Dry eye disease (DED), also known as dry eye syndrome (DES), keratoconjunctivitis sicca (KCS), and keratitis sicca, is a multifactorial disease of the tears and the ocular surface that results in discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.[1] Dry eye disease is a common form of ocular surface disease (OSD) and may overlap with other causes of OSD, such as ocular allergy and meibomian gland dysfunction (MGD).
The ocular surface is an integrated anatomical unit consisting of 7 key interactive and interdependent components: the tear film, the lacrimal and accessory lacrimal apparatus, the nasolacrimal drainage system, the eyelids, the bulbar and tarsal conjunctiva, cranial nerve V, and cranial nerve VII.[2] Abnormalities or deficiencies in any of the 7 ocular surface components may worsen dry eye disease, yet promise opportunities for effective therapeutic intervention.
The image below depicts the ocular surface anatomy.
View Image | Eye tear system anatomy, (Description) a. tear gland / lacrimal gland, b. superior lacrimal punctum, c. superior lacrimal canal, d. tear sac / lacrima.... |
Dry eye disease may be subdivided into 2 main types as follows:[3]
Alternatively, dry eye disease can also be subdivided into disease associated with Sjögren syndrome (SS) and disease not associated with SS (non-SS KCS).
Eighty-six percent of patients with dry eye disease also have signs of meibomian gland dysfunction.
Signs and symptoms
The following are the most common complaints associated with dry eye disease:
See Clinical Presentation for more detail.
Diagnosis
Studies that may be used for diagnosis include the following:
Additional tests that may be used in a research workup include:
Criteria for a diagnosis of dry eye disease associated with Sjögren syndrome (SS) include the following:
See Workup for more detail.
Management
Early detection and aggressive treatment of dry eye disease, or keratoconjunctivitis sicca (KCS), may help prevent corneal ulcers and scarring.
Pharmacologic therapy
Lubricating supplements are the medications most commonly used to treat dry eye disease. Agents that have been used to treat dry eye disease include the following:
Various other pharmacologic agents are currently being investigated, including oral lactoferrin, topical lubricin, topical lacritin, and topical thymosin β-4.[13]
In-office procedures
Several in-office procedures are available for the treatment of dry eye disease, including the following:
Therapeutic eyewear
Specially made glasses known as moisture chamber spectacles, which wrap around the eyes to retain moisture and protect against irritants, may be helpful in some cases of dry eye disease. Therapeutic contact lenses may also be helpful.
Surgical intervention
Punctal plugs, to achieve either partial or complete punctal occlusion with or without cautery, are often used in the treatment of dry eye disease. Available types include the following:
Other advanced or surgical options include the following:
See Treatment and Medication for more detail.
Dry eye disease (DED), also known as dry eye syndrome (DES), keratoconjunctivitis sicca (KCS), and keratitis sicca, is a multifactorial disease of the tears and the ocular surface that results in discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.[1] It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Multiple causes can produce either inadequate tear production or abnormal tear film constitution, resulting in excessively fast evaporation or premature destruction of the tear film.
Dry eye disease may be subdivided into 2 main types as follows:
Although dry eye disease may result purely from aqueous tear deficiency or be purely evaporative, it is usually of mixed etiology.
Patients with ATD may be further differentiated into those with dry eye disease associated with Sjögren syndrome (SS) and those with dry eye disease not associated with SS (non-SS KCS). Patients are considered to have SS-associated dry eye disease if they have concomitant xerostomia or connective tissue disease (CTD). SS-associated dry eye disease is itself subclassified as either primary SS or secondary SS. Patients with primary SS meet the diagnostic criteria for Sjögren syndrome, ie, they have evidence of a systemic autoimmune disease as manifested by the presence of serum autoantibodies with severe ATD and ocular surface disease; these patients do not meet diagnostic criteria for other CTD. Patients with secondary SS have Sjögren-type symptoms that develop in the setting of a diagnosed CTD, most commonly rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, and systemic sclerosis (scleroderma).
Dry eye disease is mostly frequently found in women, specifically those who are postmenopausal, who are pregnant, who are taking oral contraceptives, or who are on hormone replacement therapy (especially estrogen-only pills). The common denominator is a decrease in androgens, from either reduced ovarian function (in postmenopausal women) or increased levels of the sex hormone–binding globulin (in women who are pregnant or are taking birth control pills).
Meibomian gland dysfunction is a key component of evaporative dry eye disease, with a growing awareness among clinicians of the key role played by surface lipids. In Lemp et al’s cohort of 224 subjects with dry eye disease, 86% demonstrated signs of meibomian gland dysfunction based on an objective, composite, disease severity scale. The proportion of subjects exhibiting signs of evaporative dry eye resulting from meibomian gland dysfunction far outweighs that of subjects with pure aqueous deficiency dry eye in that general clinic-based patient cohort.[3]
Dry eye disease is essentially a clinical diagnosis made by combining information obtained from the history and physical examination by performing one or more tests to lend some objectivity to the diagnosis. No single test is sufficiently specific to permit an absolute diagnosis of dry eye disease, and the entire clinical context is needed to make an appropriate treatment recommendation.
Early detection and aggressive treatment of dry eye disease may help prevent corneal ulcers and scarring, as well as improve quality of life metrics. Treatment depends on the level of severity and may include medications, eye protection devices, and surgical interventions. The frequency of follow-up care depends on the severity of the signs and symptoms. Environment-related issues that may exacerbate dry eye disease should be discussed; alternatives may be needed.
The tear film covers the normal ocular surface. It is generally considered to comprise the following 3 intertwined layers (see the image below):
The lipid layer acts as a surfactant, constitutes an aqueous barrier, retards evaporation of the underlying aqueous layer, and provides a smooth optical surface. It may also act as a barrier against foreign particles, and it may possess some antimicrobial properties.
Because the meibomian glands are holocrine in nature, the secretions contain both polar lipids (aqueous-lipid interface) and nonpolar lipids (air-tear interface), as well as proteinaceous material. All of these are held together by ionic bonds, hydrogen bonds, and van der Waals forces. The secretions are subject to neuronal (parasympathetic, sympathetic, and sensory sources), hormonal (androgen and estrogen receptors), and vascular regulation. Evaporative loss is predominantly due to meibomian gland dysfunction (MGD).
The aqueous component includes about 60 different proteins, electrolytes, and water. Lysozyme, the most abundant (20-40% of total protein) and most alkaline of the tear proteins, is a glycolytic enzyme capable of breaking down bacterial cell walls. Lactoferrin has antibacterial and antioxidant functions, and epidermal growth factor (EGF) helps maintain the normal ocular surface and promote corneal wound healing. Other components include albumin, transferrin, immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG).
The secretion of the lacrimal gland is controlled by a neural reflex arc, with afferent nerves (trigeminal sensory fibers) in the cornea and the conjunctiva passing to the pons (superior salivary nucleus), from which efferent fibers pass in the nervus intermedius to the pterygopalatine ganglion and postganglionic sympathetic and parasympathetic nerves terminating in the lacrimal glands.
The glycocalyx of the corneal epithelium contains the transmembrane mucins (glycosylated glycoproteins present in the glycocalyx) MUC1, MUC4, and MUC16. These membrane mucins interact with soluble, secreted, gel-forming mucins produced by the goblet cells (MUC5AC) and also with others, such as MUC2. The lacrimal gland also secretes MUC7 into the tear film.
These soluble mucins move about freely in the tear film, a process facilitated by blinking and electrostatic repulsion from the negatively charged transmembrane mucins. Soluble mucins also function as cleanup proteins by picking up dirt, debris, and pathogens, holding fluids because of their hydrophilic nature, and harboring defense molecules produced by the lacrimal gland.
Transmembrane mucins prevent pathogen adherence and entrance. They also provide a smooth lubricating surface, allowing lid epithelia to glide over corneal epithelia with minimal friction during blinking and other eye movements. It has been suggested that the mucins are mixed throughout the aqueous layer of tears owing to their hydrophilic nature and, being soluble, move freely within this layer.
SS-Associated Dry Eye Disease (Primary or Secondary)
SS-associated dry eye disease leads to a chronic inflammatory state, with the production of autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF), fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (eg, anti-RO [SS-A] and anti-LA [SS-B]); inflammatory cytokine release; and focal lymphocytic infiltration of the lacrimal and salivary gland, with glandular degeneration and induction of apoptosis in the conjunctiva and lacrimal glands. The lymphocytic infiltrates consist mainly of CD4+ T cells but also B cells.
This results in dysfunction of the lacrimal gland with reduced tear production, as well as loss of response to nerve stimulation and less reflex tearing. Active T-lymphocytic infiltrate in the conjunctiva has also been reported in non-SS dry eye disease.
Androgens are believed to be trophic for the lacrimal and meibomian glands. They exert potent anti-inflammatory activity via production of transforming growth factor–beta (TGF-β), suppressing lymphocytic infiltration.
Both androgen and estrogen receptors are located in the lacrimal and meibomian glands. At menopause, a decrease in circulating sex hormones occurs, possibly affecting the functional and secretory aspect of the lacrimal gland. Initial interest in this area centered on evaluating estrogen or progesterone deficiency to explain the link between dry eye disease and menopause; subsequent research has tended to focus more on androgens (specifically, testosterone) or metabolites of androgens.[15, 16] A 2017 randomized, controlled trial of 46 androgen-deficient patients showed that those treated with androgen replacement had statistically significant improvements in tear breakup time, corneal staining, Schirmer scores, and Ocular Surface Disease Index (OSDI) scores at 4 weeks compared with those receiving placebo.[17]
In meibomian gland dysfunction, androgen deficiency results in loss of the lipid layer—specifically, loss of triglycerides, cholesterol, monounsaturated essential fatty acids such as oleic acid, and polar lipids, including phosphatidylethanolamine and sphingomyelin. Loss of polar lipids, which are present at the aqueous-tear interface, exacerbates evaporative tear loss, and loss of unsaturated fatty acids raises the melting point of meibomian gland secretions, or meibum, leading to thicker, more viscous secretions that obstruct ductules and cause stagnation of secretions.
Patients on antiandrogenic therapy for prostate disease also have increased viscosity of meibum, decreased tear breakup time (TBUT), and increased tear film debris, all of which indicate a deficient or abnormal tear film.
Various proinflammatory cytokines that may cause cellular destruction, including interleukin (IL)–1, IL-6, IL-8, TGF-β, tumor necrosis factor alpha (TNF-α), and chemokine ligand 5 (CCL5 or RANTES), are altered in patients with dry eye disease. IL-1β and TNF-α, which are present in the tears of patients with dry eye disease, cause the release of opioids that bind to opioid receptors on neural membranes and inhibit neurotransmitter release through production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB).
IL-2 also binds to the delta opioid receptor and inhibits cAMP production and neuronal function. This loss of neuronal function diminishes normal neuronal tone, leading to sensory isolation of the lacrimal gland and eventual atrophy.
Proinflammatory neurotransmitters, such as substance P and calcitonin gene–related peptide (CGRP), are released, and these substances recruit and activate local lymphocytes. Studies suggest that dry eye severity is directly correlated with nerve growth factor (NGF) levels and inversely correlated with CGRP and neuropeptide Y (NPY) tear levels.
NGF tear levels point to a direct relation with conjunctival hyperemia and fluorescein staining results, suggesting that tear levels of NGF are more closely connected to corneal epithelial damage, perhaps as a reflection of attempted compensatory repair responses, and that the decreased tear levels of NPY and CGRP in dry eye disease are linked to impaired lacrimal function.[18] In one study, elevated NGF tear levels were decreased by giving 0.1% prednisolone.[19]
Substance P also acts via the nuclear factor of activated T cells (NF-AT) and through the NF-κB signaling pathway. This leads to expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), adhesion molecules that promote lymphocyte homing and chemotaxis to sites of inflammation.
Cyclosporine is a neurokinin (NK)–1 and NK-2 receptor inhibitor that can down-regulate these signaling molecules. It has been shown to improve goblet cell counts and to reduce the numbers of inflammatory cells and cytokines in the conjunctiva. Another novel addition to the therapeutic armamentarium for dry eye disease is lifitegrast, which is commonly used in conjunction with cyclosporine to treat both aqueous tear deficiency and evaporative dry eye disease. Lifitegrast is a small-molecule integrin antagonist that reduces ocular surface inflammation and T-cell activation by blocking the interaction of lymphocyte function-associated antigen 1 (LFA-1) with intracellular adhesion molecule 1 (ICAM-1). It has been shown to be safe and effective and is FDA-approved for the treatment of dry eye disease.[20, 6, 7]
Inflammatory cytokines, in addition to inhibiting neural function, may also convert androgens into estrogens, resulting in meibomian gland dysfunction. An increased rate of apoptosis is also seen in conjunctival and lacrimal acinar cells, perhaps owing to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) are also present in the epithelial cells.
Mucin-synthesizing genes representing both transmembrane mucins and goblet cell–secreted soluble mucins have been isolated and designated MUC1 through MUC17. Their roles in hydration and stabilization of the tear film are being investigated in patients with KCS. Particularly significant is MUC5AC, which is expressed by stratified squamous cells of the conjunctiva and whose product is the predominant component of the mucous layer of tears. A defect in this and other mucin genes may be a factor in the development of dry eye disease.
Besides dry eye disease, other conditions may eventually lead to loss of goblet cells, including ocular cicatricial pemphigoid, Stevens-Johnson syndrome, and vitamin A deficiency. These conditions may lead to drying and eventual keratinization of the ocular epithelium. Both classes of mucins are decreased in these diseases, and, on a molecular level, mucin gene expression, translation, and posttranslational processing are altered.
Mucin deficiency leads to poor wetting of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production.
Normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin, and phospholipase A2, is decreased in dry eye disease.
Lipocalins, previously known as tear-specific prealbumin, are inducible lipid-binding proteins produced by the lacrimal glands and present in the mucous layer. They lower the surface tension of normal tears, which provides stability to the tear film and also explains the increase in surface tension seen in dry eye disease characterized by lacrimal gland deficiency. Lipocalin deficiency can lead to precipitation in the tear film, forming the characteristic mucous strands seen in patients with dry eye symptoms.
The International Dry Eye WorkShop (DEWS) developed a 3-part classification of dry eye based on etiology, mechanisms, and disease stage.[1] This classification system distinguishes 2 main categories (or causes) of dry eye states, as follows:
Evaporative loss due to meibomian gland dysfunction is the most common cause of dry eye. Causes of evaporative loss include the following:
Aqueous tear deficiency (ATD) results from insufficient tear production. Causes of deficient aqueous production include the following:
Causes of deficient aqueous production can be further classified as related or unrelated to SS.
Non-Sjögren syndrome
Primary lacrimal gland deficiencies that may impair aqueous production include the following:
Secondary lacrimal gland deficiencies that may impair aqueous production include the following:
Lacrimal obstructive diseases that may impair aqueous production include the following:
Medications that may impair aqueous production include the following:
The following conditions may lead to reflex hyposecretion:
Sjögren syndrome
Primary SS has no associated CTD.
Secondary SS may be associated with any of the following CTDs:
Causes of evaporative loss can be further classified as intrinsic or extrinsic.
Intrinsic causes
Meibomian gland disease may involve a reduced number of functioning glands, as in congenital deficiency or acquired meibomian gland dysfunction, or complete gland replacement, as in distichiasis, lymphedema-distichiasis syndrome, or metaplasia. Meibomian gland dysfunction may be divided into 3 subtypes, as follows:
Evaporative loss may result from a low blink rate caused by the following:
Evaporative loss may result from the following disorders of eyelid aperture and eyelid-globe congruity:
In addition, the actions of drugs such as isotretinoin may lead to evaporative loss.
Extrinsic causes
Vitamin A deficiency may cause dry eye as a consequence of the following:
Other extrinsic causes are as follows:
A classification of dry eye on the basis of mechanisms includes tear hyperosmolarity and tear-film instability.
For classification of dry eye disease based on severity, the Delphi Panel Report was adopted and modified as a third component of the DEWS (see the Table below).[1, 21]
Table. Dry Eye Severity Levels
View Table | See Table |
Dry eye disease is very common in the United States, affecting a significant percentage of the population, especially those older than 50 years. Prevalence estimates range from approximately 10%-30% of the population. An estimated 3.23 million women and 1.68 million men aged 50 years and older are affected.[22, 23] The prevalence of dry eye disease is also increasing among young adults aged 18-34 years, mostly owing to increased use of soft contact lenses and frequent smartphone and computer usage.[24]
Dry eye disease is one of the most common reasons for a patient to seek eye care.[25] Furthermore, its widespread prevalence has created a significant socioeconomic burden on the United States healthcare system. Lost productivity through missed work days, the rising cost of treatment, and the social and emotional stressors encountered by patients with dry eye disease are notable.[26]
As a consequence of the demographic pressure created by an aging population, meibomian gland dysfunction is expected to increase in prevalence and thus to impose a growing burden on ophthalmologic practices.[27] Development of thoughtful, effective strategies that involve the underlying mechanism of meibomian gland dysfunction is critical to the effective, patient-satisfying functioning of every ophthalmologist’s practice.
The reported frequency of dry eye in other countries closely parallels that in the United States.
Dry eye is more common in women.[22] Dry eye disease associated with SS is believed to affect 1%-2% of the population, and 90% of those affected are women. Data on race and ethnicity in dry eye disease are limited, but the frequency and the clinical diagnosis of dry eye appear to be greater in the Hispanic and Asian populations than in whites.
The prognosis of dry eye disease varies depending on the severity of the condition. Most patients have mild-to-moderate cases that can be treated symptomatically with lubricants, often providing adequate relief of symptoms. In general, the prognosis for visual acuity in patients with dry eye disease is good. Patients with SS or prolonged untreated dry eye represent a subgroup with a worse prognosis, requiring a longer course of treatment.
Dry eye may be complicated by sterile or infectious corneal ulceration, particularly in patients with SS. Ulcers are typically circular central or paracentral corneal lesions that are smaller than 3 mm in diameter. Occasionally, corneal perforation may occur. In rare cases, sterile or infectious corneal ulceration in dry eye disease can cause blindness. This risk is markedly increased with contact lens use, particularly with overnight wear.
Punctate epithelial defects (PEDs) may be present. Significant punctate epitheliopathy can lead to corneal erosions, both sterile and infectious corneal ulceration, corneal neovascularization, corneal scarring, corneal thinning, and even corneal perforation.
A wide variety of educational materials are available for patients with dry eye disease, particularly online. For patients with SS, regular dental examinations are important because dry mouth or xerostomia, a component of SS, significantly increases the risk of dental problems. Women should receive regular checkups from their gynecologists.
Patients with SS can obtain up-to-date information from the Sjögren’s Syndrome Foundation, 6707 Democracy Boulevard, Suite 325, Bethesda, MD 20817; (301) 530-4420 or (800) 475-6473; fax, (301) 530-4415.
For patient education information, see the Eye and Vision Center, as well as Dry Eye Syndrome, Pink Eye, How to Instill Your Eyedrops, and Sjögren’s Syndrome. Websites include www.mydryeyes.com/ and www.dryeyeinfo.com/Disease. See also the following topics:
Depending on the severity of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), the following are the most common patient complaints:
These symptoms are often exacerbated in smoky or dry environments, by indoor heating, by fans, or by excessive reading or computer use. These symptoms are quantified objectively in the Ocular Surface Disease Index (OSDI) questionnaire, which lists 12 symptoms and grades each on a scale of 1-4.
In dry eye disease, symptoms tend to be worse toward the end of the day, with prolonged use of the eyes, or with exposure to extreme environmental conditions. Smoking and other environmental irritants, including chronic smartphone, computer, or soft contact lens use, are important risk factors.
Patients with meibomian gland dysfunction (MGD) may complain of redness of the eyelids and conjunctiva, but in these patients, the symptoms are often worse upon awakening in the morning.
Paradoxically, some patients with dry eye disease complain of too much tearing. When evidence of dry eye disease exists, this symptom is often explained by excessive reflex tearing due to severe corneal surface disease from the dryness. Epiphora may also accompany conjunctivochalasis, which demands consideration of surgical intervention.
Certain systemic medications also decrease tear production, such as antihistamines, beta-blockers, anticholinergics, and oral contraceptives.
Many topical medications also decrease tear production, including antihistamines, beta blockers, and many other glaucoma medications.
The patient’s medical history may be significant for coexisting connective tissue disease (CTD), rheumatoid arthritis (RA), or thyroid abnormalities. A thorough review of systems should be obtained, focusing specifically on dry mouth, arthritis, cutaneous changes, malaise, weight loss, and lymphadenopathy.
Within the veteran population, a study found an increased incidence of dry eye disease in both men and women that was also strongly connected to cases of posttraumatic stress disorder and depression.[28]
Dry eye disease (DED), or keratoconjunctivitis sicca (KCS), is essentially a clinical diagnosis, made by combining information obtained from the history and from the physical examination and performing one or more diagnostic tests to lend objectivity to the diagnosis. No single test is sufficiently specific to permit an absolute diagnosis of dry eye disease. Symptom questionnaires can be used to help establish a diagnosis of dry eye disease and to assess the effects of treatments or to grade disease severity. At least 14 questionnaires are available in PubMed. Among the most commonly used and validated include the following:
Studies that may be used in the workup include impression cytology to monitor the progression of ocular surface changes, measurement of tear breakup time (TBUT), the Schirmer test, and quantification of tear components through analysis of tear proteins or tear-film osmolarity.[29] Serology for circulating autoantibodies (see below) may be indicated.
Sjögren syndrome (SS) is characterized by the combination of aqueous tear deficiency (ATD) and dry mouth (xerostomia). Patients with this syndrome may be classified into 3 subsets, as follows:
All cases of SS are characterized by a progressive infiltration of the lacrimal and salivary glands by lymphocytes, predominantly B cells and CD4+ lymphocytes, which leads to disorganization of the normal gland architecture and consequent loss of function. At this time, the most comprehensive criteria for a diagnosis of SS include the following:
A novel test called Sjo is available from IMMCO Laboratories through Bausch & Lomb. In additional to traditional ANA, RF, Ro, and La autoantibodies, it is used to evaluate for proprietary early markers of SS. These early antibodies may enable the clinician to identify SS up to 4 years earlier than the traditional antibody panel.[31]
Tear breakup time (TBUT) is determined by measuring the interval between instillation of topical fluorescein 0.5% and appearance of the first dry spots on the cornea. Measure it prior to instillation of any anesthetic eye drops. A fluorescein strip is moistened with saline and applied to the inferior cul-de-sac. After several blinks, the tear film is examined using a broad-beam of slit lamp with a blue filter for the appearance of the first dry spots on the cornea. Three consecutive measurements are taken, and the time is averaged to obtain the TBUT. A TBUT of less than 10 seconds is considered abnormal, indicative of tear instability. Several devices can measure the TBUT objectively, including the Oculus Keratograph 5M.
Rose bengal, lissamine green, and fluorescein staining are used to evaluate epitheliopathy. Rose bengal and lissamine green stain not only dead and devitalized cells but also healthy cells that are protected inadequately by a mucin coating. Fluorescein pools in epithelial erosions and stains exposed basement membrane; generally, it stains the cornea more than the conjunctiva.
Early or mild cases of dry eye disease are detected more easily with rose bengal or lissamine than with fluorescein staining, and the conjunctiva is usually stained more intensely than the cornea. Interpalpebral staining of the nasal or inferior paracentral cornea is seen in dry eye disease. A linear pattern of inferior conjunctiva and corneal staining by rose bengal or lissamine is characteristic of meibomian gland dysfunction (MGD).
Van Bijsterveld developed a scoring system for rose bengal/lissamine green staining that evaluates the intensity of staining on a scale of 0-3 in 3 areas: (1) nasal conjunctiva, (2) temporal conjunctiva, and (3) cornea. With this system, the maximum possible score is 9, and a score of 3.5 or higher is considered positive for dry eye disease. Rose bengal also possesses antiviral activity.[32]
Lissamine green staining combines the advantages of fluorescein and rose bengal staining. Like rose bengal, it stains healthy epithelial cells that are not protected by a mucin layer, and like fluorescein, it stains degenerating or dead cells. Lissamine green avoids the pain, discomfort, and corneal toxicity that are associated with rose bengal, but is somewhat less sensitive and more transient and thus may be more difficult to appreciate on slit-lamp examination.
The Schirmer test is used to test aqueous tear production. Traditionally, the Basic secretion test is performed by instilling a topical anesthetic and then placing a thin strip of filter paper in the inferior cul-de-sac. The corners of a soft tissue paper may be used to wick all liquid from the inferior fornix by capillary attraction without any wiping or direct irritation before the paper is placed. The patients’ eyes are then closed for 5 minutes, and the amount of wetting in the paper strip is measured. Less than 5 mm of wetting is abnormal; 5-10 mm is equivocal.
The Schirmer I test, which measures both basic and reflex tearing, consists of the same test without the use of a topical anesthetic agent. Less than 10 mm of wetting after 5 minutes is diagnostic of ATD. The test is relatively specific, but it is poorly sensitive.
The Schirmer II test, which measures reflex tearing, may be done if the initial Schirmer test yields abnormal results. It is essentially similar to the basic secretion test, but with the addition of nasal mucosal irritation induced with a cotton tip applicator. Wetting of less than 15 mm after 5 minutes is consistent with abnormalities of reflex secretion.
Absence of nasal lacrimal reflex tearing, presence of serum autoantibodies, and severe ocular surface disease demonstrated by rose bengal or fluorescein staining argues strongly in favor of a diagnosis of SS-associated dry eye disease.
Frankly, the authors prefer a modification of the Schirmer I test, aiming to measure basal tear secretion by minimizing reflex tearing through the application of topical anesthetic (proparacaine), followed by removal of that drug and resident tears through the capillary attraction of all liquid from the inferior fornix via 2 corners, in sequence, of a tissue paper very gently placed over the inferior tarsal conjunctiva. The patient's eyes are then closed for 5 minutes and the amount of wetting measured.
Additional tests may be performed to quantify each individual tear component.
Lipids may be tested for by collecting meibum, either by squeezing the eyelid margin to encourage expression from the meibomian glands or by using sterile curettes to suck meibum from individual gland orifices. Analysis may be accomplished by means of either high pressure liquid chromatography (HPLC) or gas chromatography with mass spectroscopy (GC-MS).
Meibomian gland morphology and density and dropout may be analyzed with meibography and/or meiboscopy to help diagnose meibomian gland dysfunction. Meiboscopy is the visualization of the meibomian gland via transillumination of the eyelid; meibography implies photographic image documentation. Meibomian gland morphology can be photographically documented by several commercially available devices, including the Oculus Keratograph 5M and the Tear Science LipiView. Dynamic Meibomian Imaging (DMI) from the LipiView device provides a distinct picture of the entire everted inferior tarsal plate, allowing both the clinician and the patient to assess the extent of meibomian gland dysfunction and its characteristic meibomian gland dropout.[33]
Meibomian gland expression of inspissated glands is another useful diagnostic and therapeutic in-office procedure.
Meibomian gland dysfunction may also be diagnosed using meibometry. Lipid on the lower central lid margin is blotted onto a plastic tape, and the amount taken up is read by optical densitometry. This provides an indirect measure of the steady state level of the meibomian lipid.
The aqueous/protein component may be tested for by measuring tear lysozyme, tear lactoferrin, epidermal growth factor (EGF), aquaporin 5, lipocalin, and immunoglobulin A (IgA) concentrations with enzyme-linked immunosorbent assay (ELISA) techniques, as well as tear-film osmolarity.
Lysozyme accounts for approximately 20-40% of total tear protein. The main disadvantage of tear lysosome testing is its lack of specificity in cases of meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. Lactoferrin has antibacterial and antioxidant functions. Lactoferrin analysis is commercially available through colorimetric solid-phase and ELISA techniques. This study offers good correlation with other tests.
Measurement of tear-film osmolarity may be performed to assess patients suspected of having dry eye disease, an application probably first considered and promoted by Gilbard et al.[34] Tear-film osmolarity has been shown to be elevated in patients with dry eyes. It is a very sensitive test for identifying a dry eye but lacks some specificity in meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. Many clinicians consider tear film osmolarity to be the objective clinical foundation for dry eye disease evaluation, staging, and ongoing monitoring of therapeutic response.
In a multicenter study of 314 consecutive subjects aged 18-82 years that compared bilateral tear osmolarity assessment, TBUT measurement, corneal staining, conjunctival staining, Schirmer testing, and meibomian gland grading, Lemp et al concluded that assessment of tear osmolarity had superior diagnostic performance and was the best single metric for diagnosing and classifying dry eye disease.[35] This test was more sensitive and specific than the others, and increasing dry eye disease severity was correlated with higher intereye differences in osmolarity.
Mucins may be analyzed by using impression cytology or brush cytology techniques, which obtain epithelial and goblet cells that can then be tested for mucin messenger RNA (mRNA) expression. Immunofluorescence, flow cytometry, ELISA, or immunoblotting techniques may also be used.
When the mucin layer of the tear is decreased, as with xerophthalmia or ocular cicatricial pemphigoid, squamous metaplasia and the following cytologic characteristics occur:
Impression cytology is highly sensitive, but it does require proper staining and expert microscopic evaluation of samples. New in-office devices that measure lipid layer thickness have emerged, although the application of these products is under further investigation.
The constitutive production of MMP-9 for epithelial maintenance may be up-regulated in dry eye disease, contact lens use, or anterior basement membrane dystrophy (ABMD). MMP-9 on the ocular surface can now be measured at the point of service in any clinical setting with a noninvasive 22-minute technician-driven test. No special equipment is required.
InflammaDry (Rapid Pathogen Screening Inc) is a rapid in-office test for diagnosing dry eye disease. The test, which takes less than 2 minutes to procure and 20 minutes to incubate, uses ocular surface samples to detect the inflammatory marker matrix metalloproteinase-9. MMP-9 has been shown to be consistently elevated in the tears of patients with dry eye disease.[36]
The tear stability analysis system (TSAS) is a noninvasive and objective test that is used to help diagnose tear-film instability.
Tear evaporation is tested by means of evaporimetry.
The tear function index (TFI; Liverpool modification) is used to evaluate the tear dynamics of production and drainage and helps to detect dry eye. The test involves the use of prepared filter paper strips that contain fluorescein, and it has been designed to allow direct measurement of the TFI through the use of these strips.
The tear ferning test (TFT) can be used to help diagnose the quality of tears (electrolyte concentration), dry eye disease, and hyperosmolarity. A drop of tear fluid is collected from the lower meniscus and placed onto a microscope slide and allowed to dry by evaporation. Different forms of branching crystallization patterns can be observed and classified. This test permits the separation of healthy eyes from dry eyes based on ferning patterns.
Meniscometry (measurement of tear meniscus radius, height, and cross-sectional area) is used to help diagnose ATD. A rotatable projection system with a target comprising black and white stripes is projected onto the lower central tear film meniscus. Images are recorded and then transferred to a computer for calculation of the radius of curvature. Several commercially available imaging devices can provide serial quantitative measurements.
Central corneal thickness is reduced in patients with dry eye disease, possibly as a consequence of the hypertonicity of the tear film in these patients. Corneal thickness has been shown to increase after treatment with artificial tears, and this may be a useful diagnostic and follow-up criterion for dry eye disease. Visual acuity and corneal topography and keratometry readings have been shown to improve after the use of artificial tears.
The tear turnover rate, defined as the percentage by which the fluorescein concentration in tears decreases per minute after instillation, is also reduced in patients with symptomatic dry eye disease. It is determined by means of fluorophotometry.
Lacrimal gland or minor (salivary) gland biopsy may be performed to aid in diagnosing SS. Conjunctival biopsy may also be performed.
Pathologic examination of the lacrimal gland in patients with dry eye disease reveals age-related changes, including lobular and diffuse fibrosis and atrophy, as well as periductal fibrosis. An underlying autoimmune mechanism represented by round-cell infiltration may be present. No circulating autoantibodies are found in patients who do not have SS with dry eye disease.
Histopathologically, dry eye disease is characterized by squamous metaplasia with loss of goblet cells, cellular enlargement, and an increase in the cytoplasm-to-nucleus ratio of the superficial conjunctival epithelial cells. The lacrimal gland and the conjunctiva are also heavily infiltrated by CD4+ T cells and B cells. In meibomian gland dysfunction, loss of glandular architecture, dilation of the ductules, ductal occlusion, and hyperkeratinization of the ductal epithelium are seen.
Early detection and aggressive treatment of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), may help prevent corneal ulcers and scarring. The frequency of follow-up care depends on the severity of the signs and symptoms.
Although supplemental lubrication is the mainstay of treatment for mild and moderate aqueous-deficient dry eye disease, any concomitant lid disease must also be treated. The use of topical cyclosporine has been shown to enhance the production of the aqueous component of the tear layer, as well as increase goblet cell density and decrease inflammatory tear cytokines. The use of oral omega-3 fatty acids has beneficial anti-inflammatory properties that aid in the production of tears. Numerous preparations of omega-3 fatty acids are available for point-of-service sales and provide pharmaceutical-grade, mercury-free sources of essential fatty acids known to improve ocular surface function.[37, 38]
Other forms of treatment include the use of plugs that block the puncta. Temporary punctal occlusion may be accomplished with collagen (dissolvable) or silicone (permanent) plugs; newer cross-linked collagen punctal plugs have a longer duration of action before dissolving, with labeling from 3-6 months postimplantation. If plugs are ineffective, electrocauterization of the inferior puncta may be performed in patients with severe dry eye disease, documented Schirmer tear test deficiency, and patent upper lid puncta. In some cases, other surgical options may be considered.
Environment-related issues that may exacerbate dry eye disease should be discussed; alternatives may be needed.
Treatment of very severe dry eye disease or dry eye disease associated with a connective tissue disorder (CTD), including Sjögren syndrome (SS), should be coordinated with an internist or a rheumatologist, as well as relevant dental and gynecologic consultants.
The Management and Therapy Subcommittee of the Tear Film and Ocular Surface Society's Dry Eye Workshop II (TFOS DEWS II) have proposed an updated (2017) algorithm to approach the treatment of dry eye. The algorithm, adapted here from the published report,[39] is presented in a stepwise approach, beginning with low-risk, highly available interventions and progressing for cases of treatment failure or severe dry eye.
Step one is as follows:
Step two (used if the above options are inadequate) is as follows:
Step three (used if the above options are inadequate) is as follows:
Step four (used if the above options are inadequate) is as follows:
Agents that have been used to treat dry eye disease include the following:
Lubricating supplements are the medications most commonly used to treat dry eye disease. If these agents are to be used more frequently than every 3 hours, preservative-free formulations are the treatment of choice. If a patient has SS, the use of systemic immunosuppressants should be considered.
Prescribe artificial tears, preferably preservative-free artificial tears, and a lubricating ointment. Mild dry eye disease can be treated with drops up to 4 times a day; more severe cases call for more aggressive treatment, such as drops 10-12 times a day. Thick artificial tear drops or gels can also be used in more severe cases, although these agents tend to blur the vision. Tear ointments can be used during the day, but they are generally reserved for bedtime use because of the poor vision after placement.
The clinical trials that led to FDA approval of topical cyclosporine 0.05% emulsion for the treatment of moderate to severe dry eye disease demonstrated statistically significant tear production increases in treated patients compared to tear-only controls. In addition, these trials demonstrated that topical cyclosporine emulsion produced no detectable serum levels, reduced concomitant artificial tear use, reduced ocular surface goblet cell density and T-cell expression based on conjunctival biopsy analysis, and reduced inflammatory tear cytokine production based on tear analysis.
A randomized, double-masked, vehicle-controlled clinical study evaluated the efficacy and safety of 2 different concentrations of cyclosporine (1% and 0.05%) in aqueous solution compared with vehicle. At day 21, noted as early in the trial, statistically significant improvement in 4 symptoms and 3 ocular signs were observed when cyclosporine 1% was administered, and equivalent improvement in 3 symptoms and 3 ocular signs was observed when cyclosporine 0.5% was used.[40]
In a 2012 study, diquafosol and sodium hyaluronate showed similar efficacy in improving fluorescein staining scores of dry eye patients and diquafosol was superior in improving rose bengal staining scores. There was no significant difference between groups in adverse event rates.[41]
The first LFA-1 antagonist, lifitegrast ophthalmic (Xiidra), was approved by the FDA in July 2016 for treatment of the signs and symptoms of dry eye disease. Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein bound on leukocytes, and blocks the interactions of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in dry eye disease; LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse, resulting in T-cell activation and migration to target tissues.
Approval of lifitegrast was based on four phase 3 trials (n >2500), OPUS-1, OPUS-2, OPUS-3, and one long-term (1-year) phase 3 safety study (SONATA).[42, 43, 20, 6, 7] Lifitegrast improved inferior corneal staining score (ICSS) in the OPUS-1 and OPUS-3 studies.[42, 43] Ocular safety and tolerability were similar to those of placebo.[6]
Several in-office procedures are available for the treatment of dry eye disease, including the following:
Intranasal tear neurostimulation is a novel approach to the treatment of dry eyes.[44] The use of neurostimulation was first introduced for the treatment of dry eye disease by Kossler et al in 2015.[45] Intranasal tear neurostimulation works via an external, nonimplantable device to stimulate the nasal mucosa and activate the nasolacrimal reflex to increase tear production and improve tear film homeostasis. Stimulation of the nasal mucosa activates the afferent branch of the nasolacrimal reflex, whereby the anterior ethmoidal nerve relays a signal to the superior salivary nucleus in the pons. The efferent branch is then activated as the parasympathetic nerves of CN VII travel to the pterygopalatine ganglion and exit via the inferior orbital fissure as the zygomaticotemporal nerve, which innervates several components of the lacrimal functional unit. Activation of the main and accessory lacrimal glands, as well as conjunctival goblet cells and meibomian glands by the stimulated zygomaticotemporal nerve, results in increased tear production and enhances tear film homeostasis.
Several clinical trials have been conducted on the use of intranasal tear neurostimulation for the treatment of dry eye disease. This treatment modality has been shown to be safe with consistent use over 3-6 months and improves dry eye symptoms and tear production and may also improve corneal and conjunctival staining.[46, 47] The device for tear neurostimulation has been shown to be superior to sham treatment.[48]
The TrueTear intranasal tear neurostimulator is FDA-approved for the treatment of dry eye disease. The current recommendation is to use the stimulator for 1-3 minutes 2-4 times daily and not to exceed 10 applications in a 24-hour period. The device is generally well tolerated, with the most common adverse effects including epistaxis and, occasionally, pain.
Specially made glasses known as moisture chamber spectacles, which wrap around the eyes to retain moisture and protect against irritants, may be helpful in some cases of dry eye disease.
Contact lenses may also be helpful; these are available in the following types:
Punctal plugs are often employed in the treatment of dry eye disease. Available types include the following:
A study by Mataftsi et al found that punctal plugs offer an effective and safe treatment for children with persistent symptoms and should be considered.[50]
If mucous strands or filaments are present, they should be removed with forceps, and 10% acetylcysteine can be administered 4 times a day. In general, surgical treatment of dry eye disease is reserved for very severe cases in which ulceration or impending perforation of the sterile corneal ulcer occurs.
Surgical options include the following:
In a study of punctal occlusion surgery using a high heat-energy–releasing cautery device to treat severe dry eye disease and recurrent punctal plug extrusion, Ohba et al concluded that the device was associated with a low recanalization rate and demonstrated improvements in ocular surface wetness and visual acuity.[52]
In patients with dry eyes, close the puncta. If plugs are not available or are repeatedly lost, cautery or hyfrecation is indicated for permanent closure, beginning with the lower puncta and then proceeding to the upper if necessary.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. For treatment of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), artificial tears are administered with and without preservatives, depending on severity. Doxycycline 100 mg daily or twice daily may be given for meibomian gland dysfunction (MGD), if indicated, followed by a supervised decrease in dosage to as low as 20 mg PO QD. Topical cyclosporine 0.05% ophthalmic emulsion has proven to be an effective FDA-approved treatment for dry eye disease.
Lifitegrast ophthalmic solution is the first prescription specifically approved for dry eye disease by the FDA. It is a lymphocyte function-associated antigen-1 (LFA-1) antagonist.
In addition to the list below, autologous serum eye drops are unpreserved, are nonantigenic by nature, and contain growth factors, fibronectin, immunoglobulins, and vitamins at concentrations similar to or higher than those in natural or artificial tears. Serum eye drops are used for severe dry eye disease with punctate epithelial defects and corneal damage to promote reepithelialization. They can be used successfully in patients who are refractory to other forms of treatment.
Clinical Context: Artificial tears are used to increase lubrication of the eye.
Clinical Context: Hydroxypropyl cellulose acts to stabilize and thicken precorneal tear film and to prolong tear breakup time (TBUT). It is applied as a once- or twice-daily insert into the inferior cul de sac, thereby reducing the ongoing need for continuous application of supplementary topical artificial tears.
Clinical Context: These substances serve as lubricants and emollients.
Lubricants act as humectants in the eye. The ideal artificial lubricant should be preservative-free; contain potassium, bicarbonate, and other electrolytes; and have a polymeric system to increase its retention time. Lubricating drops are used to reduce morbidity and to prevent complications. Lubricating ointments prevent complications from dry eyes. Ocular inserts reduce symptoms resulting from moderate to severe dry eye disease.
Clinical Context: Lifitegrast binds to the integrin lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein bound on leukocytes, and blocks the interactions of LFA-1 with its cognate ligand ICAM-1. It is indicated for treatment of the signs and symptoms of dry eye disease in adults.
Intercellular adhesion molecule-1 (ICAM-1) may be overexpressed in corneal and conjunctival tissues in dry eye disease. The integrin lymphocyte function-associated antigen-1 (LFA-1) interacts with ICAM-1 to contribute to the formation of an immunological synapse, resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells.
Clinical Context: Mucolytic agents lower mucous viscosity by digesting mucoproteins. They are used when mucous discharge or plaques are present.
Mucolytic agents such as topical 10% N-acetylcysteine lower mucous viscosity by digesting mucoproteins. They are used when mucous discharge or plaques are present.
Clinical Context: Doxycycline inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Clinical Context: Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma.
Empiric antimicrobial therapy must be comprehensive, covering all likely pathogens in the context of the clinical setting. Oral tetracycline analogues, such as doxycycline and minocycline, have been shown to be effective against meibomian gland dysfunction. They exert the following 4 types of effects:
- Antibacterial effects, resulting from a reduction in the bacterial load on the eyelid; despite considerable antimicrobial resistance in common ocular surface flora and pathogens, long-term tetracycline analogue therapy has not been shown to promote infectious complications by resistant organisms
- Antiangiogenic effects
- Anti-inflammatory effects, resulting from a decrease in activity of collagenase, phospholipase A2, and several matrix metalloproteinases (MMPs), as well as from a decrease in the production of interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α)
- Inhibition of lipase production, which decreases production of diglycerides and free fatty acid (FFA) in meibomian secretions (FFA can destabilize the tear film and can cause inflammation)
- Doxycycline and minocycline are preferred over tetracycline because they are more lipophilic and achieve a higher target tissue concentration, while having a more tolerable systemic side effect profile.
- Azithromycin is an additional antibacterial agent with anti-inflammatory effects that may be beneficial for treating dry eye disease. This drug, in low doses, inhibits the NFκB pathway with a resultant decrease in MMP activity and decreased levels of IL-8, RANTES, IL-1β, and TNF-α. However, it should be used with caution, as macrolide antibiotics may have notable systemic side effects.
Clinical Context: Cyclosporine may act as a partial immunomodulator. The exact mechanism of action is not known, although it inhibits T-cell function and inhibits calcineurin. Cyclosporine emulsion has never been shown to place patients at risk of any ocular or systemic infections.
Systemic immunosuppressants are indicated when dry eye disease is accompanied by a CTD with significant systemic complications.
Clinical Context: Loteprednol etabonate decreases inflammation by numerous mechanisms, including suppressing migration of polymorphonuclear leukocytes (PMNs), reducing production of inflammatory mediators at the nuclear mRNA level, and reversing increased capillary permeability. It is a topical ester steroid available in 0.2% and 0.5% drops that is associated with a decreased risk of glaucoma and cataractogenesis.
Clinical Context: Fluorometholone inhibits edema, fibrin deposition, capillary dilation, phagocytic migration, capillary proliferation, collagen deposition, and scar formation. It decreases inflammation and corneal neovascularization, suppresses migration of PMNs, and reverses capillary permeability. It is believed to act by inducing phospholipase A2 inhibitory proteins. Used topically, fluorometholone can elevate intraocular pressure (though more slowly than dexamethasone phosphate does) and cause steroid-response glaucoma.
Corticosteroids have anti-inflammatory properties with diverse mechanisms of action and cause profound and varied metabolic effects. They modify immune response to diverse stimuli. Inflammation is the key component of the pathogenesis of dry eye disease. Topical corticosteroids can be used to reduce the inflammation.
Clinical Context: Omega-3 fatty acids may have anti-inflammatory effects and may inhibit leukocyte function. Numerous preparations are available for point-of-service sales and provide pharmaceutical-grade, mercury-free sources of essential fatty acids known to improve ocular surface function.
Variable Dry Eye Severity Level 1 2 3 4 (must have signs and symptoms) Discomfort (severity and frequency) Mild, episodic; occurs under environmental stress Moderate, episodic or chronic; occurs with or without stress Severe, frequent or constant; occurs without stress Severe or disabling, constant Visual symptoms None or episodic mild fatigue Annoying or activity-limiting, episodic Annoying, chronic or constant, activity-limiting Constant and possibly disabling Conjunctival injection None to mild None to mild +/– +/++ Conjunctival staining None to mild Variable Moderate to marked Marked Corneal staining (severity and location) None to mild Variable Marked central Severe punctate erosions Corneal and tear signs None to mild Mild debris, decreased meniscus Filamentary keratitis, mucus clumping, increased tear debris Filamentary keratitis, mucus clumping, increased tear debris, ulceration Lid and meibomian glands MGD variably present MGD variably present MGD frequent Trichiasis, keratinization, symblepharon Tear breakup time Variable ≤ 10 s ≤ 5 s Immediate Schirmer score Variable ≤ 10 mm/5 min ≤ 5 mm/5 min ≤ 2 mm/5 min MGD=meibomian gland dysfunction.