Search continues for consensus on dry eye definition, diagnosis

Dry eye has garnered increased attention in recent years, but experts contend there is no true definition of what constitutes true dry eye disease.

The lack of a uniform definition in part reflects a lack of universally accepted diagnostic criteria, which in turn obfuscates the understanding of the impact of dry eye on both a patient and population scale. According to OSN Cornea/External Disease Board Member Terrence P. O’Brien, MD, diagnosis and management of dry eye is critically important, especially in refractive surgery candidates. But with no objective criteria and diagnostic protocols, universal treatment protocols have been difficult to develop.

“Depending on how you define [dry eye], you have a range in the population anywhere from 5% of the people all the way up to 80% of the people, depending on the population,” Dr. O’Brien said. “Historically, the challenge has been defining the condition and then setting parameters for proper diagnosis, and then, of course, the treatment spins off of that.”

Research in the past decade has narrowed the knowledge gap.

Terrence P. O’Brien, MD, noted a disconnect between dry eye symptoms that patients describe and clinical signs he observes on exam. Image: Graham WF, Bascom Palmer Eye Institute

“I think the one thing that is clear is that it is a much more prominent and prevalent condition than we thought in the past, and you need to look for it to diagnose it,” Dr. O’Brien said. “I think the role of measuring tear film osmolarity is gaining interest because it may be a game changer in terms of how we look at the ocular surface and how we approach these patients. So there may be some quantitative, or at least some semi-quantitative, numbers that would guide you as to whether you would proceed or not.”

No definitive answers

Dry eye is recognized as a spectrum disorder and is largely diagnosed based on patient-reported symptoms followed by identification of hallmark signs during clinical examination. However, Dr. O’Brien noted, there is a lack of consensus on the degree of symptomatology necessary to make a diagnosis, as well as a disconnect between what patients report and what the physician sees on exam.

“There has been a real mismatch between symptoms and signs of the disease. We will have some patients that are minimally symptomatic, but they will have significant signs, like staining of the cornea or a rapid tear film breakup time, and vice versa,” he said.

“I have been very impressed that the clinical signs do not necessarily correlate with the symptoms,” Edward J. Holland, MD, OSN Cornea/External Disease Board Member, said. “We see some patients with significant punctate staining of the cornea and you would predict that the patient would be miserable, but their complaints are pretty mild. The converse is also true with patients having minimal findings but with significant complaints regarding dry eye symptoms.”

Edward J. Holland

Although dry eye may not be readily apparent on examination, recent evidence suggests that untreated dry eye will progressively worsen.

“If you do not treat, these conditions can become chronic and progressive, and symptoms get worse over time. That has to be taken into account,” Dr. O’Brien said.

The increasing focus on dry eye, as well as the recognition of its progressive nature coupled with an increase in population-based risk factors, may suggest that dry eye is a looming public health threat. Major population-based studies have reported a wide variance in prevalence of dry eye, ranging from 5% to 30% or higher.

The wide range, though, may not reflect conflicting evidence as much as the broad range of presentation of dry eye syndrome and methodologic differences. According to Janine A. Clayton, MD, Deputy Director, Office of Research on Women’s Health, National Institutes of Health, the differences may be partly explained by the fact that the studies were conducted in different populations using different definitions of dry eye.

Dr. Clayton chaired a subcommittee on the epidemiology of dry eye disease during the 2007 International Dry Eye Workshop, which was an attempt to consolidate all of the knowledge base on dry eye. The committee’s report noted a “need to build consensus on appropriate dry eye diagnostic criteria for epidemiologic studies.”

For instance, the report noted, researchers in the U.S.-based Women’s Health Study, which relied on patient reports of severe symptoms or a physician’s diagnosis, estimated a prevalence of 7.8%. The Salisbury Eye Evaluation Study and the Beaver Dam Eye Study, using much less stringent criteria, each reported dry eye prevalence of about 14%. Meanwhile, studies in Asian populations, using patient-reported symptoms of any severity, reported prevalence as high as 35%.

In determining the actual number, the report said, “one might surmise that the true prevalence of moderate-to-severe dry eye lies somewhat close to the lower bound of the spectrum, whereas the inclusion of mild or episodic cases would bring the estimate in closer proximity to the higher estimates observed.”

“Each of those studies had some different definitions of dry eye, and they had populations that were different ages in some cases,” Dr. Clayton said. “We do see suggestions that there is some variability, some real differences in the prevalence of dry eye in various populations around the world, and that there are some ethnic and racial differences.”

Another challenge to gathering epidemiologic data is that many of the studies published so far have relied on vague or general terminology to describe symptoms. That, too, reflects the absence of a uniform definition and objective diagnostic criteria of dry eye.

“You do not have this issue when you want to look at the incidence or prevalence of hypertension because it is not symptom based and we have an objective definition for the disorder,” Dr. Clayton said. “We do not all agree upon the dry eye definition, and if we had a single objective test, then we would not have this issue.”

Public health impact

Although the impact of dry eye on various populations remains somewhat unknown, epidemiologic data has verified some risk factors that contribute to dry eye. Most prominently, women and those who are older in age face an increased chance of developing ocular surface irregularities related to tear deficiency.

Because older patients are living longer and have more active lives, coupled with the rise of video screen use and environmental pollutants that challenge the ocular surface, it is probable that dry eye will increase in prominence in the public health sphere, according to Dr. Clayton.

Janine A. Clayton

“There are more challenges to the ocular surface — be they environmental, chemical, occupational, recreational, what people want to do, be involved in the computer and the aging of the population — that will all combine to likely increase the number of people who will be seeking dry eye treatment,” Dr. Clayton said.

The 2007 dry eye report also noted that the morbidity of dry eye has the potential to have a significant impact in the years ahead given that by 2050, the number of people between the age of 65 and 84 years will rise 100% and the number of individuals over the age of 85 years will rise 333%. According to Dr. Clayton, the associated morbidity, in terms of costs and burden of patient management related to lost work time and impact on the health care system, is significant.

On an individual patient level, the impact of dry eye is something that is already being seen in research studies and by clinicians in the exam room.

“Vision is impacted by this, and in the past that is something that has been ignored, the impact on visual function, but I think dry eye certainly does contribute to visual signs and symptoms,” Dr. O’Brien said.

And while the diagnosis of dry eye is complicated by all the unknowns, the ramifications of missed diagnosis can be dire.

Diagnosis

According to Dr. O’Brien, the lack of a single, universally accepted, objective test for dry eye suggests that a battery of tests may be necessary to assess dry eye and to drive treatment decisions. A patient questionnaire, such as the Ocular Surface Disease Index, which may be particularly useful for refractive surgery candidates, can help focus the use of diagnostic tests.

In addition, vital staining of the conjunctiva and cornea, with both fluorescein and lissamine green, can be telling; as well, measures of tear film breakup time can give an indication of tear function in the eye, Dr. O’Brien said.

“We do not have any one single test that is absolutely pathognomonic or diagnostic,” he said. “In terms of the severity criteria that we used in the Delphi Panel and the Dry Eye Workshop, the severity and frequency of dry eye symptoms is one thing, and visual symptoms and signs are another.”

Patient-reported symptoms, derived either from a questionnaire or through a patient history, can be important to both narrow the differential and identify risk factors that may serve as a tip-off, according to Dr. Holland. Whereas patients may complain of burning and itching, which may also manifest from blepharitis or allergy, dry eye patients will typically have worsening symptoms as they attempt to use their vision or blink over the course of a day, as opposed to blepharitis patients, who usually have their worst symptoms in the morning. Although all three ocular surface diseases may prompt itchiness, allergy patients more often report rubbing their eyes than do blepharitis or dry eye patients.

Clinical signs may help differentiate types of dry eye and determine treatment strategies. Patients with aqueous tear deficiency typically have interpalpebral injection of the conjunctiva on lissamine green staining, and more advanced cases will have punctate staining of the cornea with fluorescein.

In comparison, patients with evaporative dry eye due to meibomian gland dysfunction produce tears, but the tears are of insufficient quality to adhere to the ocular surface. These patients, Dr. Holland said, will have neovascularization and engorged vessels around the meibomian gland orifices, abnormal secretion of oil at the lid margin or hardened secretion. Foamy tears, formed by lipases that are released due to abnormal meibomian gland secretions and from the breakdown of bacteria on the lid margin, are another telltale sign. With lissamine green staining, meibomian gland dysfunction produces uptake on the conjunctiva where it intersects the lower lid.

“These patients have a secondary dry eye because the unstable oil layer of the tear film causes an increased, more rapid deterioration of the tear. So they are making the aqueous tears, but the tears are unstable and evaporating more rapidly, leading to secondary dry eye,” Dr. Holland said.

Treatment decisions

Patients with low quantity or low quality tears may require different treatment regimens. According to Dr. Holland, treatment of meibomian gland disease starts with lid hygiene and hyperthermia therapy to the lids, typically used in conjunction with a broad-spectrum antibiotic treatment.

Dr. Holland said he prefers to use AzaSite (azithromycin, Inspire) because of the “triple threat” mechanism of this new medication.

“AzaSite improves the quality of meibomian gland secretions toward normal, has broad-spectrum anti-infective properties and has anti-inflammatory properties,” he said.

“AzaSite, being a topical medication, has taken the place of doxycycline as the second-line therapy because it is a local therapy instead of a systemic therapy. We use AzaSite like we did doxycycline. We treat the patient once a day for a month, then we rotate them off, we see how they respond, and then sometimes we rotate them back on a month or two later, and that is how we used the doxycycline oral therapy,” he said.

Therapy may be supplemented with omega-3 oral nutritional supplements, which alter meibomian gland secretions. Patients who fail this three-tiered treatment and patients with facial rosacea may require oral minocycline or doxycycline, which can act as a lipid-altering agent.

“If the patient is still very symptomatic with keratoconjunctivitis, if there are significant corneal findings with neovascularization, we recommend topical steroids for that patient,” Dr. Holland said.

Aqueous tear deficiency, whether situational or chronic, requires tear-replacement therapy, preferably with an agent that is preservative-free. Patients with chronic tear deficiency may benefit more from anti-inflammatory therapy, to both stimulate tear production and slow progression of the disease.

“If we think about patients with aqueous tear deficiency and inflammation of the lacrimal gland and the conjunctiva, we know it is a chronic disease, and we know it is going to progress. Treatment to reduce the inflammation and potentially prevent the progression makes a lot of sense to me,” Dr. Holland said. “Topical cyclosporine has been a major breakthrough in the management of dry eye. We have seen a significant improvement in symptoms, an increase in tear production and a reduction in the need for frequent artificial tears.”

However, he added, “because about 17% of patients can have discomfort with the initiation of cyclosporine alone, we pretreat the patient for 2 weeks with topical loteprednol, which is a very effective steroid with a good safety profile. This combination of induction with loteprednol and maintenance therapy with cyclosporine has been very effective in the management of aqueous tear deficiency dry eye.”

In severe cases, punctal occlusion, either with plugs or thermal cautery, can help keep tears on the ocular surface longer. – by Bryan Bechtel

Part two of this cover story will explore the ramifications of a dry eye diagnosis for refractive surgery candidates in a future issue of Ocular Surgery News.

Is Schirmer’s test of any value in evaluating dry eye?

References:

• The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):75-92.
• The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5(2):93-107.

• Janine A. Clayton, MD, can be reached at Office of Research on Women’s Health, Office of the Director, National Institutes of Health, Department of Health and Human Services, 6707 Democracy Blvd., Suite 400 MSC 5484, Bethesda, MD 20892-5484; 301-402-1770; fax: 301-402-1798; e-mail: Janine.Clayton@nih.gov.
• Edward J. Holland, MD, can be reached at Cincinnati Eye Institute, 580 South Loop Road, Edgewood, KY 41017; 859-331-9000; e-mail: eholland@fuse.net.
• Terrence P. O’Brien, MD, can be reached at Bascom Palmer Eye Institute, 7108 Fairway Drive, Palm Beach Gardens, FL 33418; 561-515-1544; fax: 561-515-1588; e-mail: tobrien@med.miami.edu.