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“What is dry eye?” The question is deceptively simple, but the answer is not straightforward. And because dry eye disease (DED) is hard to define, it is difficult to diagnose. Because the signs and symptoms of DED are also found in other ocular conditions, there is no pathognomonic set of diagnostic criteria. Advanced diagnostics are helpful in characterizing certain markers of DED, but none is specific enough to be useful on its own. Instead, the diagnosis of DED is based largely on clinical impression, supported by the weight of evidence from testing.
As a working definition, the consensus offered by the 2007 Dry Eye Workshop report offers a good starting point: “Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”1
Seven years later, a panel of DED experts gathered to update the record in light of emerging information.2 This publication affirmed that “DED is an ocular surface disorder with a complicated and multifactorial etiology,” and that “In addition to the contributing factors of aqueous tear deficiency and excessive evaporation, inflammation is a principal factor contributing to disease pathology and associated tissue damage.”
The common themes in these two publications—that DED is multifactorial and that it is an inflammatory entity—are important to recognize. Understanding these two features may provide a practical road map for how to deal with DED patients in the clinic.
A MULTIFACTORIAL DISEASE
The classic approach in a patient with a complaint of dry eyes is to try to discern whether the clinical entity in that particular patient is lipid-deficient, aqueous-deficient, or mucin-deficient DED. This approach, however, may be too simplistic, as every component of the natural tear plays a significant part in maintaining the homeostasis of the tear film. Any condition that affects any one of the components of the natural tear will influence the entire ocular environment.
The human tear film is made up of many components: water, mucin, lipids, lysozyme, lactoferrin, lipocalin, lacritin, immunoglobulins, glucose, urea, sodium, and potassium. Each element plays an important role, and when there is imbalance in the tear’s composition, compensatory mechanisms that lead to DED are initiated. Specifically, a change in the concentration of any of the ingredients causes a change in the molarity of the human tear, and the resulting irregular osmolarity can be a trigger for inflammation.
One problem in diagnosing DED is that different causes and triggers can affect different elements of the tear. Signs and symptoms alone are insufficient to explain a given case. For instance, hyperemia could be secondary to an infection that could be caused by bacterial, viral, or fungal insult. Or it may be a sign of DED caused by environmental exposure. Or it may be DED due to lipid deficiency or another cause.
The potential influence of allergies, meibomian gland dysfunction (MGD), lid conditions such as blepharitis, and Demodex infestation must also be accounted for, either as triggers for symptoms or as causes of DED in their own right. For example, an inadequate quantity of meibum due to MGD can lead to excessive tear evaporation; the resulting change in osmolarity can lead to saponification. But these soap-like deposits can also be caused by bacterial infiltration or can be related to rosacea. Thus, MGD itself can cause burning, irritation, and fluctuation of vision, and DED; but the symptoms that are associated with MGD can also be caused by a variety of other entities.
The multifactorial nature of DED means the clinician must look for clues that demonstrate what is affecting the health of the ocular surface and how severely that clinical entity is affecting the patient. But this does not necessarily have to be a needle-in-a-haystack exercise. One of the often-overlooked symptoms of DED is its impact on vision. It may be helpful to think of the tear film as a lens, because it is a refracting surface. When the tear film is disrupted in DED, the resulting abnormal tear lens negatively affects refractive quality.
This phenomenon may explain why complaints of sudden changes in quality of vision are so common in those with DED, and why DED patients may present to the clinic complaining that their prescription is no longer working. Patients who report sudden difficulty with nighttime driving or other indices of recent loss of quality of vision should be reviewed for potential DED. Their perceived loss of vision quality may be due to their prescription, corneal edema, or something more nefarious, but it should not be forgotten that the tear film represents an important factor in quality of vision.
AN INFLAMMATORY ENTITY
Although DED has many causes, the end result of all those influences is an inflammatory condition that includes activation of T cells and natural killer cells that drive inflammation, deregulation of regulatory cells, and activation of antigen-presenting cells and toll-like receptors.2 This complex inflammatory chemical cascade may be exacerbated by a variety of factors, including, but not limited to, contact lens wear, autoimmune disease, MGD, female sex, a dry environment, and use of over-the-counter medications.3-14
Fortunately, if we look at DED as a disease with inflammation at its heart, then treating it becomes vastly simplified. That is, the treatment goal for DED, regardless of its cause, should be to reduce inflammation. Secondarily, when I consider a treatment plan for a patient with DED, I also want to encourage increased production of tears.
Cyclosporine ophthalmic emulsion 0.05% (Restasis; Allergan) is an important mainstay of antiinflammatory treatment. This agent counteracts the inflammation that is present in DED of all types and levels and helps to increase tear production.1 Lifitegrast ophthalmic solution 5% (Xiidra; Shire) is a more recently introduced treatment option that addresses the signs and symptoms of DED. As this is a relatively new agent, there is not a lot of clinical experience, so we do not yet know where it should fit in the treatment paradigm. Clinical trial results suggest that it inhibits T cells that promote inflammation in some forms of DED.15 One of the unanswered questions I have with this medication is how relevant it will be for patients with MGD.
Antiinflammatory therapies can be supplemented by efforts to restore the natural homeostatic state of the natural tear. Preferably, the vehicle of the agent I use will help to stabilize the lipid layer so that it covers the potential for MGD.
Artificial tears can be looked at as supplements. Patients with significant MGD would benefit from an emulsion tear. Those with elevated osmolarity would benefit from using a tear that has a lower osmolarity. Those with milder MGD and normal osmolarity might need a tear formulation containing sodium hyaluronate or a less viscous tear supplement throughout the day. Warm compresses and lid scrubs can be added to encourage the glands secrete better, and neutraceuticals containing ingredients such as omega-3 fatty acids can also be useful.
So perhaps the answer to the question “What is dry eye?” is not as complicated as we think.
Yes, DED is multifactorial. On a given day, MGD could be exercising dominance over the condition, versus a reduction in aqueous production on another day. Perhaps the goblet cells are inflamed and are not secreting much mucin. Maybe the patient’s diabetes is inadequately controlled, leading to worsening of symptoms. Environmental stresses, such as computer use or contact lens wear, could decrease the blink rate. Figuring out the source of the DED requires diligence and persistence.
However, if the end result of all these causative processes is inflammation, that means treatment can be directed to quelling the inflammation no matter what the cause or trigger. Secondarily, we can direct efforts to help restore the eye’s ability to produce healthy tears.
With this mindset, the question “What is dry eye?” can be reframed more appropriately: “What can we do to address DED?” n
1. [No authors listed] The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92.
2. Bron AJ, Tomlinson A, Foulks GN, et al. Rethinking dry eye disease: a perspective on clinical implications. Ocul Surf. 2014;12(2 suppl):S1-31.
3. Lemp MA, Crews LA, Bron AJ, et al. Distribution of aqueous-deficient and evaporative dry eye in a clinical-based patient cohort: a retrospective study. Cornea. 2012;31(5):472-428.
4. Zhang Y, Chen H, Wu X. Prevalence and risk factors associated with dry eye syndrome among senior high school students in a county of Shandong Province, China. Ophthalmic Epidemiol. 2012;19(4):226-230.
5. Nichols JJ, Sinnott LT. Tear film, contact lens, and patient-related factors associated with contact lens-related dry eye. Invest Ophthalmol Vis Sci. 2006;47(4):1319-1328.
6. Bunya VY, Langelier N, Chen S, et al. Tear osmolarity in Sjögren’s syndrome. Cornea. 2013;32(7):922-927.
7. Gilbard JP, Farris RL. Ocular surface drying and tear film osmolarity in thyroid eye disease. Acta Ophthalmol (Copenh). 1983;61(1):108-116.
8. Iskeleli G, Karakoc Y, Abdula A. Tear film osmolarity in patients with thyroid ophthalmopathy. Jpn J Ophthalmol. 2008;52(4):323-326.
9. Fraunfelder FT, Sciubba JJ, Mathers WD. The role of medications in causing dry eye. J Ophthalmol. 2012;2012:285851.
10. Guillon M, Maissa C. Dry eye symptomatology of soft contact lens wearers and nonwearers. Optom Vis Sci. 2005;82(9):829-834.
11. Khanal S, Tomlinson A. Tear physiology in dry eye associated with chronic GVHD. Bone Marrow Transplant. 2012;47(1):115-119.
12. Akpek EK, Klimava A, Thorne JE, et al. Evaluation of patients with dry eye for presence of underlying Sjogren syndrome. Cornea. 2009;28(5):493-497.
13. Abusharha AA, Pearce EI. The effect of low humidity on the human tear film. Cornea. 2013;32(4):429-434.
14. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136(2):318-326.
15. Tauber J, Karpecki P, Latkany R, et al; OPUS-2 Investigators. Lifitegrast ophthalmic solution 5.0% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study. Ophthalmology. 2015;122(12):2423-2431.
Marc Bloomenstein, OD, FAAO
• Director of optometric services at the Schwartz Laser Eye Center in Scottsdale, Arizona.
• (919) 660-5071;
• Financial interest: a consultant to and member of the speakers’ bureau for Alcon, Allergan, Ista Pharmaceuticals, and Bausch + Lomb