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`
`The Golden Age Of Dry Eye Management
`Nearly 10% of the U.S. population has dry eye, but there are myriad options for treating this multifactorial
`disease.
`By John L. Schachet, O.D.
`
`RELEASE DATE: NOVEMBER 2008
`EXPIRATION DATE: NOVEMBER 30, 2009
`GOAL STATEMENT:
`Dry eye syndrome affects the quality of life of millions of people in the United States. It has varied causes and
`severities, and there is no single set of symptoms, so it can be difficult to classify once the initial diagnosis is
`made. This article reviews the various causes, diagnosis and treatment.
`FACULTY/EDITORIAL BOARD:
`Michael Pier, O.D.
`CREDIT STATEMENT:
`This course is COPE approved for 1 hour of CE credit. COPE ID is 23734-AS. Please check with your state
`licensing board to see if this approval counts towards your CE requirement for relicensure.
`JOINT-SPONSORSHIP STATEMENT:
`This continuing education course is joint-sponsored by the University of Alabama School of Optometry. This
`course is supported by an unrestricted educational grant from Alcon.
`DISCLOSURE STATEMENT:
`Dr. Schachet is a member of the Alcon Speaker’s Bureau, but has no other financial interest.
`
`Dry eye syndrome, one of the many conditions that affect the ocular surface, is estimated to involve nearly 10% of
`the U.S. population. As many as 20 million to 30 million people in the United States have early signs or symptoms
`of dry eye, and an estimated 6 million women and 3 million men have advanced effects of dry eye —a condition
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`that affects their quality of life.
`Dry eye also appears to be more common in older individuals (45 years or older). It has varied causes and
`2
`severities and there appears to be no unified cause. There is no single set of symptoms in which the condition
`presents itself. So, it can be very difficult to classify after the initial diagnosis is made, rendering this condition very
`difficult to treat.
`We’ll review the various causes as well as diagnosis and treatment.
`
`Dry Eye Defined
`The 1995 report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eye defines dry eye, or
`keratoconjunctivitis sicca, as a disorder of the pre-corneal tear film caused by tear deficiency or excessive tear
`evaporation that results in damage to the interpalpebral ocular surface and is associated with ocular discomfort.
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`MYLAN - EXHIBIT 1087
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`The Definition and Classification Subcommittee of the International Dry Eye Workshop (DEWS) of 2007 has
`somewhat modified this definition. DEWS determined that dry eye is a multifactorial disease of the tears and
`ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability, with potential
`damage to the ocular surface. The DEWS definition also states that dry eye is accompanied by increased
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`osmolarity of the tear film and inflammation of the ocular surface. These features lead to the dry eye cascade of
`visual degradation, epithelial cell damage and discomfort.
`Most individuals with this condition are female, ages 30 and older. According to the Women’s Health Study, the
`prevalence of dry eye affects more women as they age. Although the prevalence increases in men, too, it doesn’t
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`keep pace with the presence of dry eye in women. Also, women who used hormone replacement therapy (HRT)
`had a 69% greater risk of developing dry eye syndrome. If estrogen therapy was combined with
`5
`progesterone/progestin, the risk went up another 29%. The risk of dry eye increased 15% for every three-year
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`interval that the women remained on HRT. Many patients develop a dry eye condition over years and decades
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`before it is recognized.
`
`The Causes
`Stephen Pflugfelder, M.D., a member of DEWS, says the sequence of events leading to dry eye or ocular surface
`disease is exacerbated by “an unstable tear film of altered composition that inadequately supports the health of
`the ocular surface.”
`6
`Many factors can cause dry eye or exacerbate an existing dry eye condition. These include:
`◾ Extended visual tasks, such as prolonged computer use.
`◾ Systemic medications that have drying side effects, including antihistamines, hormone replacement
`therapy, diuretics, antidepressants and antianxiety medications, cancer treatments and some sleep aids.
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`◾ Excessive consumption of alcoholic beverages.
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`◾ Long-term exposure to dry air, as found in the desert Southwest, for example, or windy climates.
`◾ Extreme use of forced-air heat or air conditioning.
`◾ Air pollutants, such as tobacco smoke, smog or excessive exhaust fumes.
`◾ Contact lens wear and refractive surgery. Dry eye symptoms may adversely affect contact lens wearing
`time (and often is the most common reason for discontinuing lens wear) or corneal healing, respectively.
`9,10
`◾ Dietary considerations, such as the reduced intake of omega-3 fatty acids, increased omega-6
`consumption, reduced water intake (individuals should drink at least eight glasses of water daily) and
`increased intake of soft drinks and/or caffeine (caffeine itself is a drying agent).
`
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`
`A Historical Perspective
`An understanding of dry eye disease starts with the historical perspective of the tear layer and ocular surface. E.
`Wolff first described the multi-layer tear film in 1946. This concept involves three distinct and separate layers of
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`the tears: the aqueous, mucin and lipid layers. Each layer, he said, has its own function.
`In 1973, Frank J. Holly, Ph.D., explained that mucin had a much greater role than previously thought. The
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`soluble mucins are produced primarily from the goblet cells and the insoluble mucins from the corneal epithelial
`cells. So, if there is a deficiency in mucin production, breaks in the surface tension of the ocular surface would
`result, and the tear film would not spread evenly over the corneal epithelium.
`In 1997, Scheffer Tseng, M.D., Ph.D., showed that the ocular surface and tear film interacted in such a way that
`the layers do not have separate functions after all. Rather, they are inextricably intertwined to produce a healthy
`ocular surface. This led to the realization that dry eye is not simply a disease process but a complex,
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`multifactorial disorder. When we think of the tear layer, we must think globally to understand what might have
`resulted in the dry eye condition.
`Some facts: The pH of a normal tear film is about 7.4, but for a dry eye it is about 7.9. Also, the osmolarity of the
`tear film is higher for the dry eye than the normal eye.
`Cholinergic drugs increase tear production, while anti-
`14,15
`cholinergic drugs decrease tear production. Finally, tear production is increased with androgen hormones and
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`decreased with estrogen hormones.
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`The Role of Inflammation
`The most recent concept in dry eye pertains to the role of inflammation. Opinions vary as to whether inflammation
`initiates or occurs in the middle of the dry eye cycle. Still, once inflammation begins, damage can occur to the
`ocular structures. This, in turn, perpetuates and intensifies the signs and symptoms of dry eye. No matter what the
`cause, we must break the cycle in this cascade.
`Inflammation can be present with Sjögren’s and non-Sjögren’s types of dry eye, and may be present in the
`lacrimal glands, conjunctiva and meibomian glands. Inflammation is mediated by pro-inflammatory cytokines in
`the tear layer; delayed tear clearance accentuates this effect. Also, inflammation adversely affects neural
`transmission, a key component in the health of the tear film.
`The condition of the meibomian glands is one of the most common concerns with dry eye. Dry eye often begins
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`in the meibomian glands or may be exacerbated due to the inflammatory nature of meibomian gland dysfunction.
`These glands provide the sebaceous layer of the tear film; when this layer is abnormal, tear break-up time is
`reduced, and the tear film evaporates too quickly.
`This may initiate the dry eye cycle. Debris and toxins, resulting from chronic infections of the meibomian glands
`and the eyelids (marginal blepharitis), are released into the tear film, creating ocular irritation and redness. Left
`untreated, internal hordeola, pannus, corneal ulcers and corneal scarring may result.
`Look at the meibomian glands with transillumination to determine if they appear normal or appear to have lost
`their structure entirely; this will help you determine the extent of the problem. When the meibomian glands seem
`to have dropped-out from view with transillumination, the treatment protocol will need to be more aggressive than
`if in earlier stages of degradation.
`
`Making the Diagnosis
`Several tests can aid in diagnosis of dry eye. The first is always a good history. Some things to look for:
`◾ Systemic conditions that increase the likelihood of dry eye symptoms. Ask about a history of collagen
`vascular or autoimmune diseases that may increase the risk. Rheumatoid or osteoarthritis, systemic lupus
`erythematosus and fibromyalgia may increase the risk of dry eye or at least warrant further testing.
`◾ Other ocular conditions. Patients with keratoconus or those with epithelial basement membrane dystrophy
`(EBMD) or map-dot dystrophy are certainly at risk. Patients with EBMD (map-dot dystrophy) have recurring
`erosions, so we manage them as though they are dry eye patients. Reduced contact lens wearing time in
`keratoconus patients may be due to dry eye as well.
`◾ Medications. Several types of medications increase a patient’s risk of dry eye. Among them: selective
`serotonin reuptake inhibitors, which are used to treat depression and anxiety disorders. These medications
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`include Prozac (fluoxetine, Eli Lilly), Paxil (paroxetine, GlaxoSmithKline), Zoloft (sertraline, Pfizer) and
`Lexapro (excitalopram oxalate, Forest Pharmaceuticals). A newer drug, Cymbalta (duloxetine, Eli Lilly), a
`reuptake inhibitor of both serotonin and norepinephrine, also falls into this category of potential drying
`agents.
`After you record the history, examine the patient. Be sure to:
`◾ Examine the lid margins for blepharitis/meibomitis.
`◾ Pay special attention to the tear layer during the biomicroscopic examination. Look at the tear meniscus
`height and tear film break-up time (TFBUT), any evidence of fluorescein staining on the cornea and tear
`consistency, looking at thickness, debris, oil and sebaceous secretions.
`◾ Perform further tests, such as a Schirmer test or phenol red thread test, to rule out dry eye. The Schirmer
`test measures tear production, while the phenol red thread test measures the fluid present in the
`conjunctival sac. Lissamine green staining would follow; any staining of the bulbar conjunctiva indicates
`dryness of the conjunctiva. Finally, use collagen plugs to test for subjective responses to increased tear
`volume over several days, indicating a possible need for non-dissolvable plugs.
`◾ Look beyond the eyes. Look for signs of acne rosacea by examining the nose and forehead of men and the
`cheeks of women for signs of telangiectasia. Also, look at the patient’s hands for typical changes
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`suggestive of rheumatoid arthritis or osteo-arthritis. Distal joints of the hands could reveal the presence of
`Heberden’s nodes, which involve nodular swelling of the distal joints. This suggests osteoarthritis, even if
`the patient isn’t aware of other symptoms.
`
`A ‘Cookbook’ Approach?
`Once you establish that a dry eye condition exists, the treatment goal is to create a more normal tear film
`environment for epithelial healing to take place. We must stabilize the tear film by increasing lubricity, increasing
`aqueous production, decreasing inflammation, or using some combination of these approaches.
`In 2006, the Dysfunctional Tear Film Study Group, with its Delphi Panel, tried to determine how to manage dry
`eye syndrome. The group attempted to categorize dry eye into four general categories and proposed a
`“cookbook”-type approach to managing the disease based upon the level of the severity.
`(See Delphi Panel
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`Consensus for Dry Eye Management,” below.)
`
`Delphi Panel Consensus for Dry Eye Management
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`Severity Signs and Symptoms
`Recommended Treatment
`1
`Mild to moderate symptoms; no
`Patient counseling, preserved tears,
`signs.
`environmental management, use of
`Mild to moderate conjunctival
`hypoallergenic products, water intake.
`signs.
`Moderate to severe symptoms.
`Tear film signs, mild corneal
`punctate staining, corneal
`staining, visual signs.
`Severe symptoms. Marked
`corneal punctate staining,
`central corneal staining,
`filamentary keratitis.
`Severe symptoms. Severe
`corneal staining, erosions,
`conjunctival scarring.
`
`2
`
`3
`
`Unpreserved tears, gels, ointments,
`cyclosporine A, secretagogues,
`topical steroids, nutritional support
`(flaxseed oil).
`Tetracyclines, punctal plugs.
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`
`Systemic anti-inflammatory therapy,
`oral cyclosporine, moisture goggles,
`acetylcysteine, punctal cautery,
`surgery.
`Some doctors believe they failed to address a first-line approach to dry eye treatment before the disease
`progresses to the more severe stages. Others criticize the early use of cyclosporine and recommended later use
`of punctal/lacrimal occlusion instead of the opposite approach. Still, this was an attempt to develop a protocol for
`treating dry eye.
`
`Lubricant Drops
`Lubricant eye drops all have differing active and inactive ingredients. The four categories are based on the
`science behind the product.
`◾ Cellulose derivative products. These further break down in carboxymethylcellulose (CMC) products, such
`as Refresh Tears (Allergan) or Refresh Liquigel (Allergan), and hydroxymethylcellulose (HPMC) products
`such as Tears Naturale (Alcon), Genteal (Novartis) or TheraTears (Advanced Vision Research).
`◾ Glycerin-containing products. These break down into two additional categories: glycerin plus CMC as in
`Visine Tears Dry Eye Relief (Pfizer) or Optive Lubricant Eye Drops (Allergan), and glycerin plus HPMC as
`in Tears Naturale Forte (Alcon) or Advanced Eye Relief Dry Eye (Bausch & Lomb).
`◾ Oil-based emulsion products, such as Refresh Endura (Allergan), which contains castor oil, and Soothe
`(Bausch & Lomb), which uses mineral oil as a primary ingredient.
`◾ Polyethylene glycol (PEG) and propylene glycol (PG) products, such as Systane (Alcon) and Systane
`ULTRA lubricant eye drops (Alcon).
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`A recent addition, Systane ULTRA, spreads evenly over the cornea, has prolonged retention time and shows
`objective and subjective improvement in patient signs and symptoms. The drop was formulated to balance
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`viscosity and elasticity. The reason: Normally, increased viscosity means increased blur, while decreased
`elasticity means decreased corneal retention time. This drop contains what its manufacturer describes as an
`“intelligent delivery system.” The interactions of active and inactive ingredients follow an “intelligent” biochemical
`design in which each action leads to another, eventually rebuilding the tear film and the underlying epithelial cells.
`Systane ULTRA contains PG and PEG as active demulcents, polyquad as its preservative and a pH stabilizer to
`get the pH to 7.9. Sorbitol was added to create a loosely held cross-linking to the HP Guar and effectively
`inactivate some of the borate cross-links, which normally bind to the HP Guar, thus increasing viscosity. On the
`eye, sorbitol dissipates very quickly, optimizing viscosity. None of my patients have reported blur, however. The
`borate cross-links with the HP Guar to begin rebuilding the tear film. These interactions in the presence of the
`PEG and PG effect the elasticity change that occurs and rebuilds the tear layer.
`
`New Beginnings for Old Treatment
`There are several emerging strategies for dry eye treatment to look forward to in
`the future, such as natural hormonal controls, secretagogues, mucomimetics, anti-
`evaporatives, new anti-inflammatories and other improved polymers for use with
`dry eye patients.
`An older dry eye treatment, autologous serum therapy, is finding a new beginning.
`This procedure utilizes autologous platelet concentrate mixed with calcium chloride
`and thrombin for gelling to be applied to the corneal surface. A venous blood
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`draw is performed and centrifuging techniques are used to obtain adequate serum
`volume. The residual concentrate can be mixed with lubricating eye drops to gel at
`a 25% concentrate to be used for adjunct therapy. The gelling seems to prolong
`the effect of numerous growth factors and other essential components and
`enhances epithelial surface proliferation and differentiation during the healing
`phase.
`This technique was first used successfully in 1984 for keratoconjunctivitis sicca
`(KCS) in a 50/50 mixture of autologous serum with preservative-free sterile
`saline. Other researchers have experimented using 20% autologous serum drops
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`to treat neurotrophic keratitis, recurrent erosion, KCS, Sjögren’s syndrome,
`superior limbic keratoconjunctivitis and ocular surface reconstruction surgery.
`Future studies will examine the possibility of using platelet gelling on multiple
`occasions in home settings instead of hospital settings as it is currently done.
`Lastly, researchers believe that the optimal serum drop concentration has not yet
`been found and future work needs to be done on this dilemma as well. One
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`caveat: This procedure should be avoided in host-graft disease patients.
`
`Other Regimens
`While inflammation has become a primary concern, not all dry eye is inflammatory. At times, we may need a
`13
`treatment regimen that combines more than one product in to stabilize the tear film. Products such as Restasis
`(cyclosporine, Allergan) and anti-inflammatories such as Lotemax or Alrex (loteprednol etabonate 0.5% and 0.2%,
`respectively, Bausch & Lomb) may be used alone or in combination along with lubricating drops, gels or ointments
`for more aggressive therapy.
`Punctal occlusion is another option. The rationale is that, if done properly, “normal tears” can adequately lubricate
`the ocular surface. This is accomplished by plugging the tear ducts (sometimes two puncta or all four in more
`severe cases). The types of plugs used depends on the preference and comfort level of the doctor; there is no
`right or wrong approach; it just depends on your comfort level. One advantage to using short-term plugs: their
`ability to dissolve quickly, especially if epiphora results.
`These various measures may be used in concert with one another or alone, depending on what you want to
`accomplish with a given patient.
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`Dry eye treatment also may involve nutritional supplementation. The American diet generally is lacking in foods
`containing omega-3 essential fatty acids, which are present in such foods as salmon, cold-water fish, flaxseed,
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`leafy green vegetables and certain beans. Without enough omega-3, tear production may be reduced, the
`balance of the proper nutrients in the tear layer may be compromised, and there is an increase in meibomitis.
`According to William Townsend, O.D., of Canyon, Texas, the key ingredients to look for should an omega-3
`supplement be necessary are at least 200mg of docosohexanoic acid (DHA) and 300mg of eicosopentanoic acid
`(EPA), two nutrients found in fish and flaxseed oils. Do be aware, however, that omega-3s can decrease blood
`22
`pressure, increase clotting time, or cause diarrhea or loose stools, and some fish contain excess mercury. Take
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`heed of this caution in certain patients.
`
`Conclusion
`It has been said that we are in the “golden age” of dry eye management. If this is so, embarking upon a sub-
`specialty in dry eye will be tremendously beneficial to your patients and to your practice. Study all that you can
`about this multifactorial disease process and become a true “expert” in the diagnosis and treatment of dry eye and
`ocular surface disease.
`Dr. Schachet is in private practice in Englewood, Colo., specializing in dry eye, contact lens care, allergy and
`corneal refractive therapy.
`
`References
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`2. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003
`Aug; 136(2):318-26.
`3. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. CLAO J 1995 Oct;21(4):221-32.
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`14. Farris RL, Stuchell RN, Mandel ID. Tear osmolarity variation in the dry eye. Trans Am Ophthalmol Soc 1986;84:250-68.
`15. Tomlinson A, Khanal S, Ramaesh K, et al. Tear film osmolarity: determination of a referent for dry eye diagnosis. Invest Ophthalmol
`Vis Sci 2006 Oct;47(10):4309-15.
`16. Duncan G, Collision DJ. Role of the non-neuronal cholinergic system in the eye: a review. Life Sci 2003 Mar 28;72(18-19):2013-9.
`17. Sullivan DA, Krenzer KL, Sullivan BD, et al. Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear
`deficiency? Invest Ophthalmol Vis Sci 1999 May;40(6):1261-5.
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`19. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006
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`20. Roberts CW, Carniglia PE, Brazzo BG. Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of
`dry eye. Cornea 2007 Aug;26(7): 805-9.
`21. Linus Pauling Institute. Micronutrient Information Center. Essential fatty acids. Available at:
`http://lpi.oregonstate.edu/infocenter/othernuts/omega3fa/ (Accessed October 7 2008).
`22. Townsend W. Personal communication.
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`23. Koffler BH. Autologous serum therapy of the ocular surface with novel delivery by platelet concentrate gel. Ocul Surf 2006 Oct;4(4):
`188-95.
`24. Fox RI, Chan R, Michelson JB, et al. Beneficial effect of artificial tears made with autologous serum in patients with
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`
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