Article Date: 5/1/2003

dry eye
Welcoming New Tools in the Fight Against
Learn about the newest entrants into the dry eye management market, including how they work.
BY DEEPAK GUPTA, O.D., Stamford, Conn.

 One of the most common complaints we hear in the office pertains to dry eye syndrome. Until research in this area progresses far enough to propel us to change management strategies, lubricating drops, ointments and punctal plugs are our current mainstays of therapy.

Because recent months have unveiled several new products to help us manage dry eye syndrome, I'll devote this article to updating you on them. But first, let's review our means of diagnosing this condition.

Getting to know your patient

As with any disease, proper management begins with proper diagnosis. For the purposes of this article, proper diagnosis starts by taking a thorough history to identify risk factors for dry eyes. Along with a patient's complaints associated with dry eyes, you should ask her if she works in a dry environment or one that uses heating and air conditioning units. Also find out how much time she spends at a computer.

Ask your patient if she's taking any systemic medications, such as antihistamines, antidepressants, antipsychotics, hormone replacement therapy and oral contraceptives because these types of medications all contribute to ocular dryness. Keep in mind that contact lens wear has been shown to decrease corneal sensation and to disrupt the mucin layer of tear film, thereby contributing to dry eyes.

In addition to patient-report-ed symptoms for a dry eye diagnosis, you can choose from many tests to assess her tear function.

Testing tear function

The most commonly used tests in the clinical setting include the Schirmer test, phenol red thread test, fluorescein, rose bengal staining, tear break-up time (TBUT) and tear meniscus height measures. The major problem with most of these is that they lack repeatability. In addition, studies generally show a lack of association between test signs and patient-reported symptoms.

Other tests, which are laboratory based, provide more precise measures of dryness but most are limited clinically by either cost or by difficulty in use. Therefore I'll only discuss them briefly.

► Advanced Instruments, Inc. produces three models of advanced osmometers (3900, 3300 and 3D3) that use freezing point depression osmometry to calculate tear film osmolarity. All three models are fairly accurate and are reportedly quite sensitive to dry eyes.

► The Touch Tear Lactoferrin MicroAssay by Touch Scientific, Inc., is a commercially available instrument that measures tear lactoferrin concentration. Lactoferrin is an iron-binding protein produced by the lacrimal gland in the aqueous tears. Measuring its concentration is an indirect way of measuring tear volume.

► Fluorophotometry was originally developed to measure leakage of fluorescein into the retina, but we can also use it to manage dry eye. The Fluorotron Master by Ocumetrics, Inc. has been used to assess corneal pH, epithelial permeability, endothelial permeability and tear turnover.

Regardless of diagnostic techniques, once you've made your definitive diagnosis of dry eye syndrome, the next step is to categorize the patient's symptoms.

Mild, moderate or severe?

Your treatment plan will vary depending on whether your patient's symptoms are mild, moderate or severe. Here's an easy way to classify symptom severity:

Mild. This is the patient for whom you would recommend artificial tears to lubricate the compromised ocular surface. The number of over-the-counter (OTC) products available is staggering. While many of them are functionally the same, keep in mind that many dry eye patients will instill the artificial tears several times a day.

Also keep in mind that many patients run into problems with preservative sensitivity and corneal toxicity. Theoretically, you can recommend non-preserved tears, although they usually come in single-use plastic vials that are inconvenient. The more practical solution is the use of lubricant formulations with "disappearing" preservatives such as GenTeal and Refresh Tears, which serve the same function as preservative-free formulations, but are much easier to carry in a bag or purse.

The other product that's nice for mild dry eye patients is TheraTears, which is specially formulated to correct and balance the hyperosmolarity of the tear film. Along with lubricating the ocular surface, TheraTears helps normalize the electrolyte balance in the tear film.

The biggest advantage to the use of artificial tears is that they're available OTC and provide immediate relief for many patients. One drawback is that frequent instillation is necessary for relief, which may result in poor compliance. Plus, artificial tears don't address any inflammation already in progress, and may further dilute an already compromised lipid layer. Fortunately, in most cases of mild dry eyes, this isn't a major concern.

Moderate. In more difficult cases of dry eye, you can keep a patient on lubricating drops during the day and add gels and ointments at bedtime. These supplements last longer, but may periodically blur a patient's vision, which is why q.h.s. dosing is usually the best option. For longer-term lubrication, newer carbomer gels such as GenTeal and Tears Again cause less of a disruption in vision than ointments, and they leave less residue in the eye the morning after.

In cases that are not responsive to these two products, you can prescribe the overnight use of mineral oil- or lanolin-based products such as Refresh PM. Be warned, however, that if your dry eye patient has accompanying meibomian gland dysfunction (which many of them do), then the use of thick gels and ointments may exacerbate an already oily tear layer and lid margin.

Severe. Many severe dry eye patients demonstrate mild to moderate inflammation of the anterior segment. Topical steroids can combat this inflammation but are undesirable as a long-term treatment because of problems such as the increased risk of ocular infection and elevated IOP.

Some of the milder steroids are really nice to use in this situation. Both loteprednol etabonate 0.2% (Alrex) and loteprednol etabonate 0.5% (Lotemax) do an excellent job at decreasing inflammation but are far less likely to cause IOP increases.

In addition, they have a much better safety profile than the stronger steroids. In most cases, you should prescribe a steroid only as short-term management. Once the inflammatory process is under control, you should taper steroid use and initiate a long-term management program.

Keep in touch with patients

Regardless of severity, you should always see your dry eye patient back for a follow up to make sure that the condition is under control. Such a visit will allow you to make further recommendations if the situation hasn't resolved, and will underscore the importance of thinking of dry eye syndrome as a legitimate medical condition.

If your artificial tear therapy failed to relieve your patient's symptoms, then consider punctal occlusion. Now that we've gone over how to diagnose dry eye, let's take see we now have available to us for treating the condition.

Occluding severe dry eyes

Typically you'll start out by inserting temporary collagen plugs in the lower puncta of both eyes and scheduling the patient for a follow-up visit in 10 to 14 days.

Many patients won't need lubricating drops at all after the procedure, while others will notice a decreased dependency on them. Either way, have the patient keep track of his symptoms because the collagen plugs self dissolve in three to seven days. If the collagen plugs worked, then insert silicone plugs for long-term management.

Most insurance policies have a 10-day post-op period with punctal occlusion, so you should wait until that before inserting the silicone plugs. In some instances, permanent plugs may recurrently dislodge even with a proper fit. If this happens, your patient might benefit from punctual cautery.

Getting acquainted

Now that we've established an organized and systematic approach to managing dry eye, let's find out about the newest drugs on the market.

Restasis. After years of anticipation, Allergan received FDA approval in late 2002 for Restasis (cyclosporine ophthalmic emulsion, 0.05%). After an initial unsuccessful trial, Restasis demonstrated statistically and clinically significant relevant increases in Schirmer wetting at six months. The trials also showed a dramatic improvement in conjunctival Rose Bengal staining and corneal superficial punctate keratitis (SPK).

From a clinical standpoint, Restasis has also shown improvement in patient's subjective measurement of dry eyes. The drug is indicated in patients with keratoconjunctivitis sicca caused by ocular inflammation.

Research shows that Restasis may reduce the cell-mediated inflammatory responses of ocular surface disease, specifically in the activation of T lymphocytes. Thus, the drug reduces the inflammatory response and allow those cells to recover their normal activity.

The most common side effects in the trials were ocular burning (~17% of patients) and conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging and blurring of vision (1% to 5%). I think this drug will fit in for the moderate to severe dry eye patient who isn't doing well with drops and ointments.

One of the biggest drawbacks of Restasis is that it make take up to six months for it to take full effect, although some improvement may be seen as early as one month. Another problem with its use is that Restasis works best in patients who have an inflammation of the lacrimal gland, which is usually not detectable in the usual clinical setting. Instead, we must make the assumption of this inflammation in severe cases of dry eyes.

Refresh Endura. Allergan recently marketed a new artificial tear drop, Refresh Endura, which was initially the vehicle used in the Restasis clinical trials. This oil-based emulsion consists of a low electrolyte formulation that interacts with the tear in a way that causes the emulsion to break down and release the oil. Once released, the oil can then migrate and supplement the lipid layer in the tears. The emulsion has shown to increase tear break-up time (TBUT) and improve patient symptoms.

Once again, this should serve as a nice weapon in our arsenal for moderate to severe dry eyes.

Systane. A new lubricant drop called Systane, by Alcon Laboratories, develops into a gel-like covering that offers a prolonged dwell time. As a drop of the product is dispensed from the bottle, the pH changes from 7.0 to the physiological pH of about 7.4. The higher pH causes the borate ions present in the formulation to thicken into a soft gel, which spreads quickly over the entire ocular surface where it can continue to lubricate during the normal blinking process and retard dessication of the tear film.

Unlike conventional tear substitutes that wash quickly from the ocular surface, the polymerized membrane persists and acts like a bandage, promoting epithelial repair in the underlying healthy environment. I see it's clinical use in the same category as Genteal (Novartis). Exactly how much it blurs vision will determine the extent to which it will be used in dry eye management.

Future research

In addition to the newly released products, many products being researched can help us combat the symptoms of dry eyes. One homeopathic treatment gaining recognition is flaxseed oil. One tablespoon in the patient's juice of choice in the morning may provide some relief for dry eyes associated with a rapid TBUT. This mixture appears to reduce T cell lymphocyte proliferation. One problem that might limit its widespread clinical use is the side effect of transient facial acne.

Inspire Pharmaceuticals, Inc. has initiated the Phase III clinical program for INS365 Ophthalmic for the treatment of dry eye. INS365 is a small-molecule drug that stimulates the P2Y (2) receptor, a key mediator of mucosal-surface hydration and lubrication. The company expects this new product to enhance the eye's natural cleansing and protective systems by stimulating the release of salt, water, mucus and other natural tear components, which should increase hydration and lubrication of the ocular surface and decrease patient complaints.

A recent study also showed that INS365 may promote corneal integrity by inducing production of a mucin-like glucoprotein in the dry eye rabbit model. Responses from the FDA are expected within the next year. If the responses are positive, then the medication may be available in late 2003 or early 2004.

Based on the large body of evidence of the positive influence of androgens on the lacrimal gland-ocular surface unit, Allergan is investigating the use of topical testosterone eye drops in managing dry eye. These studies are now in Phase II FDA trials.

Also under investigation are two new tear augmentation agents. The first of these is trehalose, which may prevent or slow the rate of epithelial cell death by drying. Also being investigated is sodium hyaluronate, which has been shown to offer objective and subjective improvement in patients who have dry eye syndrome.

Striving to provide relief

By managing dry eye syndrome as a legitimate medical condition and by using these new products, we should be able to tailor a patient's medical regimen to his needs and hopefully provide him with relief. Try these new products and keep your eyes out for newer ones.

References available on request.

Dr. Gupta practices full-scope primary care optometry. He has no financial interests in any of the companies or products mentioned in this article. You can reach him at deegup4919@hotmail.com.

 


Optometric Management, Issue: May 2003