Csincsik L, Muldrew KA, Bettiol A, et al. The Double Layer Sign Is Highly Predictive of Progression to Exudation in Age-Related Macular Degeneration. Ophthalmol Retina. 2024;8(3):234-245. doi:10.1016/j.oret.2023.10.006Csincsik L, Muldrew KA, Bettiol A, et al. Ophthalmology Retina. Published online October 13, 2023. doi:10.1016/j.oret.2023.10.006

Question

Is the presence of a double-layer sign and a shallow irregular retinal pigment epithelium elevation able to predict progression to exudative macular neovascularization in the unaffected fellow eyes of patients with age-related macular degeneration recently diagnosed with unilateral exudative macular neovascularization?

Background/Summary of Findings

Exudative macular degeneration is a sight-threatening condition that can remain undetected on its first occurrence unilaterally, and even when the patient is aware of their first eye having exudation, they may be unaware of changes that arise in the fellow eye. As early treatment is critical toward preserving macular structural integrity and central vision, identifying eyes at risk of progressing to exudative disease becomes an even more critical first step in the treatment and preservation process. Spectral domain optical coherence tomography and optical coherence tomography angiography are powerful tools that can be used to capture macular tissues affected by age-related macular degeneration. However, optical coherence tomography angiography is neither as universally available in routine clinical practice nor as well understood as traditional spectral domain optical coherence tomography. Therefore, the ability to detect features/biomarkers consistent with exudative disease, as well as features that may predict the development of exudative macular degeneration, that can be specifically captured on conventional optical coherence tomography would be beneficial.

Recent spectral domain optical coherence tomography studies have detected dormant layers of blood vessels between the retinal pigment epithelium and its basement membrane, vessels that show no overt signs of exudation. Even more clearly delineated through the use of optical coherence tomography angiography and labeled as nonexudative macular neovascularization, these vessel layers are associated with a low-lying elevation of the retinal pigment epithelium on optical coherence tomography B scan analysis. Initially this low-lying elevation of the retinal pigment epithelium was known as the double-layer sign and defined by the presence of a highly reflective inner layer consisting of the retinal pigment epithelium and coupled with an additional highly reflective outer layer composed by Bruch’s membrane. The initial double-layer sign characteristics were refined to include length and height dimensions (≥1000 μm in length and <100 μm in height) and ultimately became known as the shallow irregular retinal pigment epithelium elevation sign.

In this retrospective reanalysis of 3 years of follow-up spectral domain optical coherence tomography scan data from the Early Detection of Neovascular AMD study, the values of irregular elevations, double-layer sign, and shallow irregular retinal pigment epithelium elevation signs in predicting progression to exudative macular neovascularization were respectively assessed.

The authors found that when study eyes were grouped by the presence of irregular elevations, double-layer sign, or shallow irregular retinal pigment epithelium elevation, all three features/biomarkers increased the risk of progression to exudative macular neovascularization, with the highest rate of progression (41% of patients progressing to exudative macular neovascularization over 3 years) and four times greater hazard of exudative macular neovascularization in patients with the double-layer sign. Interestingly, fulfilling the more specific optical coherence tomography moniker of shallow irregular retinal pigment epithelium elevation did not increase the predictive value for progression to exudative macular neovascularization. The authors concluded pragmatically that the dimensions of the double-layer sign are less important than its presence alone and that patients with these irregular elevations should be surveilled more closely with spectral domain optical coherence tomography and with optical coherence tomography angiography if available.

Clinical Value/Implications

The evolution of optical coherence tomography in characterizing diseases of the eye has led to an increasingly complicated nomenclature that is constantly evolving and often difficult to keep abreast of in clinical practice. This study supports that it is likely more critical to be able to recognize the presence of and even qualitative aspects of various optical coherence tomography biomarkers, rather than obsess over achieving certain quantitative dimensions in order to use these biomarkers prognostically. The double-layer sign is an important biomarker that we all should be aware of when managing our patients with age-related macular degeneration.

Prognostication in Stargardt Disease Using Fundus Autofluorescence: Improving Patient Care

Daich Varela M, Laich Y, Hashem SA, Mahroo OA, Webster AR, Michaelides M. Prognostication in Stargardt Disease Using Fundus Autofluorescence: Improving Patient Care. Ophthalmology. 2023;130(11):1182-1190. doi:10.1016/j.ophtha.2023.06.010

Question

Can fundus autofluorescence provide a useful surrogate to conventional electrodiagnostic testing for classifying Stargardt disease?

Background/Summary of Findings

Stargardt disease is a common genetic retinal dystrophy. Prognosis of the condition is highly variable depending on the phenotype and is tied relatively tightly to classification with electroretinography. The mildest stage—group ERG1—shows severe abnormality of macular function and normal full-field peripheral function. Group ERG2 demonstrates severe macular dysfunction with additional generalized cone dysfunction. Group ERG3 demonstrates the same findings as group ERG2 with the addition of generalized rod dysfunction. Within this classification system, group ERG1 has a relatively good prognosis, ERG2 has a variable prognosis, and ERG3 has a poor prognosis. Furthermore, these groups are generally stable over time. Although electroretinography correlates well with prognosis, it is not widely available, is dependent on patient and center reliability, and is somewhat invasive. This review looks at whether fundus autofluorescence would be a reliable surrogate for ERG in the management of disease in patients with Stargardt disease.

This single-center retrospective review looked at 234 patients who had been monitored for Stargardt disease, had been classified with electrodiagnostic, and who also had ultra-widefield fundus autofluorescence performed to assess for agreement between fundus autofluorescence and electroretinography staging. The patients were categorized into groups based on fundus autofluorescence characteristics. Fundus autofluorescence 1 showed only central hypo autofluorescence, fundus autofluorescence 2 showed central hypo autofluorescence and a heterogeneous background, and fundus autofluorescence 3 was defined as having multiple areas of hypo autofluorescence within the posterior pole as well as a heterogeneous background. The review found that, in general, fundus autofluorescence staging corresponded with electrodiagnostic staging, with fundus autofluorescence matching electrodiagnostic staging 73% of the time. The 27% where fundus autofluorescence and electrodiagnostics disagreed was evenly split between fundus autofluorescence overestimating 13% of patients’ disease stages compared with electrodiagnostics and underestimating 14%. The greatest variability between fundus autofluorescence and electrodiagnostics was in very young patients (10 years old or younger). Subgroup analysis comparing ultra-widefield fundus autofluorescence with 30° and 55° fundus autofluorescence showed 97% and 98% agreement.

Clinical Value/Implications

This review shows reasonable agreement between an objective, noninvasive, widely available technology—fundus autofluorescence—and the subjective, less available technology with greater potential for intertest variability—electrodiagnostics—in assessment and prognosis of patients with Stargardt disease. As such, fundus autofluorescence appears to be a useful surrogate for most patients with the disease. When managing children with Stargardt disease, electrodiagnostics may provide a superior level of confidence in prognosis.

Evaluation of the Consistency of Glaucomatous Visual Field Defects Using a Clustered SITA-Faster Protocol

Tan JCK, Phu J, Go D, et al. Evaluation of the Consistency of Glaucomatous Visual Field Defects Using a Clustered SITA-Faster Protocol. Ophthalmology. 2023;130(11):1138-1148. doi:10.1016/j.ophtha.2023.06.018

Question

Can frontloading SITA-faster visual fields provide repeatable data that can be used to evaluate the consistency of pattern deviation defects in glaucoma?

Background/Summary of Findings

Although functional testing is an incredibly important aspect of glaucoma diagnosis and management, it exhibits a substantial amount of variability and requires a great deal of testing to minimize that variability in order to provide information sufficient to confidently determine whether glaucoma is or is not progressing. This requirement for a large amount of data results in a burden to both the patient and the perimetrist alike and contributes to a lack of real-world data acquisition when compared with published guidelines on the optimal number and frequency of visual fields necessary to make sound management decisions. The addition of the SITA-faster algorithm has greatly reduced the time required to acquire visual field data, and the authors of this paper recently determined that SITA-faster could be successfully clustered in the same visit, and that this clustering was acceptable to both patients taking and technicians administering the SFRs.

Using a prospective, cross-sectional study design, the authors acquired two SITA-faster tests on the same visit on patients with suspected or confirmed glaucoma having undergone Sita-standard testing on a previous visit. Global sensitivity, reliability indices, and pointwise deviation map probability scores from the pattern deviation grid were compared across the three visual fields to evaluate the consistency of detecting the visual field defects. The authors found no significant difference in global sensitivity across the three fields or in the rate of obtaining at least one reliable test among the three. Notably, the frontloaded SITA-faster tests confirmed existing Sita-standard pointwise deviation defects in 62% of cases and reversed Sita-standard defects in 8.2%. Importantly, a new defect of at least three contiguous points was detected in 20.1% of eyes with the frontloading of SITA-faster tests.

The authors concluded that frontloading SITA-faster tests can provide repeatable data that can be used to determine the consistency of pattern deviation visual field defects, without being compromised by testing fatigue, and performing at a level equivalent to a single SITA-standard test. They mentioned that this might provide a new strategy by which an appropriate level of visual fields can be acquired while reducing the traditional burden involved in meeting established guidelines.

Clinical Value/Implications

Practice guidelines in glaucoma show that there is a consistently insufficient number of visual fields performed in order to determine whether progression of the disease has occurred. This lack of testing can result in a delayed ability to detect change and the rate of that change, leading to worse outcomes in faster progressors. The clustering of visual fields provide a potential new approach to help overcome this issue and, in this study, has been shown to be effective in a real-world glaucoma practice. These results could spark additional conversation about how functional testing can be optimized in our practices to best serve the needs of our patients with glaucoma.

Maintenance of Vision Needed to Drive After Intravitreal Anti-VEGF Therapy in Patients With Neovascular AMD and Diabetic Macular Edema

Emami-Naeini P, Garmo V, Boucher N, Fernando R, Menezes A. Maintenance of Vision Needed to Drive after Intravitreal Anti-VEGF Therapy in Patients with Neovascular Age-related Macular Degeneration and Diabetic Macular Edema. Ophthalmol Retina. Published online October 20, 2023. doi:10.1016/j.oret.2023.10.010

Question

What is the association between intravitreal anti–vascular endothelial growth factor injections and visual acuity/driving in patients with neovascular age-related macular degeneration or diabetic macular edema?

Background/Summary of Findings

Neovascular age-related macular degeneration and diabetic macular edema are both common causes of central vision loss, which can negatively impact patients’ ability to drive, subsequently affecting their independence and quality of life. Driving cessation specifically has been associated with decreased mobility and out-of-home activities, depression, greater risk of entry into a long-term care facility, and increased risk of mortality. Although the addition of anti–vascular endothelial growth factor agents has substantially improved both anatomical and visual outcomes, the burden of treatment is high.

This was a retrospective, observational, real-world cohort study of visual acuity and driving vision maintenance over time in patients with neovascular age-related macular degeneration and diabetic macular edema having received anti–vascular endothelial growth factor therapy using data collected from the Vestrum Health database between January 1, 2014, and June 30, 2019. The Vestrum database consists of electronic health record data obtained from more than 360 US retinal specialists.

Outcome measures were mean change in visual acuity over time and by baseline visual acuity, driving vision maintenance over time and stratified by injection frequency and baseline factors predictive of driving vision maintenance.

In the initial year of treatment, patients with neovascular age-related macular degeneration and diabetic macular edema gained, on average, 8.5 and 9.5 ETDRS letters, respectively. Between years 1 and 4, patients with neovascular age-related macular degeneration and diabetic macular edema lost 6.6 and 2.7 ETDRS letters, respectively. The probability of maintaining driving vision over 4 years was 56% in patients with neovascular age-related macular degeneration and 72% in those with diabetic macular edema. There was a dose-related response, and in patients receiving 1-5, 6-7 and ≥8 anti–vascular endothelial growth factor injections in year 1, the corresponding probabilities of maintaining driving were 50%, 56%, and 65% in patients with neovascular age-related macular degeneration and 63%, 72%, and 77% in patients with diabetic macular edema. Baseline factors associated with driving loss included older age, worse index visual acuity, geographic atrophy, and worsening baseline diabetic retinopathy.

Clinical Value/Implications

This study supports early and frequent intervention with anti–vascular endothelial growth factor injections in patients with neovascular age-related macular degeneration and diabetic macular edema. These results provide us with important real-world data that can be used to inform our conversations with patients who have concerns of losing their ability to drive and, subsequently, their independence. Advising them to commit to the recommended course of injections, especially early in the course of treatment, can help empower them to reduce their risk of vision loss.

Placebo Effect and Its Determinants in Ocular Hypotensive Therapy. Meta Analysis and Multiple Meta-regression Analysis

Choe S, Kim YK, Chung W, et al. Placebo Effect and Its Determinants in Ocular Hypotensive Therapy: Meta-analysis and Multiple Meta-regression Analysis. Ophthalmology. 2023;130(11):1149-1161. doi:10.1016/j.ophtha.2023.06.012

Question

Is intraocular pressure influenced by the placebo effect?

Background/Summary of Findings

The placebo effect has been identified in many surprising physiologic processes that go beyond subjective patient experiences. This large meta-analysis looks at 40 randomized clinical trials on ocular hypotensive treatments and their respective control groups to assess whether the placebo effect may exert an influence on intraocular pressure. Broadly, this review assessed the difference in intraocular pressure between placebo groups (those applying a nontreatment eye drop: n = 2055 eyes) and untreated eyes (n = 1184 eyes). The pretreatment intraocular pressure was compared with posttreatment intraocular pressure among the study group (those receiving true therapy) and control groups (comparing placebo treatments with nontreated control patients)

Clinical Value/Implications

Interestingly, a relatively robust placebo effect did materialize. Placebo treatment control individuals had, on average, 2.27 mm Hg lower intraocular pressure compared with untreated control individuals. Just as interesting, the degree of placebo effect seemed to be relative to the degree of intraocular pressure reduction in the actual treatment group. Placebo-treated patients achieved 0.45 mm Hg intraocular pressure reduction for every 1 mm Hg intraocular pressure reduction achieved by the actual treatment group. Finally, substudy analysis showed the magnitude of the placebo effect was related to the sample size assessed. Although interesting, results of this study are probably most appropriately confined to academic interpretation of efficacy studies on glaucoma treatments.