Dry Eye Disease (Keratoconjunctivitis Sicca) 

Updated: Oct 09, 2017
Author: C Stephen Foster, MD, FACS, FACR, FAAO, FARVO; Chief Editor: Andrew A Dahl, MD, FACS 

Overview

Practice Essentials

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.

Eye tear system anatomy, (Description) a. tear gla Eye tear system anatomy, (Description) a. tear gland / lacrimal gland, b. superior lacrimal punctum, c. superior lacrimal canal, d. tear sac / lacrimal sac, e. inferior lacrimal punctum, f. inferior lacrimal canal, g. nasolacrimal canal.

Dry eye disease may be subdivided into 2 main types as follows:

  • Dry eye disease associated with Sjögren syndrome (SS)
  • Dry eye disease unassociated with SS (non-SS KCS)

Dry eye disease can also be subdivided into pure aqueous deficiency dry eye and evaporative dry eye.[3] 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:

  • Foreign-body sensation and ocular dryness and grittiness
  • Hyperemia
  • Mucoid discharge
  • Ocular irritation
  • Excessive tearing (secondary to reflex secretion)
  • Photophobia
  • Fluctuating or blurry vision

See Clinical Presentation for more detail.

Diagnosis

Studies that may be used for diagnosis include the following:

  • Vital staining of corneal and conjunctival epithelium with fluorescein, lissamine green, or rose bengal
  • Tear film osmolarity
  • Ocular surface matrix metalloproteinase 9 (MMP-9)
  • Measurement of tear breakup time (TBUT)
  • The Schirmer test
  • Tear meniscus height
  • Quantification of tear components through analysis of tear proteins
  • Impression cytology to monitor progression of ocular surface changes

Additional tests that may be used in a research workup include:

  • The tear stability analysis system (TSAS)
  • The tear function index (TFI; Liverpool modification)
  • The tear ferning test (TFT)

Criteria for a diagnosis of dry eye disease associated with Sjögren syndrome (SS) include the following:

  • Abnormally low Schirmer test result
  • Objective evidence of low salivary flow
  • Biopsy-proven lymphocytic infiltration of the labial salivary glands
  • Dysfunction of the immune system, as manifested by the presence of serum autoantibodies (eg, antinuclear antibody [ANA], rheumatoid factor [RF], and anti-Ro [SS-A] and anti-La [SS-B] antibodies)

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:

  • Artificial tear substitutes
  • Gels, emulsions and ointments
  • Topical anti-inflammatory agents: Topical cyclosporine, [4, 5] topical corticosteroids
  • Topical or systemic omega-3 fatty acids: Omega-3 fatty acids inhibit the synthesis of lipid mediators and block the production of interleukin (IL)–1 and tumor necrosis factor alpha (TNF-α)
  • Topical or systemic tetracyclines
  • Secretagogues: Diquafosol, which is approved in Japan [6, 7] but not in the United States
  • Topical hyaluronic acid, which is also approved in Japan [8]
  • Autologous or umbilical cord serum
  • Systemic immunosuppressants

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 are often used in the treatment of dry eye disease. Available types include the following:

  • Absorbable plugs
  • Nonabsorbable plugs
  • Thermoplastic plugs
  • Hydrogel plugs

Other advanced or surgical options include the following:

  • Sealing of the perforation or descemetocele with corneal cyanoacrylate tissue adhesive
  • Corneal or corneoscleral patching for an impending or frank perforation
  • Lateral tarsorrhaphy - Temporary tarsorrhaphy (50%) is indicated in patients with dry eye disease secondary to exposure keratitis after facial nerve paralysis and after trigeminal nerve lesions that give rise to dry eye disease secondary to loss of corneal sensation
  • Conjunctival flap
  • Conjunctivoplasty excision of symptomatic conjunctivochalasis
  • Surgical cautery occlusion of the lacrimal drainage system
  • Mucous membrane grafting
  • Salivary gland duct transposition
  • Amniotic membrane transplantation or amniotic membrane contact lens therapy
  • Prosthetic replacement of the ocular surface ecosystem (PROSE) lens therapy

See Treatment and Medication for more detail.

Background

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:

  • Dry eye disease associated with Sjögren syndrome (SS)
  • Dry eye disease unassociated with SS (non-SS KCS)

Patients with aqueous tear deficiency (ATD) have SS if they have associated xerostomia or connective tissue disease (CTD). Patients with primary SS have evidence of a systemic autoimmune disease, as manifested by the presence of serum autoantibodies and severe ATD and ocular surface disease. These patients, who are mostly women, do not have a separate, identifiable CTD. Subsets of patients with primary SS lack evidence of systemic immune dysfunction but have a similar clinical ocular presentation.

Secondary SS is defined as dry eye disease that is associated with a diagnosable CTD, which is most commonly rheumatoid arthritis (RA) but could also be systemic lupus erythematosus (SLE) or systemic sclerosis.

Non-SS dry eye disease is mostly found in postmenopausal women, women who are pregnant, women who are taking oral contraceptives, or women 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 also a key component of 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]

Androgens are believed to be trophic for the lacrimal and meibomian glands. They also exert potent anti-inflammatory activity through the production of transforming growth factor beta (TGF-β), suppressing lymphocytic infiltration.

Dry eye disease is essentially a clinical diagnosis, made by combining information obtained from the history and from the physical examination and 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.

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.

Anatomy

The tear film covers the normal ocular surface. It is generally considered to comprise the following 3 intertwined layers (see the image below):

  • A superficial thin lipid layer (0.11 µm) – This layer is produced by the meibomian glands, and its principal function is to retard tear evaporation and to assist in uniform tear spreading [9]
  • A middle thick aqueous layer (7 µm) – This layer is produced by the main lacrimal glands (reflex tearing), as well as by the accessory lacrimal glands of Krause and Wolfring (basic tearing)
  • An innermost hydrophilic mucin layer (0.02-0.05 µm) – This layer is produced by both the conjunctiva goblet cells and the ocular surface epithelium and associates itself with the ocular surface via its loose attachments to the glycocalyx of the microplicae of the epithelium; it is the hydrophilic quality of the mucin that allows the aqueous layer to spread over the corneal epithelium
  • Diagram of three layers of tear film layer. Diagram of three layers of tear film layer.

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. 

Pathophysiology

A genetic predisposition in SS-associated dry eye disease exists, as is evidenced by the high prevalence of human leukocyte antigen B8 (HLA-B8) haplotype in these patients.

This condition 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.

Sex hormone deficiency

Both androgen and estrogen receptors are located in the lacrimal and meibomian glands. SS is more common in postmenopausal women. 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.

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.

Proinflammatory activity

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 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.[10] In one study, elevated NGF tear levels were decreased by giving 0.1% prednisolone.[11]

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 novel addition to the therapeutic armamentarium for dry eye, being used to treat both aqueous tear deficiency and meibomian gland dysfunction. It 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.

These 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 deficiency

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.

Reduced tear protein 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.

Etiology

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:

  • An evaporative state
  • An aqueous deficiency state

Evaporative loss due to meibomian gland dysfunction is the most common cause of dry eye. Causes of evaporative loss include the following:

  • Meibomian gland dysfunction
  • Disorders of lid aperture
  • Low blink rate
  • Drug action (eg, isotretinoin)
  • Vitamin A deficiency
  • Topical drugs and preservatives
  • Contact lens wear
  • Ocular surface disease (eg, allergy)

Aqueous tear deficiency (ATD) results from insufficient tear production. Causes of deficient aqueous production include the following:

  • SS dry eye (primary and secondary)
  • Lacrimal gland deficiency
  • Lacrimal gland duct obstruction
  • Reflex hyposecretion
  • Systemic drugs

Etiology: deficient aqueous production

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:

  • Idiopathic
  • Age-related dry eye
  • Congenital alacrima (eg, Riley-Day syndrome)
  • Familial dysautonomia

Secondary lacrimal gland deficiencies that may impair aqueous production include the following:

  • Lacrimal gland infiltration
  • Sarcoidosis
  • Lymphoma
  • AIDS
  • Graft vs host disease
  • Amyloidosis
  • Hemochromatosis
  • Lacrimal gland infectious diseases
  • HIV diffuse infiltrative lymphadenopathy syndrome
  • Trachoma
  • Systemic vitamin A deficiency (xerophthalmia) – Malnutrition, fat-free diets, intestinal malabsorption from inflammatory bowel disease, bowel resection, or chronic alcoholism
  • Lacrimal gland ablation
  • Lacrimal gland denervation

Lacrimal obstructive diseases that may impair aqueous production include the following:

  • Trachoma
  • Ocular cicatricial pemphigoid
  • Erythema multiforme and Stevens-Johnson syndrome
  • Chemical and thermal burns
  • Endocrine imbalance
  • Postirradiation fibrosis

Medications that may impair aqueous production include the following:

  • Antihistamines
  • Beta blockers
  • Phenothiazines
  • Atropine
  • Oral contraceptives
  • Anxiolytics
  • Antiparkinsonian agents
  • Diuretics
  • Anticholinergics
  • Antiarrhythmics
  • Topical preservatives in eye drops (eg, benzalkonium chloride [BAK], thimerosal)
  • Topical anesthetics
  • Isotretinoin

The following conditions may lead to reflex hyposecretion:

  • Neurotrophic keratitis – Cranial nerve (CN) V/ganglion section/injection/compression
  • Corneal surgery - Limbal incision (eg, extracapsular cataract extraction), keratoplasty, and refractive surgery
  • Infective - Herpes simplex keratitis and herpes zoster ophthalmicus
  • Topical agents - Topical anesthesia
  • Systemic medications – Beta blockers and atropinelike drugs
  • Chronic contact lens wear
  • Diabetes
  • Aging
  • Trichloroethylene toxicity
  • CN VII damage
  • Multiple neuromatosis

Sjögren syndrome

Primary SS has no associated CTD. Secondary SS may be associated with any of the following CTDs:

  • RA
  • SLE
  • Progressive systemic sclerosis (scleroderma)
  • Primary biliary cirrhosis
  • Interstitial nephritis
  • Polymyositis and dermatomyositis
  • Polyarteritis nodosa
  • Hashimoto thyroiditis
  • Lymphocytic interstitial pneumonitis
  • Idiopathic thrombocytopenic purpura
  • Hypergammaglobulinemia
  • Waldenstrom macroglobulinemia
  • Wegener granulomatosis

Etiology: evaporative loss

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: 

  • Hypersecretory - Meibomian seborrhea
  • Hyposecretory - Retinoid therapy
  • Obstructive - This may be simple, primary or secondary to local disease (eg, anterior blepharitis), systemic disease (eg, acne rosacea, seborrheic dermatitis, atopy, ichthyosis, or psoriasis), syndromes (eg, anhidrotic ectodermal dysplasia, ectrodactyly syndrome, or Turner syndrome), or systemic toxicity (eg, 13- cis retinoic acid or polychlorinated biphenyls); or it may be cicatricial, primary or secondary to local disease (eg, chemical burns, trachoma, pemphigoid, erythema multiforme, acne rosacea, vernal keratoconjunctivitis [VKC], or atopic keratoconjunctivitis [AKC])

Evaporative loss may result from a low blink rate caused by the following:

  • Physiologic phenomenon, such as may occur during performance of tasks that require concentration (eg, working at a computer or a microscope)
  • Extrapyramidal disorder, such as Parkinson disease (decreasing dopaminergic neuron pool)

Evaporative loss may result from the following disorders of eyelid aperture and eyelid-globe congruity:

  • Exposure (eg, craniostenosis, proptosis, exophthalmos, and high myopia)
  • Lid palsy
  • Ectropion
  • Lid coloboma

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:

  • Development disorder of goblet cells
  • Lacrimal acinar damage

Other extrinsic causes are as follows:

  • Topical drugs and preservatives that cause surface epithelial cell damage
  • Contact lens wear
  • Ocular surface disease (eg, allergy)

Mechanisms

A classification of dry eye on the basis of mechanisms includes tear hyperosmolarity and tear-film instability.

Severity

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, 12]

Table. Dry Eye Severity Levels (Open Table in a new window)

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.

Epidemiology

Dry eye disease is very common in the United States, affecting a significant percentage of the population, especially those older than 40 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.[13]

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.[14] 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.[13] 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.

Prognosis

The prognosis of dry eye disease varies depending on the severity of the condition. Most patients have mild-to-moderate cases, and they can be treated symptomatically with lubricants, 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 oval or circular, less than 3 mm in diameter, and located in the central or paracentral cornea. 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.

Patient Education

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:

 

Presentation

History

Depending on the severity of dry eye disease (DED), or keratoconjunctivitis sicca (KCS), the following are the most common patient complaints:

  • Foreign-body sensation
  • Grittiness
  • Hyperemia
  • Mucoid discharge
  • Ocular irritation
  • Ocular dryness
  • Excessive tearing (secondary to reflex secretion)
  • Photophobia
  • Itching
  • Fluctuating or blurry vision

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. 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, 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.[15]

 

DDx

Diagnostic Considerations

The differential diagnoses for dry eye disease (DED), or keratoconjunctivitis sicca (KCS), are numerous. Conditions to consider are those that include conjunctivitis (allergic, bacterial, giant papillary, and viral, as well as atopic and vernal keratoconjunctivitis), filamentary keratitis, infectious diseases (chlamydia, herpes simplex and herpes simplex keratitis, and herpes zoster), corneal abnormalities (abrasion, erosion, foreign body, and mucous plaques), and other keratitis (interstitial) and keratopathies (neurotrophic and pseudophakic bullous).

Other problems to consider include the following:

  • Cranial nerve V trauma
  • Cranial nerve VII trauma or disease such as Bell palsy
  • Corneal surgery
  • Medications, topical and systemic
  • Nocturnal lagophthalmos and lid deformities
  • Thygeson superficial punctate keratopathy

Differential Diagnoses

 

Workup

Approach Considerations

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 additional 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 ideal questionnaires are available in PubMed. Among the most commonly used and validated include the following:

  • OSDI (Ocular Surface Disease Index)
  • SPEED (System for Patient Evaluation of Eye Dryness)
  • VAS (Visual Analog Scale)
  • McMonnies Questionnaire
  • SANDE (Symptom Assessment in Dry Eye)

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.[16] Serology for circulating autoantibodies (see below) may be indicated.

Sjögren syndrome

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:

  • Patients who have systemic immune dysfunction but no defined connective tissue disease (CTD) – These patients have primary SS
  • Patients who lack evidence of systemic immune dysfunction and have no defined CTD
  • Patients who have a defined CTD, most commonly rheumatoid arthritis (RA) – These patients have secondary SS; dry eye disease is common in patients with RA, including those without SS [17] ; thus, dry eye disease should always be taken into consideration regardless of RA activity, because the severity of dry eye disease is independent of RA activity

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:

  • Abnormally low Schirmer test result
  • Objective evidence of low salivary flow
  • Biopsy-proven lymphocytic infiltration of the labial salivary glands
  • Dysfunction of the immune system, as manifested by the presence of serum autoantibodies (eg, antinuclear antibody [ANA], rheumatoid factor [RF], and anti-Ro [SS-A] and anti-La [SS-B] antibodies)

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.[18]

Tear Breakup Time

Tear breakup time (TBUT) is determined by measuring the interval between instillation of fluorescein 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. Decreased 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.

Epithelial Staining

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 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.[19]

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.

Schirmer Test

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, to the best extent possible, basal 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.

Tests to Quantify Tear Components

Additional tests may be performed to quantify each individual tear component.

Lipid 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).

Aqueous component

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.[20] 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.[21] This test was more sensitive and specific than the others, and increasing dry eye disease severity was correlated with higher intereye differences in osmolarity.

Mucin component

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:

  • Loss of goblet cells
  • Enlargement of superficial epithelial cells and an increase in their cytoplasm-to-nucleus ratio
  • Keratinization

Impression cytology is highly sensitive, but it does require proper staining and expert microscopic evaluation of samples.

Matrix metalloproteinase 9

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.

In December 2013, the FDA approved InflammaDry (Rapid Pathogen Screening Inc), 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.[22]

Meibography

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.[23]

Other Tests

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.

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 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.

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.

Histologic Findings

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.

 

Treatment

Approach Considerations

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.[24, 25]

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.

DEWS II treatment recommendations

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,[40] 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:

  • Educating the patient regarding the condition, management, and prognosis
  • Modifying the patient’s local environment
  • Educating the patient on dietary modifications (including oral essential fatty acid supplementation)
  • Identifying any potentially etiologic systemic/topical medications and considering modification or elimination of offending agents
  • Applying ocular lubricants (lipid-containing supplements in patients with MGD)
  • Instituting proper lid hygiene and applying warm compresses

Step two (used if the above options are inadequate) is as follows:

  • Use of nonpreserved ocular lubricants to minimize preservative-induced toxicity
  • Tea tree oil therapy to treat demodicosis, if present
  • Tear conservation therapy (punctal occlusion, moisture chamber spectacles/goggles)
  • Overnight treatments (eg, ointment or moisture chamber devices)
  • In-office, physical heating and expression of the meibomian glands (including device-assisted therapies [eg, LipiFlow])
  • In-office intense pulsed light therapy to treat MGD
  • Prescription drug therapy (topical antibiotic with or without steroid applied to lid margins for anterior blepharitis, limited-duration topical corticosteroid, topical secretagogues, topical nonglucocorticoid immunomodulators (eg, cyclosporine), topical LFA-1 antagonists (eg, lifitegrast), oral macrolide or tetracycline antibiotics

Step three (used if the above options are inadequate) is as follows:

  • Oral secretagogue therapy
  • Application of autologous/allogeneic serum eye drops
  • Therapeutic contact lenses (soft bandage lenses, rigid scleral lenses)

Step four (used if the above options are inadequate) is as follows:

  • Longer-duration topical corticosteroid therapy
  • Amniotic membrane grafting
  • Surgical punctal occlusion
  • Other surgical options (eg, salivary gland transplantation, tarsorrhaphy)

Pharmacologic Therapy

Agents that have been used to treat dry eye disease include the following:

  • Artificial tear substitutes
  • Gels, emulsions and ointments
  • Anti-inflammatory agents - Topical cyclosporine, [4, 5] topical corticosteroids
  • Topical or systemic omega-3 fatty acids: Omega-3 fatty acids inhibit the synthesis of lipid mediators and block the production of interleukin (IL)–1 and tumor necrosis factor alpha (TNF-α)
  • Topical or systemic tetracyclines
  • Secretagogues - Diquafosol (approved in Japan [6, 7] but not in the United States)
  • Autologous or umbilical cord serum
  • Systemic immunosuppressants
  • Lymphocyte function-associated antigen 1 (LFA-1) antagonists

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.

Patch with lubrication at night. Place an artificial tear insert into the inferior cul-de-sac every morning.

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.[27]

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.[28]

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).[29, 30, 31, 32] Lifitegrast improved inferior corneal staining score (ICSS) in the OPUS-1 and OPUS-3 studies.[29, 30] Ocular safety and tolerability were similar to those of placebo.[32]

Eye Protection

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:

  • Silicone rubber lenses
  • Gas permeable scleral-bearing hard contact lenses with or without fenestration
  • Highly oxygen-permeable lenses (overnight wear)
  • Cryopreserved sutureless amniotic membrane is available as a 5- to 10-day contact lens [33]

Punctal Occlusion and Other Surgical Interventions

Punctal plugs are often employed in the treatment of dry eye disease. Available types include the following:

  • Absorbable plugs - These plugs are made of collagen or polymers and either dissolve by themselves or may be removed by saline irrigation; occlusion duration ranges from 7-180 days
  • Nonabsorbable plugs - These plugs are made of silicone; 2 main categories of silicone plugs are available for dry eye, capped punctal plugs and intracanalicular plugs
  • Thermoplastic plugs (eg, SmartPLUG; Medennium, Irvine, CA) – These plugs is made of a thermosensitive, hydrophobic acrylic polymer that changes from a rigid solid to a soft, cohesive gel when its temperature changes from room temperature to body temperature
  • Hydrogel plugs (eg Oasis Form Fit; Sigma Pharmaceuticals, Monticello, IA)

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.[34]

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:

  • Sealing of the perforation or descemetocele with corneal cyanoacrylate tissue adhesive
  • Corneal or corneoscleral patching for an impending or frank perforation
  • Lateral tarsorrhaphy - Temporary tarsorrhaphy (50%) is indicated in patients with dry eye disease secondary to exposure keratitis after facial nerve paralysis and after trigeminal nerve lesions that give rise to dry eye disease secondary to loss of corneal sensation
  • Conjunctival flap
  • Conjunctivoplasty excision of symptomatic conjunctivochalasis
  • Surgical cautery occlusion of the lacrimal drainage system [35]
  • Mucous membrane grafting
  • Salivary gland duct transposition
  • Amniotic membrane transplantation or amniotic membrane contact lens therapy
  • Prosthetic replacement of the ocular surface ecosystem (PROSE) lens therapy

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.[36]

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.

 

Medication

Medication Summary

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.

Ophthalmic Lubricants

Class Summary

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.

Artificial tears (Advanced Eye Relief, Bion Tears, Hypo Tears, Murine Tears, Tears Naturale II)

Artificial tears are used to increase lubrication of the eye.

Hydroxypropyl cellulose (Lacrisert)

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.

Carboxymethylcellulose (GenTeal, Lubricating Plus Eye Drops, Refresh Celluvisc, Refresh Optive, Theratears, Ultra Fresh)

These substances serve as lubricants and emollients.

LFA-1 Antagonists

Class Summary

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.

Lifitegrast ophthalmic (Xiidra)

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.

Mucolytic Agents

Class Summary

Mucolytic agents such as topical 10% N-acetylcysteine lower mucous viscosity by digesting mucoproteins. They are used when mucous discharge or plaques are present.

Acetylcysteine

Mucolytic agents lower mucous viscosity by digesting mucoproteins. They are used when mucous discharge or plaques are present.

Antibiotics, Systemic

Class Summary

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 (Acticlate, Adoxa, Doryx, Doxy 100, Solodyn, Targadox, Vibramycin)

Doxycycline inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Minocycline (Minocin, Solodyn)

Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible Chlamydia, Rickettsia, and Mycoplasma.

Immunosuppressants

Class Summary

Systemic immunosuppressants are indicated when dry eye disease is accompanied by a CTD with significant systemic complications.

Cyclosporine ophthalmic (Restasis)

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.

Corticosteroids

Class Summary

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.

Loteprednol etabonate (Alrex, Lotemax)

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.

Fluorometholone (Flarex, FML, FML Forte)

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.

Nutritionals, Other

Class Summary

Certain dietary supplements may have beneficial effects.

Omega-3 fatty acids (Lovaza)

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.

 

Questions & Answers

Overview

What is dry eye disease (keratoconjunctivitis sicca)?

What are the types of dry eye disease (keratoconjunctivitis sicca)?

What are the clinical features of dry eye disease (keratoconjunctivitis sicca)?

Which tests are performed in the workup of dry eye disease (keratoconjunctivitis sicca)?

Which tests are used in research studies to evaluate dry eye disease (keratoconjunctivitis sicca)?

What are diagnostic criteria for dry eye disease associated with Sjögren syndrome (SS)?

What are the benefits of early detection and aggressive treatment of dry eye disease (keratoconjunctivitis sicca)?

Which types of medications are used to treat dry eye disease (keratoconjunctivitis sicca)?

What is the role of therapeutic eyewear in the treatment of dry eye disease (keratoconjunctivitis sicca)?

Which punctal plugs are used in the treatment of dry eye disease (keratoconjunctivitis sicca)?

What are the surgical options for the treatment for dry eye disease (keratoconjunctivitis sicca)?

What is dry eye disease (keratoconjunctivitis sicca)?

Which diseases are associated with dry eye disease (keratoconjunctivitis sicca)?

What is the anatomy of tear film relevant to dry eye disease (keratoconjunctivitis sicca)?

What is the anatomy of dry eye disease (keratoconjunctivitis sicca)?

What is the pathophysiology of dry eye disease (keratoconjunctivitis sicca)?

What is the role of sex hormone deficiency in the pathogenesis of dry eye disease (keratoconjunctivitis sicca)?

What is the role of inflammation in the pathogenesis of dry eye disease (keratoconjunctivitis sicca)?

What is the role of mucin deficiency in the pathogenesis of dry eye disease (keratoconjunctivitis sicca)?

How does dry eye disease (keratoconjunctivitis sicca) affect tear protein production?

What causes dry eye disease (keratoconjunctivitis sicca)?

What causes evaporative loss in dry eye disease (keratoconjunctivitis sicca)?

What causes deficient aqueous production (ATD) in dry eye disease (keratoconjunctivitis sicca)?

What are the primary lacrimal gland deficiencies in dry eye disease (keratoconjunctivitis sicca) unassociated with SS (non-SS KCS)?

What are the secondary lacrimal gland deficiencies in dry eye disease (keratoconjunctivitis sicca) unassociated with SS (non-SS KCS)?

Which lacrimal obstructive diseases may impair aqueous production in dry eye disease (keratoconjunctivitis sicca) unassociated with SS (non-SS KCS)?

Which medications may impair aqueous production in dry eye disease (keratoconjunctivitis sicca) unassociated with SS (non-SS KCS)?

Which conditions may cause reflex hyposecretion in dry eye disease (keratoconjunctivitis sicca) unassociated with SS (non-SS KCS)?

Which connective tissue diseases (CTDs) are associated with dry eye disease (keratoconjunctivitis sicca) associated with Sjögren syndrome (SS)?

What is the role of meibomian gland dysfunction in the etiology of dry eye disease (keratoconjunctivitis sicca)?

What causes a low brink rate in dry eye disease (keratoconjunctivitis sicca)?

What is the role of eyelid aperture and eyelid-globe congruity disorders in the etiology of dry eye disease (keratoconjunctivitis sicca)?

What are the extrinsic causes of dry eye disease (keratoconjunctivitis sicca)?

How is dry eye disease (keratoconjunctivitis sicca) classified based on mechanism?

What is the classification of dry eye disease (keratoconjunctivitis sicca) based on severity?

What is the prevalence of dry eye disease (keratoconjunctivitis sicca) in the US?

Which patient groups have the highest incidence of dry eye disease (keratoconjunctivitis sicca)?

What is the prognosis of dry eye disease (keratoconjunctivitis sicca)?

What should be included in patient education about dry eye disease (keratoconjunctivitis sicca)?

Presentation

What are the most common patient complaints of dry eye disease (keratoconjunctivitis sicca)?

Which clinical history findings are characteristic of dry eye disease (keratoconjunctivitis sicca)?

DDX

What are differential diagnoses for dry eye disease (keratoconjunctivitis sicca)?

What are the differential diagnoses for Dry Eye Disease (Keratoconjunctivitis Sicca)?

Workup

How is Sjögren syndrome (SS) diagnosed in patients with dry eye disease (keratoconjunctivitis sicca)?

How is dry eye disease (keratoconjunctivitis sicca) diagnosed?

Which studies may be performed in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of tear breakup time (TBUT) testing in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of epithelial staining in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of Schirmer test in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of lipid testing in the workup of dry eye disease (keratoconjunctivitis sicca)?

How is the aqueous component in dry eye disease (keratoconjunctivitis sicca) assessed?

How are mucins analyzed in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of matrix metalloproteinase 9 (MMP-9) assessment in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of meibography in the workup of dry eye disease (keratoconjunctivitis sicca)?

Which tests are performed to measure the tear components in dry eye disease (keratoconjunctivitis sicca)?

How is meibomian gland morphology analyzed in the workup of dry eye disease (keratoconjunctivitis sicca)?

What is the role of meniscometry in the workup of dry eye disease (keratoconjunctivitis sicca)?

Which histologic findings are characteristic of dry eye disease (keratoconjunctivitis sicca)?

Treatment

What are the treatment options for dry eye disease (keratoconjunctivitis sicca)?

What is step one of the treatment for dry eye disease (keratoconjunctivitis sicca) algorithm proposed by TFOS DEWS II?

What is step two of the treatment for dry eye disease (keratoconjunctivitis sicca) algorithm proposed by TFOS DEWS II?

What is step three of the treatment for dry eye disease (keratoconjunctivitis sicca) algorithm proposed by TFOS DEWS II?

What is step four of the treatment for dry eye disease (keratoconjunctivitis sicca) algorithm proposed by TFOS DEWS II?

Which types of medications are used to treat dry eye disease (keratoconjunctivitis sicca)?

What is included in pharmacologic therapy for the treatment for dry eye disease (keratoconjunctivitis sicca)?

What is the efficacy of diquafosol and sodium hyaluronate in the treatment of dry eye disease (keratoconjunctivitis sicca)?

/what is the role of eye protection in the treatment of dry eye disease (keratoconjunctivitis sicca)?

What types of punctal plugs are used in the treatment of dry eye disease (keratoconjunctivitis sicca)?

What are the surgical options for the treatment of dry eye disease (keratoconjunctivitis sicca)?

Medications

What is the role of drug treatment for dry eye disease (keratoconjunctivitis sicca)?

Which medications in the drug class Nutritionals, Other are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?

Which medications in the drug class Corticosteroids are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?

Which medications in the drug class Immunosuppressants are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?

Which medications in the drug class Antibiotics, Systemic are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?

Which medications in the drug class Mucolytic Agents are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?

Which medications in the drug class LFA-1 Antagonists are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?

Which medications in the drug class Ophthalmic Lubricants are used in the treatment of Dry Eye Disease (Keratoconjunctivitis Sicca)?