eMedicine Specialties > Ophthalmology > Lacrimal System

Dry Eye Syndrome

C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution
Erdem Yuksel, MD, Fellow, Department of Ophthalmology, Massachusetts Eye Research and Surgery Institute, Medical School of Gazi University; Fahd Anzaar, MD, Fellow, Massachusetts Eye Research and Surgery Institute; Clinical Research and Education Coordinator, Ocular Immunology and Uveitis Foundation; Anthony S Ekong, MD, Consulting Staff, Department of Ophthalmology, Marshfield Clinic

Updated: May 13, 2009

Introduction

Background

Dry eye is a multifactorial disease of the tears and the ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface.¹ Dry eye is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.¹

The tear layer covers the normal ocular surface. Generally, it is accepted that the tear film is made up of 3 intertwined layers, as follows:

1. A superficial thin lipid layer (0.11 µm) is produced by the meibomian glands, and its principal function is to retard tear evaporation and to assist in uniform tear spreading.
2. A middle thick aqueous layer (7 µm) is produced by the main lacrimal glands (reflex tearing), as well as the accessory lacrimal glands of Krause and Wolfring (basic tearing).
3. An innermost hydrophilic mucin layer (0.02-0.05 µm) 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 to spread over the corneal epithelium.

Pathophysiology

A genetic predisposition in SS associated KCS exists as evident 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, fodrin (a cytoskeletal protein), the muscarinic M3 receptor, or SS-specific antibodies (eg, anti-RO [SS-A], anti-LA [SS-B]), inflammatory cytokine release, and focal lymphocytic infiltration (ie, mainly CD4⁺ T cells but also B cells) of the lacrimal and salivary gland, with glandular degeneration and induction of apoptosis in the conjunctiva and lacrimal glands. This results in dysfunction of the lacrimal gland, with reduced tear production, and loss of response to nerve stimulation and less reflex tearing. Active T lymphocytic infiltrate in the conjunctiva also has been reported in non-SS associated KCS.

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 (ie, estrogen, androgen) occurs, possibly affecting the functional and secretory aspect of the lacrimal gland. Forty years ago, initial interest in this area centered on estrogen and/or progesterone deficiency to explain the link between KCS and menopause. However, recent research has focused on androgens, specifically testosterone, and/or metabolized androgens.

It has been shown that in meibomian gland dysfunction, a deficiency in androgens results in loss of the lipid layer, specifically triglycerides, cholesterol, monounsaturated essential fatty acids (eg, oleic acid), and polar lipids (eg, phosphatidylethanolamine, sphingomyelin). The loss of polar lipids (present at the aqueous-tear interface) exacerbates the evaporative tear loss, and the decrease in unsaturated fatty acids raises the melting point of 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 break-up time, and increased tear film debris, all indicative of a deficient or abnormal tear film.

Various proinflammatory cytokines that may cause cellular destruction, including interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), TGF-beta, TNF-alpha, and RANTES, are altered in patients with KCS. IL-1 beta and TNF-alpha, which are present in the tears of patients with KCS, cause the release of opioids that bind to opioid receptors on neural membranes and inhibit neurotransmitter release through NF-K b production. 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, which recruit and activate local lymphocytes. Substance P also acts via the NF-AT and NF-K b signaling pathway leading to ICAM-1 and VCAM-1 expression, adhesions molecules that promote lymphocyte homing and chemotaxis to sites of inflammation. Cyclosporin A is an NK-1 and NK-2 receptor inhibitor that can downregulate these signaling molecules and is a novel addition to the therapeutic armamentarium for dry eye, being used to treat both aqueous tear deficiency and meibomian gland dysfunction. It has been shown to improve the 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, as discussed above. An increased rate of apoptosis is also seen in conjunctival and lacrimal acinar cells, perhaps due to the cytokine cascade. Elevated levels of tissue-degrading enzymes called matrix metalloproteinases (MMPs) are also present in the epithelial cells.

Mucin synthesizing genes, designated MUC1-MUC17, representing both transmembrane and goblet-cell secreted, soluble mucins, have been isolated, and their role in hydration and stability of the tear film are being investigated in patients with dry eye syndrome. Particularly significant is MUC5AC, 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 dry eye syndrome development. In addition to dry eye, other conditions, such as ocular cicatricial pemphigoid, Stevens-Johnson syndrome, and vitamin A deficiency, which lead to drying or keratinization of the ocular epithelium, eventually lead to goblet cell loss. Both classes of mucins are decreased in these diseases, and, on a molecular level, mucin gene expression, translation, and posttranslational processing are altered.

Normal production of tear proteins, such as lysozyme, lactoferrin, lipocalin, and phospholipase A2, is decreased in KCS.

Frequency

United States

Dry eye is a very common disorder affecting a significant percentage (approximately 10-30%) of the population, especially those older than 40 years. 

In the United States, an estimated 3.23 million women and 1.68 million men, a total of 4.91 million people, aged 50 years and older are affected.

International

The frequency of dry eye in other countries closely parallels that of the United States.

Mortality/Morbidity

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 syndrome can cause blindness. Other complications include punctate epithelial defects (PEDs), corneal neovascularization, and corneal scarring.

Race

The frequency and the clinical diagnosis of dry eye are greater in the Hispanic and Asian populations than in the Caucasian population.

Sex

Dry eye may be slightly more common in women. KCS associated with SS (a type of dry eye) is believed to affect 1-2% of the population, and 90% of those affected are women.

Clinical

History

• Ocular irritation of dry sensation, burning, itching, pain, foreign body sensation, photophobia, and blurred vision are common in patients with dry eye. These symptoms are often exacerbated in smoky or dry environments, by indoor heating, 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 KCS, 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 may complain of redness of the eyelids and conjunctiva, but, in these patients, the symptoms are worse on awakening in the morning.
• Paradoxically, some patients with dry eye syndrome complain of too much tearing. When evidence of dry eye syndrome exists, this symptom often is explained by excessive reflex tearing due to severe corneal surface disease from the dryness.
• Certain systemic medications also decrease tear production, such as antihistamines, beta-blockers, and oral contraceptives.
• Past medical history may be significant for coexisting connective tissue disease, rheumatoid arthritis, or thyroid abnormalities. A thorough review of systems should be obtained, asking specifically about dry mouth.

Physical

• Signs of a dry eye include the following:
  • Bulbar conjunctival vascular dilation
  • Decreased tear meniscus
  • Irregular corneal surface
  • Decreased tear break-up time
  • Punctate epithelial keratopathy
  • Corneal filaments
  • Increased debris in the tear film
  • Conjunctival pleating
  • Superficial punctuate keratitis, with positive fluorescein staining
  • Mucous discharge
  • Corneal ulcers in severe cases
• Symptoms often do not correlate with signs.
• In severe cases, there may be an epithelial defect or a sterile corneal infiltrate or ulcer. Secondary infectious keratitis also can develop. Both sterile and infectious corneal perforations can occur.

Causes

The International Dry Eye WorkShop (DEWS) recently developed a 3-part classification of dry eye, based on etiology, mechanisms, and disease stage.¹

The classification system, which is updated as an etiopathogenic classification by the DEWS Subcommittees, formulated by the National Eye Institute (NEI)/Industry Dry Eye Workshop Report in 1995, distinguishes 2 main categories (or causes) of dry eye states, as follows: an aqueous deficiency state and an evaporative state.

• Deficient aqueous production
  • Sjogren syndrome dry eye
    • Primary
    • Secondary
  • Non-Sjogren syndrome dry eye
    • Lacrimal gland deficiency
    • Lacrimal gland duct obstruction
    • Reflex hyposecretion
    • Systemic drugs
• Evaporative
  • Intrinsic causes
    • Meibomian gland dysfunction
    • Disorders of lid aperture
    • Low blink rate
    • Drug action (eg, Accutane)
  • Extrinsic causes
    • Vitamin A deficiency
    • Topical drugs and preservatives
    • Contact lens wear
    • Ocular surface disease (eg, allergy)

Deficient aqueous production can be further classified as follows:

• Non-Sjögren syndrome
  • Primary lacrimal gland deficiencies
    •  Idiopathic
    • Age-related dry eye
    • Congenital alacrima (eg, Riley-Day syndrome)
    • Familial dysautonomia
  • Secondary lacrimal gland deficiencies
    • 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 disease 
    • Trachoma
    • Ocular cicatricial pemphigoid
    • Erythema multiforme and Stevens-Johnson syndrome
    • Chemical and thermal burns
    • Endocrine imbalance
    • Postradiation fibrosis
  • Medications – Antihistamines, beta-blockers, phenothiazines, atropine, oral contraceptives, anxiolytics, antiparkinsonian agents, diuretics, anticholinergics, antiarrhythmics, topical preservatives in eye drops, topical anesthetics, and isotretinoin
  • Reflex hyposecretion – Reflex sensory block and reflex motor block 
    • Neurotrophic keratitis - Fifth nerve/ganglion section/injection/compression
    • Corneal surgery - Limbal incision (eg, extracapsular cataract extraction), keratoplasty, refractive surgery (eg, PRK, LASIK, RK)
    • Infective - Herpes simplex keratitis, herpes zoster ophthalmicus
    • Topical agents - Topical anesthesia
    • Systemic medications – Beta blockers, atropine-like drugs
    • Chronic contact lens wear
    • Diabetes
    • Aging
    • Trichloroethylene toxicity
    • Cranial nerve VII (CN VII) damage
    • Multiple neuromatosis
• Sjögren syndrome 
  • Primary (no associated connective tissue disease [CTD])
  • Secondary (associated CTD) 
    • Rheumatoid arthritis
    • Systemic lupus erythematosus
    • Progressive systemic sclerosis (scleredema)
    • Primary biliary cirrhosis
    • Interstitial nephritis
    • Polymyositis and dermatomyositis
    • Polyarteritis nodosa
    • Hashimoto thyroiditis
    • Lymphocytic interstitial pneumonitis
    • Idiopathic thrombocytopenic purpura
    • Hypergammaglobulinemia
    • Waldenstrom macroglobulinemia
    • Wegener granulomatosis

Evaporative loss can be further classified as follows:

• Intrinsic causes
  • Meibomian gland disease
    • Reduced number - Congenital deficiency, acquired meibomian gland dysfunction
    • Replacement - Distichiasis, distichiasis lymphedema syndrome, metaplasia
    • Meibomian gland dysfunction
      • Hypersecretory - Meibomian seborrhea
      • Hyposecretory - Retinoid therapy
      • Obstructive – Simple, primary or secondary to local disease (eg, anterior blepharitis), systemic disease (eg, acne rosacea, seborrheic dermatitis, atopy, ichthyosis, psoriasis), syndromes (eg, anhidrotic ectodermal dysplasia, ectrodactyly syndrome, Turner syndrome), and systemic toxicity (eg, 13-cis retinoic acid, polychlorinated biphenyls); or cicatricial, primary or secondary to local disease (eg, chemical burns, trachoma, pemphigoid, erythema multiforme, acne rosacea, VKC, AKC) 
  • Low blink rate
  • Physiological phenomenon, such as 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)
  • Disorders of eyelid aperture and eyelid/globe congruity
    • Exposure (eg, craniostenosis, proptosis, exophthalmos, high myopia)
    • Lid palsy
    • Ectropion
    • Lid coloboma
  •  Drug action (eg, Accutane)
•  Extrinsic causes
  • Vitamin A deficiency
  • Development disorder of goblet cells
  • Lacrimal acinar damage
  • Topical drugs and preservatives (surface epithelial cell damage)
  • Contact lens wear
  • Ocular surface disease (eg, allergy)

Dry Eye Severity Levels^1,2

Differential Diagnoses

Other Problems to Be Considered

Cranial nerve V trauma or corneal surgery
Medicamentosa
Nocturnal lagophthalmos
Thygeson superficial punctate keratopathy

Workup

Laboratory Studies

• Conjunctival impression cytology can be used to monitor the progression of ocular surface changes. 
• Serology for circulating autoantibodies, including ANA or SS antibodies (ie, SS-A, SS-B), anti-Ro, anti-La, anti-M3 receptor, and anti-fodrin, as well as ANCA and Rh-F, may be indicated.

Other Tests

• Dry eye is essentially a clinical diagnosis, combining information obtained from both the history and the examination and performing 1 or more tests to lend some objectivity to the diagnosis. No one test is sufficiently specific to permit an absolute diagnosis of dry eye.
• Symptom questionnaires can be used to help establish a diagnosis of dry eye and to assess the effects of treatments or to grade disease severity. Fourteen ideal questionnaires are available in Pubmed. 
• Tear break-up test (TBUT) is determined by measuring the time lapse 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.
• Use rose bengal and fluorescein staining to evaluate epitheliopathy. Rose bengal stains 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. Lissamine green B and sulforhodamine also have been used as staining agents.
• Early or mild cases of KCS are detected more easily with rose bengal than with fluorescein staining, and the conjunctiva usually is stained more intensely than the cornea. Interpalpebral staining of the nasal and/or inferior paracentral cornea is seen in KCS. A linear pattern of inferior conjunctiva and corneal staining by rose bengal is characteristic of meibomian gland dysfunction.
• Van Bijsterveld developed a scoring system for rose bengal that evaluates the intensity of staining based on a scale of 0-3 in 3 areas: nasal conjunctiva, temporal conjunctiva, and cornea. With this system, the maximum possible score is 9. According to this system, a score of 3.5 or greater is considered positive for KCS.
• Lissamine green staining combines the advantages of fluorescein and rose bengal staining; it stains healthy epithelial cells that are not protected by a mucin layer (similar to rose bengal) and also stains degenerating or dead cells (similar to fluorescein). It avoids the pain, discomfort, and corneal toxicity associated with rose bengal but is somewhat less sensitive and more transient, so it is more difficult to appreciate on slit lamp examination.
• Use the Schirmer test to test aqueous tear production. It is performed by placing a thin strip of filter paper in the inferior cul-de-sac; then, the eyes are closed for 5 minutes, and the amount of wetting of the paper strip is measured. Traditionally, the basic secretion test is performed following the instillation of topical anesthetic and the placement of a thin strip of filter paper in the inferior cul-de-sac. The authors prefer this technique and use the corners of soft tissue to wick, by capillary attraction (without any wiping action), all liquid from the inferior fornix prior to placement of the Schirmer paper. Measurement of less than 5 mm 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 aqueous tear deficiency. The test is relatively specific, but it is poorly sensitive.
• The Schirmer II test measures reflex tearing. It is performed similar to the basic secretion test, with the addition of nasal mucosal irritation 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 KCS.
• 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. They may be analyzed by high pressure liquid chromatography (HPLC) or gas chromatography with mass spectroscopy (GC-MS).
• The aqueous/protein component may be tested for by measuring the tear film osmolarity, tear lysozyme, tear lactoferrin, EGF, aquaporin 5, lipocalin, and IgA concentrations with ELISA. 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 specificity in meibomitis, herpes simplex keratitis, and bacterial conjunctivitis. The test often is not used because of the lack of commercially available equipment for its measurement.
• 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 mRNA expression. Immunofluorescence, flow cytometry, ELISA, or immunoblotting techniques may also be used.
• Conjunctival biopsy for in situ hybridization and immunohistochemistry may also be used.
• 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 evaporimetry.
• The tear function index (TFI) (Liverpool modification) evaluates the tear dynamics of production and drainage and helps detect subjects suffering from dry eye. The test depends on using prepared filter paper strips containing fluorescein, and it has been designed to allow the direct measurement of the TFI using the prepared tear strips.
• The tear ferning test (TFT) can be used to help diagnose the quality of tears (electrolyte concentration), KCS, and hyperosmolarity. A drop of tears is collected from the lower meniscus and then 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 on the basis of the ferning patterns.
• Impression cytology: In mucin layer deficiency, the epithelium may undergo squamous metaplasia, resulting in a loss of goblet cells. This method is very sensitive but requires proper staining and expert analysis of the slide.
• Meibography/meiboscopy: Meibomian gland morphology and density and dropout may be analyzed by using meibography/meiboscopy to help diagnose meibomian gland dysfunction.  Meiboscopy is the visualization of the meibomian gland by transillumination of the eyelid. Meibography implies photographic documentation.
• Meibometry: Meibomian gland dysfunction may be diagnosed by 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 (tear meniscus radius, height, and cross-sectional area): Meniscometry is used to help diagnose aqueous tear deficiency. 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 to calculate the radius of curvature.
• Patients with dry eye have reduced central corneal thickness values. This is thought to somehow result from the hypertonicity of the tear film in these patients. The corneal thickness increases after therapy with artificial tears, and this has been suggested as a new diagnostic and follow-up criterion for dry eye. 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 decrease of the fluorescein concentration in tears per minute after instillation, is also reduced in patients with symptomatic dry eye. It is tested by using fluorophotometry.

Procedures

• Lacrimal gland or minor (salivary) gland biopsy may be performed to aid in diagnosing SS.

Histologic Findings

Histopathologically, squamous metaplasia with loss of goblet cells, cellular enlargement, and increase in cytoplasmic/nuclear ratio of the superficial conjunctival epithelial cells are present in patients with KCS. The lacrimal gland and the conjunctiva are also heavily infiltrated by CD4⁺ T cell (and B cell) lymphocytes.

In meibomian gland dysfunction, loss of glandular architecture, dilation of the ductules, ductal occlusion, and hyperkeratinization of the ductal epithelium are seen.

Treatment

Medical Care

The International Dry Eye WorkShop (DEWS) Subcommittee members reviewed the Delphi Panel (the Dry Eye Preferred Practice Patterns of the AmericanAcademy of Ophthalmology and the International Task Force Delphi Panel on Dry Eye) approach to the treatment of dry eye and modified it.¹

Treatment recommendations are based on disease severity.

• Level 1
• Education and environmental/dietary modifications
• Elimination of offending systemic medications
• Preserved artificial tear substitutes, gels, and ointments
• Eyelid therapy
• Level 2 – If level 1 treatment is inadequate, add the following: 
• Nonpreserved artificial tear substitutes
• Anti-inflammatory agents
• Topical corticosteroids
• Topical cyclosporine A
• Topical/systemic omega-3 fatty acids
• Tetracyclines (for meibomianitis, rosacea)
• Punctal plugs  (after control of inflammation)
• Secretagogues
• Moisture chamber spectacles
• Level 3 - If level 2 treatment is inadequate, add the following: 
• Autologous serum, umbilical cord serum
• Contact lenses
• Permanent punctal occlusion
• Level 4 – If level 3 treatment is inadequate, add the following:
• Systemic anti-inflammatory agents
• Surgery
• Lid surgery
• Tarsorrhaphy
• Mucous membrane grafting
• Salivary gland duct transposition
• Amniotic membrane transplantation
• See related CME at Topical Cyclosporine May Be Helpful for Dry Eye Disease.

Consultations

A rheumatologist can be consulted if a systemic collagen vascular disease is suspected.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Treatments of dry eye syndrome include the following:

• Artificial tear substitutes
• Gel/ointments
• Moisture chamber spectacles
• Anti-inflammatory agents
  • Topical cyclosporine A
  • Topical corticosteroids
  • Topical/systemic omega-3 fatty acids: Omega-3 fatty acids inhibit the synthesis of these lipid mediators and block the production of IL-1 and TNF-alpha.
• Topical/systemic tetracyclines
• Punctal plugs
  • Absorbable - Made of collagen or polymers. The occlusion duration ranges from 7-180 days. The plugs dissolve by themselves or may be removed by saline irrigation.
  • Nonabsorbable - Made of silicone. Two main categories of silicone plugs are available for dry eye: punctum plugs and intracanalicular plugs.  
  • Cylindrical Smartplug® - 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.
• Secretagogues - Diquafosol (INS365, DE-089) – P2Y2 receptor agonist
• Autologous/umbilical cord serum
• Contact lenses  
  • Silicone rubber lenses
  • Gas permeable scleral-bearing hard contact lenses with or without fenestration
  • Highly oxygen-permeable lenses (overnight wear)
• Systemic immunosuppressives
• Surgery  
  • Amniotic membrane transplantation
  • Lid surgery
  • Tarsorrhaphy
  • Mucous membrane/salivary gland transplant

Ophthalmic agents and 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.

Artificial tears (hydroxypropyl methylcellulose (HPMC), carboxyl methylcellulose (CMC), polyvinyl alcohol (PVA), glycerine artificial tears)

Used to increase lubrication of the eye.

Dosing

Adult

1-2 gtt qd/qid (may use more if preservative-free)

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity to preservatives (eg, benzalkonium chloride)

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Avoid frequent dosing of preserved tears; if wearing contact lenses, use rewetting or lubricating drops specifically for contact lenses; discontinue with eye pain, redness, or visual changes

White petrolatum, castor oil, hydroxypropyl-guar, mineral oil, hydroxy methylcellulose, carboxyl methylcellulose, and similar lubricants (Duolube, HypoTears, Refresh Endura, Systane, Refresh PM, Tears Naturale PM, GenTeal Gel, Tears Again Night&Day)

Serves as lubricant and emollient.

Dosing

Adult

Pull down lid of affected eye, and apply small amount (0.25 in) of ointment to inside of the lid from every hour to just at bedtime depending on severity

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Do not use with contact lenses; discontinue use if eye pain, irritation, continued redness, or vision changes occur

Ocular inserts

Reduce symptoms resulting from moderate-to-severe dry eye syndromes.

Hydroxypropyl cellulose (Lacrisert)

Acts to stabilize and thicken precorneal tear film and to prolong tear film breakup time, which occurs with dry eye states.

Dosing

Adult

Insert 5 mg qd into inferior cul-de-sac beneath the base of the tarsus; some patients may require bid frequency

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Hyperemia, photophobia, stickiness of eyelashes, ocular discomfort, or irritation may occur

Mucolytic agents

Lower mucous viscosity by digesting mucoproteins. Use when mucous discharge or plaques are present.

10% N-acetylcysteine drops (Mucomyst)

This mucolytic agent can be used successfully in patients with corneal filaments secondary to extreme keratitis sicca.

Dosing

Adult

1 gtt tid/qid

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Do not use simultaneously with contact lenses

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use in patients with a possible infectious ulcer or concomitantly with topical antibiotics

Antibiotics

Empiric antimicrobial therapy must be comprehensive, covering all likely pathogens in the context of the clinical setting.

Tetracycline analogues, such as doxycycline and minocycline, have been shown to be effective on meibomian gland dysfunction. The effects of these antibiotics occur via 4 ways: (1) Antibacterial effects by causing a reduction in the bacterial load on the eyelid; (2) antiangiogenic effects; (3) anti-inflammatory effects resulting from a decrease in activity of collagenase, phospholipase A2, and several matrix metalloproteinases, and from a decrease in the production of IL-1 and TNF-alpha; and (4) 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 (Bio-Tab, Doryx, Vibramycin)

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

Dosing

Adult

100 mg PO qd/bid if indicated for meibomian gland dysfunction

Pediatric

<8 years: Not recommended
>8 years: 2-5 mg/kg/d PO in 1-2 divided doses; not to exceed 200 mg/d

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Minocycline (Dynacin, Minocin)

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

Dosing

Adult

100 mg PO qd for at least 3 mo if indicated for meibomian gland dysfunction/acne rosacea

Pediatric

<8 years: Not recommended
>8 years: 4 mg/kg PO initially, followed with 2 mg/kg q12h

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy; tetracyclines can increase hypoprothrombinemic effects of anticoagulants

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines; hepatitis or lupus-like syndromes may occur

Immunomodulators

Cyclosporine may act as a partial immunomodulator. The exact mechanism of action is not known.

Cyclosporine (Restasis, Neoral, Sandimmune)

Used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation, and also meibomian gland dysfunction.

Dosing

Adult

Topical: Instill 1 gtt in each eye q12h
Oral: 1.25 mg/kg PO bid

Pediatric

<16 years: Not established
>16 years: Administer as in adults

Interactions

When administering systemic dose carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another resulting in increased plasma levels of each drug

Contraindications

Documented hypersensitivity; ocular infection; in systemic dose, contraindications include uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Herpes keratitis; do not administer while wearing contact lenses; may cause ocular burning, conjunctival hyperemia, ocular discharge, excessive tearing, eye pain, foreign body sensation, pruritus, stinging, or blurred vision;
When administering systemic dose, evaluate renal and liver functions by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO
Only physicians experienced in immunosuppressive therapy should prescribe cyclosporine; manage patients in facilities equipped and staffed with adequate lab and supportive medical resources; may increase susceptibility to infection and development of neoplasia;
may administer Sandimmune with adrenal corticosteroids but not with other immunosuppressants

Autologous serum eye drops

Are unpreserved, are nonantigenic by nature, and contain growth factors, fibronectin, immunoglobulins, and vitamins at similar (or higher) concentrations than in tears. Used for severe dry eye with punctate epithelial defects and corneal damage to promote reepithelialization.

Autologous serum (20%) and umbilical cord serum (20%) eye drops

Serum eye drops can be used successfully in patients refractory to other forms of treatment.

Dosing

Adult

Instill 1 gtt in the affected eye(s) 8 times/d; discard bottle at end of day and open new bottle every day

Pediatric

<16 years: Not established
>16 years: Administer as in adults

Interactions

None reported

Contraindications

Patients with blood-borne infectious diseases (eg, hepatitis B and C, HIV, syphilis); anemia

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

No major complications; isolated reports of scleral vasculitis/melting in patients with rheumatoid arthritis, immune complex deposition, and microbial keratitis; prepare under sterile conditions to avoid microbial contamination; freeze at +4°C (up to 1 mo) or -20°C (up to 3 mo)

Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. Inflammation is the key component of the pathogenesis of dry eye. Topical corticosteroid agents can be used to reduce the inflammation.

Loteprednol etabonate (Alrex, Lotemax)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Topical ester steroid drop with decreased risk of glaucoma. Available in 0.2% and 0.5% drops.

Dosing

Adult

Instill 1-2 gtt qd/qid; shake vigorously before using

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hypertension; known to cause cataract formation with long-term use; long-term local steroid application may result in fungal infections of cornea; consider possibility of fungus invasion if corneal ulcerations persistent (perform fungal cultures when appropriate); monitor intraocular pressure if used for 10 days or longer (may be difficult in children and uncooperative patients)

Fluorometholone (Flarex, Fluor-Op, FML, FML Forte)

Inhibits edema, fibrin deposition, capillary dilation and phagocytic migration of acute inflammatory response and capillary proliferation, collagen deposition, and scar formation. Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses capillary permeability. Believed to act by the induction of phospholipase A-2 inhibitory proteins.
Used topically, it can elevate IOP and cause steroid-response glaucoma. In clinical studies of documented steroid responders, fluorometholone demonstrated a significantly longer average time to produce a rise in IOP than dexamethasone phosphate. In a small percentage of individuals, a significant rise in IOP occurred within 1 wk. The ultimate magnitude of the rise was equivalent.

Dosing

Adult

Ointment: Apply qd/qid
Solution: Instill 1-2 gtt qd/qid; shake vigorously before using

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Documented hypersensitivity; herpes simplex, keratitis, viral and fungal diseases of the ocular structure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hypertension; known to cause cataract formation with long-term use; long-term local steroid application may result in fungal infections of cornea; consider possibility of fungus invasion if corneal ulcerations persistent (perform fungal cultures when appropriate); prolonged use my result in elevated intraocular pressure or glaucoma (monitor intraocular pressure if used for 10 d or longer; may be difficult in children and uncooperative patients)

Dietary supplements

Certain dietary supplements may have beneficial effects.

Omega-3 fatty acid (Coromega, Longs Fish Oil, Max Epa, Omega-3, Salmon Oil, Superepa)

These agents may have anti-inflammatory effects. May inhibit leukocyte function.

Dosing

Adult

0.3-0.5 g of daily EPA + DHA and 0.8-1.1 g of linolenic acid

Pediatric

Not established

Interactions

May reduce effects of aspirin, vitamin supplements (especially containing vitamins A and/or D), blood thinners (eg, warfarin), antiplatelet drugs (eg, clopidogrel, ticlopidine), diabetes medicine (eg, glyburide, insulin), cyclosporine, etretinate, and other natural/herbal products

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Caution in diabetes, certain hereditary conditions (eg, familial adenomatous polyposis), and hemodynamic problems

Follow-up

Further Outpatient Care

• Follow-up care is based on the severity of symptoms.

Inpatient & Outpatient Medications

• Artificial tears with and without preservatives depending on severity
• Doxycycline 100 mg qd/bid if indicated for meibomian gland dysfunction

Complications

• Decreased visual acuity
• Blindness

Prognosis

• In general, the prognosis for visual acuity in patients with dry eye syndrome is good.

Patient Education

• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education articles How to Instill Your Eyedrops and Dry Eye Syndrome.

Miscellaneous

Medicolegal Pitfalls

• Early detection and aggressive therapy will reduce the incidence of corneal ulcer.

References

1. Dry Eye Workshop (DEWS) Committee. 2007 Report of the Dry Eye Workshop (DEWS). Ocul Surf. April 2007;5(2):65-204. [Full Text].

2. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. Sep 2006;25(8):900-7. [Medline].

3. Abelson MB. Dry eye, today and tomorrow. Review in Ophthalmology. 2000;11:132-34.

4. American Academy of Ophthalmology. External disease and cornea. In: Section Seven: Basic & Clinical Science Course. American Academy of Ophthalmology; 2007-2008.

5. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea. Mar 2003;22(2):97-101. [Medline].

6. Bron AJ, Tiffany JM, Gouveia SM, et al. Functional aspects of the tear film lipid layer. Exp Eye Res. Mar 2004;78(3):347-60. [Medline].

7. Geerling G, Maclennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol. Nov 2004;88(11):1467-74. [Medline].

8. Gilbard JP. Dry eye disorders. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Vol 2. WB Saunders Co; 2000:982-1000.

9. Karadayi K, Ciftci F, Akin T, et al. Increase in central corneal thickness in dry and normal eyes with application of artificial tears: a new diagnostic and follow-up criterion for dry eye. Ophthalmic Physiol Opt. Nov 2005;25(6):485-91. [Medline].

10. McCulley JP, Shine WE. The lipid layer of tears: dependent on meibomian gland function. Exp Eye Res. Mar 2004;78(3):361-5. [Medline].

11. Murube J, Nemeth J, Hoh H, et al. The triple classification of dry eye for practical clinical use. Eur J Ophthalmol. Nov-Dec 2005;15(6):660-7. [Medline].

12. Ohashi Y, Dogru M, Tsubota K. Laboratory findings in tear fluid analysis. Clin Chim Acta. Jul 15 2006;369(1):17-28. [Medline].

13. Perry HD, Donnenfeld ED. Dry eye diagnosis and management in 2004. Curr Opin Ophthalmol. Aug 2004;15(4):299-304. [Medline].

14. Pflugfelder SC. Advances in the diagnosis and management of keratoconjunctivitis sicca. Curr Opin Ophthalmol. Aug 1998;9(4):50-3. [Medline].

15. Stern ME, Gao J, Siemasko KF, et al. The role of the lacrimal functional unit in the pathophysiology of dry eye. Exp Eye Res. Mar 2004;78(3):409-16. [Medline].

16. Tatlipinar S, Akpek EK. Topical ciclosporin in the treatment of ocular surface disorders. Br J Ophthalmol. Oct 2005;89(10):1363-7. [Medline].

17. Yoon KC, Heo H, Im SK, et al. Comparison of autologous serum and umbilical cord serum eye drops for dry eye syndrome. Am J Ophthalmol. Jul 2007;144(1):86-92. [Medline].

18. Zoukhri D. Effect of inflammation on lacrimal gland function. Exp Eye Res. May 2006;82(5):885-98. [Medline].

Keywords

dry eye syndrome, dry eye, dry eye disease, DES, keratoconjunctivitis sicca, KCS, Sjögren syndrome, SS, Sjögren syndrome associated keratoconjunctivitis sicca, non-Sjögren syndrome associated keratoconjunctivitis sicca, Sjögren syndrome associated KCS, non-Sjögren syndrome associated KCS, tear film disorder, decreased tear production, aqueous tear deficiency, ATD, deficient aqueous production, evaporative loss

Contributor Information and Disclosures

Author

C Stephen Foster, MD, FACS, FACR, FAAO, Clinical Professor of Ophthalmology, Harvard Medical School; Consulting Staff, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary; Founder and President, Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research and Surgery Institution
C Stephen Foster, MD, FACS, FACR, FAAO is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Association of Immunologists, American College of Rheumatology, American College of Surgeons, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, American Uveitis Society, Association for Research in Vision and Ophthalmology, Massachusetts Medical Society, Royal Society of Medicine, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Erdem Yuksel, MD, Fellow, Department of Ophthalmology, Massachusetts Eye Research and Surgery Institute, Medical School of Gazi University
Disclosure: Nothing to disclose.

Fahd Anzaar, MD, Fellow, Massachusetts Eye Research and Surgery Institute; Clinical Research and Education Coordinator, Ocular Immunology and Uveitis Foundation
Disclosure: Nothing to disclose.

Anthony S Ekong, MD, Consulting Staff, Department of Ophthalmology, Marshfield Clinic
Anthony S Ekong, MD is a member of the following medical societies: American Academy of Ophthalmology and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Jack L Wilson, PhD, Distinguished Professor, Department of Anatomy and Neurobiology, University of Tennessee at Memphis
Jack L Wilson, PhD is a member of the following medical societies: American Association of Anatomists, American Association of Clinical Anatomists, and American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Jefferson Medical College of Thomas Jefferson University; Co-Chairman of the Cornea Service, Co-Chairman of Refractive Surgery Department, Wills Eye Institute
Christopher J Rapuano, MD is a member of the following medical societies: American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery, Contact Lens Association of Ophthalmologists, Cornea Society, Eye Bank Association of America, International Society of Refractive Surgery, and Pan-American Association of Ophthalmology
Disclosure: Allergan Honoraria Speaking and teaching; Allergan Consulting fee Consulting; Alcon Honoraria Speaking and teaching; Inspire Honoraria Speaking and teaching; RPS Ownership interest Other; Vistakon Honoraria Speaking and teaching

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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