Source: Healio Interviews
Disclosures: Coroneo reports he has patents/royalties with Allgenesis, DORC Dutch Ophthalmic International, Insight Surgical, Katena Products and Novartis Pharma; is a consultant/adviser for DORC Dutch Ophthalmic International, Katena Products and Novartis Pharma; and receives grant support from DORC Dutch Ophthalmic International. Gupta reports she is a consultant for Allergan and Novartis. Nijm reports she has relevant financial disclosures with Alcon, Allergan and Novartis. Samuelson reports no relevant financial disclosures.
November 17, 2020
9 min read
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Balance needed between glaucoma treatment, management of ocular surface disease

Source: Healio Interviews
Disclosures: Coroneo reports he has patents/royalties with Allgenesis, DORC Dutch Ophthalmic International, Insight Surgical, Katena Products and Novartis Pharma; is a consultant/adviser for DORC Dutch Ophthalmic International, Katena Products and Novartis Pharma; and receives grant support from DORC Dutch Ophthalmic International. Gupta reports she is a consultant for Allergan and Novartis. Nijm reports she has relevant financial disclosures with Alcon, Allergan and Novartis. Samuelson reports no relevant financial disclosures.
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Glaucoma-related ocular surface disease is a significant and often underdiagnosed ocular comorbidity that can significantly affect quality of life.

This comorbidity is common, affecting between 40% and 59% of patients with glaucoma across continents, Lisa M. Nijm, MD, JD, founder and medical director of Warrenville EyeCare & LASIK, said.

Lisa M. Nijm, MD, JD
Dry eye disease, which can be related to glaucoma therapy, not only has a negative impact on patient compliance but it also has a detrimental effect on daily activities, according to Lisa M. Nijm, MD, JD.

Source: Grace Mirsky, PhD

Ocular surface disease causes burning, stinging and irritation. A poor ocular surface can also affect the reliability of perimetry testing. With just the use of an artificial tear, not only is reliability of visual field testing improved, but also test time is reduced, Nijm said.

“Glaucoma medications induce an inflammatory cascade with the release of cytokine and proinflammatory mediators that self-perpetuate in a vicious cycle. The pathophysiology of glaucoma-related ocular surface disease is likely due to a combination of induced tear film abnormalities and instability due to chronic inflammation,” she said.

Ocular surface disease is sometimes coincidental and sometimes a direct result of the glaucoma therapeutic itself, OSN Glaucoma Section Editor Thomas W. Samuelson, MD, said.

In most instances, a predisposition for ocular surface disease is exacerbated by topical glaucoma medication, which may result from the active drug itself, such as brimonidine tartrate, or a preservative or excipient, such as benzalkonium chloride (BAK), he said.

Clinicians can reduce the toxic effects of topical glaucoma therapy by selecting preservative-free options, using selective laser trabeculoplasty and taking advantage of depot delivery such as intracameral bimatoprost. Such measures not only reduce the adverse effect of the drug on the ocular surface but also help with noncompliance, Samuelson said.

Nijm, along with a slate of international co-authors, examined the effect of glaucoma management on the ocular surface in a comprehensive review scheduled for publication in Asia-Pacific Journal of Ophthalmology.

Compliance and quality of life for patients with glaucoma and dry eye disease are greatly diminished if dry eye disease is not adequately managed. Studies have shown that patients’ utility scores for moderate to severe dry eye syndrome are comparable to those for angina and dialysis.

“Dry eye disease not only has a negative impact on patient compliance but it also has a detrimental effect on daily activities such as reading, driving, and using smartphones and tablets. Studies show these patients have greater visual difficulty with text-based searches. Further, there is a significant correlation between the severity of DED and symptoms of depression and anxiety,” Nijm said.

Highly correlated with age

Dry eye disease, glaucoma and cataracts are all highly correlated with increasing age. The PHACO study showed that between 60% and 70% of patients scheduled for routine cataract surgery have signs of dry eye, but almost 60% never complained of a foreign body sensation.

“So, it is not surprising that an intervention such as cataract surgery would tip a good proportion of such patients into being symptomatic of dry eye syndrome, a leading cause of dissatisfaction in patients who have had cataract surgery,” Minas T. Coroneo, MD, MS, FRACS, professor and chairman, department of ophthalmology, UNSW at Prince of Wales Hospital, said.

The mechanics of cataract and glaucoma surgery are similar, and the mechanisms of induction of dry eye disease are also similar for each procedure. Furthermore, both surgeries are not infrequently conducted at the same time, he said.

Minas T. Coroneo, MD, MS, FRACS
Minas T. Coroneo

“The ocular surface did not evolve to be bombarded by drugs that affect aqueous secretion and outflow. Many of these medications still contain preservatives, so medical treatments are well known to contribute to dry eye syndrome and meibomian gland disease. It would seem that it is only in more recent times that dry eye syndrome has appeared to be of concern in the glaucoma literature,” Coroneo said.

Many common topical glaucoma medications, such as prostaglandins and beta-blockers, have been shown to result in obstructive meibomian gland dysfunction. It happens to a lesser degree with fixed-combination medications and preservative-free eye drops, Nijm said.

The ongoing use of timolol should be evaluated due to evidence of tachyphylaxis and its possible injurious effect on the ocular surface, in that it may be associated with conjunctival cicatrization with long-term treatment, Coroneo said.

“Apart from the usual dry eye parameters, the conjunctival fornices should also be examined, looking for shortening and symblepharon formation,” he said.

More medications, more dry eye

According to a 2020 study in Eye & Contact Lens, common topical management of glaucoma with beta-adrenergic antagonists, alpha-adrenergic agonists, prostaglandin analogs and topical carbonic anhydrase inhibitors can cause or worsen ocular surface disease. This is typically caused by an added preservative or the active ingredient of the medication itself. As a patient uses more glaucoma medications, the prevalence and severity of dry eye increase.

Many patients require multiple topical IOP-lowering medications, and 49% of patients with ocular hypertension will require at least two topical medications within 5 years of their diagnosis, the study said.

Beta-blockers can suppress lacrimal function, and prostaglandin analogs can directly cause meibomian gland dysfunction. If these conditions are left untreated or if chronic inflammation is present, patients can experience meibomian gland atrophy, OSN Cornea/External Disease Board Member Preeya K. Gupta, MD, said.

“The therapies for glaucoma can induce dry eye, and patients who suffer from glaucoma often have preexisting dry eye that might even be worsened by the glaucoma therapies. There is a lot of overlap between the two,” Gupta said.

Preeya K. Gupta, MD
Preeya K. Gupta

Patients are often older, have multiple comorbidities and have undergone previous ocular surgeries, she said.

Ophthalmologists are beginning to realize the high prevalence of ocular surface disorders in patients with glaucoma, but screening for ocular surface disorders or dry eye disease during basic glaucoma examinations is not yet the norm, she said.

“Increasing awareness of this connection among clinicians is the first step. It’s the doctors on the front line who are making these treatment decisions. It’s not typical for a patient to understand there’s a laser treatment that may be available for them instead of a drop,” Gupta said.

Screening is necessary

Whatever intervention is planned can affect or be influenced by the ocular surface, Coroneo said, so all patients, particularly those in whom glaucoma interventions are proposed, should be screened for dry eye disease.

Each assessment should begin with a complete systemic review to diagnose any conditions and optimize management.

“This may involve discussions with other specialists such as cardiologists so that, for example, the management of hypertension is optimized with minimal use of drugs known to be associated with dry eye disease, such as diuretics and beta-blockers,” Coroneo said.

Screening for ocular surface disorders can be adequately performed by adding a few questions to a history of present illness discussion, and examination can be completed during the initial baseline glaucoma examination.

“If you think about it, we already evaluate many aspects of the ocular surface in a typical glaucoma evaluation — lids and lashes to evaluate for blepharitis and meibomian gland dysfunction, the cornea and conjunctiva to note tear lake, tear breakup time and staining patterns. Incorporating these findings into your diagnosis and treatment will allow you to easily identify these patients in your clinic,” Nijm said.

If dry eye disease or an ocular surface disorder is identified, a strategy for addressing the comorbidity while treating the patient’s glaucoma should be explored. Ophthalmologists should look at steroid-saving strategies if these comorbidities are present, Coroneo said.

Sleep quality should be examined as well. Snoring and lethargy may suggest sleep apnea, which is associated with floppy eyelid syndrome and may contribute to dry eye disease and meibomian gland dysfunction, as well as low-tension glaucoma, Coroneo said.

Clinicians need to evaluate the total picture. Glaucoma causes visual dysfunction that leads to alterations in a patient’s quality of life, but so does dry eye disease and ocular surface disorders, Gupta said.

“If you ask the average glaucoma specialist, they’ll tell you many of their patients feel as if they don’t see well. Part of that is the underlying disease, but part of that is also the ocular surface disease that exacerbates the dysfunction of the tear film and results in declining visual function,” she said.

Balance treatment

If dry eye disease or an ocular surface disorder is diagnosed, clinicians must take greater care when moving forward with a glaucoma therapy plan to not exacerbate these comorbidities, Nijm said.

Medications free of BAK are an important first step, according to Nijm. The Tear Film and Ocular Surface Society Dry Eye Workshop II report said that BAK can induce corneal and conjunctival epithelial cell apoptosis, delay corneal wound healing, interfere with tear film stability, damage corneal nerves and cause loss of goblet cells.

The report also discussed one in vitro study in which BAK concentration in excess of 0.005% compromised the morphology of the tear lipid layer and significantly impaired lipid spreading.

Apart from the use of preservative-free lubricants, ophthalmologists should use unpreserved glaucoma medications, which in many instances are restricted to prostaglandin analogs, Coroneo said.

When two to three medications become necessary to control IOP, a patient should be evaluated for SLT as an alternative treatment. If a patient’s angles are narrow, a peripheral iridectomy can be considered. However, if cataract is present and the patient is symptomatic, they should be evaluated for refractive cataract surgery, he said.

The role of cataract surgery in uncontrolled angle closure is well accepted, but there is also good evidence of sustained reduction of IOP after cataract surgery in primary open-angle glaucoma as well, he said.

“Depending on factors such as the age and ability of the patient to comply with treatment and the severity of disease, combining cataract surgery with a minimally invasive procedure such as intraocular micro-stenting, trabeculotomy or viscocanalostomy conjunctival- and corneal-sparing surgeries may avoid or decrease reliance on topical glaucoma drugs and potentially reduce the risk of progression of ocular surface disorder,” Coroneo said.

Evaluate medications

Early treatment with ocular surface immune-modulating agents, such as Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan) or Xiidra (lifitegrast ophthalmic solution 5%, Novartis), should be considered. Management of the ocular surface inflammatory response can increase patient comfort and compliance while improving IOP control, Coroneo said.

An astute clinician will be able to identify which glaucoma drug is causing surface toxicity and discontinue its use, often lessening the need for dry eye therapy, Samuelson said. The most common offenders are alpha agonists, Rho kinase inhibitors and topical carbonic anhydrase inhibitors.

“As a consultative glaucoma specialist, I often see patients who are maintained on complex multidrug glaucoma regimens causing surface changes that may range from mild punctate keratopathy to overt follicular conjunctivitis. Such patients are often subsequently treated with drugs for dry eye such as cyclosporine or mast cell stabilizers, which adds to the complexity of the drug regimen,” Samuelson said.

Adding drugs to manage secondary ocular surface disease may complicate a drop schedule. It is usually a better option to cease using the offending agent and select an alternative therapeutic, either interventional or topical, Samuelson said.

Treatment for meibomian gland disorders should also not be overlooked. Using warm compresses at home and implementing thermal pulsation therapy in the office can address this aspect of the pathophysiology of glaucoma-related ocular surface disease, Nijm said.

“I was surprised by how much evidence there is in the literature demonstrating the presence of obstructed meibomian glands in these patients,” she said.

Sustained-release therapies are also an interesting option for this subgroup of patients. Durysta (bimatoprost implant, Allergan) and/or SLT should be considered if multiple eye drops are needed to control IOP, Nijm said.

Alternatives to drops

Alternative treatments need to be considered for patients with glaucoma and ocular surface disorders. The LiGHT trial provided compelling evidence that SLT is an excellent first-line treatment based on efficacy and reduction in secondary interventions. It can also reduce medication-induced surface toxicity, Samuelson said.

MIGS options should also be adopted early, Gupta said.

“Being proactive with these interventional therapies earlier, not saving them for patients with a later stage of the disease, can be very effective,” she said.

MIGS requires less topical medical therapy postoperatively. The HORIZON study for the Hydrus microstent (Ivantis) found 73% of patients remained medication-free at 36 months, Samuelson said.

For patients with the most severe ocular surface disease, including those that require ongoing topical steroid therapy, transscleral procedures such as traditional trabeculectomy, tube shunts or novel gel stents can reduce the need for glaucoma medications. This allows for chronic steroid therapy because the resulting outflow is non-trabecular, he said.

“Of course, while the less invasive gel stents generally result in a more comfortable, low and diffuse bleb, filtration procedures may result in bleb dysesthesia, so care should be taken to select the most favorable location for a bleb, generally directly superior or slightly temporal to the vertical midline,” Samuelson said.

Surgeons should remember to treat surface inflammation with a steroid before filtration surgery to lessen postoperative fibrosis of the conjunctival and Tenon’s tissue, he said.

Understanding the pathogenesis of glaucoma-related ocular surface disease, recognizing its risk factors, and incorporating diagnostics and therapeutic strategies to restore surface homeostasis will result in improved care, Nijm said.

“On top of that, it will result in long-term visual outcome improvements, improvements in patient compliance, quality of life and satisfaction of care,” she said.

Click here to read the Point/Counter to this Cover Story.