External photograph demonstrating ocular adnexal erythema and edema as a result of chronic topical medications (in this case due to BAK allergy)
Slit-lamp photograph demonstrating abnormal epithelial sheet extending from limbus superiorly and late staining with fluorescein. This sheet of epithelium regressed completely when BAK was eliminated and the patient was treated with preservative-free steroids and topical vitamin A ointment
What Diagnosis Do These Findings Suggest?
We have encountered a patient with ocular surface disease in the setting of chronic topical medication use. The patient has a chronic conjunctivitis along with periorbital skin changes suggestive of allergy. The late staining opaque epithelium extending into the visual axis from the superior limbus represents conjunctival-type epithelium and is consistent with the diagnosis of limbal stem cell deficiency (LSCD) . The etiology of the LSCD was not quite clear at this initial visit. Given the superior location, the differential included superior limbal keratoconjunctivitis and contact lens-induced LSCD. There was no redundancy/staining of the conjunctiva superiorly, but upon questioning the patient did report a past history of soft contact lens wear for a number of years; however she had not worn lenses for over 10 years. The patient’s dry eyes and meibomian gland disease also contribute to her surface disease and inflammation. The other important contributing factor to her ocular surface disease is her history of glaucoma medication use.
What Is the Basic Pathophysiology of the Ocular Surface Disease in the Setting of Glaucoma?
Ocular surface disease and dry eye syndrome (DES) are present in 15% of the elderly population and have been reported in up to 60% of glaucoma patients using topical therapy [1, 2]. OSD in glaucoma patients is often overlooked since the focus of management is typically on the possibility of glaucomatous progression.
Symptoms such as redness, stinging, burning, irritation, and dryness are common presentations of ocular surface disease related to IOP-lowering therapy. Examination findings often include superficial punctate keratitis of the cornea and conjunctiva, tear-film instability, and allergic reactions . Long-term use of topical glaucoma medications may cause conjunctival inflammation and subconjunctival fibrosis (illustrated by the next case).
All classes of glaucoma medications have been reported as a cause of allergic reaction, and each drug class can manifest different allergic and/or toxic reactions. For example, beta blockers cause contact dermatitis in 11–13% of patients, and prostaglandin analogs can manifest as a mild allergic conjunctivitis in 1.5% . Brimonidine-induced ocular allergies have been reported 9–11.5% .
Epithelial toxicity has been of particular interest in glaucoma therapy, most commonly associated with topical beta blockers and prostaglandin analogs .
Topical glaucoma medications can cause disruption of tear-film integrity. It is reported that tear-film breakup time and Schirmer values are abnormal in over 60% of glaucoma patients in addition to significant tear-film hyperosmolarity and meibomian gland loss [6, 7]. Laser scanning confocal microscopy and impression cytology documented glaucoma therapy-induced morphologic alterations of limbus, which may play a role in the glaucoma related ocular surface disease .
Glaucoma medication-induced allergic reaction can present as conjunctival hyperemia, eyelid erythema, and/or eczema. A type IV hypersensitivity reaction typically manifests as chronic eyelid inflammation and contact dermatitis. As this reaction may occur months after exposure, it may be difficult to distinguish this entity from a chronic blepharitis or a low-grade ocular toxicity secondary to preservative exposure. Follicular conjunctival reactions, a combination of type I and IV reactions, have been reported in the literature as common presentations of allergic reactions to glaucoma medications .
Differentiation between ocular surface allergy and toxicity is difficult in daily practice as they are usually coexistent. Allergic reaction presentation can vary from a typical periorbital dermatitis and papillary conjunctivitis to more subtle allergic blepharitis .
Ocular surface disease occurs due to both active compounds and preservatives, and differences are seen among the various classes of therapy [3, 9]. Most of the time, a trial-and-error approach may be necessary in order to reach to the diagnosis. After distinguishing allergy from toxicity, it is critical to discriminate whether the allergy is secondary to the active ingredient versus the preservative. Currently published data are inconclusive, but some studies have found a significant difference in the degree of SPK in patients maintained on preserved versus non-preserved topical glaucoma medications .
Benzalkonium chloride (BAK) is one of the first ophthalmic preservatives introduced and the most commonly used today. It is a cell wall and cytoplasmic membrane detergent and prevents microbial contamination in multi-dose containers. Its cationic quaternary ammonium structure allows it to promote drug transmission into the anterior chamber. BAK has toxic effects on ocular tissues . Polyquarternium-1 is another quaternary ammonium preservative considered to be less toxic to the ocular surface based on studies examining toxicity to corneal and conjunctival epithelial cells; however it has also been shown to cause dendritic keratopathy. A newer generation preservative, SofZia (Alcon, Fort Worth, Texas, USA), functions as a microbicidal agent through oxidative properties and converts to nontoxic by-products after contact with the ocular surface.
In the presented case, multiple factors can contribute to the clinical picture. She has suffered at least two “hits” to her limbus, one is her history of contact lens wear and the other is her glaucoma medication usage. Other factors such as dry eye and inflammation clearly exacerbate the picture. Another common cause of superior LSCD in glaucoma patients is previous glaucoma surgeries like trabeculectomy with or without mitomycin C (Fig. 9.3). These factors tend to have additive effects and ultimately lead to surface failure focally (or globally).
Patient with history of extracapsular cataract extraction and long history of using glaucoma drops presents with superior limbal stem cell deficiency (i.e., iatrogenic LSCD). The patient had a partial response to stopping topical medications and using acetazolamide along with serum tears. He ultimately required a conjunctival limbal autograft from the other eye (which was no-light perception due to end-stage glaucoma)
What Is the Next Step in the Management of This Patient?
In a glaucoma patient with non-visually significant surface disease (mainly bothered by symptoms), the first step is to look for signs of allergy (skin changes, follicles) and discontinue suspected agent (e.g., brimonidine). The next step for a non-visually significant ocular surface disease is to change all drops to preservative-free. In a glaucoma patient with visually significant ocular surface disease, one should be more aggressive, and the first step is usually to hold all topical medications and temporarily use an oral agent (methazolamide or acetazolamide) to control the IOP. Short-term use of corticosteroid drops should also be considered, although one must be alert to the possibility of a steroid-induced elevation in IOP (Table 9.1).
Stepwise management of OSD in glaucoma patients
• Begin with standard management of OSD (i.e., non-preserved artificial lubricants, aggressive treatment of MGD). If definite signs of allergy to topical medications (periocular skin changes, follicular reaction) stop or switch the offending agent (particularly brimonidine)
• If patient is still symptomatic, switch all glaucoma drops to preservative-free agents
• In more severe disease (e.g., visually significant limbal stem cell deficiency or active cicatricial disease), consider stopping all topical medications and temporarily using only oral agents
• A short trial of topical steroids (preferably preservative-free)—if positive response may add topical cyclosporine or lifitegrast for long-term maintenance
• May reintroduce topical glaucoma therapy (one at a time) using preservative-free or non-BAK preserved medications
• Consider SLT/ALT or minimally invasive procedures (e.g., iStent if undergoing cataract surgery) to eliminate or reduce the need for topical medications
In this case, all topical medications including the loteprednol and timolol were discontinued. IOP-lowering therapy with oral acetazolamide was initiated. To help with ocular surface inflammation, preservative-free topical steroid (compounded methylprednisolone 1%) was started at a frequency of every 6 h in each eye. Preservative-free artificial lubricating drops were continued. Oral doxycycline along with lid hygiene/massage was also recommended for her MGD. Finally, to help the LSCD, the patient was also prescribed topical vitamin A 0.01% qhs; however the patient did not get this until a few weeks later.
After 3 weeks, the patient had experienced remarkable improvement with significant reduction in her presenting symptoms. Patient reported that her eyes had not felt this good in years. We concluded that she definitely was allergic to BAK .
Once the surface disease has improved, a trial of a topical medication from a different class of active compound should be implemented but the possibility for cross-reaction should be noted. In cases where recurrent allergy is identified in association with multiple agents of differing drug classes, a BAK allergy must be suspected and a trial of BAK-free or preservative-free medication may be tried.
The concern for ocular surface damage from preservatives, especially BAK, has prompted the shift toward entirely preservative-free medications in single-unit dose vials. Preservative-free timolol has been available for several years in the USA and Europe. Preservative-free prostaglandin analog, tafluprost (Zioptan; Merck, Whitehouse Station, New Jersey, USA), and preservative-free dorzolamide/timolol combination (Cosopt PF; Merck, Whitehouse Station, New Jersey, USA) have been released in the USA as well.
Several studies have reported improved ocular surface symptoms with preservative-free agents , but the results from alternative preservative formulations, particularly with the prostaglandin travoprost-Z (SofZia; Alcon), have been inconsistent . Though efficacious in decreasing ocular surface disease and allergy, the higher cost of these medications largely limits their widespread application.
Three recent trials have studied the two preservative-free therapies approved in the USA, preservative-free tafluprost and dorzolamide/timolol. Significant decreases in subjective symptoms and tear-film abnormalities were found with both agents . Our own clinical experience with these agents confirms that, in glaucoma patients with dry eye symptoms, switching to preservative–free medications help reduce the symptom burden (not eliminate it).
Finally, a patient with multiple allergies or severe ocular surface disease may not be able to tolerate any topical medication. For these patients, laser treatments such as argon laser trabeculoplasty, selective laser trabeculoplasty, or laser cyclophotocoagulation may be considered prior to proceeding with surgical interventions. It has been shown that a longer duration of glaucomatous disease is significantly correlated with worsening of OSD symptoms. In one study, patients with glaucoma diagnoses of less than 6 years had a significantly lower mean Ocular Surface Disease Index score relative to patients with glaucoma diagnoses of 6 years or more .
What About the Long-Term Management of This Patient’s Glaucoma and OSD?
Moderate to severe OSD frequently requires a change of glaucoma medications. Switching to a different topical medication or systemic therapy with carbonic anhydrase inhibitor or performing laser trabeculoplasty or other surgery along with adding treatment to alleviate ocular surface symptoms is possible. Modification of glaucoma therapy due to OSD is practiced in approximately 40% of patients .
In a study of rabbit eyes, the beneficial effects of topical cyclosporine have been demonstrated to reverse adverse ocular surface changes produced by long-term glaucoma medical therapy . It has been shown that glaucoma patients with significant ocular surface changes after topical glaucoma medication usage have altered morphology of subbasal nerve fibers. One study highlights that topical cyclosporine therapy seems to have beneficial effects in dry eye disease due to long-term topical hypotensive medications with improvement in ocular surface changes and central corneal subbasal nerve fiber density. Therefore, topical cyclosporine 0.05% (or perhaps lifitegrast) may be considered in eyes with dry eye disease due to long-term topical glaucoma therapy .
In this case, the patient was started on Zioptan while her acetazolamide was discontinued. Her IOP has remained well controlled. She was started on Restasis in order to help get her off the steroids; however she required a very prolonged taper and continues to require very low dose (one drop every few days) to help control her inflammation and symptoms. Her topical vitamin A was discontinued after 3–4 months but did require repeat treatment later in her course for mild recurrence of the LSCD. At last follow-up, her visual acuity was 20/20 OU with well-controlled IOPs on preservative-free prostaglandin drops.
Case 2: Glaucoma Patient with Chronic Conjunctivitis and Scarring
The patient is a 57-year-old male with complaints of red eyes, foreign body sensation, light sensitivity, and tearing. He has been followed more than 15 years for an underlying diagnosis of primary open angle glaucoma for which has been treated with multiple topical IOP-lowering agents. His symptoms began about 3 years ago and were diagnosed as dry eyes and meibomian gland disease. In addition, he has had recurrent trichiasis of the lower and upper lids which has required multiple epilations. He denies any history of chemical injury or exposure. He works as an employee in an electrical engineering company and does not report any occupational exposure. His current IOP-lowering medical regimen includes fixed-combination dorzolamide/timolol twice daily in both eyes. His past treatments have included tobramycin-dexamethasone, olopatadine, Restasis, and doxycycline.