One of the great puzzles we face with our dry eye patients is the determination of the exact pathophysiology and the severity of their disease. If we knew that, perhaps we could tailor our treatment more easily to each specific patient.

That's no easy task when you consider the prevalence of patients with dry eye syndrome. The condition affects more than 3.2 million American women middle-aged and older alone.¹ When you consider the number of contact lens wearers, computer users, patients who live and/or work in dry environments, and patients with autoimmune disease, the number is certainly higher.

In addition, dry eye comes in many stripes. J.M. Albietz identified different subtype categories, such as lipid anomaly dry eye, aqueous tear deficiency, primary mucin anomalies, allergic/toxic dry eye, primary epitheliopathies and lid surfacing/ blinking anomalies.²

Although we may not completely cure a patient's dry eye, we can improve or stabilize the patient's condition and reduce their symptoms with appropriate treatment.³ But we cannot rely on a one-size-fits-all approach. Here, we'll look at how to tailor your treatment plan to each individual patient.

Proper Diagnosis

We must do a thorough work-up to determine the pathophysiology before we can decide on a treatment plan. This work-up should consist, in this order, of:

• History. A thorough history is essential, especially when you consider that grading of dry eye tends to correlate more highly with patient symptoms than clinical signs.⁴

One suggestion: Use a questionnaire in which you ask the patient to describe the symptoms, including their severity and frequency. For example, patients with keratoconjunctivitis sicca—both Sjögren's and non-Sjögren's—reported in one study frequent and intense ocular surface symptoms in the evening, some of which correlated moderately with clinical test results.⁵

Include demographic information such as age and gender, and ask about the presence of autoimmune disease and contact lens wear. Also ask about any systemic medications that may result in dryness and prior ocular surgeries. This, too, can help you pinpoint the etiology.

• Schirmer test. Do this before any other tests because once you add drops to the ocular surface, you'll change the results of the Schirmer test. Generally, you'll want to perform this test without anesthetic. The reason: Aqueous tear production decreases after anesthetizing the ocular surface.⁶ (If you're used to using anesthetic for the Schirmer test, you no doubt account for this in determining normal tear flow.) A finding of less than 10mm in 5 minutes is considered diagnostic.

Realize that you may need to do multiple Schirmer's tests without anesthetic. You might have more than 15mm on the first round due to reflex tearing and less than 5mm the second time, because reflex tearing has been minimized by the irritation of the strip no longer being felt.

• Tear break-up time. Less than 15 seconds before break-up is considered significant. About 10-15 seconds would be mild to moderate, and less than 10 would be moderate to severe.

• Fluorescein staining. Assess the degree of ocular surface staining of the cornea and conjunctiva, and the positioning of the staining, to determine whether keratitis is present. Inferior staining suggests probable lid etiology such as lagophthalmos, meibomitis or blepharitis.

• Rose Bengal or lissamine green staining. This second form of staining is essential to determine the degree of dryness of the ocular surface. Patients can usually tolerate lissamine green better than rose Bengal, and lissamine green is equally as effective as rose bengal in evaluating the ocular surface in keratoconjunctivitis sicca.⁷

Give the dye two minutes and allow the patient to blink so that the dye can penetrate those dry cells. Then grade the staining on a scale of 0-3 in each of these areas: nasal conjunctiva, cornea, and temporal conjunctiva. Add up the total score to determine the degree of ocular surface staining out of 9.

• Lid examination. Inspect the lids for the presence of any blepharitis with scaling or lash inflammation. Chronic blepharitis has associated meibomian abnormalities that lead to defects in the tear lipid layer. These, in turn, may result in an unstable tear film that often is associated with evaporative dry eye.⁸

Rose Bengal staining of the bulbar conjunctiva is another way to diagnose dry eye syndrome.

Next, express the meibomian glands and record their viability. For example, you may determine that 80% of the glands are functioning. Also grade the secretions and how easy it is to obtain that secretion. If the secretion is easy to obtain and the appearance is similar to a light, clear baby oil, the patient's system is functioning perfectly. If the fluid is difficult to obtain and has a cloudy appearance that's similar to toothpaste, the meibomian glands are obviously malfunctioning. The glands most likely are harboring bacteria that secrete exotoxins that cause problems on the ocular surface, particularly inferior staining.

Once you've performed these steps, you can determine whether dry eye exists, the degree of dry eye (mild, moderate or severe) and whether meibomian gland dysfunction is present. You might also be able to determine the etiology, such as Sjögren's syndrome or rheumatoid arthritis, or if hormonal factors are at work, as in menopausal women.

A Mild Problem

Now, you're ready to develop your treatment plan. Let's start with the mild to moderate dry eye patient who only experiences symptoms occasionally, such as in the wintertime, when working on a computer or when wearing contact lenses. Chances are these are younger patients who may experience symptoms but few signs.

For these patients, start with your usual workup, making sure there's more than 10mm of tear flow in the eyes and minimal ocular surface staining. In these cases, the cornea is usually spared, and the conjunctiva may have mild or moderate staining that more likely occurs nasally than temporally. These people also are likely to have meibomian gland dysfunction and/or mild blepharitis, so you'll want to prescribe lid scrubs and warm compresses.

Advise these patients to drink plenty of fluids, especially while working in a dry atmosphere or on a computer, and consume water-containing fruits and vegetables as part of their diet. Also encourage them to consume less caffeine and avoid smoking.

Meibomian gland dysfunction is another etiology of dry eye. Note the toothpaste-like appearance of the meibum here.

Then advise these patients to use artificial tears on an as-needed basis. Generally, you'll have the patient instill drops tid-qid. Patients with mild to moderate dry eye often require a milder lubricant such as Refresh Tears (Allergan) or GenTeal (CIBA Vision) with a disappearing preservative rather than a thicker gel. For mild dry eye, I would start with a lower density drop and then move to a gel formulation if needed. For moderate dry eye, I would start with a stronger drop. (See "Not All Tears are Alike," below.)

Follow-up is essential. Have patients with mild to moderate dry eye return in two weeks. This way you can make sure they've complied with the regimen of artificial tears, ensure that the drops are working, and ensure that there are no reactions to the mild preservatives in the agent. If lid disease was present, make sure the lid scrubs and hot soaks have improved the functioning of the meibomian glands.

Punctal Occlusion

Patients who present with severe dry eyes (less than 5mm on Schirmer testing) would likely benefit from punctal occlusion. Punctal occlusion results in improved tear film stability, ocular surface staining scores, conjunctival squamous metaplasia grades and goblet cell density, possibly by increasing ocular surface exposure to essential tear components.⁹ Not only that, but by blocking the outflow system, you allow artificial tears or any other drops you prescribe to remain on the ocular surface.

A few caveats, however: If you determine that the etiology of the patient's condition is inflammatory, such as with Sjögren's, you must treat and reduce the inflammation before punctal occlusion. Otherwise, you would in effect be keeping a cesspool of inflammatory mediators on the surface rather than trying to flush them out.

Also, I generally consider punctal occlusion to be contraindicated in younger patients with Schirmer values higher than 10mm (some practitioners use 15mm), as epiphora would likely result. Also, the cause is likely inflammatory rather than tear deficiency.

Not All Tears Are Alike Just as there is no one-size-fits-all plan for treating dry eye patients, there's no one-tear-fits-all approach either. Different formulations are available depending on the severity of the patient's symptoms. Here are a few new products worth mentioning. • Refresh Endura (Allergan). This castor-oil based drop grew out of the clinical trials for Restasis (cyclosporine, Allergan), an immunomodulator used in severe dry eye. Restasis uses castor oil as the vehicle for delivery of cyclosporine to the ocular surface, and patients in the control group received castor oil alone. The concept behind Refresh Endura was that the extra oil on the ocular surface would prevent evaporation of the underlying aqueous layer of the tear film. This, in turn, would reduce the burning and stinging that results when tear films evaporate on the surface of the eye. So Endura holds promise as a drop that might be especially useful for patients with low lipid layers or very thin lipid layers. • Systane (Alcon). In dry eye disease, the architecture of the epithelial cells breaks down, but this product attempts to re-create that architecture at the level of the epithelial cells at the conjunctiva and the cornea. This, in turn, helps maintain the mucous layer, aqueous layer and lipid layer longer on the surface of the eye. In other words, the product creates an ocular shield to slow tear break-up time and allow the epithelial cells to repair themselves. In clinical trials, Systane demonstrated a 51% reduction in corneal staining from baseline. • TheraTears (Advanced Vision Research). The advantage to this formulation is its extra potassium, which improves tear film osmolarity. We know that in patients with dry eye disease, especially moderate to severe forms, tear film osmolarity increases. This threatens the health of the epithelial cells. When dry eye occurs, it's important to restore the normal osmolarity of the tear film. TheraTears, which comes in a preservative-free unit-dose dropper, has been shown to improve the health of the epithelial cells with frequent use. • Hyaluronic acid. This chemical, which occurs naturally in the human body, is a useful structural tool. Though long-term studies have yet to be done, treatment with sodium hyaluronate appears to accelerate recovery of the damaged cornea.19 Specifically, sodium hyaluronate eye drops increase precorneal tear film stability and corneal wettability, reduce the tear evaporation rate, and the healing time of corneal epithelium.20 Sodium hyaluronate can be found in AQuify contact lens comfort drops (CIBA Vision).—B.C.

If the patient experiences symptoms despite other treatments such as artificial tears, however, I would perform punctal occlusion using removable silicone plugs or acrylic plugs such as the SmartPlug . This way, if the patient develops excessive tearing or eliminates dry eye through a change in lifestyle factors, I can remove the plugs and allow the eye to drain naturally.

For some patients, cauterization of the puncta is the more appropriate alternative. The rule of thumb at my clinic is to choose cauterization for patients with less than 3mm on Schirmer's testing. For example, while patients with Sjögren's syndrome often respond well to punctal occlusion, they also present with extreme dryness and silicone plugs often fall out easily in these particular patients. The reason for this most likely is that the puncta and cannalicula have poor epithelial cell linings and therefore are not moist enough to retain the plugs. 

Anti-Inflammatory Therapy

When other therapies such as lid scrubs, hot soaks, gel-based lubricants and punctal occlusion fail, you may need to move on to therapy to address underlying inflammation. In recent years, research has increasingly focused on underlying inflammation in dry eye disease. We know that dry eye disease is accompanied by an increase in the proinflammatory forms of interleukin-1, and that the conjunctival epithelium appears to be one source of this increased concentration in the tear fluid of patients with dry eye disease.¹⁰

Also, the balance of cytokines in the tear fluid and conjunctival epithelium is altered in patients with Sjögren's syndrome. The severity of keratoconjunctivitis sicca in this condition increases as tear fluid epidermal growth factor concentration decreases, and levels of inflammatory cytokines in the conjunctival epithelium increase.¹¹

Shield Your Dry Eye Patients An additional approach our clinic uses to treat dry eye patients is to fit them with humidity shields. In other words, we take the patient's own glasses and put plastic shields around them so they become similar to goggles, though not as tight fitting. This reduces the amount of wind current that goes in front of the eye when the patient is outdoors, reduces evaporation and increases humidity at eye level. We accompany these shields with discussions about humidifying their homes and offices appropriately, and aiming vents in automobiles away from their face.—B.C.

One immunomodulator specifically approved for dry eye is Restasis (cyclosporine A, Allergan). The mechanism of action is not clearly understood, though it is believed to be related to inhibition of T-cell production. However, this ophthalmic emulsion has been shown to improve tear production which leads to significant improvement in ocular surface integrity which, in turn, resolves dry eye symptoms and returns the surface of the eye to a more normal state.

The FDA initially rejected Restasis because it failed to demonstrate a therapeutic effect. We now know that it takes three to four months to achieve a clinically significant effect, and about six months before it achieves the full therapeutic potential.¹² This is due to the life cycle of T cells (approximately 120 days). Researchers have found that treatment of dry eye syndrome for six months with topical CsA resulted in an increase in goblet cell numbers in patients with and without Sjögren's, and a decrease in epithelial turnover in patients with non-Sjögren's KCS. Reducing ocular surface inflammation might have an effect on the proliferative activity of the epithelium.¹³

One study found a decrease in interleukin-6 levels in the conjunctival epithelium of moderate to severe dry eye patients treated with 0.05% CsA for six months.¹⁴

Less than 10mm on the Schirmer test is considered diagnostic for dry eye.

Severe cases, in which the ocular surface is filled with inflammatory mediators, will likely get results from low-dose steroids, though in most cases this is still an off-label use. Topical corticosteroids have a beneficial effect on the subjective and objective clinical parameters of moderate to severe dry eye patients. These effects were associated with a reduction of inflammation markers of conjunctival epithelial cells.¹⁵

Another study found that topical nonpreserved methylprednisolone is an effective treatment option for patients suffering from severe keratoconjunctivitis sicca who continue to experience bothersome eye irritation despite maximum aqueous enhancement therapies.¹⁶ Still, the researchers caution that careful monitoring is essential in dry eye patients treated with corticosteroids for more than two weeks since steroid-related complications (increased intraocular pressure and cataract formation) were observed after several months of therapy.

Given the chronic nature of this disease and the likelihood of patients developing steroid-related complications with long-term use, topical nonpreserved methylprednisolone therapy appears to be most appropriate for short-term "pulse" treatment of exacerbations of keratoconjunctivitis sicca.¹⁶

Some specialists recommend using a soft steroid such as Alrex (loteprednol 0.2%, Bausch & Lomb) or Lotemax (loteprednol 0.5%, Bausch & Lomb) qid for two weeks, bid for one to two weeks, repeated q4-6 months prn.¹⁵ This might be considered an off-label use, though the labeling on Lotemax states that it is approved for inflammatory responsive conditions on the ocular surface.

Keep in mind that the etiology is often mixed (secretive and evaporative), so various strategies may be needed. For example, the patient may require a soft steroid for 3-4 weeks plus tears and even cyclosporine concomitantly.

Nutrition

Excess dietary fats, salt, cholesterol, alcohol, protein, and sucrose are associated with or suggested as causes of tear dysfunction.¹⁷ But we've also learned how improved nutrition can help prevent dry eye or at least help alleviate symptoms. The essential fatty acid, gamma-linolenic acid (GLA), is useful in Sjögren's syndrome and may help in other dry eye conditions.¹⁸ And omega-3 fatty acids and flaxseed oil may promote healthier tear films.

There are supplements available such as TheraTears Nutrition (Advanced Vision Research) and Hydrate Essential (Cynacon/Ocusoft). Given the lack of research on supplementation, I encourage patient to obtain these and other nutrients from food. I tell them to drink lots of water, eat fruits and vegetables (including leafy green vegetables), and eat salmon at least once a week (though the FDA has issued some warnings on excessive seafood consumption). Patients can also purchase flaxseed meal to add to foods such as breakfast cereals. I also tell patients to consume less caffeine and alcohol and not to smoke.

Dry eye is one of those conditions that we cannot cure, yet we can bring improvement to patient's symptoms and clinical signs. But we cannot use a one-size-fits-all approach. A careful workup to determine the pathophysiology and severity can help you put together an effective treatment plan.

Dr. Caffery is in private practice in Toronto, and works part-time at the Sjögren's Syndrome Clinic at Toronto Western Hospital. She has a master's degree in nutrition and has been involved with many dry eye research teams since 1977.