The State of Glaucoma Care

The pathophysiology of glaucoma has been associated with upregulation of pathological cell cascades that can lead to apoptosis of retinal ganglion cells (RGCs). When RGCs undergo programmed cell death, their axons, which comprise the retinal nerve fiber layer (RNFL), ultimately degenerate. This leads to the RNFL thinning that is observed on OCT and typically characteristic of glaucomatous progression.

The exact pathway that links IOP to RGC apoptosis is unknown, but I believe it involves dysregulated axoplasmic flow that causes an accumulation of toxins and lack of nutrient flow. Axoplasm flows anterogradely from the ganglion cell to the axon (nerve fiber), across the lamina cribrosa, and into the retrobulbar optic nerve; it ultimately synapses in the lateral geniculate nucleus. Axoplasm flows retrogradely in the opposite direction. Elevated IOP seems to disrupt the translaminar pressure difference (difference between IOP and intracranial pressure across the lamina cribrosa).

The flow of fluid inside of the eye begins with aqueous humor production and transudation through the ciliary processes. Fluid then flows from behind the iris into the anterior chamber, egresses through the trabecular meshwork (TM) into Schlemm canal, and moves out through the collector channels and into the episcleral venous plexus. From there, fluid enters the normal venous drainage system from the face (cavernous sinus into jugular vein). This pathway is known as the conventional pathway. In a second pathway known as the uveoscleral pathway, aqueous transudates across the iris and ciliary body and moves directly into the venous system.

The most common site of resistance in the outflow system is within the TM, although resistance can occur at any portion distal to the TM as well. Aqueous is not typically overproduced in the eye; instead, it simply may not drain properly. In eyes with open-angle glaucoma, IOP is high, and the angle is open on gonioscopy; in eyes with closed-angle glaucoma, the IOP is high, but the angle is narrow or closed. Closed-angle glaucoma is a unique subtype that is anatomic and requires opening the angle either with a laser peripheral iridotomy or with lens removal.

Currently, no treatment is available to address apoptosis of RGCs. If such a drug existed, it would be considered neuroprotective, meaning it could prevent RGC death, regardless of IOP. Instead, available treatments are designed to lower IOP, the only modifiable risk factor in glaucoma. This can be done by placing medication on the eye (drops) or in the eye (drug delivery), via treatment with a small laser (selective laser trabeculoplasty [SLT]) or a big laser (cyclophotocoagulation), or via a small surgery (MIGS) or a big surgery (trabeculectomy and tube shunts).

Challenges With Topical Therapy

Glaucoma eye drops lower IOP via two different mechanisms: (1) inflow reduction and (2) outflow increase. Beta blockers, alpha agonists, and carbonic anhydrase inhibitors reduce the production of aqueous in the ciliary processes. Prostaglandin analogues and Rho kinase inhibitors increase outflow through the uveoscleral pathway or conventional pathway. Regardless of how much inflow is reduced and outflow is increased, however, IOP is always limited by episcleral venous pressure. This relationship is problematic, as episcleral venous pressure is typically around 9 mm Hg, yet rare patients require lower IOPs.

The greatest limitation of topical glaucoma therapy is that many patients have difficulty adhering to their prescribed regimens. Drop use is associated with several side effects, including redness, irritation, blurry vision, periorbital hyperpigmentation, and decreased quality of life.

Diagnosis and Staging of Glaucoma

Another limitation of glaucoma care relates to the ability to accurately diagnose and stage the disease. Without proper staging, it is impossible to set a target IOP for an individual based on the specifics of their disease. To stage the disease, we currently evaluate a patient’s IOP, central corneal thickness (thin corneas are at higher risk of progression), OCT scan of the ganglion cell layer and RNFL, and visual field. Diagnostic limitations include the subjective nature of visual field testing and the fact that changes detected on OCT mean damage has already occurred.

This is where the concept of interventional glaucoma comes in. By adopting an interventional mindset and practice, ophthalmologists can efficiently diagnose a patient with glaucoma, stage their disease, set a target IOP, and then perform an intervention to achieve that IOP without relying on the patient’s compliance.

To aid in more rapid and accurate diagnosis, virtual reality (VR)–based visual field tests have emerged. Patients typically find wearing a VR headset to be more comfortable than sitting in the standard fishbowl-shaped perimeter. Additionally, from an operational perspective, less technician time is needed to administer a VR-based visual field test.

Another emerging technology that may enable earlier diagnosis of glaucoma is the Detection of Apoptosing Retinal Cells, or DARC. Phosphatidylserine is a cell signaling moiety that is upregulated in cells undergoing programmed cell death. A dye that binds to phosphatidylserine is injected into a patient’s veins. A scanning laser ophthalmoscope is used to excite the dye, and cells that are actively undergoing programmed cell death can be visualized. If validated, this technology will facilitate ophthalmologists’ ability to monitor patients’ treatment response more quickly than with current methods. DARC will also be useful for evaluating the neuroprotective effects of drugs.

Drug Delivery, Lasers, and Surgery

To combat the lack of compliance to topical therapy, drug delivery, lasers, and surgery are implemented. Drug delivery for glaucoma currently exists in two forms: intracameral bimatoprost SR (Durysta, AbbVie) and intracameral travoprost TR (iDose, Glaukos). Durysta is approved for single administration, elutes medicine over 4 months, and may last up to 2 years. iDose is also approved for a single administration and elutes medicine over 3 years. Durysta, the first foray in glaucoma drug delivery, is limited mostly by its inability to be repeated on label and relatively short treatment effect. iDose enables the consistent delivery of medication for multiple years, but it is an expensive therapy. Time will help sort these logistics.

SLT has emerged as a first-line therapy for primary open-angle glaucoma. The procedure uses a frequency-doubled Nd:YAG laser and is easily performed in the office. By inciting a small amount of inflammation directly at the TM, macrophages are recruited and the debris in the TM is removed. The Laser in Glaucoma and Ocular Hypertension (LIGHT) trial¹ proved that SLT is both cost effective and efficacious. One downside is that there is significant pleomorphism among surgeons in technique and approach to SLT. Therefore, there is significant variability.

In response, direct SLT (DSLT; Voyager, Alcon) has been developed as an ab externo, contact-free, transconjunctival approach. The DSLT machine uses registration software to determine the location of the TM and then directs uniform energy 360° around the angle. The barriers to adoption of DSLT include the cost of the platform and the workflow of determining how often to treat a patient.

More aggressive laser procedures, such as micropulse cyclophotocoagulation, endoscopic cyclophotocoagulation, and conventional cyclophotocoagulation, work by ablating the ciliary processes with an ab externo or ab interno approach. Although these treatments effectively reduce aqueous humor production, they do cause increased inflammation due to the destructive nature of the technique and yield a higher incidence of cystoid macular edema.

MIGS procedures have come to market in the form of TM bypass stents, goniotomy devices, canaloplasty devices, and trabeculotomy devices. While new technologies continue to emerge, general principles still apply, as they all target the conventional pathway. Further, they all work to achieve about a 20% reduction in IOP, similar to the efficacy of a single eye drop. The latest trend has been the ability to perform standalone MIGS without concurrent cataract surgery.

As of late, the supraciliary space is being explored again, years after the CyPass suprachoroidal microstent (Alcon) was recalled due to concerns of endothelial cell loss. AlloFlo (Iantrek), the newest supraciliary device, uses gamma-irradiated scleral tissue to stent the supraciliary space. Safety and efficacy outcomes with this device are being compiled.

When the conventional pathway no longer functions, it is necessary to bypass the TM. This historically was done with trabeculectomy and tube shunt surgery, but, in recent years, has been done with minimally invasive bleb surgery (MIBS). In the United States, the Xen Gel Stent (AbbVie), a stent with a 45-µm lumen that extends from the anterior chamber to under the conjunctiva, has introduced a more minimally invasive approach to filtering surgery. Current limitations of MIBS are the variability in results, the need for bleb management, and the limited availability of products like Preserflo (Santen) and Xen63 (AbbVie) to outside the United States.

Finally, in certain circumstances, incisional glaucoma surgery such as trabeculectomy and tube shunt placement is required. These procedures are useful for refractory cases of glaucoma in which patients need lower IOPs. Although they come with increased risks of hypotony, infection, and endothelial cell loss, occasionally these risks must be taken.

Protocols—Or Lack Thereof

In the current glaucoma landscape, a great number of products can be used for a single patient. Unlike in the retina space, where defined protocols exist for various conditions, glaucoma is considered to be more of an art than a science. I believe, however, that we can protocolize glaucoma care. In my practice, I use what I call the Shafer Protocol. This begins with SLT and moves to drug delivery, next to MIGS, then to MIBS, and last to incisional surgery. Drops are used as a bridge between interventions rather than as a replacement for surgery. My protocol also includes specific timepoints for follow-up, IOP targets, and stop gaps for when an IOP threshold is exceeded. Although more data are needed to validate this protocol, I believe it is a step forward in standardizing treatment to give my patients the best outcomes possible.

Summary

The glaucoma space is alive and well. Interventional glaucoma is changing the approach that surgeons take to maintain IOP without relying on patient compliance. Continuing this forward progress requires innovation in several areas:

• Advanced detection of ganglion cells undergoing apoptosis;
• Improved detection of visual field defects;
• Improved drug delivery with more medications, longer durations of effect, and repeatable treatments;
• Improved access to SLT with more consistent treatment approaches;
• Increased access to MIBS procedures available outside the United States; and
• Standardized approach to management of glaucoma.

I welcome GT readers to share their own perspectives on the current and future state of glaucoma care by contacting the team here.