The Diagnosis and Management of Dry Eye Disease
Michael A. Lemp
Gary N. Foulks
Dry eye has been a subject of great interest affecting many people throughout the world. This topic has been the focus of intensive laboratory and clinical research over the last four decades. The pace of this research has accelerated over the last fifteen years resulting in a profound alteration in our understanding of the prevalence, pathogenesis, diagnosis and management of the disease. In this chapter we will trace the progress in our knowledge of the clinical entity called dry eye disease (DED).
Our understanding of the characteristics of DED has grown from that of a simple deficiency in tear volume to encompass a series of pathological events involving practically all the structures of the ocular surface, lids, lacrimal glands, and drainage pathways. Indeed the term dry eye has been criticized as being misleading in that dryness is not always a prominent feature.1 The term, however, has widespread acceptance and is embedded in medical and lay literature; it is used synonymously with keratoconjunctivitis sicca.2 Central to an understanding of DED is the realization that the ocular surface and its adnexal structures form a tightly integrated system termed the ocular surface functional unit.3 The principal parts of this unit include; the lacrimal glands, the meibomian glands of the eyelids, the cornea and conjunctiva with their mucin secretory components, and the nasolacrimal duct system. All of these parts are linked by a neural signaling pathway enabling each part to communicate and respond to signals by altering secretory activity.
The Scope of the Problem
Although clinicians have long known that DED is a common problem, only recently has the scope of the problem been documented. Surveys of specific populations, such as the elderly, have suggested a prevalence of about 15% with a preponderance of women.4,5,6 More recent studies have greatly expanded that estimate. A survey of ophthalmologists in the United States found that approximately 30% of patients present with symptoms consistent with DED.7 A large epidemiologic study of nearly 40,000 women in the United States reported an estimated prevalence in both sexes of over 9 million subjects with moderate to severe dry eye.8 It is thought that for every one of these subjects there are several with a milder or episodic form of the disease. The total estimates for the number of people suffering from DED in the United States are from 40 to 60 million or about 20% of the population. About 80% of these are women but both sexes show a significant prevalence increasing with age. The demographics listed here have stimulated great interest in the pharmaceutical industry and a substantial number of new products are in varying stages of clinical testing.
In 1993 to 1994, there was an international group of laboratory and clinical scientists and clinicians who met over a 2-year period attempting to reach a consensus on the nature of DED, its pathogenesis, clinical manifestations, the best way to design clinical trials to test new drugs, and on the management of the disease.9 The report of this meeting was published in 1995 and has formed the basis for the general understanding of these issues. Recently a large international group of experts met to update advances in these areas and have published an authoritative paper, the report of the Dry Eye Workshop (DEWS). This report contains a contemporary definition of DED: “Dry eye is 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 in the ocular surface.”10
This definition points out the salient features of DED that can vary from episodic discomfort to a severe debilitating condition with a significant effect on vision and quality of life. Prominent symptoms of DED include ocular discomfort with the subjective descriptors including dryness, itching, grittiness, scratchiness, foreign body sensation, photophobia, and eye fatigue. In mild cases, there is a paucity of clinical findings; as the disease progresses, a decrease in tear secretion can be measured and damage to the ocular surface is manifest with staining of the cornea and conjunctiva. How does this disease process begin and progress?
Pathogenesis of DED
A half century ago it was assumed that dry eye was the result of decreased secretion of the lacrimal glands and that it was more common in perimenopausal women, therefore suggesting a relationship to decreased estrogen secretion. In the 1970s, attention was focused on patients in whom the primary finding was an instability of the tear film, sometimes with normal tear secretion. This led to the concept of the “mucin deficient” dry eye with loss of the mucin-producing goblet cells of the conjunctiva.11 Although goblet cell depletion was seen in all forms of dry eye, it was most prominent is patients with severe inflammatory disease of the conjunctiva, such as erythema multiforme (Stevens-Johnson disease), cicatrizing ocular pemphigoid, and severe trachoma. The hallmark of the “mucin deficient” dry eye is rapid beak up of the tear film between blinks.12
In the later 1970s, the concept of “the ocular surface” emerged; this was described as an integrated functional unit linked by a neural pathway allowing components to communicate3. Newer methods of identifying different epithelial types by their intracellular keratin profiles allowed investigators to differentiate conjunctival, limbal, and corneal epithelium and to delineate the process by which new cells arise from a resident stem cell population in the limbus, migrate centripetally toward the center of the cornea as they differentiate, and ultimately reach the cornea surface from which they are shed.13,14 This process of production of new cells is in fine balance with the exfoliative loss of aging cells from the surface. Alterations in either aspect of this process can lead to severe changes in the morphology of the ocular surface. In DED, there is a loss of lubrication between the upper lid and the cornea with resultant accelerated exfoliative shedding and damage to the remaining surface.15
The Role of Meibomian Glands
The role of the meibomian glands of the eyelids in the maintenance of a normal tear film and ocular surface is a major one. The lipids produced by these glands form the outermost layer of the tears and limit evaporative tear loss contributing to the stability of the tear film between blinks. There are age-related changes in the function of these glands, which are thought to be related to hormonal changes, leading to quantitative and qualitative alterations in composition of the lipids. These lead to excessive evaporative loss of aqueous tears, instability of the tear film and increased osmotic forces in the tear film with resultant damage to the ocular surface.16 Meibomian gland dysfunction (MGD) is extremely common. It is thought that more than 60% of patients with Sjögren-associated DED have MGD;17 a similar percentage of non-Sjögren DED patients are thought to have MGD.18 Although most cases of DED demonstrate a decrease in aqueous tear secretion and MGD, dysfunction of the meibomian glands is probably the most common feature of DED.
Hormonal Factors
As mentioned earlier, an association of DED with hormonal abnormalities has long been noted. The much higher prevalence of DED in women led to the assumption that a decrease in available estrogen was the most probable causal link. Recent studies have called this into question, and there is substantial evidence that a drop in available androgen is the likely culprit. Deprivation of androgen in animal models has led to dysfunction of the lacrimal and meibomian glands with increased inflammation.19 In patients with the most severe form of DED, Sjögren-associated DED, patients have decreased androgen levels.20 Additional clinical evidence comes from patients with a rare congenital disease, complete androgen insensitivity syndrome,21 and in patients undergoing antiandrogen therapy22 both of which groups show an increased incidence of DED. Androgens in addition to direct supportive effects on the secretory processes, suppress inflammatory changes in the glands protecting the secretory cells.
A major topic of interest in dry eye has been the role of inflammation in DED. Clinically evident inflammation is well known in patients with severe Sjögren-associated DED. Inflammation in the lacrimal glands, conjunctiva and sclera is well known. More severe inflammation-related clinical findings include inflammatory nodules, degradation of the sclera leading to scleromalacia perforans and corneal ulceration.23 More recent evidence of subclinical inflammatory infiltrates in the conjunctiva, lacrimal and meibomian glands in non-Sjögren DED have been described.24 Further evidence includes the presence of elevated inflammatory cytokines in the tears of patients.25 This suggests that inflammation is a global characteristic in all forms of dry eye which leads to tissue destruction.
There are two other abnormalities occurring in DED that are thought to be “global” characteristics (i.e., increased osmolarity of the tear film and tear film instability).9 These two features are found in all types of dry eye and probably represent early events in the breakdown of the tear film, which led to damage to the ocular surface. In 1954, Balik first proposed increased osmolarity of the tear film in dry eye patients.26 In 1961, Mastman first demonstrated hyperosmolarity of the tear film in patients,27 and subsequently a considerable literature has developed substantiating a shift to a hyperosmolar tear film in dry eye. Despite limitations with the instrumentation for measuring osmolarity, the utility of tear hyperosmolarity as a marker for dry eye has been established and has been considered a “gold standard” in the diagnosis of the disease (see the subsequent text).28
Tear Film Instability
Closely linked to tear hyperosmolarity is tear instability. The tear film is a metastable film that maintains a continuous covering over the ocular surface between blinks. It is composed of three basic components that form semidiscrete boundaries. The epithelial cells display a pattern of microvillous projections, which greatly increase their surface area facilitating connections between the cells and the tears. Two major types of mucin play a major role in the formation and maintenance of the tear film. The first of these are membrane spanning mucins, the products of the epithelial cells. This mucin forms an outer covering of the cells called the glycocalyx. The mucins forming this layer are thought to contribute to the microvillous structure and to protect the epithelial cells.29 Overlying this is the aqueous layer of tears, the product primarily of lacrimal gland secretion but about 10% of aqueous tear may be the result of trans-conjunctival fluid movement. Within this layer are soluble and gel-forming mucins, produced by the goblet cells of the conjunctiva. These are thought to interact with the outermost lipid layer to stabilize the tear film and act as a cleansing mechanism entrapping exfoliated cells, debris, and other foreign material advancing them toward the inner canthus. The lipid layer, the product of the meibomian glands, forms a discrete layer which retards evaporative tear loss. The maintenance of a stable tear film between blinks is dependant on the finely regulated interaction of all these tear film components. Compromise of any one results in a cascade of malfunctions characterized by tear thinning and disruption.
Closely linked to tear breakdown is hyperosmolarity of the tear film. This can happen as a result of changes in volume and composition of lacrimal gland-derived aqueous tears; it is also the consequence of increased evaporative tear loss which concentrates the solutes in tears.30 Elevated tear solute concentration, particularly electrolytes, has been shown not only to lead to desiccative effects on the ocular surface but to initiate an inflammatory cascade within the epithelium leading to cell damage.31 In the presence of inflammation there are changes in corneal sensation indicating damage to the critical nerve endings, which act as monitors and initiate reparative responses mediated by changes in the secretion of the lacrimal glands.32 Over 500 proteins have been identified in aqueous tears; they are present mostly in minute quantities, but the composition can vary greatly in response to signals of ocular surface distress. When the nerves are compromised this reparative capacity is diminished and this allows further degradation of the ocular surface.
Another factor operative in DED is decreased lubricity between the upper lid and the corneal surface. The controlled friction in the normal eye is an important driver of exfoliative cell loss; in DED, friction is increased which leads to mechanical injury and accelerated corneal epithelial loss.33
Associated Conditions
Although the initiating events leading to the development of clinically recognizable DED are still insufficiently understood, there are a number of factors that place people at risk for DED. These include: a genetic predisposition and exposure to certain viral diseases (i.e., Epstein-Barr, cytomegalovirus, human immunodeficiency virus, and hepatitis C virus). These may trigger glandular dysfunction in genetically predisposed individuals. As mentioned earlier, hormonal changes, particularly androgen deficiency, but also estrogen replacement therapy and treatment with antiandrogen medications, play a role in initiating disease. Increasing age with the breakdown in normal apoptotic cellular mechanisms is associated with the onset of DED.34
Iatrogenic associations with the development of DED include: contact lens wear, the use of antimuscarinic systemic drugs and, as noted recently, the chronic use of topical antiglaucoma drugs. A subject of much interest over the last few years is the impact of environmental factors on both the development and exacerbation of dry eye. Most prominent examples of these are: the daily use of video display terminals (VDTs) for prolonged periods and exposure to dry windy conditions. The decrease in blink rate with accelerated evaporative tear loss with VDT and the rapid rise in evaporation with air movement are major factors in DED.35
Perhaps the most dramatic rise in a dry eye population has been in patients undergoing LASIK refractive surgery. In this procedure, in which approximately 60% of the corneal nerve fibers are severed, more than 50% of patients experience dry eye symptoms postoperatively. This is thought to be due to a form of neurotrophic keratopathy.36
An Approach to the Pathogenesis of Dry Eye Disease
In the recently published DEWS report,10 a figurative representation of the sequence of events operative in the causation of DED is presented (Fig. 1). It is envisioned that a number of different primary events, such as systemic autoimmune disease, effects of aging, environmental exposure, local alterations in lid function, neurological deficits, contact lens wear, refractive surgery and other less well understood phenomena, result in either decreased lacrimal secretion, excessive evaporative tear loss, or both. This leads to tear film instability and a compositional tear imbalance. This initial change at the tear film-ocular surface interface is characterized by increasing tear osmolarity, tear film thinning, and premature disruption between blinks. Hyperosmolarity of the tear films leads to desiccative effects on surface cells and initiates an inflammatory cascade within the epithelium involving MAP kinases and NFkB signaling pathways with the production of inflammatory cytokines. “Tear hyperosmolarity is regarded as the central mechanism causing inflammation, ocular surface damage, symptoms, and the initiation of compensatory events in dry eye.”10
 FIGURE 1. Etiologic development of dry eye disease |
As a consequence of inflammation, there is increased apoptotic cell death in corneal and conjunctival epithelial cells, including loss of goblet cells with a concomitant reduction in soluble and gel-forming mucins in the tear film. Trans-membrane mucins of the epithelial cells are also involved which further alter the surface. It is impossible to consider one of these mechanisms or components in isolation as they all interact; with compromise of one or more elements, there is a general breakdown in the structure and function of the tear film.
These events lead to compensatory changes. Initially the surface changes activate the neurosensory pathways which stimulate lacrimal gland secretion, an increased blink rate, and possibly changes in goblet cell and meibomian gland secretion. Effective reparative responses from the lacrimal gland are dependent on sufficient functioning acinar cells. Chronic stimulation of lacrimal secretion may lead to a neurogenic inflammatory cytokine response with “lacrimal exhaustion” of the gland due to excessive stimulation.37 Eventually these compensatory mechanisms begin to breakdown; as with lacrimal exhaustion, they can lead to secondary problem such as blepharospasm from the chronic stimulation of the blink reflex.
As shown Figure 2, these varied events lead to a “vicious cycle,” which exacerbates the breakdown and dysfunction of the ocular surface functional unit.
 FIGURE 2. The vicious circle of dry eye disease |
Diagnosis of Dry Eye Disease
Symptoms
The presence of DED has routinely been diagnosed by symptoms and signs. As a multifactorial disease symptomatology is somewhat problematic since several anterior segment diseases can share the same symptoms as dry eye, notably anterior blepharitis and ocular allergy. Nevertheless, a great deal of clinical research has occurred to define the symptoms of dry eye and to develop questionnaires that accurately capture those symptoms. It should be noted that one peculiarity of DED is that symptoms and signs do not always parallel each other. One observation that must be recognized before evaluating the symptoms and methods available for categorizing such symptoms is a feature of DED that can be confounding to the clinician. This feature is that corneal and ocular surface sensation is modified by DED. It is frequently observed that corneal sensation is reduced in longstanding or more severe DED32 and that symptoms may be less intense in patients with more severe surface disease.38 Conversely, it has been shown in patients with early or mild DED that there exists a state of hyperesthesia.39 These findings may explain the clinical observation that patients with early disease often complain more severely about symptoms that those patients with chronic disease and ocular surface damage. With that caveat, it is possible to use symptoms to establish the presence of DED.
Symptoms of dry eye are usually those of discomfort and/or disturbance of visual function. Although the verbal description of symptoms of discomfort vary widely among patients, the most commonly used terms are burning, stinging, itching, dryness, and sensation of something in the eye (like sand).40,41,42 Fatigue is a frequent descriptor in Asian patients. Nichols has succinctly reviewed the symptomatology of dry eye and has catalogued the available questionnaires, including the McMonnies, OSDI, IDEEL, etc.8,40 Schaumberg et al., in an attempt to simplify such questionnaires has identified three questions that provide optimal power to detect dry eye:
(a) Have you ever been diagnosed by a physician as having dry eye syndrome?;
(b) How often do your eyes feel dry (not wet enough){constantly, often, sometimes, never}?; and
(c) How often do your eyes feel irritated {constantly, often, sometimes, never}?
Dry eye was considered as the presence of dryness and irritation constantly or often.8 To better evaluate the symptoms of dry eye, Schaumberg et al. developed a method to quantitate the severity and frequency of dry eye symptoms: the SANDE questionnaire.43 From a practical approach, however, determination of the presence of dry eye is often made by the simple questions: “Do your eyes burn or sting or feel like there is something in the eye? If so, is it worse late in the day, when you are reading, or when you work on a computer?”
Disturbance of vision is a second type of symptom that is often described in dry eye. It is usually reported as a fluctuation in vision, particularly upon performing visual tasks, such as reading or computer use. Characteristically the vision improves with blinking. Snellen acuity is usually not decreased when tested in the usual clinical manner since the patient is able to compensate for the tear instability that produces the visual disturbance by blinking. Tsubota et al. have developed instrumentation that is able to demonstrate reduction in functional visual acuity, however, by presenting optotypes to the patient in such rapid sequence that they are not able to compensate by blinking.44,45 It is important to document the patient’s visual complaint, because it is often a good monitor of response to therapy.
Signs
The signs of DED are those dependent upon tear function and ocular surface integrity. As the severity of the disease increases, signs of ocular surface inflammation appear. Tear film instability is a feature common to both aqueous production deficient and evaporative dry eye. Reduction of tear volume is typically seen in aqueous deficient dry eye and can be monitored by the height and contour of the inferior tear meniscus.46,47,48 Tear production, as measured by the Schirmer test or cotton thread test, is reduced in aqueous deficient dry eye but is normal in evaporative dry eye. Improved tests of tear function are described in the following section and may provide the basis for more precise diagnosis in the future as availability of instrumentation improves.
Ocular surface integrity is dependent upon tear function but in the presence of dry eye will deteriorate. Such deterioration can be identified and monitored by vital stains, including fluorescein, rose bengal, and lissamine green.49,50 Although the typical description of ocular surface staining due to dry eye is that of an interpalpebral band, clinical trials have shown that the more frequent staining patterns of the cornea are in the inferior cornea, then the nasal cornea, and then the central and temporal cornea with superior staining less commonly observed.51 Staining of the interpalpebral conjunctiva is reliably present as the condition progresses.
In summary, diagnosis of dry eye at the present time combines evaluation of symptoms of discomfort and/or fluctuating visual disturbance in the context of identified decrease in tear film function (stability, volume, or production) with evaluation of the health of the ocular surface to determine the severity of the disease. The precision in diagnosis is determined by the accuracy and reproducibility of the diagnostic test used, as well as the sensitivity and specificity of the test.52 However, at the present time, clinical judgment using a combination of symptoms, tests of tear function, and evaluation of ocular surface health is the clinical standard.
Tests of Tear Function and Ocular Surface Health
As previously mentioned, no single test is diagnostic of DED but several practicable tests of tear function are useful.53,54 A more complete catalogue of available tests with description of their utility and documentation of their use and validation is available in the Report of the DEWS.10 For the purpose of this chapter, the selection includes those that are, or soon will be, applicable in the clinic setting.
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