine
1997;6:39-45.
35. Danjo Y, Watanabe H, Tisdale AS, George M, Tsumura T, Abelson MB, et
al. Alteration of mucin in human conjunctival epithelia in dry eye. Invest
Ophthalmol Vis Sci 1998;39:2602-9.
36. Methodologies to diagnose and monitor dry eye disease: Report of the
Diagnostic Methodology Subcommittee of the International Dry Eye
WorkShop (2007). Ocul Surf 2007;5:108-52.
37. Perry HD. Dry Eye Disease: Pathophysiology, classifcation, and
diagnosis. Am J Manag Care 2008;14(3 Suppl):S79-87.
38. Cintia S, DE Pavia, Pfugfelder SC. Diagnostic approaches to lacrimal
keratoconjunctivitis. In: Pfugfelder SC, editors. Dry eye and ocular surface
disorders. New York: Marcel Dekker; 2004. p. 270.
39. Perry HD, Donnenfeld ED. Dry eye diagnosis and management in 2004.
Curr Opin Ophthalmol 2004;15:299-304.
40. Meyer D. Diagnostic tests and principles in dry eye syndrome. In: Garg A,
editor. Clinical diagnosis and management of dry eye and ocular surface
disorders (Xero-Dacryology). 1
st
ed. New Delhi: Jaypee; 2006. p. 65-82.
41. Murube J, Nemeth J, Hoh H. The triple classifcation of dry eye for practical
clinical use. In: Garg A, editor. Clinical diagnosis and management of dry
eye and ocular surface disorders (Xero- Dacryology). 1
st
ed. New Delhi:
Jaypee; 2006. p. 45-59.
42. Yokoi N, Komuro A. Non-invasive methods of assessing the tear flm. Exp
Eye Res 2004;78:399-407.
43. Van Bijsterveld OP. Diagnostic test in sicca syndrome. Arch Ophthalmol
1969;82:10-4.
44. Afonso AA, Monroy D, Stern ME, Feuer WJ, Tseng SC, Pfugfelder SC.
Correlation of tear fuorescein clearance and Schirmer test scores with
ocular irritation symptoms. Ophthalmology 1999;106:803-10.
45. De Paiva CS, Lindsey JL, Pfugfelder SC. Assessing the severity of keratitis
sicca with videokeratoscopic indices. Ophthalmology 2003;110:1102-9.
46. Huang FC, Tseng SH, Shih MH, Chen FK. Effect of artifcial tears on
corneal surface regularity, contrast sensitivity, and glare disability in dry
eyes. Ophthalmology 2002;109:1934-40.
47. Calonge M, Diebold Y, Saez V, Enrquez de Salamanca A, Garca-
Vzquez C, Corrales RM, et al. Impression cytology of the ocular surface:
A review. Exp Eye Res 2004;78:457-72.
48. Tomlinson A, Khanal S, Ramaesh K, Diaper D, McFadyen A. Tear Film
Osmolarity: Determination of a Referent for dry eye diagnosis. Invest
Ophthalmol Vis Sci 2006;47:4309-15.
49. Tsubota K, Yamada M, Urayama K. Spectacle side panels and moist
inserts for the treatment of dryeye patients. Cornea 1994;13:197-201.
50. Pfugfelder SC, Stern ME. Therapy of Lacrimal Keratoconjunctivitis. In:
Pfugfelder SC, Roger WB, editors. Dry eye and ocular surface disorders.
New York: Marcel Dekker; 2004. p. 309-20.
51. American Academy of Ophthalmology. Punctal occlusion for the dry eye.
Three-year revision. ophthalmic procedure assessment. Ophthalmology
1997;104:1521-4.
52. Awan KJ. Laser punctoplasty for the treatment of punctual stenosis. Am J
Ophthalmol 1985;100:341-2.
53. Lemp MA. Artifcial tear solutions. Int Ophthalmol Clin 1973;13:221-9.
54. Haung FC, Tseng SH, Shih MH, Chen FK. Effect of artifcial tears on
corneal surface regularity, contrast sensitivity and glare disability in dry
eyes. Ophthalmology 2002;109:1934-40.
55. Kymionis GD, Bouzoukis DI, Diakonis VF, Siganos C. Treatment of chronic
dry eye: Focus on cyclosporine. Clin Ophthalmol 2008;2 Suppl 4:829-36.
Bhavsar, et al.: Dry eye disease
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal
56 Oman Journal of Ophthalmology, Vol. 4, No. 2, 2011
56. Gunduz K, Ozdemir O. Topical cyclosporin treatment of keratoconjunctivitis
sicca in secondary Sjgrens syndrome. Acta Ophthalmol (Copenh)
1994;72:438-42.
57. Sall KN, Cohen SM, Christensen MT, Stein JM. An evaluation of the
effcacy of a cyclosporine-based dry eye therapy when used with
marketed artifcial tears as supportive therapy in dry eye. Eye Contact
Lens 2006;32:21-6.
58. Salib GM, McDonald MB, Smolek M. Safety and effcacy of cyclosporine
0.05% drops versus unpreserved artifcial tears in dry-eye patients having
laser in situ keratomileusis. J Cataract Refract Surg 2006;32:772-8.
59. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized
studies of the effcacy and safety of cyclosporine ophthalmic emulsion
in moderate to severe dry eye disease. CsA Phase 3 Study Group.
Ophthalmology 2000;107:631-9.
60. Matsuda S, Koyasu S. Mechanism of action of cyclosporine.
Immunopharmacology 2000;47:119-25.
61. Sjogren H. Keratoconjunctvitis sicca. In: Ridly F, Sorsby A, editors. Modern
Trends in Ophthalmology. London: Butterworth; 1940. p. 403-13.
62. Marsh P, Pfugfelder SC. Topical nonpreserved methylprednisolone
therapy for keratoconjunctivitis sicca in Sjgren syndrome. Ophthalmology
1999;106:811-6.
63. Hong S, Kim T, Chung SH, Kim EK, Seo KY. Recurrence after topical
nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in
Sjgrens syndrome. J Ocul Pharmacol Ther 2007;23:78-82.
64. Pfugfelder SC. Antiinfammatory therapy for dry eye. Am J Ophthalmol
2004;137:337-42.
65. Rosenberg ES, Asbell PA. Essential fatty acids in the treatment of dry eye.
Ocul Surf 2010;8 Suppl 1:18-28.
66. Barabino S, Roland M, Camicione P, Ravera G, Zanardi S, Giuffrida S,
et al. Systemic linoleic acid and gamma linolenic acid therapy in dry eye
syndrome with an anti-infammatory component. Cornea 2003;22:97-101.
67. Aragona P, Bucolo C, Spinella R, Giuffrida S, Ferreri G. Systemic omega-6
essential fatty acid treatment and pge1 tear content in Sjgrens syndrome
patients. Invest Ophthalmol Vis Sci 2005;46:4474-9.
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, Confict of Interest: None declared.
Bhavsar, et al.: Dry eye disease
68. Roncone M, Bartlett H, Eperjesi F. Essential fatty acids for dry eye: A
review. Cont Lens Anterior Eye 2010; 33 Suppl 2:49-54; quiz 100.
69. Hayashi Y, Ishimaru N, Arakaki R, Tsukumo S, Fukui H, Kishihara K, et
al. Effective treatment of a mouse model of Sjgrens syndrome with
eyedrop administration of anti-CD4 monoclonal antibody. Arthritis Rheum
2004;50:2903-10.
70. Fox RI, Dixon R, Guarrasi V, Krubel S. Treatment of primary Sjgrens
syndrome with hydroxychloroquine: A retrospective, open-label study.
Lupus 1996;5 Suppl 1:S31-6.
71. Yavuz S, Asfurolu E, Bicakcigil M, Toker E. Hydroxychloroquine improves
dry eye symptoms of patients with primary Sjogrens syndrome. Rheumatol
Int 2010 [In press].
72. Seo MJ, Kim JM, Lee MJ, Sohn YS, Kang KK, Yoo M. The therapeutic
effect of DA-6034 on ocular infammation via suppression of MMP-9 and
infammatory cytokines and activation of the MAPK signaling pathway in
an exp erimental dry eye model. Curr Eye Res 2010;35 Suppl 2:165-75.
73. Garg A. In: Garg A, editor. Clinical diagnosis and management of dry
eye and ocular surface disorders (Xero-Decryology). New Delhi: Jaypee;
2006. p. 99.
74. Ono M, Takamura E, Shinozaki K, Tsumura T, Hamano T, Yagi Y, Tsubota
K. Therapeutic effect of cevimeline on dry eye in patients with Sjgrens
syndrome: A randomized, double-blind clinical study. Am J Ophthalmol
2004;138 Suppl 1:6-17.
75. Avni I, Garzozi HJ, Barequet IS, Segev F, Varssano D, Sartani G, et al.
Treatment of Dry Eye Syndrome with Orally Administered CF101 Data
from a Phase 2 Clinical Trial. Ophthalmology 2010;117:1287-93.
76. Lee MS, Shin BC, Choi TY, Ernst E. Acupuncture for treating dry eye: A
systematic review. Acta Ophthalmol 2011;89:101-6.
Announcement
Android App
A free application to browse and search the journals content is now available for Android based
mobiles and devices. The application provides Table of Contents of the latest issues, which
are stored on the device for future offline browsing. Internet connection is required to access the
back issues and search facility. The application is compatible with all the versions of Android. The
application can be downloaded from https://market.android.com/details?id=comm.app.medknow.
For suggestions and comments do write back to us.
[Downloadedfreefromhttp://www.ojoonline.orgonSaturday,August31,2013,IP:114.79.13.49]||ClickheretodownloadfreeAndroidapplicationforthisjournal