The Ocular Surface in Glaucoma
Christophe Baudouin
There is a large body of evidence from experimental and clinical studies that the long-term use of topical drugs may induce major ocular surface changes. Many clinical manifestations associated to a low grade chronic inflammation have been described in patients receiving antiglaucoma treatments for long periods of time.1,2 Glaucoma treatment may cause chronic inflammation or aggravate a concomitant ocular surface disease. In clinical practice, glaucoma treatment often last for decades. Patients may present pre-existing ocular surface impairment, such as dry eye, meibomian gland dysfunction or chronic allergy, and are very frequently treated with two or more topical ophthalmic formulations. Indeed the OHTS reports that 40% of patients were using more than one drug after five years, and the CIGTS showed 75% of patients using two or more drugs within two years of initial glaucoma treatment. These findings explain that clinical practice often does not fit the apparent safety profiles of drugs tested in clinical trials for short period of time, alone, and only in patients without active ocular surface disorders.
The need for sterility in multidose eyedrops lead to the inclusion of an antimicrobial preservative in these solutions, most frequently the quaternary ammonium benzalkonium chloride (BAK). In some patients - and with long-term treatments - allergic or inflammatory reactions are experienced, including redness, stinging, burning, irritation, eye dryness, or less frequently, conjunctivitis or corneal damage. Most studies imply a direct correlation between the presence of preservatives and the symptoms experienced during antiglaucoma therapy.1,2 In a recent large scale European observational study,2 involving 9658 patients, all recorded symptoms and signs were significantly more frequent in patients taking preserved medications compared with those taking preservative-free formulations (p < 0.0001 for all). For example, foreign body sensation was experienced by 42% of the preservative recipients compared with 15% of those taking non-preserved medication, while stinging or burning was noted in 48% versus 19%, and dry eye sensation in 35% versus 16% of the recipients, respectively.
Most effects observed in glaucoma patients are therefore unlikely to be due to the active ingredients in all cases, since toxicity of the preservatives has been well documented experimentally as well as harmlessness of most active compounds when unpreserved.
BAK-containing eye drops reduce the stability of the tear film via a detergent effect on the lipid layer that increases the rate of tear evaporation. These alterations to the function of the tear film are associated with a conjunctival inflammatory response and an epithelial metaplasia affecting goblet cells and transmembrane mucins. Ocular surface imprints from glaucoma patients on long-term treatment thus showed a reduction of almost 50% in the density of goblet cells and conjunctival inflammatory changes in patients receiving treatments with BAK compared to unpreserved beta-blockers.3
A range of conjunctival epithelium changes is also observed in long-term users of antiglaucoma medication.4,5,6 These include conjunctival epithelium metaplasia, inflammatory infiltrates throughout the conjunctiva, increased release of proinflammatory cytokines and overexpression of immune-associated markers, such as HLA DR, interleukins or receptors associated to TH1 and TH2 cells.5 These inflammatory changes are observed in more than 60% of asymptomatic patients and all patients with clinical evidence of ocular surface impairment. They are directly related to the number of preservative containing eye drops.3-5 Immunohistochemical studies have also indicated that progressive subconjunctival fibrosis can occur, even without clinical sign of intolerance, which could directly influence the outcome of filtration surgery. The success rate of surgery thus varies widely, from 90% in previously non-treated patients, down to 45% in patients receiving long term treatments.7 Hence it appears that prolonged use of topical antiglaucoma medications can compromise trabeculectomy. Given that ocular toxicity of preservatives is well documented in a large variety of experimental or in vitro studies,8-10 it seems highly likely that preservatives, particularly BAK, are associated with a higher risk of trabeculectomy failure.
The use of preserved eye drops thus induces side effects of variable intensity and severity, which affect the ocular surface as well as deeper ocular structures, and are not fully the reflect of short-term clinical trials. These side effects may decrease treatment compliance and enhance the failure of glaucoma surgery, resulting in inadequate control of intraocular pressure in glaucoma patients. Studies both in vitro and in vivo have widely demonstrated that exposure to preservatives (even at low doses) results in histological, inflammatory, and toxic changes at the surface of the eye. Therefore, on the basis of all these experimental and clinical reports it is advisable to use benzalkonium-free solutions whenever these are available on the market.