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Purpose: To investigate the changes in aqueous humor cytokine levels in response to short-term aflibercept therapy in treatment-naive patients with center-involving diabetic macular edema (DME). Methods: This is a prospective cohort study that included patients with treatment-naive DME with central subfield macular thickness ≥310 μm on optical coherence tomography from July 2015 to May 2017. Patients received 3 monthly intravitreal aflibercept injections. Aqueous samples for cytokine analysis were obtained before the first and third injections. Levels of various cytokines were measured using multiplex immunoassay. Main outcome measures were changes in aqueous cytokine levels from baseline to month 2. Results: A total of 17 patients were enrolled and 16 completed the study. The mean age was 57.2 ± 8.1 years. The following cytokines were significantly higher at month 2 versus baseline: transforming growth factor-beta (TGF-β)1 ( P  = 0.004), TGF-β2 ( P  = 0.017), inducible protein (IP)-10 ( P  = 0.011), and hepatocyte growth factor (HGF) ( P  = 0.02). There were significant reductions in the levels of vascular endothelial growth factor (VEGF) ( P  < 0.001), placental growth factor (PlGF) ( P  = 0.028), interleukin (IL)-6 ( P  = 0.011), and platelet-derived growth factor-AA (PDGF-AA) ( P  = 0.003). Conclusions: In treatment-naive patients with DME, short-term aflibercept therapy not only results in VEGF and PlGF suppression, but also leads to reduced levels of IL-6 and PDGF-AA and higher concentrations of TGF-β1, TGF-β2, HGF, and IP-10.

Purpose: To evaluate the periodicity of the intervals of lesion reactivation in patients with neovascular age-related macular degeneration (AMD). Methods: This retrospective study included 139 eyes diagnosed with treatment-naive neovascular AMD and treated with antivascular endothelial growth factor (VEGF) therapy. Patients were initially treated with 3 loading anti-VEGF injections using either ranibizumab or aflibercept. Additional treatment was administered only when lesion reactivation was noted. The difference between the time intervals to the first and the second reactivations was evaluated. The included eyes were divided into 2 groups according to the time interval to the first reactivation: the early reactivation group (≤6 months, n  = 86) and the late reactivation group (>6 months, n  = 53). The association between the time intervals to the first and the second reactivations was evaluated within each group. Results: The mean follow-up period was 52.7 ± 8.9 months. The first reactivation was noted at mean 9.4 ± 10.4 months after the loading injections. The second reactivation was noted at mean 6.2 ± 4.9 months after the treatment for the first reactivation. The time interval to the second reactivation was significantly shorter compared with the first reactivation ( P  = 0.018). The association between the time interval to the first and the second reactivations was significant only in the early reactivation group ( P  = 0.002). Conclusions: A short first reactivation interval suggests that there is a high likelihood that the second reactivation will also be short. However, a long first reactivation interval does not suggest that the second reactivation interval will be similarly long.

Retinal gene therapy is a rapidly growing field with numerous clinical trials underway, and route of delivery is a critical contributor to its success. Subretinal administration, which involves pars plana vitrectomy in the operating room, offers targeted delivery to retinal-pigment epithelium cells and photoreceptors. Due to the immune-privileged nature of the subretinal space, the risk of an immune reaction against viral capsid antigens is minimized, an advantage of subretinal administration in patients with preexisting neutralizing antibodies. Intravitreal administration, with fewer procedure-related complications, is challenged by potential immune response and incomplete vector penetration through the internal limiting membrane. However, novel vectors, optimized by "directed evolution" may address these issues. Nonsurgical in-office suprachoroidal gene delivery offers the potential for greater surface-area coverage of the posterior segment compared to focal subretinal injection, and is not hindered by the internal limiting membrane. However, the vector must pass through multiple layers to reach the targeted retinal layers, and there is a risk of immune response. This review highlights recent developments, challenges, and future opportunities associated with viral and nonviral suprachoroidal gene delivery for the treatment of chorioretinal diseases. While ocular tolerability and short-term effectiveness of suprachoroidal gene delivery have been demonstrated in preclinical models, durability of gene expression, long-term safety, potential systemic exposure, and effective delivery to the macula require further exploration. Although the safety and efficacy of suprachoroidal gene delivery are yet to be proven in clinical trials, further optimization could facilitate nonsurgical in-office suprachoroidal gene therapy.

Purpose: Photoreceptor degeneration is a major cause of blindness. Microglia are known to play key roles in the pathogenesis and progression of neural degeneration. We examined the possible use of apigenin, which is a naturally occurring flavonoid, for the treatment of photoreceptor degeneration through regulation of microglial activities. Methods: As in vitro analyses, BV2 and MG5 mouse microglia cell lines were stimulated in the presence or absence of apigenin, and their activation profile was examined. In vivo study was done using rd1 photoreceptor degeneration model, and apigenin was administered by intravitreal injection, and pathological feature was examined. Results: Cell survival was not affected by apigenin in either BV2 and MG5. Apigenin suppressed lipopolysaccharide (LPS)-induced chemokine production in both BV2 and MG5 cells, but phagocytosis was suppressed in MG5 cells but not in BV2 cells. Apigenin inhibited LPS-induced M1 activation but could not drive microglia toward the M2 phenotype. Apigenin suppressed the expression of miR-155 in a dose-dependent manner. Furthermore, the Ets protein level was suppressed by treatment of BV2 cells with apigenin. When rd1 mice were treated with apigenin by intravitreal injection, the expression of inflammatory chemokines in the retina was reduced, and activation of microglia and Müller glia was suppressed. Furthermore, the thickness of the outer nuclear layer of the retina of rd1 mice was thicker in apigenin-treated retinas. Conclusions: Taken together, local administration of apigenin to the retina is a potential therapeutic treatment for photoreceptor degeneration, which involves downregulation of microglia in the retina when photoreceptors are damaged.

Purpose: To evaluate the efficacy of dexamethasone intravitreal implants (DEX implant) in patients with treatment-resistant macular edema (ME) owing to branch and central retinal vein occlusion (BRVO/CRVO), and the influence of prior vitrectomy on this treatment. Methods: Multicenter retrospective chart review was performed on 40 CRVO and 32 BRVO eyes with persistent ME despite intravitreal anti-vascular endothelial growth factor agents and/or intravitreal triamcinolone, and/or laser therapy. Each patient received ≥1 dexamethasone 700 μg implant between March 2011 and December 2015. Thirteen patients underwent prior vitrectomy. Data were collected on best-corrected visual acuity (BCVA), central macular thickness (CMT), time to relapse, and adverse events. Results: At the end of follow-up, BRVO eyes had a lesser CMT reduction from baseline compared to CRVO eyes (-122.50 ± 152.47 μm and -202.26 ± 194.09 μm, respectively). Neither BRVO nor CRVO eyes had a sustained BCVA benefit ( P  = 0.7041 and P  = 0.7027, respectively). Vitrectomized and nonvitrectomized eyes overall had a sustained significant CMT reduction throughout the study with -192.46 ± 172.62 μm and -164.02 ± 180.36 μm, respectively, at final follow-up. Similar time to relapse of 24.4 ± 6.5 and 23.3 ± 13.5 weeks, respectively, was observed. By the end of follow-up, BCVA had only improved in vitrectomized eyes. However, multivariable regression analyses showed no significant association between vitrectomy status and CMT or BCVA change after the first and last injection. Cataract formation and ocular hypertension occurred in 25% and 17%, respectively. Conclusions: Multiple DEX implant are effective in reducing CMT in patients resistant to previous treatments and appear to be similarly effective in vitrectomized and nonvitrectomized eyes.

Purpose: To evaluate safety and efficacy of the vascular endothelial growth factor binding protein abicipar pegol (abicipar) versus ranibizumab for neovascular age-related macular degeneration. Methods: Phase 2, multicenter, randomized, double-masked comparison (REACH study, stage 3). Patients ( n  = 64) received intravitreal injections of abicipar 1 mg or 2 mg at baseline, week 4, and week 8 (3 injections) or ranibizumab 0.5 mg at baseline and monthly (5 injections). Results: In the abicipar 1 mg ( n  = 25), abicipar 2 mg ( n  = 23), and ranibizumab ( n  = 16) arms, respectively, least-squares mean best-corrected visual acuity (BCVA) change from baseline was +6.2, +8.3, and +5.6 letters at week 16 (primary endpoint) and +8.2, +10.0, and +5.3 letters at week 20. Least-squares mean central retinal thickness (CRT) reduction from baseline was 134, 113, and 131 μm at week 16 and 116, 103, and 138 μm at week 20. Intraocular inflammation adverse events (AEs), reported in 5/48 (10.4%) abicipar-treated patients, resolved without sustained vision loss or other sequelae. Conclusions: Abicipar demonstrated durability of effect: BCVA and CRT improvements were similar between abicipar and ranibizumab at weeks 16 and 20 (8 and 12 weeks after the last abicipar injection and 4 weeks after the last ranibizumab injection). No serious AEs were reported.

Purpose: To describe the outcomes of concurrent Ozurdex implantation during anterior segment surgery in patients with chronic recurrent uveitis., Methods: Retrospective chart review. Data recorded from preoperative and 1-, 3-, and 6-month postoperative visits included visual acuity, intraocular pressure (IOP), medications, and clinical examination findings of inflammation., Results: Twelve patients (12 eyes) with chronic, recurrent noninfectious uveitis undergoing cataract extraction (n=9) or intraocular lens (IOL) explantation (n=3) were included. Mean duration of follow-up after Ozurdex implantation was 12.9 months. There was a significant reduction (n=10, P=0.02) in the average number of inflammation recurrences 6 months before surgery compared to 6 months after surgery with Ozurdex in affected eyes. IOP remained stable in the postoperative period. One patient undergoing anterior chamber IOL (ACIOL) explantation experienced migration of Ozurdex into the anterior chamber resulting in corneal edema that resolved after 1 month., Conclusions: Ozurdex safely and effectively controlled postoperative inflammation in eyes with chronic recurrent uveitis when concurrently implanted during anterior segment surgery in our patients. Caution should be exercised in cases of IOL explantation, as Ozurdex use is now contraindicated in eyes with posterior capsule rupture and ACIOLs.

Purpose: This study evaluated the vitreous pharmacokinetics and vitreous bioavailability of memantine following posterior-subtenon administration (PST) compared to intravitreal (INT) and intravenous routes (INV) in rabbits., Methods: Vitreous pharmacokinetic analysis was performed on female New Zealand (NZ) albino rabbits after PST, INT, and INV administration and calculating the pharmacokinetic parameters that describe memantine vitreous distribution. The vitreous bioavailability (F) and the relative vitreous bioavailability of memantine was estimated after posterior-subtenon administration (Frel (pst/int)) and after intravenous route (Frel (inv/int)) compared with intravitreal administration. Relative vitreous bioavailability of memantine was also estimated following PST administration compared with vitreous concentrations after intravenous administration (Frel (pst/inv))., Results: Memantine kinetics in the vitreous of NZ albino rabbits after PST administration can be explained by a one-compartment model, which was characterized by a fast absorption process, and a short terminal half-life. Vitreous pharmacokinetics following INV administration was also characterized by a fast absorption process, a terminal half-life significantly longer than the subtenon route, and low area under the curve values. High vitreous bioavailability after PST was observed, and the relative vitreous bioavailability of memantine following PST administration (0.53%) was greater than for intravenous administration (0.02%)., Conclusions: Our results suggest that memantine reaches the vitreous after PST administration by local diffusion. These data also show that local diffusion of the drug is responsible for greater vitreous availability of memantine following PST administration compared with INV administration.

Purpose: To evaluate the efficacy of intravitreal bevacizumab (IVB) injection combined with anterior retinal cryotherapy (ARC) in the treatment of proliferate diabetic retinopathy (PDR) with vitreous hemorrhage (VH)., Methods: A retrospective case controlled study was performed on 67 cases (67 patients) with PDR and persistent VH obscuring the fundus detail for ≧3 weeks. The follow-up period was ≧6 months. Cases with extensive vitreo-retinal adhesion by ultrasonography were excluded. In the study group, transconjunctival ARC (a total of 12 spots) followed by IVB 1.25 mg was performed in the same setting; in the control group, only IVB was given. Panretinal photocoagulation was performed when possible. Repeated IVB was performed in both groups if VH persisted for >4 weeks following the initial treatment. Vitrectomy was performed if VH showed no improvement for 12 to 16 weeks. The vitreous clear-up time (VCUT) in the posterior pole and the rate of vitrectomy were compared between the 2 groups., Results: In the study group (n=35), second treatment was required in 7 out of 35 patients (20.0%). Vitrectomy was performed in 5 (14.3%) patients. In the control group (n=32), 8 out of 32 eyes (25.0%) underwent second injection. Four eyes (12.5%) had vitrectomy within the follow-up time. VCUT in the study and the control group was 6.9±8.7 weeks and 13.0±9.3 weeks respectively (P=0.003)., Conclusion: Combined treatment of ARC and IVB is associated with more rapid clearing of VH in eyes with PDR compared with IVB alone.

Purpose: To study the visual outcomes and change in central macular thickness (CMT) in patients with neovascular age-related macular degeneration (AMD) who were previously treated with ranibizumab (Lucentis) and/or bevacizumab (Avastin) and were subsequently switched to aflibercept (VEGF Trap-Eye; Eylea)., Methods: Retrospective study of patients who received intravitreal aflibercept from December 2011 to December 2012 and had previous anti-vascular endothelial growth factor treatment for AMD. The main outcome measures were best-corrected visual acuity (BCVA) and CMT as measured by optical coherence tomography., Results: The study population included 30 patients aged 80.4±1.45 (mean±SEM) who received 6.27±0.37 (range 4-11) aflibercept injections. Eighteen patients had previously received only bevacizumab (12.4±2.18 injections), 2 had received only ranibizumab (19±6 injections), and 10 had received both ranibizumab and bevacizumab (mean 19.3 injections). BCVA logMAR at the initial visit (aflibercept initiation) was 0.506±0.054 (mean VA 20/64), and then, follow ups at 1-month 0.504±0.055 (20/64) P=0.903, 3-months 0.458±0.061 (20/57) P=0.112, 6-months 0.413±0.071 (20/52) P=0.036, and 12-months 0.521±0.076 (20/66) P=0.836. CMT at the initial visit was 261±10.9, and then, at 1-month 238±12.4 P=0.021, 3-months 245±10.6 P=0.102, 6-months 245±10.4 P=0.099, and 12-months 237±10.2 P=0.012. Results were similar in a subset of patients (n=15) with central macular edema or submacular fluid at aflibercept initiation. While on aflibercept, 2 patients developed intraocular pressure increases that required treatment., Conclusions: These findings demonstrate a significant decrease in CMT but no statistically significant improvement in BCVA through the 12-month follow up in patients previously treated who were switched to aflibercept for AMD. Patients may develop ocular hypertension after multiple aflibercept injections.

Purpose: Cystoid macular edema (CME) is a rarely reported side effect of nanoparticle albumin bound (nab)-paclitaxel therapy-an antimitotic agent used for breast cancer. We describe a patient with bilateral CME secondary to Abraxane that was minimally responsive to intravitreal bevacizumab. To our knowledge, this is the first reported case of the use of intravitreal bevacizumab for this condition. A previous report has described the ineffectiveness of concurrent intravenous bevacizumab with Abraxane. This lack of efficacy and knowledge of the mechanism of paclitaxel may provide insights into the mechanisms of CME without angiographic leakage., Methods: Retrospective, interventional case report of a patient with bilateral CME after starting Abraxane therapy for recurrent breast cancer treated with intravitreal bevacizumab (1.25 mg/0.05 mL) every 4 weeks. Records were reviewed for visual acuity and macular edema as assessed by spectral-domain optical coherence tomography (SD-OCT)., Results: A 73-year-old patient with recurrent, metastatic breast cancer presented with bilateral visual loss 3 months after nab-paclitaxel was initiated. Baseline visual acuities (VA) were 20/50 in the right eye (OD) and 20/80 in the left eye (OS). Fundus exam showed marked CME in both eyes (OU). Fluorescein angiography was notable for the marked absence of petalloid late-phase leakage characteristic of vascular, ischemic, and inflammatory causes of CME. SD-OCT showed marked cystoid spaces predominantly involving the outer and inner nuclear layers with central subfield thicknesses (CST) of 398 μm OD and 441 μm OS. Serial intravitreal bevacizumab injections (OD, 2 injections; OS, 3 injections) were administered on a 4-week basis with an improvement and stabilization of VA at 20/50 OD and 20/70 OS. However, CME on SD-OCT persisted with CST of 492 μm OD and 478 μm OS., Conclusions: The pathogenesis of CME without leakage is poorly understood; however, fluid accumulation in Muller cells due to toxicity has been proposed. The persistence of CME suggests that additional nonvascular endothelial growth factor-mediated mechanisms are involved. Improved understanding of the mechanisms underlying paclitaxel-associated CME is needed, especially in patients with limited systemic options for metastatic carcinoma.

Purpose: To compare the effects of straight, oblique, and double-plane tunnel scleral intravitreal injection techniques, on short-term intraocular pressure (IOP) changes, occurrence of vitreous reflux (VR), and/or other complications., Methods: A total of 105 patients were included in this prospective study. Patients were assigned randomly to one of the straight injection group (SI; n=35), oblique injection group (OI; n=35), or double-plane tunnel injection group (DPTI; n=35). The occurrence of VR and preinjection and postinjection IOP at 2 and 6 h were compared between groups, and complications were assessed., Results: The mean patient age was 71.1±6.6 years (range 58 to 86 years; 50 women and 55 men). In the SI, OI, and DPTI groups, VR occurred in 18 (51.4%), 12 (34.3%), and 6 patients (17.1%), respectively. Mean preinjection IOPs were 15.4, 14.8, and 15.6 mmHg, and changed to 17.3, 18.0, and 20.0 mmHg at the second hour, and 15.7, 16.2, and 16.1 mmHg at the sixth hour, respectively. No significant differences among the groups were found in terms of complications such as transient mild uveitis or subconjunctival hemorrhage., Conclusion: Double-plane tunnel injection prevents VR from the injection site and has no additional complications than other techniques.

Purpose: Malignant hypertensive retinopathy is a rare, but serious, complication of uncontrolled systemic hypertension for which no treatment has been established yet. We report 2 patients with malignant hypertensive retinopathy who recovered promptly following intravitreal bevacizumab injection., Methods: Intravitreal bevacizumab (1.25 mg/0.05 mL) was injected in 4 eyes of 2 patients having malignant hypertensive retinopathy with optic disc edema, macular edema, and retinal exudates. A complete ophthalmic examination, including the best-corrected visual acuity (BCVA), central macular thickness (CMT) on optical coherence tomography (OCT), and fluorescein angiography (FAG), was performed before and after the treatments., Results: Two eyes in 1 patient received two intravitreal injections of bevacizumab, whereas 2 eyes in the other patient received a single treatment. All 4 eyes had improvement of macular edema on OCT at 1 month and decreased fluorescein leakage on FAG 3 months after the treatment, which led to improvements in the BCVA in 3 eyes. In 1 eye with foveal atrophy, no change in the BCVA occurred despite the improved macular edema on OCT., Conclusions: The results suggest that intravitreal bevacizumab injections might be a useful adjunctive treatment of malignant hypertensive retinopathy in some selected cases. However, further studies are mandatory to determine the safety and the efficacy of such injections in this disease.

Purpose: To evaluate the amount of reflux and degree of pain with intravitreal injection (IVT) using 6 different types of syringes/needles and 5 techniques of scleral incision, including 3 modifications of a beveled scleral incision., Methods: This was a study conducted in 205 eyes of 205 patients. IVT of bevacizumab for retinal pharmacotherapy with 6 types of needles and 5 techniques of scleral incision. The severity of subjectively evaluated pain (0-10) and the width of the subconjunctival bleb arising from the vitreal reflux. Secondary outcomes were increase in intraocular pressure and complication rate., Results: The straight technique caused greater vitreal reflux than the beveled approaches, when compared individually or as a group (P < 0.01). No difference in the severity of pain was found among all 5 types of incisions (P > 0.05). There was greater reflux with 26- and 27-gauge needles in comparison to 29- and 30-gauge needles (P < 0.001); however, the width of the needle significantly affected the degree of reflux only when using the nonbeveled incision (P < 0.001). The patients injected with the 26- or 27-gauge needle experienced more pain matched to the 29- and 30-gauge needles (P < 0.001). No difference was found between the incision technique or width of subconjunctival reflux and the increase in intraocular pressure (P > 0.05). Postinjection events included transient mild uveitis, disease-related vitreous hemorrhage, foreign body sensation, conjunctival hemorrhage, and mild punctuate keratitis., Conclusions: The beveled scleral incision showed benefit in performing IVTs. The 29- and 30-gauge needles caused less pain.