A national survey found DED in 16.5% of glaucoma patients, significantly higher than 5.6% in non-glaucoma individuals1). Aging is a common risk factor for both diseases, but even after adjusting for age, the prevalence of OSD is higher in glaucoma patients, suggesting the involvement of antiglaucoma medications1).
OSD related to glaucoma treatment is defined as “a chronic imbalance of ocular surface homeostasis caused by the toxic effects of topical medications, leading to tear film instability, epithelial damage, and inflammation.” Preservative-containing antiglaucoma drugs can not only worsen existing OSD but also induce new OSD2)3).
Typical symptoms include dryness, hyperemia, lacrimation, irritation, burning sensation, foreign body sensation, photophobia, and blurred vision. They are assessed using the Ocular Surface Disease Index (OSDI) or DEQ-5 questionnaire. It is not uncommon for symptoms and objective findings to be discordant.
Superficial punctate keratitis (SPK): Observed in 18–54% of glaucoma patients undergoing topical treatment 1). Primarily caused by corneal epithelial damage due to BAK-containing medications.
Decreased tear film breakup time (TBUT): Abnormal TBUT and Schirmer test values have been reported in over 60% of glaucoma patients 1).
Increased tear osmolarity: The number of preserved eye drops used shows a positive correlation with tear osmolarity 1).
Vortex keratopathy: Appears in about 20% of patients using netarsudil, but does not cause visual impairment and resolves upon discontinuation.
Changes in the Conjunctiva and Eyelids
Allergic reactions: Present as hyperemia, conjunctival edema, and eyelid edema. Brimonidine causes follicular conjunctivitis in up to 11.5% of cases.
Meibomian gland dropout: Significantly greater meibomian gland dropout in patients using preserved medications 1). Prostaglandin analogs are associated with increased prevalence of MGD.
Decreased conjunctival goblet cell density: After one year of antiglaucoma medication, the proportion of patients with goblet cell density <50 cells/HPF increased from 2.2% to 32% 1).
Benzalkonium chloride (BAK) is the most widely used preservative in antiglaucoma eye drops 2)3). BAK is a quaternary ammonium compound that disrupts cell membranes and cannot distinguish between pathogen membranes and normal ocular cell membranes.
Switching from BAK-containing medications to preservative-free medications significantly improves ocular surface disease symptoms 2)3). Long-term BAK use is also associated with reduced success rates of filtration surgery2)3).
Number of Medications and Ocular Surface Disease Risk
The risk of DED increases stepwise with the number of medications used1). An increase in the number of daily eye drops is also associated with worsening corneal staining scores and shortened TBUT1).
Even preservative-free formulations can contribute to OSD1). Preservative-free timolol showed shortened TBUT, and preservative-free tafluprost showed increased OSDI1). Beta-blockers were associated with corneal epithelial damage even after adjusting for BAK exposure1).
After trabeculectomy, the presence of a bleb can destabilize the tear film1). However, due to the improvement in the ocular surface from discontinuing medications, some reports indicate that operated eyes have longer TBUT and less corneal staining compared to fellow eyes under medical treatment1).
QDo all glaucoma eye drops have a negative effect on the ocular surface?
A
Not all, but most eye drops can contribute to OSD. BAK-containing drugs have the greatest impact, but even preservative-free formulations have effects from the active ingredient itself 1). Alpha-agonists (brimonidine) have been reported not to be associated with an increased risk of DED when Purite® is used as a preservative 1).
It is recommended to perform a baseline evaluation of OSD before starting antiglaucoma medications 1). This allows appropriate assessment of changes after treatment initiation.
Symptom assessment: The DEQ-5 questionnaire is appropriate for glaucoma patients (because the visual function items of OSDI may be affected by visual field defects due to glaucoma) 1)
QWhich dry eye questionnaire is appropriate for glaucoma patients?
A
DEQ-5 (Dry Eye Questionnaire-5 item) is recommended 1). Since OSDI includes questions about visual function, visual field defects due to glaucoma can affect the score. DEQ-5 evaluates only ocular surface symptoms, allowing a more accurate assessment.
Switch to preservative-free medications: Changing from BAK-containing medications to preservative-free medications significantly improves OSD symptoms 1)2)3). Adherence also improves 1)
Use of fixed combinations: Reducing the number of instillations can decrease total BAK exposure 2)3)
Use of alternative preservatives: SofZia® (travoprost) and Purite® (brimonidine) have less impact on the ocular surface compared to BAK
Sustained-release formulations: Bimatoprost SR (Durysta™) achieves IOP reduction for up to 24 months with intracameral placement, potentially reducing the burden of eye drops
Reduction of Medication Burden via Laser and Surgery
Considering SLT as a first-line treatment can avoid or reduce the use of eye drops 1). MIGS is associated with decreased medication use and improvement in OSD symptoms 1).
Artificial tears: Preservative-free lubricants are recommended 2)3)
Anti-inflammatory treatment: Cyclosporine eye drops and lifitegrast eye drops are effective. Short-term steroid eye drops may also be considered, but caution is needed for long-term use due to complications.
QDoes treatment of ocular surface disease affect the course of glaucoma?
A
Yes, it does. Improvement in IOP reduction has been reported with ocular surface management 1). Additionally, patients with a high number of conjunctival inflammatory cells before surgery have a higher failure rate of trabeculectomy, and long-term BAK use has been reported to reduce the success rate of filtration surgery2)3). Management of ocular surface disease also leads to improvement in OCT signal quality 1).
BAK destroys cell membranes as a surfactant. It exhibits dose- and time-dependent toxicity to corneal epithelial cells, conjunctival epithelial cells, and goblet cells. When multiple eye drops are needed per day, the cumulative exposure to BAK increases, leading to accumulated damage to the ocular surface.
In eyes treated with antiglaucoma medications, inflammatory cytokines such as IL-6, IL-8, IL-1β, and TNF-α are elevated in tears 1). In eyes using BAK-containing medications, elevation of mucosal pemphigoid-9 (a marker of ocular surface inflammation and damage) was observed in 46.7%, significantly higher than 16.7% in eyes using preservative-free medications 1). Both Th1 and Th2 pathways are involved.
Long-term use of antiglaucoma medications reduces the density of corneal sub-basal nerve fibers and increases their tortuosity 1). Damage to the corneal nerve plexus leads to decreased corneal sensitivity, reduced tear secretion, and delayed epithelial healing, worsening ocular surface disease. In animal models, BAK has been shown to significantly reduce corneal nerve fiber density 1).
The group using preserved medications shows greater meibomian gland dropout compared to the preservative-free group 1). Even preservative-free medications have adverse effects on meibomian glands, but the presence of preservatives further exacerbates MGD1). PG formulations have a higher prevalence of MGD compared to non-PG formulations 1).
Nijm et al. (2023) comprehensively reviewed the prevalence, mechanisms, and management strategies of DED in glaucoma patients 1). They showed that evaluation and treatment of ocular surface disease can improve adherence, quality of life, and even optimize intraocular pressure management. A systematic ocular surface disease assessment protocol including symptom evaluation with DEQ-5, inflammation assessment with mucous membrane pemphigoid-9 test, and MGD evaluation with meibography has been proposed 1).
Novel DDS such as intracameral bimatoprost sustained-release implant (Durysta™) and bimatoprost ring (forniceal placement) may reduce the need for eye drops and decrease the burden on the ocular surface 1). The microdose dispenser (Optejet™) delivers microdroplets at a speed faster than the blink reflex, minimizing ocular surface exposure to drugs and preservatives, and is under development.
