Saturday, November 13, 2010

Dry Eye Syndrome

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
Coauthor(s): 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
Contributor Information and Disclosures

Updated: May 13, 2009



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.
The lipid layer produced by the meibomian glands acts as a surfactant, as well as an aqueous barrier (retarding evaporation of the underlying aqueous layer), and provides a smooth optical surface. It may also act as a barrier against foreign particles and may also have some antimicrobial properties. The glands are holocrine in nature, and so 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 is produced by the lacrimal glands. This component includes about 60 different proteins, electrolytes, and water. Lysozyme is the most abundant (20-40% of total protein) and also the most alkaline protein present in tears. It is a glycolytic enzyme that is capable of breaking down bacterial cell walls. Lactoferrin has antibacterial and antioxidant functions, and the epidermal growth factor (EGF) plays a role in maintaining the normal ocular surface and in promoting corneal wound healing. Albumin, transferrin, immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin G (IgG) are also present.

Aqueous tear deficiency (ATD) is the most common cause of dry eye, and it is due to insufficient tear production. 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.

Keratoconjunctivitis sicca (KCS) is the name given to this ocular surface disorder. KCS is subdivided into Sjögren syndrome (SS) associated KCS and non-SS associated KCS. Patients with aqueous tear deficiency have SS if they have associated xerostomia and/or connective tissue disease. Patients with primary SS have evidence of a systemic autoimmune disease as manifested by the presence of serum autoantibodies and very severe aqueous tear deficiency and ocular surface disease. These patients, mostly women, do not have a separate, identifiable connective tissue disease. Subsets of patients with primary SS lack evidence of systemic immune dysfunction, but they have similar clinical ocular presentation. Secondary SS is defined as KCS associated with a diagnosable connective tissue disease, most commonly rheumatoid arthritis but also SLE and systemic sclerosis.

Non-SS KCS is mostly found in postmenopausal women, in women who are pregnant, in women who are taking oral contraceptives, or in women who are on hormone replacement therapy (especially estrogen only pills). The common denominator here is a decrease in androgens, either from reduced ovarian function in the postmenopausal female or from increased levels of the sex hormone binding globulin in pregnancy and birth control pill use. 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-beta), suppressing lymphocytic infiltration.

Lipocalins (previously known as tear-specific prealbumin), which are present in the mucous layer, are inducible lipid-binding proteins produced by the lacrimal glands that lower the surface tension of normal tears. This provides stability to the tear film and also explains the increase in surface tension that is seen in dry eye syndromes characterized by lacrimal gland deficiency. Lipocalin deficiency can lead to the precipitation in the tear film, forming the characteristic mucous strands seen in patients with dry eye symptomatology.

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 like 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), functioning as clean-up proteins (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) and provide a smooth lubricating surface, allowing lid epithelia to glide over corneal epithelia with minimal friction during blinking and other eye movements. Recently, 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.

Mucin deficiency (caused by damage to the goblet cells or the epithelial glycocalyx), as seen in Stevens-Johnson syndrome or after a chemical burn, leads to poor wetting of the corneal surface with subsequent desiccation and epithelial damage, even in the presence of adequate aqueous tear production.


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.


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.


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


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.


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


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.



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.


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.


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)

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

For a classification of dry eye on the basis of severity, the Delphi Panel Report was adopted and modified as a third component of the DEWS.1 See Table.

Table. Dry Eye Severity levels1,2

Open table in new window

Dry Eye Severity level1234 (Must have signs and symptoms.)
Discomfort, severity & frequencyMild and/or episodic; occurs under environmental stressModerate episodic or chronic, stress or no stressSevere frequent or constant without stressSevere and/or disabling and constant
Visual symptomsNone or episodic mild fatigueAnnoying and/or activity-limiting episodicAnnoying, chronic and/or constant, limiting activityConstant and/or possibly disabling
Conjunctival injectionNone to mildNone to mild+/–+/++
Conjunctival stainingNone to mildVariableModerate to markedMarked
Corneal staining (severity/location)None to mildVariableMarked centralSevere punctate erosions
Corneal/tear signsNone to mildMild debris, decreased meniscusFilamentary keratitis, mucus clumping, increased tear debrisFilamentary keratitis, mucus clumping, increased tear debris, ulceration
Lid/meibomian glandsMGD variably presentMGD variably presentFrequentTrichiasis, keratinization, symblepharon
TFBUT (sec)Variable≤10≤5Immediate
Schirmer score (mm/5 min)Variable≤10≤5≤2
Dry Eye Severity level1234 (Must have signs and symptoms.)
Discomfort, severity & frequencyMild and/or episodic; occurs under environmental stressModerate episodic or chronic, stress or no stressSevere frequent or constant without stressSevere and/or disabling and constant
Visual symptomsNone or episodic mild fatigueAnnoying and/or activity-limiting episodicAnnoying, chronic and/or constant, limiting activityConstant and/or possibly disabling
Conjunctival injectionNone to mildNone to mild+/–+/++
Conjunctival stainingNone to mildVariableModerate to markedMarked
Corneal staining (severity/location)None to mildVariableMarked centralSevere punctate erosions
Corneal/tear signsNone to mildMild debris, decreased meniscusFilamentary keratitis, mucus clumping, increased tear debrisFilamentary keratitis, mucus clumping, increased tear debris, ulceration
Lid/meibomian glandsMGD variably presentMGD variably presentFrequentTrichiasis, keratinization, symblepharon
TFBUT (sec)Variable≤10≤5Immediate
Schirmer score (mm/5 min)Variable≤10≤5≤2