May 2010

 

COVER FEATURE

 

Ocular Surface & Dry Eye

Behind the tear


by Enette Ngoei Senior EyeWorld Staff Writer

 

At a glance

• Research may soon deliver gold standard clinical tests for dry eye as well as help determine which treatments are most effective • A study at the annual AAO meeting showed that tear film osmolarity is a more accurate determinate of dry-eye disease compared with any of the other tests currently in use • The ophthalmology community might see a mini revolution in osmolarity measurement —Dr. Sheppard • A new osmometer, TearLab Osmolarity, is a non-invasive, quick, and easy-to-use tool —Dr. Foulks • In a 2008 study, Dr. Pflugfelder and colleagues concluded that cyclosporine emulsion made a difference in goblet cell density and production of TGF-beta2 in the bulbar conjunctiva • In the laboratory setting, ongoing biochemistry research into the levels of cytokines or inflammatory mediators in the tear film and on the ocular surface may help physicians determine the most effective treatments for dry-eye patients —Dr. Sheppard

 

A look at how advanced research can help the dry-eye patient

In recent years, experts in the ophthalmology community have increasingly stressed the importance of identifying and treating dry-eye patients. They explain that the pain, itching, grittiness, and blurred vision experienced by dry-eye patients are not only a source of discomfort, but if left untreated, can adversely affect outcomes of LASIK and cataract surgery. Clinicians currently detect dry eye and its level of severity using some combination of Schirmer’s test scores, ocular surface staining, and tear film break-up time, none of which are as accurate or specific as stand-alone tests. However, research into advanced biophysical and biochemical measurements may soon deliver gold standard clinical tests for dry eye as well as help determine which treatments are most effective.

Measuring osmolarity

In a previous interview with EyeWorld, Michael A. Lemp, M.D., clinical professor, Georgetown and George Washington Universities, Washington, D.C., said that increased tear osmolarity is not only a marker for dry eye disease, but also a mechanism that causes damage and pain.

In October 2009, Gary N. Foulks, M.D., Arthur and Virginia Keeney professor of ophthalmology, University of Louisville, Louisville, Ky., presented a study at the annual American Academy of Ophthalmology meeting that showed tear film osmolarity is a more accurate determinate of dry-eye disease compared with any of the other tests currently in use, whether it’s the Schirmer’s test, tear break-up time, ocular surface staining, or the symptomatic assessment on the Ocular Surface Disease Index, he said.

Until recently, osmolarity measurement tools have been either too complex or too cumbersome to use in the clinical setting. However, according to John D. Sheppard, M.D., professor of ophthalmology, microbiology, and immunology, Eastern Virginia Medical School, Norfolk, Va., the ophthalmology community might see a mini revolution in osmolarity measurement. A new osmometer, TearLab Osmolarity (TearLab, San Diego), which received FDA 510(k) clearance and is awaiting a Clinical Laboratory Improvement Amendments waiver for use in a clinical setting, is a non-invasive, quick, and easy-to-use tool, said Dr. Foulks. “It uses a very small amount of tear so that you don’t induce reflux tearing when you collect the tears. It gives you a very rapid result, and in most cases a very accurate result,” he added. The TearLab osmometer sends electrical conductants across the less than 50 nL of tear sample to determine the level of osmolarity.

There are also several other companies, including a start-up in Washington, D.C., that are working on devices that don’t require any sampling but simply a test to the ocular surface using gold plated electrodes, Dr. Sheppard said.

However, he added that the reimbursement for such data collection is not very good and almost a money-losing effort to obtain. Reimbursement for the Schirmer’s test was discontinued about 15 to 16 years ago, he said, and the test now is something clinicians perform to gain information at an overhead cost.

The biochemical approach

In the laboratory setting, there is exciting ongoing biochemistry research into the levels of cytokines or inflammatory mediators in the tear film and on the ocular surface that may help physicians determine the most effective treatments for dry-eye patients, Dr. Sheppard said.

For example, he and colleagues are running a protocol to evaluate the efficacy of nutritional therapy for dry eye and are looking at cell surface markers for inflammation and goblet cell density using a very old test with a highly sophisticated new amino chemistry analysis called impression cytology. “We do this by putting a little bit of filter paper against an anesthetized eye surface,” he explained. The paper is only about 4 mm in diameter but is able to measure the exact cellular content of the surface of the eye. Changes in the content are then analyzed following topical or oral therapy or medication, he said.

“We’re very excited about this new approach to an old test. In the past, we would just look at goblet cell densities. Now we can look at the actual cell surface markers to see whether the inflammatory markers are mediated or suppressed,” Dr. Sheppard said.

This makes it possible for researchers to look for dynamic changes in the biochemistry of the eye with the understanding that dry eye is truly a result of surface inflammation throughout the secretory apparatus, that is, the major and minor lacrimal glands, the conjunctiva and the lid margins, and all the cells that make up the ocular surface, he said.

Through impression cytology, Stephen C. Pflugfelder, M.D., professor of ophthalmology, Baylor College of Medicine, Houston, and colleagues were also able to compare the effects of sequential treatment with artificial tears and cyclosporine emulsion on conjunctival goblet cell density and production of transforming growth factor (TGF)-beta2 in patients with dry-eye disease. In the 2008 study, Dr. Pflugfelder and colleagues concluded that cyclosporine emulsion, but not artificial tears, made a difference in goblet cell density and production of the immunoregulatory factor TGF-beta2 in the bulbar conjunctiva.

The study results mean that artificial tears, which are the starting point of treatment for many dry-eye patients, lubricate the eye, but they don’t really do anything to regenerate the natural cells on the eye, Dr. Pflugfelder explained. On the other hand, cyclosporine did regenerate not only the number of goblet cells, which was significantly increased in either 6 or 12 weeks of treatment depending on the location, but also increased one of the important secretions of the goblet cells called TGF-beta 2, he said. TGF-beta2 is an important cyctokine that helps to suppress inflammation on the surface of the eye especially on the cornea so when that goes down, presumably inflammation would go up, he added.

Another test that’s being conducted is tear film analysis, where a very small sample of tear film is taken and researchers study the inflammatory mediators secreted on microchip rays, which are incredibly convenient yet sophisticated microchips that respond directly to nanomolar concentrations of chemical programmed into the chip, Dr. Sheppard said.

“We can look for subtle changes in classified populations of patients based upon the compilation of the tear film. That’s a very reliable tool to evaluate morbidity as well as response to therapy,” he said.

Nutritional therapy

As for how far the research has come to support nutritional therapy, Dr. Foulks said it is possible that supplements such as fish oil might increase goblet cells. In some studies of dry eye in mice, fish oils and fish oil-like molecules have been shown to increase goblet cells in dry eye, but in humans there haven’t been any studies yet he’s aware of, he said.

“We’ve certainly come full circle in realizing that nutritional therapy is essential to the treatment of dry eye,” Dr. Sheppard said. “You can tell patients in very simple terms what to do.”

There is a tremendous number of nutritional supplements available but the most scientifically formulated one, HydroEye, comes from ScienceBased Health (Houston), Dr. Sheppard said. Formulation of supplements will change as the research findings in dry eye change in the accepted circles of cutting edge analysis of the disease. If a particular omega-6 fatty acid or protein proves to be better or worse based on new research, the formula will be adjusted so clinicians can simply prescribe what’s most up to date, he explained.

Editors’ note: Dr. Foulks has financial interests with TearLab Corporation (San Diego). Dr. Sheppard has financial interests with Alcon (Fort Worth, Texas), Allergan (Irvine, Calif.), Bausch & Lomb (Rochester, N.Y.), and Vistakon (Jacksonville, Fla.). Dr. Pflugfelder has financial interests with Abbott Medical Optics (Santa Ana, Calif.), Allergan, and Bausch & Lomb.

Contact information

Foulks: 502-852-6150, gnfoul01@gwise.louisville.edu
Pflugfelder: 713-798-4944, stevenp@bcm.tmc.edu
Sheppard: 757-622-2200, docshep@hotmail.com

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