Article Date: 2/1/2002

New information on the theories behind the etiology of this condition.

In the last year we've seen a tremendous leap in our knowledge of what's likely the most common eye disease that we see in our clinics on a daily basis: Dry eye syndrome. Patients suffering from dry eye are reaching record, if not epidemic, levels as the population increases in age and awareness of their condition. The rapid rise of refractive surgery and the environmental changes that the population faces on a daily basis has dramatically increased the amount of patients that are reporting symptoms of dry eye.

As our knowledge of the potential pathophysiology of dry eye and related ocular surface diseases has progressed, exciting new products have emerged to more effectively diagnose, manage and treat this condition. In this two-part series, we'll review the new theories on the pathophysiology of this intricate disease as well as new diagnostic tools, products and advances in treatment.

The Dry Eye Environment
BY SCOT MORRIS, O.D., F.A.A.O., Centennial, Colo.

As defined by the Classification Study Group of the National Institute of Health (NIH), dry eye is a disorder of the tear film caused by tear deficiency or excessive tear evaporation. This in turn causes damage to the interpalpebral ocular surface and is associated with ocular discomfort.

This definition is fairly broad and encompassing, but it provides an excellent reference to the diagnostic and pathophysiological changes we need to be cognizant of as we examine our patients.

Who's affected? First we need to look at the population we're dealing with. As we age, the prevalence of dry eye symptoms increases for numerous reasons. We're only just beginning to discover the degree that dry eye syndrome affects our population.

New Product Overview

Strength of a Gel, Convenience of a Drop

At December's American Academy of Optometry meeting, Allergan, Inc. announced the arrival of its new solution for the treatment of dry eye symptoms: Refresh Liquigel Lubricant Eye Drops.

The company says that Refresh Liquigel combines the strength of a gel with the convenience of a liquid eye drop. The new product features a proprietary blend of molecular weights that strike an ideal balance between performance and comfort. The special formulation also includes the preservative Purite, which breaks down into the components of natural tears. It's available in 15-mL bottles.

New Drop Coming Down the Line

In November 2000, Inspire Pharmaceuticals revealed that it had a P2Y2 receptor agonist in a Phase II, multi-center, placebo-controlled, dose-ranging trial for the treatment of dry eye disease.

Since that last update, Inspire has signed a marketing partnership agreement with Allergan, Inc. The P2Y2 receptor agonist, INS365, is currently in Phase III and the company expects results from this stage in the coming months.

With a baby boomer reaching the age of 65 every 5 minutes, millions of people are suffering from dry eyes and that number is increasing dramatically every day. This generation wants results and they want an eyecare provider -- any eyecare provider -- to make them see better and feel better. Whether it be to decrease their symptoms to continue their contact lens wear, pursue refractive surgery or simply make their eyes more comfortable, the baby boomers and their dry eyes are here to stay.

Budding awareness. As the population of people affected with this condition increases, the laws of supply and demand hold true in many aspects. As the economy turned downward, many of us began looking for other ways to generate revenue and keep our patient bases while maintaining or increasing profits.

Aware of the remuneration afforded for punctal occlusion procedures, many clinicians quickly increased their internal and external marketing about the existence of this condition to the general population. This led to the development of niche practices focused specifically on dry eye management. Companies even market solutions directly to your patients.

Even the media has jumped in to promote eye health as evidenced by the presence of tear supplements in local grocery stores. This increased awareness of not only the condition and its symptoms but also the multiple treatment options that are available means that you'll find more people than ever questioning you about their dry eyes.

Refractive surgery. As refractive surgery boomed (and lulled) this past year, we've seen a resurgence of concern among both the public and the eyecare profession about the effects of preoperative dry eye and the resulting dry eye conditions related to refractive surgery. This publicity has made for better informed consumers, but has also caused enough fear in many to avoid refractive surgery and continue their contact lens wear.

The environment. Our environment has also added to the dry eye problem. As a record number of people use computers, we've seen a dramatic increase in dry eye symptoms and the development of computer vision syndrome (CVS). The arid environments of most offices, in addition to the continual recirculation of dry air and allergens, has led to an epidemic of allergic and dry-eye related issues.

Also, our population is slowly migrating toward more arid climates and the amount of environmental pollution is reaching all-time highs. All of these elements contribute to the dry eye epidemic. For a refresher on the topic, see "Tear Film Dynamics: A Review" on page 62. But now we'll take a look at new theories behind the etiology of dry eye and how to effectively treat it.


Dry Eye a Side Effect of HRT?


Could estrogen directly effect the quantity and/or quality of meibomian gland secretions? A recent study points to "Yes." Published in the November 7th issue of The Journal of the American Medical Association, data from the study of more than 25,000 postmenopausal women suggest that women who use hormone replacement therapy (HRT), particularly estrogen alone, are at increased risk of dry eye syndrome.

Women in the study who used estrogen alone were 69% more likely to have been diagnosed with dry eye syndrome or symptoms of the condition than their peers who had never used HRT. The report indicates that the risk of developing the condition rose 15% for each 3-year interval that women remained on HRT.

The study's lead author, Dr. Debra A. Schaumberg, of Brigham and Women's Hospital in Boston, emphasized that the findings are preliminary and that further studies are needed to confirm them and to investigate exactly how estrogen may contribute to dry eye syndrome.

New theories in pathophysiology

In the past, eyecare providers (ECPs), as well as other healthcare providers have only been managing the symptoms of dry eye. But in the recent years, research has yielded a dramatic number of new discoveries about the cause and new treatments of the condition. These new therapies show great promise and we may soon find ourselves treating dry eye -- not just managing it.

Probably the greatest shift in thinking addresses the fact that dry eye syndrome isn't solely a lack of aqueous production, but is actually affected by disturbance of one or more of the tear constituents resulting in a disruption of the fine tear film balance and ocular surface disease. In the following section, we'll discuss many of the new concepts of the etiology behind dry eye and its associated ocular surface disease.

The inflammatory constituent. Without a doubt, the most prevalent increase in our knowledge about dry eye syndrome comes from the study of the effects of the inflammatory cascade on tear film production and the associated effects on the ocular surface.

Stephen Pflugfelder, M.D., has shown that the lacrimal gland produces certain chemical compounds such as lactoferrin and various interleukins that help to modulate inflammation on the ocular surface. With various forms of dry eye syndrome, the lacrimal gland is a target site for lymphocytic infiltration.

Ultimately the exocrine glands are damaged and affect the composition and volume of the aqueous. As the lacrimal gland undergoes atrophic changes on a cellular level, the volume of aqueous secreted decreases, resulting in an increase in the overall osmolarity. The production of protective agents, such as lactoferrin and lysozymes, also decreases. This is further compounded by an increased release of pro-inflammatory cytokines, cellular components and various proteolytic enzymes, which contribute to enhancement of the inflammatory process and ocular surface damage.

Sheer forces created by the lid, hyperosmolarity, free oxygen radicals and other inflammatory factors such as antihistamines have also been shown to increase the production of inflammatory cytokines. This complex cascade of inflammatory agents and their interaction with the ocular surface seems to be responsible for many types of ocular surface disease, including dry eye syndrome. With this knowledge, there's been a renewed interest in anti-inflammatory agents and immunomodulation in the treatment of dry eye, which we'll discuss in part two of this series.

Neurosecretory. As mentioned earlier, there's also a complex neurosecretory relationship between the ocular surface and the lacrimal gland. We've long known that loss or damage to the reflex arc between the ocular surface and the lacrimal gland via the afferent trigeminal nerve will result in a decrease in stimulation of the efferent parasympathetic secretor motor fibers and subsequently a decrease in the tear reflex.

With the success of laser-assisted in situ keratomileusis (LASIK) and other types of refractive surgery, we're once again reminded of the importance of this reflex arc. Though with contact lenses there's a moderate decrease in threshold stimulus with many of the refractive surgery options available today, total resection of these nerves is commonplace. The result is an increasing dry eye epidemic among our refractive surgery patients. Patients who suffer from even borderline to mild cases of dry eye symptom are becoming symptomatic in the postoperative period. However, we also need to remember to look at the neuro-secretory process in reverse. Remember that the efferent corneal nerves supply the ocular surface with various neurotrophic growth factors.

Researchers believe that the severing of the corneal nerves during the keratectomy and the disruption of the efferent pathway may play a larger role in the development of post-op dry eye than the effect of severing the afferent nerves. The result of the efferent disruption is a "neurotrophic-like" epitheliopathy.

Resolution of LASIK-induced neurotrophic epitheliopathy. Dr. Steven E. Wilson showed in a retrospective case control study that this LASIK-induced neurotrophic epitheliopathy tended to resolve approximately 6 months after the surgery as the corneal nerves regenerated back into the flap. Eric Donnefeld, M.D., conducted a case study evaluating hinge placement and its effect on post-op dry eye. His study, confirmed by many others, demonstrated that nasal-based hinges appeared to preserve corneal sensation better than superior hinges and also appeared to alleviate many dry eye symptoms. This is likely because the nasal flap spares fibers originating from the major nasal ciliary nerve, whereas superior hinges sever both the nasal and temporal ciliary nerves.

Sensory threshold. Another piece of new research shows that serum antibodies produced in some autoimmune diseases act to block the cholinergic receptors of the lacrimal gland thereby blunting the stimulus to produce aqueous. We've long known that extended wear contact lens wearers suffer from dry eye in part because of a reduction in the sensory threshold of the ocular surface nerves.

Similarly, Dr. Pflugfelder showed in another study that patients with severe ocular surface staining might demonstrate a similar reduction of sensory threshold that further degrades the neurosecretory process. The result is once again reduced tear production that furthers the progression of ocular surface diseases. Though there may actually be multiple etiologies behind the loss of neurosecretory function, the fact remains that it's an important element to the health of the ocular surface.

Meibomian glands and the lipid layer

It's been shown that our meibomian glands contain androgen receptors and various enzymes that convert various androgenic hormones and testosterone into other androgenic forms as part of a complex and intricate lipid production process. A variety of lipid classes are also regulated by these androgenic hormones and compose the outer lipid layer that forms the barrier to evaporation of the aqueous component of the tear film.

The lacrimal gland and the aqueous component

Androgen receptors have been found within the lacrimal gland as well. Androgens also appear to have an immunomodulating or regulatory effect within the lacrimal gland. As our hormonal levels change or, more specifically, as the levels of various systemic androgenic hormones decrease, there's a resultant increase in inflammatory cytokines, lymphocytes and other inflammatory mediators that are then available to infiltrate the lacrimal glands. The result: programmed cell death, a subsequent decrease in function and production of the lacrimal gland in addition to initiation of the inflammatory cascade.

This hormonal influence is supported by the fact that aqueous insufficiency becomes prominent during pregnancy, oral contraceptive use and meno-pause, when the ovaries, which are responsible for up to 50% of the circulating androgens, atrophy. This may provide one explanation for the increased incidence of severe dry eye in women than men of the same age group.

The ocular surface

Androgens secreted within the tear film act to regulate the inflammatory cycle at the cellular level. As the normal androgenic levels decrease with age, the corneal and conjunctival epithelial cells secrete more cytokines leading to initiation of the inflammatory cascade and subsequent ocular surface damage. Interestingly, another groundbreaking study has shown that the use of topical beta-estradiol may have some positive effects of the healing of the ocular surface.

Though oral estrogens haven't shown significant improvement in dry eye conditions and may actually be detrimental to overall tear film/ocular surface health, it appears that specific estrogen receptors on the ocular surface may be essential in maintaining the health of the corneal and conjunctival epithelium.

It appears that the topical solution doesn't interfere with the circulating androgen produced in the lacrimal glands and secreted on to the ocular surface. Phase III of the FDA's study of topical estradiol has recently begun as we await the results.

From theory to treatment

Overall, the information that has been gathered about dry eye syndrome and new theories relating to various pathophysiological changes that occur with the disease have been astounding. In the part two of this series, which will appear in the October issue, we'll discuss new therapies and management pearls that have developed out of this new information.


Tear Film Dynamics: A Review

The paradigm of the tear film has changed in the last decade. The old model of the tear film having three distinct layers has given way to a newer, two-layered model consisting of the outer lipid layer and an intricately balanced aqueous-mucin layer that coats the ocular surface.

There's also a change in thought in that the ocular surface and the lacrimal gland are no longer considered separate entities but function as a complex secretory unit controlled by various hormonal, chemical and neurosecretory feedback mechanisms. The lipid layer maintains surface tension and structural integrity and provides a protective barrier against evaporation and desiccation. The aqueous-mucin layer is a delicate and intricate balance of a variety of mucins produced by the conjunctival goblet cells and aqueous fluid produced by the lacrimal glands. The mucins coat the hydrophobic corneal epithelium, hydrate the ocular surface, reduce surface tension and transport various foreign particles from the ocular surface.

The mucin-producing goblet cells are under the control of complex neurosecretory and hormonal feedback system. The lacrimal gland produces and secretes aqueous which provides essential nutrients and growth factors to the ocular surface. The aqueous also acts to remove metabolic waste and foreign debris from the ocular surface. It also contains antibacterial and immunological elements to protect the ocular surface from pathogens and the inflammatory pathway. Aqueous production is likewise under the control of a complex neurosecretory and hormonal feedback system. All of these tear film components act in harmony to protect the eye and provide a smooth refractive surface.

When any one of these components is altered, the intricate balance is consequently disrupted, and dry eye syndrome or other associated ocular surface diseases may result.



Scot 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.


Optometric Management, Issue: February 2002