Volume 12, Number 6
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.
Congenital Ocular Findings in Microcephaly With Presumed Zika Infection
Researchers described the ocular findings of three cases of suspected congenital Zika viral infection with microcephaly and maculopathy, as part of a retrospective, consecutive case series.
Three male infants born in northern Brazil whose mothers demonstrated a viral syndrome during the first trimester and who subsequently were born with microcephaly were included in an observational report of macular findings. The main outcome measure was continued observation.
Three male infants were born with microcephaly to mothers who had a viral syndrome during the first trimester of gestation in an area that subsequently has demonstrated epidemic Zika infection, a flavivirus related to Dengue. Ocular examination was performed. All six eyes demonstrated a pigmentary maculopathy, ranging from mild to pronounced. In four eyes, well-delineated macular chorioretinal atrophy with a hyperpigmented ring developed. Three eyes demonstrated vascular tortuosity, and two eyes demonstrated a pronounced early termination of the retinal vasculature on photographic evaluation. Two eyes demonstrated a washed out peripheral retina with a hypolucent spot. One eye had scattered subretinal hemorrhages external to the macula. Finally, one eye demonstrated peripheral pigmentary changes and clustered atrophic lesions resembling grouped congenital albinotic spots (polar bear tracks).
The Zika virus has been linked to microcephaly in children of mothers with a viral syndrome during the first trimester of pregnancy, researchers wrote. Ocular findings previously described a pigmentary retinopathy and atrophy that now can be expanded to include torpedo maculopathy, vascular changes and hemorrhagic retinopathy, they added. Researchers suggested that ophthalmologic screening guidelines need to be defined to determine which children would benefit from newborn screening in affected regions.
SOURCE: Miranda HA 2nd, Costa MC, Frazão MA, et al. Expanded spectrum of congenital ocular findings in microcephaly with presumed zika infection. Ophthalmology. 2016; May 25. [Epub ahead of print].
Enhanced Benefit in DME from AKB-9778 Tie2 Activation With VEGF Suppression
Scientists analyzed the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema, as part of a Phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial.
Subjects (n=144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography were enrolled at 36 sites. They were randomized to: AKB-9778 monotherapy, i.e., subcutaneous AKB-9778 15 mg twice per day (BID) with monthly sham intraocular injections; combination therapy, i.e., subcutaneous AKB-9778 15 mg BID with monthly 0.3 mg ranibizumab; or ranibizumab monotherapy, i.e., subcutaneous placebo injections BID with monthly 0.3 mg ranibizumab. Best-corrected visual acuity and CST were measured at baseline and every four weeks.
The primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments and Diabetic Retinopathy Severity Score (DRSS).
At week 12, mean change from baseline CST was significantly greater in the combination group (−164.4 ±24.2 μm) than the ranibizumab monotherapy group (−110.4 ±17.2 μm; p=0.008) and was 6.2 ±13.0 μm in the AKB-9778 monotherapy group. In the combination group, mean CST at week 12 was 340.0 ±11.2 μm with 29.2 percent of eyes having resolved edema compared with the ranibizumab monotherapy group, where mean CST at week 12 was 392.1 ±17.1 μm with 17.0 percent of eyes having resolved edema. Mean change from baseline BCVA (letters) was 6.3 ±1.3 in the combination group; 5.7±1.2 in the ranibizumab monotherapy group; and 1.5±1.2 in the AKB-9778 monotherapy group. In the AKB-9778 monotherapy group, the percentage of study eyes that gained ≥10 letters was 8.7 percent, and the percentage gaining ≥15 letters was 4.3 percent. In the ranibizumab monotherapy group, the percentage of study eyes that gained ≥10 letters was 29.8 percent, and the percentage gaining ≥15 letters was 17.0 percent. In the combination group, the percentage of study eyes that gained ≥10 letters was 35.4 percent, and the percentage gaining ≥15 letters was 20.8 percent. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥two-step change was 11.4 percent in all AKB-9778-treated subjects compared with 4.2 percent in the ranibizumab monotherapy group. AKB-9778 was shown to be well-tolerated, with no clear by-treatment differences in adverse events.
Scientists found that Tie2 activation by subcutaneous injections of AKB-9778 combined with suppression of VEGF caused a significantly greater reduction in DME than that seen in suppression of VEGF alone.
SOURCE: Campochiaro PA, Khanani A, Singer M, et al. Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression. Ophthalmology. 2016; May 27. [Epub ahead of print].
Protective Effects of DPP4 Inhibitors on DR Type 2 Diabetes Progression
Scientists analyzed the effects of dipeptidyl peptidase-4 (DPP4) inhibitors on the progression of diabetic retinopathy in individuals with type 2 diabetes based on the DR severity scale, as part of a randomized, double-blind, placebo-controlled trial.
The medical records of 82 individuals with type 2 diabetes enrolled from 2005 to 2015 were retrospectively reviewed. Fundus photographs were graded using Early Treatment Diabetic Retinopathy Study methods. The associations between baseline risk factors and progression of DR were investigated.
Seven of 28 people treated with DPP4 inhibitors and 26 of 54 treated with other hypoglycemic agents showed progression of retinopathy, defined as one or more steps on the ETDRS scale (p=0.043). Only treatment with DPP4 inhibitors significantly reduced the progression of DR in individuals after propensity score matching (p=0.009). Treatment with DPP4 inhibitors was associated with a lower risk of DR progression (p=0.011).
Scientists concluded that treatment with DPP4 inhibitors was the independent protective factor against the progression of DR, aside from improving glycemic control. They noted that this is the first study to show the benefits of DPP4 inhibitors in reducing DR progression, and provides encouraging preliminary data for further evaluation of DPP4 inhibitors in the progression of DR.
SOURCE: Chung YR, Park SW, Kim JW, et al. Protective effects of dipeptidyl peptidase-4 inhibitors on progression of diabetic retinopathy in patients with type 2 diabetes. Retina. 2016; June 9. [Epub ahead of print].
Baseline VA Strongly Predicts VA Gain in DME Following Anti-VEGF Treatment
Researchers evaluated the correlation of baseline visual acuity with VA outcome in response to anti-vascular endothelial growth factor in diabetic macular edema using a retrospective analysis of nine clinical trials to assess the relevance of VA gain comparisons across trials.
A correlation analysis was performed between mean baseline VA and VA gain at month 12 for 1,616 individuals with DME across nine randomized clinical trials (RESOLVE; RISE; RIDE; RESTORE; RETAIN; DRCR.net Protocol I; DA VINCI; VIVID; and VISTA) with anti-VEGF treatment regimens ranibizumab 0.5 mg and aflibercept 2 mg.
The mean baseline VA ranged from 56.9 to 64.8 Early Treatment Diabetic Retinopathy Study letters. The mean VA gain at month 12 ranged from 6.8 to 13.1 ETDRS letters across trials. There was a strong inverse correlation between mean baseline VA and VA gain at month 12 (r=-0.85). The mean VA at 12 months plateaued at ~70 (68.5-73.0) ETDRS letters (20/40 Snellen VA equivalent) for the anti-VEGF treatment groups from all trials, regardless of dosing regimens and agents.
Researchers concluded that cross-trial comparisons based on changes in BCVA should be done cautiously and only after adjusting for BCVA at baseline. Furthermore, they wrote, the total VA afforded by treatment appeared to be subject to a plateau effect, warranting further exploration.
SOURCE: Dugel PU, Hillenkamp J, Sivaprasad S, et al. Baseline visual acuity strongly predicts visual acuity gain in patients with diabetic macular edema following anti-vascular endothelial growth factor treatment across trials. Clin Ophthalmol. 2016;10: 1103-10.
OCTA of the Foveal Avascular Zone in DR
Researchers analyzed foveal avascular zone (FAZ) dimensions and symmetry in individuals with diabetic retinopathy compared to healthy controls, using optical coherence tomography angiography.
OCTA via an Avanti RTVue 100 XR OCT system (Optovue) was performed on individuals with diabetes mellitus (DM) and healthy adults. A frame centered on the fovea captured FAZ measurements. Borders of the superficial vascular layer were defined as 3 μm below the internal limiting membrane (ILM) and 15 μm below the inner plexiform layer (IPL). Borders of the deep vascular layer were defined as 15 μm below the ILM and 70 μm below the IPL. Angles of maximum FAZ diameter were measured in all eyes by two graders.
In healthy eyes (n=25), FAZ surrounding vascular arcades were intact, showing a vertical or horizontal oval and symmetrical formation, with a maximum diameter typically on the horizontal or vertical axis. Diabetic eyes (n=29) presented with disintegrity of the vascular arcades, resulting in an enlarged FAZ. In the superficial layer, the mean horizontal FAZ diameter was significantly larger in the DR group (753 μm ±272 μm) than in the control group (573 μm ±177 μm (p=0.029). The difference was more pronounced in the deep layer, with a mean value of 659 μm ±194 μm in the control group and 1,009 μm ±342 μm in the DR group (p=0.001). Furthermore, in the superficial layer, the angle of the maximum FAZ diameter was 0 degrees (±15 degrees) or 90 degrees (±15 degrees) in 72.0 percent of healthy eyes. In eyes with DR, the angle of the maximum FAZ diameter was 0 degrees (±15 degrees) or 90 degrees (±15 degrees) in only 6.9 percent of cases due to the irregular configuration of the FAZ.
Researchers determined that OCTA is capable of imaging retinal vasculature without dye injection. Data suggested that the imaging modality can detect disintegrity of the vascular arcades surrounding the FAZ, thus differentiating DM from healthy eyes. Researchers noted that vascular abnormalities were more pronounced in the deep vascular layer.
SOURCE: Freiberg FJ, Pfau M, Wons J, et al. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefe’s Arch Clin Exp. 2016; 254 (6):1051-8.
Outcome Predictors in nAMD Cases Switched from Ranibizumab to Aflibercept
Investigators assessed the outcomes over 12 months of individuals with neovascular age-related macular degeneration with insufficient response to ranibizumab who were switched directly to eight-week fixed dosing of aflibercept without a loading phase, as part of a retrospective, interventional study.
Consecutive cases with nAMD who were switched from pro re nata intravitreal ranibizumab to eight-week fixed aflibercept because of persistent disease activity from November 1, 2013, to September 30, 2014, were included.
Demographic data, visual acuity and spectral-domain optical coherence tomography characteristics over time were evaluated to determine the prognostic indicators of final visual outcome at 12 months.
Main outcome measures included: the VA; central subfield thickness; presence of macular fluid at month 12 compared with baseline; and the definition of prognostic indicators of final visual outcome at month 12.
A total of 431 individuals (447 eyes) were included in this study. There was no statistically significant difference in VA between baseline and month 12 (p=0.79), whereas the CST significantly decreased at month 12 compared with baseline (p<0.001). At the 12-month follow-up, 48.3 percent of eyes had no macular fluid compared with 8.5 percent at baseline. The mean number of injections at month 12 was 6.8 ±1.75. Poor prognostic indicators included increasing age; increasing CST; the presence of intraretinal fluid; pigment epithelial detachment; and subfoveal thickening.
Investigators wrote that those who have not yet "responded" to p.r.n. ranibizumab seem to exhibit retinal dehydration after switching to aflibercept, whereas there was no demonstration of VA benefit. They also determined that baseline features at the point of switching can independently predict outcomes.
SOURCE: Chatziralli I, Nicholson L, Vrizidou E, et al. Predictors of Outcome in Patients with Neovascular Age-Related Macular Degeneration Switched from Ranibizumab to 8-Weekly Aflibercept. Ophthalmology. 2016; June 9. [Epub ahead of print].
Intravitreal Aflibercept Injection for AMD Resistant to Ranibizumab
Investigators described the one-year efficacy of aflibercept in Japanese cases of age-related macular degeneration resistant to ranibizumab treatment, as part of a retrospective case series.
Fourteen consecutive eyes of 14 individuals with AMD and no substantial response or developed resistance to intravitreal ranibizumab injections were enrolled.
All cases were subcategorized into one of two subtypes of AMD: seven with occult choroidal neovascularization and seven with polypoidal choroidal vasculopathy (PCV). Serial intravitreal aflibercept (IVA) injections were administered. Comprehensive ophthalmic examinations, including optical coherence tomography, were conducted at baseline and at follow-up examinations at one, three, six and 12 months after the initial IVA injection. The best-corrected visual acuity converted to logarithm of the minimum angle of resolution and central macular thickness at each follow-up visit were compared with baseline values. Anatomic response was also assessed with absorption or reduction of fluid in the subretina or subretinal pigment epithelial space.
The logMAR BCVA improved significantly at three, six and 12 months in the total cohort—at three and six months in individuals with occult CNV, and at three and 12 months in individuals with PCV. CMT decreased significantly at all follow-up visits in the total cohort as well as in both subtypes, except for CMT at six months in individuals with PCV. Anatomic improvement was also demonstrated in all cases, and pigment epithelial detachments tended to be resolved more rapidly in individuals with PCV than those with occult CNV.
Investigators found conversion to IVA to be effective in individuals with AMD resistant to ranibizumab, showing rapid morphologic improvement. LogMAR VA was raised significantly within 12 months, and investigators suggested the clinical course of VA improvement may differ according to the AMD subtypes.
SOURCE: Hirakata T, Fujinami K, Watanabe K, et al. One-year outcome of intravitreal aflibercept injection for age-related macular degeneration resistant to ranibizumab: rapid morphologic recovery and subsequent visual improvement.
Clin Ophthalmol. 2016;10: 969-77.
Comparing Monitoring Modalities in nAMD Detection: Home Study
Researchers determined the effectiveness of different monitoring modalities to detect incident neovascularization associated with age-related macular degeneration, as part of the Home Study, Report Number 3.
Secondary analyses compared rates of detecting incident nAMD in: prescheduled office visits; office visits triggered by monitoring device or symptom realization in a randomized trial evaluating a home telemonitoring device along with standard care (device arm); and standard care alone.
At prescheduled office visits, nAMD was detected in 14/1927 visits (0.7 percent, 95 percent confidence interval [CI]: 0.4 percent-1.1 percent) in the device arm; and 14/1949 visits (0.7 percent, 95 percent CI: 0.3 percent-1.1 percent) in the standard care alone arm. Thirty-seven participants with nAMD were detected in 318 office visits (11.6 percent, 95 percent CI: 8.1 percent-15.2 percent) triggered by device or symptom realization; and 17 nAMD cases were found during 65 office visits (26 percent, 95 percent CI: 15.5 percent-36.8 percent) triggered by symptom realization in the device and standard care alone arms. The home device strategy had a higher nAMD detection rate than prescheduled office visits (relative risk=16.0 [95 percent CI: 8.8-29.3]). Cases of nAMD detected at triggered visits were associated with less vision loss from baseline in the device arm (-three letters) vs. standard care alone arm (-11.5 letters) (p=0.03).
Researchers suggested that telemonitoring may alter the management of individuals with AMD and improve vision outcomes.
SOURCE: Chew, EY, Clemons TE, Harrington M, et al. Effectiveness of different monitoring modalities in the detection of neovascular age-related macular degeneration: the Home Study, Report Number 3. Retina. 2016; May 27. [Epub ahead of print].
SFCT Changes After Intravitreal Dexamethasone Implant for ME Due To RVO
Investigators assessed changes in choroidal thickness after intravitreal injection of a dexamethasone implant for macular edema due to retinal vein occlusion.
Thirty-one eyes of 31 subjects, treated with a single dose of a dexamethasone implant for retinal vein occlusion-associated macular edema, were included. Subfoveal choroidal thickness and central macular thickness of the affected eyes were compared with those of the normal contralateral eyes at baseline, and one; three; and five months after injection.
The mean SFCT of the affected eyes (296.3 µm ±61.6 µm) was significantly higher than that of the contralateral eyes (251.2 µm ±57.7 µm; p<0.001) at baseline. After injection, the mean SFCT was decreased compared with baseline in the treated eyes at months one, three and five. There was a correlation between SFCT and central macular thickness in the affected eyes at baseline (r=0.397, p=0.027). The change in SFCT was not correlated with the change in central macular thickness after injection. In the contralateral eyes, the mean SFCT did not change significantly.
Investigators found that subfoveal choroidal thickness in eyes with macular edema due to retinal vein occlusion was higher than that of the contralateral eyes. In addition, they determined that intravitreal injection of a dexamethasone implant was associated with a reduction in the choroidal thickness of the treated eye.
SOURCE: Esen E; Sizmaz S, Demircan N, et al. Choroidal thickness changes after intravitreal dexamethasone implant injection for the treatment of macular edema due to retinal vein occlusion. Retina. 2016; June 14. [Epub ahead of print].
Recurrent ROP Management Post-intravitreal Bevacizumab Monotherapy
Researchers determined incidence, risk factors, risk period and characteristics of recurrent retinopathy of prematurity treated by intravitreal bevacizumab monotherapy. They conducted a retrospective case series involving premature infants with type 1 ROP (subdivided into Stage III+ ROP and aggressive posterior ROP [APROP]) in zone I or zone II posterior who received IVB monotherapy and were followed up for at least 65 weeks adjusted age (AA).
The series included infants who demonstrated recurrence of type 1 ROP after IVB monotherapy, by way of examination on RetCam fundus photographs and fluorescein angiograms. Intravitreal bevacizumab monotherapy in 241 infants (471 eyes) was reviewed.
Recurrence incidence was 8.3 percent (20/241) for infants and 7.2 percent (34/471) for eyes. Recurrence risk factors of greatest significance were: appearance of neovascularization as APROP (p=0.006); extended duration of hospitalization (p=0.01); and lower birth weight (p=0.024). Recurrence risk period was between approximately 45 and 55 weeks AA (90.0 percent [18/20] for infants and 94.1 percent [32/34] for eyes), with mean recurrence of 51.2 weeks AA (±4.6 weeks; range, 45.7-64.9 weeks) and mean interval of 16.2 weeks (±4.4 weeks) between treatments. Recurrence characteristics included plus disease (20/20 infants [100 percent]) and neovascularization, which appeared at the following sites: Stage III+ROP with confluent neovascularization recurred both at the advancing edge and at the initial ridge and extraretinal fibrovascular proliferative complex (12/14 infants [85.7 percent]). However, APROP (6/6 infants [100 percent]) and Stage III+ROP with nonconfluent neovascularization (2/14 infants [14.3 percent]) recurred only at the advancing edge. Also, the anterior extent of retinal vascularization was decreased (mean, 1.76 disc diameters [DD] vs. 4.48 DD) in those with recurrence, and the rate of retinal vascularization was delayed in those without recurrence (mean, 0.11 DD/week vs. 0.23 DD/week). After retreatment with IVB, retinal vascularization proceeded minimally and slowly.
Researchers wrote that though premature children with severe ROP are being treated successfully with IVB monotherapy, recurrence is not uncommon, so vigilant follow-up is necessary to ensure timely re-treatment. They added that knowledge of recurrence incidence, risk factors, risk period and characteristics paves the way for tailored clinical management.
SOURCE: Mintz-Hittner HA, Geloneck MM, Chuang AZ, et al. Clinical Management of Recurrent Retinopathy of Prematurity after Intravitreal Bevacizumab Monotherapy. Ophthalmology. 2016; May 27. [Epub ahead of print].
SD-OCT Image Contrast & Settings Influence Retinal Structure ID
Scientists evaluated image contrast and color settings on assessment of retinal structures and morphology on spectral-domain optical coherence tomography.
Two hundred and forty-eight Spectralis SD-OCT B-scans of 62 individuals were analyzed by four readers. B-scans were extracted in four settings: W+N (white background with black image at normal contrast 9); W+H (white background with black image at maximum contrast 16); B+N (black background with white image at normal contrast 12); B+H (black background with white image at maximum contrast 16). Readers analyzed the images to identify morphologic features. Interreader correlation was calculated, and differences between Fleiss-kappa correlation coefficients were examined using bootstrap method. Any setting with significantly higher correlation coefficient was deemed superior for evaluating specific features.
Correlation coefficients differed among settings. No single setting was superior for all respective SD-OCT parameters (p=0.3773). Some variables showed no differences among settings. Hard exudates and subretinal fluid were best seen with B+H (kappa=0.46, p=0.0237 and kappa=0.78, p=0.002). Microaneurysms were best seen with W+N (kappa=0.56, p=0.025). Vitreomacular interface, enhanced transmission signal and epiretinal membrane were best identified using all color/contrast settings together (kappa=0.44; p=0.042; kappa=0.57; p=0.01; and kappa=0.62, p<=0.0001).
Scientists concluded that contrast and background affected the evaluation of retinal structures on SD-OCT images. They determined that no single setting was superior for all features, though certain changes were best seen with specific settings.
SOURCE: Palma CV, Amin R, Huf Wolfgang, et al. Spectral domain-optical coherence tomography image contrast and background color settings influence identification of retinal structures. Retina. 2016; May 23. [Epub ahead of print].
Valved vs. Nonvalved Cannula Small-gauge PPV for RD With Grade C PVR
Investigators compared outcomes and postoperative complication rates of valved vs. nonvalved cannula small-gauge PPV for repair of retinal detachments complicated by Grade C proliferative vitreoretinopathy.
A retrospective chart review of 364 consecutive eyes with valved or nonvalved cannula PPV for RD repair was performed. Primary outcomes were single surgery and final anatomic success, and change in best-corrected visual acuity for repair of RDs complicated by Grade C PVR.
Investigators identified 36 eyes in the valved group and 31 eyes in the nonvalved group with Grade C PVR RD. Single surgery success was 83 percent in the valved group vs. 77 percent in the nonvalved group (p=0.555); final anatomic success was 94 percent in the valved group vs. 87 percent in the nonvalved group (p=0.404). The mean final VA gain was −0.36 logarithm of the minimum angle of resolution (logMAR; approximate Early Treatment Diabetes Retinopathy Study [ETDRS] score=17 letters) in valved eyes vs. −0.33 logMAR (approximate ETDRS score=16 letters) in nonvalved eyes (p=0.81). No statistically significant difference was found in postoperative complication rates, including postoperative day one hypotony, hypertony and anterior chamber fibrin formation; postoperative retention of intraocular or subretinal perfluorocarbon liquid; and subsequent epiretinal membrane peel.
Investigators concluded that valved cannula PPV yielded equivalent VA and anatomic outcomes without increased postoperative complication rates compared with traditional nonvalved cannula PPV for Grade C PVR-associated RD repair.
SOURCE: Oellers P, Stinnett S, Hahn P. Valved versus nonvalved cannula small-gauge pars plana vitrectomy for repair of retinal detachments with Grade C proliferative vitreoretinopathy. Clin Ophthalmol. 2016;10:1001-6.