Volume 13, Number 1
WELCOME to Review
of Ophthalmology's Retina
Online e-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.
OCTA Changes in Early Type 3 Neovascularization After Anti-VEGF
Researchers examined morphologic changes on optical coherence tomography angiography of treatment-naive type 3 neovascularization secondary to exudative age-related macular degeneration after one year of anti-vascular endothelial growth factor therapy.
Researchers enrolled consecutive individuals diagnosed with treatment-naive early-stage type 3 neovascularization in the retrospective study. All individuals underwent color fundus photographs/MultiColor (Heidelberg Engineering) imaging, fluorescein angiography, indocyanine green angiography, structural spectral-domain OCT and OCTA Optovue RTVue XR Avanti (Optovue) at baseline, and repeated OCTA and structural SD-OCT at month 12. Researchers then compared qualitative analysis of the 3 x 3 OCTA exams at baseline and month 12 to assess changes after anti-VEGF therapy.
A total of 15 treatment-naive eyes of 15 consecutive individuals were included in the analysis. At 12-month follow-up after pro re nata anti-VEGF therapy (5.75 ±1.48 injections of ranibizumab and injections of 6.33 ±1.21 of aflibercept), OCTA demonstrated persistence of the deep capillary plexus abnormalities in 13 of 15 eyes. In the outer retina and choriocapillaris, the initial lesion became undetectable in seven of 15 cases, accompanied by choriocapillaris atrophy. The abnormal vascular complex persisted in the form of a tuft-shaped lesion in the outer retinal segmentation in nine of 15 eyes, which in the choriocapillaris segmentation was associated with subretinal pigment epithelium neovascularization in eight cases.
Researchers noted that, after one year of anti-vascular endothelial growth factor therapy, the tuft-shaped abnormal outer retinal lesion seen on OCTA—frequently associated with a small, clew-like flow signal in the choriocapillaris—either became undetectable or developed sub-retinal pigment epithelium neovascularization.
SOURCE: Miere A, Querques G, Semoun O, et al. Optical coherence tomography angiography changes in early type 3 neovascularization after anti-vascular endothelial growth factor treatment. Retina 2017; Jan 10. [Epub ahead of print].
Switching to Aflibercept for Treatment-resistant Neovascular AMD
Scientists systematically reviewed anatomical and functional outcomes subsequent to switching from bevacizumab/ranibizumab to aflibercept monotherapy (Eylea; Bayer/Regeneron) in individuals with treatment-resistant neovascular age-related macular degeneration, as part of a systematic review and meta-analysis. One of the researchers is a consultant for Bayer.
The researchers searched Medline, PubMed, Embase and Cochrane databases up to July 2016 for available scientific literature that met inclusion criteria. Eligible studies reported visual and anatomical outcomes with at least six months of follow-up among individuals with nAMD and persistent or resistant exudative fluid despite previous anti-vascular endothelial growth factor therapy (bevacizumab and/or ranibizumab) and were switched to aflibercept monotherapy. Mean changes in best-corrected visual acuity and central retinal thickness were pooled using random-effects models with CIs.
Of 82 papers reviewed, 28 studies met inclusion criteria of this review. Pooled results showed a small mean improvement in BCVA at six and 12 months following switching (1.11 letters: CI, 0.25 to 2.46; p=0.17; and 0.63 letters: CI, -0.26 to 1.52; p=0.17, respectively). There was a significant improvement in mean CRT following switching (-61.90 µm: CI, -77.10 to -46.80; p<0.001; and -50.00 µm: CI -63.20 to -36.80; p<0.001 at six and 12 months, respectively).
Pooled analysis demonstrated significantly improved anatomical outcomes, although visual function remained stable with a comparable effect to other anti-VEGF agents in preservation of vision. Scientists wrote that, given the fact that subjects had poorly responsive chronic disease with limited potential for visual recovery, switching to aflibercept with frequent monitoring might be a suitable option for individuals who have developed treatment resistance.
SOURCE: Spooner K, Hong T, Wijeyakumar W, et al. Switching to aflibercept among patients with treatment-resistant neovascular age-related macular degeneration: A systematic review with meta-analysis. Clin Ophthalmol 2017;11:161-7.
Short-term Safety of 2 Mg Intravitreal Ziv-Aflibercept
Researchers assessed the safety of single intravitreal 2 mg ziv-aflibercept (0.08 mL) injections for the treatment of choroidal neovascular membranes.
Eyes with choroidal neovascular membranes received single intravitreal injections of 2 mg ziv-aflibercept (0.08 mL). Comprehensive ophthalmic exams and detailed systemic evaluations were performed at baseline and days one, seven and 30 after injections. Standard electroretinography was performed at baseline and day 30. Primary outcome measures consisted of safety assessments (signs of clinical toxicity and electroretinographic abnormalities). Secondary outcome measures included changes in best-corrected visual acuity and central subfield thickness of the macula.
Twenty-one eyes of 20 individuals (12 males) received injections. Etiologies responsible for the choroidal neovascular membranes included: age-related macular degeneration (14), polypoidal choroidal vasculopathy (3), myopia (2) and idiopathic juxtafoveal telangiectasia (2). No individuals complained of worsening vision or pain after the intravitreal injections, and no intraocular inflammation was seen. No significant changes in the electroretinographic b/a ratio from baseline to one month were measured (scotopic: p=0.89; photopic: p=0.13), and mean intraocular pressures were unchanged (14.2 ±3.6 vs. 13.7 ±3 mmHg; p=0.62). Mean BCVA didn’t change significantly from baseline to one month (0.66 ±0.37 logMAR [Snellen equivalent: 20/100] vs. 0.61 ±0.35 logMAR [Snellen equivalent: 20/80]; p=0.72) but significant improvements in central subfield thickness were seen (343 ±177 vs. 210 ±133 µm; p=0.01).
Researchers wrote that single intravitreal injections of 2 mg ziv-aflibercept (0.08 mL) appeared to be safe through one month.
SOURCE: Chhablani J, Dedhia CJ, Peguda HK, et al. Short-term safety of 2 mg intravitreal ziv-aflibercept. Retina 2017; Jan 2. [Epub ahead of print].
ENDURANCE 12-Month Extension Study: As-needed Aflibercept & Macular Laser
Researchers determined whether the efficacy and safety achieved with 2 mg intravitreal aflibercept injections for diabetic macular edema during the phase III VISTA DME trial were maintained with individualized, as-needed treatment, as part of a Phase IV, multicenter, open-label extension study.
Sixty individuals completing VISTA DME elected to enter the ENDURANCE extension study. All individuals received IAIs in the presence of clinically relevant DME and were observed at four-, eight- or 12-week intervals depending on the need for treatment. Main outcome measures were mean IAIs given through month 12, the proportion of individuals receiving no IAIs and the role of macular laser in decreasing treatment burden among individuals requiring ongoing IAIs.
A mean of 4.5 IAIs were administered through month 12. Eighteen (30 percent) individuals required no IAIs, and among those who met IAI retreatment criteria, a mean of 6 IAIs were administered through month 12. Best-corrected visual acuity gains achieved during VISTA DME were maintained and stable, with individualized dosing during ENDURANCE fluctuating by a mean of <1.5 letters from the baseline at all time points. Likewise, mean central retinal thickness remained relatively stable during ENDURANCE. Thirty-seven (62 percent) individuals met macular laser criteria at a mean of 19.5 weeks, with no significant difference in the frequency of IAIs before or after macular laser.
Researchers determined that vision gains achieved during the three-year VISTA DME trial were maintained through month 12 of the ENDURANCE extension study with a reduced treatment frequency, with 30 percent of individuals receiving no IAIs. They observed no significant reduction in IAI frequency after macular laser application.
SOURCE: Wykoff CC, Le RT, Khurana RN, et al. Outcomes with as-needed aflibercept and macular laser following the Phase III VISTA DME trial: ENDURANCE 12-month extension study. Am J Ophthalmol 2017;173:56-63.
Long-term Effects of Intravitreal 0.19 mg Fluocinolone Acetonide Implant on DR Progression & Regression
Researchers examined the effects of fluocinolone acetonide on the progression to proliferative diabetic retinopathy, and the impact of FAc on changes in the Early Treatment Diabetic Retinopathy Study diabetic retinopathy severity scale grade during the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) A and B Phase III clinical trials.
The post hoc analysis of data from the 36-month prospective, randomized, FAME A and B trials included individuals with diabetic macular edema who received sham control or FAc 0.2 or 0.5 μg/day.
A masked reading center from the University of Wisconsin-Madison determined DRSS grade using standard 7-field stereo fundus photography and retinal perfusion status using fluorescein angiography. Retinopathy changes over time were determined by DRSS step differences from baseline to month 36. Pairwise comparisons between the three treatment groups were performed using a log-rank test without adjustment for covariates, with the primary comparison between sham control and 0.2 μg/day FAc.
Main outcome measures included study-eye progression to PDR based on a composite clinical outcome of: progression from nonproliferative diabetic retinopathy to PDR based on graded fundus photographs; panretinal photocoagulation or pars plana vitrectomy for PDR; and study eye changes on the DRSS.
In the integrated FAME data set, compared with sham control-treated subjects, time to first PDR event was significantly delayed in subjects treated with FAc (p<0.001), and this effect was confirmed in subgroups with more severe DR and chronic DME at baseline. In addition, subjects with retinal nonperfusion at baseline showed greater reduction in progression to PDR with FAc treatment. Both FAc dosages demonstrated statistically significant improvements in mean DR severity compared with sham treatment at months six, 12 and 18. More subjects who received FAc experienced two-or-more- or three-or-more-step improvements in DR severity compared with subjects who received sham; conversely, fewer subjects treated with FAc experienced two-or-more- or three-or-more-step worsening in DR severity. The three-or-more-step improvement with 0.5 μg/day FAc was statistically significantly different from sham control.
Scientists determined that, in subjects with DME, sustained intraocular delivery of FAc slowed development of PDR and progression of diabetic retinopathy.
SOURCE: Wykoff CC, Chakravarthy U, Campochiaro PA, et al. Long-term effects of intravitreal 0.19 mg fluocinolone acetonide implant on progression and regression of diabetic retinopathy. Ophthalmology 2017; Jan. 9. [Epub ahead of print].
Review of Automated DR Image Assessment Software
Researchers wrote that automated diabetic retinopathy image assessment systems (ARIAS) may provide clinically effective and cost-effective detection of retinopathy. They aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders, as part of an observational measurement comparison study of human graders following a national screening program for DR vs. ARIAS.
Researchers included retinal images from 20,258 consecutive individuals attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013.
They manually graded retinal images following a standard national protocol for DR screening and processed them with by iGradingM, Retmarker and EyeArt. They sent discrepancies between manual grades and ARIAS results to a reading center for arbitration.
Main outcome measures included screening performance (sensitivity, false-positive rate) and diagnostic accuracy (CI, screening-performance measures). Economic analysis estimated the cost per appropriate screening outcome.
Researchers noted the following sensitivity point estimates (CI) of the ARIAS. For EyeArt, they were: 94.7 percent (94.2 to 95.2 percent) for any retinopathy; 93.8 percent (92.9 to 94.6 percent) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative or proliferative); 99.6 percent (97 to 99.9 percent) for proliferative retinopathy. For Retmarker, they were: 73 percent (72 to 74 percent) for any retinopathy; 85 percent (83.6 to 86.2 percent) for referable retinopathy; 97.9 percent (94.9 to 99.1 percent) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost-effective.
Researchers concluded that Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders, and had sufficient specificity to make them cost-effective alternatives to manual grading alone. They added that ARIAS have the potential to reduce health-care costs and aid delivery of DR screening in developing or remote health-care settings.
SOURCE: Tufail A, Rudisill C, Egan C, et al. Automated diabetic retinopathy image assessment software: Diagnostic accuracy and cost-effectiveness compared with human graders. Ophthalmology 2016; Dec 23. [Epub ahead of print].
Type 2 Diabetes Genetic Variants & Risk of DR
Investigators wrote that genetic association studies to date have not identified any robust risk loci for diabetic retinopathy. They hypothesized that individuals with more diabetes genetic risk alleles had a higher risk of developing DR, as part of a case-control genetic association study.
Investigators evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1,528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study. A total of 547 (35.8 percent) had DR.
Participants underwent a comprehensive ocular exam including dilated fundus photography. Investigators graded retinal photographs using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. They identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms, and constructed multilocus genetic risk scores for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. They generated two GRSs: an overall GRS including all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Investigators determined the discriminating ability of the GRSs by the area under the receiver operating characteristic curve. The main outcome measure included the odds ratios on DR.
Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were twofold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels; however, addition of the GRSs to traditional risk factors improved the AUC modestly—by 3 to 4 percent.
Investigators concluded that type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors.
SOURCE: Chong YH, Fan Q, Tham YC, et al. Type 2 diabetes genetic variants and risk of diabetic retinopathy. Ophthalmology 2016; Dec 27. [Epub ahead of print].
Factors Influencing Acute Central Serous Chorioretinopathy Episode Duration
Scientists looked at the influence of clinical and multimodal imaging parameters on the duration of acute central serous chorioretinopathy episodes.
They prospectively included consecutive individuals with first, treatment-naive central serous chorioretinopathy episodes presenting within 20 days of symptoms onset, and reevaluated them 15 days to 20 days later, followed by monthly evaluation for six months. Scientists analyzed the following; subfoveal choroidal thickness; fluorescein leakage intensity on fluorescein angiography; elevation of retinal pigment epithelium lesions at leakage sites; focal/multifocal pattern of indocyanine green angiography at baseline; time-dependent pattern of subretinal fluid resorption on OCT using volume segmentation; history of corticosteroid intake; and mean blood pressure using univariate (Log rank test) and multivariate (Cox proportional hazard regression) survival analysis.
Of 31 participants (26 men, five women, mean age: 40 ±8.9 years, range: 24 to 58), 26 (84 percent) had episode resolution by six months. Using univariate analysis, episode duration was longer in cases with subfoveal choroidal thickness ≥500 µm (p=0.0002), retinal pigment epithelium elevation at leakage sites ≥50 µm (p=0.033) and a peak in subretinal fluid observed during follow-up (p=0.013). Scientists determined a near-significant association of intense fluorescein leakage (p=0.074) with longer episodes. Using multivariate analysis, subfoveal choroidal thickness ≥500 µm (p=0.017), RPE elevation at leakage sites ≥50 µm (p=0.010) and participant age ≥40 years (p=0.010) were significantly and independently associated with longer episodes. Indocyanine green angiography pattern, corticosteroid intake and blood pressure didn’t influence episode duration.
Scientists concluded that older age, higher subfoveal choroidal thickness and higher degree of RPE alteration at leakage sites were independent factors for longer acute central serous chorioretinopathy episodes.
SOURCE: Daruich A, Matet A, Marchionno L, et al. Acute central serous chorioretinopathy: Factors influencing episode duration. Retina 2017; Jan 6. [Epub ahead of print].
Macular Pigment Response to Zeaxanthin Supplementation in Macular Telangiectasia Type 2
Investigators analyzed macular pigment amount and distribution in individuals with macular telangiectasia type 2 receiving oral zeaxanthin supplementation, in a randomized, open-label, interventional trial.
Eight individuals with macular telangiectasia type 2 were randomized to 10 mg or 20 mg of zeaxanthin per day. At each visit, best-corrected visual acuity, contrast sensitivity, fundus biomicroscopy, color fundus photography, autofluorescence imaging, optical coherence tomography and serum carotenoid levels were tested. Individuals were assessed at baseline and after six, 12, 18 and 24 months of zeaxanthin supplementation. Investigators analyzed and calculated concentration of MP from autofluorescence imaging obtained at 488-nm excitation wavelength. High-performance liquid chromatography provided serum carotenoid levels.
The majority of individuals had definite increases in the intensity of hypofluorescent ring of MP, with none depositing MP centrally at the fovea. Although some individuals noted subjective improvements in vision, no objective improvements could be documented, and no changes could be seen in foveal OCT features. Yellowish, hypofluorescent crystals appeared in one individual's macular region, yielding no change in visual acuity. These inner retinal crystals disappeared several months after discontinuing a 20-mg zeaxanthin supplement.
Investigators determined that zeaxanthin supplementation didn’t result in any visual benefit in individuals with macular telangiectasia type 2 and did not reestablish a normal peaked distribution of MP in the fovea. Furthermore, they found, one individual developed a novel, reversible, crystalline maculopathy in response to zeaxanthin supplementation that was reminiscent of canthaxanthin crystalline maculopathy.
SOURCE: Choi RY, Gorusupudi A, Wegner K, et al. Macular pigment distribution responses to high-dose zeaxanthin supplementation in patients with macular telangiectasia type 2. Retina 2017; Jan 10. [Epub ahead of print].
Surgical Outcomes of 27-Gauge Vitrectomy for Various Vitreous Diseases
Investigators evaluated the safety and efficacy of 27-ga. vitrectomy for various vitreoretinal disorders, as part of a retrospective, comparative study.
A total of 163 consecutive eyes with various diseases underwent 27-ga. pars plana vitrectomy with or without ultraspeed transformer (which enables high cutting and aspiration rates) by a single surgeon from June 2012 through December 2014. Investigators analyzed the eyes for best-corrected visual acuity, intraocular pressure, intraoperative and postoperative complications, and surgery time.
In two eyes (1.2 percent), peripheral retina breaks were encountered intraoperatively, yet no other complications were found in those eyes. No cases required larger-gauge vitrectomy. Mean BCVA improved from 20/58 (logMAR: 0.46 ±0.64) preoperatively to 20/32 (LogMAR: 0.20 ±0.40) postoperatively (p<0.001). Mean follow-up was 16.7 months (range: 6 to 33 months). Intraocular pressure remained stable throughout the postoperative course. Hypotony was seen in 15 eyes (9.2 percent) at one-day postoperative, yet that spontaneously improved within one week. No case of retinal detachment or endophthalmitis was recorded. In macular surgeries, such as idiopathic epiretinal membrane and macular hole combined with cataract surgery, mean surgery time was 32.1 ±6.9 minutes with ultraspeed transformer (n=38) and 37.1 ±7.7 minutes without ultraspeed transformer (n=40) (p=0.004).
Investigators found the 27-ga. pars plana vitrectomy to be safe and effective for treating various vitreoretinal disorders.
SOURCE: Yoneda K, Morikawa K, Oshima Y, et al. Surgical outcomes of 27-gauge vitrectomy for a consecutive series of 163 eyes with various vitreous diseases. Retina 2017; Jan 4. [Epub ahead of print].