REVIEW CURRENT OPINION Glaucoma therapy and ocular surface disease: current literature and recommendations Zane Anwara,b, Sarah R. Wellika,b, and Anat Galora,b Purpose of review To provide an update on clinical and experimental literature for ocular surface effects of glaucoma therapy and to provide practical guidelines for ophthalmologists treating glaucoma patients with ocular surface disease (OSD). Recent findings Preservatives, notably benzalkonium chloride (BAK), continue to contribute to OSD and demonstrate a variety of toxic ocular effects both in-vitro, and in animal/human studies. Recent literature frequently compares BAK with Polyquad, SofZia, and preservative-free therapies. Some clinical benefit has been demonstrated with newer BAK-free alternatives. Summary BAK-free and preservative-free therapies are becoming available but are not always a feasible alternative. It is important to recognize different clinical manifestations of allergy and chronic inflammation and to discuss options for patients experiencing OSD. Keywords benzalkonium chloride, glaucoma, ocular surface disease, preservatives, recommendations INTRODUCTION photophobia, and distorted vision [3]. OSD primar- Over 60 million individuals worldwide suffer from ily manifests in the cornea and conjunctiva as glaucoma, projected to increase to almost 80 million superficial punctate keratitis (SPK), tear-film insta- in 2020 [1]. Up to 40% of the glaucoma population bility, and allergic manifestations. in the USA requires more than one agent to effec- tively lower intraocular pressure (IOP) [2]. Ocular Superficial punctate keratitis surface disease (OSD) and dry eye syndrome (DES) are present in 15% of the elderly population and SPK encompasses lesions of the corneal epithelium have been reported in several studies to be more that are classified by morphology, and include common in patients with glaucoma. Using the punctate epithelial erosions (Fig. 1), fine and ocular surface disease index (OSDI) score, it has been coarse punctate epithelial keratitis, areolar punctate shown that up to 60% of glaucoma patients have keratitis, and filamentary keratitis. Keratoepithelial OSD, both of which can independently impact chemical toxicity leading to SPK has been of particu- quality of life and compliance [3,4&&,5]. It has lar interest in glaucoma therapy, most commonly been postulated that multiple, daily exposures associated with topical prostaglandin analogs, beta- of the ocular surface to active compounds and blockers, and cholinergics [6]. Early studies esti- preservatives can worsen the burden of OSD in mated a prevalence of 44–46% of SPK in glaucoma this population. aMiami Veteran Affairs Medical Center and bDepartment of Ophthal- mology, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, CLINICAL MANIFESTATIONS OF OCULAR USA SURFACE DISEASE FROM Correspondence to Sarah R. Wellik, MD, Bascom Palmer Eye Institute, ANTIGLAUCOMA THERAPIES 900 NW 17th Street, Miami, FL 33136, USA. Tel: +1 305 326 6000; fax: The clinical presentation of OSD varies in severity +1 305 575 3312; e-mail: [email protected] and includes symptoms of dryness, redness, Curr Opin Ophthalmol 2013, 24:136–143 tearing, irritation, burning, foreign body sensation, DOI:10.1097/ICU.0b013e32835c8aba www.co-ophthalmology.com Volume 24 Number 2 March 2013 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Glaucoma therapy and ocular surface disease Anwar et al. [3,14&,15,18&&]. Hyperosmolarity is likely an import- KEY POINTS ant factor, but as yet understudied due to its OSD secondary to glaucoma therapy commonly inability to be readily obtained clinically [19]. manifest as SPK, allergy, and tear-film instability. Recent in-vivo and animal studies continue to Allergic manifestations demonstrate the toxic effects of preservatives, mainly Allergy induced by topical glaucoma treatment is BAK, through various mechanisms. primarily seen in the conjunctiva and periorbital Although many crossover clinical trials show benefit to areas as conjunctival hyperemia, chemosis, lid preservative-free therapies, there are multiple studies edema, periorbital erythema or eczema, and itching that show no improvement of OSD after crossover. [20]. These symptoms are mediated through IgE In patients with medication related OSD (but not type I hypersensitivity or delayed type IV hyper- allergy), artificial tears, anti-inflammatory therapy, and sensivity which resolve after withdrawal of the BAK-free or preservative-free therapy can be used if offending agent. Clinical presentation from an feasible for the patient. allergic reaction can vary between a typical peri- orbital dermatitis and papillary conjunctivitis to more subtle allergic blepharitis [21]. Drug-induced allergic reactions occur due patients on pilocarpine [7,8]. More recently, large to both active compounds and preservatives and multicenter studies from Europe found a SPK preva- differences are seen between the classes of therapy lence of 18–31% and smaller studies from Japan [20,22,23]. Allergic conjunctivitis and dermatitis have found SPK to be present in 20–54% of patients to prostaglandin analogs are relatively rare and are on antiglaucoma therapies [9&,10–12]. Furthermore, reported at 1.5% in patients on latanoprost [20]. the European studies found a significant difference Beta-blockers, however, have been shown to cause of SPK in patients on preservative versus nonpreser- contact dermatitis in 11–13% of patients [24] and vative topical antiglaucoma therapy (25 versus 9% dorzolamide has reported rates of 3% dermatitis and and 19% versus 9%) [11,12]. 4% conjunctivitis [6]. Ocular allergy to brimonidine has been reported at 9 and 11.5% in two separate long-term studies [25,26]. Tear-film instability The disruptive effects of topical glaucoma medi- cations on tear film integrity are well known Other manifestations [13,14&,15–17]. Objective measures of tear-film A variety of other clinical manifestations of break-up time (TBUT), Schirmer’s test, osmolarity, topical glaucoma treatments are possible. Pseudo- and meibomian gland score have been used to assess pemphigoid is a cicatrizing conjunctivitis that tear-film functionality of patients on long-term mimics ocular mucous membrane pemphigoid and short-term therapy. It is reported that TBUT (MMP) in presentation and is distinguished by con- and Schirmer values are abnormal in over 60% of junctival biopsy. A 2004 study from Thorne et al. glaucoma patients in addition to significant tear- [27] evaluating MMP and pseudopemphigoid found film hyperosmolarity and meibomian gland loss that the most common associated diagnosis of the FIGURE 1. Superficial punctate keratitis identified in the left eye of a patient with primary open angle glaucoma on travoprost preserved with Sofzia (in comparison to the patient’s right eye on no topical therapy). 1040-8738 ß 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-ophthalmology.com 137 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Glaucoma pseudopemphigoid cohort was glaucoma with long- proposed to promote drug transmission into the term topical treatment (28%), and that most of anterior chamber. these patients were receiving multiple agents BAK has been under much scrutiny due to its (97%) including a beta-blocker (87%). Recurrent toxic effects on ocular tissues. Recent reviews herpes simplex keratitis secondary to latanoprost, have demonstrated the large body of literature on bimatoprost, and travoprost has also been described effects of BAK on a variety of clinically relevant in case reports. It has been suggested that the ocular tissues [21,32]. Table 1 summarizes the most prostaglandin analogs promote viral shedding in recent in-vitro and animal studies [33,34&,35,36&, ganglion cells leading to flare-ups directly associated 37–39,40&,41&,42&&,43–45]. Most of the in-vitro with the prostaglandin use in these patients literature has studied corneal and conjunctival [28,29]. In addition, corneal decompensation after epithelial cell viability with BAK exposure from 5– dorzolamide use has been reported in two series. 30 min. BAK-preserved antibiotics have been shown A presumed decreased in endothelial function to significantly decrease in the tear film starting at from previous intraocular surgery was thought to 30 s, thus, challenging the clinical value of the many potentiate the toxic effects of dorzolamide [30,31]. studies with relatively long exposure times [46]. To date, vernal-like keratoconjunctivitis charac- Polyquarternium-1 (Polyquad) is another qua- terized by tarsal or limbal papillae has not been ternary ammonium preservative considered to be reported in the literature as a secondary effect of less toxic to the ocular surface based on studies antiglaucoma therapy. Figure 2 demonstrates a examining toxicity to corneal and conjunctival patient seen in our clinic with primary open angle epithelial cells. A newer generation preservative glaucoma on brimonidine who presented with SofZia (Alcon, Fort Worth, Texas, USA) functions superior limbal Horner Trantas Dots and superior as a microbicidal agent through oxidative pro- tarsal follicles that resolved after discontinuation perties. This ionic buffer solution, comprised of of brimonidine (Wellik S, Galor A, personal borate, propylene glycol, sorbitol, and zinc chloride, communication). converts to nontoxic byproducts after contact with ocular surface cations. More recently,