New Tools for Diagnosing Dry Eye

By Linda Roach

Both clinical trial data and practical experience have demonstrated that high LASIK satisfaction correlates directly with patients’ improvement in UCVA and inversely with the severity of post-op dry eye.

Refractive surgeons have found that, in general, patients tolerate dry eye if it is mild, temporary and amenable to treatment. However, the handful of LASIK patients who develop severe, painful and chronic dry eye are likely to be extremely unhappy about it.

So how can ophthalmic surgeons efficiently and effectively identify before refractive surgery the people who have undiagnosed dry eye disease – a condition that, without pre-treatment, could develop into severe dry eye after surgery?

In the last year, a pair of high-tech, low-fuss diagnostic devices have garnered attention among refractive surgeons who want to answer this question. These tests are minimally invasive, do not require a long period of patient cooperation and take just minutes to complete.

Messages in the Molecules

These tests are part of a new generation of molecular diagnostic tests based on improved understanding of what goes wrong at a molecular level to cause dry eye disease.

The first of the two devices to gain regulatory approval was the TearLab Osmolarity System (TearLab, San Diego), which gained the European CE Mark in 2008 and FDA approval in 2009. It tests for tear hyperosmolarity, which is regarded as the central mechanism responsible for causing ocular surface inflammation, damage and symptoms.

A second innovative diagnostic test received European marketing approval in 2011. Called the RPS InflammaDry Detector (Rapid Pathogen Screening, Sarasota, Fla.), it is a self-contained single-use device that detects an excess of a nonspecific inflammatory marker, matrix metalloproteinase-9 (MMP-9).

Varying Perspectives

When Refractive Surgery Outlook contacted three early explorers of this testing frontier, their assessments reflected the unsettled nature of the field, with a response of ho-hum in Italy, cautious intrigue in Canada, and total enthusiasm in Ireland.

“It is important to diagnose all these conditions of the ocular surface and eyelids and treat them before refractive surgery, cataract surgery or any other kind of ocular surgery,” said Stefano Barabino, MD, PhD, a dry-eye expert and associate professor in the Department of Neurosciences, Ophthalmology and Genetics at the University of Genoa in Italy.

“It is much easier and better to avoid causing problems than to try to control them when the conditions have become very severe after the surgery,” he added.

However, Prof. Barabino regards the TearLab and InflammaDry tests as unnecessary outside of research settings. “I don’t think that it’s important for the average clinician to have these additional devices,” he said.

Cautious Interest

Despite the obvious attractiveness of fast results that can be obtained with a tool that is painlessly high-tech, key questions about the tests must be answered before their full potential becomes clear, said W. Bruce Jackson, MD, PhD, professor of ophthalmology and director of refractive surgery at the University of Ottowa Eye Institute in Toronto. These include:

Which surgical patients should be offered the tests, and at what point(s) in their care?
How should the test results affect clinical and surgical decisions?
What is the significance of an ambiguous test outcome?
How likely is it that either test might provide results sufficiently robust to give clinicians the first single-step diagnostic tool for dry eye?

“We also don’t know if they will predict those patients who will, for example, have increased dry eye following surgery,” Dr. Jackson said. “This is one of the really big areas we’d like to investigate.”

So far, he said he is not yet convinced that the two tests will yield better diagnoses than already can be achieved with a conventional combination of familiar tear tests. But he includes TearLab testing in his pre-op refractive surgery assessments, and he expects to add InflammaDry when it becomes available in Canada.

“I don’t think there would be any question that we should test for dry eye before every refractive surgery,” he said. “But we’ve had some patients where the TearLab has been positive and other tests have been negative. So you still have to be able to put all these things together to make a real diagnosis of dry eye,” he said.

However, Arthur B. Cummings, MD, FRCS, medical director of Wellington Eye Clinic in Dublin, Ireland, credits TearLab with reducing the incidence of dry eye and its sequelae in his refractive surgery patients.

After buying the device for his clinic last year, Dr. Cummings analyzed the 121 early cases in which the TearLab test was used and found that osmolarity was a more reliable predictor of post-op dry eye than the widely used Schirmer test of tear production. (See his PowerPoint presentation.)

“The correlation of TearLab and what you finally see in terms of postoperative dry eye was a lot stronger for the osmolarity test than it was for a standard Schirmer’s test,” Dr. Cummings said. “So we started basing our treatment decisions on what the TearLab said.”

“This year we’ve seen some patients who had terrible Schirmer’s numbers, including results as low as 2, but as long as the TearLab results indicated that surgery would be okay for these people, we have had no problem with dry eye developing postop,” he said.

TearLab: Using Osmolarity to Uncover Dry Eye

Early this year, a regulatory waiver removed an FDA barrier that prevented eye care practitioners without Clinical Laboratory Improvement Amendments (CLIA) certification from performing TearLab tests in their offices and clinics. The waiver cleared the way for wider commercialization than has been possible since the device’s U.S. approval three years ago.

In contrast to the international norm, American ophthalmic practices can be reimbursed for testing tear osmolarity in Medicare patients. The health care program for the elderly and disabled pays 100 percent of a standardized fee for the test, currently set at $23.40. This is billed as a clinical laboratory fee, separately from the physician charges.

TearLab is configured with a cutoff between normal and abnormal osmolarity of greater than or equal to 308 mOsms/L – the reading that, in a 300-patient clinical study, had 88 percent specificity and 75 percent sensitivity in mild/moderate dry-eye disease. The dividing line between mild and moderate/severe disease is considered to be 316 mOsms/L.

Like the femtosecond laser and other high-tech innovations in eye surgery, TearLab is expensive to buy (approximately €4,000) and operate, Dr. Cummings said. Bilateral testing of one person requires about €30 in disposable supplies, which must be discarded after a single use, he said.

Because the Irish health care system will not pay for the test, the patient or the surgeon must bear the cost.

Dr. Cummings said he worried initially about his practice losing money on every €100 refractive surgery consultation during which TearLab found undiagnosed dry eye, with the fee wiped out by multiple osmolarity tests.

Instead, he was surprised by a subsequent boost in business, which more than covered the cost of buying a TearLab system. He attributes this to two possible factors:

1. Performing successful LASIK or PRK on patients after they were treated for dry eye detected by TearLab. Without TearLab testing, they might not have been approved for surgery at all.

2. Less post-op dry eye has led to happier patients and a jump in the number of friends and family members referred to the practice.

InflammaDry: MMP-9 in Tears Indicates Inflammation

Matrix metalloproteinases are proteolytic enzymes produced by stressed epithelial cells on the ocular surface. MMP-9 appears to be involved in the process by which the cornea’s protective outer barrier cells are damaged by tear film dysfunction. This leads in turn to ocular irritation and visual symptoms.

Studies have demonstrated that elevated MMP-9 is present in patients with more severely dry eyes, and that the levels correlate with clinical exam findings. Although other matrix metalloproteinases also are involved, the level of MMP-9, in particular, in the tears rises, according to the device’s package insert (at: http://www.rpsdetectors.com/in/products/inflammadry/resources/downloads/).

The test consists of a small, handheld, single-use unit that looks somewhat like an over-the-counter pregnancy test kit. In contrast to TearLab, doctors do not need to buy expensive equipment to use InflammaDry, making it easier for physicians to adopt. Although pricing details are murky, Dr. Jackson said he expects the price to be about $20 per test unit.

Positive or Negative? Look for the Red Line

Inside the InflammaDry tester, the tear sample undergoes 10 minutes of micro-filtration to trap MMP-9 molecules between a specific collection of monoclonal and polyclonal antibodies. A red line in a results window indicates MMP-9 is present with a concentration of at least 40 ng/ml, the level indicative of mild dry eye.

Dr. Jackson is hoping to use InflammaDry to investigate why some glaucoma patients also develop dry eye and meibomian gland dysfunction.

“There is a question about what causes these co-morbidities,” he said. “Is it the glaucoma drops themselves? Or do these patients have inflammatory tears? If the MMP-9 came back positive, this would be a glaucoma patient group that we might want to treat with cyclosporine (Restasis, Allergan). Without a test for MMP-9, we might not know a patient like this needed treatment.”