THE LATEST PUBLISHED RESEARCH

Welcome to Review of Ophthalmology's Retina Online newsletter. Each month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with this timely and easily accessible report to keep you up to date on important information affecting the care of patients with vitreoretinal disease.

INSIDE THIS ISSUE:

• SS-OCTA Characteristics of Treatment-naïve Nonexudative MNV in AMD Prior to Exudation
• nAMD Managed by a Treat-Extend-Stop Protocol
• Predicting Short-term Anti-VEGF Treatment Effects in nAMD
• Effect of Residual Retinal Fluid on Visual Function in Ranibizumab-treated nAMD
• Predominantly Persistent Subretinal Fluid in CATT
• Differentiating Exudative Macular Degeneration and PCV Using OCT B-scan
• GA Incidence and Progression Following Intravitreal Injections of Anti-VEGF Agents for AMD
• Intravitreal Application of Epidermal Growth Factor in Non-Exudative AMD
• Comparing Treatment Outcomes Between Subthreshold Micropulse Laser and Aflibercept for DME
• Incidence & Risk Factors for Macular Edema After Primary RRD Surgery
• Noteworthy

SS-OCTA Characteristics of Treatment-naïve Nonexudative MNV in AMD Prior to Exudation

Investigators assessed the characteristics of treatment-naïve nonexudative macular neovascularization in age-related macular degeneration before the onset of exudation, using swept-source optical coherence tomography angiography.

They evaluated the following measurements at two visits prior to exudation: MNV area; choriocapillaris (CC) flow deficits; vessel area density (VAD); vessel skeleton density (VSD); retinal pigment epithelial detachment (PED) volume; mean choroidal thickness (MCT); and choroid vascularity index (CVI). They compared measurements made at the second visit and the rate of change between visits in eyes with and without exudation. The differences in these parameters between eyes with and without subsequent exudation were summarized with 95 percent confidence intervals.

Twenty-one eyes with nonexudative MNV were identified and followed. Here are some of the findings:
• Nine eyes developed exudation, and 12 eyes didn’t.
• Differences between these groups of eyes for all parameters tended to be small, and the 95 percent CIs largely ruled out any substantial differences.
• Overall, eyes with exudation had:
   o 24 percent smaller VAD;
   o 20 percent smaller VSD; and
   o 33 percent smaller PED volume measurements.
• No noteworthy differences were observed for MNV area, CC flow deficits, MCT or CVI measurements.

Investigators concluded that the onset of exudation was correlated with lesions having less vascularity and smaller PED volume measurements, but measurements of MNV area, CC flow deficits, MCT and CVI weren’t correlated with near-term exudation. They added that investigations are ongoing to further explore these and other anatomic changes as harbingers of near-term exudation.

SOURCE: Shen M, Zhang Q, Yang J, et al. Swept-source OCT angiographic characteristics of treatment-naïve nonexudative macular neovascularization in AMD prior to exudation. Invest Ophthalmol Vis Sci 2021;3;62:6:14.

nAMD Managed by a Treat-Extend-Stop Protocol  

Investigators assessed vision, injection quantity, initial lesion size and final anatomic status in patients with nAMD completing the treat-extend-stop protocol.

Patients with nAMD received ≥3 monthly anti-VEGF injections followed by one- to two-week injection interval extensions, with intra-/subretinal fluid resolution on SD-OCT to 12 weeks. With quiescent disease and two quarterly injections, patients were monitored alone beginning at four weeks extending by one- to two-week intervals until quarterly monitoring.

Eighty-eight of 143 eyes with nAMD completed the TES protocol without disease recurrence. Here are some of the findings:
• Sixteen (18.2 percent) developed subfoveal geographic atrophy, 25 (28.4 percent) developed fibrovascular scarring (FV) and 47 (53.4 percent) developed regressed choroidal neovascularization (rCNV) with 16.9 ±13.3 average injections between the three groups, which wasn’t statistically significant.
• Average treatment time was 30.3 ±26.1 months, and subsequent follow-up was 23.2 ±19.8 months.
• Average lesion size for FV was 18.77 ±10.8 mm² vs. GA at 12 ±9.99 mm² vs. regressed CNV at 7.12 ± 6.5 mm² (p<0.05).
• Pre-, post- and final vision for GA was 39.6 letters (20/160) vs. 32.7 letters (20/200 + 2, p=0.4725) vs. 25 letters (20/320, p=0.0865).
• FV was 22.4 letters (20/400 + 2) vs. 11.6 letters (20/640, p=0.0351) vs. 11 letters (20/640 + 1; p=0.0226); and rCNV was 56.4 letters (20/80 + 1) vs. 69.5 letters (20/40, p<0.001) vs. 67.3 letters (20/40-2, p=0.0016).
• In the rCNV group, 17/46 eyes gained ≥3 lines and 30/46 eyes achieved ≥ 20/40 vision.
• Non-central GA expanded 0.226 ±0.126 mm vs. 0.225 ±0.098 mm during and after treatment completion over 24 months (p=0.99).

Investigators wrote that central GA or FV was associated with worse visual outcomes (as opposed to rCNV) after cessation of therapy. They added that anti-VEGF therapy may not affect the rate of GA expansion and that final anatomic character and location are key determinants of final vision.

SOURCE: Adrean SD, Chaili S, Pirouz A, et al. Results of patients with neovascular age-related macular degeneration managed by a treat-extend-stop protocol without recurrence. Graefes Arch Clin Exp Ophthalmol 2021; Jul 12 [Epub ahead of print].

Predicting Short-term Anti-VEGF Treatment Effects in nAMD

Researchers predicted short-term anti-vascular endothelial growth factor treatment responders/non-responders for neovascular age-related macular degeneration patients based on optical coherence tomography images.

A total of 4,944 OCT scans from 206 patients with nAMD were the basis of a responder/non-responder prediction method for the short-term effect of anti-VEGF therapy. A deep learning architecture named a “sensitive structure-guided network (SSG-Net)” was created for prediction using pre- and post-treatment images. To verify its clinical efficiency, two deep learning methods and four experienced ophthalmologists evaluated the performance of the developed model.

Here are some of the findings:
• For the testing dataset, SSG-Net could predict the response by an accuracy of 84.6 percent and an area under the receiver curve (AUC) of 0.83, with a sensitivity of 0.692 and specificity of 1.
• In contrast, one comparison deep learning method achieved an accuracy of 65.4 percent with a sensitivity of 0.461 and specificity of 0.846; and the other achieved an accuracy of 73.1 percent with a sensitivity of 0.692 and specificity of 0.846.
• The predicted accuracy for four experienced ophthalmologists was 53.8 to 76.9 percent, with sensitivity of 0.538 to 0.923, and specificity of 0.385 to 0.846, respectively.

Researchers wrote that the proposed SSG-Net was effective in predicting the short-term efficacy of anti-VEGF treatment for nAMD patients. They noted that the technique could possibly help clinicians explain the necessity of anti-VEGF treatment to potential responders and avoid unnecessary treatment for non-responders.

SOURCE: Zhao X, Zhang X, Lv B, et al. Optical coherence tomography-based short-term effect prediction of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration using sensitive structure guided network. Graefes Arch Clin Exp Ophthalmol 2021; Jun 7. [Epub ahead of print].

Effect of Residual Retinal Fluid on Visual Function in Ranibizumab-treated nAMD

Researchers looked at the relationship between retinal fluid and vision in ranibizumab-treated patients with neovascular age-related macular degeneration, as part of a clinical cohort study using a post hoc analysis of clinical trial data.

Within the HARBOR Phase III, randomized, controlled trial, 917 patients ages ≥50 years with subfoveal nAMD associated with subretinal (SRF) and/or intraretinal fluid (IRF) at baseline, screening or week one were treated with intravitreal ranibizumab 0.5 or 2.0 mg (all treatment arms pooled).

Main outcome measures included mean best-corrected visual acuity and BCVA change from baseline at months (M)12/24 evaluated by presence/absence of SRF and/or IRF.

Here are some of the findings:

• Baseline BCVA was higher with residual versus resolved SRF at M12 (mean [CI, 58.8 letters [57.2 to 60.4] vs. 53.5 [52.4 to 54.5]) and M24 (59.3 letters [57.8 to 60.8] vs. 53.5 [52.5 to 54.5]).
• Mean BCVA change (adjusted for baseline) to M12 was greater with residual versus resolved SRF (CI, +2.4 letters [+0.1 to +4.7]), but lower with residual vs. resolved IRF (-3.5 letters [-5.8 to -1.2]).
• Eyes with residual SRF (no IRF) exhibited the largest mean BCVA gains (M12, +14.1 letters; M24, +13.2), followed by:
• resolved SRF/IRF (M12, +10.6 letters; M24, +10);
• residual SRF/IRF (M12, +7.2 letters; M24, +8.5); and
• residual IRF only (M12, +5.5 letters; M24, +3.6).

Researchers reported that vision outcomes (adjusted for baseline BCVA) through M24 were better in ranibizumab-treated eyes with residual vs. resolved SRF, and worse with residual vs. resolved IRF. They added that presence of residual retinal fluid requires a complex and nuanced assessment and interpretation in the context of nAMD management.

Predominantly Persistent Subretinal Fluid in CATT

Investigators described predominantly persistent subretinal fluid in eyes receiving ranibizumab or bevacizumab for neovascular age-related macular degeneration and compared visual acuity to eyes with non-persistent SRF, as part of a cohort within the randomized Comparison of Age-related Macular Degeneration Treatments Trials (CATT) clinical trial. The participants included CATT patients assigned to a pro re nata treatment.

Reading center graders evaluated optical coherence tomography scans at baseline and monthly follow-up visits for SRF. Predominantly persistent SRF through week 12 was defined as SRF at baseline, weeks four, eight and 12. Predominantly persistent SRF through one or two years was defined as SRF in ≥80 percent of visits by year one or two, respectively. Adjusted mean VA score and VA change from baseline were compared between eyes with predominantly persistent SRF and eyes with non-persistent SRF over the same duration using linear regression models, including baseline predictors of VA and predominantly persistent intraretinal fluid (IRF).

Primary outcome measures included predominantly persistent SRF through year one, adjusted VA score and VA change, and SRF thickness at the foveal center.

Here are some of the findings:
• Among 406 eyes with baseline SRF, SRF persisted in 108 (26.6 percent) through week 12, 94 (23.2 percent) through year 1, and 77 (19 percent) through year two.
• The mean adjusted VA (letters) at year one was similar between eyes with predominantly persistent vs. non-persistent SRF by week 12, (68.1 vs. 70.2; p=0.18), year one (67.6 vs. 70.2; p =0.11), and year two (71.4 vs. 70.9; p =0.78).
• The mean adjusted change in VA at year one was similar between eyes with predominantly persistent vs. non-persistent SRF by week 12 (6.3 vs. 7.6; p =0.38), year 1 (5.5 vs. 7.8; p =0.14), and year two (8.1 vs. 7.7; p =0.78).
• Among eyes with predominantly persistent SRF through year one, SRF was absent in the foveal center in 46 (48.9 percent), thickness was 1 to 200 μm in 48 (50 percent) and >200 μm in 1 (1.1 percent) at year one.

Investigators found that eyes with predominantly persistent and non-persistent SRF through week 12, year one or year two had similar VA outcomes after adjustment for baseline covariates and persistent IRF. At the foveal center, predominantly persistent SRF was most commonly absent or present in small quantities.

SOURCE: Core JQ, Pistilli M, Daniel E, et al; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Predominantly persistent subretinal fluid in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmol Retina 2021; Jun 11. [Epub ahead of print].

Differentiating Exudative Macular Degeneration and PCV Using OCT B-scan

Although polypoidal choroidal vasculopathy is best diagnosed with indocyanine green angiography, ICGA is often unavailable or not ordered. Optical coherence tomography is widely available, and OCT B-scans can visualize polypoidal lesions diagnostic of PCV as inverted U-shaped elevations of the retinal pigment epithelium with heterogeneous reflectivity and sometimes ring-shaped lesions within the polypoidal lesion. This study aimed to differentiate findings between eyes diagnosed with PCV or typical exudative age-related macular degeneration using ICGA, and then compared findings noted on the OCT B-scan line scan in each group.

The retrospective chart review compared clinical features of PCV eyes and typical exudative AMD based on ICGA. Eyes with PCV were evaluated for inverted U-shaped polypoidal lesions, which are the main differentiating finding of PCV from typical exudative AMD. Data collected included: presence of subretinal fluid (SRF); macular edema or intraretinal edema (ME); subretinal hyperreflective material (SHRM); and retinal pigment epithelial detachment (RPED). These findings were evaluated at baseline and after six to nine months of antiangiogenic therapy. Additionally, analysis was performed for the presence of polypoidal lesions before and after treatment. A total of 112 eyes of 106 patients were included.

The researchers found the following:
• Sixty-nine eyes were diagnosed with PCV and 43 were diagnosed with typical exudative AMD.
• Compared to AMD eyes, PCV eyes had an increased prevalence of SRF at baseline and after six to nine months of treatment, but the prevalence of ME, SHRM and RPED were similar at baseline and at six to nine months after treatment.
• In PCV eyes, the presence of visible polypoidal lesions decreased from 56.5 to 24.6 percent after treatment.

Investigators wrote that a characteristic inverted U-shaped elevation was present in more than half of eyes with polypoidal choroidal vasculopathy on OCT B-scan at baseline, but it disappeared following antiangiogenic therapy in 56.4 percent of cases. They added that subretinal fluid was more prevalent in PCV eyes than non-PCV AMD eyes. Investigators suggested that, if PCV is suspected in an anti-vascular endothelial growth factor-resistant case of exudative AMD, it's important in the absence of ICGA availability to look at the baseline B-scan OCT prior to therapy for evidence of polypoidal lesions.

GA Incidence and Progression Following Intravitreal Injections of Anti-VEGF Agents for AMD

Since geographic atrophy can occur in advanced neovascular age-related macular degeneration, researchers sought to estimate the incidence and progression of GA following intravitreal injections of anti-vascular endothelial growth factor agents in eyes with nAMD.

The investigators searched Ovid MEDLINE, Embase and Cochrane Central from inception to May 2020. They included studies that reported on the progression or development of GA in eyes with nAMD following anti-VEGF therapy.

They found 31 articles consisting of 4,609 study eyes (4,501 patients). Eyes received a mean of 17.7 injections over 35.2 months. Here are some of the findings:
• The prevalence of GA at baseline was 9.7 percent.
• The pooled incidence of GA was 30.5 percent at the end of follow-up.
• There was a positive, moderate linear correlation between the mean total number of injections and GA incidence at final follow-up (R²0.30; p=0.01).
• Monthly treatment was associated with a significantly higher risk for GA development relative to PRN (RR=1.40, CI, 1.21 to 1.61; p<0.001).
• Risk factors for GA development included GA in the fellow eye, retinal angiomatous proliferation, drusen and reticular pseudodrusen.

Investigators found an association between the frequency and number of treatments with anti-VEGF agents and the development of GA in nAMD. They suggested that future studies should clarify risk factors, population characteristics, and the relative contributions of treatment and disease progression on GA development in this context.

SOURCE: Eshtiaghi A, Issa M, Popovic MM, et al. Geographic atrophy incidence and progression following intravitreal injections of anti-vascular endothelial growth factor agents for age-related macular degeneration: A meta-analysis. Retina 2021; May 17. [Epub ahead of print].

Intravitreal Application of Epidermal Growth Factor in Non-Exudative AMD

Researchers assessed the safety of intravitreally applied epidermal growth factor (EGF).

The clinical interventional, prospective, single-center case series study included patients with age-related macular degeneration-related geographic atrophy, in whom the eye with the worse best-corrected visual acuity underwent a single, or repeated, intravitreal injection of EGF (0.75 µg in 50 µL). At baseline and afterwards, the eyes underwent ophthalmological exams.

The study included seven patients (mean age: 70.0 ±12.2 years (range: 54 to 86 years), with five patients receiving a single injection and two patients receiving two intravitreal injections in an interval of four weeks. Here are some of the findings:
• Mean duration of follow-up was 97 ±97 days (median: 35 days; range: 7 to 240 days).
• Mean BCVA was lower at baseline than at study end (1.41 ±0.44 logMAR vs. 0.97 ±0.12 logMAR; p=0.03).
• Mean size of the GA lesions didn’t differ significantly between baseline and study end (29,212 ±22,887 pixels vs. 29,300 ±22,905 pixels; p =0.59) nor did that of the mean perimetric mean defect (-10.3 ±5.9 dB vs. 12.0 ±8.8 dB; p =0.35) or that of the electroretinographical b-wave amplitude (44.53 ±31.7 µV vs. 64.5 ±25.5 µV; p =0.12).
• After a second injection four weeks after the first injection, one of two patients developed cystoid macular edema in association with an induced incomplete posterior vitreous detachment. It persisted for three weeks. Visual acuity in this eye improved from 1.0 logMAR at baseline to 0.80 logMAR at study end.

Researchers reported that, with the exception of one eye with temporary, self-resolving cystoid macular edema, single and repeated intravitreal applications of EGF (0.75 µg) in patients with GA didn’t lead to intraocular inflammations or any observed intraocular side effect.

SOURCE: Bikbov MM, Khalimov TA, Panda-Jonas S, et al. Intravitreal application of epidermal growth factor in non-exudative age-related macular degeneration. Br J Ophthalmol 2021; Jul 14. [Epub ahead of print].

Comparing Treatment Outcomes Between Subthreshold Micropulse Laser and Aflibercept for DME

Researchers compared two-year treatment outcomes of subthreshold micropulse (577 nm) laser and aflibercept for diabetic macular edema, as part of a retrospective case-control study.

A total 164 eyes in 164 DME patients treated with either micropulse laser (86 eyes) or intravitreal aflibercept monotherapy (78 eyes) were recruited. Main outcome measures included at least five Early Treatment Diabetic Retinopathy Study letters' improvement from baseline at six, 12 and 24 months.

Here are some of the findings:
• Rescue aflibercept was initiated in 24 percent of eyes in the micropulse laser group.
• At the six-month visit, the aflibercept group achieved a higher percentage of eyes with at least five-letter visual acuity improvement than the micropulse laser group (56 vs. 38 percent; p=0.044); however, this wasn’t the case at 12-month visits (45 vs. 49 percent; p=0.584) and 24-month visits (49 vs. 57 percent; p=0.227).
• At six-month visits, the aflibercept group had a higher percentage of eyes with at least a 10-percent improvement of central macular thickness (73 vs. 49 percent; p=0.005), but this wasn’t the case at 12-month visits (73 vs. 70 percent; p=0.995) and 24-month visits (85 vs. 84 percent, p=0.872).

Researchers found that aflibercept achieved faster and higher rates of anatomical and functional improvement than micropulse laser in DME patients, though long-term efficacy of treatment didn’t result in significant differences between aflibercept monotherapy and micropulse laser. Researchers suggested that micropulse laser potentially could serve as primary treatment with deferred aflibercept rescue without reducing the chance of visual improvement in DME eyes.