Volume 14, Number 1 |
January 2018 |
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.
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Efficacy & Safety of Ranibizumab for Treatment of Macular Edema from Uncommon Causes
Investigators evaluated the efficacy and safety of ranibizumab 0.5 mg in adults with macular edema resulting from causes other than diabetes, retinal vein occlusion or neovascular age-related macular degeneration, as part of a Phase III, 12-month, double-masked, randomized, sham-controlled, multicenter study partially supported by Novartis, marketer of Lucentis outside of the United States.
A total of 178 eligible individuals ages ≥18 years participated. Individuals were randomized 2:1 to receive ranibizumab 0.5 mg (n=118) or sham (n=60) at baseline and month one. From month two, individuals in both arms received open-label individualized ranibizumab treatment based on disease activity. A preplanned subgroup analysis summarized the primary endpoint on five baseline ME etiologies (post-uveitis inflammation, pseudophakic or aphakic, central serous chorioretinopathy, idiopathic and miscellaneous).
Main outcome measures included changes in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letters) from baseline to month two (primary endpoint) and month 12, and safety over 12 months.
A total of 156 individuals (87.6 percent) completed the study. The baseline characteristics were balanced between treatment arms. Overall, ranibizumab showed superior efficacy vs. sham from baseline to month two (least squares mean BCVA, +5.7 letters vs. +2.9 letters; one-sided p=0.0111)—a treatment effect of +2.8 letters. The mean BCVA gain from baseline to month 12 was 9.6 letters with ranibizumab. The treatment effect at month two was variable in the five predefined etiology subgroups, ranging from >5-letter gain to 0.5-letter loss. Safety findings were consistent with the well-established safety profile of ranibizumab.
Investigators determined that the primary endpoint was met; ranibizumab showed superiority in BCVA gain over sham in treating ME due to uncommon causes, with a treatment effect of +2.8 letters vs. sham at month two. At month 12, the mean BCVA gain was 9.6 letters in the ranibizumab arm; however, the treatment effect was variable across the etiology subgroups, reaching a BCVA treatment effect that was greater than one line in individuals with ME from inflammatory conditions post-uveitis or after cataract surgery. Overall, investigators found that ranibizumab was well-tolerated with no new safety findings up to month 12.
Source: Staurenghi G, Lai TYY, Mitchell P, et al. Efficacy and safety of ranibizumab 0.5 mg for the treatment of macular edema resulting from uncommon causes. Ophthalmology 2018; Jan. 19. [Epub ahead of print].
Plasma VEGF Levels After Intravitreal Injection of Bevacizumab, Aflibercept or Ranibizumab for DME
Investigators analyzed changes in plasma vascular endothelial growth factor levels, depending on the severity of diabetic retinopathy or diabetic macular edema after intravitreal injection of bevacizumab, aflibercept or ranibizumab for treatment of DME.
They evaluated plasma VEGF levels in 72 individuals with DR, and changes in 42 people with DME receiving intravitreal injections of bevacizumab, aflibercept or ranibizumab at initial injections.
Investigators found no correlations between plasma VEGF levels and severity of DME or DR. With bevacizumab, baseline plasma VEGF levels (51.9 pg/mL) were significantly reduced to 11.9 pg/mL after one week (p=0.0130), and to 24.1 pg/mL after four weeks (p=0.0201). In aflibercept-treated eyes, plasma VEGF decreased from 52.2 pg/mL to 7.8 pg/mL after one week, and to 12.6 pg/mL after four weeks (both p<0.001). No such reductions were observed in those receiving ranibizumab.
Investigators wrote that baseline plasma VEGF levels showed no correlations with DR or DME severity, whereas intravitreal injection of bevacizumab or aflibercept significantly reduced plasma VEGF for up to four weeks; ranibizumab produced no such effects. They added that changes in plasma VEGF levels didn’t appear to be critical to the progression or treatment of DME and DR.
SOURCE Hirano T, Toriyama Y, Iesato Y, et al. Changes in plasma vascular endothelial growth factor level after intravitreal injection of bevacizumab, aflibercept, or ranibizumab for diabetic macular edema. Retina 2017; Dec 21. [Epub ahead of print].
Disorganization of Inner & Outer Retinal Morphology in DME
Investigators examined associations between DR severity, retinal morphology on SD-OCT and visual acuity in participants with DME, as part of a cross-sectional, observational case series conducted at a single tertiary care referral center.
They analyzed the demographics, visual acuity, SD-OCT and color fundus photographs of 80 individuals with DME (102 eyes) seen between Dec. 28, 2013, and April 30, 2014, and between May 1, 2016, and July 31, 2016.
The main outcome measures were features captured on SD-OCT and thickness metrics. On SD-OCT, investigators graded:
• type and shape of DME;
• shape and presence of septae within intraretinal cystoid abnormalities;
• presence of hyperreflective dots and foci;
• integrity of the external limiting membrane and ellipsoid zone;
• presence and extent of disorganization of the inner retinal layers; and
• the status of the vitreomacular interface and epiretinal membrane.
They measured retinal thickness at the fovea and at the site of maximum pathology, choroidal thickness at the fovea, and 1,000 μm temporal and nasal to the fovea. As well, they graded color photographs to derive a DR severity stage.
The mean (SD) age was 63 (11) years, and 30 participants (37.5 percent) were women. The odds of having DRIL were greater in eyes with:
• disrupted external limiting membrane (OR, 4.4; CI, 1.6 to 12.0; p=0.003);
• disrupted ellipsoid zone (OR, 2.7; CI, 1.0 to 7.2; p=0.03);
• presence of epiretinal membrane (OR, 2.8; CI, 1 to 7.4; p=0.03); and
• increased retinal thickness at the fovea (OR, 1.6; CI, 1.1 to 2.2; p<0.001).
Occurrence of DRIL was more likely in eyes with proliferative DR (OR, 7.3; CI, 1.7 to 31.4; p=0.007). Mean VA decreased by approximately 4.7 letters for each 100-μm increase in the average global DRIL (CI, -7.9 to 1.4; p=0.006).
Investigators found an association between DRIL, outer retina disruption and increasing DR severity. They suggested that further longitudinal studies were warranted to determine whether DRIL was a clinically relevant noninvasive morphological marker in eyes with DME.
SOURCE Das R, Spence G, Hogg RE, et al. Disorganization of inner retina and outer retinal morphology in diabetic macular edema. JAMA Ophthalmol 2018; Jan 11. [Epub ahead of print].
Retinal Photocoagulation for DME With Peripheral Retinal Nonperfusion
Researchers evaluated the effect of targeted retinal photocoagulation (TRP) on visual and anatomic outcomes, and the treatment burden in eyes with diabetic macular edema, as part of a Phase I/II prospective, randomized, controlled clinical trial. They included 40 eyes of 29 individuals with center-involved macular edema secondary to diabetes mellitus.
Eyes with center-involved DME and Early Treatment Diabetic Retinopathy Study best-corrected visual acuity between 20/32 and 20/320 (Snellen equivalent) were randomized 1:1 to monotherapy with 0.3-mg ranibizumab (Lucentis, Genentech) or combination therapy with 0.3-mg ranibizumab and TRP guided by wide-field fluorescein angiography. All eyes received four monthly ranibizumab injections followed by monthly examinations and pro re nata retreatment through 36 months. Targeted retinal photocoagulation was administered outside the macula to areas of retinal capillary nonperfusion plus a one-disc area margin in the combination therapy arm at week one with retreatment at months six, 18 and 25, if indicated. Main outcome measures included mean change in ETDRS BCVA from baseline and number of intravitreal injections administered.
At baseline, the mean age was 55 years, the mean BCVA was 20/63 (Snellen equivalent) and the mean central retinal subfield thickness was 530 μm. Thirty-four eyes (85 percent) completed the 36-month follow-up, at which point mean BCVA improved 13.9 and 8.2 letters (p=0.20) in the monotherapy therapy arm, and mean CRT improved 302 μm in the monotherapy therapy arm and 152 μm (p=0.03) in the combination therapy arm. The mean number of injections administered through month 36 was 24.4 (range: 10 to 34) in the monotherapy therapy arm and 27.1 (range: 12 to 36) in the combination therapy arm; 73 percent (362/496) of PRN injections were administered in the monotherapy therapy arm, and 80 percent (433/538) of PRN injections were administered in the combination therapy arm (p=0.004). Goldmann visual field isopter III-4e area decreased by 2 percent in the monotherapy therapy arm and 18 percent in the combination therapy arm (p=0.30).
Researchers found no evidence that combination therapy with ranibizumab and TRP improved visual outcomes or reduced the treatment burden compared with ranibizumab alone.
Source: Brown DM, Ou WC, Wong TP, et al. Targeted retinal photocoagulation for diabetic macular edema with peripheral retinal nonperfusion. Ophthalmology 2018; Jan 11. [Epub ahead of print].
Predicting Diabetic Retinopathy in Type 2 Diabetics
Researchers wrote that fatty acid binding protein 4 has been implicated in the pathology of diabetes and macrovascular diseases. As such, they set out to determine serum FABP 4 levels in type 2 diabetics without diabetic retinopathy at admission to investigate a possible contribution of FABP 4 to the increased risk of five-year incidence of DR, as part of a cohort study.
A total of 738 individuals with type 2 diabetes without DR were consecutively enrolled and followed. Ophthalmologists performed annual retinopathy evaluations in the following five years, while researchers performed multivariate analyses using logistic regression models.
During the follow-up period, 152 (20.60 percent [CI, 17.68 to 23.51 percent]) individuals developed DR, and 60 (8.13 percent [CI: 6.16 to 10.10 percent]) individuals developed vision-threatening DR. Nonparametric Spearman rank correlation revealed a statistically significant positive correlation between serum FABP 4 level and international Clinical Diabetic Retinopathy Severity Scales (r=0.348; p<0.001). After adjusting for other established risk factors, FABP4 levels in multivariate models compared with the first quartile were associated with DR; the adjusted risk of DR increased by 124 percent (OR=2.24 [CI 1.65 to 3.68] p=0.006) in the third quartile and by 27 percent (3.27 [2.04 to 5.56], p<0.001) in the fourth quartile. Similarly, the adjusted risk of VTDR increased by 140 percent (OR=2.40 [CI 1.32 to 3.82], p=0.001) in the third quartile and 278 percent (3.78 [2.17 to 6.59], p<0.001) in the fourth quartile.
Researchers concluded that FABP 4 showed potential as a novel biomarker for DR prediction in a Chinese population with T2DM. They added that strict glycemic control and more frequent retinal exams should be emphasized for T2DM cases with the highest quartile range of FABP 4.
SOURCE: Zhang XZ, Tu WJ, Wang H, et al. Circulating serum fatty acid binding protein 4 levels predict the development of the diabetic retinopathy in type 2 diabetic patients. Am J Ophthalmol 2018; Jan 2. [Epub ahead of print].
Characterizing Disease Burden & Progression of GA Secondary to AMD
Scientists in the United Kingdom aimed to understand levels of disease burden and progression in a real-world setting in patients with bilateral geographic atrophy secondary to age-related macular degeneration, as part of a retrospective cohort analysis of a multicenter electronic medical record database.
Participants were age 50 and above, with bilateral GA and no history of choroidal neovascularization, who attended one of 10 clinical sites. Investigators constructed a de-identified data set from EMR records. An algorithm helped to extract 1,901 bilateral GA cases forming the basis of this report. A sample of records randomly selected from each center helped to validate disease definitions. Main outcome measures included progression to blindness (visual acuity <20 letters or Snellen 3/60 in the better-seeing eye), driving ineligibility (VA ≤70 letters or Snellen 6/12 in the better-seeing eye), progression to CNV, loss of 10 or more letters and mean change in VA over time.
At the first record of GA, 7.1 percent had VA in the better-seeing eye equal to or lower than the cutoff for blindness registration, and 71.1 percent had a VA that would have rendered them ineligible to drive. Over time, 16 percent became legally blind (median time to outcome: 6.2 years), and 66.7 percent became ineligible to drive (median time to outcome: 1.6 years). In the worse eye, 40.1 percent lost ≥10 letters in 2.4 years. Among subjects with baseline and 24-month VA measurements, the mean VA decline was 6.1 letters in the worse eye (n=413) and 12.4 letters in the better eye (n=414). The rate of progression to CNV in either eye was 7.4 percent per patient-year.
Investigators wrote that a high proportion of individuals with bilateral GA were ineligible to drive at initial diagnosis, based on VA in the good eye, and approximately 7 percent were eligible for U.K. blindness registration. They added that the subsequent reduction in VA in the better eye would render another two-thirds ineligible to drive. Investigators wrote further that these findings emphasize the severity of the visual disability associated with GA secondary to AMD.
SOURCE: Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing disease burden and progression of geographic atrophy secondary to age-related macular degeneration. Ophthalmology 2018; Jan. 22. [Epub ahead of print].
Bevacizumab Injection in nAMD Increases Angiogenic Biomarkers
Researchers evaluated the expression of 19 angiogenic biomarkers in the aqueous humor before and after intravitreal bevacizumab injection in eyes with neovascular age-related macular degeneration, as part of a prospective, noncomparative, interventional case series.
The study included 23 eyes of 23 treatment-naïve cases with choroidal neovascularization secondary to AMD. Eyes diagnosed with CNV secondary to AMD were treated with three monthly IVBs. Aqueous humor samples were obtained by anterior chamber paracentesis at baseline and immediately before each intravitreal bevacizumab injection.
Main outcome measures included aqueous humor levels of 19 angiogenic biomarkers:
• angiopoietin 2;
• bone morphogenetic protein 9;
• epidermal growth factor;
• endoglin;
• endothelin 1;
• fibroblast growth factor-1 and -2;
• follistatin;
• granulocyte colony-stimulating factor;
• heparin-binding EGF-like growth factor;
• hepatocyte growth factor;
• interleukin 8;
• leptin;
• placental growth factor;
• vascular endothelial growth factor-A, -C and -D; and
• tissue inhibitor of metalloproteinases-1 and -2.
Researchers also evaluated best-corrected visual acuity, spectral-domain OCT parameters and intraocular pressure.
Baseline aqueous VEGF-A expression was elevated in all study eyes before treatment initiation. Researchers noted a statistically significant decrease of VEGF-A at the one- and two-month follow-ups. They also determined a statistically significant increased concentration in seven biomarkers:
• VEGF-C;
• angiopoietin 2;
• endothelin 1;
• follistatin;
• HB-EGF;
• HGF; and
• interleukin 8
The following 11 study biomarker levels didn’t show any significant difference during follow-up:
• VEGF-D;
• BMP-9;
• EGF;
• endoglin;
• FGF-1 and -2;
• GCSF;
• leptin;
• PLGF; and
• TIMP-1 and -2.
The BCVA statistically improved significantly at two months. Spectral-domain OCT parameters improved significantly at all follow-ups. Mean intraocular pressure values weren’t statistically different during the study period.
Researchers concluded that, despite a decrease in VEGF-A, the aqueous levels of VEGF-C, angiopoietin 2, endothelin 1, follistatin, HB-EGF, HGF and interleukin 8 increased significantly after intravitreal injection of bevacizumab. They suggested that these upregulated angiogenic biomarkers might represent new therapeutic targets in exudative AMD.
SOURCE: Cabral T, Lima LH, Mello LGM, et al. Bevacizumab injection in patients with neovascular age-related macular degeneration increases angiogenic biomarkers. Ophthalmology Retina 2018;2:1:31-7.
Long-term Outcomes for Total Exudative Retinal Detachments in Stage 3B Coats’ Disease
Researchers evaluated the long-term treatment outcomes of total exudative retinal detachments secondary to Coats’ disease (stage 3B) and the role of vitrectomy, as part of a retrospective, observational case series.
A total of 16 eyes in 16 subjects undergoing treatment for total ERD secondary to Coats’ disease with at least five years of follow-up were included. Researchers reviewed the records of individuals with stage 3B Coats’ disease. Interventions—
including the timing of vitrectomy, if used, and clinical course—were recorded. Main outcome measures included visual acuity at the most recent appointment, progression to neovascular glaucoma or phthisis bulbi, and need for enucleation.
All individuals received ablative treatment (photocoagulation or cryotherapy); eight experienced scleral buckling and six had external drainage of subretinal fluid. Of 12 individuals who had pars plana vitrectomy, eight had early PPV (EV) in the first year after presenting, and four of eight in the expectant management group had late PPV with a mean of 4.3 years post-presentation treatment of significant traction retinal detachment. The other four in the expectant management group didn’t require vitrectomy. Mean follow-up was 9.5 years. At the last follow-up, half of the patients had no light perception or light perception vision, which was consistent across subgroups that underwent EV (4/8), late vitrectomy (2/4) or no PPV (2/4). Four of 16 individuals had progression to NVG or phthisis, with one requiring enucleation.
Researchers concluded that ablative therapy combined with PPV, XD or SB was effective in preventing progression to NVG or phthisis and preserving the globe in the majority of individuals. They found that half of individuals (4/8) who didn’t undergo PPV in the early vitrectomy group developed late-onset TRD, suggesting a possible role for early prophylactic vitrectomy with SB and XD; however, they noted that this finding was tempered by the other half of individuals (4/8) in the expectant management group who didn’t require vitrectomy.
SOURCE: Li AS, Capone Jr. A, Trese MT, et al. Long-Term Outcomes of Total Exudative Retinal Detachments in Stage 3B Coats Disease. Ophthalmology 2018; Jan. 18. Epub ahead of print].
Retinal Vascular & Neural Remodeling Secondary to Optic Nerve Degeneration
Scientists investigated the pathophysiologic interrelations between retinal neural and vascular changes detected by spectral-domain optical coherence tomography and OCT angiography, resulting from optic nerve axonal degeneration.
In the observational, case-control study, 26 individuals with optic nerve axonal degeneration secondary to posterior optic pathway glioma involving the chiasma, the postchiasmatic visual pathway or both (but not involving optic nerves) were included, and 24 gender- and age-matched healthy participants were included consecutively.
Best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study score) was measured, and SD-OCT (Heidelberg Engineering) and OCTA (Nidek RS-3000 Advance device; Nidek) were performed. Scientists analyzed peripapillary retinal nerve fiber layer, macular ganglion cell complex and inner nuclear layer using SD-OCT. Using OCTA, they also analyzed the radial peripapillary capillary plexus, full-thickness peripapillary retinal vascularization, the macular superficial plexus (SCP) and deep capillary plexus (DCP).
Peripapillary retinal nerve fiber layer and GCC thickness were reduced in eyes affected by OPG (p<0.0001) as were radial peripapillary capillary plexus perfusion (p<0.01), full-thickness peripapillary retinal vascularization (p<0.05) and macular DCP perfusion (p<0.05). In addition:
• SCP perfusion didn’t differ between the groups p>0.05;
• global pRNFL thickness reduction correlated with the peripapillary perfusion reduction (p<0.01);
• macular GCC thickness reduction didn’t correlate with SCP reduction (p>0.05); and
• macular DCP perfusion reduction didn’t correlate with inner nuclear layer thickness (p>0.05).
Scientists noted that retinal neural remodeling secondary to optic nerve axonal degeneration resulting from OPG located at or posterior to the chiasm was accompanied by a secondary retinal vascular remodeling involving not only the peripapillary area, but also the macular area (DCP).
SOURCE: Parrozzani R, Leonardi F, Frizziero L, et al Retinal vascular and neural remodeling secondary to optic nerve axonal degeneration: A study using OCT angiography. Ophthalmology Retina 2018; Jan 6. [Epub ahead of print].
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