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Review of Ophthalmology
Optometric Study Center:February 2005
6th Annual Dry Eye Report: Take Your Care Beyond The Surface
Dry eye is more than a symptomatic disorder. Here, we'll look at pathologic mechanisms and treatments of this multifactorial disease.
By ALAN G. KABAT, O.D.
Self-Assessment Examination
Print Version
Release Date: February 2005
Expiration Date: February 28, 2006
Goal Statement: Clinicians can no longer view dry eye as merely a symptomatic disorder that has no significant or permanent sequelae. Rather, dry eye is—and must be viewed as—a multifactorial ocular surface disease of which the manifestations and degrees of severity vary. This course looks at the theories behind dry eye, conditions associated with dry eye and management options.
Faculty/Editorial Board: Alan G. Kabat, O.D.
Credit Statement: COPE approval for 2 hours of CE credit is pending for this course. Please check with your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Please check with your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Joint-Sponsorship Statement: This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Disclosure Statement: Dr. Kabat has disclosed that he is on the speakers' bureau for Alcon Laboratories.
I still cringe when I recall an incident that occurred during my residency in a Philadelphia hospital. The staff ophthalmologist was examining a glaucoma patient who complained of chronic ocular discomfort, telling her, "I'm sorry, but it's just dry eye. There's nothing we can do."
Admittedly, dry eye was not as well understood or managed in 1990 as it is today. In 2005, we better understand the disease processes that cause dry eye, and have more therapeutic options available. So, we can no longer tell patients that there is "nothing we can do" when it comes to dry eye.
Nor can we tell them that "no one goes blind from dry eye." Although rare, some patients may eventually experience vision loss and disability without prompt and aggressive intervention. We cannot view dry eye as merely a symptomatic disorder that has no significant or permanent sequelae.
Dry eye is—and must be viewed as—a multifactorial ocular surface disease of which the manifestations and degrees of severity vary. Some individuals manifest mild or episodic symptoms that are easily controlled with an ocular lubricant. Others, however, present with severe complications from keratoconjunctivitis sicca. Most sequelae are inflammatory in nature, but patients with dry eye disease are also at risk for infection, epithelial metaplasia, glandular dysfunction and neurotrophic damage.
Case Report : Severe Dry Eye
Doesn't Respond to Tears
A 63-year-old black female with severe dry eye that was unresponsive to artificial tears was referred to our clinic. The patient has a history of diabetes, hypertension, arthritis, and was recently diagnosed with Sjögren's syndrome.
The patient's eye in primary gaze
(figure 1) demonstrates her gross appearance. As the patient looks up and to the right (figure 2), notice the lackluster corneal reflex, increased vascularity and hyperemia around the limbus. Also, the areas of green (with lissamine green staining) represent mucin filaments.
Fluorescein staining (figure 3) demonstrates that the tear film is not uniform (she had an immediate tear breakup time in certain areas). The speckled appearance represents punctate epithelial keratopathy, and the shiny areas correspond with mucus filaments.
Given this patient's history of diabetes and Sjögren's syndrome, she may have lacrimal gland burnout. However, we started her on a combination of Restasis and Systane, which offered some relief, and she has done well taking this combination for nine months. We've also removed the mucus strands on several occasions.
Figure 1
Figure 2
Figure 3
Functional Unit
To understand dry eye disease, one must first appreciate the normal mechanisms that produce tears and maintain homeostasis of the ocular surface. Most individuals have sufficient quantity and quality of tears to adequately hydrate, lubricate and nourish the tissues of the ocular surface.
Tears are an elaborate admixture of three intertwined elements:
* An aqueous layer, or water layer, secreted by the primary and accessory lacrimal glands.
* A lipid layer, produced chiefly by the meibomian glands.
* A mucin layer, derived from the conjunctival goblet cells.
The tear film wets the cornea and conjunctiva, dilutes noxious stimuli, and supplies oxygen, vitamin A and other nutrients to the ocular surface. Also, tears possess antimicrobial proteins—such as lysozyme, lactoferrin, B lysin and immunoglobulins A and G—and growth factors that help maintain corneal integrity and regulate cellular processes.
The tear film and ocular surface structures are interdependent upon one another.1-3 Specifically, the cornea, conjunctiva, meibomian glands, goblet cells and lacrimal glands are intricately linked to one another via neural, hormonal and chemical feedback mechanisms. These constitute a "functional unit" for tear secretion.1,2 Damage or alteration of any one structure may negatively affect the remaining components of this functional unit.
This theory emphasizes autoimmunity and inflammation. Recent studies have found that dry eye disease often manifests as a chronic, low-grade inflammatory state of the ocular surface. Researchers have identified pro-inflammatory cytokines and activated T-cells in the lacrimal glands and conjunctiva of dry eye patients, both with and without Sjögren's syndrome.3,4
These inflammatory effects do more than simply cause ocular irritation. Short-term changes can result in excess mucus production and precipitate the formation of mucin strands or filaments. Reduction in the overall tear volume can hasten allergic responses in predisposed individuals and rob the eye of its natural antimicrobial defenses.
Over the long term, chronic inflammation tends to damage the cornea's sensitive nerve fibers, leading to neurotrophic effects on the ocular surface. Besides wreaking havoc on corneal integrity, inflammatory stimulation of the neural receptors can feed back to the lacrimal glands via efferent nerves, resulting in a downregulation of the lacrimal stimulatory process.
Case Report: Filament Masquerades as Corneal Erosion
A 42-year-old white female presented complaining of mild discomfort in her left eye and pronounced discomfort in her right eye. Her medical history is negative for illness, but the patient is mildly mentally handicapped and was brought to the clinic by a caretaker. On initial presentation, the patient looked as though she had a recurrent corneal erosion. Artificial tears and ointment provided relief, but a week later, she returned with the same complaints.
I was asked to evaluate the patient, and an almost circular-shaped filament was evident (figure 1). Filamentary keratitis can mimic a corneal abrasion or erosion because it will stain with fluorescein, and the patient had similar symptomology, namely unilateral discomfort.
We manually removed the filaments from her eye using forceps (figure 2) and prescribed a regular course of artificial tears, which led to rapid improvement.
Figure 1
Figure 2
Associated Conditions
To better understand the potential complications of dry eye disease, consider the conditions that may coincide with severe dry eye states:
* Ocular allergy. Many patients who are prone to dry eye also suffer from allergies. Tears not only provide a nutritional reservoir for the ocular surface; they also entrap and wash away harmful particulate matter, including potential allergens. In a dry eye state, allergens may achieve greater concentrations on the ocular surface, leading to potentially greater and more symptomatic responses.
While most ocular allergic responses are not sight threatening, they can result in significant discomfort and diminished quality of life. However, proper maintenance of the precorneal tear film significantly reduces symptomatic responses in patients who are predisposed to ocular allergy.
* Filamentary keratitis. More than half the patients who have moderate or severe dry eye commonly demonstrate mucin strands or filaments within the tear film.5
The etiology is likely multifactorial. Diminished aqueous allows lipids to contaminate the mucin component, resulting in poor adhesion to the epithelial glycocalyx.6 Meanwhile, mucus secretion is promoted by certain eicosanoids (e.g., prostaglandins and leukotrienes) and the cytokines that are released as part of the normal inflammatory response. Hence, the low-grade inflammation believed to be inherent in dry eye disease may result in enhanced mucus production.7,8
Mucin that is not anchored to the corneal surface can bind with loose, compromised epithelial cells, another potential sequela of a decompensated ocular surface.9,10 Long filaments then form in the tear film and adhere to damaged sites on the corneal surface. Lid closure creates traction between these tough filaments and the corneal surface, resulting in pain, irritation and increased inflammation.
* Ocular infection. Dry eye disease predisposes individuals to chronic or recurrent microbial infections of the lid margins, conjunctiva or cornea.
All eyelids, regardless of personal hygiene, are abundantly colonized by bacteria.11 While these bacteria may result in mild inflammation and irritation (i.e., blepharitis), acute or severe infection typically does not occur. The tear film protects against infection with its numerous enzymes, immunoglobulins and other proteins.
Lactoferrin is probably the most notable antimicrobial component of the tear film. An iron-binding glycoprotein, lactoferrin exerts a bactericidal effect by damaging the outer cell membranes of certain bacteria.12 Lysozyme and immunoglobulin A (IgA) also have significant antimicrobial properties.13,14
However, all three molecules are characteristically diminished in patients who have dry eye disease.15-18 As the eye loses its natural protective mechanisms, the "normal flora" of the ocular surface can proliferate to pathological levels, resulting in frank microbial infections. So, while infectious disorders, such as blepharitis or viral conjunctivitis, can lead to symptoms of dry eye, dry eye actually predisposes patients to microbial conjunctivitis or keratitis.
* Ocular surface inflammation and neurotrophic effects. Our current understanding of dry eye disease recognizes an inflammatory process, both of the ocular surface and in the primary lacrimal gland.3,4,19 But, we still don't know whether lacrimal gland inflammation triggers ocular surface inflammation or vice versa. One theory: Both mechanisms may exist, creating a vicious cycle of lacrimal gland-ocular surface inflammation.
In patients with autoimmune disorders, such as Sjögren's syndrome, infiltration of the lacrimal gland by B and T cells results in the enhanced production of cytokines, such as interleukin-1 (IL-1), IL-2 and tumor necrosis factor (TNF).20 Lactoferrin normally helps downregulate the release of these pro-inflammatory mediators, but lactoferrin is secreted at diminished levels in dry eye disease.12 So, IL-1, IL-2 and TNF accumulate in the tear film. This triggers an inflammatory response on the ocular surface that results in irritation and epithelial disruption.
However, the story does not end there. Inflammation of the cornea and conjunctiva, whether primary or secondary to lacrimal gland disease, stimulates expression of immune activation and adhesion molecules, such as human leukocyte antigen (HLA)-DR and intercellular adhesion molecule 1 (ICAM-1). These attract and retain inflammatory cells in the conjunctiva.21,22 W.D. Mathers and others have suggested that the accumulation of these inflammatory cells on the ocular surface produces hyperstimulation of corneal nerves, which are tied to the lacrimal gland via a neural feedback loop.2,23,24 Ultimately, these nerves may suffer a type of "burnout," leading to diminished neural control and subsequently resulting in abnormal lacrimal organelle trafficking, apoptosis and diminished tear production.2,23,24
This theory, unusual as it may sound, has been illustrated using corneal wounding models as well as cholinergic stimulation of the ocular surface.25 In essence, inflammation of the ocular surface may, over time, actually lead to diminished tear production by damaging the lacrimal gland.
Neurotrophic corneal ulceration occurs when corneal sensation is diminished or absent. Neurotrophic ulceration most commonly occurs secondary to herpetic infection, but it may also be associated with trauma to the trigeminal nerve, corneal dystrophy, topical medication, toxic exposure and numerous systemic diseases.26
Neurotrophic keratitis likely involves a decrease in intracellular acetylcholine. This, in turn, leads to diminished epithelial cell mitotic activity.27 Epitheliopathy ultimately results, followed by stromal edema and stromal lysis in severe instances. While dry eye disease generally cannot cause such profound keratitis, it is common to see epithelial changes, such as diminished tear break-up time, punctate fluorescein staining, rose bengal and/or lissamine green staining, and even recurrent erosions. All these findings are common in early neurotrophic keratitis.
Could the common ocular surface changes noted in chronic dry eye disease—traditionally attributed to simple desiccation—actually be neurotrophic in nature? If so, this lends even greater credibility to the inflammatory theory of dry eye, and supports the idea of neural burnout in dry eye disease.
Tears Over Dry Eye
Unlike early artificial tears, a number of products currently on the market show evidence of therapeutic potential. Here are some examples:
* TheraTears (Advanced Vision Research). This hypotonic solution is designed to enhance tear volume and reduce the osmolarity of the tear film. Increased tear osmolarity can potentially induce pathological changes, including loss of conjunctival goblet cells and desquamation of conjunctival epithelium, to the ocular surface.49 Jeffrey Gilbard, M.D., who created TheraTears, suggests that "saturation dosing" with this product can diminish symptoms of dryness and help restore the normal physiology and health of the ocular surface. A study of post-LASIK patients demonstrated that prolonged therapy with TheraTears helped restore normal conjunctival goblet cell density, while treatment with a preservative-free control did not.50
* Refresh Endura (Allergan) and Soothe Emollient Eye Drops (Alimera Sciences). In patients with meibomian gland dysfunction (MGD), reduced lipid secretion leads to enhanced tear evaporation, and subsequently to symptoms of dry eye disease. Evaporative dry eye may be the most common etiology of this disease, and addressing the lipid element may help to significantly diminish tear evaporation.51-53
Both Endura and Soothe are topical emulsions that contain both an aqueous and a lipid component, much like the composition of normal human tears. Endura incorporates castor oil as its active ingredient, which has been shown to be beneficial in the management of MGD and associated tear film and ocular surface dysfunction.54 Soothe features a proprietary combination of highly refined mineral oils (Drakeol-15 and Drakeol-35) in a compound called Restoryl, a lipid restorative.
* Systane (Alcon Laboratories). Systane incorporates hydroxypropyl (HP) guar, which increases the product's viscosity and residence time after application. The mechanism is described as a cross-linking of the HP-guar molecules to borate and calcium ions in the product; this process is chemically induced by the slightly alkaline pH of the normal ocular surface.
According to the manufacturer, this network of molecules subsequently binds to areas of epithelial disruption and simulates the normal architecture of the corneal glycocalyx. Hence, Systane helps increase residence time of the tear film, simulates the mucin aspect of tears, and may provide a temporary "bandage" for the damaged corneal epithelium to heal itself.55
Clinical studies of Systane have shown that it ameliorates dry eye symptoms, extends tear break-up time and diminishes corneal epitheliopathy.56,57—A.G.K.
Managing Dry Eye Disease
Given that dry eye is a multifaceted disorder that has extremely variable symptomatology and manifestations, there are many management options for this condition. Some of the more common treatment modalities today include:
* Artificial tears. The basic rationale for artificial tears is simple: Add fluid to the ocular surface to replenish moisture and perhaps wash away accumulated debris. Unfortunately, the earliest artificial tears were little more than saline solution, so they offered a very limited duration of action and required frequent instillation. Also, the preservatives used to extend shelf life, most notably benzalkonium chloride, have been shown to result in cytotoxicity to the ocular surface when used chronically.28,29
Ideally, an artificial tear should not only impart moisture to the ocular tissues and flush antigens from the surface; it should also possess the benefit of increased "residence time" (i.e., increased duration of contact with the ocular surface tissues). Also, the "perfect" artificial tear should diminish and even reverse the pathological changes induced by desiccation, restoring the ocular surface to homeostasis.
Unlike early artificial tears, a number of products currently on the market show evidence of therapeutic potential. (See "Tears Over Dry Eye." )
* Punctal occlusion. The rationale behind punctal occlusion is straightforward: to preserve the tears already on the ocular surface by preventing drainage through the lacrimal canaliculus.30 Some suggest that this is actually a "healthier" alternative to artificial tear products, since natural tears contain essential elements, such as lysozyme and lactoferrin, which manufactured products cannot offer.
Many clinicians advocate the use of punctal plugs as a primary management option for dry eye, arguing that insertion is a simple, effective, safe and reversible method to treat aqueous tear deficiency and other ocular surface diseases.31 Further, they say punctal occlusion in keratoconjunctivitis sicca improves tear film stability, ocular surface staining scores, conjunctival squamous metaplasia grades and goblet cell density.32
However, while many patients experience early symptomatic relief, recent reports question whether punctal occlusion is beneficial in the long term. In 1998, T.G. Slusser and G.E. Lowther reported on 35 patients who underwent punctal occlusion therapy for contact lens-related dry eye. Although there was early improvement in symptoms and signs, the benefits tended to decline within four to five weeks.33
Also, a 2001 study concluded that patients who undergo punctal occlusion may experience diminished ocular surface sensation and a concomitant decrease in tear production.34 The authors believe that decreased tear clearance results in accumulation of inflammatory cytokines in the tear film (commonly known as the "cesspool effect") and/or a rise in tear osmolality. Both of these may affect the sensory threshold of the ocular surface.34
Given this new information, it certainly seems prudent to refrain from punctal occlusion in patients who exhibit obvious signs of surface inflammation or meibomian gland dysfunction. At the very least, one should strive to identify and treat any underlying inflammation before considering this option.
* Immunomodulators. Restasis (0.5% cyclosporine, Allergan) was the first FDA-approved therapeutic agent specifically indicated for the treatment of dry eye. Restasis works by preventing activation and nuclear translocation of cytoplasmic transcription factors, which are required for activation of T cells and production of inflammatory cytokines.22,35 It is currently the only approved topical agent to target immune-mediated inflammation at the level of the ocular surface. Patients typically respond well to this agent, though in some, the onset may be somewhat slow, taking three to six months to achieve maxium efficacy.
* Topical steroids. In recent studies, topical corticosteroids have shown promising results in treating dry eye. Steroids may help increase goblet cell density and reduce the accumulation of inflammatory cells within ocular surface tissues.36-38 Dr. Pflugfelder and colleagues found that topical Lotemax (loteprednol etabonate 0.5%, Bausch & Lomb) q.i.d. may benefit patients who have keratoconjunctivitis sicca that has at least a moderate inflammatory component.38
However, corticosteroids have been associated with increased infection, IOP elevation, and cataract formation after prolonged use. Only one steroid, Alrex (loteprednol etabonate 0.2%, B&L), has been shown to have minimal deleterious effects on the ocular surface tissues after prolonged use.39 Currently, however, the use of steroids for dry eye is strictly "off label."
* Investigational agents. Other topical and systemic agents that are under investigation as potential dry eye therapies include these categories:
—Secretagogues, designed to increase secretion of mucin and glycoproteins, and rehydrate the ocular surface. Drugs under investigation include cevimeline, diquafosol tetrasodium (INS365), 15-S-HETE, rebamipide and ecabet sodium.40-44
—Androgen therapy, including an investigational transdermal testosterone cream.45 Research has shown that androgen deficiency may be a critical factor in dry eye.46
—Tetracyclines, which are widely used for the management of meibomian gland dysfunction, do not have a current indication for dry eye. Current investigations, however, show that there may be an anti-inflammatory effect of these agents as well.47,48
Figure 1
Case Report: Patient Attempts Solution with Fingernails
A 63-year-old white female with a history of hypertension presented complaining of "terrible dry eye." She also reported the presence of "strands" in her eyes that interfered in her daily activities, especially driving. She said she removed these with her fingernails.
Evaluation revealed that her condition was evaporative secondary to meibomian gland dysfunction. The area of staining (with lissamine green) by the inner canthus shows where she's been scraping with her fingernail (figure 1). Note the particulate matter at the corneal limbus, as seen on staining and filaments (figure 2). Her attempts to remove the strands herself resulted in an inflammatory reaction, causing the eye to produce even more mucus. This condition is commonly known as "mucus fishing syndrome."
We educated her not to attempt removal herself, and prescribed a course of oral doxycycline and •Restasis.
Figure 2
Dry eye is not simply the benign nuisance we sometimes imagined it to be. Rather, this disorder can lead to serious complications in some patients. However, early detection via a careful history and appropriate testing ensures the best possible prognosis for these patients.
Many forms of therapy available today can arrest or even reverse the pathological changes associated with dry eye disease. And, they can ameliorate the nagging, chronic symptomatology associated with ocular surface disease, thus enhancing patients' quality of life.
Dr. Kabat is an associate professor at Nova Southeastern University College of Optometry and one of the authors of Review of Optometry's "Handbook of Ocular Disease Management.
1. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: The interaction between the ocular surface and lacrimal glands. Cornea 1998 Nov;17(6):584-9.
2. Mathers WD. Why the eye becomes dry: A cornea and lacrimal gland feedback model. CLAO J 2000 Jul;26(3):159-65.
3. Pflugfelder SC, Wilhelmus KR, Osato MS, et al. The autoimmune nature of aqueous tear deficiency. Ophthalmology 1986 Dec;93(12):1513-7.
4. Pepose JS, Akata RF, Pflugfelder SC, Voigt W. Mononuclear cell phenotypes and immunoglobulin gene rearrangements in lacrimal gland biopsies from patients with Sjögren's syndrome. Ophthalmology 1990 Dec;97(12):1599-605.
5. Whitcher JP. Clinical diagnosis of the dry eye. Int Ophthalmol Clin 1987 Spring; 27(1):7-24.
6. Holly FJ. Formation and rupture of the tear film. Exp Eye Res 1973 May 10;15(5): 515-25.
7. Jumblatt MM, McKenzie RW, Steele PS, et al. MUC7 expression in the human lacrimal gland and conjunctiva. Cornea 2003 Jan;22(1):41-5.
8. Hibino SH, Watanabe H. Mucins and ocular surface disease. Adv Exp Med Biol 2002;506(Pt A):275-81.
9. Zaidman GW, Geeraets R, Paylor RR, Ferry AP. The histopathology of filamentary keratitis. Arch Ophthalmol 1985 Aug;103(8):1178-81.
10. Albietz J, Sanfilippo P, Troutbeck R, Lenton LM. Management of filamentary keratitis associated with aqueous-deficient dry eye. Optom Vis Sci 2003 Jun;80(6):420-30.
11. Mathers WD. Meibomian gland disease. In: Pflugfelder SC, Beuerman RW, Stern ME. Dry Eye and Ocular Surface Disorders. New York: Marcel-Dekker, 2004.
12. Caccavo D, Pellegrino NM, Altamura M, et al. Antimicrobial and immunoregulatory functions of lactoferrin and its potential therapeutic application. J Endotoxin Res 2002;8(6):403-17.
13. Selinger DS, Selinger RC, Reed WP. Resistance to infection of the external eye: the role of tears. Surv Ophthalmol 1979 Jul-Aug;24(1):33-8.
14. Bron AJ, Seal DV. The defences of the ocular surface. Trans Ophthalmol Soc UK 1986;105(Part 1):18-25.
15. Johnson ME, Murphy PJ. Changes in the tear film and ocular surface from dry eye syndrome. Prog Retin Eye Res 2004 Jul;23(4):449-74.
16. Janssen PT, van Bijsterveld OP. A simple test for lacrimal gland function: A tear lactoferrin assay by radial immunodiffusion. Graefes Arch Clin Exp Ophthalmol 1983;220(4):171-4.
17. Mackie IA, Seal DV. The questionably dry eye. Br J Ophthalmol 1981 Jan;65(1):2-9.
18. Mackie IA, Seal DV. Diagnostic implications of tear protein profiles. Br J Ophthalmol 1984 May;68(5):321-4.
19. Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci 2001 Sep;42(10):2283-92.
20. Pflugfelder SC, Jones D, Ji Z, et al. Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjögren's syndrome keratoconjunctivitis sicca. Curr Eye Res 1999 Sep;19(3):201-11.
21. Brignole F, Pisella PJ, Goldschild M, et al. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci 2000 May;41(6):1356-63.
22. Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol 2004 Feb;137(2):337-42.
23. Baudouin C. The pathology of dry eye. Surv Ophthalmol 2001 Mar;45 Suppl 2:S211-20.
24. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: The interaction between the ocular surface and lacrimal glands. Cornea 1998 Nov;17(6):584-9.
25. Thompson HW, Beuerman RW, Cook J, et al. Transcription of message for tumor necrosis factor-alpha by lacrimal gland is regulated by corneal wounding. Adv Exp Med Biol 1994;350:211-7.
26. Pflugfelder SC, Solomon A. Dry eye. In: Holland EJ, Marks MJ. Ocular Surface Disease: Medical & Surgical Management. New York: Springer-Verlag Telos, 2002.
27. Cavanagh HD, Colley AM. The molecular basis of neurotrophic keratitis. Acta Ophthalmol Suppl 1989;192:115-34.
28. Ichijima H, Petroll WM, Jester JV, Cavanagh HD. Confocal microscopic studies of living rabbit cornea treated with benzalkonium chloride. Cornea 1992 May;11(3):221-5.
29. Tripathi BJ, Tripathi RC, Kolli SP. Cytotoxicity of ophthalmic preservatives on human corneal epithelium. Lens Eye Toxicity Res 1992;9(3-4):361-75.
30. Cohen EJ. Punctal occlusion. Arch Ophthalmol 1999 Mar;117(3):389-90.
31. Tai MC, Cosar CB, Cohen EJ, et al. The clinical efficacy of silicone punctal plug therapy. Cornea 2002 Mar;21(2):135-9.
32. Dursun D, Ertan A, Bilezikci B, et al. Ocular surface changes in keratoconjunctivitis sicca with silicone punctum plug occlusion. Curr Eye Res
Review of Ophthalmology
Optometric Study Center:February 2005
6th Annual Dry Eye Report: Take Your Care Beyond The Surface
Dry eye is more than a symptomatic disorder. Here, we'll look at pathologic mechanisms and treatments of this multifactorial disease.
By ALAN G. KABAT, O.D.
Self-Assessment Examination
Print Version
Release Date: February 2005
Expiration Date: February 28, 2006
Goal Statement: Clinicians can no longer view dry eye as merely a symptomatic disorder that has no significant or permanent sequelae. Rather, dry eye is—and must be viewed as—a multifactorial ocular surface disease of which the manifestations and degrees of severity vary. This course looks at the theories behind dry eye, conditions associated with dry eye and management options.
Faculty/Editorial Board: Alan G. Kabat, O.D.
Credit Statement: COPE approval for 2 hours of CE credit is pending for this course. Please check with your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Please check with your state licensing board to see if this approval counts toward your CE requirement for relicensure.
Joint-Sponsorship Statement: This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Disclosure Statement: Dr. Kabat has disclosed that he is on the speakers' bureau for Alcon Laboratories.
I still cringe when I recall an incident that occurred during my residency in a Philadelphia hospital. The staff ophthalmologist was examining a glaucoma patient who complained of chronic ocular discomfort, telling her, "I'm sorry, but it's just dry eye. There's nothing we can do."
Admittedly, dry eye was not as well understood or managed in 1990 as it is today. In 2005, we better understand the disease processes that cause dry eye, and have more therapeutic options available. So, we can no longer tell patients that there is "nothing we can do" when it comes to dry eye.
Nor can we tell them that "no one goes blind from dry eye." Although rare, some patients may eventually experience vision loss and disability without prompt and aggressive intervention. We cannot view dry eye as merely a symptomatic disorder that has no significant or permanent sequelae.
Dry eye is—and must be viewed as—a multifactorial ocular surface disease of which the manifestations and degrees of severity vary. Some individuals manifest mild or episodic symptoms that are easily controlled with an ocular lubricant. Others, however, present with severe complications from keratoconjunctivitis sicca. Most sequelae are inflammatory in nature, but patients with dry eye disease are also at risk for infection, epithelial metaplasia, glandular dysfunction and neurotrophic damage.
Case Report : Severe Dry Eye
Doesn't Respond to Tears
A 63-year-old black female with severe dry eye that was unresponsive to artificial tears was referred to our clinic. The patient has a history of diabetes, hypertension, arthritis, and was recently diagnosed with Sjögren's syndrome.
The patient's eye in primary gaze
(figure 1) demonstrates her gross appearance. As the patient looks up and to the right (figure 2), notice the lackluster corneal reflex, increased vascularity and hyperemia around the limbus. Also, the areas of green (with lissamine green staining) represent mucin filaments.
Fluorescein staining (figure 3) demonstrates that the tear film is not uniform (she had an immediate tear breakup time in certain areas). The speckled appearance represents punctate epithelial keratopathy, and the shiny areas correspond with mucus filaments.
Given this patient's history of diabetes and Sjögren's syndrome, she may have lacrimal gland burnout. However, we started her on a combination of Restasis and Systane, which offered some relief, and she has done well taking this combination for nine months. We've also removed the mucus strands on several occasions.
Figure 1
Figure 2
Figure 3
Functional Unit
To understand dry eye disease, one must first appreciate the normal mechanisms that produce tears and maintain homeostasis of the ocular surface. Most individuals have sufficient quantity and quality of tears to adequately hydrate, lubricate and nourish the tissues of the ocular surface.
Tears are an elaborate admixture of three intertwined elements:
* An aqueous layer, or water layer, secreted by the primary and accessory lacrimal glands.
* A lipid layer, produced chiefly by the meibomian glands.
* A mucin layer, derived from the conjunctival goblet cells.
The tear film wets the cornea and conjunctiva, dilutes noxious stimuli, and supplies oxygen, vitamin A and other nutrients to the ocular surface. Also, tears possess antimicrobial proteins—such as lysozyme, lactoferrin, B lysin and immunoglobulins A and G—and growth factors that help maintain corneal integrity and regulate cellular processes.
The tear film and ocular surface structures are interdependent upon one another.1-3 Specifically, the cornea, conjunctiva, meibomian glands, goblet cells and lacrimal glands are intricately linked to one another via neural, hormonal and chemical feedback mechanisms. These constitute a "functional unit" for tear secretion.1,2 Damage or alteration of any one structure may negatively affect the remaining components of this functional unit.
This theory emphasizes autoimmunity and inflammation. Recent studies have found that dry eye disease often manifests as a chronic, low-grade inflammatory state of the ocular surface. Researchers have identified pro-inflammatory cytokines and activated T-cells in the lacrimal glands and conjunctiva of dry eye patients, both with and without Sjögren's syndrome.3,4
These inflammatory effects do more than simply cause ocular irritation. Short-term changes can result in excess mucus production and precipitate the formation of mucin strands or filaments. Reduction in the overall tear volume can hasten allergic responses in predisposed individuals and rob the eye of its natural antimicrobial defenses.
Over the long term, chronic inflammation tends to damage the cornea's sensitive nerve fibers, leading to neurotrophic effects on the ocular surface. Besides wreaking havoc on corneal integrity, inflammatory stimulation of the neural receptors can feed back to the lacrimal glands via efferent nerves, resulting in a downregulation of the lacrimal stimulatory process.
Case Report: Filament Masquerades as Corneal Erosion
A 42-year-old white female presented complaining of mild discomfort in her left eye and pronounced discomfort in her right eye. Her medical history is negative for illness, but the patient is mildly mentally handicapped and was brought to the clinic by a caretaker. On initial presentation, the patient looked as though she had a recurrent corneal erosion. Artificial tears and ointment provided relief, but a week later, she returned with the same complaints.
I was asked to evaluate the patient, and an almost circular-shaped filament was evident (figure 1). Filamentary keratitis can mimic a corneal abrasion or erosion because it will stain with fluorescein, and the patient had similar symptomology, namely unilateral discomfort.
We manually removed the filaments from her eye using forceps (figure 2) and prescribed a regular course of artificial tears, which led to rapid improvement.
Figure 1
Figure 2
Associated Conditions
To better understand the potential complications of dry eye disease, consider the conditions that may coincide with severe dry eye states:
* Ocular allergy. Many patients who are prone to dry eye also suffer from allergies. Tears not only provide a nutritional reservoir for the ocular surface; they also entrap and wash away harmful particulate matter, including potential allergens. In a dry eye state, allergens may achieve greater concentrations on the ocular surface, leading to potentially greater and more symptomatic responses.
While most ocular allergic responses are not sight threatening, they can result in significant discomfort and diminished quality of life. However, proper maintenance of the precorneal tear film significantly reduces symptomatic responses in patients who are predisposed to ocular allergy.
* Filamentary keratitis. More than half the patients who have moderate or severe dry eye commonly demonstrate mucin strands or filaments within the tear film.5
The etiology is likely multifactorial. Diminished aqueous allows lipids to contaminate the mucin component, resulting in poor adhesion to the epithelial glycocalyx.6 Meanwhile, mucus secretion is promoted by certain eicosanoids (e.g., prostaglandins and leukotrienes) and the cytokines that are released as part of the normal inflammatory response. Hence, the low-grade inflammation believed to be inherent in dry eye disease may result in enhanced mucus production.7,8
Mucin that is not anchored to the corneal surface can bind with loose, compromised epithelial cells, another potential sequela of a decompensated ocular surface.9,10 Long filaments then form in the tear film and adhere to damaged sites on the corneal surface. Lid closure creates traction between these tough filaments and the corneal surface, resulting in pain, irritation and increased inflammation.
* Ocular infection. Dry eye disease predisposes individuals to chronic or recurrent microbial infections of the lid margins, conjunctiva or cornea.
All eyelids, regardless of personal hygiene, are abundantly colonized by bacteria.11 While these bacteria may result in mild inflammation and irritation (i.e., blepharitis), acute or severe infection typically does not occur. The tear film protects against infection with its numerous enzymes, immunoglobulins and other proteins.
Lactoferrin is probably the most notable antimicrobial component of the tear film. An iron-binding glycoprotein, lactoferrin exerts a bactericidal effect by damaging the outer cell membranes of certain bacteria.12 Lysozyme and immunoglobulin A (IgA) also have significant antimicrobial properties.13,14
However, all three molecules are characteristically diminished in patients who have dry eye disease.15-18 As the eye loses its natural protective mechanisms, the "normal flora" of the ocular surface can proliferate to pathological levels, resulting in frank microbial infections. So, while infectious disorders, such as blepharitis or viral conjunctivitis, can lead to symptoms of dry eye, dry eye actually predisposes patients to microbial conjunctivitis or keratitis.
* Ocular surface inflammation and neurotrophic effects. Our current understanding of dry eye disease recognizes an inflammatory process, both of the ocular surface and in the primary lacrimal gland.3,4,19 But, we still don't know whether lacrimal gland inflammation triggers ocular surface inflammation or vice versa. One theory: Both mechanisms may exist, creating a vicious cycle of lacrimal gland-ocular surface inflammation.
In patients with autoimmune disorders, such as Sjögren's syndrome, infiltration of the lacrimal gland by B and T cells results in the enhanced production of cytokines, such as interleukin-1 (IL-1), IL-2 and tumor necrosis factor (TNF).20 Lactoferrin normally helps downregulate the release of these pro-inflammatory mediators, but lactoferrin is secreted at diminished levels in dry eye disease.12 So, IL-1, IL-2 and TNF accumulate in the tear film. This triggers an inflammatory response on the ocular surface that results in irritation and epithelial disruption.
However, the story does not end there. Inflammation of the cornea and conjunctiva, whether primary or secondary to lacrimal gland disease, stimulates expression of immune activation and adhesion molecules, such as human leukocyte antigen (HLA)-DR and intercellular adhesion molecule 1 (ICAM-1). These attract and retain inflammatory cells in the conjunctiva.21,22 W.D. Mathers and others have suggested that the accumulation of these inflammatory cells on the ocular surface produces hyperstimulation of corneal nerves, which are tied to the lacrimal gland via a neural feedback loop.2,23,24 Ultimately, these nerves may suffer a type of "burnout," leading to diminished neural control and subsequently resulting in abnormal lacrimal organelle trafficking, apoptosis and diminished tear production.2,23,24
This theory, unusual as it may sound, has been illustrated using corneal wounding models as well as cholinergic stimulation of the ocular surface.25 In essence, inflammation of the ocular surface may, over time, actually lead to diminished tear production by damaging the lacrimal gland.
Neurotrophic corneal ulceration occurs when corneal sensation is diminished or absent. Neurotrophic ulceration most commonly occurs secondary to herpetic infection, but it may also be associated with trauma to the trigeminal nerve, corneal dystrophy, topical medication, toxic exposure and numerous systemic diseases.26
Neurotrophic keratitis likely involves a decrease in intracellular acetylcholine. This, in turn, leads to diminished epithelial cell mitotic activity.27 Epitheliopathy ultimately results, followed by stromal edema and stromal lysis in severe instances. While dry eye disease generally cannot cause such profound keratitis, it is common to see epithelial changes, such as diminished tear break-up time, punctate fluorescein staining, rose bengal and/or lissamine green staining, and even recurrent erosions. All these findings are common in early neurotrophic keratitis.
Could the common ocular surface changes noted in chronic dry eye disease—traditionally attributed to simple desiccation—actually be neurotrophic in nature? If so, this lends even greater credibility to the inflammatory theory of dry eye, and supports the idea of neural burnout in dry eye disease.
Tears Over Dry Eye
Unlike early artificial tears, a number of products currently on the market show evidence of therapeutic potential. Here are some examples:
* TheraTears (Advanced Vision Research). This hypotonic solution is designed to enhance tear volume and reduce the osmolarity of the tear film. Increased tear osmolarity can potentially induce pathological changes, including loss of conjunctival goblet cells and desquamation of conjunctival epithelium, to the ocular surface.49 Jeffrey Gilbard, M.D., who created TheraTears, suggests that "saturation dosing" with this product can diminish symptoms of dryness and help restore the normal physiology and health of the ocular surface. A study of post-LASIK patients demonstrated that prolonged therapy with TheraTears helped restore normal conjunctival goblet cell density, while treatment with a preservative-free control did not.50
* Refresh Endura (Allergan) and Soothe Emollient Eye Drops (Alimera Sciences). In patients with meibomian gland dysfunction (MGD), reduced lipid secretion leads to enhanced tear evaporation, and subsequently to symptoms of dry eye disease. Evaporative dry eye may be the most common etiology of this disease, and addressing the lipid element may help to significantly diminish tear evaporation.51-53
Both Endura and Soothe are topical emulsions that contain both an aqueous and a lipid component, much like the composition of normal human tears. Endura incorporates castor oil as its active ingredient, which has been shown to be beneficial in the management of MGD and associated tear film and ocular surface dysfunction.54 Soothe features a proprietary combination of highly refined mineral oils (Drakeol-15 and Drakeol-35) in a compound called Restoryl, a lipid restorative.
* Systane (Alcon Laboratories). Systane incorporates hydroxypropyl (HP) guar, which increases the product's viscosity and residence time after application. The mechanism is described as a cross-linking of the HP-guar molecules to borate and calcium ions in the product; this process is chemically induced by the slightly alkaline pH of the normal ocular surface.
According to the manufacturer, this network of molecules subsequently binds to areas of epithelial disruption and simulates the normal architecture of the corneal glycocalyx. Hence, Systane helps increase residence time of the tear film, simulates the mucin aspect of tears, and may provide a temporary "bandage" for the damaged corneal epithelium to heal itself.55
Clinical studies of Systane have shown that it ameliorates dry eye symptoms, extends tear break-up time and diminishes corneal epitheliopathy.56,57—A.G.K.
Managing Dry Eye Disease
Given that dry eye is a multifaceted disorder that has extremely variable symptomatology and manifestations, there are many management options for this condition. Some of the more common treatment modalities today include:
* Artificial tears. The basic rationale for artificial tears is simple: Add fluid to the ocular surface to replenish moisture and perhaps wash away accumulated debris. Unfortunately, the earliest artificial tears were little more than saline solution, so they offered a very limited duration of action and required frequent instillation. Also, the preservatives used to extend shelf life, most notably benzalkonium chloride, have been shown to result in cytotoxicity to the ocular surface when used chronically.28,29
Ideally, an artificial tear should not only impart moisture to the ocular tissues and flush antigens from the surface; it should also possess the benefit of increased "residence time" (i.e., increased duration of contact with the ocular surface tissues). Also, the "perfect" artificial tear should diminish and even reverse the pathological changes induced by desiccation, restoring the ocular surface to homeostasis.
Unlike early artificial tears, a number of products currently on the market show evidence of therapeutic potential. (See "Tears Over Dry Eye." )
* Punctal occlusion. The rationale behind punctal occlusion is straightforward: to preserve the tears already on the ocular surface by preventing drainage through the lacrimal canaliculus.30 Some suggest that this is actually a "healthier" alternative to artificial tear products, since natural tears contain essential elements, such as lysozyme and lactoferrin, which manufactured products cannot offer.
Many clinicians advocate the use of punctal plugs as a primary management option for dry eye, arguing that insertion is a simple, effective, safe and reversible method to treat aqueous tear deficiency and other ocular surface diseases.31 Further, they say punctal occlusion in keratoconjunctivitis sicca improves tear film stability, ocular surface staining scores, conjunctival squamous metaplasia grades and goblet cell density.32
However, while many patients experience early symptomatic relief, recent reports question whether punctal occlusion is beneficial in the long term. In 1998, T.G. Slusser and G.E. Lowther reported on 35 patients who underwent punctal occlusion therapy for contact lens-related dry eye. Although there was early improvement in symptoms and signs, the benefits tended to decline within four to five weeks.33
Also, a 2001 study concluded that patients who undergo punctal occlusion may experience diminished ocular surface sensation and a concomitant decrease in tear production.34 The authors believe that decreased tear clearance results in accumulation of inflammatory cytokines in the tear film (commonly known as the "cesspool effect") and/or a rise in tear osmolality. Both of these may affect the sensory threshold of the ocular surface.34
Given this new information, it certainly seems prudent to refrain from punctal occlusion in patients who exhibit obvious signs of surface inflammation or meibomian gland dysfunction. At the very least, one should strive to identify and treat any underlying inflammation before considering this option.
* Immunomodulators. Restasis (0.5% cyclosporine, Allergan) was the first FDA-approved therapeutic agent specifically indicated for the treatment of dry eye. Restasis works by preventing activation and nuclear translocation of cytoplasmic transcription factors, which are required for activation of T cells and production of inflammatory cytokines.22,35 It is currently the only approved topical agent to target immune-mediated inflammation at the level of the ocular surface. Patients typically respond well to this agent, though in some, the onset may be somewhat slow, taking three to six months to achieve maxium efficacy.
* Topical steroids. In recent studies, topical corticosteroids have shown promising results in treating dry eye. Steroids may help increase goblet cell density and reduce the accumulation of inflammatory cells within ocular surface tissues.36-38 Dr. Pflugfelder and colleagues found that topical Lotemax (loteprednol etabonate 0.5%, Bausch & Lomb) q.i.d. may benefit patients who have keratoconjunctivitis sicca that has at least a moderate inflammatory component.38
However, corticosteroids have been associated with increased infection, IOP elevation, and cataract formation after prolonged use. Only one steroid, Alrex (loteprednol etabonate 0.2%, B&L), has been shown to have minimal deleterious effects on the ocular surface tissues after prolonged use.39 Currently, however, the use of steroids for dry eye is strictly "off label."
* Investigational agents. Other topical and systemic agents that are under investigation as potential dry eye therapies include these categories:
—Secretagogues, designed to increase secretion of mucin and glycoproteins, and rehydrate the ocular surface. Drugs under investigation include cevimeline, diquafosol tetrasodium (INS365), 15-S-HETE, rebamipide and ecabet sodium.40-44
—Androgen therapy, including an investigational transdermal testosterone cream.45 Research has shown that androgen deficiency may be a critical factor in dry eye.46
—Tetracyclines, which are widely used for the management of meibomian gland dysfunction, do not have a current indication for dry eye. Current investigations, however, show that there may be an anti-inflammatory effect of these agents as well.47,48
Figure 1
Case Report: Patient Attempts Solution with Fingernails
A 63-year-old white female with a history of hypertension presented complaining of "terrible dry eye." She also reported the presence of "strands" in her eyes that interfered in her daily activities, especially driving. She said she removed these with her fingernails.
Evaluation revealed that her condition was evaporative secondary to meibomian gland dysfunction. The area of staining (with lissamine green) by the inner canthus shows where she's been scraping with her fingernail (figure 1). Note the particulate matter at the corneal limbus, as seen on staining and filaments (figure 2). Her attempts to remove the strands herself resulted in an inflammatory reaction, causing the eye to produce even more mucus. This condition is commonly known as "mucus fishing syndrome."
We educated her not to attempt removal herself, and prescribed a course of oral doxycycline and •Restasis.
Figure 2
Dry eye is not simply the benign nuisance we sometimes imagined it to be. Rather, this disorder can lead to serious complications in some patients. However, early detection via a careful history and appropriate testing ensures the best possible prognosis for these patients.
Many forms of therapy available today can arrest or even reverse the pathological changes associated with dry eye disease. And, they can ameliorate the nagging, chronic symptomatology associated with ocular surface disease, thus enhancing patients' quality of life.
Dr. Kabat is an associate professor at Nova Southeastern University College of Optometry and one of the authors of Review of Optometry's "Handbook of Ocular Disease Management.
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