Pondering the Dry Eye Puzzle

Questions remain about the role of osmolarity in diagnosis and treatment.

BY RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

Dry eye may be one of the most written-about topics in the eyecare field, but that doesn't mean that clinicians have a good grip on the problem yet, according to many doctors who specialize in dry eye. Important pieces of the puzzle are still either missing or poorly understood.

“Dry eye has become a much more intriguing and potentially challenging disease category because there's such a wide variety of presentations, a host of mechanisms and, therefore, a number of therapeutic regimens that need to be titrated to the specific patient's needs,” says John D. Sheppard, MD, professor of ophthalmology, microbiology and immunology at Eastern Medical School in Norfolk, Va.

“We're always learning new things about it,” says Kevin L. Waltz, OD, MD, in practice at Eye Surgeons of Indiana in Indianapolis. “I would say as a general statement, most doctors don't understand dry eye.”

Houston's Stephen C. Pflugfelder, MD, agrees. “Dry eye is no longer just a disease of deficient tears in terms of volume,” says Dr. Pflugfelder. “It is not just somebody with a low Schirmer test; I think it's really appreciating that dry eye presents in a lot of different ways.”

Among the components getting a great deal of scrutiny lately is the meaning and role of tear film osmolarity.

Is Osmolarity a Major Player?

Dr. Pflugfelder notes that clinicians have known for decades that osmolarity increases in dry eye, but it has been more of a “research concept” than something having value in the clinical setting, as there were no practical methods to evaluate osmolarity there. The FDA's 510(k) clearance for TearLab's Osmolarity System last year, however, should change that and clear up some mystery regarding osmolarity's role in dry eye.

According to Dr. Sheppard, osmolarity is a phenomenon worthy of further study. “Not only does it indicate pathology, but it parallels function in the eye and parallels to a very reliable degree the pathology seen on the surface of the eye,” he explains.

TearLab's vice president of marketing, Tracy Puckett, notes that the Dry Eye Workshop Study of 2006 adjusted the definition of dry eye to note that it is accompanied by heightened osmolarity, regardless of the underlying disease process.

Yet while osmolarity may be important, awareness about it among ophthalmologists is “tremendously variable,” Dr. Sheppard finds. “A general ophthalmologist who concentrates on medical diseases or cataract surgery may not look upon it as the most important coding, diagnostic or therapeutic issue.”

Dr. Waltz concurs. “I think that the role of inflammation is better understood and better appreciated than the role of osmolarity.”

Osmolarity Questions

Adding to the confusion is the fact that there's no “normal” value established regarding osmolarity scores, according to Esen K. Akpek, MD, associate professor of ophthalmology, and director of the Ocular Surface Diseases and Dry Eye Clinic at Wilmer Eye Institute of Johns Hopkins University in Baltimore. Unlike cholesterol or IOP, there is no settled definition of normal for tear film osmolarity.

“If we do have the normal established, with good cut-off points, it could be pretty useful in terms of diagnosing patients, and also managing them,” Dr. Akpek says.

Yet even if a range could be established, Jean-Michel Gries, PhD, vice president of Alcon's Pharmaceutical Product Development, notes that the FDA does not recognize osmolarity as an endpoint for dry eye. “It's hard to differentiate dry eye patients from normal patients just by osmolarity alone.”

In a study Alcon cosponsored with TearLab on its osmolarity system, one of the findings was a lack of correlation of osmolarity to symptoms of dry eye, or cornea fluorescein staining. “It's that old issue — the lack of correlation between the signs and symptoms of dry eye,” Dr. Gries says.

An Inflammatory Relationship?

Some of the questions pertaining to osmolarity's role in dry eye is due, in part, to the confusion that remains regarding its relationship with inflammation. Does osmolarity trigger inflammation, or is it a product of inflammation? According to Dr. Sheppard, its a “which came first, the chicken or the egg?” issue.

For example, contact lenses may tip borderline patients into dry eye.“Contact lens-induced ocular surface trauma and hypoxia may trigger the mediator cascade to where inflammation occurs, subsequent hyposecretion of tears is triggered, and the tear osmolarity increases,” he explains. “It may be that the soft contact lens simply absorbs a certain number of tears and so its matrix reduces the tears available for the ocular surface, and therefore tear osmolarity, which then triggers an inflammatory cascade. Also, blink rates often decrease with contact lens use, thus increasing evaporative aqueous tear loss.”

Other patients — those with primary or secondary Sjögrens syndrome, those taking a variety of medications that can decrease tear production, patients in hostile environments such as factories, or those with chronic outdoor sun exposure — may have an evaporative or hyposecretory decrease in tear osmolarity, which then leads to inflammation. “Alternately,” Dr. Sheppard notes, “patients who have inflammatory ocular surface disease from surgery, injury or autoimmunity, have T-cell and tear cytokine-induced inflammation causing hyposecretion that in turn causes decreased osmolarity. So both those scenarios can occur, and they can both occur in the same patient at the same time.”

Dr. Pflugfelder says that increased osmolarity triggers an inflammatory response. When osmolarity in creases, cells produce inflammatory mediators. “It seems to be a key factor driving the inflammation that develops in dry eye.”

Dr. Waltz believes that osmolarity is probably the result of inflammation, though “that's less clear,” he says. “There could be a back-and-forth mechanism here.”

Dr. Akpek believes that is the case. “I think osmolarity and inflammation are totally interrelated,” she says. “If you start secreting hyperosmolar tears, that's going to cause inflammation on the surface and then damage.”

Additionally, she says, sometimes patients with Meibomian gland dysfunction, for example, get viscous tears and hyperosmolarity at the beginning, followed by on-going surface problems from the chemical damage from hyperosmolar tears. “Then they develop k. sicca. Whereas in the case, for example, of patients with Sjögren's, first they get inflamed and then their tears become dysfunctional and hyperosmolar. So it works both ways. “

Perhaps Ms. Puckett captures the problem best: “It's a ‘roach motel’ — once you get in, you can't get out! Osmolarity is indicative of the dry eye disease, but once osmolarity is heightened, it also induces additional inflammation,” she explains. “So it's truly a loop.” (See Figure, below.)

Knowing the Score

Given the lack of clarity regarding osmolarity's role with respect to dry eye's inflammatory cycle, and given that there is currently no treatment for the reduction of osmolarity, some might question the value of an osmometer. According to the FDA's intended-use language for the TearLab system, it would have to be used in conjunction with other tests, such as tear break-up time or corneal staining, to diagnose dry eye. Additionally, there's uncertainty regarding what to do with the information once it is obtained.

TearLab calls its system a disposable “lab-on-a-chip” that functions as both a tear-collection device and a measurement system. While it has won 510(k) clearance from the FDA, the company anticipates CLIA (Clinical Laboratory Improve ment Amendments) later this year. It enables tears to be collected directly from the eye, eliminating the need for a standard glass capillary tube. Embedded nanofluidic channels move the tear sample to the measuring electrodes; a desktop instrument converts the electrical signals generated from the lab card into a quantitative measurement and displays it to the user. This workflow, from sample to result, requires less than two minutes. A technician can perform the test.

What then? Dr. Waltz, a fan of osmometers, says no one is sure. “It's an interesting device. How it plays into the process, I don't know. For instance, I've sent a patient who has an asymmetric dry eye to a friend in town who has the device to go get his osmolarity checked,” Dr. Waltz ex plains. “And his osmolarity is in the drier eye. What that means, I don't know. But there's definitely something to consider.”

Worthwhile Knowledge

For all the uncertainty, however, dry eye experts still regard osmolarity levels as potentially valuable information. At this point, explains Dr. Akpek, clinicians are left with a patient's signs and symptoms as guides to designing a management strategy. A common one is to put patients on artificial tears for years at a stretch. “They don't know if the disease is progressing or not, and before we actually do detect a significant progression of the dryness, then it's usually too late to reverse the disease process,” she says.

The anti-inflammatory therapies commonly used may be misguided, Dr. Akpek suggests. “Maybe that patient was just having some dryness temporarily because of computer use or some office situation or something. I think the osmolarity test would be really useful during the follow-up, to determine what's going on with the patient, because usually the signs and symptoms do not correlate in the case of dry eye.”

Dr. Apek says that she would like to diagnose dry eye before a patient experiences dryness. Currently, before the onset of symptoms and k. sicca, there is very little for a clinician to go on, in terms of diagnosis and patient management — she hopes a tear osmometer would change that, enabling a diagnosis much earlier in the process of the disease. “In some cases, it takes months and months before you can make a decision as to whether the treatment is working,” she says.

A tear osmometer would be very helpful, she believes, even if osmolarity levels still require some study. “Once patients become really dry, there is not much therapy can do. I think those patients can only benefit from tear-conserving strategies, such as plugs or cauterization.”

According to Dr. Waltz, further knowledge about osmolarity and correct levels could have an impact on tear product formulation.

“A lot of people think that the osmolarity will have an effect on patient comfort and effectiveness of the dry eye drop,” he says. “Years ago, an artificial tear called Hydrotears was introduced. It had a low osmolarity, the idea being that there's a high osmolarity in the tears of a dry-eye patient, so by giving a drop of Hydrotears, it would lower osmolarity, it would equal that out. But you'll get patients that react quite strongly occasionally to different brands of artificial tears for reasons that aren't really clear. And one of the thoughts is perhaps osmolarity is one of the drivers of that.” OM