Glaucoma and ocular surface

Recent predictions on glaucoma-related ocular morbidity project about 112 million patients to be affected globally by the year 2040.[1,2] Topical instillation of anti-glaucoma medications has been noted to cause pro-inflammatory cytokine secretion by conjunctival cells.[3,4,5] Three or more months of therapy may be enough to cause significant sub-clinical inflammation, which reflects as an increased expression of HLA-DR on conjunctival epithelial cells.[6] Symptomatic assessments place the prevalence of glaucoma-related ocular surface disease to range between 48% and 59%, while that based on signs has been noted to be as high as 78%.[7,8,9] Female gender, increasing age, pre-existing dry eye disease (DED), type and duration of glaucoma, number and frequency of glaucoma medications, and benzalkonium chloride (BAK) preservatives are the prominent risk factors for DED in glaucoma patients.[10,11,12] The reported adverse effects of topical glaucoma medications include worsening of DED, drug-induced dermato-conjunctivitis, follicular conjunctivitis, allergic contact dermatitis, impairment of corneal wound healing, corneal limbal stem cell deficiency, and also severe reactions such as pseudo-pemphigoid and mucous membrane pemphigoid.[13] The most commonly used anti-glaucoma medications, timolol and latanoprost, on long-term instillation result in chronic ocular surface disease with timolol-induced corneal punctate erosions, burning sensation, hyperemia, tear film alterations, and corneal anesthesia. Topical latanoprost therapy results in increased pigmentation of the iris, hypertrichosis, hyperemia, allergic contact dermatitis, and cystoid macular edema.

The mechanisms of BAK toxicity include a detergent effect that alters the tear film stability, direct damage to the corneal/conjunctival epithelium, and immune allergic reaction.

The influence of the active ingredients in glaucoma medications on all the components of the ocular surface including the nasolacrimal duct and periorbital area have also been elaborately reported in the literature.[13] Long-term anti-glaucoma therapy-induced dry eye has been observed to be associated with decreased corneal sub-basal nerve fiber layer density.[14] BAK preservative in anti-glaucoma medications promotes the activation of lipooxygenases, synthesis and secretion of eicosanoids, inflammatory mediators, and many cytokines such as interleukin (IL)-1a, tumor necrosis factor, IL-8, and IL-10, which cause irritation, delayed hypersensitivity, and allergic reactions.[15] Besides long-term anti-glaucoma therapy affecting the ocular surface due to the adverse influence of the ocular hypotensive drug ingredients and BAK preservatives, glaucoma filtering surgeries, adjunct procedures such as bleb needling, and anti-metabolite treatments used during the surgical procedures also have an adverse influence through direct toxic effects to the ocular surface epithelium and the limbal stem cells, meibomian glands or goblet cell damage, interference with the optimal tear resurfacing, and predisposition to ocular surface infections.[13,16,17] Newer anti-glaucoma medications such as netarsudil also affect the ocular surface with reticular macrocellular corneal edema.[18] Significant ocular surface disease in patients with glaucoma results in poorer quality of life and patient compliance to treatment adherence, worsening the vision-related quality of life in these patients.[19]

Adopting treatment protocols to include mandatory periodical ocular surface evaluations in glaucoma patients on long-term medications will benefit early detection, DED treatment initiation, and ocular hypotensive therapy modification in these eyes for DED. Though the role of preservative-free anti-glaucoma medications has been heralded to help ocular surface optimization in these eyes, evaluation of altered tear neuropeptide levels and central corneal SBNFL density in eyes on chronic topical hypotensive therapy did not seem to show a significant difference between the BAK preservative and BAK-free anti-glaucoma therapy.[20]

Management of DED in patients with glaucoma necessitates modifications in the treatment medications, addition of adjunct therapy with topical lubricants, and immuno-modulating agents.[21] Newer preservatives, such as stabilized oxychloro complex, polyquaternium-1, sodium perborate, and edetate disodium, and SofZia, which contains ion-buffered borate, zinc, and sorbitol, have been heralded as more ocular surface epithelium-friendly agents.[22] Adopting selective laser trabeculoplasty or minimally invasive glaucoma surgery can serve to decrease or eliminate topical therapy, thus contributing to alleviating ocular and systemic side effects associated with chronic topical therapy.[23] In conclusion, glaucoma and DED are diseases that have an increasing prevalence with age with resultant poor quality of life. Hence, there is a greater need to evaluate ocular surfaces optimally in patients of glaucoma to detect therapy-related or surgery-related ocular surface disease and institute therapy in order to lessen the burden of ocular surface morbidity in these patients.