DRY EYE: A Common And Complicated Problem

BY BARBARA CAFFERY, M.S., O.D., JANIS COTTER, O.D., & PAUL WHITE, O.D.
MAY 1997

Research into dry eye has produced important new findings. Here, we present the current concepts, the relationship of systemic diseases, diagnosis and available treatments.

The 1995 National Eye Industry workshop defines dry eye 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." About 15 million people in the United States use artificial tears or other therapies for dry eye. Most of them are women, with a nine-to-one female-to-male ratio in Sjögren's syndrome-related dry eye.

For most patients, dry eye causes mild to moderate symptoms and tissue disturbance, but a small yet significant group of patients experience very severe symptomatology and ocular surface disruption.

CURRENT CONCEPTS

Adequate moistening of the ocular surface requires sufficient quantity and normal composition of the preocular tear film, as well as normal blinking and eyelid congruity. The preocular tear film is frequently disturbed by systemic diseases, chemicals, drugs, allergic reactions, chronic inflammations and environmental factors, which create dryness, burning, sandiness or watering symptoms and structural changes of the conjunctiva and cornea. The two major classes of dry eye are aqueous tear-deficient and evaporative.

Aqueous Tear-Deficient Dry Eye

Aqueous tear-deficient dry eye may or may not be associated with Sjögren's syndrome. Sjögren's syndrome dry eye is more severe, produces more severe ocular surface disease and is immunologically mediated. Viruses may also contribute to decreased tear production. Epstein-Barr, cytomegalovirus, and herpesvirus 6, which have been found in the lacrimal and salivary glands of Sjögren's syndrome patients, may induce immune activity.

Although the exact mechanism that triggers Sjögren's syndrome is unknown, it seems that some event causes changes in the cell membranes of certain glands, such that the immune system attacks the glands as if they were foreign. The lymphocytic attack that characterizes the disease destroys the lacrimal and salivary glands. The infiltrative cells seen on gland biopsy are specific to Sjögren's syndrome, and they differ in type and number from the infiltration that occurs as a function of aging. Primary Sjögren's syndrome, or sicca complex, manifests as dry eye and dry mouth, while secondary Sjögren's syndrome is also associated with some other systemic connective tissue disorders.

With aging, the quantity and quality of the tear film decreases as does the eyelid tonus, which reduces the spreading of tear film. Age-related tear decrease is very common and may be caused by alterations in circulating hormonal levels, especially considering the high prevalence of Sjögren's syndrome in women during and after menopause. Many autoimmune disorders are also more common in women. Estrogens and prolactin increase disease severity in women, while androgens often suppress autoimmune pathology; i.e., estrogens up-regulate and androgens down-regulate immune activity.

Evaporative Dry Eye

The eyelid's meibomian glands are the major producers of the superficial lipid layer which retards the evaporation of tears. An abnormal lipid layer leads to greater loss of tears from evaporation and to ocular discomfort. Meibomian gland dysfunction (MGD) is more common with aging, and it manifests as clogged meibomian gland openings and a changed appearance and consistency of the meibomian secretion, which is usually a clear fluid. With MGD, the secretion is turbid, has a toothpaste consistency or cannot be expressed. With severe obstructive MGD, there is excessive tear evaporation, increased tear film osmolarity (tonicity) and ocular surface damage.

Patients with marginal aqueous tear production and even mild MGD often have significant symptoms. More severe MGD can lead to hordeolum and chalazia. Neither the mechanisms regulating meibomian gland production nor the pathogenesis producing meibomian gland obstruction are understood well, but research indicates that endocrine changes may influence the meibomian glands. Blepharitis alone can alter the lipid layer, or blepharitis may be associated with meibomitis. Common classes of blepharitis are staphylococcal, simple seborrheic, meibomian seborrheic and angular.

SYSTEMIC DISEASE

Sjögren's Syndrome

The most common autoimmune disease linked to ocular dryness is primary Sjögren's syndrome, which includes dryness, keratoconjunctivitis sicca (KCS) and xerostamia (dry mouth). The strict San Diego criteria used in North America indicate a 0.1 percent prevalence of the disease, while the Copenhagen criteria used in Europe indicate a five percent prevalence. This discrepancy is due to the fact that the Copenhagen criteria do not require serum analysis or biopsy and depend more upon the clinical diagnosis of lacrimal insufficient dry eye syndrome with ocular surface disease and symptomatic dry eye (Table 1).

The onset of Sjögren's syndrome is most common between ages 20 to 40 and over 60, with fewer systemic complications in the older group. Primary Sjögren's syndrome is characterized by dry eye and dry mouth, and by swollen parotid and submandibular glands, myalgia, arthralgia and fatigue. Secondary Sjögren's syndrome is linked to rheumatoid arthritis, systemic lupus erythmatosus, progressive systemic sclerosis (scleroderma), dermatomyositis and primary biliary cirrhosis.

Rheumatoid Arthritis and Systemic Lupus Erythmatosus

Rheumatoid arthritis is the most common autoimmune disorder associated with dry eye, and up to 20 percent of patients with severe cases develop KCS, which usually occurs many years after joint symptoms appear. Nodular scleritis and corneal vasculitis (corneal melting) may also develop. Readily observable clinical features include symmetrical involvement of wrists and proximal finger joints.

In systemic lupus erythmatosus patients, a malar rash, which is a macular rash over the nose and cheeks but sparing the nasolabial fold, is often apparent. Dry eye symptoms usually manifest in patients ages 20 to 30 or over 50.

Acne Rosacea

Acne rosacea is a dermatologic disorder of the face's sebaceous glands. It is probably an immunologic disorder and occurs almost exclusively in fair-skinned people of British or Scandinavian descent. The autoimmune response within the sebaceous glands changes the normal bacterial flora and the secreted sebum's chemistry, which produces a flushing across the nose and cheeks. The flushing may lead to pustule formation, and it is exacerbated by red wine, coffee and other foods. Because the face's sebaceous glands and the meibomian glands work similarly, dry eye patients with MGD who are of British or Scandinavian descent should be suspected of acne rosacea and referred to a dermatologist.

Sarcoid Disease

Sarcoid disease is occasionally associated with dry eye syndrome. Pathophysiology of sarcoid disease involves the granulomatous infiltration of several secretory glands and lymph nodes, especially the chest's hilar lymph nodes. Sarcoid patients present with general malaise, chest pain and possibly joint pain caused by focal infiltration. The granulomatous inflammatory cells are attracted to old scars, causing irritation and an orange-colored swelling. When the lacrimal glands are involved in the inflammatory response, aqueous-deficient dry eye results. The disease is confirmed by its general manifestations, and a chest x-ray is necessary when hilar adenopathy is visible.

DIAGNOSIS AND TESTING

Dry eye is often unrelated to systemic disease, but it must be ruled out. Women in the appropriate age categories with a family history of autoimmune disease, symptoms of dry mouth, fatigue, myalgia, or arthralgia and true aqueous-deficient dry eye are Sjögren's syndrome suspects. Rheumatologists confirm this with a full system workup and blood testing for rheumatoid arthritis, systemic lupus erythmatosus, scleroderma and primary biliary cirrhosis. The blood serum is analyzed for the specific anti-Ro and anti-La antinuclear antibody markers of Sjögren's syndrome, which come from the affected lacrimal and salivary glands.

Patients should not use contact lenses, eye drops or eye makeup for 24 hours prior to being tested for dry eye. A standardized dry eye questionnaire is essential and a valid indicator of the presence and severity of dry eye. Position the patient in the slit lamp biomicroscope, using about 15x to 25x magnification. Examine eyelids for meibomitis, MGD and blepharitis. Evaluate the quantity and quality of the lower lacrimal reservoir, and the color and apparent thickness of the lipid layer. Thin lipid layers with excess debris suggest poor tear film stability, which may be confirmed by tear film breakup time (TBUT) testing.

Although the Schirmer tear test without anesthesia is not fully reliable, it does produce some sense of tear flow and helps categorize the tears as lacrimal sufficient or insufficient. Apply liquid fluorescein or a fluorescein strip saturated with non-preserved saline on the inferior tarsal plate. After several blinks, determine the patient's TBUT with the cobalt blue light and a wratten #12 filter. Record areas of TBUT of less than 10 seconds, as well as areas of epithelial staining. Instill liquid lissamine green (Dakryon Pharmaceuticals) or rose bengal, and observe and diagram staining patterns after the patient blinks several times. To aid interpretation, fluorescein staining is recorded in green, and rose bengal or lissamine green in red or blue. Clinical signs of dry eye include reflex tearing, conjunctival hyperemia, keratinization of the lid margins, punctate keratitis and conjunctival stippling.

Fluorescein remains extracellular and shows epithelial defects, while one percent rose bengal has an affinity for devitalized epithelial cells and mucus. Punctate epithelial erosions demonstrated with fluorescein often appear on the inferior cornea. Even mild degrees of KCS are apparent with rose bengal, typically seen as a staining of the interpalpebral conjunctiva in a nasal and temporal triangular pattern with the base at the limbus. Rose bengal also detects corneal filaments and plaques. Filaments appear as small comma-shaped opacities with the unattached end lying over the cornea, while mucus plaques appear as semi-translucent, whitish-gray, elevated lesions. Rose bengal can cause discomfort, but it should not be used with an anesthetic as this may produce a false positive diagnosis. Lissamine green does not sting and may be used instead of rose bengal.

The combination of these tests establishes the severity of dry eye and guides treatment. Grade I dry eye is associated with mild symptomatology and ocular surface disease (OSD). Grade II presents moderate symptomatology and OSD. Grade III is usually reserved for Sjögren's syndrome patients who have almost no Schirmer-determined secretion and very severe symptomatology and OSD.

TREATMENT

Conventional treatment for Grade I aqueous-deficient dry eye is the use of artificial tears supplemented by instillation of lubricating ointments before sleep when needed. Non-preserved formulations will reduce or eliminate toxic responses that may occur with frequent or extended use of artificial tears. Artificial tears and overnight lubricating ointments may also be used for Grade II aqueous-deficient dry eyes, but sustained-release tear inserts (Ocusert, Lacrisert) or mucolytic agents are often required. Grade III usually necessitates punctal occlusion, bandage soft contact lenses or moisture chamber goggles. Punctal occlusion also may be used with Grade I or II when other treatments are inadequate.

In severe cases, tarsorrhaphy and systemic immunosuppression for severe inflammation may be required. A combination topical steroid antibiotic will suppress acute inflammation. For long-term treatment, prescribe systemic broad-spectrum antibiotics such as doxycycline (50mg b.i.d.) and tetracycline (250mg b.i.d.) for two months.

To treat MGD, have the patient apply warm compresses to the lid surface two to four times daily to soften and liquefy the secretion; massage the lid margins for two minutes to express meibomian gland secretion; and clean the area with a detergent-based lid scrub.

Artificial Tears

By far, the most common treatment for run-of-the-mill dry eye is the use of artificial tears. These contain water, salts, polymers and often preservatives. Purified water is the most important component to coat the ocular surface and to protect surface tissue cells. Salts such as sodium chloride and potassium chloride are used typically at a level (osmolarity) similar to that found in the precorneal fluid. However, some artificial tears are hypotonic to neutralize the hypertonicity of the precorneal fluid found in some dry eye patients and to establish a more normal osmotic relationship.

Polymers such as methylcellulose (a highly viscous polysaccharide) and related derivatives such as hydroxy-propyl methylcellulose increase the viscosity of artificial tears and their retention time on the eye, but at a level that doesn't blur vision. Preservatives are usually used in multidose containers for bacteriostatic reasons. Commonly used preservatives include benzalkonium chloride, thimerosal, chlorobutanol, sorbic acids or sorbates, Polyquad and Dymed. The first three are more likely to produce toxic or allergic reactions than the last three.

Because there is much unknown about the precorneal fluid in general and that of any patient in specific, it is difficult to know which artificial tear is most efficacious based solely on its biophysical properties or chemical composition. Trial-and-error often determines both the best artificial tear and the frequency of its application. Unfortunately, retention, duration and overall efficacy of artificial tears are below what is required by most patients.

Rewetting or reconditioning drops for contact lens wearers are similar to artificial tears. However, these products must be formulated to also be compatible with the contact lens itself. For the same reasons as artificial tear substitutes, overall efficacy of contact lens rewetting drops is somewhat limited.

Two other problems with artificial tear use are poor patient compliance and preservative toxicity, which produces epithelial damage and slow epithelial healing. Non-preserved, unit-dose artificial tears eliminate the latter, but reduce patient compliance because of inconvenience and cost. GenTeal (CIBA Vision Ophthalmics) addresses both of these problems. It is in a multidose bottle with the preservative system sodium perborate, an oxidizing agent that dissociates to produce minute quantities of hydrogen peroxide. This preservative is converted to nontoxic oxygen and water by the tear film's catalase, superoxide dismutase and glutathione peroxide. GenTeal's active ingredient is the conventional hydroxypropyl methylcellulose to provide viscosity.

TheraTears (ATF) (Advanced Vision Research) is a new product based upon the hypothesis that increased tear osmolarity is the link between decreased tear production, increased evaporation and the resultant OSD. Osmolarities equivalent to those of dry eye patients are toxic to corneal epithelium; and the ocular surface changes of dry eye disease are consistent with, dependent upon, and proportional to increases in tear film osmolarity which show a positive correlation with rose bengal staining. The results of the research leading to the development of TheraTears (ATF) demonstrate that dry eye disease evolves cumulatively through: 1) decreased tear production or increased tear film evaporation (increased tear osmolarity); 2) decreased conjunctival goblet-cell density; 3) increased corneal epithelial desquamation; and 4) destabilization of the cornea-tear surface. Demulcents in artificial tears decrease tear film instability. Preservative-free solutions decrease corneal desquamation. TheraTears (ATF) in preclinical studies restores conjunctival goblet cells and improves tear osmolarity after three months of treatment four times a day. The electrolyte balance of TheraTears (ATF) matches that of human tear film.

Other chemical treatments for dry eye under research include: bromhexine hydrochloride, which may increase the amount of mucous secretion and break it down into smaller particles for increased moisture; vitamin A; topical fibronectin; and sodium sucrose-sulfate.

Acne Rosacea

Mild acne rosacea is treated with antibacterial soap and topical methronidazole (Metrogel from Galderma Laboratories). For severe cases, oral antibiotics such as tetracycline are prescribed for three months. Patients on this therapy will sunburn readily, and women should not conceive while on oral tetracycline. Other tetracycline analogs with fewer side effects are available. Oral antibiotic treatment can improve meibomian gland function and reduce symptoms after two weeks. Lid scrubs and hot compresses daily encourage meibomian gland secretion. Topical antibiotics (tetracycline) may also help.

Mucin-Deficient Conditions

Treat mild mucin deficiency with non-preserved topical lubricants. Severe mucin-deficient conditions include ocular cicatricial pemphigoid, Stevens-Johnson syndrome and erythema multiforme.

Ocular cicatricial pemphigoid is a chronic, progressive autoimmune disease that is often overlooked in the workup of dry eye patients. The early symptoms of irritation, burning and tearing found in older women can be attributed to other dry eye conditions. As the disease advances, fibrosis of the conjunctival epithelium results in fornix foreshortening, MGD, goblet cell loss, trichiasis, distichiasis, symblepharon, entropion, lagophthalmos and ocular surface keratinization.

Conjunctival changes that create an adverse ocular environment as well as the presumed loss of corneal limbal stem cells can cause: exposure keratitis, mechanical abrasions due to the abnormal lid margins, persistent and recurrent epithelial defects, extensive corneal neovascularization and conjunctivalization of the corneal surface.

Early diagnosis is important for the long-term management of ocular cicatricial pemphigoid. Systemic immunosuppressive agents may reduce the conjunctival immune-mediated inflammation. Local therapies to improve the ocular environment include artificial tears, permanent destruction of the follicles of aberrant lashes, mucous membrane grafting, tarsorrhaphy, therapeutic soft lenses, and most recently, rigid gas permeable scleral lenses (Fig. 1). These must be combined with systemic immunotherapy to manage this relentlessly progressive disease.

FIG 1: FLUID RESERVOIR OF A GAS PERMEABLE SCLERAL CONTACT LENS.

Stevens-Johnson syndrome is an acute, self-limiting (2 to 6 weeks), mucocutaneous, type III hypersensitivity reaction with severe ocular morbidity in a significant number of patients. A precipitating agent can be identified in 70 percent of cases. Sulfonamides, penicillin, vaccines, seizure medications and non-steroidal anti-inflammatories (NSAIDs) have been implicated. Herpes simplex, mycoplasma pneumonia, and neoplastic etiologies have also been suggested. Stevens-Johnson syndrome primarily affects children and young adults. The acute disease is characterized by a prodrome of flu-like respiratory and systemic symptoms followed by extensive cutaneous target lesions. Mortality is 5 to 20 percent.

The acute ocular manifestations are swollen, erythematous and encrusted eyelids, conjunctival hyperemia and bullae, and membranous conjunctivitis. Fornix foreshortening, symblepharon, goblet cell loss, obliteration of meibomian gland orifices, trichiasis, distichiasis, keratinization, and lagophthalmos represent the chronic conjunctival and lid manifestations. As in ocular cicatricial pemphigoid, corneal changes are a result of these mechanical and exposure factors, but are also due to the presumed loss of corneal limbal stem cells. Persistent and recurrent epithelial defects, neovascularization, scarring, and stromal ulceration and perforation can produce devastating visual loss.

Stevens-Johnson syndrome management typically does not include long-term immunosuppression since the ocular morbidity is not a result of ongoing, progressive scarring of the conjunctiva. Treatment of the acute disease is supportive and is aimed at preventing symblepharon formation with the use of topical steroids and with separation of any formed adhesions. Prophylactic topical antibiotics are also prescribed. Treatment of the chronic disease is mainly palliative and includes correction of abnormal lids and lashes (epilation, diathermy, cryo, mucous membrane grafting, tarsorrhaphy); management of MGD; lubrication; scraping of keratinized lid margins; and application of therapeutic soft lenses and scleral RGP lenses. Recent developments in the surgical reconstruction of the ocular surface for severe Stevens-Johnson syndrome and ocular cicatricial pemphigoid using limbal allograft and amniotic membrane grafting may represent significant progress in managing these devastating ocular diseases (Figs. 2 & 3).

FIG. 2: PERSISTENT KERATITIS IN PATIENT WITH STEVENS-JOHNSON SYNDROME, COPIOUS LUBRICATION & MUCOUS MEMBRANE GRAFTING.

FIG. 3: RESOLUTION OF KERATITIS FOLLOWING APPLICATION OF SCLERAL RGP LENS.

Drugs Can Exacerbate Dry Eye

Alcohol, baclofen (Lioresal), barbiturates, cocaine, diazepam (Valium), heroin, marijuana, and piroxicam (Feldene) affect blinking. Adrenergic agonists, antihypertensives and cholinergic agonists increase aqueous tear secretion. Antianxiety agents, anticholinergics, antihistamines, beta adrenergic blockers, phenothiazines, vitamin A analogs and tricyclic antidepressants decrease aqueous secretion.

CONTACT LENSES

The ocular tear film is the host environment for contact lenses in vivo, and the importance of its effect on contact lens wear cannot be overestimated. An inappropriate precorneal fluid quantity or quality can cause vision and comfort problems, lens deposits and tissue complications because of drying, flushing, rubbing or binding problems.

Drying includes 3 and 9 o'clock staining on the cornea not covered by the contact lens, or a decreased TBUT on the cornea covered by the contact lens. Flushing involves inadequate debris removal between the contact lens and the cornea and subsequent debris decomposition, which may foster corneal infiltration. Improper flushing may also lead to a buildup of carbon dioxide. Rubbing from a rough contact lens anterior surface (e.g. from deposits) may induce GPC, and a rough posterior contact lens surface may mechanically abrade the cornea. Binding of soft lenses may manifest as bulbar conjunctival vessel blanching or injection and also as acute red eye.

Many contact lens deposits and coatings are related to the components and amount of precorneal fluid, by the interaction of the contact lens material with the precorneal fluid (i.e., ionic attraction), by the fit of the contact lens, by the blink pattern, and by how patients care for their lenses. Mucus, protein, lipids, mucopolysaccharides and calcium in the precorneal fluid may deposit separately, or they may bind together in an amorphous coating of plaque.

With rigid gas permeable contact lenses, the plaque may develop centrally or peripherally on either the front or back surface. The plaque is multi-layered, matted, and is from one to three microns thick.

With hydrogel lenses, interaction between the lens surface and the precorneal fluid begins within the first minute of wear and depends primarily on the polymer's water content and degree of ionization, as well as the patient's precorneal fluid and blinking characteristics. Mucin, lipids, glycoprotein, lactoferrin, immunoglobulin and lysozyme are involved. Lysozyme is a component of many coatings because its positive ionic charge is readily attracted to the negative ionic charge inherent in many lens materials.

Mucin is the initial major deposition. Denatured and inactivated mucoprotein remnants are soon bound to the polymer matrix. With wear, an adherent coating largely of proteins and mucins (a pellicle) forms over this. High water content lenses have larger pores than low water content lenses, so they are probably more susceptible to precorneal fluid components entering their matrix. High water content lenses also have a larger gross mass change from dehydration. Low water and nonionic (less surface reactive) materials are often preferable. Coatings on hydrogel lenses can also change lens dimensions, fitting relationships and dehydration.

There are four major groupings of hydrogel lens deposits: organic deposits (proteins, lipids, mucin, polysaccachrides and organic pigments); inorganic deposits (calcium salts of phosphate and carbonate, mercury, iron, and sodium salts); mixed deposits (mucoprotein-lipid complexes, which may also have calcium and other organic or inorganic components); and microbial contaminants. CLS

Barbara Caffery, O.D., M.S., practices in Toronto, Canada, and is also a member of a multi-disciplinary team at Toronto Western Hospital involved with dry eye care. Janis Cotter, O.D., is the Executive Vice President of the Boston Foundation For Sight. Paul White, O.D., is a professor at the New England College of Optometry.

References are available from: Paul White, O.D., New England College of Optometry, 424 Beacon St., Boston, MA 02115.