Dry eye disease: A review of diagnostic approaches and treatments

Abstract

Dry eye (DE) is a common ocular disease that results in eye discomfort, visual disturbance and substantially affects the quality of life. It has a multifactorial etiology involving tear film instability, increased osmolarity of the tear film and inflammation of the ocular surface with potential damage to the ocular surface. This review discusses the classification, diagnostic approaches and treatments of DE.

Introduction

Dry eye (DE) is 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, accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.¹ Estimated prevalence ranges from about 5% to over 35% in different age groups.² Despite its high prevalence, DE is frequently under-recognized. Owing to its negative influence on patients’ visual function and quality of life, DE represents a big burden in public healthcare. Therefore, attempts to find better diagnostic approaches and appropriate treatment for DE are worthy of consideration. This review discusses the classification, diagnostic approaches and treatments of DE.

Classification

The major classes of DE, as identified by the International Dry Eye Workshop (DEWS) report are aqueous deficient dry eye (ADDE) and evaporative dry eye (EDE).¹ Although both ADDE and EDE present with similar signs of reduced stability and increased tear film osmolarity, ADDE chiefly refers to a failure of lacrimal secretion and EDE is due to excessive water loss from the exposed ocular surface in the presence of normal lacrimal secretory function. It is also important to recognize that ADDE and EDE may coexist. The main etiopathogenic classification is illustrated in Fig. 1.

Figure 1.

Etiopathogenic classification (modified from 2007 DWES report).¹

Diagnostic assessment

Although literature provides an extensive discussion on the role and appropriateness of 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.³ The suggested sequence of DE diagnostic tests is: history and examination followed by a symptom questionnaire; tear break-up time and ocular surface fluorescein staining; Schirmer test; lid and meibomian morphology and meibomian expression.² In Delphi panel, the most frequently cited tests were slit-lamp examination and fluorescein staining (100%) followed by tear breakup time and medical history (both 94%).³ An ideal diagnostic method should be preferably noninvasive, objective, specific, reproducible and sustainable in terms of cost and time. At present, none of the current tests for DE diagnosis altogether meet these features.

Subjective evaluation

The symptoms and history of DE patients vary widely; therefore, validated questionnaires have been developed to ensure consistency in recording symptomatic information. A comparative listing of DE questionnaires is available in the report of the Epidemiology Subcommittee of the International DEWS 2007.² 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.⁴ This lack of consistency between signs and symptoms presents a problem not only in the diagnosis of the disease, but also in assessment of severity and in the evaluation of the clinical efficacy of treatments.

Objective evaluation

A scientific roundtable on dry eye ranked tear break up time (93%), corneal staining (85%), tear film assessment (76%), conjunctival staining (74%), and the Schirmer test (54%) as the most commonly used diagnostic tests for initial assessment of dry eye.⁵ Apart from these traditional clinical tests, we will discuss more about the less invasive evaluations based on the recently developed technologies related to tear hyperosmolarity, tear film instability and inflammation.

Tear osmolarity

An increase in tear osmolarity is common to all types of DE. It is suggested that osmolarity values greater than 308 mOsms/l are a sensitive indicator of mild DE and values greater than 312 mOsms/l are indicative of moderate to severe DE (sensitivity 73%; specificity 92%).⁶ The difference in the tear osmolarity values among normal, mild, moderate or severe dry eye patients is so small that precision is critical. Tear film osmolarity can be measured in three ways: freezing point depression (FPD), (considered to be the gold standard);⁷ vapor pressure⁸ and electrical conductivity or impedance.⁹ 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.¹⁰ The TearLab system (TearLab Inc., San Diego, CA, USA) uses this method to determine tear osmolarity. While recent studies have demonstrated the correlation between increased osmolarity and DE disease severity, it is also observed that “tear osmolarity cannot be used as the sole indicator of dry eye disease”.¹¹

Assessment of tear stability

The measurement of tear film stability is fundamental to the diagnosis of dry eye.¹² A variety of methods are available to assess different aspects of the tear film and provide insights into its “stability”. Tear break-up time (TBUT), introduced by Norn,¹³ remains the most frequently used diagnostic test to determine tear film instability.¹⁴ Generally, the non-invasive tear break-up time (NIBUT) involves the observation of an illuminated grid pattern reflected from the anterior tear surface. NIBUT can be measured by corneal topography, interferometry, aberrometry, functional visual acuity assessment, and confocal microscopy. A regular image of the reflected target indicates a stable tear film. 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

Non-invasive tear film particle assessment technique to measure tear film’s upward spread and stability can potentially be used for the precise and objective evaluation of tear film.^12,15 Tear film particle velocity is measured as an assessment 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 upwards in the tear film. This technique has been applied to the pre-contact lens tear film to differentiate the wetting characteristics of various contact lens materials, but can potentially be used for clinical evaluation of tear film stability more precisely and objectively.

Topographical analysis systems

Corneal topography systems like TMS-1¹⁶ and high speed videokeratoscopy (HSV)¹⁷ have replaced keratometers in clinical settings to evaluate indices like surface regularity index (SRI), surface asymmetry index (SAI) and topographic pattern – that can be used to evaluate corneal surface regularity and tear film stability. These videokeratoscopy indices enable objective quantification of the quality of the tear film, its breakdown and also consequent effects on image quality.¹⁸ According to a 2008 survey, most of the experts chose videokeratoscopy for initial evaluation of post-LASIK dry eye.¹⁴

Interferometry

Interferometry is based on the colored fringes that arise from interference between light reflected from the surface of the lipid layer and from the interface between the lipid layer and the aqueous layer of the tear film. These interference patterns could be used to observe the nature, thickness and rupture of the lipid layer.¹⁹ Besides lipid layer thickness, interferometry can also measure NIBUT i.e., the time between the last blink and the appearance of the first lipid layer discontinuity. LipiView (TearScience Inc., Morrisville, NC) is a commercially available interferometer that provides quantitative values of the tear-film lipid layer thickness (LLT), and this automated assessment of the LLT might be a suitable screening test for detecting meibomian gland dysfunction (MGD).²⁰ Other instruments, software and prototypes are also being developed.^21,22

Aberrometry

Wavefront aberrometry allows the non-invasive assessment of the visual disturbances caused by higher order aberrations arising from tear film instability and break-up. Any local changes in tear film thickness and regularity such as those associated with tear break-up 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 dry eyes.^18,23,24 Low tear volumes in severe DE may cause increased, but stable, aberrations. This may be the result of irregular, damaged epithelium in the optic zone in the absence of dynamic tear film changes.²⁵ The instillation of artificial tears has been shown to reduce aberrations in dry eye when the measurement is taken after several seconds²⁶; however, when measured 2 s after a blink, an initial increase in aberrations was found because of the tear film disturbances induced by increase in tear volume.²⁷ A paper presented at a recent conference suggested that aberrometry could be utilized for not only detecting DE but also for monitoring the efficacy of treatments.²⁸

Functional visual acuity

Despite normal conventional visual acuity, DE patients often complain about decreased visual acuity when driving, reading, and using a computer. Since the ocular surface tends to dry out when normal blinking is suppressed during gazing, patients with dry eye may have problems maintaining clear vision while gazing. To simulate visual acuity while gazing, functional visual acuity (FVA) was conceptualized. FVA is a measure of visual acuity during sustained eye opening without blinking.

FVA was originally defined as the monocular recognition acuity at a specific time point. 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.²⁹ It has been documented that FVA decreases significantly in both non-Sjögren’s syndrome (NSS) and Sjögren’s syndrome (SS) dry eye patients.³⁰ Despite the criticism that patients are required to keep their eyes open longer than normal, FVA tests have been commonly used to assess visual disturbances in DE patients. To further 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.³¹ The methodology has been useful for evaluating patients with tear instability and it has been reported that the assessments correlate with TBUT.³²

Optical coherence tomography

The anterior segment optical coherence tomography (OCT) can measure the tear film thickness³³ and tear meniscus parameters³⁴ which indicate total tear volume. Due to its high resolution, non-invasiveness, good accuracy, and repeatability, OCT is a useful tool to diagnose DE. Nguyen et al. found that lower tear meniscus measurement with Fourier-domain-OCT correlates well with symptoms of DE and the Schirmer test.³⁵ Shen suggested that lower tear meniscus height and radius were the best indicators of DE with a cut-off meniscus height of 1.64 mm and radius of 1.82 mm.³⁴ It is important to factor in the role of tear secretion, location of the punctum, lacrimal drainage, lid length, eyelid tension, and palpebral aperture while interpreting tear meniscus dimensions. Additionally, OCT has recently been used to grade lid parallel conjunctival folds (LIPCOF),³⁶ to map 3-dimensional corneal epithelial thickness,³⁷ and to investigate meibomian gland structures based on the more developed techniques,³⁸ which would provide deeper insights into DE diagnosis and follow-up.

Non-contact confocal microscopy

A non-contact, tandem-scanning confocal microscope demonstrating real-time images has been used by some researchers to observe the tear film.³⁹. 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

Corneal in vivo confocal microscopy (IVCM) is a novel, noninvasive, high-resolution tool that allows imaging the cornea at the cellular level and provides images comparable to histochemical methods. IVCM enables the study of corneal epithelium, corneal stroma and keratocytes, endothelial cells, corneal nerves, corneal immune and inflammatory cells, conjunctiva and meibomian glands 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 non-invasive impression cytology in DE evaluation.⁴⁰

IVCM observations in DE patients demonstrated significantly decreased cell densities in the superficial, intermediate, and basal epithelial layers,⁴¹ presumably due to increased desquamation of the superficial cell layer⁴² and activation of corneal keratocytes in the stroma.⁴³ IVCM also demonstrated a substantial decrease in number and density of sub-basal and stromal nerve cells in DE related conditions. Further, IVCM has demonstrated the abnormal morphology of sub-basal nerves such as increase in bead-like formation, sprouts, tortuosity, irregular branching patterns, and neuromas, which may be explained by nerve degeneration and regeneration, leading to active neural growth.⁴⁴ More recently, the non-invasive assessment of immune and inflammatory changes has become possible by laser IVCM that allows visualization of the cell components that could not be visualized earlier with previous white light IVCM machines. This is of particular interest in DE patients as over the past decade, the role of inflammation in DE disease has become clearly apparent. This technique could be used for non-invasive impression cytology.⁴⁰ The increased density of epithelial dendritic cells (Langerhans cells) observed by Lin et al. may indicate the heightened immune status of the cornea in DE.⁴⁵ Dynamic in vivo assessment of the central corneal inflammatory cell density may serve as an indicator of DE severity and provide new insight for DE treatment. Recently, IVCM has also been applied for the examination of meibomian glands, providing a new tool to assess their morphologic changes.⁴⁶ Finally, IVCM evaluation of conjunctival epithelium in DE demonstrated conjunctival epithelial cyst formation, decreased density of conjunctival epithelial cells, goblet cells and increased inflammatory cell density.^47,48

Meibomian gland evaluation

Meibomian glands are the source of lipids in the lipid layer of the tear film. Since MGD is the most common cause of evaporative dry eye, the International Workshop on MGD recommended performing gland expression routinely for all asymptomatic patients.⁴⁹ Meibomian glands can be assessed visually using a slit lamp and an appropriate grading system.⁵⁰ Meiboscopy involves the trans-illumination of the eyelid using a white light, which has been described as “useful, quick and patient-friendly”.⁵¹ Meibography is a method of quantification of meibomian gland drop-out that enables masked evaluation and therefore increases objectivity in clinical trials.⁵² Meibometry involves the use of a plastic tape to blot the central lower lid margin. The lipid blot changes the optical density and can be measured in a photometer to distinguish patients with MGD.⁵³

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.⁵⁴ The repeatability of staining tests has been found to be poor,⁵⁵ and they lack discriminatory power in mild to moderate cases of dry eye.⁵⁶

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 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 future classification criteria”.⁵⁷

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.⁵⁸ Studies have demonstrated that cytokines IL-1a, mature IL-1b, and IL-1Ra are found in a significantly greater percentage of conjunctival cytology specimens from eyes with SS, than in those from normal eyes.⁵⁹ Further, combined with flow cytometry, dry eye group was found to have a significant difference in the CD4/CD8 ratio compared with normal eyes, and almost double the number of CD14 positive cells (monocytes/macrophages). HLA-DR expression in CK19 positive conjunctival epithelial cells and matrix metalloproteinases levels were also found to be elevated in DE patients.^59,60 These studies illustrate how immune cells isolated from the superficial layer of the conjunctiva may influence the pathogenesis of DE. Flow cytometry analysis of epithelial and immune cells of the conjunctiva may emerge as new biomarkers of DE.

Conjunctival brush cytology using a soft brush obtains superficial cells (as in impression cytology) as well as basal cells. The sample can then be assessed for the presence of squamous metaplasia, inflammatory cells, and the expression of surface markers on the ocular surface epithelium.^61,62 This is often combined with flow cytology, which gives a highly sensitive and specific analysis of epithelial cell markers, inflammatory cells, and goblet cells.⁶²

Other tests

Fluorophotometry measures the uptake of fluorescein at the center of the cornea and is considered “a sensitive measure of epithelial integrity”.⁶³ 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.⁶⁴ Tear protein analysis and tear lipid analysis may provide more information on the etiology of DE as different tear proteins are present in DE with or without meibomian gland disease.^64,65 While the mild cases of DE exhibit normal tear production levels with no fluorescein staining, an increase in inflammatory cells could still be present. This indicates that inflammatory mediators in the tears are perhaps a better indicator of DE disease than the measure of tear production or staining. Recent advances in tear lipid analysis technology and instrumentation have seen huge progress in the field of lipidomics, which involves the identification and quantification of lipid molecular species and their interactions with other molecules, which can be used to diagnose MGD.⁶⁶

Treatment

Only a handful of therapies are available for DE patients and are used according to the disease severity.⁶⁷ Artificial tears provide palliative relief to eye irritation in patients with aqueous tear deficiency, but do not prevent the underlying inflammation or reverse conjunctival squamous metaplasia in chronic DE. Combinations of artificial tears, oral omega-3 essential fatty acid supplements, mucin secretagogues, short-term steroids, and daily cyclosporine A (CsA) are used to combat underlying inflammation and restore normal tear film in patients with mild-to-moderate disease. Use of more aggressive treatment options, such as autologous serum, oral tetracyclines, prosthetic lens, and systemic immune-suppressants is restricted to patients with more severe forms of DE. The most severe forms of chronic DE, often associated with systemic diseases – SS and Stevens–Johnson syndrome, may benefit from surgical intervention, including tarsorrhaphy and amniotic membrane transplant. The Delphi panel suggested that the severity of disease (categorized according to patient’s signs and symptoms, not tests) should be the primary determinant for the therapeutic strategy chosen. Additionally, a stepwise guide to approach the best combination of medications to avoid symptoms of DE was also recommended.³

Anti-inflammatory treatments

Cyclosporine A

Inflammation is a key pathogenic factor in DE. Cyclosporine A (CsA) exerts immunosuppressive and anti-inflammatory activity through several pathways. Since the 1980s, several reports highlighted that topical CsA can be used to treat a variety of ocular inflammatory conditions including DE, high-risk corneal transplants, autoimmune uveitis, and vernal keratoconjunctivitis. Recent studies have shown that topical administration of CsA not only controls ocular surface inflammation, but 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.⁶⁸

Topical CsA significantly alleviates the signs and symptoms of DE and is often prescribed for long-term use by eye care practitioners. The cumulative findings of several clinical trials using 0.05% CsA ophthalmic emulsion for long-term have indicated improvement in both objective (like corneal surface staining and Schirmer test with anesthesia) and, subjective findings (like blurred vision and frequency of artificial tear application).⁶⁹ In addition, topical CsA treatment may be associated with a significant improvement in many of the cellular and molecular markers of disease severity.⁷⁰ Although higher dosing frequencies may increase treatment efficacy, some patients experience bothersome adverse effects (e.g., burning or irritation) that impair medication tolerability. The beneficial effects of CsA treatment in DE are well established; however, many patients with DE do not show a consistent therapeutic response to topical CsA.

Steroids

Topical steroids are also used to dampen 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 this form of therapy has been efficacious in practice.⁷¹ Corticosteroids also exert local immuno-modulatory 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.⁷² Unfortunately, long term topical or systemic corticosteroid use is associated with deleterious adverse effects, such as ocular hypertension, cataracts, and opportunistic infections. Repetitive short-term pulsatile administration of topical corticosteroids is a promising method of harnessing their beneficial effects, while minimizing the risk of adverse events.⁷³

Hormonal therapy

Receptors for androgens, estrogens, progesterone and prolactin have been identified in several ocular tissues, including the lacrimal gland and meibomian glands.^74–76 Experimental and human studies have demonstrated that adequate androgen, prolactin and estrogen levels are essential for normal lacrimal gland function and structural organization.^77–79 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 lipid layer thickness with corresponding symptomatic relief. ^80,81 Systemic replacement with combined esterified estrogen and methyl-testosterone for 4–24 months was found to reduce symptoms and promote clinical improvement in postmenopausal women with DE.⁸²

Antibiotics

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 dry eye secondary to ocular rosacea and blepharitis.⁸³ Experimental investigations have demonstrated that the tetracycline derivative, doxycycline, can inhibit c-Jun N-terminal kinase, extracellular signal-related kinase and mitogen-activated protein kinase signaling in epithelial cells of the ocular surface exposed to hyperosmolar stress. Additionally, doxycycline is also known to down-regulate the expression of CXCL8 and proinflammatory cytokines IL-1β and TNF⁸⁴ and inhibit the activity of MMPs (e.g., MMP-9).⁸⁵ Similarly, the tetracycline derivative minocycline inhibits the expression of cell associated pro-inflammatory molecules.⁸⁶ Despite extensive evidence from experimental trials indicating the potential benefits of administration of tetracycline derivatives in the treatment of DE, clinical evidence of their efficacy remains limited.⁸⁷

Supplementary treatments

Essential Fatty Acids (EFAs)

Omega-3 (alpha-linolenic acid) and omega-6 (linoleic acid) are biologically necessary fatty acids that must be ingested because they cannot be synthesized de novo by the human body. EFAs are the precursors of eicosanoids (prostaglandins, prostacyclins, thromboxanes, and leukotrienes) that modulate immune responses; while omega-3 FAs are generally classified as anti-inflammatory, omega-6 FAs are considered proinflammatory.⁸⁸ Investigations on the use of EFAs in the treatment of DE have produced conflicting results; however, most of the available evidence suggests that systemic administration of anti-inflammatory omega-3 FAs, can lessen DE severity.^89,90 Topical EFAs have also been evaluated in murine DE models and showed potential therapeutic effect in the form of decreased ocular surface staining, cytokine expression, and immune cell infiltration.⁹¹ Similarly, topical administration of resolvin E1, an omega-3 FA derivative increased tear production, helped maintain ocular surface integrity, decreased cyclooxygenase 2 expression, and decreased immune cell infiltration in experimental dry eye.⁹² Available data suggest that using EFAs to treat dry eye disease is a promising frontier in ocular surface therapeutics and worthwhile subject for future research in DE; however, more evidence is needed to identify the most efficacious forms and doses of EFAs.

Nerve growth factor (NGF)

NGF has been observed to increase ocular surface sensitivity, inhibit inflammatory reactions and regulate tear film production.⁹³ Thus, NGF seems to a play a pivotal role in the pathophysiology of DE and may be a promising therapeutic option.⁹⁴ Data from several studies seem to be supporting this hypothesis. For instance, tear concentration of NGF has been observed to be increased as a compensatory mechanism in DE,⁹⁴ particularly under hyperosmolar stress,⁹⁵ suggesting that NGF may be involved in reducing the apoptosis of corneal epithelial cells triggered by hyperosmolarity. Additionally, NGF has been shown to regulate conjunctival epithelial differentiation into MUC5AC-secreting goblet cells.⁹⁶. Therefore, exogenous NGF administration may be beneficial in recovering ocular surface damage due to chronic hyperosmolarity; for example, topical NGF administration has been observed to increase tear production and conjunctival goblet cell density in a dog experimental model of dry eye.⁹⁷

Autologous serum

Autologous and umbilical cord serum contains substances that support the proliferation, differentiation, and maturation of the normal ocular surface epithelium⁹⁸ and therefore, finds application in the treatment of severe DE.⁹⁹ In 1984, Fox and colleagues reported the beneficial effects of autologous serum in SS.¹⁰⁰ Documenting similar findings, Tsubota and Bradley attributed the improvements to the presence of EGF, vitamin A, lysozyme, fibronectin and TGF-beta.^101,102 Autologous serum eye drops have been found to be better than conventional therapy utilizing artificial tears in less severe cases of DE as well. For instance, a prospective randomized, controlled, crossover study comparing 50% autologous serum eye drops with conventional therapy utilizing artificial tear solutions confirmed that ocular surface vital staining score and cytological improvements were due to serum drops, as the effects were reversed when treatment was reverted to conventional therapy.¹⁰³ Similarly, another 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.¹⁰⁴

Acupuncture

The use of acupuncture as a treatment for eye disease is based on the claims that acupuncture modulates autonomic nervous system and immune system,^105,106 which in turn might regulate lacrimal gland function. It therefore seems pertinent to evaluate the effectiveness of acupuncture as a treatment for DE. To date, more than 70 papers have examined the effect of acupuncture in treating DE. While some authors have suggested that acupuncture can influence lacrimal gland secretions,¹⁰⁷ others have postulated that it can alleviate pain intensity (or increase pain threshold).¹⁰⁸

Surgical treatment

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 test (with anesthesia) result of less than 5 mm at 5 min, and showing the evidence of ocular surface dye staining.¹⁰⁹ Several techniques of punctal occlusion have been studied. For instance, temporary occlusion that dissolves in 1 or 2 weeks can be achieved by inserting collagen plugs into the canaliculi. Long-lasting collagen plugs that take 2–6 months to dissolve are also available. Silicon plugs are commonly used as reversible prolonged occlusion. Punctal occlusion using atelocollagen causes fewer complications when compared to insoluble plugs.¹¹⁰ Permanent punctal occlusion may be achieved surgically using cauterization. Combined use of punctal plugs and cyclosporine 0.05% demonstrated better improvement in Schirmer scores and rose bengal staining, and reduced overall artificial tear use compared to either treatment alone. ¹¹¹

Salivary gland procedures

Surgical procedures involving salivary glands for the management of DE have been explored since 1951, when Filatov and Chevalijev described the parotid duct transfer to the conjunctival fornix.¹¹² Murube described the transfer of the submandibular salivary gland to the temporal region and implant of the Wharton duct into the upper fornix.¹¹³ Studies have also reported the use of a graft of labial mucosa and minor salivary glands to treat severe dry eye.¹¹⁴ Soares and Franca have routinely performed this surgery in their clinic in Brazil between 2000 and 2004¹¹⁵ on patients with severe dry eye caused by Stevens–Johnson syndrome, chemical burns, pemphigoid, SS, and surgical removal of the lacrimal gland. The patients reported a subjective relief in DE symptoms immediately after surgery.

Subcutaneous abdominal artificial tear pump-reservoir

The artificial tear pump-reservoir was suggested by Murube for the treatment of severe dry eye.¹¹⁶ 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.

Conclusion

In conclusion, 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.

Disclosure

• a.Financial Support: An unrestricted grant from Research to Prevent Blindness.
• b.Financial Disclosure(s): The authors have no financial interests in the topic of this manuscript. No conflicting relationship exists for any author.

Conflict of interest

The authors declared that there is no conflict of interest.