Dry Eye
Plugs, Drugs and Tears: A Dry Eye Update, Part Two
BY SCOT MORRIS, O.D., F.A.A.O., Centennial, Colo.

In the first part of our dry eye update (Feb. 2002), I discussed the various theories regarding dry eye syndrome (DES). Now we'll discuss newer therapies for treating DES.

ILLUSTRATION BY NICK ROTONDO

Tweaking our treatment

Until recently, artificial tear supplements have been our mainstay treatment for the various forms of DES. As our knowledge about the possible etiologies of dry eye progresses, new therapies such as hormone therapy, prescription oral agents and homeopathic agents that increase tear production have entered the market as a whole body approach to treating DES. Topical hormones, immunomodulating agents, anti-evaporative agents and new advances in surgical transplantation, tear supplements and "tear-enhancing" agents help to complete our "new" treatment regimen.

Tackling lid-related disorders

In treating eyelid-related disorders we often overlook the fact that we can treat incomplete blink/closure throughout the day with many artificial tear supplements. At night, the more viscous lubricants still rank as the most common treatment choice. "Gooey" eyelids in the morning were a detractor of viscous lubricants, but with the development of Genteal Gel and Tears Again gel, we now have an equally effective solution without the detracting side effects.

In more severe cases, patients can use Eagle Vision Moist Eye moisture shields or swim goggles comfortably as moisture chambers. Patients often preferred them over other surgical options.

Weapons to rely on

In treating lipid-based disorders, we have a few options at our disposal. Here are a few:

Lipid emulsifiers. In lipid-based disorders, such as evaporative dry eye related to meibomian gland dysfunction (MGD), hot compresses, lid hygiene and doxycycline or minocycline remain mainstays.

• Using hot compresses for 5 to 10 minutes at least two to three times each day often provides relief by "melting" the inpissated meibomian gland debris, especially when combined with proper lid hygiene.
• One relatively major change in lid hygiene philosophy that's becoming more prevalent is the avoidance of baby shampoo scrubs to treat non-seborrhic evaporative DES. Many patients who have evaporative dry eye also already have inflamed eyelids and meibomian gland orifices, resulting in altered lipid integrity and ultimately lipid deficiency. Detergents alter the tear prism stability by the addition of soaps (which break down lipid) that the tear prism can't clear or dilute properly. This tear prism alteration combined with the mechanical trauma or abrasive "rubbing" will further increase local inflammation.
• Doxycycline or minocycline have also gained popularity as an initial treatment of various lipid disorders because of their ability to down-regulate the inflammatory process as well as to alter many of the chemical processes in lipid production and secretion.

Lipid agonists. Once the meibomian glands have been damaged, we face a larger challenge in replacing or enhancing production of the outer lipid layer. Fortunately, the new liposome technology has recently made its way from Europe to North America.

Patients can spray Tears Again liposome spray (OcuSoft) on the outside of their eyelids. Reportedly, one proposed mechanism of this product is that the liposomes penetrate through the eyelid where they then deposit on the palpebral conjunctival surface. Other proposed mechanisms include the liposome spray that slowly runs externally to the lid margin where the liposomes break on the ocular surface.

Dietary habits. Supplementing the diet with omega-3 essential fatty acids (EFAs) such as 1,000 mg of fish oil has shown to increase the stability and fluidity of the lipid component from the meibomian glands. Not only do EFAs alter the polar characteristics of the lipid, but they've also been shown to help regulate the immune system by inhibiting arachadonic acid. This prevents the conversion of various types of inflammatory leukotrienes and prostaglandins and reduces T-cell lymphocyte proliferation.

Patients may take nutritional supplementation with generic EFAs or pre-formulated preparations such as HydroEyes (Science Based Health) to provide the necessary EFAs.

Hormone adjustments

Though we need to perform further studies, we may eventually treat DES by altering a person's hormonal status. Here's what's going on in this topic:

The study of both topical and oral androgens is underway as a possible alternative to controlling meibomian gland inflammation. The thought is that by down-regulating the immune system, these agents may help to protect the ocular surface and also to stimulate production of meibomian gland secretions by enhancing the expression of certain genes for protein synthesis. Allergan has a topical androgen-based drug in Phase II currently.

Increasing evidence has surfaced that hormone replacement therapy (HRT) may be detrimental to the health of the lacrimal gland by enhancing pro-inflammatory effects. A recent Harvard study found that women using a combination therapy (estrogen + progesterone) had a 27% higher chance of having DES than women not on HRT. More interestingly, women on estrogen alone had an almost 70% higher chance of developing DES than women who did not use HRT.

Treating deficiencies

When treating aqueous deficient dry eye we need to decrease the mechanical trauma of the eyelids, wash out environmental toxins, increase tear volume, increase corneal wetting, maintain homeostasis and provide a barrier to environmental elements. It's important to keep these goals in mind as we determine the proper therapy for dealing with the aqueous and aqueous-mucin component of the tear film.

The following section will review some of the prescription and commercial products available.

Artificial tears. In many instances, aqueous deficient dry eye results from a decrease in the normal production or secretion of the aqueous component of the tear film. Most tear supplements are isotonic or hypotonic and combine various electrolytes, viscous agents and surfactants to improve cell health, increase tear film break-up time, tear stability and mimic the normal human tear.

Probably the most notable addition to artificial tear supplements is the use of "disappearing preservatives" such as sodium perborate and purite, which break down on the ocular surface and provide a safer alternative for patients who need frequent dosing but want comfort and ease of use.

For severe dry eyes we still have the mainstay ointments such as Hypotears, Moisture Eyes, Refresh PM, Tears Naturale PM and Lacri-Lube, but more recently we've seen gel formulations such as Genteal gel and Tears Again gel, which are becoming more common replacements for the ointments because of their reduced side effects and similar efficacy.

There is a fine balance between increased viscosity, which may decrease tear clearance, and actual retention time on the ocular surface. While many of the artificial tear supplements attempt to increase the hydration level of the cornea, we're beginning to see the addition of viscous agents to duplicate the mucin component as well. Allergan's tear supplement, Refresh Endura, contains an agent that's an emulsion of water in oil and is reported to increase the levels of the aqueous mucin and lipid layer.

Though these synthetic polymers can't replicate the function of the true mucin glycoproteins, they may help to increase tear film spread, lubricate the ocular surface and prevent evaporation. Remember that the less viscous the tear supplement the more frequent the supplement must be used. Most have a relatively short retention time (60 to 120 seconds), so patients should use them at least hourly. See "Products Currently Available" for a list of some of the various tear formulations.

Systemic drugs. Other investigators are looking at ways to increase lacrimal gland production and secretion of the aqueous component.

• Two approved agents, Cevimeline and Salagen, used to treat dry mouth associated with Sjogren's syndrome, are now being studied to measure their affect on tear film production. However, we must all remember to use these drugs carefully because they have more significant systemic side effects (e.g., brow ache, miosis and GI upset).
• Another drug in the pipe-line is Etanercept -- an injectable drug in Phase II trials for the treatment of dry eye associated with Sjogren's syndrome and other auto-immune diseases.

By activating certain muscarinic receptors (M3) in the lacrimal gland, these drugs may help to increase secretions.

K Nutritional supplementation. We've recently seen an increase in the volume of homeopathic and nutritional products available to the public. One of the better studied and prominent formulations is HydroEyes. This, like many other eye health supplements, blends omega-3 fatty acids, mucin complexes and other anti-oxidants and essential nutrients that are proposed to promote ocular surface health.

The general thought is that these essential oils help create healthier mucin and lipid layers while the other nutrients may improve lacrimal gland health. Moistur-Eyes contains vitamins A, E, C, and B6 and EFAs such as EPA, DHA and GLA. Note that many of these supplements may take weeks to a month to achieve the intended effect.

Immunomodulators. We've long used immunomodulating drugs such as topical antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids to control ocular surface inflammation. These drugs may also be effective in modulating the inflammatory processes of the lacrimal gland-ocular surface gland unit.

Restasis is a promising new drug still in Phase III, but it will hopefully gain FDA approval this year for the treatment of moderate to severe aqueous deficient dry eye. I often use immunomodulating drugs initially as a short course therapy to modulate the inflammatory component of DES and return the tear film and often the ocular surface to a more normal level.

Punctal occlusion. In the temporary plug arena, Oasis has made adaptations to the edges of the collagen plugs to allow for easier insertion. Oasis also has an extended duration synthetic collagen-like plug that may last in the eye up to 12 weeks after insertion. This may well be the answer for many of our refractive surgery patients who suffer from postoperative dry eye.

The standard intracanalicular silicone implants still exist but have undergone "cosmetic surgery" and now come in colors to enhance our ability to detect their presence after insertion.

The many different styles of the "Freeman" or true punctal plugs are also still available today. They come in all different shapes, surface profiles, sizes, colors and inserter devices, depending on your preference and dexterity. Odyssey, FCI Ophthalmics, Surgidev, Tears Naturale and Eagle Vision are all competitors in this market.

The newest addition to the occlusion market is Alcon's port injection system, which allows for customized occlusion by injecting a heated silicone complex in the punctum. The complex then molds to the contours of the punctum and solidifies into its semi-solid form. The question that remains is the ease of removal if epiphora develops.

Certainly surgical methods of occlusion including thermocautery and laser punctoplasty are still options, though they're falling out of favor because of the ease of therapy with the other methods. Remember to use punctal occlusion cautiously in individuals who have blepharitis or other inflammatory dry eyes to prevent a worsening of the symptoms caused by a disruption of the normal drainage of the ocular surface contaminants and various inflammatory cytokines/mediators.

Treating surface disorders

In the area of ocular surface disease, there have likewise been a few advancements including better immunomodulating agents and secretagogues.

Anti-inflammatory agents. There's a newly found interest in using topical anti-inflammatory agents to treat DES. Inflammatory cytokines may be a fundamental element in the develop ment and progression of DES. By controlling the inflammatory cascade and by blocking cytokine action, we may be able to prevent the cascade that results in programmed cell death of the ocular surface.

Designer steroids such as Alrex are taking their place among the anti-inflammatory treatments of choice. This soft steroid has relatively little intraocular activity and thus has a better safety profile on the ocular surface. While topical non-steroidal and steroids can treat some parts of the inflammatory pathway, there's great interest in the development of an approved topical cyclosporine agent to down regulate the production of cytokines and suppress cytolytic T-lymphocyte action thus inhibiting epithelial cell death. While we're still waiting for the FDA to approve Restasis for the treatment of dry eye, many clinicians are going to compounding pharmacies for cyclosporine compounds.

Mucin secretagogues. Two products that are in development and being studied claim to up-regulate mucin gene expression on the ocular surface, thereby stimulating the conjunctival goblet cells to secrete mucins as well as certain important electrolytes such as chloride.

The first agent, Inspire's INS365, acts to improve the eye's natural cleansing system by activating the P2Y2 receptors on the ocular surface. This muco-adhesive agent is proposed to increase mucosal hydration and muco-ciliary clearance, which should in theory aid in the removal of foreign particles, metabolic waste and inflammatory cytokines while at the same time aiding in the lubrication and protecting of the ocular surface from both mechanical forces and environmental agents. INS365 is currently in Phase III of the FDA trials.

Alcon is also working on a similar agent called HETE (hydroxyeicosatetraenoic acid) to increase the viscosity of the surface mucins, which may act to re-establish tear film integrity. This agent has not started human studies yet and actual clinical data is unknown at this time.

Autologous serum. In severe cases of ocular surface disease there have been studies showing beneficial use of autologous serum. This is thought to be related to the presence of various growth factors: Fibronectin Vitamin A, epidermal growth factor, other cytokines and various antiproteases. Fortunately, the potential risk of contamination and infection as well as the cost of production are cost prohibitive at this time.

Contact lens improvements. In cases of severe dry eye, many clinicians use non-ionic, low water, high-Dk hydrogel contact lenses such as the Extreme H₂0 lens or the new Focus Night & Day silicone lenses to protect the ocular surface from evaporative effects. The use of the bandage contact lens is meant to "trap" the tear film under the lens, allowing for greater surface contact time and decreased evaporative effect and resultant desiccation of the ocular surface. This therapy is useful for short-term only. A key point to remember is to fit the lens correctly to allow for proper tear flow exchange and to observe the already compromised corneal epithelium for signs of infection frequently.

Environmental therapy. Don't forget to inform your patients that they may reduce some of their symptoms by controlling certain environmental factors. For example, they may need to adjust their computers to reduce eye fatigue and change aperture size. They may need to move fans or change desk positions to avoid the currents from air vents or overhead fans and to reduce the amount of circulating air that may lead to an increased rate of evaporation.

Preparing for treatment

Develop a thorough understanding of ocular surface disease if you want to treat dry eye effectively. Once you've done that, you can consider all of your exam findings to develop a diagnosis. Based on this diagnosis, you can then develop a treatment plan suited for each patient. And always remember, if you're going to treat dry eye, then treat it aggressively from the start.

A Look at the Latest Dry Eye Products

A handful of new products to treat dry eye have recently hit the market. See what some of them are and what their makers say about them.   HYDRATE ESSENTIAL. Cynacon/OcuSoft recently introduced Hydrate Essential, a patent-pending formulation combining proprietary liposome technology with peer-reviewed ingredients for treating dry eye. Hydrate Essential contains the n-3 fatty acid, flaxseed oil and evening primrose oil. These essential fatty acids have been combined with bilberry extract and are believed to provide anti-inflammatory properties.   Says OcuSoft President Cynthia Barratt, "Once doctors have had the opportunity to evaluate their patients after using Hydrate Essential, I fully expect it to become a standard of care in managing dry eye syndrome." Visit www.ocusoft.com for more information. THERATEARS LIQUID GEL. TheraTears Liquid Gel for nighttime is the first preservative-free, electrolyte-balanced nighttime liquid gel for dry eye. According to Advanced Vision Research, this formulation doesn't produce the crusting and significant blurring that patients experience with other brands. The company also introduced its TheraTears Nutrition for Dry Eyes, an Omega-3 supplement with EPA and DHA-enriched flaxseed oil that targets dry eye ocular surface disease. The patent-pending blend of Omega-3s in TheraTears Nutrition work to decrease meibomitis and to augment the oil and water layers of the tear film. For more information on either product call 1-800-579-8327.   REFRESH ENDURA. Yet another newcomer to the dry eye armamentarium, Allergan, Inc.'s Refresh Endura is, according to the company, the first lubricant eye drop for dry eye that treats all three layers of the tear film.   The oil in Refresh Endura enhances the lipid layer (to minimize evaporation), the water enhances the aqueous layer (to keep eyes wet) and the oil complex enhances the mucin layer (to keep the cornea lubricated). Learn more by visiting www.allergan.com.

Dr. Morris is a member of the Spivack Vision Centers refractive surgery team and the American Optometric Association. He's also a fellow of the American Academy of Optometry.