Health of the ocular surface is important in treating glaucoma

Patients being treated for glaucoma should avoid unnecessary BAK exposure and undergo diagnostic testing.

Issue: May 15, 2007

ByTerrence P. O'Brien, MD

Terrence P. O’Brien, MD
Terrence P. O’Brien

Ocular surface disease, and dry eye in particular, should not be underestimated in managing glaucoma. Patients with glaucoma and concomitant ocular surface disorders may have incomplete responses to IOP-lowering medications, due in part to damage to the ocular surface. Similarly, some glaucoma treatments may have toxic effects on the ocular surface, and treatment may exacerbate ocular surface disease.

Many glaucoma patients will report to their ophthalmologist or technician that their eyes are chronically dry and irritated. Medications that contain detergents such as benzalkonium chloride (BAK) are harmful to the ocular flora and are likely to exacerbate the pre-existing dry eye condition. Patients being treated for glaucoma should avoid unnecessary BAK exposure and undergo diagnostic testing to detect early changes to the ocular surface. These measures will help ensure that glaucoma management does not threaten the health of the ocular surface.

A new understanding of dry eye

With about 3 million people having glaucoma and about 40 million with some form of dry eye in the United States, it is inevitable that a significant number of glaucoma patients will also have ocular surface disease. Surveys reveal that up to 40% of glaucoma patients report dry eye symptoms.¹

Dry eye affects not only the quantity of tears, but also the quality.
— Terrence P. O’Brien, MD

The term “dry eye” may be inadequate to describe the changes this condition inflicts on the ocular surface. Dry eye affects not only the quantity of tears, but also the quality. Patients with dry eye typically present with abnormal composition of their tear film and the presence of molecular factors on the ocular surface that have deleterious effects on the health of the eye. Recent reports refer to the condition as “dysfunctional tear syndrome” to reflect the range and severity of symptoms.²

Dry eye syndrome may involve loss of goblet cells and stem cells, macropannus, filamentary keratitis and neurotrophic keratopathy. The damage to the ocular nerves may explain the disconnect between signs and symptoms seen in many patients with ocular surface disease – these patients may not be aware of the severe effect of the disease on the ocular surface because of diminished sensation.³

There are several potential causes of dysfunctional tear syndrome including environmental triggers, pollutants, computer use and the rebound effect from over-the-counter vasoconstrictors. Further complicating ocular surface disease is that there are often several concurrent abnormalities on the tear layer that worsen dysfunctional tear syndrome.

BAK effects

BAK is a known contributor to dysfunctional tear syndrome. It is present in many glaucoma medications, especially commonly used prostaglandins. BAK is a quaternary ammonium compound that acts as a cationic surfactant. Although it may increase drug penetration of the corneal epithelium, BAK indiscriminately kills bacteria, microbes and healthy human ocular cells.⁴

BAK toxicity is dose dependent and proportional to the duration of total exposure.
— Terrence P. O’Brien, MD

BAK toxicity is dose dependent and proportional to the duration of total exposure. At low concentration, about 0.0001%, BAK may arrest cellular growth on the ocular surface. Medium concentrations, about 0.01%, can lead to programmed cell death. At high concentration, about 0.05% to 0.1%, necrosis of the cell can occur.^5-7 Specifically, BAK penetrates the cellular membrane, leading to discharge of cellular components and a breakdown of the cell with leakage of intracellular compounds including ions and small molecules.

In short, the presence of BAK on the ocular surface can have negative effects for glaucoma patients, including decrease in corneal epithelial integrity, secondary increase in corneal and conjunctival inflammatory cells, loss of goblet cells and reduction in tear function.⁸ These effects may be more pronounced for glaucoma patients who take several drugs that contain BAK as a preservative.⁹ Extended duration of topical therapy, regardless of type, has been identified as a risk factor for failure of trabeculectomy.¹⁰

BAK may also lead to a decrease in tear-film break-up time, or the time between completion of the blink impulse and evaporation of the tear film.¹¹ This is a significant marker for dysfunctional tear syndrome because if the interblink interval is longer than tear film break-up time (if the tear film is cleared prior to the resurfacing caused by a subsequent blink), then the ocular surface is exposed to external insults.

Another common marker for dysfunctional tear syndrome is inflammation on the ocular surface, which can be expressed by intracellular inflammatory markers present in conjunctiva epithelial cells. In a retrospective review using confocal microscopy of conjunctiva from patients treated with no, one or two or more antiglaucoma medications, Baudouin and colleagues⁹ found significantly higher levels of human leukocyte antigen-expressing cells, an intraepithelial inflammatory marker, in conjunctiva exposed to one or more antiglaucoma medications compared with nontreated conjunctiva. Higher levels of the inflammatory cells were detected in patients with more exposure to drugs containing BAK. The evidence confirms a dose-dependent relationship for inflammation associated with BAK that is exacerbated by exposure to multiple BAK-containing antiglaucoma medications.

Diagnostic testing

Reducing IOP, limiting damage to the optic nerve and maintaining the visual field should be of primary importance in the management of glaucoma. Due to the high incidence of dysfunctional tear syndrome and because its effects on the ocular surface can hamper the effectiveness of glaucoma therapy, it is wise to examine the health of the ocular surface before initiating or continuing therapeutic management. This is especially true for patients who present in the clinic with complaints of ocular dryness and irritation.

There are several useful diagnostic tests for dry eye syndrome. Perhaps the most important is lissamine green stain because it is nontoxic and comfortable for the patient and allows visualizing cells in the dysfunctional state before they become devitalized (Figure 1). Lissamine green stains cells earlier in the degenerative process than either rose bengal or fluorescein stain, allowing for earlier detection of ocular surface disorders. Lissamine green may also be less irritative than other dyes.


Figure 1. Lissamine green stain of dry eye. The punctate green areas indicate dryness.	Figure 2. Fluorescein stain depicting dry eye. The black swirls indicate areas of poor tear flow.

Topical fluorescein stain is useful for evaluating tear-film break-up time (Figure 2). Visualizing the associated changes may be difficult because break-up time can be rapid, but it is vital in detecting inflammation on the ocular surface.

Schirmer’s test can also be useful for evaluating tear production. Results can be difficult to interpret, and there is ongoing debate about the use of anesthesia. However, if anesthesia is not used, and there is no wetting after the filter paper is left in the eye for 5 minutes, then this is a good indication of a severe aqueous deficiency.

Another diagnostic method is clinical examination under confocal microscopy, which can help identify changes to the ocular surface in patients with dry eye.

Conclusions

The interrelationship between dysfunctional tear syndrome and glaucoma is an emerging area of study in ophthalmology. Although understanding the consequences of an unhealthy ocular surface on the management of glaucoma is still expanding, the goal of preserving ocular health remains central. Treatment for one ocular condition, whether dysfunctional tear syndrome or glaucoma, should not damage other parts of the eye, and awareness of the interplay between the ocular surface and lowering IOP should expand so that ophthalmologists can maximize patient outcomes.

References

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