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Dry Eye Disease: Pathophysiology, Classification, and Diagnosis
Henry D. Perry, MD

Dry Eye Disease: Pathophysiology, Classification, and Diagnosis

Henry D. Perry, MD

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
The lacrimal functional unit (LFU) includes the lacrimal glands, ocular surface (cornea and conjunctiva), eyelids, meibomian glands, and associated sensory and motor nerves.3 Figure 1 also notes the goblet cells in the conjunctiva that contribute to the tear film.

The tear film consists of 3 components or layers: mucous, aqueous, and lipid. Functions of the tear film include lubricating the ocular surface and eyelids4; providing a smooth, regular optical surface for the eye4,5; supplying nutrients to the ocular surface4; removing foreign material and microbes from the ocular surface4; protecting the ocular surface against pathogens by means of antibacterial substances4; and promoting tissue maintenance and wound healing of the ocular surface.6

Blinking spreads the tear film over the ocular surface toward the medial canthus. There the tears are drawn into the superior and inferior puncta (one punctum in each eyelid) to enter the lacrimal canaliculi. The canaliculi convey the tears to the lacrimal sac, the upper end of the nasolacrimal duct, which drains into the nose. (See Figure 2.)

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
• Tear film instability can arise secondary to hyperosmolarity, or can be the initiating event (eg, lipid layer abnormalities in meibomian gland disease). Tear film instability results in increased evaporation, which contributes to tear hyperosmolarity.3

Regardless of the initiating event or etiology, inflammation is usually a key factor in perpetuating DED.1 Chronic DED may result in further pathologic changes. For example, patients with moderate to severe DED may develop reversible squamous metaplasia and punctate erosions of the ocular surface epithelium.20 DED is also the most common cause of filamentary keratitis (FK), a condition characterized by strands of degenerated epithelial cells and mucus attached to the cornea. Friction between the filaments and the eyelid during blinking can result in further epithelial damage, inflammation, and filament formation; thus, FK often becomes chronic, and is a common finding in severe DED.21,22 Rarely, severe DED may lead to complications such as ocular surface keratinization; microbial keratitis; corneal neovascularization, ulceration, perforation, and scarring; and severe vision loss.20

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

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 (Table 1).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
• Sjögren syndrome is considered primarily an aqueous-deficient disorder; however, increased evaporation due to meibomian gland destruction is also common in this disease, and may be a contributing factor.25

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

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