Seeing the story
The story of glaucoma is often told through a patient’s eyes and how they change over time, and structural biomarkers are key metrics in assessing this. “Structural biomarkers are key for diagnosing glaucoma and following patients temporally,” explains Dr. Chaglasian. “The retinal nerve fiber layer (RNFL) is our lead indicator, but it’s sometimes less helpful in advanced disease because of the floor effect. Ganglion cell–inner plexiform layer (GCL-IPL) macular changes tend to start later and last longer, and are a great complement to RNFL. The best practice is to look at both; when they agree, you have a higher level of confidence.”
In 2018, he observed fluctuations in intraocular pressure (IOP) in a 70-year-old female patient who had been diagnosed with glaucoma a decade earlier. He referred to the Guided Progression Analysis (GPA) report of her structural biomarkers obtained from the ZEISS Humphrey Field Analyzer to assess her condition. “I typically look at the GPA report when following a patient’s ocular coherence tomography (OCT) biomarkers, combining this with the functional assessment I obtain with a perimeter also capable of detailed progression analysis,” Dr. Chaglasian says. “Measuring the rate of progression enables me to estimate biomarker loss.”
His analysis proved particularly beneficial here; although little difference was observed through comparison of the patient’s fundus photography imagery between 2010 and 2022, the RNFL GPA report highlighted that the superior RNFL was quickly decreasing in thickness, with a rate of change of -1.97 μm between 2020 and 2023. This change became more pronounced in 2024 and was confirmed with GCL-IPL analysis. “Using these biomarkers, we identified the case as being one of OCT structural progression, and, knowing that, we were able to then consider management options with the patient.”
There are new biomarkers on the horizon that may further shape glaucoma identification and management once clinically employed, including vascular biomarkers such as foveal avascular zone, flow density, and flow index, which can be captured through AngioPlex OCT Angiography using the
ZEISS CIRRUS 6000. As Dr. Chaglasian explains, a GPA is only as useful as the data it contains. “Biomarkers really start with your OCT scan and device. They require high-quality, high-raster scans to identify the structural changes related to glaucoma occurring in the back of the eye.”
Some advancements are available today. The ZEISS CIRRUS 6000 now features enhanced biomarker analysis capabilities thanks to the recent release of an upgraded reference OCT database, RDB2. This new database is three times larger than most previous databases and includes a greater diversity of patients and age ranges. “Using OCT for a high-quality scan with a great reference database really helps us as clinicians get the best data possible,” Dr. Chaglasian explains.
Context is key
A patient’s GPA report shows apparent significant progress over four months. Should you be worried?
Dr. Gleason, who has experienced this, explains that the answer is not always yes. “Anytime there’s rapid progression, you should consider data confounders,” she says. When Dr. Gleason initially examined this patient, she noted elevated intraocular pressure (IOP) and glaucoma in the left eye, which was evident during dilation. After conducting a structural analysis, Dr. Gleason performed a raster scan due to a significant area of elevation that complicated her ability to accurately measure the thickness of the GCL-IPL using OCT. “Whenever you observe asymmetric glaucoma, you should consider an etiology that isn’t POAG,” Dr. Gleason says. This scan uncovered glaucoma-associated peripapillary retinoschisis due to the displacement and formation of focal defects in the lamina cribrosa (LC) caused by high IOP.
“Retinoschisis is present in approximately 6% of glaucoma or glaucoma suspect patients, and occurring in areas where RNFL defects are already present,” Dr. Gleason explains.1 “This condition isn’t a good prognostic indicator—it’s associated with more rapid progression, twice as fast as measured by RNFL, and 4–6 times faster when measured by visual test measurement mean deviation.” To address this, Dr. Gleason prescribed a dorzolamide-timolol combination, which, four months later, resolved the retinoschisis and reduced her IOP but resulted in the previously mentioned GPA report. “It was interesting to look at this patient’s GPA because over a four-month period, she appeared to progress quite significantly—if we weren't aware of the retinoschisis,” says Dr. Gleason. “Instead of progressing significantly, the true GCL-IPL thickness was likely becoming apparent. A patient like this needs to be re-baselined at this point, so we can monitor more moving forward.”
However, Dr. Gleason notes that retinoschisis is typically an incidental finding in OCT—it was likely just fortunate timing that the active retinoschisis was present when this patient was symptomatic for glaucoma. This, alongside the long-term LC-remodeling that occurs in glaucoma,
2 is why Dr. Gleason believes that the LC will serve as a key structural biomarker of not just retinoschisis, but of glaucoma in general. “Looking ahead to the future, as our ability to measure and monitor the LC improves, I believe that it will become very important in the management of all of our
glaucoma cases,” she forecasts. “We should start thinking increasingly about the LC as it relates to our glaucoma patients and realize that there may be morphological glaucoma-associated changes in the LC that can cause glaucoma-related complications.”
Taking in the full picture
Although structural biomarker changes often indicate glaucomatous developments, it’s crucial to confirm that any observed changes result from glaucoma. Dr. McCann illustrates this through his case study of an 83-year-old patient who had previously been managed for glaucoma for several years. Upon examining the patient’s structural biomarkers in ZEISS Glaucoma Workspace, Dr. McCann noticed several discrepancies. While the progression maps of the patient’s GCL-IPL analysis showed visible progression in both eyes, the progression maps for RNFL did not. “Something wasn’t adding up,” he said. “When this happens, it’s important to make sure that you consider a patient’s results within the context of the entire eye and that you’re not focusing solely on glaucoma when considering any change potentially indicative of the disease.”
By expanding his focus to include the patient’s retinal imaging, it became clear that there had been significant changes in the macula over time. Further analysis using OCT and infrared imaging confirmed the presence of substantial geographic atrophy, which aligned with the changes in the GCL-IPL highlighted on the progression maps. “Look at your dilated fundus exam, alongside your retinal imaging, OCT, and visual field tests to ensure things match up and make sense,” Dr. Wesdon says. “It’s important to watch for ancillary diseases occurring at the same time, that may not be related to glaucoma, but could still be creating changes in your GPA and the biomarkers that you're utilizing to analyze glaucoma.”
Management of glaucoma is a practice that requires patience, and one in which clinicians typically have ample time to determine if
progressive pathology is occurring. Dr. Wesdon encourages clinicians to use this time to collect all the necessary information before moving forward. “I think it's important not to jump too fast on things, because there are many factors to consider,” he says. “We need to know exactly what we’re looking at and how everything adds up. Once you’ve asked yourself all the necessary questions and determined the answers, you’ll have enough to move forward in making a clinical decision. I educate my patients that if things aren’t progressing, then they’re okay, and I can follow them closely so that we can make a good clinical decision.”