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 Table of Contents  
Year : 2021  |  Volume : 59  |  Issue : 1  |  Page : 38-51

Current concepts and future trends in dry eye syndrome – A review of literature

1 Department of Cornea, Aravind Eye Hospital, Puducherry, India
2 Department of Pediatric Ophthalmology and Squint, Aravind Eye Hospital, Puducherry, India

Date of Submission09-Aug-2020
Date of Acceptance10-Nov-2020
Date of Web Publication27-Mar-2021

Correspondence Address:
Dr. Kirandeep Kaur
Department of Pediatric Ophthalmology and Squint, Aravind Eye Hospital, Puducherry - 605 007
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjosr.tjosr_108_20

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Keratoconjunctivitis sicca, also known as dry eye (DE), is an extremely common and often unrecognized pathological entity. It is characterized by decreased tear production or increased evaporation and manifests with a wide spectrum of signs and symptoms. Due to multifactorial and elusive etiology, it is often a challenge to treat DE syndrome. Ocular surface disorders are also clinically very important to manage especially in terms of visual acuity. A comprehensive understanding of the pathophysiology and etiology of DE disease (DED) leads to more meticulous management and treatment of the pathological process. The present review article after detailed literature review aims to provide information on the definition, epidemiology, classification, causes, diagnostic tests, and medical and surgical management and futures trends of DED.

Keywords: Dry eye syndrome, dry eyes, Sjogren's syndrome, tear film

How to cite this article:
Gurnani B, Kaur K, Kumar MC. Current concepts and future trends in dry eye syndrome – A review of literature. TNOA J Ophthalmic Sci Res 2021;59:38-51

How to cite this URL:
Gurnani B, Kaur K, Kumar MC. Current concepts and future trends in dry eye syndrome – A review of literature. TNOA J Ophthalmic Sci Res [serial online] 2021 [cited 2021 Oct 20];59:38-51. Available from: https://www.tnoajosr.com/text.asp?2021/59/1/38/312271

  Introduction Top

Dry eye (DE) is a multifactorial disease of the tears and ocular surface that is characterized by symptoms of discomfort, visual disturbance, tear film disturbance, and instability with potential damage to the ocular surface, accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.[1] DE syndrome (DES) is also called keratitis sicca, keratoconjunctivitis sicca (KCS), sicca syndrome, xerophthalmia, ocular surface disease (OSD), DE disease (DED), or dysfunctional tear syndrome (DTS), or simply DEs.[2] DES is associated with decreased ability to perform certain activities such as reading, driving, and computer-related work, which require visual attention. Patients experience DE symptoms constantly and severely, affecting their quality of life.[3],[4],[5],[6],[7] Despite its high prevalence, DE is frequently under-recognized and misdiagnosed. Owing to its negative influence on patient's visual function and quality of life, DE represents a big burden in public healthcare and sometime poses challenges for a cornea specialist to manage. Therefore, attempts to find advances in diagnostic approaches and appropriate treatment for DE are worthy of consideration. This review discusses the definition, epidemiology, classification, causes, diagnostic tests, and medical and surgical management and futures trends of DED.

  Literature Search Top

A systematic literature review was performed using PubMed, Google Scholar, ePub, and Cochrane Library databases in two steps. The first step was oriented to search articles published for dry eyes AND (review) AND (treatment OR updates), dry eye, dry eye disease, dry eye syndrome (DES), keratoconjunctivitis sicca, and Sjogren syndrome. The second search was focused on the role of inflammation, anti-inflammatory therapy, and management of DED. Relevant articles were reviewed from various national and international journals. A total of 144 articles were searched, 102 articles were selected and included based on the relevance, and the rest 42 articles were excluded based on similar literature. The search strategy was not limited only by the year of publication. A manual literature search was also undertaken from authentic reference books on OSDs.

  Definition Top

The dynamic definition for DED has been revised multiple times. In 1995, the National Eye Institute (NEI) defined DED as “a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.[8]” This definition was later modified by, in 2007, International DE Work Shop. They defined it 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] In 2017, International DE Workshop II (DEWS II) report described DE as “a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”[9]

  Epidemiology Top

Estimated prevalence ranges from about 5% to over 35% in different age groups.[10] DED is seen with an increased prevalence in patients affected with autoimmune diseases,[11] which affect approximately 8% of the population, of whom major chunk around 78% are women.[12] According to various studies, how the study is cited, how the pathology is diagnosed, and which population is surveyed, the prevalence of DED is estimated to be 7.4%–33.7%.[13],[14] The Beaver Dam population-based study reported the DED prevalence rate to be 14% in adults aged 48–91 years.[15] In Australia, the prevalence of DED is approximately 7.4%, with a significant increase of prevalence in elderly patients and a significant decrease of tear production in women between 50 and 59 years of age.[14] The prevalence of DE is approximately 27.5% in Indonesia, with increased prevalence associated with age, cigarette smoking, and pterygium.[16] In Taiwan, the prevalence of DED is 33.7% in a tested elderly population.[13] The prevalence of DE is also estimated at 25% in Canada[17] and 33% in Japan.[18] It is worth noting that the prevalence and incidence of DED, in the clinical setting, may also be under-reported, as patients may fail to recognize the symptoms of DED or do not report the problem to a physician.

  Tear Fluid Composition Top

The anatomy of tear film is divided into three main layers. The three-layered model of the tear film was proposed by Wolff and it is simple and logical: it consists of a mucin layer which covers the ocular surface and lowering the supposed hydrophobicity of the epithelial cells; an aqueous layer to nourish the exposed ocular epithelium by providing lubrication, some nutrients, antimicrobial proteins, and appropriate osmolarity; and finally a lipid layer to prevent further loss of the aqueous layer through overspill and evaporation.[9] Further, the innermost thinnest layer is produced by the cells of conjunctiva called mucin or mucus layer. The mucus facilitates the overlying watery layer to spread evenly over the eye. The middle aqueous layer is the largest and thickest produced by the glands of upper lids and the accessory tear glands and contains essentially a very dilute saltwater solution. This layer helps in maintaining moisture over the eyes and removal of any dust, debris, or foreign particles. Defects of this layer cause DES in most cases.[19] The uppermost lipid layer of tear film is a very thin layer produced by the  Meibomian gland More Detailss and the glands of Zeis (oil glands in the eyelids). This layer helps reduce evaporation of the watery layer beneath it. The mucous also decreases the surface tension between the lipid layer and the water layer, thus contributing to the stability of the tear film. The tear fluid also consists of a complex mixture of proteins, immunoglobulins, mucins, electrolytes, cytokines, lysozymes, lactoferrin, and growth factors.[20]

[TAG:2]The Recent Concept (Tear Film and Ocular Surface Society's Dry Eye Workshop II Tear Film Report)[10][/TAG:2]

Lipid layer

Lipid layer consists of nonpolar and polar (amphiphilic) lipids. This layer plays a vital role in stabilizing the whole of the tear film – by lowering the surface tension of the tear film. It is a known fact that the removal of lipids will enhance tear film evaporation; therefore, the lipid layer in consonance with other components of the tear film plays a role in preventing evaporation of water. The polar lipid (O-acyl)-hydroxy fatty acids (FAs) is vital in the dispersion of the whole lipid layer over the muco-aqueous layer.

Muco-aqueous phase

Muco-aqueous phase is made up of four major mucins and more than 1500 different proteins and peptides. These glycosylated proteins help to hydrate the tears. Diminished levels of MUC5AC expression in DED have been a regular finding, and deregulation of mucin synthesis is an important factor in OSD. A variety of proteins and peptides found in the muco-aqueous phase are known to change with DED.

Vitali et al. while writing about the harmonized classification criteria for Sjogren's syndrome (SS) mentioned that classification criteria are not necessarily appropriate for use in diagnosis and may lead to misclassification of a disease entity, particularly in its early stages.[21]

Although the NEI/Industry Workshop Classification[8] has served as a useful and reproducible scheme for over a decade, it does not reflect newer knowledge on pathophysiological mechanisms, effects on vision, and the utility of an assessment of severity of disease. Recently, two new classification schemes were published. These include the Triple Classification[22],[23] and the report of the Delphi Panel.[24] The Triple Classification evolved from the reports presented at the 14th Congress of the European Society of Ophthalmology.[21] An updated version was published in 2005, with further clinical upgradation which presented three separate schemes: one based on etiopathogenesis; one based on the glands and tissues targeted in DE; and one based on disease severity.[24] The Delphi Panel was a consensus group that met to review the classification of DE.[24] The Panel suggested that the name more accurately reflects the pathophysiological events in DE and proposed changing the name of DED to DTS.

Etiopathogenic classification of DED is shown in [Figure 1][1],[8] and conditions associated with non-SS (NSS) are shown in [Figure 2].[1],[8] The Revised International Classification criteria for ocular manifestations of SS are highlighted in [Table 1].[8],[9]
Figure 1: Broad classification of dry eye syndrome

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Figure 2: Conditions associated with non-Sjogren's syndrome

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Table 1: The revised international classification criteria for ocular manifestations of Sjogren's syndrome

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Mechanism of dry eye figure

The mechanism of DEs involves interaction of central nervous system, ocular surface, and lacrimal apparatus along with a multitude of factors plays a role in final outcom [Figure 3] and [Figure 4].[9]
Figure 3: Mechanism of dry eyes at the level of central nervous system, ocular surface, and lacrimal apparatus

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Figure 4: Detailed mechanism of dry eyes

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  Pathogenesis Top

Various studies performed on the proteomics of the ocular surface comparing DE with normal eyes using enzyme-linked immunosorbent assay have depicted decrease in lactoferrin and epidermal growth factor in DEs. Aquaporin P-5 found in acinar cells of the lacrimal gland was found to be increased in the Sjogren's type of DES, indicating possible leakage of such proteins into the tear film due to lymphocytic infiltration of the lacrimal gland.[25] Solomon et al.[26] showed an increase in inflammatory cytokines, i.e., interleukin (IL)-1 alpha and beta, in both meibomian gland dysfunction (MGD) and SS, indicating high protease activity on the ocular surface, mainly in the conjunctival epithelial surface. IL-6 was also increased in SS,[27] indicating an inflammatory pathology in this entity of DE. Another study evaluating sialic acid, a component of mucin in the tear film, found a lower level in DE patients compared to controls, indicating a change in quantity and quality of tear film glycoproteins in DED.[28] These changes in tear protein profile in DE patients, especially in Sjogren's disease, have given insights on mechanisms of DE.

  Etiology and Risk Factors Top

The mechanisms governing the association of inflammation with reduced tear secretion and subsequent trauma to the ocular surface have led to the proposal of a unified concept of DED.[29] Older age and female sex (particularly perimenopausal and postmenopausal age) are more prone to DED.[30],[31] Hormonal studies suggested that sex hormones alter ocular surface conditions through their effects on tear secretion, meibomian gland function, and conjunctival goblet cell density.[32] Chronic androgen deficiency is liked with MGD, and postmenopausal women who use hormonal replacement therapy – especially estrogen alone, have a higher prevalence of DED.[33] Other factors include smoking,[16] extended visual tasking during computer use, television watching, prolonged reading,[34] long-term contact lens wear, and refractive surgeries such as laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy.[35] DE can also be worsened by low relative humidity such as office environment, air-conditioned, airplane cabins, and extreme hot or cold weather.[36] Frequent use (>4–6 times daily) of preserved eye drops (including antiglaucoma medications and artificial tears) may contribute to DED because of the toxicity profile of preservatives such as benzalkonium chloride.[37]

  Symptoms and Signs Top

DE can present with varied symptoms and signs such as irritation, tearing, burning, stinging, dry or foreign body sensation, mild itching, photophobia, blurry vision, contact lens intolerance, redness, mucous discharge, increased frequency of blinking, diurnal fluctuation, and symptoms that worsen later in the day. Exacerbating conditions include wind, air travel, decreased humidity, and prolonged visual efforts associated with decreased blink rate such as reading or watching TV.[38] The DE severity grading scheme is tabulated in [Table 2].[1],[9]
Table 2: The dry eye severity grading scheme

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  Diagnostic Assessment Top

Although literature review provides an extensive discussion on the role and appropriateness of the currently used tests to diagnose DE, there is no gold standard test or even a panel of tests or well-established cutoff values for the available tests. The suggested sequence of DE diagnostic tests is history and examination followed by a symptom questionnaire; tear breakup time (TBUT) and ocular surface fluorescein staining; Schirmer's test; lid and meibomian morphology and meibomian expression. In Delphi Panel, the most frequently cited tests were slit lamp examinat'ion and fluorescein staining (100%) followed by TBUT and medical history (both 94%). An ideal diagnostic method should be preferably noninvasive, objective, specific, reproducible, and sustainable in terms of cost and time[24] [Figure 5].[1],[9],[11],[14] A review of diagnostic approaches are summarized in [Table 3].
Table 3: Tear Film and Ocular Surface Society's Dry Eye Workshop II diagnostic methodology report[10]

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Figure 5: Tests to diagnose and monitor dry eye disease

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  Subjective Evaluation Top

The symptoms and history of DE patients vary widely; therefore, validated questionnaires have been formulated to make sure consistency in recording symptomatic information. A comparative listing of DE questionnaires is available in the report of the Epidemiology Subcommittee of the International DEWS, 2007.[10] Previously, it was believed that DE can be diagnosed largely on the basis of symptoms; however, recent studies have questioned this opinion as there is often a lack of correlation between the severity of the symptoms and signs of DE.[39]

  Objective Evaluation Top

Objective evaluation can be in the form of TBUT, corneal staining, tear film assessment, conjunctival staining, and the Schirmer's test as the most commonly used diagnostic tests for the initial assessment of DE.[40] Apart from these traditional clinical tests, other less invasive evaluations available are tear hyperosmolarity, tear film instability, and inflammation.

Tear osmolarity

Tear osmolarity usually increases in all types of DE. A value >308 mOsms/L is a sensitive indicator of mild DE and values >312 mOsms/L are indicative of moderate-to-severe DE (sensitivity 73%; specificity 92%).[41] Tear film osmolarity can be measured in three ways: freezing point depression, (considered to be the gold standard);[42] vapor pressure,[43] and electrical conductivity or impedance.[44] Since the electrical impedance of tear samples requires a small sample size (0.05 μL) and short test duration (30 s), it is considered more suitable for clinical use.[45]

Assessment of tear stability

TBUT, described by Norn,[46] remains the most frequently used diagnostic test to determine tear film instability.[47] In addition, the noninvasive TBUT (NIBUT) involves the observation of reflection from the anterior tear surface of an illuminated grid pattern. It can be measured using topography, aberrometry, interferometry, functional visual acuity (FVA) measurement, and confocal microscopy. The time (in seconds) from the last blink to the appearance of the first discontinuity or break in the reflected image is recorded.

Tear film particle assessment

The tear film's upward spread and stability can be used for the precise and objective measurement of tear film by noninvasive tear film particle assessment technique.[48] Tear film particle velocity is a measure of tear hydrodynamics by tracking the movement of reflective particles in the tear film. Digital images of the central region of the ocular surface are collected for 10 s to visualize the naturally seen particles in the tear film following a natural blink. Software determines the velocity of the particles as they traverse upward in the tear film. This technique has been applied to the precontact lens tear film and also used for clinical evaluation of tear film stability more precisely and objectively.

Topographical analysis systems

Topographic modeling system-1[49] and high-speed video keratoscopy[50] are new topographical systems that have replaced older keratometers in clinical settings to evaluate indices such as surface regularity index, surface asymmetry index, and topographic pattern – that can be used to evaluate the corneal surface regularity and tear film stability. According to a 2008 survey, most of the experts chose video keratoscopy for initial evaluation of post-LASIK DE.[47]


The interference patterns of colored fringes between light and lipid layer and aqueous of tear film could be used to observe the nature, thickness, and rupture of the lipid layer.[51] Besides lipid layer thickness (LLT), interferometry can also assess NIBUT, i.e., the time between the last blink and the appearance of the first lipid layer discontinuity. Another commercially available interferometer is LipiView (TearScience Inc., Morrisville, NC, USA) that provides quantitative values of the tear film LLT, and this automated assessment of the LLT might be a suitable screening test for detecting MGD.[52]


Wave-front aberrometry is a noninvasive assessment of the visual disturbances caused by higher order aberrations arising from tear film instability and breakup. Any local changes in tear film thickness and regularity such as those associated with tear breakup introduce aberrations and subsequently reduce retinal image quality. Changes in tear volume and dynamics induce changes in higher order aberrations, which appear as characteristic patterns in both normal and DEs.[53],[54]

Functional visual acuity

The ocular surface becomes dry when normal blinking is reduced during gazing; patients with DES may have problems maintaining clear vision while gazing. FVA is an assessment of visual acuity during sustained eye opening without blinking. Later studies used a range of values, as well as the visual maintenance ratio (the ratio between the FVA and the baseline visual acuity) to reflect everyday vision more accurately.[55] Studies have proven that FVA decreases significantly in both SS DE patients NSS patients.[56] To improve FVA measurements, a new continuous FVA measurement system (FVAM, NIDEK, Gamagori, Japan) was developed, which allows continuous monocular visual acuity measurement during a 30 s blink-free period.[57]

Optical coherence tomography

The anterior-segment optical coherence tomography (OCT) can measure the tear film thickness[58] and tear meniscus parameters[59] which indicate total tear volume. Nguyen et al. found that lower tear meniscus measurement with Fourier-domain OCT correlates well with the symptoms of DE and the Schirmer's test.[60] It is important to factor in the role of tear secretion, location of the punctal, lacrimal drainage, lid length, eyelid tension, and palpebral aperture while interpreting tear meniscus dimensions. In addition, OCT has recently been used to grade lid parallel conjunctival folds,[61] to map 3-dimensional corneal epithelial thickness,[62] and to investigate meibomian gland structures based on the more developed techniques,[63] which would provide deeper insights into DE diagnosis and follow-up.

Noncontact confocal microscopy

A noncontact, tandem-scanning confocal microscope demonstrating real-time images has been used by some researchers to observe the tear film.[64] Debris was discovered in the central corneal region of tear film in dry and normal eyes. They concluded that the minimal alteration of tear film function and excellent focusing characteristics makes this a valuable tool for detailed imaging of tear film.

Evaluation of ocular surface and inflammation

Confocal microscopy

In vivo confocal microscopy enables the study of corneal epithelium, corneal stroma and keratocytes, endothelial cells, corneal nerves corneal immune and inflammatory cells, conjunctiva, and meibomian in different ocular and systemic diseases that is not possible with direct slit lamp examination. It may not only be used for diagnostic purposes but may also serve as a valuable tool to monitor the disease and measure therapeutic efficacy in patients with DE. It is has been suggested that this technique could be used for noninvasive impression cytology in DE evaluation.[65]

Meibomian gland evaluation

MGD is the most common cause of evaporative DE; the International Workshop on MGD recommended performing gland expression routinely for all asymptomatic patients.[66] Meibomian glands can be assessed visually using a slit lamp and an appropriate grading system.[67] Meiboscopy means transillumination of the eyelid using a white light, which is very “useful, quick, and patient-friendly.”[68] Meibography is a method of quantification of meibomian gland dropout that enables masked evaluation and therefore increases objectivity in clinical trials.[69]

Corneal and conjunctival staining

Corneal and conjunctival staining is an invasive procedure which enables the assessment of ocular surface damage by instilling a dye such as sodium fluorescein, rose Bengal, or lissamine green. Evaluation of ocular surface staining is highly subjective, but the use of charts such as the Oxford, Van Bijsterveld, and CLEK grading scheme can facilitate consistent recording of staining severity.[70] The repeatability of staining tests has been found to be poor,[71] and they lack discriminatory power in mild-to-moderate cases of DE.[72] The SS International Registry modified the Oxford grading scheme to enable concurrent grading of the cornea and bulbar conjunctiva using a combination of one drop of 0.5% fluorescein for corneal staining and one drop of 1% lissamine green for conjunctival staining. On a specially designed form, grades between 0 and 3 are assigned for staining the cornea, the nasal conjunctiva, and the temporal conjunctiva. This gives a maximum possible total of 9 points. Three additional points are then allocated for fluorescein only if there are confluent staining (t1), staining in the pupillary area (t1), or if one or more filaments are present (t1), giving a maximum possible score of 12. This study concluded that this would be a suitable test “for diagnosing the ocular component of SS in the future classification criteria.”[73]

Conjunctival impression cytology or brush cytology

Impression cytology is a rapid, minimally invasive, and relatively painless method of harvesting conjunctival epithelial, goblet, and inflammatory cells from the bulbar mucosa.[74] Fluorophotometry measures the uptake of fluorescein at the center of the cornea and is considered “a sensitive measure of epithelial integrity.”[75] As such, patients with DE demonstrate an increased corneal permeability and a slower rate of fluorescein elimination compared to patients with normal eyes. A correlation between tear cytokine levels and the severity of symptoms and ocular surface signs in all forms of DE has been found.[76]

  Management - Medical and Surgical Top

The management of DED is highly complicated because of its multifactorial etiology associated with many mechanisms.[10] Therefore, while diagnosing a patient with DE, clinicians should carefully determine the underlying etiology, such as evaporative or aqueous deficiency DE, which are the mechanisms that cause DED, and/or other OSDs, and they should administer relevant treatments accordingly.[77],[78] The ultimate goal of DED treatment is to restore homeostasis of the ocular surface and tear film by breaking the vicious cycle of the disease.[79] Besides short-term therapies, it is always necessary to consider long-term treatment by taking into consideration the sequelae that can occur during the chronic DEs. Various management algorithms are structured to propose a series of treatment protocols according to disease stage. Implementation of the management and therapeutic algorithm according to disease severity can be summarized in four steps [Table 4]. The initial step includes alteration of the local environmental milieu, dietary changes (including oral essential fatty acid [EFA] supplementation), patient education, identification and definitive modification/elimination of offending systemic and topical drugs, addition of ocular lubricants of various types (if MGD is suspected, then consider lipid-containing supplements), lid and ocular hygiene, and warm compresses. In the second step, the various treatment modalities include Demodex tea tree oil, preservative-free artificial tear drops, moisture chamber devices and goggles to maintain moisture and temperature, punctal plugs, ointment application, warming and expression device (such as Lipiflow) for opening the blocked meibomian glands using an intense pulsed based light therapy for MGD, and topical drugs such as corticosteroids, antibiotics, secretagogues, nonglucocorticoid immunomodulators (cyclosporine and tacrolimus),[80] LFA-1 antagonist drugs (lifitegrast), and oral macrolide or tetracycline antibiotics. If the above treatment options are not feasible, then oral secretagogues, autologous/allogenic serum eye drops, and rigid and soft contact lenses need to be considered in addition to the third-step treatment. In the last fourth step, if there are more severe complications associated with DEs, the clinician has to resort to additional treatment options, such as application of topical corticosteroid, amniotic membrane grafts (AMGs), surgical punctal occlusion, and other surgical approaches (e.g., tarsorrhaphy, salivary gland transplantation).[81]
Table 4: Tear Film and Ocular Surface Society's Dry Eye Workshop II management and therapy report[81]

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A combination of oral omega-3 fatty acid supplements, secretagogues, steroids, cyclosporine A (CsA), and artificial tears are used to combat underlying inflammation and restore normal tear film in patients with mild-to-moderate disease. Use of additional aggressive treatment options such as autologous serum, oral tetracycline, prosthetic lens, and systemic immunosuppressants is restricted to patients with more severe forms of DE. The most severe forms of chronic DE, often associated with systemic diseases such as SS and Steven Johnson syndrome, may benefit from surgical intervention, including tarsorrhaphy and AMGs. In addition, a stepwise guide to approach the best combination of medications to avoid symptoms of DE was also recommended.[82]

  Anti-Inflammatory Treatments Top

Cyclosporine A

CsA exerts immunosuppressive and anti-inflammatory activity through several pathways. Recently published literature has proven that topical administration of CsA controls ocular surface inflammation and is also effective in increasing tear secretion and tear film stability (possibly by promoting the local release of parasympathetic nervous system and through an increase in goblet cell density). Consequently, CsA may help in restoring epithelial damage and reducing disease recurrences over the long term.[83]


Topical corticosteroids are also used to reduce inflammation on the ocular surface in DE, often in combination with CsA. The effect of corticosteroids on the inflammatory cascade, specifically the blockade of cyclooxygenase, production of prostanoids from arachidonic acid, and stimulation of the apoptosis of lymphocytes, is well known and is likely the reason that this form of therapy has been efficacious in practice.[84] Corticosteroids also exert local immunomodulatory activity through the inhibition of certain transcription factor activity. Clinical trials have demonstrated the efficacy of topical corticosteroid treatment at diminishing symptom severity and minimizing ocular surface staining.[84]

Steroids treatment compared to cyclosporine[10]

Steroids help in neural pain modulation; topical corticosteroids are effective in breaking the vicious cycle of immune responses in DED, modulate anterior segment inflammation, restore tear production, and significantly improve the ocular surface.

The response is seen within days, but the disadvantage with steroids is that overuse can result in various complications ocular hypertension, cataracts, and opportunistic infections, even after short periods. In comparison, immunomodulators such as cyclosporine have anti-inflammatory properties, inhibit IL-2 activation of lymphocytes, improve tear production, reduce elevated tear osmolarity, and have antiapoptotic effects. The response usually delayed after 6 weeks of starting the therapy. Studies have shown that 0.5% loteprednol therapy 2 weeks before the initiation of long-term topical 0.05% cyclosporine provided rapid resolution of Schirmer'S scoring, corneal fluorescein and lissamine green staining, and signs and symptoms, than topical cyclosporine or artificial tears alone.

Hormonal therapy

Receptors for androgens, estrogens, progesterone, and prolactin have been identified in several ocular tissues, including the lacrimal gland and meibomian glands.[85] Administration of topically applied androgen and estrogen steroid hormones for 3–4 months has also been found to show clinical improvement in the form of increased tear production TBUT and LLT with corresponding symptomatic relief.[86] Systemic administration of combined esterified estrogen and methyl-testosterone for 4–24 months was found to reduce symptoms and promote clinical improvement in the postmenopausal women with DE.[86]

  Antibiotics Top

In addition to the antibacterial effect, macrolide antibiotics (azithromycin) and tetracycline derivatives (tetracycline, doxycycline, and minocycline) have immunomodulatory properties which have been noted to decrease ocular surface inflammation and normalize lipid production by the meibomian glands. These may be particularly useful in DE secondary to ocular rosacea and blepharitis. In addition, doxycycline is also known to downregulate the expression of CXCL8 and proinflammatory cytokines IL-1β and tumor necrosis factor (TNF) and inhibit the activity of matrix metalloproteinase activities (MMPs) (e.g., MMP-9). Similarly, the tetracycline derivative minocycline inhibits the expression of cell-associated proinflammatory molecules.[87]

  Supplementary Treatments Top

Investigations on the use of omega-3 (alpha-linolenic acid) and omega-6 (linoleic acid) EFAs in the treatment of DE have produced variable results; however, majority of the available evidence suggests that systemic administration of anti-inflammatory omega-3 FAs can lessen DE severity.[88] Topical EFAs have also been tried in murine DE models and have demonstrated potential therapeutic effect in the form of decreased ocular surface staining, cytokine expression, and immune cell infiltration. Similarly, topical administration of resolvin E1, an omega-3 FA derivative, has helped in increasing tear production, maintaining ocular surface integrity, alleviating cyclooxygenase 2 expression, and reducing immune cell infiltration in experimental models of DES.[89]

  Nerve Growth Factor Top

Nerve growth factor (NGF) has been observed to increase ocular surface sensitivity, inhibit inflammatory reactions, and regulate tear film production. Thus, NGF seems to a play a pivotal role in the pathophysiology of DE and may be a promising therapeutic option. For instance, tear concentration of NGF has been observed to be increased as a compensatory mechanism in DE, particularly under hyperosmolar stress, suggesting that NGF may be involved in reducing the apoptosis of corneal epithelial cells triggered by hyperosmolarity. In addition, NGF has been shown to regulate conjunctival epithelial differentiation into MUC5AC-secreting goblet cells.[90],[91]

  Autologous Serum Top

Autologous and umbilical cord serum contains substances that support the proliferation, differentiation, and maturation of the normal ocular surface epithelium and therefore finds application in the treatment of severe DE. Autologous serum eye drops have been found to be better than conventional therapy utilizing artificial tears in less severe cases of DE as well. A double-blind randomized clinical trial reported that a short-term treatment with 20% autologous serum eye drops achieved better symptomatic improvement than conventional artificial tears in DE patients.[92]

  Acupuncture Top

The use of acupuncture as a treatment for eye disease is based on the claims that acupuncture modulates autonomic nervous system and immune system, which in turn might regulate lacrimal gland function. While some authors have suggested that acupuncture can influence lacrimal gland secretions, others have postulated that it can alleviate pain intensity (or increase pain threshold).[93]

  Surgical Treatment Top

Punctal occlusion

Punctal occlusion reduces drainage, preserves natural tears, and prolongs the effect of lubricants. It is indicated in patients refractory to medical treatment, having a Schirmer's test result of <5 mm at 5 min, and showing the evidence of ocular surface dye staining. For instance, temporary occlusion that dissolves in 1 or 2 weeks. Long-lasting collagen plugs take approximately 2–6 months to dissolve. Silicon plugs are commonly used as reversible prolonged occlusion. Punctal occlusion using atelocollagen causes fewer complications. Permanent punctal occlusion may be achieved surgically using cauterization. Combined use of punctal plugs and cyclosporine 0.05% demonstrated better improvement in Schirmer's scores and rose Bengal staining and reduced overall artificial tear use compared to either treatment alone.[94]

  Salivary Gland Procedures Top

In 1951, when Filatov and Chevalijev described the parotid duct transfer to the conjunctival fornix, Murube et al. described the transfer of the submandibular salivary gland to the temporal region and implant of the Wharton duct into the upper fornix. Studies have also reported the use of a graft of labial mucosa and minor salivary glands to treat severe DE. Soares and Franca have routinely performed this surgery on patients with severe DE caused by SJS syndrome, chemical burns, pemphigoid, SS, and surgical removal of the lacrimal gland.[95]

  Subcutaneous Abdominal Artificial Tear Pump Reservoir Top

The artificial tear pump reservoir was suggested by Murube et al. for the treatment of severe DE. It was implanted into a subcutaneous pocket of the anterolateral abdominal wall and the silicon tube catheter is passed via chest, neck, and face to the upper conjunctival fornix.[96]

  Conclusion Top

The understanding of the pathogenesis and specific cellular responses involved in different forms of DE could result in the development of other treatment strategies for a better management and long-lasting results. The evidence implicating inflammation in the pathogenesis of DE has opened up new avenues for the treatment of this complex disorder. Development of additional treatment options in the form of compounds targeting specific components such as the epithelial barrier, corneal nerves, conjunctival goblet cells, or immune cells and cytokines involved in the ocular inflammatory reaction would provide hope for the millions of individuals who daily experience this deleterious condition.

Future trends – The future of dry eye treatment

The newer treatment modalities under investigation are:[97]

  1. Lifitegrast 5%: Small-molecule integrin antagonist
  2. Rebamipide: Quinolinone derivative mucin secretagogue
  3. MIM-D3 (Mimetogen Pharmaceuticals; Gloucester, MA, USA): Nerve growth factor peptidomimetic, mucin secretagogue
  4. OTX-DP: Sustained release dexamethasone-loaded punctal plug 0.4 mg
  5. EBI 005 (Eleven Biotherapeutics): Protein-based IL-1 inhibitor
  6. Diquafosol: P2Y2 receptor agonist
  7. RU-101: Recombinant human serum albumin
  8. KPI-121/LE-MMP 0.25%: Loteprednol etabonate mucus-penetrating particle, glucocorticoid receptor agonist
  9. Oculeve neurostimulator device: Intranasal lacrimal stimulator for DE
  10. Ocular iontophoresis with EG-437 (40 mg/mL dexamethasone phosphate solution).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

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