Dry Eye Disease: Pathophysiology, Classification, and Diagnosis

April 15, 2008
Henry D. Perry, MD

Supplements and Featured Publications, Management and Pharmacoeconomics of Dry Eye Disease: The Role of Cyclosporine, Volume 14, Issue 3 Suppl

Dry eye disease (DED) is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort, visual disturbance, and often ocular surface damage. Although recent research has made progress in elucidating DED pathophysiology, currently there are no uniform diagnostic criteria. This article discusses the normal anatomy and physiology of the lacrimal functional unit and the tear film; the pathophysiology of DED; DED etiology, classification, and risk factors; and DED diagnosis, including symptom assessment and the roles of selected diagnostic tests.

(Am J Manag Care. 2008;14:S79-S87)


Dry eye disease (DED)—also called keratoconjunctivitis sicca or, more recently, dysfunctional tear syndrome1—has been defined in various ways that have changed over time as understanding of the disease process has evolved. For example, in 1995 the National Eye Institute defined DED as “a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface and is associated with symptoms of ocular discomfort.”2 In 2007, the International Dry Eye WorkShop defined it as “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”3 The newer definition emphasizes symptoms and global mechanisms (to be discussed below), while recognizing the multifactorial nature of DED.

Normal anatomy and physiology

Figure 1

The lacrimal functional unit (LFU) includes the lacrimal glands, ocular surface (cornea and conjunctiva), eyelids, meibomian glands, and associated sensory and motor nerves.3 also notes the goblet cells in the conjunctiva that contribute to the tear film.

The mucous component is the innermost layer of the tear film. The mucous layer contains multiple mucins, some of which are anchored to the ocular surface epithelium.7,8 Mucins are produced by conjunctival goblet cells9 and by stratified squamous cells of the cornea and conjunctiva.7 Laboratory experiments suggest that conjunctival P2Y2 nucleotide receptors may play a role in regulating mucin secretion.10 Functions of the mucous layer include lubricating the ocular surface9 and providing an adsorbent interface between the aqueous layer and the hydrophobic ocular surface epithelium.8 It also traps foreign particles, cellular debris, and microbes which, with blinking, are moved to the medial canthus where they exit the eye.9

The aqueous component, the main portion of the tear film, lies on top of the mucous layer. It is produced by the lacrimal glands, which include: (1) the main lacrimal gland (located in the superior temporal region of the orbit) and its palpebral lobe (extending into the upper eyelid), and (2) the accessory lacrimal glands of Krause and Wolfring (located in the conjunctival fornices [ie, where the conjunctiva is reflected from the eyelid to the eyeball]).9

Aqueous tear secretion appears to have 2 modes, basal and stimulated. A major portion of tear production is reflexive via stimulation of the ocular surface and nasal mucosa11; this reflexive secretion is thought to arise primarily from the main lacrimal gland and its palpebral lobe.12 Basal secretion (ie, occurring in the absence of neural stimulation) is believed to come from the accessory lacrimal glands13; however, some experts have questioned whether basal tear secretion exists.14 It has been proposed that so-called basal tearing may result from continuous corneal stimulation that is below the threshold of perception.15 On the other hand, some laboratory experiments suggest that basal tearing may be nonglandular, arising from active transport of fluid and chloride across the conjunctival epithelium. This active transport is mediated by P2Y2 receptors; whether it also occurs in response to neural stimulation is unknown.12

The composition of the aqueous component includes water and electrolytes4; antibacterial proteins such as lysozyme, lactoferrin, and immunoglobulins (especially IgA)4; vitamins, particularly vitamin A (retinol, which is required for corneal maintenance)16; and growth factors (eg, epidermal growth factor, hepatocyte growth factor).6 Functions of the aqueous layer include hydrating the mucous layer9; supplying oxygen and electrolytes to the ocular surface9; antibacterial defense8,17; maintenance and renewal of the ocular surface6; and promotion of wound healing via proliferation and differentiation of ocular surface epithelial cells.6

The lipid component covers the aqueous layer and is the outermost layer of the tear film. It is produced by the meibomian (tarsal) glands, located in the tarsal plates of the eyelids, which open onto the lid margin just posterior to the eyelashes.8,9 There is also a small contribution from the glands of Zeis, which open into the eyelash follicles.

Functions of the lipid layer include slowing tear evaporation,8,9,18,19 enhancing tear film spreading,18 providing a smooth optical surface,18,19 preventing contamination of the tear film by skin lipids,19 preventing overflow of tears (in the absence of excessive reflex tearing),19 and sealing the apposed lid margins during sleep.18


DED is a multifactorial disorder involving multiple interacting mechanisms. Dysfunction of any LFU component can lead to DED by causing alterations in the volume, composition, distribution, and/or clearance of the tear film. Two mutually reinforcing global mechanisms, tear hyperosmolarity and tear film instability, have been identified.3

• Tear hyperosmolarity can arise from either low aqueous flow or excessive tear film evaporation. Hyperosmolar tears can damage the ocular surface epithelium by activating an inflammatory cascade, with release of inflammatory mediators into the tears. While acute inflammation may initially be accompanied by increased reflex tearing and blinking, chronic inflammation may result in reduced corneal sensation and decreased reflex activity, leading to increased evaporation and tear film instability. Inflammation can also result in goblet cell loss and decreased mucin production, which further contributes to tear film instability.3

There are 2 major etiologic categories of DED: aqueous-deficient and evaporative.3

Table 1

Aqueous-deficient DED is classified as either Sjögren or non-Sjögren. Primary Sjögren syndrome is an autoimmune disorder in which the lacrimal and salivary glands are infiltrated by activated T-cells, resulting in symptoms of dry eye and dry mouth. Secondary Sjögren syndrome is Sjögren syndrome associated with other autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus.3 Non-Sjögren aqueous-deficient DED can result from lacrimal gland insufficiency (various etiologies), lacrimal duct obstruction, or reflex hyposecretion ().3

Evaporative DED also has various causes, including meibomian gland disease, eyelid aperture disorders or lid/globe incongruity, blink disorders, and ocular surface disorders (Table 1).2,3 The most common cause is meibomian gland dysfunction (MGD; also called posterior blepharitis), a condition of meibomian gland obstruction.3,18

Although these major categories seem clear-cut, in reality there is considerable overlap between them. First, any form of dry eye may be associated with any other form.2 Second, because of the interaction (described above) between the 2 global DED mechanisms, tear hyperosmolarity and tear film instability, the differentiation between aqueousdeficient and evaporative DED is often unclear. Third, certain DED etiologies involve multiple mechanisms. For example:

• Contact lens wear may result in decreased corneal sensitivity, with reflex sensory block leading to aqueous deficiency.3 At the same time, contact lens wear may also result in increased evaporation due to a reduced blink rate and/or incomplete lid closure during blinking.23,24 In addition, poor lens wettability may also contribute to increased evaporation.3,23 • Vitamin A deficiency can cause xerophthalmia, due to both impaired goblet cell development and lacrimal gland damage.3

Older age3,26 and female sex26 are well-known risk factors for DED. Other risk factors include:

• Environmental conditions. Low humidity, high temperature, and wind or high air velocity increase evaporation.3,26,27 Poor air quality or air pollution (eg, tobacco smoke)27 may cause irritation, worsening DED symptoms.26

• Nutritional factors. A diet low in omega-3 fatty acids, or with a high ratio of omega-6 to omega-3 fatty acids, may contribute to DED.26,29 Low vitamin A intake can predispose to DED (see also above under Etiology and classification).26

• Systemic medications. Drugs that have been associated with DED include anticholinergics (eg, antihistamines, antispasmodics, tricyclic antidepressants, diphenoxylate/atropine),3,20,26,32 beta-blockers,3,20,26 diuretics,3,20,26,32 systemic isotretinoin,33,34 amiodarone,35-37 interferon,38,39 postmenopausal hormone replacement therapy (estrogen alone more so than estrogen plus progestin),26,40 and antiandrogenic agents.26,30 In contrast, one population study found that angiotensin-converting enzyme inhibitors were associated with a lower risk of DED.32

• Contact lens wear (see above under Etiology and classification).

• Parkinson’s disease. Reduced blink rate is a common feature of this disease, resulting in increased evaporation.3,26

Currently, there are no uniform criteria for the diagnosis of DED. Traditionally, combinations of diagnostic tests have been used to assess symptoms and clinical signs.45

Table 2

Table 3

Common DED symptoms are listed in . Symptoms tend to be worse later in the day,20,46 and may also be exacerbated by factors such as low humidity, smoky environments, and prolonged use of the eyes.46 In addition to the clinical history, use of a validated symptom questionnaire is helpful.2,45 A number of questionnaires are available for evaluation of various aspects of DED symptomatology, including severity, effect on daily activities, and quality of life.26 Some widely used DED symptom questionnaires are listed in .

Physical examination includes visual acuity measurement, external examination, and slit-lamp biomicroscopy.20 Additional diagnostic tests may be performed to assess tear film instability, ocular surface damage, and aqueous tear flow.

Tear film instability is commonly evaluated by performing a tear breakup time (TBUT) test. A widely used method involves instillation of fluorescein dye into the eye. After the dye has been distributed throughout the tear film by blinking, the patient is asked to stare straight ahead without blinking. Under slit-lamp examination, the time between the last blink and the appearance of the first break in the fluorescent tear film is measured.2,45 Values of <10 seconds have traditionally been considered abnormal; however, more recently, cutoffs as low as <5 seconds have been recommended.45

Ocular surface damage is commonly assessed by staining with rose bengal, lissamine green, or fluorescein dye. Abnormal corneal and/or conjunctival staining patterns, observed on slit-lamp examination, are a sign of damage. The staining pattern can be photographed and graded using one of several scoring systems. Fluorescein dye is well tolerated, but results may be variable. Rose bengal produces more consistent results, but is irritating to the eye. Lissamine green is similar to rose bengal in its staining characteristics, and is as well tolerated as fluorescein.2,45

Aqueous tear flow is commonly assessed by performing a Schirmer test. In this test, a specified type of paper strip is placed over the lower lid margin, in contact with the ocular surface. This can be done either without topical anesthesia (to measure reflex tearing) or with anesthesia (to measure basal tearing by minimizing ocular surface reflex activity). To measure maximal reflex tearing, the test without anesthesia can be performed with stimulation of the nasal mucosa by means of a cotton swab.65 The paper strip is removed after 5 minutes, and the amount of wetting is measured. Wetting of ≤5.5 mm has traditionally been considered abnormal, and a cutoff no lower than ≤5 mm is currently recommended.45

Other diagnostic tests that may be performed include:&#8226; Fluorescein clearance. This test measures tear clearance or turnover. Delayed clearance has been associated with increased tear cytokine concentration, which may contribute to chronic inflammation.66

&#8226; Impression cytology. This test serves as a minimally invasive alternative to ocular surface biopsy. Superficial layers of the ocular surface epithelium are collected (eg, by applying filter paper) and examined microscopically. Impression cytology is useful for detecting abnormalities such as goblet cell loss and squamous metaplasia.70

Although useful for confirming the diagnosis, diagnostic test results generally correlate poorly with symptoms.1,26,47 This may be due, in part, to the subjective nature of symptoms.26 However, other factors also may account for the poor correlation; for example, severe disease may result in relatively mild symptoms if corneal hypesthesia is present.26 Patients with early or mild disease may have symptoms prior to the appearance of objective signs.1,20 Conversely, some individuals may have objective signs without symptoms. (Although the latter do not meet strict criteria for DED&#8212;which is considered a symptomatic disease&#8212;it has been suggested that the diagnosis may nevertheless be extended to them.45) Diagnostic test results also tend to vary more from visit to visit than subjective symptoms, but may be more reliable in severe than in mild DED.71

Tear hyperosmolarity is a global mechanism of DED whose measurement could potentially provide a &#8220;gold standard&#8221; for DED diagnosis. Currently there is no simple, widely available tear osmolarity test; however, a practical clinical test may soon become available. Meanwhile, TBUT may be the best clinical alternative because it also measures a global mechanism, has good overall accuracy,45 and appears to be more repeatable (varies less from visit to visit) than many other diagnostic tests.71


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