What Can Go Wrong?
Ocular surface disease experts have new theories on how the tear film becomes compromised. Here's what to consider.

"With the recognition of tear film dysfunction, we have solid evidence that some ill-defined complaints we've been hearing from patients can be linked to dry eye." -- Michael Lemp, M.D.

The eye is in a constant state of renewal. Sensory nerve endings on the surface send signals that are mediated by tears to control production of varying types and volumes of tears. These nerve endings must remain intact to ensure a finely regulated system, which is important for replacing cells, responding to injury and protecting the eye.

Researchers have been looking at how this system relates to lacrimal glands, meibomian glands and lids and why the whole network breaks down to cause problems for an estimated 60 million people in the United States.

At the 2004 annual meeting of the American Academy of Ophthalmology, a panel of experts discussed these underlying issues and how they affect patient care.

Key factors to consider

Aqueous tear deficient and evaporative forms of dry eye compromise the ocular surface. These conditions can result from a myriad of issues, including:

• Decreased tear secretion
• Blepharitis and meibomian gland dysfunction, found in more than 40% of dry eye cases in some studies
• Autoimmune disorders, such as Sjögren syndrome
• Ectropion associated with lid dysfunction
• A senescent process manifested as a decreased blink rate, which can cause evaporative tear loss
• Androgen deficiency, particularly in women, which contributes to decreased tears, decreased homeostasis of the ocular surface, as well as an upgrade in inflammation and up-regulation of the expression of inflammatory cell surface markers
• Primary neurologic diseases that break down the tear control mechanism
• Iatrogenic factors, such as severed nerve connections, which may occur when the cornea is cut during refractive surgery.

Many of these issues affect elderly people, especially women, who are the vast majority of ocular surface disease patients. But to some extent, all patients have experienced some form of ocular surface discomfort.

"All these conditions lead to common events that occur at the ocular surface in an interaction between the tear film and the epithelial cells," says Michael Lemp, M.D., a clinical professor of ophthalmology at Georgetown and George Washington universities. "That's the zone of interaction, and it has to do with universal findings in all forms of dry eye, whether it's evaporative or aqueous tear deficient. In fact, most patients have a combination of both."

Meibomian gland inspissation contributes to abnormal ocular surface lipids, which results in an evaporative dry eye.

When good tears go bad

A healthy tear film is "best considered as a hydrated mucin gel with interaction of lipids, proteins, electrolytes and water that maintains a continuous protective film across the ocular surface," according to the latest consensus reached at the 4th International Conference on the Lacrimal Gland, Tear Film, Ocular Surface and Dry Eye Syndromes: Basic Science and Clinical Relevance in Puerto Rico in November 2004.

But healthy tear film turns dysfunctional when affected by hyperosmolarity, which leads to disruptions of the ocular surface. "Hyperosmolarity initiates a cascade of enzymatic effects in the cells promoting inflammation," Dr. Lemp says. "The kinase systems are activated, and inflammatory changes occur in the epithelial cells. The changes in the electrolyte concentration alter the character and behavior of the mucins on the surface of the eye. This alters the interaction between the lipid layer and the mucins. So these interactions cause a series of failures, regardless of the initial cause."

Ophthalmologists are familiar with the common complaints of dry eye, such as stinging, burning, itching, foreign body sensation and photophobia. "But now, with the recognition of tear film dysfunction, we have solid evidence that some of the ill-defined complaints we've been hearing from patients for years can be linked to dry eye," Dr. Lemp says. "These are the patients who've been telling us their eyes are tired or they can't see properly."

"During the first couple of months after LASIK, patients' blink rates decrease, so the evaporative component comes into play." -- Ella G. Faktorovich, M.D.
"I have hundreds of patients whom I've treated as a refractive surgeon who magically, at 3 to 6 months, are cured of dry eye." -- Richard Lindstrom, M.D.

When tear film becomes unstable and breaks up between blinks, patients can suffer discomfort and vision problems. "These people are having trouble seeing because their blink rate can't keep up with the breakup of their tear film under normal conditions," Dr. Lemp says. "That's not apparent when you check their vision on a vision chart, because they blink and momentarily restore their tear film, and they can read it. But the tear film is breaking up, and that's the whole concept of tear film instability, which is central to our contemporary understanding of this problem."

Rethink dry eye

New data¹ are changing how aqueous tear deficient dry eye is categorized, says Dr. Lemp. In the past, experts believed dry eye was either senescent or inflammatory. But such a distinction can no longer be made, according to the panelists.

"Evidence suggests that even in the milder forms of dry eye, there is an increase in inflammatory cytokines in the tear film as well as histologic evidence of inflammatory cells on the surface of the eye," Dr. Lemp says.

John Sheppard, M.D., of the Eastern Virginia Medical School, agrees with this new thinking. He participated in clinical trials for cyclosporine ophthalmic emulsion 0.05% (Restasis) trials that confirmed the inflammatory component in all forms of dry eye.

"We looked at the tear film cytokines and the expression of T-cell surface activation markers on the surface conjunctival cells," Dr. Sheppard says. "Universally, after the cyclosporine therapy, the cytokines and T-cell surface activation markers were significantly decreased, often four- to six-fold, in patients who had received the drug, regardless of the etiology of the dry eye."

	When tear film becomes unstable and breaks up between blinks (as shown at left), patients can suffer discomfort and vision problems.

More aggressive care

Based on this new evidence, many ophthalmologists take an aggressive approach with all ocular surface disease patients, most of whom don't seek attention until their conditions have deteriorated significantly.

"By the time patients arrive in my office with punctate epithelial erosions or punctate epithelial keratitis, almost all of them have lid disease, inflammation and tear film dysfunction," says Richard Lindstrom, M.D., founder and managing partner of Minnesota Eye Consultants in Minneapolis.

If a patient has staining when he comes to see you, assume he's had the disease for a while and several of the components have gone awry, says Dr. Lemp. Recognizing ocular surface disease can prevent a misdiagnosis.

"In the past, we might have said, 'Oh, you have a little bit of burning here. Just use some artificial tears and you'll be OK.' But now we know ocular surface disease can be very debilitating," says Edward Manche, M.D., director of cornea and refractive surgery at Stanford University in Stanford, Calif. "I'm glad this condition is finally getting the attention it deserves."

References

1. Stern MF, Pflugfelder SC. Inflammation in dry eye. The Ocular Surface. 2004;2:1124-1130.