As a molecular biologist, I find simplifying complex concepts to be an interesting task. We’re all familiar with the International Dry Eye Workshop (DEWS) Report,¹ which splits the major etiological causes of dry eye into aqueous-deficient dry eye and evaporative dry eye. In my opinion, however, the most important mechanism is the chronic cycle of inflammation, illustrated by the solid red arrows in Figure 1. Inflammation begets inflammation in a vicious cycle. It drives aqueous deficiency and evaporative dry eye, and then cycles back around. As this process continues, the ocular surface suffers.

Dry Eye Disease (DED) results from an aberrant activation of our native immunologic defenses.¹ The human immune system is in a constant state of checks and balances, with one foot on the brake and one on the gas in a normal, healthy state. Loss of immunoregulatory control fuels the cycle of chronic inflammation. Figure 2 is a summary of peer-reviewed literature that illustrates what is happening on a molecular level. I think of ocular surface disease (OSD) immunopathophysiology as a novel with 20 chapters with several notable parts. The process involves an initial aberrant activation phase (release of acute phase cytokines) and an early amplification phase (early MMP-9 activity and Dendritic cell activation). This is followed by a T-cell differentiation and recruitment phase (a naive T-cell becomes an activated T-cell), a T-cell response phase with four parts: (1) adhesion, (2) migration, (3) activation and cytokine release, (4) and a chronic, self-perpetuating damage phase that trips the cycle of aberrant activation all over again in a chronic, downward spiral. The pharmacologic strategies we employ to combat this saga have specific targets and impacts.

Figure 3 visually represents the mechanisms of action of Restasis (cyclosporine, Allergan) and Xiidra (lifitegrast, Shire), as well as HydroEye (ScienceBased Health), based on peer-reviewed literature. The gamma linolenic acid (GLA) in HydroEye has some interesting immunopathophysiologic calming effects. In addition to promoting the development of anti-inflammatory prostaglandins and leukotrienes² when given in proper ratio with DHA and EPA,³ GLA can also calm dendritic cell activation³ as well as directly stimulate tear production from the lacrimal gland via activity on the beta-adrenergic receptor.⁴

Despite the fascinating complexities of dry eye disease immunopathophysiology, it is possible for treating physicians to employ the KISS principle — keep it super simple — to bring relief to patients.

K is for Keratitis

If you are just beginning to treat dry eye, all you need is a Bio-Glo strip (Accutome), with one drop of liquid 1% lissamine green (compounding pharmacies) on one side and a squirt of preservative-free sterile saline on the other side of the strip. Allow the excess to drip off the end of the strip. Turn the strip vertically and gently tap the posterior aspect of each lower lid margin. This technique prevents flooding of dye and masking of findings while efficiently identifying the OSD staining pattern of the conjunctiva (lissamine green staining viewed shortly after instillation under white slit lamp light) and the cornea (superficial punctate keratitis viewed with fluorescein under blue slit lamp light properly viewed starting 90-120 seconds after instillation), just as your careful external exam and optic nerve exam is being completed. Fluress (Akorn), used in checking IOP with a Goldman tonometer, is not enough fluorescein to see the staining pattern. In a short period of time, the stains provide a great deal of information about the ocular surface. Tear break-up time measures tear stability with fluorescein under blue light as the interval of time between a complete blink and the appearance of the first black area. An incomplete tear, wet and spread across the cornea, suggests a significant loss of mucin, produced by goblet cells. This finding pushes me to reach for goblet cell density-improving therapeutics as well as benzalkonium chloride (BAK)-minimizing strategies.

I is for Image and Illuminate

A picture is worth a thousand words, and that saying is also true in our specialty. I appreciate the power of a slit lamp camera with a photo management system, because in real time, I can capture and share a communication-enhancing image with the patient. The meibography feature of the LipiView ocular surface interferometer imaging technology (TearScience) helps us efficiently demonstrate the anatomic impacts of meibomian gland dysfunction (MGD). Patients quickly grasp the magnitude of their gland compromise when shown a photo of normal meibomian glands compared with their own.

As vision starts with the tear film (the first refractive interface), OSD is a vision-impacting disease. When the tear film is disrupted, quality of vision is affected, which not only creates problems for patients, but also wreaks havoc on your refractive surgical practice and premium IOL practice. Wavefront analysis is a fast and easy method to judge the visual impact of the ocular surface. In the presence of dry eye disease, higher-order aberrations increase in between blinks (Figure 4). I’ve found that sharing these images helps patients feel heard in their complaints, builds the doctor-patient relationship, and helps the patient to understand the relationship between DED and their visual fluctuations.

A fast and simple tool to illuminate ocular structures is your trusty muscle light. With the patient at the slit lamp, turn off the room light and slit lamp light, position the muscle light at the lash base of the lower lid, and use the light to gently evert the lid and transilluminate the meibomian glands. You’ll be amazed at how much MGD you have missed compared with just using your slit lamp.

You can also efficiently use your muscle light to reveal an incomplete lid seal. To look for this common finding, which contributes to symptoms of irritation upon awakening, have the patient close his eyes and relax his face, then place the muscle light gently at the superior tarsus, aimed inferiorly at the interpalpebral fissure. If light leaks “under the door” at the interpalpebral fissue, that is an inefficient lid seal and a $50 nighttime silicone mask (Eyeseals, Eye Eco) is an easy KISS fix to this common component of OSD.

S is for Salt and Swamp

Patients with OSD often have hyperosmolar tears (“salt”) as well as dirty tears (“swamp”) full of inflammatory mediators as discussed above. How do we assess the salt load?

The TearLab Osmolarity test is a rapid point-of-care test that quickly provides a snapshot of how healthy or unhealthy the tear film is. It enables me to understand the high-symptoms/low-findings patient (often times, these patients are hyperosmolar and the surface damage will come later as the disease progresses).

Osmolarity testing also helps me to track a patient’s response to therapeutics over time. Because osmolarity improvements can precede symptom improvements, the physiologic normalization of osmolarity at follow-up visits is a great way to encourage patients to stay the therapeutic course. What’s more, tear osmolarity has been found to have a significant impact on preoperative planning and implications for surgical outcomes.⁵

InflammaDry (RPS) is another valuable diagnostic test, as it detects MMP-9, an inflammatory marker that is consistently elevated in the tears of patients with dry eye disease.⁶ MMP-9 also increases with increasing disease activity.

The osmolarity and inflammatory load testing tools help determine the quality of the tear film and guide treatment. Our therapeutic mindset is to achieve physiologic restoration with a healthy, free-flowing lacrimal functional unit. Late Stage 3 or Stage 4 DED patients aside, inserting punctal plugs before the inflammatory load is under control may make the patient feel better, but there is goblet cell recovery to consider. Plug insertion performed before tear clean up is achieved (a negative MMP-9) results in a poor quality, inflammatory-mediator-laden tear film being trapped on the ocular surface. The short hand way of describing the physiologic restoration philosophy is “drugs before plugs.”

S is for Select and Simplify

We have a full battery of treatment options to help us control the inflammatory load associated with OSD. Restasis and Xiidra are proven effective therapies. Steroids certainly have a role for induction and acute exacerbations, although it will be interesting to see if the steroid-like effect of Xiidra will obviate the need for steroids for pulse dosing and, thus, eliminate the risks associated with steroids, such as cataractogenesis.

Also, take care to choose a nutritional supplement that has scientific data to support its use,^2-4 such as HydroEye.

Restoring the lacrimal functional unit is a philosophical mindset. When I see a compromised ocular surface, my goals and interventions are aimed at restoring the entire homeostasis-maintaining system that Mother Nature designed.

S is for Supply and Support

Your patients will appreciate easy access to the therapies you are recommending, whether you stock them in your office or make them available through an online portal. This also helps prevent patients from wasting money on the wrong products.

Consider giving each patient a starter kit with coupons and information sheets. Also, be sure to direct your patients to reputable online resources. MyDryEyes.com , sjogrens.org , NotADryEye.org , and nei.nih.gov/health/dryeye are great examples. Spend some time yourself on these reputable sites to further your understanding of the significant impacts OSD can have on quality of life. Steer your patients away from blogs — the misinformation prevalent on the Internet is shocking.

S is for Screen and Substitute

Part of your dry eye workup will include gathering a careful and complete list of their current and past medications, some of which may exacerbate their OSD. You can find the chart in the March 2015 issue of Ophthalmology Management (Figure 5).⁷

You can train your technician to screen the patient’s medication list and cross-reference the drugs to this dry eye disease-exacerbating medication list, and then suggest less drying alternatives within the same class. Within classes of drugs, the highest exacerbators are listed first, and less OSD-offensive drugs are listed lower in each section. For example, diuretics negatively affect the lacrimal gland, and beta-blockers negatively affect the lacrimal gland, goblet cells, and meibomian glands. Asking a patient to check in with his primary care physician (PCP) and discuss possibly switching to a calcium channel blocker or an angiotensin-converting enzyme inhibitor can make a difference in the functionality of the lacrimal functional unit. Clinically, I have found the over-the-counter and prescription systemic medication list and substitutions made with the PCP to be a helpful adjunct in helping the OSD patient.

In Summary

OSD is a complicated disease, but it doesn’t have to be complicated to manage. My advice to anyone still sitting on the sidelines is to dive in and get started with staining. Add on diagnostics as you can. You don’t have to make an overwhelming investment; just start somewhere, and your dry eye practice will grow naturally and evolve. I hope you find your OSD management journey to be as enjoyable and rewarding as I have. ■

References

1. 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;5:75-92.
2. Kapoor R et al. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006;6:531-534.
3. Sheppard JD, Pflugfelder SC, et al. Long-term supplementation with n-6 and n-3 PUFAs improves moderate-to-severe Keratoconjunctivitis Sicca: A randomized double-blind clinical trial. Cornea. 2013;32:1297-1304.
4. Pholpramool C. and Tangkrisanavinont V. Evidence for the requirement of sympathetic activity in the PGE1-induced lacrimal secretion in rabbits. Arch Int Pharmacodyn Ther. 1983 Sep;265(1):128-137.
5. Epitropoulos AT, Matossian C, Berdy GJ, Malhotra RP, Potvin R. Effect of tear osmolarity on repeatability of keratometry for cataract surgery planning. J Cataract Refract Surg. 2015;41:1672-1677.
6. Chotikavanich S, de Paiva CS, Li de Q, et al. Production and activity of matrix metalloproteinase-9 on the ocular surface increase in dysfunctional tear syndrome. Invest Ophthalmol Vis Sci. 2009;50:3203-3209.
7. Periman L. Safeguarding the cornea: Clues to DTS may lurk on meds list. Ophthalmology Management. 2015;19:36-39.