Overview
A consensus from the recent International Dry Eye Workshop revised the definition of dry-eye disease to: “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 of the ocular surface.” The tear film, which is altered in dry-eye disease, is produced by multiple types of ocular surface epithelia and the ocular adnexa ( Figure 14.1 ). The meibomian glands that line the eyelid secrete the outer lipid layer of the tear film. The lacrimal gland, accessory lacrimal glands, conjunctival epithelium, and corneal epithelium secrete the aqueous component. The conjunctival goblet cells and stratified squamous cells of the conjunctiva and cornea secrete the mucous component. The lacrimal glands, lids, ocular surface (including the meibomian glands, corneal epithelium, and conjunctival epithelium), and the nerves that innervate these tissues function together to produce and maintain the tear film. These structures have been termed the lacrimal gland functional unit or ocular surface system and together represent the targets of dry-eye disease. The present chapter, however, will focus on the lacrimal gland and its role in dry-eye disease with the following caveats: (1) the lacrimal gland is part of a functional unit and is rarely the only target of dysfunction in dry-eye disease and (2) alteration in lacrimal gland secretion can alter the homeostasis of the ocular surface, causing secondary disease in this tissue that in turn can affect neural stimulation of lacrimal gland secretion.
Clinical background
Overview
Dry-eye disease can be divided into two major groups: aqueous-deficient and evaporative ( Figure 14.2 ). The lacrimal gland is the target of aqueous-deficient disease, which is usually classified into Sjögren syndrome dry eye (autoimmune) or non-Sjögren dry eye. The present chapter will focus predominantly on non-Sjögren dry eye, as Sjögren syndrome dry eye will be discussed in Chapter 15 .
Key symptoms and signs
Dry eye can be graded according to severity using the symptoms and signs listed in Table 14.1 . Symptoms are those derived from activation of the sensory nerves in the cornea and conjunctiva and result in feelings of ocular surface discomfort, including irritation, dryness, grittiness, burning, itching, and photophobia. Validated questionnaires that can be used to evaluate the symptoms of dry-eye disease can be found in Smith et al. The signs of dry eye include: visual symptoms; conjunctival injection; conjunctival staining with lissamine green or rose Bengal; corneal staining with fluorescein; evaluation of the cornea and tears for debris, mucus, or keratitis; evaluation of the lids and meibomian glands (evaporative dry eye), tear film break-up time (usually indicates evaporative dry eye); and Schirmer score. These tests are described in detail in Bron et al. Detailed descriptions of a standardized method for using these tests is provided in the index to the article by Bron et al. New tests are being developed; potentially the most influential one that could become the gold standard is the measurement of tear film osmolarity. In the absence of osmolarity measurements, better performance of the tests for dry eye can be achieved by using selected tests in series or in parallel.
| Dry-eye severity level | ||||
|---|---|---|---|---|
| Symptom | 1 | 2 | 3 | 4 * |
| Discomfort, severity and frequency | Mild and/or episodic; occurs under environmental stress | Moderate, episodic or chronic, stress or no stress | Severe, frequent or constant without stress | Severe and/or disabling, constant |
| Visual symptoms | None or episodic mild fatigue | Annoying and/or activity-limiting episodic | Annoying, chronic and/or constant, limiting activity | Constant and/or possibly disabling |
| Conjunctival injection | None to mild | None to mild | +/− | +/++ |
| Conjunctival staining | None to mild | Variable | Moderate to marked | Marked |
| Corneal staining (severity/location) | None to mild | Variable | Marked central | Severe punctate erosions |
| Corneal/tear signs | None to mild | Mild debris, ↓ meniscus | Filamentary keratitis, mucus clumping, ↑ tear debris | Filamentary keratitis, mucus clumping, ↑ tear debris, ulceration |
| Lid/meibomian glands | MGD variably present | MGD variably present | Frequent | Trichiasis, keratinization, symblepharon |
| TFBUT (seconds) | Variable | ≤ 10 | ≤ 5 | Immediate |
| Schirmer score (mm/5 minutes) | Variable | ≤ 10 | ≤ 5 | ≤ 2 |
Epidemiology
There have been eight large, population-based epidemiologic studies of dry eye in the USA, Australia, and Asia. In these studies the prevalence of dry eye varied from 5% to 35% including all age categories. The two largest studies estimated that in the USA about 3.32 million women and 1.68 million men 50 years old and over have severe dry eye. Many more individuals have less severe dry eye, i.e., occurring in adverse environments or during contact lens wear. The risk for dry eye is greater in women and with increasing age. There are limited data indicating that the prevalence of severe dry eye may be greater in Hispanic and Asian compared to Caucasian women.
Based on data repositories and a variety of databases, the incidence of dry eye cases per 100 fee-for-service beneficiaries increased from 1.22 in 1991 to 1.92 in 1998. An excellent summary of the epidemiology of dry-eye disease can be found in Smith et al.
Diagnostic workup
The Dry Eye Workshop recommends the following diagnostic tests for dry eye which do not depend on tests only available in specialty clinics or tests subject to bias:
- 1.
Use of a validated dry-eye questionnaire. Seven are available and one can be chosen and used routinely. They can be found in Smith et al.
- 2.
Diagnosis of Sjögren syndrome dry eye. The international criteria that require one ocular symptom and one ocular sign be satisfied can be used. These are described in Vitali et al or in Bron et al.
- 3.
Evaluation of tears. Measurement of noninvasive tear film breakup time following the template in Bron et al and the use of the tear function index (TFI) should be used. The TFI is the quotient of the Schirmer value and the tear clearance rate. Methodology for both tests is described in Bron et al. An alternative evaluation is the workup described in Table 14.1 that can also be used to evaluate the severity of dry-eye disease.
- 4.
Better performance can be achieved when tests are used in parallel or in series, as described in Bron et al.
Differential diagnosis
Dry-eye disease is symptom-based, varying in severity from mild (nuisance) to severely disabling. Tests described in Table 14.1 are necessary to distinguish its severity and type to allow directed treatment. It is also important to distinguish between other symptomatic ocular surface diseases such as meibomian gland disease, allergic eye disease, chronic conjunctivitis, and keratoconjunctivitis. More detailed information can be found in Gulati et al and Bron et al.
Treatment
In the past several years, treatment has shifted from lubricating and hydrating the ocular surface providing symptomatic relief to developing compounds that stimulate the natural production of tears. The few current treatments that target the lacrimal gland include the following systemically administered drugs: anti-inflammatory agents (omega-3 fatty acids), secretagogues (muscarinic acetylcholine receptor 3 agonists), immunosuppressive drugs (ciclosporin), and sex hormones (androgens, estrogens, and combinations).
Treatments of aqueous deficiency that directly target lacrimal gland disease have been difficult to develop because of drug delivery problems. Topical treatments rarely penetrate to the lacrimal gland unless they are lipid-soluble, whereas systemic treatments have substantial side-effects in other tissues that possess the same receptors as the lacrimal gland. The lacrimal gland has not yet been shown to have any unique receptors or signaling pathways that would allow systemic use of drugs at effective levels that do not affect other tissues. A treatment that potentially could be successful is systemic omega-3 fatty acids that are currently marketed as dietary supplements. An epidemiologic study suggests that women with high intake of omega-3 fatty acids have a decreased incidence of dry-eye syndrome. Experimentally, lacrimal gland secretion from aging mice appears to be susceptible to oxidative damage. Finally evidence in abstract form (Sicard P et al IOVS 2007;e-abstract 1906) suggested that the lacrimal gland can take up 100-fold more omega-3 fatty acids than the retina. A large clinical trial would be necessary to determine the effectiveness of omega-3 fatty acids.
Prognosis and complications
Complications from the decrease in lacrimal gland secretion in aqueous-deficient dry eye are infections, blepharitis, and conjunctivitis. Dry-eye patients who wear contact lens are particularly susceptible to these complications. Keratinization is a second complication that comes from a loss of conjunctival goblet cells that produce the gel-forming mucins in the mucous layer of the tear film. Other complications that can be the result of severe aqueous deficiency such as occurs in Sjögren syndrome dry eye are band keratopathy, limbal stem cell deficiency, sterile stromal ulcers and corneal perforation, and keratoconus-like changes. Lacrimal gland deficiency is not the only contributor to these complications. Finally chronic aqueous tear-deficient dry eye, especially Sjögren syndrome, can have debilitating psychological effects, because of the lack of definitive treatments and cures, and can have substantial implications for quality of life.
Pathology
The difficulty in removing biopsy samples from the human lacrimal gland makes pathological studies of the lacrimal gland difficult, although postmortem samples can be obtained. Available evidence indicates that there is an age-dependent lymphocytic infiltration of the lacrimal gland in dry eye similar to that which occurs in Sjögren syndrome. The indirect effects of aqueous deficiency on the conjunctiva can be measured by impression cytology and conjunctival biopsy and include loss of goblet cells, squamous cell metaplasia, increased desquamation, and eventually keratinization.
Etiology
The etiology of aqueous deficiency dry eye can be divided into Sjögren and non-Sjögren dry eye ( Figure 14.2 ). Non-Sjögren dry eye can result from a variety of causes that include alteration of tear secretion, destruction of the lacrimal gland, or closure of the lacrimal gland secretory ducts ( Figure 14.3 ). Obstruction of the tear drainage system or an alteration in its drainage properties can also affect the amount of tears in the tear film. Two important mechanisms for the alteration or loss of lacrimal gland secretion are changes in the sensory nerves in the cornea that drive lacrimal gland secretion and systemic medications. Laser in situ keratomileusis (LASIK) surgery and contact lens wear cause dry eye from the alteration in corneal activity. For a complete listing of etiology of aqueous-deficiency dry eye, see Gulati and Dana.
Pathophysiology
Mechanisms of aqueous-deficiency dry eye
As proposed by the 2007 International Dry Eye Workshop and the Cullen Symposium, the core mechanisms of dry eye can be divided into tear hyperosmolarity and tear film instability. Lacrimal gland deficiency primarily contributes to tear hyperosmolarity resulting from a decrease in fluid secretion. The causes of lacrimal gland deficiency can be divided into three categories: (1) alteration in stimulation of secretion; (2) destruction of the lacrimal gland; and (3) occlusion of lacrimal secretory ducts ( Figure 14.3 and Box 14.1 ).
Neuronal
- •
Cholinergic agonists stimulate secretion using the phospholipase C/Ca 2+ /protein kinase C pathways, but attenuate secretion using phospholipase D and p44/p42 mitogen-activated protein kinase (MAPK) pathways
- •
α 1D -Adrenergic agonists stimulate secretion using the nitric oxide/cyclic guanosine monophosphate and Ca 2+ /protein kinase C pathways, but attenuate secretion using the endothelial growth factor (EGF)/EGF receptor/ p44/p42 MAPK pathway
- •
Vasoactive intestinal peptide stimulates secretion using the cyclic adenosine monophosphate and Ca 2+ pathways
Hormonal
- •
Androgens regulate secretory immunoglobulin A production
- •
Prolactins regulate cellular trafficking of secretory proteins
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