Education Committee Highlights WGC-2021 | part 5.3

Glaucoma Progression: what’s new?

New tools for detecting progression (e.g. DARC)
Dr. Francesca Cordeiro described the detection of apoptotic retinal cells (DARC) technology which is based on the binding of fluorescently labeled AnnexinV (ANX776) to apoptotic cells.

The Phase I clinical trial was conducted to assess the safety and tolerability of ANX776 as well as the efficacy of DARC counts in normal controls versus glaucoma patients. Increased activity was identified in glaucomatous disease and proposed as a potential novel biomarker for early detection of neurodegeneration and prompt treatment response.

The Phase II trial assessed the efficacy of DARC in visualizing apoptotic retinal cells, as in Phase I, but with a single dosage in more patients and diseases, and evaluated the safety and tolerability of DARC. 113 participants enrolled to receive intravenous administration of 0.4 mg ANX776 and images were recorded at baseline, 15 min, 2h, and 4h postinjection. There were 20 patients in the glaucoma cohort who had at least one eye progressing. Initially, five masked operators detected ANX776 positive spots, but the observers did not agree with each other. So they moved on to deep learning- a CNN-aided method for predicting glaucoma progression using DARC.

In the trial, the CNN algorithm was tested on glaucoma patients 18 months after their DARC assessment. In counting DARC spots, CNN count had higher sensitivity and specificity. Interestingly, all glaucoma patients with DARC counts greater than 30 went on to progress obtained by OCT RNFL at 18 months.

Dr. Cordeiro stated that they employed DARC technology to detect new lesions in dry and wet AMD, and DARC was able to predict disease progression and expanding geographic atrophy. The research team is also interested in finding less invasive ways, such as intranasal administration, which enters the retina quickly, and requires a lower dosage (reducing cost).

Dr. Cordeiro concluded that DARC technology maybe used as a clinical biomarker to detect disease activity in glaucoma, wet AMD, and geographic atrophy as well as the risk of rapid progression and treatment efficacy.

Risk factors for rapid progression (incorporate new risk factors e.g. CH, genetics?)
Dr. Monisha Nongpiur described that the rate of glaucoma progression varies among patients. While some patients have aggressive disease with rapid progression that can cause significant visual impairment, others progress relatively slow.

She stated that trend analysis can be used to quantify visual field (VF) progression rate, which is expressed as dB/year (MD change) or %/year (VFI). Large clinical population studies suggest that the majority of patients have modest rates of VF progression, with only 6-8% having catastrophic progression. Although there are a limited number of studies investigating risk factors for fast progression, the presence of cardiovascular disease, higher peak IOP, older age, and higher VCDR at presentation were associated with rapid progression.

Dr. Nongpiur further mentioned that corneal hysteresis (CH) and genetics are newer risk factors in glaucoma progression. Lower baseline CH is associated with an increased risk of developing glaucoma over time. She pointed out that CH is a more specific predictor of progression than central corneal thickness, emphasizing the importance of CH as one of the factors to consider when assessing glaucoma progression.

She suggested that genetics and glaucoma may be linked in terms of disease progression. The polygenic risk score has the potential to aid in the development of a tailored approach for the earlier treatment of high-risk individuals, with less rigorous monitoring and treatment for those at lower risk.

Dr. Nongpiur emphasized that all glaucoma patients should be evaluated for risk factors for glaucoma progression. This would allow for the identification of people who are most at risk for severe disease as well as personalized surveillance and monitoring for those individuals.

The importance of combining structure and function
Dr. Linda Zangwill emphasized the importance of structural (OCT imaging) and functional assessment (visual field tests) in diagnosing glaucomatous progression. She highlighted the importance of knowing the rate of glaucomatous change and recommended trend-based progression analysis, which detects change earlier than event-based guided progression analysis.

She indicated that both ONH and macula scans should be obtained at baseline and serially. Numerous studies showed that eyes with RNFL defects have detectable macular damage in the corresponding location. However, in advanced glaucoma, there is an RNFL thickness measurement floor effect where RNFL changes cannot be identified because the neural tissue has already atrophied. To detect progression in advanced glaucoma, macula OCT scans are recommended. Dr. Zangwill underlined the importance of monitoring the central visual field at all stages of glaucoma. In advanced glaucoma, 10-2 VF testing is useful to detect progressive central VF loss. Even in early to moderate glaucoma, monitoring central VF with 24-2 or 10-2 is critical.

Dr. Zangwill also discussed which tests to perform based on the stage of the disease. In early glaucoma, she recommended OCT (RNFL and macula) and VF (24-2 and 10-2 in some patients), while in more advanced cases, she recommended OCT (macula) and 10-2 VF. She also said even in eyes with early glaucoma, local structural (OCT) and functional (OCT) damage agree. When they don’t, it is equally likely to see abnormal regions first on VFs as it is on OCT. She recommended using both 10-2 and 24-2 VFs, both RNFL and RGC+ probability maps, and comparing local VF and OCT probability/deviation maps for the best agreement. Finally, Finally, Dr. Zangwill stressed the importance of reviewing the OCT image for quality issues and other diseases.

What is significant progression? Statistically significant versus clinically meaningful
Dr. Chota Matsumoto discussed glaucoma progression analyses and underlined the relevance of trend analysis, which is useful in determining not only the presence of change but also the rate of change over time. He also mentioned that newly diagnosed glaucoma patients should have VF tests three times per year for the first two years.

He stated that predicting glaucoma progression is clinically critical in determining whether or not glaucoma treatment is effective. When considering the patient’s everyday life, we must concentrate on the central 10-degree VF and binocular VF, which are closely related to their QoL. He demonstrated 10-2 VFs from early and advanced glaucoma cases. He added that there are also limitations for binocular VF testing: no fixation monitor, no normative database, and additional binocular examinations are needed with follow-up monocular tests. Patients with faster rates of integrated VF change are more likely to experience anomalies in vision-related QoL. Several Bayesian models have recently been developed to better detection of glaucoma VF progression.

Dr. Matsumoto concluded that event and trend-based analysis are the fundamental approaches for monitoring the progression of glaucoma, and Bayesian studies have the potential to increase accuracy. The central 10-degree VF progression should be given more consideration when monitoring the patient’s quality of life. Binocular VF is closely correlated with patients’ QoL and should be taken into account in glaucoma follow-up strategies.

Detecting progression in advanced glaucoma
Dr. Jayme R. Vianna explained the goals of care in advanced glaucoma which include avoiding visual disability (acting quickly to prevent additional loss) and avoiding causing harm (side effects of possibly unnecessary drugs and procedures).

He stated that no single technique or single examination is likely to deliver a conclusive answer. As a result, he advised applying various examinations (VF, OCT RNFL, and OCT macula) and repeating examinations frequently. He added that multiple VFs are needed to detect progression and that three exams per year would reliably detect progression in two years. It remains the most important factor to improve reliable detection of progression with VFs.

He mentioned that in advanced cases, OCT can detect progression. The floor effect in OCT is a general tendency rather than a strict limitation in detecting progression in single patients. OCT can sometimes provide a good clinical decision for specific patients. According to Dr. Vianna, a localized loss may often be noticed in eyes with minimal change in global metrics. He cautioned against focusing just on global metrics, stating that if we look at the localized profile, we may often detect progression even in advanced cases. He also added that macular ganglion cell layer metrics may be more useful in advanced cases.

Dr. Vianna concluded that several tests (VF+ OCT nerve + OCT macula) should be used to minimize both under and over-detection of progression, and that examinations should be repeated often.

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