The intersection of topical therapy for elevated IOP and ocular surface damage has become an increasingly important focus for eye-care practitioners. The prevalence of glaucoma for populations aged 40 to 80 years is 3.54% globally and 3.36% in North America based on the 2013 Meta-Analysis by Tham, Yin-Chung et al.¹ Up to 5 million people in North American alone have primary open-angle glaucoma (POAG) or primary angle-closure glaucoma (PACG), and these prevalence rates are projected to increase with an aging population.¹

The use of ocular hypotensive medications is associated with decreased tear production, allergic reactions, hypersensitivity reactions, foreshortening of conjunctival fornices and conjunctival scarring, all of which can contribute to development of dry eye disease (DED) in a population already at increased risk due to advanced age (Table 1). Preservatives, including benzalkonium chloride (BAK), are one of the most guilty and common contributors, well known to damage the ocular surface. Timoptic (timolol maleate, BAK), for example, is a routinely prescribed, now generic ocular hypotensive and well known to create significant signs of DED. With progression of glaucoma, the increased frequency, variety and number of aqueous suppressants and other agents strategies added to the drop regimen increase exposure to subsequent doses of preservatives, leading to worsening corneal surface toxicity. Newer preservatives, including Purite (Allergan), sorbic acid, SofZia (borate, sorbitol, propylene glycol and zinc, Alcon) and Polyquad (Alcon), have lower ocular surface toxicity.

PATHOPHYSIOLOGY

Dry eye disease

The development of DED is at least in part the result of tear hyperosmolarity on the ocular surface. Increased osmolarity triggers the release of inflammatory mediators, like IL-1+, TNF-alpha and matrix metalloproteases, which leads to detachment and apoptosis of the corneal epithelium and loss of goblet cells, which produce the mucin layer of the tear film. The result is tear film instability and further propagation of this inflammatory cascade. This inflammatory cycle damages the epithelium, causing discomfort and dry eye sensation. Corneal nerve damage leads to neurogenic inflammation of the ocular surface epithelium and subsequent lacrimal gland insufficiency with subsequently reduced lacrimal outflow. Topical preservatives, like BAK, used long term can also lead to tear film instability and trigger this inflammatory cascade.

Impact of glaucoma and concomitant dry eye

Medication compliance is an important hurdle every glaucoma specialist battles for control of this blinding chronic disease. Even the most determined patient can be discouraged when DED begins to affect their vision while adhering to a prescribed glaucoma treatment regimen.

The psychological impact of battling a vision-threatening disease while dealing with bothersome ocular surface compromise can significantly affect quality of life and create a major barrier to treatment. Not surprisingly, research supports this observation, including an observational cross-sectional study by Rossi et al grading quality of life based on the Ocular Surface Disease Index (OSDI).²

The OSDI is a validated symptom inventory consisting of 12 questions frequently used to measure the severity of DED in clinical trials based on ocular discomfort, visual disturbance, and visual function. This study analyzed 61 patients treated with topical glaucoma medications and demonstrated that quality of life was significantly reduced among those patients with concomitant DED. Even more compelling, DED had a greater negative influence on the quality of life in this population than the presence of glaucoma itself.²

Clearly, quality of life dictates that glaucoma needs to be treated concurrently with DED.

DRY EYE TREATMENT CONSIDERATIONS IN GLAUCOMA

Treatment paradigm

Dry eye treatment in glaucomatous populations starts with minimization of exposure to unnecessary preservatives by early intervention with laser therapy and alternative treatments including selective laser trabeculoplasty (SLT), compounding drops and preservative-free (PF) drops as well as surgical interventions such as minimally invasive glaucoma surgery (MIGS). The use of PF drops has been shown to reduce dry eye sensation relative to preservative (P) eyedrops, as seen in the evaluation of PF vs. P beta-blocking eyedrops in Jaenen et al. In their study, 16% of patient on PF drops reported dry eye sensation vs. 35% on P drops. Furthermore, PF drops demonstrated reduced foreign body sensation.³

Additionally, Uusitalo et al compared BAK latanoprost to PF tafluprost in a meta-analysis of 339 glaucoma patients and demonstrated a significant decrease in ocular surface disease symptoms with tafluprost. In addition, PF tafluprost was non-inferior to BAK-preserved latanoprost in reducing IOP.⁴ Cost, however, becomes an important consideration depending on the patient population. For example, timolol (Timoptic, Bausch + Lomb) (P) is $7 while Ocudose (PF) is $500 with a GoodRx coupon.

Alternatively, fixed combination glaucoma medications like timolol/dorzolamide (Cosopt, Akorn), timolol/brinzolamide, and brinzolamide/brimonidine (Simbrinza, Alcon), despite their cost, are commonly utilized as they improve compliance while also reducing exposure to preservatives.

Finally, multiple combinations of ocular hypotensive active pharmaceutical ingredients are available with full advance cash payment, off label and without FDA approval, from compounding pharmacies like Imprimis and Ocular Sciences.

Selective laser trabeculoplasty

Early treatment with SLT has become increasingly popular as it has shown to be comparable to aqueous suppressant monotherapy, with IOP reduction between 10% to 40%. The clinical effect wanes over time, requiring repeat SLT.

A prospective randomized controlled clinical study by Lai et al evaluating 29 patients with POAG or ocular hypertension in patients without previous treatment compared randomized 360-degree SLT vs. topical medication in the contralateral eye and found similar reductions in mean IOP: 32.1% reduction with SLT and 33.2% in topically treatment eyes.⁵ The failure rate of SLT defined as an IOP >21 mm Hg at 5 years in this study was 27.6%. In conclusion, this study demonstrated that approximately three out of four patients had a sustained response to SLT, favorably compared to topical medications as a first-line therapy.

Katz et al also demonstrated similar results over a shorter study treatment period of 9 to 12 months with an IOP reduction of 34.6% in SLT eyes vs. a 39.5% reduction in the prostaglandin medical therapy group.⁶

An important consideration for uninsured or underinsured patient populations is cost. A 2019 study from Gazzard et al demonstrated that SLT was more cost effective compared to conventional therapy.⁷ Gazzard et al explored the use of SLT as a first-line treatment of ocular hypertension and glaucoma vs. eyedrops. This multicenter randomized control trial enrolled 718 patients and demonstrated that 74.2% of the patients receiving SLT did not require drops to maintain target IOP after 36 months, and the target IOP was maintained at 93% of follow-up visits compared to 91.3% in the group with eyedrops.⁷ This paper supports a change in clinical practice with SLT arguably being the superior first-line therapy rather than conventional eyedrops.

MIGS and other novel treatments

MIGS represents a growing field in recent years and can be broadly categorized into four approaches. Trabecular meshwork bypass includes the Trabectome, Goniotome (MST, Inc., formerly NeoMedix), Kahook Dual Blade, gonioscopy-assisted transluminal trabeculotomy (or GATT) and the iStent (Glaukos). The TM bypass approach with the iStent and iStent Inject (Glaukos) and Hydrus (Ivantis) are approved to be done in conjunction with cataract surgery.

The second approach is a long established ciliary destructive procedure, endocyclophotocoagulation (ECP), which reduces aqueous production utilizing focal thermal injury to the secretory ciliary epithelium. Originally, ECP was indicated for uncontrolled end-stage secondary glaucoma, but it has been more recently presented an effective alternative for patients with a poor prognosis for penetrating drainage surgery.

Suprachoroidal shunts represent a third approach, including the CyPass micro-stent (Alcon), which was recently removed from the market following an FDA warning regarding delayed endothelial cell loss. Finally, sub-conjunctival filtration can be used with the XEN gel stent (Allergan).

Novel therapies emerging also include the iDose Travaprost (Glaukos), which is a biodegradable implant placed in the anterior chamber; Bimatoprost Ring (Allergan), which is a silicone ocular insert that releases PF bimatoprost to the ocular surface; and Bimatoprost SR (Allergan), which is a titanium implant that releases the active ingredient in Lumigan into the anterior chamber with first-order pharmacokinetics, utilizing a trans-corneal 28-gauge needle (Table 2).

Treatment of DED

When treating DED, first-line treatments for aqueous tear deficiency are focused on the use of artificial tears. For patients with mild disease four times a day or less, use of P-containing artificial tears can be an accepted therapy, although as mentioned previously, the cumulative P effects can lead to tear film instability. Therefore, in more advanced DED, PF tears should ideally be used less than hourly in conjunction with additional interventions, including nutrition (omega-3 fatty acids), environmental modifications, prescription DED pharmaceuticals (cyclosporine 0.05% [Restasis, Allergan], cyclosporine 0.09% [Cequa, Sun Ophthalmics], lifitegrast [Xiidra, Novartis]), systemic medication optimization, punctal occlusion and MGD directed interventions.

The other spectrum of aqueous tear deficiency (ATD) is evaporative DED, which is commonly seen in conjunction with ATD. Of DED patients, 86% experience some degree of meibomian gland dysfunction (MGD).⁸ The primary target becomes MGD, with initial emphasis upon liquification of clogged meibomian glands with warm compresses and eyelid massages one to four times a day to expresses inspissated meibomian glands.

Arita et al looked at the long-term use of antiglaucoma eyedrops and demonstrated alterations in meibomian gland morphology and function. This study concluded that patients with long-term use of antiglaucoma drops demonstrated lid margin abnormalities, superficial punctate keratopathy and permanent changes in the meibomian glands.⁹ Meibomian gland atrophy is believed to be irreversible.

Thus, targeting this ultimately destructive cascade with anti-inflammatory medications like Restasis, Cequa or Xiidra twice a day to slow the course of meibomian atrophy is important. Note that Restasis can take months to take full effect, and a short course of topical steroids are typically administered initially with this medication.¹⁰

Pay special attention to monitoring for steroid response, especially in patients with glaucoma. In these cases, medications such as loteprednol have been shown to have significantly lower rates of IOP elevation compared to standard topical steroids such as prednisone acetate.¹¹

Meibography (LipiScan [Johnson & Johnson Vision], Keratograph 5M [Oculus], HD Analyzer [Visiometrics]) represents a useful imaging modality to evaluate the morphology of meibomian glands. It should be implemented early in treatment.

Other highly effective options for treating MGD include thermal pulsation therapy, which has been shown to be superior to warm compresses in a meta-analysis by Pang et al. Nevertheless, this treatment is not covered by insurance at this time.¹² Options for thermal pulsation therapy include LipiFlow (Johnson & Johnson Vision), TearCare (Sight Sciences) and iLux (Alcon). Punctal occlusion in patients with active MGD increases retention of toxic secretions and can exacerbate evaporative eye disease. Punctal occlusion can also increase the potency of preservatives and likely represents a poor option for management in the glaucoma patient population. Temporary options include collagen plugs, which can be placed in the inferior puncta vs. longer acting silicone or collagen plugs.

CONCLUSION

The prevalence of DED in glaucoma patients is high, and both of these chronic diseases require concurrent treatment to maximize vision potential and quality of life. SLT represents a highly effective first-line treatment. MIGS procedures offer an outstanding opportunity, with or without cataract surgery, to reduce dependence upon topical medications to control IOP.

Ultimately, the options for simultaneous DED management in glaucoma patients are extensive, and therapy should be tailored to each individual. OM

REFERENCES

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2. Rossi GC, Tinelli C, Pasinetti GM, et al. Dry eye syndrome-related quality of life in glaucoma patients. Eur J Ophthalmol. 2009;19;572–579.
3. Jaenen N, Baudouin C, Pouliquen P, et al. (2007). Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J of Ophthalmol. 2007;17:341–349.
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