Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability, and has the potential to damage the ocular surface. The disease is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.

Dry eye syndrome affects approximately 15% of the U.S. population. A thorough understanding of the tear film structure and underlying factors of dry eye syndrome is necessary to properly diagnose and treat the disease. Treatment includes tear substitutes to help improve lubrication, stabilize the tear film, protect the epithelium, and reduce evaporation.

Ocular Surgery News, with the support of Alcon Laboratories, Inc., assembled a panel of experts at the 2008 Hawaiian Eye Meeting to discuss the diagnosis and epidemiology of dry eye, an update on clinical research, and management options. I would like to thank the faculty members for their participation and Alcon Laboratories, Inc., for its support of this Ocular Surgery News roundtable symposium and monograph project.

Richard L. Lindstrom, MD
Chief Medical Editor
Ocular Surgery News

This monograph includes discussion of off-label uses for approved pharmaceuticals. These statements are neither endorsed nor supported by Alcon Laboratories, Inc.

Sponsored as an educational service by Alcon Labratories, Inc.

Moderator Richard L. Lindstrom, MD, is Adjunct Professor Emeritus at the University of Minnesota Department of Ophthalmology and founder and attending surgeon at Minnesota Eye Consultants. Dr. Lindstrom is also the chief medical editor of Ocular Surgery News.
	Penny Asbell, MD, is professor in the Department of Ophthalmology at Mount Sinai School of Medicine and director of the Cornea Service and Refractive Surgery Center.		Francis S. Mah, MD, practices treatment of the cornea and external disease and performs refractive surgery at the University of Pittsburgh Medical Center Eye Center, is co-medical director of the Charles T. Campbell Ophthalmic Laboratory at the University of Pittsburgh School of Medicine, and is a member of the Ocular Surgery News Editorial Board.
	James P. McCulley, MD, FACS, FRCOphth, is Chairman of the Department of Ophthalmology at UT Southwestern Medical Center, and holder of the David Burton, Jr. Chair in Ophthalmology		Terrence P. O’Brien, MD, is a member of the Ocular Surgery News Editorial Board and professor of ophthalmology and Charlotte Breyer Rodgers Distinguished Chair in Ophthalmology at Bascom Palmer Eye Institute, University of Miami School of Medicine.
	Clark L. Springs, MD, is assistant professor of clinical ophthalmology at Indiana University School of Medicine.

© Copyright 2008, SLACK Incorporated. Ocular Surgery News® and its logo are copyrights of SLACK Incorporated. All rights reserved. No part of this publication may be reproduced without written permission. The ideas and opinions expressed in this Ocular Surgery News monograph do not necessarily reflect those of the editor, the editorial board, or the publisher, and in no way imply endorsement by the editor, the editorial board, or the publisher.

Strategies for Managing Dry Eye

Richard L. Lindstrom, MD: Dry eye syndrome affects approximately 15% of the U.S. population, and the prevalence in Asia may be as high as 20% to 30%.¹ Numerous underlying risk factors and diseases are associated with dry eye, and most people experience symptoms of dry eye at some point in their lives. A thorough understanding of the underlying factors is necessary to properly diagnose and treat dry eye.

What is the prevalence of dry eye in the United States, and how often do patients present with dry eye in a typical ophthalmologic practice? Have changing patient population demographics affected the incidence of dry eye?

Clark L. Springs, MD: Dry eye is a disease that increases in prevalence and incidence with age. According to a 2004 U.S. Census Bureau report, between 2000 and 2050, the number of people between age 65 and 84 will increase by 100%, and the number of people older than 85 will increase by 333%.² Therefore, comprehensive ophthalmologists will likely treat more patients with dry eye.

Dry eye is a disease that increases in prevalence and incidence with age.
— Clark L. Springs, MD

It is important to recognize underlying factors that contribute to dry eye, which is best accomplished with a complete medical history. Autoimmune diseases such as Sjögren’s syndrome and rheumatoid arthritis are well known contributors to dry eye, as are dermatoses such as acne rosacea and atopy. First-generation topical preservatives, such as benzalkonium chloride (BAK), are often under-recognized contributors to dry eye and should be avoided, if possible. Women, contact lens wearers, and patients who underwent keratorefractive surgery are at a higher risk for developing dry eye. The risk of dry eye is also related to hormonal status. For example, by definition, patients with complete androgen insensitivity syndrome have dry eye; similarly, there is an increase in the incidence of dry eye among postmenopausal women. Nutritional status and the contributory roles of omega 3 fatty acids, vitamin A, bariatric surgery, and use of drugs such as anticholinergics are also factors.

Terrence P. O’Brien: I think that there have been significant challenges in epidemiologic investigations related to the incidence of dry eye in the United States due in part to difficulty in diagnosis and the lack of a single diagnostic test. In addition, there is a notorious lack of correlation between clinical tests and patient signs and symptoms. Studies conducted provide us with a range from approximately 3.5% to 15%. Nevertheless, from experience in an academic clinical practice setting, it appears that the incidence is perhaps as high as 30% to 35%, with application of careful diagnostic criteria.

It is clear, however, that there is significant underdiagnosis of the condition as well as a lack of appreciation of the impact that dysfunctional tear states have on activities of daily living and quality of living.

Lindstrom: Some have suggested that ophthalmologists will spend as much as 10% to 20% of the work week treating patients with external diseases, such as ocular surface disease manifesting as dry eye, lid disease, or allergy.³ Do you agree with that estimate?

Francis S. Mah, MD: Treating patients with ocular surface complaints is routine in a general ophthalmology practice. Many epidemiologic studies show that in the United States, 10% to 15% of the general population and up to 20% of people age 65 to 85 have dry eye,¹ which means that 1 to 5 million people have dry eye. I think it is reasonable to estimate that ophthalmologists spend approximately 30% of their time on patients with external diseases.

Patients often have both visual and surface complaints. They complain of itching or burning, foreign body sensation, and fluctuations in vision. Some patients already may have realized that they have dry eye, and some already have been diagnosed. Others may think they have allergies or contact lens intolerance. Some patients who know that they have allergic conjunctivitis may not realize that they could also have secondary dry eye due to the conjunctivitis or the medication.

O’Brien: Despite the popularity of refractive surgery, there are still approximately 30 million wearers of contact lenses in the United States, and each year there is a small but significant number of individuals who become intolerant to contact lenses due to dry eye or a combination of dry eye and ocular allergy.

Differential diagnosis

Lindstrom: What key patient history do you obtain from patients who complain about symptoms of ocular surface disease to differentiate dry eye from other conditions such as lid disease or allergy?

Springs: Patients will either complete a 21-item questionnaire developed by my colleague, Carolyn Begley, or the ocular surface disease index (OSDI). These questionnaires are one of the best validated tools for the diagnosis of dry eye. Patient history questionnaires help ophthalmologists determine whether patients have mild, moderate, or severe dry eye, exactly what type of symptoms they have, and which symptoms are bothersome to them. These questionnaires then serve as the platform for further discussion to suggest other confounding conditions such as allergy and lid disease.

Mah: I think that the majority of general ophthalmologists do not use the OSDI, although it is an excellent research tool. I focus more on individual history and try to differentiate when symptoms worsen. Symptoms that are worse in the morning are typical of blepharitis. Symptoms that are worse later in the day are typical of aqueous tear deficiency. Itching is a symptom that may be indicative of allergic conjunctivitis. I also discuss whether patients experience symptoms during driving, reading, or using the computer, which is typical of evaporative tear deficiency.

Ophthalmologists should also ask whether the patient uses any medications, including topical drops or over-the-counter medications. A patient who uses Visine four to six times a day likely has dry eye but may also have medicamentosa from preservatives in these formulations.

Patients also should be asked about smoking habits, because smoking has been linked to dry eyes, as well as about contact lens wear, previous ocular surgery, and systemic disease history.

James P. McCulley, MD: Intermittent quality of vision degradation is the first symptom that differentiates dry eye from other conditions.

The symptom that most helps me identify seasonal allergic conjunctivitis is extreme itchiness directly over the caruncle.
— Richard L. Lindstrom, MD

O’Brien: Validated symptom survey instruments can be a helpful adjunct in obtaining pertinent historical information. I find that patients will often omit systemic medications, especially over-the-counter or those related to mental health disorders, and ophthalmologists must specifically probe to obtain accurate information. There is no single symptom pathognomonic for dry eye, yet itching, which compels rubbing, is indeed helpful in distinguishing an allergic component. Yet, there may be a significant percentage of patients who suffer from dry eye and allergy concomitantly, or blepharitis and dry eye together, or all three at once.

Lindstrom: I have mild dry eye, some blepharitis, and seasonal allergic conjunctivitis. The symptom that most helps me identify seasonal allergic conjunctivitis is extreme itchiness directly over the caruncle, particularly when I am exposed to an antigen that causes sensitivity. What other symptoms help to differentiate dry eye from seasonal or perennial allergic conjunctivitis?

Mah: Itching is a specific symptom of allergic conjunctivitis. If a patient’s most important concern is to treat itchiness rather than foreign body sensation or fluctuation in vision, then allergic conjunctivitis is usually the primary condition. Dry eye is likely secondary to the allergic conjunctivitis.

Springs: I ask the patient if his or her lid is stuck to the eye when first waking up in the morning. This symptom is typical of dry eye. Asking this question is helpful because patients may not otherwise volunteer this information.

O’Brien: Ocular allergy may also be associated with an excess of mucin secretion and a stringy, ropy white discharge. A subset of patients may habitually try to remove the discharge with their fingertips, further exacerbating the condition and leading to more irritation of the conjunctiva and an increased discharge having a mucoid character (ie, mucus fishing syndrome).

Lindstrom: While examining the ocular surface, surgeons should evaluate eyelids. As a consultative ophthalmologist, approximately 70% of my ocular surface disease patients have lid disease. How frequently do your patients have lid disease associated with dry eye?

Springs: Lid disease is commonly associated with dry eye. I recommend that ophthalmologists examine the meibomian gland orifices for areas of telangiectasias. Ophthalmologists can also put slight pressure on the lid to inspect the viscosity of the meibum. If viscosity is thick, similar to the consistency of toothpaste, the meibum cannot prevent evaporation.

In addition to noting any mechanical difficulties such as lagophthalmos, loose lids, floppy eyelid syndrome, and extensive plastic surgery, ophthalmologists should also look for sleeves and collarettes. The presence of collarettes indicates anterior staphylococcal blepharitis. Sleeves on lashes are indicative of Demodex folliculorum infestation. Demodex brevis is another hair follicle mite that lives in the meibomian gland. I often pluck a lash and examine it under a microscope for confirmation.

It is not uncommon for patients to have variable lid margin disease in association with a dysfunctional tear syndrome.
— Terrence P. O'Brien, MD

Mah: Between 30% and 50% of patients referred to me have some type of meibomian gland dysfunction or posterior blepharitis. Often, the referring ophthalmologists appropriately treated the dry eye but did not note how the meibomian glands relate to the disease or treat the posterior blepharitis of the meibomian gland.

McCulley: Lid disease and dry eye are commonly associated. These conditions can be a cause and effect, such as meibomianitis with tear lipid abnormalities, or simply occur concurrently.

O’Brien: It is not uncommon for patients to have variable lid margin disease in association with a dysfunctional tear syndrome. Anterior blepharitis is characterized by excessive colonization of the lid margin with bacteria, notably coagulase negative staphylococci, corynebacteria and Propionibacterium acnes. The role of parasitic infestation with Demodex species is less clearly understood. The parasites appear to ingest meibum and may be present in a significant number of patients increasing with age. Posterior lid margin disease is commonly associated with a secondary aqueous tear layer insufficiency due to an unstable lipid layer, accelerating evaporative loss of tears. Lid margin bacteria may contribute bacterial lipases that enzymatically cleave meibum into free fatty acids and soaps through saponification. The presence of soaps along the lid margins or in the canthal area may be a clinical sign of this activity. The free fatty acids are particularly irritating to the ocular surface and may worsen hyperemia leading to increased redness and, with chronicity, the development of lid margin telangiectasias in association with unchecked inflammation.

Testing methods

Lindstrom: What are some of the tools and tests used to detect dry eye in patients? Are some more effective than others?

McCulley: The most important tool/test is vital stain drops to identify interpalpebral fissure ocular surface dry spots.

Springs: Various vital stains, such as lissamine green and rose bengal, are helpful during slit-lamp examination. I prefer to use lissamine green because it detects ocular surface disease in an earlier phase. Lissamine green detects cells that lack a protective mucin and glycocalyx coating, whereas fluorescein will detect more advanced ocular surface diseases. Fluorescein will show denuded areas in a patient’s cornea and conjunctiva, and stains basement membrane.

Schirmer testing is a specific test for aqueous tear deficiency and is helpful in two situations. If the Schirmer strips are completely dry, the patient has some component of aqueous tear deficiency. If the Schirmer strips are completely wet, however, the patient likely does not have aqueous tear deficiency.

Mah: Schirmer testing is used to evaluate whether a patient can stimulate tear function. Although I perform Schirmer testing, the method is not particularly specific. Low Schirmer test values most likely indicate that a patient has an aqueous tear deficiency. However, patients with Schirmer test values that are not significantly low but who still complain of dry eye symptoms may have dry eye.

On initial examination, I will perform Schirmer testing with and without anesthetic on patients with suspected dry eye. Most patients with non-Sjögren’s associated or nongraft-versus-host-associated dry eye can wet the Schirmer strips without the use of anesthesia. Then, I perform Schirmer testing with anesthesia to evaluate the basal tear film, which is helpful for most patients with dry eye, such as postmenopausal women or patients with allergic or post-LASIK dry eye.

O’Brien: I agree that Schirmer testing and interpretation is somewhat frustrating for both physicians and patients. Nevertheless, I still perform Schirmer testing without anesthesia (Schirmer I), as I think it is certainly valuable information if the result is extremely low (less than 7 mm at 5 minutes). In addition, the tear film break-up time (TFBUT) is a useful clinical tool, especially if the tear film is breaking up faster than 7 seconds. If the TFBUT exceeds the inter-blink interval, the ocular surface will be vulnerable, and symptoms will soon appear. However, physical staining of the ocular surface, preferably visualized with lissamine green solution rather than strips, is the most specific and reliable clinical sign.

Examination protocol and chart information

Lindstrom: What type of information does slit lamp examination provide? What information do you note on the chart?

McCulley: I note standard observations of ocular surface and anterior segment examination and, most importantly, pattern of vital staining, if it exists.

Mah: During slit lamp examination, I note any punctal malpositioning or lid eversion. I study the bulbar conjunctiva for any scarring, which may indicate conjunctivitis such as ocular cicatricial pemphigoids. If the conjunctival appears to be healthy and there is no conjunctival aclasis, then I use lissamine green for conjunctival staining. For corneal staining, I prefer to use fluorescein or rose bengal. In my experience, staining and TFBUT testing methods are more reliable than Schirmer testing.

Using TFBUT is straightforward. The ophthalmologist should instill fluorescein in the eye and instruct the patient to blink several times. The patient should then hold the blink while the ophthalmologist counts the seconds until the tear film breaks up in a manner similar to water beading on a newly washed and waxed car. Tear film break up usually takes at least 10 seconds for a patient who has a normal tear film, but some patients will experience faster TFBUTs. Tear film break-up tests are relatively reliable, especially for patients with posterior blepharitis of the meibomian gland or evaporative tear deficiency.

The use of staining can assist ophthalmologists in patient management. Staining results are tangible evidence. For example, ophthalmologists can demonstrate to patients how many punctate stains they have compared with previous staining results

Staining is also useful in monitoring vision. Many patients, especially those who have undergone LASIK surgery, will have punctate staining across the center and may not understand why their vision is fluctuating. I often use an analogy to explain the fluctuating vision. The visual experience is similar to taking a small pin or needle and drawing it up and down on their glasses. Patients will understand and realize that they must use either artificial tears or some other means to manage the dryness.

Penny Asbell, MD: I use the slit lamp examination to evaluate tear volume in terms of the height of the meniscus. I study the tears for any evidence of mucous strands or debris within the tear film, which is typical of patients with moderate or severe dry eye. Patients with significant dry eye will have punctate staining.

I also use TFBUT testing because it provides a good representation of tear film quality in terms of wetting the ocular surface. Other times, in addition to fluorescein staining, I may use lissamine green staining or perform Schirmer testing. A patient with Schirmer test value of 0 to 2 has significant dry eye.

Springs: Another factor to note is that patients with staining underneath the lids may have medication-induced ocular surface toxicity.

If a patient has dry eye symptoms, a reduced tear meniscus, a reduced TFBUT, and lissamine green staining, I diagnose the patient as having “ocular surface disease” and differentiate if the condition is predominantly due to aqueous tear deficiency, evaporative tear loss, or a combination of the two. Then, I note whether the dry eye is associated with lid disease and grade the condition as mild, moderate, or severe, similar to the Delphi panel’s dry eye severity grading scheme (Table), which was later adopted by the Dry Eye Workshop (DEWS).^1,4

Asbell: When I diagnose a patient with dry eye disease, I will also grade the condition as mild, moderate, or severe. Although the different testing methods are relatively uncomplicated to perform in the office, classifying dry eye disease is not easy. Ophthalmologists require noninvasive tests and better diagnostic tools to determine some of the multifactorial issues of dry eye and more appropriately focus on what is important to each patient, subsequently providing better treatment.

Role of surgery, contact lens wear

Lindstrom: What is the role of LASIK and PRK in dry eye syndrome? Is it important to diagnose dry eye before refractive surgery?

McCulley: It is critical to diagnose dry eye before refractive surgery. Every potential candidate should have a vital stain instilled to rule out subclinical dry eye.

Mah: I inform all patients who are considering LASIK that dry eye commonly occurs after the procedure. Studies suggest that 50% of patients experience dry eye for 6 months post-LASIK.^1,5 Although not all patients will experience dry eye after LASIK, it is important that they are aware of the condition’s commonality. If a patient has any sign of dry eye or rosacea preoperatively, I recommend that the patient use an artificial tear such as Systane Lubricant Eye Drops (Alcon Laboratories, Inc.), and cyclosporine ophthalmic emulsion (Restasis, Allergan) two times a day and continue to use them for approximately 3 months postoperatively. Post-LASIK dry eye typically subsides within 3 to 6 months.

PRK, or surface ablation, induces less dry eye than LASIK, and I will perform PRK on patients with existing dry eye because the disease does not usually worsen post-PRK.

I will delay refractive surgery for up to 6 months while treating preexisting dry eye in a patient to achieve a clean ocular surface. I do not recommend any type of refractive surgery for a patient who has significant dry eye, however.

Springs: Preoperative treatment is also necessary for patients with allergies because they have a higher risk of developing diffuse lamellar keratitis (DLK).⁶ I recommend using a topical drop, combination mast cell stabilizer and an antihistamine, such as olopatadine hydrochloride ophthalmic solution 0.2% (Pataday, Alcon Laboratories, Inc.).

O’Brien: Previous surveys indicate that dry eye is probably the most frequent complication arising as a result of LASIK and that it probably is the most common cause of dissatisfaction among patients who have undergone otherwise technically proficient laser vision correction. Ophthalmologists are also gaining appreciation for the impact of dry eye on the ability of patients who have undergone laser vision correction to perform their activities of daily living. What is less clear and quantified is the overall impact on quality of life. It was long thought that the temporary neurotrophic keratopathy in association with severing the subbasal plexus of corneal nerves with the microkeratome, femtosecond laser or excimer laser was the sole culprit contributing to the dry eye syndrome. However, more recent evidence links the ultraviolet exposure from the excimer laser operating at the 193 nm wavelength as possibly contributing a role to the dry eye following laser vision correction. Whatever the exact pathogenesis, it is imperative that refractive surgeons carefully screen for patients who may be at an increased risk and preferably pretreat with a multifaceted approach as outlined for 6 to 8 weeks before a planned laser vision correction to allow a better tolerance of the challenge that laser vision correction poses to the health of the tear film and ocular surface.

Lindstrom: What is the role of contact lens wear in dry eye syndrome? What effect does contact lenses have on patients with dry eye?

Asbell: Contact lens wear worsens preexisting dry eye, leading many patients to discontinue wearing contacts. Also, some patients who do not have preexisting dry eye experience symptoms because of contact lens wear, especially when wearing lenses that interfere with the flow of the tear film and the wetting of the ocular surface.

A clear ocular surface is essential for achieving the best outcomes after cataract surgery.
— Penny Asbell, MD

Many contact lens manufacturers have developed lens materials that have better wetting capability and less risk of deposit formation. Some of the newer soft materials, including the combination silicone acrylates, are better for the ocular surface, particularly when combined with surface treatments used to increase wetness.

Dry eye must be treated before fitting a patient for contact lenses. Although not well documented, some ophthalmologists believe that patients with severe dry eye may be more at risk for complications related to contact lens wear than are other patients. Therefore, as with patients undergoing refractive surgery, they must understand the risks of wearing contact lenses, such as abrasion or infections related to an unhealthy ocular surface.

Although some patients who wear contact lenses develop ocular toxicity or other adverse effects on the ocular surface, patients dispose the new soft lenses more frequently. They seem to be satisfied with the vision result and comfort of the new soft lenses. In addition, newer variations of the soft lenses are being developed with better lens fitting capabilities, avoiding the tightness associated with some of the earlier combination lens materials.

Lindstrom: Is it important to diagnose ocular surface disease before a patient undergoes cataract surgery?

Asbell: A clear ocular surface is essential for achieving the best outcomes after cataract surgery. I was recently referred a patient who had undergone cataract surgery with a premium, multifocal IOL. Although the surgery was successful and his eyes appeared to be healthy, the patient was unsatisfied with his resulting vision. His quality of vision decreased partly because of undiagnosed dry eye.

Mah: Cataract surgery patients have increased their quality of vision expectations. They no longer accept postoperative results of 20/25, 20/30, or 20/40. Therefore, cataract surgeons must treat dry eye and other ocular surface conditions.

O’Brien: Certainly, cataract surgery patients are by definition at greater risk given age and other factors. There is a small subset of patients who may develop a particular dry eye syndrome and ocular discomfort in association with the clear corneal incision that may interrupt a nerve bundle.

McCulley: Cataract surgery may cause a patient with subclinical dry eye to experience significant dry eye symptoms postoperatively. Also, patients undergoing refractive IOL surgery, such as with presbyopia-correcting IOLs, may require a keratorefractive touch-up, which will have dry eye implications.

Update in clinical research: DEWS

Lindstrom: The 2007 Report of the International Dry Eye Workshop (DEWS) includes several updates in the study and treatment of dry eye.¹ What are some of the outcomes from the 2007 DEWS report? How has the definition of dry eye disease changed since the 1995 National Eye Institute/Industry Dry Eye Workshop?

Asbell: Significant progress has been made since the 1995 NIH workshop on dry eyes. More than 70 people, including scientists, clinicians, clinical researchers, and representatives from pharmaceutical companies, participated in the 2007 DEWS, leading to a more comprehensive document.

This new report indicated a consensus on the official definition of dry eye disease as a multifactorial condition involving symptoms of discomfort and changes in quality of vision and tear instability that lead to ocular surface damage.

Also, although increased osmolarity and inflammation of the ocular surface were included in the definition of dry eye disease, some controversy remains regarding the inclusion of these symptoms, emphasizing that additional study of dry eye disease is necessary.

McCulley: Ophthalmologists must understand that dry eye disease is a compartmentalized condition and that most of the evaporation occurs in the precorneal tear film between blinks. Current methods of measuring tear film osmolarity include evaluating a sample from the tear meniscus, which may show minimal increase in tear osmolarity but may not reflect a significant increase in tear osmolarity in the precorneal tear film.

Current technological measures of tear osmolarity show an overlap between patients with healthy eyes and patients with dry eyes. An effective osmometer to measure tear film osmolarity would be useful in my research. The tool could be used to assess the effectiveness of therapy in clinical trials.

Furthermore, inflammation is a part of dry eye. Inflammation is the universal response when normal physiology is perturbed. Approximately 10% to 15% of patients with dry eye develop the disease from primary inflammation. For the majority of patients with dry eye, however, inflammation occurs as a secondary phenomenon. Once the inflammation occurs, it can have secondary adverse effects on the tear film, triggering a cascade of events including tear film hyperosmolarity and instability of the tear film.

Ophthalmologists working on the DEWS report realized that additional study of dry eye is needed. Many older concepts about dry eye provide poor understanding of the disease.

For example, the tear film is no longer considered a simple three-layer film. The tear film is intricate and involves many different interactions among the traditional three layers. The corneal epithelium, which is hydrophobic, may be considered the first part of the tear film. The other parts include a surfactant layer, the mucin layer that supports the hydrophilic environment; the aqueous layers; the aqueous mucin, which consists of many different molecules; and the hydrophobic lipid layer. The surfactant layer between hydrophilic aqueous mucin and hydrophobic lipids is complex. The nonpolar lipids on top of the surfactant layer prevent evaporation.

Asbell: Treatment approaches to dry eye are also evolving. Ophthalmologists are learning that a single treatment method may not be appropriate for all patients. Instead, combination treatment titrated to the patient’s findings and presentation is needed. Artificial tears that improve the quality of the tear film may be used in addition to anti-inflammatory agents that remove inflammatory mediators and cytokines.

Treating mild dry eye disease

Lindstrom: Please discuss the use of tear substitutes for dry eye treatment and compare and contrast the clinical results of the different tear substitutes currently available.

Springs: Regardless of the severity of the dry eye, a lubricating eye drop is used in all patients at all levels of severity. Ophthalmologists must understand the attributes and differences among the various lubricating eye drops available. It is helpful to view the eye drops in a manner similar to how glaucoma treatments are viewed, that is by differentiating the mechanism of action. Similarly, lubricating eye drops, can be differentiated by mechanism of action. For instance, most lubricating eye drops have a polymeric system that increases retention, such as carboxymethylcellulose or HP-Guar, as in Systane Lubricant Eye Drops.

Some lubricating eye drops can be either hypo-osmolar or hyperosmolar. One example of a hypo-osmolar eye drop is TheraTears (Advanced Vision Research).

Other lubricating eye drops are lipid-based emulsions, which may be helpful in treating patients with evaporative tear loss.

The addition of preservatives in eye drops is also a factor in dry eye treatment options. It is important, therefore, that ophthalmologists recommend a specific regimen to patients and be familiar with the differences between the lubricant eye drops.

Clinical results show that Systane decreases tear film evaporation by 15% for 30 minutes to 1 hour.
— James P. McCulley, MD

My preferred lubricating eye drop is Systane based on my clinical experience and also the peer-reviewed literature. Systane contains polyethylene glycol/propethylene glycol and HP-Guar as a gelling agent. Systane acts as a mucin-mimetic coating dessicated cells, allowing healing to occur. Further, these properties of Systane are activated upon instillation in the eye due to a gel meshwork that forms, which is activated by the pH of tears. Peer-reviewed literature shows that Systane has superior lubrication,^7,8 improvements in TFBUT,^9,10 corneal staining,¹¹ and symptom control.¹¹

Lindstrom: What is your approach to treating patients with mild dry eye disease?

McCulley: My treatment protocol begins with Systane instilled four times a day. Systane has a mild preservative or is preservative free, coats the ocular surface, and decreases evaporation. Clinical results show that Systane decreases tear film evaporation by 15% for 30 minutes to 1 hour.¹⁰ I recommend a dosing frequency of only four times a day because some patients may experience blurred vision for up to 90 seconds after instilling the eye drop.¹² Other patients, however, may choose to use Systane every 1 to 2 hours.

Sometimes I supplement the Systane eye drop with a carboxymethylcellulose eye drop that is less viscous, such as Optive (Allergan) or Bion Tears (Alcon Laboratories Inc.), and recommend that patients use a lubricating ointment at night or take omega-3 fatty acids.

Asbell: I do not have a universal treatment protocol, but I try to match what I think may work best for each individual.

Artificial tear products differ from one another. Ophthalmologists and patients now expect artificial tears to improve the ocular surface in addition to wetting the eye as a palliative agent.

Clinical data show that Systane not only improves lubrication in dry eye but continued use reduces damage revealed by staining techniques.^{10, 12-14} In addition, Systane is shown to be beneficial when used concomitantly with cyclosporine ophthalmic emulsion when used for dry eye disease.¹¹

Patients who prefer to instill drops frequently (eg, every 30 minutes), may benefit, however, from using a thinner, preservative-free wetting agent to avoid irritation.

Artificial tears can also be used before lens insertion to make contact lenses more comfortable to wear for patients. For example, Systane can be instilled before and after removing a contact lens, providing an additional 3 hours of more comfortable wear time.¹⁵

Mah: I frequently treat patients who experience dry eye symptoms only during specific activities such as using a computer, driving, or reading. If patients can identify these activities, they can be easily treated with tear substitutes.

Systemic medication, such as antihistamines, may also cause eye dryness in some patients. Modifying the medication can reduce dry eye symptoms.

To further reduce dry eye symptoms, I recommend using Systane three to four times a day. For patients who prefer to use eye drops more frequently, I recommend a pure, nonpreserved tear substitute.

In addition, I advise patients not to use red eye- or allergy-reducing products, such as Visine-A (Johnson & Johnson), which have a vasoconstrictor, concomitantly with artificial tears such as Systane.

Treating moderate dry eye disease

Lindstrom: Please discuss your approach to treating patients with moderate dry eye disease. Do you combine treatment with other agents, such as anti-inflammatory agents or punctual plugs?

Springs: For patients who do not respond to topical eye drops alone, I recommend adding omega-3 fatty acids to the diet. Study results showed a 60% reduction in the incidence of dry eye in women who ate five or more servings of fish a week and a 30% reduction in the risk of dry eye for each additional gram of omega-3.¹⁶

Patients with meibomian gland dysfunction may benefit from 20 mg of the antibiotic doxycycline two times a day. A recent study demonstrated that low doses of doxycycline work as well as high doses of doxycycline.¹⁷

I also recommend adding topical cyclosporine to treat patients with mild dry eye disease but who are still symptomatic after using an artificial tear. If a patient is symptomatic after 6 weeks of cyclosporine therapy, then I will consider using a punctal plug.

Mah: In the past, my treatment approach included using punctal plugs right away if a patient was not responding to tear supplements. My approach has changed, however, and I now recommend adding cyclosporine two times a day before inserting punctal plugs.

Ophthalmologists must discuss treatment options with patients. Some patients may prefer using punctal plugs that could potentially clear their symptoms without having to add medications. Other patients do not like the concept of undergoing a procedure or permanently blocking the tear duct.

For patients with evaporative tear film loss, acne rosacea, or meibomian gland dysfunction, I recommend 20 mg of doxycycline, a low-dose but extended-release medication that works well. It is important to educate patients about the antibiotic and to discuss how the agent affects the oil glands in the eye lids and helps repair tissues.

In my experience, the use of steroids in conjunction with cyclosporine is necessary in approximately 10% to 20% of patients. It is important to inform patients that steroids may cause a burning or stinging sensation.

The majority of my patients with dry eye will experience the benefits of topical cyclosporine 2 to 4 weeks after the start of therapy, although studies show that it may take up to 4 to 6 months for some patients.¹⁸Most of my patients report an improvement in symptoms at the 6-week follow-up visit, but ophthalmologists should inform patients that symptoms may not subside until after 4 to 6 months of treatment.

McCulley: I try not to stagnate the tear film when the ocular surface remains unhealthy by inserting punctal plugs, and also prefer to prescribe cyclosporine before recommending punctal plugs. Some patients cannot tolerate cyclosporine, but a short course of steroids can reduce inflammation and improve tolerance of cyclosporine, and may help some patients overcome the lack of tolerance to achieve positive outcomes. Ophthalmologists should prescribe a steroid that is less likely to increase intraocular pressure, and they should stress that patients use the steroid for no more than 2 to 4 weeks.

Although it is known that approximately 50% of tears evaporate, additional data on evaporative dry eye due to meibomian gland dysfunction are necessary. Typically, I reserve oral tetracycline analogs for patients with significant meibomian gland inflammation. Oral tetracycline should not be used in patients who only have turbid or meibomian secretions that are difficult to express in the absence of clinical inflammation, ie, meibomianitis.

My preferred tetracycline analogue is oral minocycline. My colleagues and I performed a study evaluating the effects of a 3-month course of 50 mg to 100 mg of oral minocycline on patients with primary meibomianitis.¹⁹ Study results showed that minocycline treatment resulted in clinical improvement that persisted after cessation of therapy. It also has been shown to penetrate well and be less photosensitizing. I recommend that ophthalmologists avoid prescribing a low-dose oral antibiotic for long-term treatment.

If a patient has a bacterial infection, I recommend using a topical antibiotic ointment such as bacitracin, which is bactericidal and does not cause sensitivity. A topical fluoroquinolone ointment, such as ciprofloxacin (Ciloxan, Alcon Laboratories, Inc.), is my preferred second line of treatment.

O’Brien: Bacitracin is an excellent topical antibiotic ointment. The antibiotic has a spectrum of activity similar to that of penicillin, and because it is not available for systemic use, the rate of resistance is low. The ocular isolates remain highly susceptible, unlike with penicillin or other agents that are widely used systemically.

Macrolides, such as topical azithromycin 1% (AzaSite, Inspire Pharmaceuticals), are an alternative treatment option. Although the spectrum of activity is similar to that for erythromycin, azithromycin’s tissue pharmacokinetic activity is more favorable, and high concentrations of topical azithromycin can be achieved in the eyelids, conjunctiva, and tear film. Azithromycin 1% can be used two times a day for 1 week, then once a day for 2 to 3 weeks, depending on the severity of the disease.

Treating severe dry eye

Lindstrom: Please discuss your approach to treating patients with moderately severe and severe dry eye disease.

Asbell: Severe dry eye can be difficult to manage. Ophthalmologists should begin by combining tear substitute treatment with topical cyclosporine. Although this combination approach may not prove effective immediately, studies show that patients often benefit from the treatment.¹¹ Patients must understand that they will need to use cyclosporine for a considerable period before deciding whether the treatment is effective.

I do not often prescribe steroids to treat dry eye. Compliance is a concern because patients may use the steroid long term, against a physician’s instructions.

I sometimes use punctal plugs for patients with severe dry eye, but I am not entirely convinced of their ability to reverse ocular surface disease or reduce dry eye symptoms.

Wearing contact lenses can reduce symptoms of severe filamentary keratitis, which occurs in patients with severe dry eye. The lenses can alleviate severe chronic pain and improve vision, providing a new surface for better quality optics.

I frequently prescribe Oracea (doxycycline, Collagenex Pharmaceuticals), which is dose released over the day—20 mg in the morning and then 20 mg released slowly throughout the day. Data show that Oracea does not alter the bacterial spectrum found on the skin or in the gastrointestinal tract and has a good safety profile and anti-inflammatory activity. Oracea is approved for treating rosacea, but I have found that it is also effective for treating eye lids as well.

McCulley: Although I would recommend bandage contact lenses for some patients with severe dry eye, ophthalmologists should be cautious because of the risk of infection.

O’Brien: Ophthalmologists should also exercise caution when prescribing topical corticosteroids, but a brief course of corticosteroid as an adjunctive measure can help control severe dry eye.

Rather than prescribing a commercially available topical corticosteroid, at Bascom Palmer Eye Institute, my colleagues and I produce a preservative-free methylprednisolone. In my experience, patient compliance improves because patients cannot obtain the steroid elsewhere and often use the agent in the prescribed manner, alleviating some of the concern about excessive steroid use.

Springs: Patients with moderate to severe dry eye also require treatment with a lubricant eye drop. In a study evaluating the efficacy of artificial tears as a supportive therapy to cyclosporine ophthalmic emulsion, patients using Systane Lubricant Eye Drops and cyclosporine showed less corneal staining and better symptom control than patients using Refresh Tears (Allergan) and cyclosporine (Figure 2 and Figure 3).¹¹ Patients using Systane showed better corneal staining data and experienced less ocular burning, stinging, grittiness, and dryness.¹¹

Ophthalmologists may want to consider ocular surface disease in the same manner as other physicians consider reflux disease. For example, Carafate, a therapy for reflux disease, coats areas that are lacking mucin in the gastrointestinal tract. Similarly, Systane coats corneal and conjunctival epithelial cells that lack mucin and glycocalyx, thus helping to stabilize the ocular surface.^9-13

Patients with severe dry eye often have chronic pain syndrome. Studies show that patients with moderate to severe dry eye experience a quality of life similar to that of patients with moderate to severe angina.²⁰For this reason, I may prescribe oral secretagogues such as oral pilocarpine or cevimeline for severe dry eye. In my experience, patients with severe dry eye disease are often willing to endure the unpleasant side effects of oral secretagogues, such as sweats and frequent bathroom use.

Figure 2. Six-month clinical study results show that the decrease in corneal staining from baseline in patients using cyclosporine ophthalmic emulsion (Restasis, Allergan) and Systane (Alcon Laboratories, Inc.) was statistically superior to the decrease in corneal staining from baseline of the patients using cyclosporine ophthalmic emulsion and Refresh Tears (Allergan). Adapted from data published in: Sall KN, Cohen SM, Christensen MT, Stein JM. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as supportive therapy in dry eye. Eye Contact Lens. 2006;32(1):21-26.

Figure 3. Study results show that cyclosporine ophthalmic emulsion (Restasis, Allergan) and Systane (Alcon Laboratories, Inc.), as well as Systane alone were more effective in reducing four symptoms commonly associated with dry eye and ocular discomfort than cyclosporine ophthalmic emulsion and Refresh Tears (Allergan). Adapted from data published in: Sall KN, Cohen SM, Christensen MT, Stein JM. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as supportive therapy in dry eye. Eye Contact Lens. 2006;32(1):21-26.

Mah: I often prescribe serum drops to treat severe dry eye, severe filamentary keratitis, and superior limbal keratitis.

Punctal plugs, however, are not effective for treatment of severe dry eye, as in patients with Schirmer test values of 0.

Patients with extremely severe dry eye, such as those with neurotrophic components or persistent epithelial defects, may require tarsorrhaphy. Although patients are not often easily convinced to undergo the procedure, tarsorrhaphy heals neurotrophic ulcers and persistent epithelial defects caused by severe dry eye. A small lateral tarsorrhaphy is less cosmetically noticeable.

McCulley: Tarsorrhaphy or tarsalconjunctival pillars should be reserved for the most severe cases of dry eye. Collagen filler may be an option for some patients. Recently, I referred a woman with a lower lid droop to one of our ophthalmic plastic surgeons to inject collagen in her lower lid. The collagen raised the lower lid significantly and narrowed the interpalpebral fissure.

Conjunctival resection may be appropriate for some patients with conjunctivochalasis and severe dry eye because maintaining conjunctival lubrication is difficult when the conjunctiva corrugates onto the lid margin.

O’Brien: Topical vitamin A, which is readily available, is another option for treating patients with severe dry eye.

In addition, moisture goggles can be used to reduce dry eye symptoms. Commercially available panoptics incorporate a gasket to seal in moisture and can reduce the environmental insult that exacerbates severe dry eye conditions. The newer designs are not only cosmetically more acceptable but also seal in moisture more effectively than older designs.

Lindstrom: Most of the general population will experience dry eye at some point. Therefore, understanding the associated diseases and underlying factors is necessary to diagnose and treat dry eye appropriately.

Regardless of the severity of the disease, strategies for managing dry eye include tear substitutes to help improve lubrication and reduce evaporation to protect the ocular surface. Management may require a combination of therapies, however, including anti-inflammatory therapy such as cyclosporine ophthalmic emulsion and corticosteroids. In select patients, punctal plugs or punctal occlusion are helpful. Concomitant treatment of lid disease and allergy is often required. Fortunately, the management options available to ophthalmologists and patients have expanded significantly in recent years.

I thank Ocular Surgery News for organizing this roundtable symposium and Alcon Laboratories, Inc., for its sponsorship. I also thank the panel members for their participation in this discussion and monograph project.

References

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11. Sall KN, Cohen SM, Christensen MT, Stein JM. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as supportive therapy in dry eye. Eye Contact Lens. 2006;32(1):21-26.
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17. Yoo SE, Lee DC, Chang MH. The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction. Korean J Ophthalmol. 2005;19(4):258-263.
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19. Aronowicz JD, Shine WE, Oral D, Vargas JM, McCulley JP. Short term oral minocycline treatment of meibomianitis. Br J Ophthalmol. 2006;90(7):856-860.
20. Schiffman RM, Walt JG, Jacobsen G, Doyle JJ, Lebovics G, Sumner W. Utility assessment among patients with dry eye disease. Ophthalmology. 2003;110(7):1412-1419.

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