Endothelial contraction of retinal veins.

We have previously reported that porcine retinal veins can be contracted by vasoactive factors such as endothelin-1, but it is still unknown which cells play the major role in such contraction responses. This study seeks to confirm whether retinal vein endothelial cells play a significant role in the endothelin-1 induced contraction of porcine retinal veins. This is a novel study which provides confirmation of the endothelial cells' ability to contract retinal veins using a live vessel preparation. Retinal veins were isolated from porcine retina and cannulated for perfusion. The vessels were exposed to extraluminal delivery of endothelin-1 (10-8 M) and change in vessel diameter recorded automatically every 2 s. A phase contrast objective lens was also used to capture images of the endothelial cell morphometries. The length, width, area, and perimeter were assessed. In addition, vein histology and immuno-labeling for contractile proteins was performed. With 10-8 M endothelin-1 contractions to 63.6% of baseline were seen. The polygonal shape of the endothelial cells under normal tone became spindle-like after contraction. The area, width, perimeter and length were significantly reduced by 54.8%, 48.1%, 28.5% and 10.5% respectively. Three contractile proteins, myosin, calponin and alpha-SMA were found in retinal vein endothelial cells. Retinal vein endothelial cells contain contractile proteins and can be contracted by endothelin-1 administration. Such contractile capability may be important in regulating retinal perfusion but could also be a factor in the pathogenesis of retinal vascular diseases such as retinal vein occlusion. As far as we are aware, this is the first study on living isolated veins to confirm that endothelial cells contribute to the endothelin-1 induced contraction.

IMPACT OF RETINAL FLUID-FREE MONTHS ON OUTCOMES IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Treatment Agnostic Analysis of the HAWK and HARRIER Studies.

PURPOSE: To assess the effect of the total number of fluid-free months after loading on visual and anatomical outcomes in neovascular age-related macular degeneration patients receiving anti-vascular endothelial growth factor therapy. METHODS: This post hoc analysis pooled patient-level data from the brolucizumab 6 mg (n = 718) and aflibercept 2 mg (n = 715) arms of the HAWK and HARRIER randomized clinical trials. Based on data from Weeks 12 to 96, patients were assigned to one of five categories based on fluid-free visits (FFVs; the total number of monthly visits at which they were observed to be without retinal fluid). Three definitions of "fluid-free" were explored based on the location of the fluid observed. RESULTS: Patients allocated to Categories 4 (15-21 FFV) and 5 (22 FFV, always dry) consistently had the best visual and anatomical outcomes at Week 96, whereas patients allocated to Categories 1 (0 FFV, never dry) and 2 (1-7 FFV) consistently had the worst visual and anatomical outcomes. Variability in retinal thickness over time was lowest in Categories 4 and 5. CONCLUSION: Absence of retinal fluid at more visits after loading has a positive association with visual and anatomic outcomes in neovascular age-related macular degeneration patients, regardless of fluid type.

SIBLING CONCORDANCE IN SYMPTOM ONSET AND ATROPHY GROWTH RATES IN STARGARDT DISEASE USING ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE.

PURPOSE: To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point. METHODS: In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test. RESULTS: Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences ( P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences ( P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant ( P = 0.44 for area GR and P = 0.61 for radius GR). CONCLUSION: There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation.

CLASSIFYING ABCA4 MUTATION SEVERITY USING AGE-DEPENDENT ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE-DERIVED TOTAL LESION SIZE.

PURPOSE: To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification. METHODS: A retrospective study of patients with biallelic ABCA4 mutations that were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria, and mutation severities were classified based on the current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild, and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS. RESULTS: Eighty-one patients with STGD1 (mean age = 42 ± 20 years and mean visual acuity = 20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n = 6) demonstrated an increase in TLS during their second decade reaching a mean ± SD of 796 ± 29 mm2 by age 40. Those harboring mild mutations c.5882G>A or c.5603A>T had lesions confined to the posterior pole with a mean ± SD TLS of 30 ± 39 mm2. Intermediate mutations c.6079C>T or c.[2588G>C;5603A>T] in trans with a null/severe mutation had a mean ± SD TLS of 397 ± 29 mm2. Thirty-two mutations were predicted to cause severe (n = 22), intermediate (n = 6), and mild (n = 5) impairment of ABCA4 function based on age of symptom onset and TLS. CONCLUSION: Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies to confirm its validity.

Macular Atrophy in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial Comparing Ranibizumab and Aflibercept (RIVAL Study).

PURPOSE: To investigate differences in the development of macular atrophy (MA) over 24 months between treat-and-extend (T&E) ranibizumab and aflibercept in patients with neovascular age-related macular degeneration (nAMD). DESIGN: A phase 4 randomized, partially masked, multicenter study. PARTICIPANTS: Individuals 50 years of age or older diagnosed with active, treatment-naïve subfoveal choroidal neovascularization secondary to nAMD with baseline best-corrected visual acuity (BCVA) of 23 logarithm of minimum angle of resolution letters or more. METHODS: Patients were randomized 1:1 to receive either intravitreal injections of ranibizumab 0.5 mg or aflibercept 2.0 mg and were treated according to the same reading center-guided T&E regimen after 3 initial monthly injections. MAIN OUTCOME MEASURES: The primary outcome was mean change in square root area of MA from baseline to month 24. Key secondary outcomes included number of injections and mean change in BCVA from baseline to months 12 and 24. RESULTS: Two hundred seventy-eight patients were included in the analysis (ranibizumab 0.5 mg, n = 141; aflibercept 2.0 mg, n = 137). Mean change in square root area of MA from baseline to month 24 was +0.36 mm (95% confidence interval [CI], 0.27-0.45 mm) for ranibizumab and +0.28 mm (95% CI, 0.19-0.37 mm) for aflibercept (treatment difference, +0.08 mm [95% CI, -0.05 to 0.21 mm]; P = 0.24). The proportion of patients with MA increased from 7% (10/141) to 37% (43/117) for ranibizumab and from 6% (8/137) to 32% (35/108) for aflibercept from baseline to month 24. The average number of injections received per year was similar between both groups: 9.6 (95% CI, 9.2-10.0) for ranibizumab and 9.5 (95% CI, 9.1-9.9) for aflibercept. The mean change in BCVA from baseline to month 24 was +6.6 letters (95% CI,4.7-8.5 letters) for the ranibizumab group and +4.6 letters (95% CI, 2.7-6.6 letters) for the aflibercept group ( P = 0.15). Rates of adverse events (AEs) were similar between both groups. CONCLUSIONS: No significant differences in the rate of development or growth of MA over 24 months were observed between ranibizumab and aflibercept in nAMD patients treated using an identical T&E regimen.

SURGICAL MANAGEMENT OF TRAUMATIC MACULAR HOLE: Optical Coherence Tomography Features and Outcomes.

PURPOSE: To report the outcomes of eyes receiving surgical management for traumatic macular holes. To describe the preoperative and postoperative optical coherence tomography features of traumatic macular holes and to explore associations between preoperative clinical and optical coherence tomography features, and visual outcome. METHODS: Retrospective study of patients undergoing vitrectomy for traumatic macular hole and entered into the Australian and New Zealand Society of Retinal Specialists surgical registry. Preoperative clinical data, surgical details, and 3-month postoperative outcomes were recorded prospectively. Longer-term outcomes at 12 months were requested retrospectively, as were preoperative and postoperative optical coherence tomography scans. RESULTS: Hole closure was achieved in 91% (21/23) of patients with a single procedure. The average preoperative visual acuity was 20/120. At 3 months postoperatively, the mean visual acuity had improved to 20/70 (P < 0.001), 11/23 (48%) of eyes improved ≥15 letters, and the number of eyes with 20/40 acuity or better increased from 1/23 to 7/23. Eyes with worse visual outcomes (visual acuity < 20/80) had larger holes, worse preoperative acuity, and a greater extent of preoperative ellipsoid band attenuation than those with better postoperative visual acuity. CONCLUSION: Eyes receiving surgical management for traumatic macular hole achieved good anatomical results and approximately half had a substantial improvement in acuity. Ellipsoid band attenuation on preoperative optical coherence tomography and worse preoperative acuity were associated with poorer visual outcomes.

Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen: FLUID Study 24-Month Results.

PURPOSE: To test the hypothesis that tolerating some subretinal fluid (SRF) in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab using a treat-and-extend (T&E) regimen can achieve similar visual acuity (VA) outcomes as treatment aimed at resolving all SRF. DESIGN: Multicenter, randomized, 24-month, phase 4, single-masked, noninferiority clinical trial. PARTICIPANTS: Participants with treatment-naïve active subfoveal choroidal neovascularization (CNV). METHODS: Participants were randomized to receive ranibizumab 0.5 mg monthly until either complete resolution of SRF and intraretinal fluid (IRF; intensive arm: SRF intolerant) or resolution of all IRF only (relaxed arm: SRF tolerant except for SRF >200 µm at the foveal center) before extending treatment intervals. A 5-letter noninferiority margin was applied to the primary outcome. MAIN OUTCOME MEASURES: Mean change in best-corrected VA (BCVA), and central subfield thickness and number of injections from baseline to month 24. RESULTS: Of the 349 participants randomized (intensive arm, n = 174; relaxed arm, n = 175), 279 (79.9%) completed the month 24. The mean change in BCVA from baseline to month 24 was 3.0 letters (standard deviation, 16.3 letters) in the intensive group and 2.6 letters (standard deviation, 16.3 letters) in the relaxed group, demonstrating noninferiority of the relaxed compared with the intensive treatment (P = 0.99). Similar proportions of both groups achieved 20/40 or better VA (53.5% and 56.6%, respectively; P = 0.92) and 20/200 or worse VA (8.7% and 8.1%, respectively; P = 0.52). Participants in the relaxed group received fewer ranibizumab injections over 24 months (mean, 15.8 [standard deviation, 5.9]) than those in the intensive group (mean, 17 [standard deviation, 6.5]; P = 0.001). Significantly more participants in the intensive group never extended beyond 4-week treatment intervals (13.5%) than in the relaxed group (2.8%; P = 0.003), and significantly more participants in the relaxed group extended to and maintained 12-week treatment intervals (29.6%) than the intensive group (15.0%; P = 0.005). CONCLUSIONS: Patients treated with a ranibizumab T&E protocol who tolerated some SRF achieved VA that is comparable, with fewer injections, with that achieved when treatment aimed to resolve all SRF completely.

Neuronal degeneration and associated alterations in cytokine and protein in an experimental branch retinal venous occlusion model.

The mechanisms of neuronal degeneration and associated acute alterations in intraretinal cytokine and protein levels remain poorly understood in variable ischaemic retinopathies such as in branch retinal vein occlusion (BRVO). Herein we investigate neuronal damage and alterations in retinal cytokines and proteins in a pig model of acute BRVO. Twelve pigs had a BRVO induced photothrombotically in both eyes. Three pigs (6 eyes) each at 2, 6, 10 and 20 days were sacrificed together with an additional 3 control (6 eyes), enucleated, retinas dissected and processed. Apoptosis in the inner retina was determined by terminal deoxyynuclotidyl transferase mediated dUTP nick end labelling (TUNEL) and histology. Expression of glial acidic fibrillary protein (GFAP), aquaporin-4 (AQP4), inward rectifier potassium channel 10 protein (Kir 4.1) encoded by KCNJ10 gene, vascular endothelial growth factor (VEGF), stromal derived growth factor-1α (SDF-1) encoded by CXCL12 gene and interleukin (IL) -6 and 8 were analysed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunohistochemistry. TUNEL labelling showed positive nuclei in the ganglion cell layer (GCL) and the inner nuclear layer (INL) which was significantly higher at 2 days after BRVO compared to other time points (p < 0.05). Analysis by RT-qPCR revealed that compared with controls, BRVO significantly increased mRNA expression of GFAP at 6, 10 and 20, AQP4 at 20, VEGF at 6, SDF-1 at 20 and IL-8 at 2 and 10 days respectively (p < 0.05): Kir 4.1 at 6, VEGF at 2 and 10, and IL-6 at 2 days were significantly decreased (p < 0.05). This study indicates that neural cell death occurs early in this acute model and the responses include inflammation and breakdown of osmohomeostasis as evidenced by the upregulation of GFAP and IL-8 and down regulation of Kir 4.1 associated with glyotic changes. Early short term VEGF upregulation seen may be related to involvement of Muller glial cells. These findings support the development of acute therapeutic strategies aimed at preservation of retinal neural cells as part of an overall management plan for BRVO.

Quantitative comparisons between optical coherence tomography angiography and matched histology in the human eye.

The aim was to quantitatively compare retinal vascular detail as seen on optical coherence tomography angiography (OCTA) and matched histology in the human eye. 13 normal human donor eyes were used. The central retinal artery was cannulated after which human packed red blood cells were perfused through the retinal vasculature. Retinal vessels were imaged using a custom-built OCTA device during red blood cell perfusion. The eye was subsequently perfused with endothelial cell antibodies and the flat-mounted retina studied histologically using a confocal scanning laser microscope. Qualitative and quantitative comparisons of retinal vascular information as seen on OCTA and histology from the same region of interest were performed. Gradable OCTA images were acquired from 4 of 13 eyes with mean postmortem-to-OCTA imaging time of 4.5 ±â€¯1.3 h 23 pairs of OCTA-histology matched images were evaluated. The retinal arteries and veins had similar pixel intensity on OCTA images. The diameter of retinal veins was significantly greater than its paired artery on OCTA (P < 0.001). The density of vascular structures on OCTA (40.2% ±â€¯10.1%) was significantly less than matched histology (52.1% ±â€¯9.3%, P < 0.001). Mean capillary diameter on OCTA (10.2 ±â€¯2.4 µm) was significantly greater than histology (8.2 ±â€¯2.4 µm; P < 0.001). This is the first study to directly compare OCTA against histology from the same human eye. OCTA visualizes many of the vascular structures in the human retinal circulation but does not exactly match what is seen on histologic examination.

Clinical and social characteristics associated with reduced visual acuity at presentation in Australian patients with neovascular age-related macular degeneration: a prospective study from a long-term observational data set. The Fight Retinal Blindness! Project.

IMPORTANCE: Identifying variables that influence presenting visual acuity (VA) in patients with neovascular age-related macular degeneration (nAMD) is important because it is a strong predictor of long-term outcomes. BACKGROUND: To assess the clinical and social characteristics associated with low presenting VA in nAMD patients. DESIGN: The present study is a cross-sectional analysis from a prospective, observational database. PARTICIPANTS: We identified 3242 treatment-naïve patients from 54 Australian practices in the Fight Retinal Blindness! registry. METHODS: Age, gender, ethnicity and VA were recorded at the baseline visit. Socio-economic status was determined using the Australian Bureau of Statistics socio-economic indexes for areas. MAIN OUTCOME MEASURES: Association between clinical and socio-economic characteristics with presenting VA was identified. RESULTS: Poor VA (≤35 letters) in the presenting eye was associated with older age (adjusted odds ratio [AOR]: 1.33 for patients aged ≥80 years vs. <80 years [95% confidence interval, CI: 1.04, 1.71]), treatment at a public practice (AOR: 1.91 for public vs. private practices [95% CI: 1.46, 2.50]) and intermediate (36-69 letters) VA in the fellow eye (AOR: 0.67 [95% CI: 0.47, 0.95] and 0.64 [95% CI: 0.48, 0.85] for poor [≤35 letters] and good [≥70 letters] VA vs. intermediate VA in the fellow eye). Gender, ethnicity and socio-economic status were not independently associated with VA at presentation. CONCLUSIONS AND RELEVANCE: Poor presenting vision is detrimental to the long-term outcomes of nAMD. Poor presentation of nAMD in Australia may not be related to socio-economic circumstances, but due to systems of care. Further research is warranted to determine why patients at public practices present with worse vision compared with private practices in Australia.

The Effect of Postoperative Face-Down Positioning and of Long- versus Short-Acting Gas in Macular Hole Surgery: Results of a Registry-Based Study.

PURPOSE: To determine whether sulfur hexafluoride (SF6) gas is noninferior to longer-acting gases in macular hole surgery and whether withholding postoperative face-down positioning (FDP) is noninferior to FDP. DESIGN: Registry-style, prospective, nonrandomized, observational cohort study. PARTICIPANTS: Patients with idiopathic macular holes undergoing primary surgery. METHODS: Surgeons were invited to submit clinical details of all macular hole cases receiving surgery. Baseline demographic and clinical information were collected, as well as details of surgical intervention and postoperative posturing advice. Primary follow-up data were collected 3 months postoperatively. MAIN OUTCOME MEASURES: Macular hole closure at 3 months. A noninferiority approach was used, with a noninferiority margin set at 5% decreased frequency of success. RESULTS: A total of 2456 eyes of 2367 patients were included in the study. Outcomes were available in 94.9% of cases (2330/2456). The rate of macular hole closure was 95.0% (2214/2330). Sulfur hexafluoride gas was found to be noninferior to longer-acting gases (95% confidence interval [CI] for adjusted effect on success, -1.76 to +2.25), and noninferiority was demonstrated regardless of macular hole size. Although withholding FDP was found to be noninferior to FDP for the study population as a whole (95% CI for adjusted effect on success, -4.21 to +0.64), the result was inconclusive in holes >400 µm in diameter (95% CI, -9.31 to +1.04). Lack of internal limiting membrane (ILM) peel, increasing hole size, hole duration ≥9 months, increasing age, and 20-gauge surgery all were associated with lower odds of success. Vitreous attachment to the hole margin was not associated with outcome when corrected for hole size, and combined phacovitrectomy surgery was not observed to affect the odds of success in phakic eyes. CONCLUSIONS: Sulfur hexafluoride gas tamponade was noninferior to longer-acting gases in the surgical management of macular hole. Withholding FDP was noninferior to FDP in holes ≤400 µm in diameter. In holes >400 µm in diameter, noninferiority of withholding FDP could not be concluded. We would advise caution if posturing is withheld in this group on the basis of the results of this study and of others.

Treatment Patterns and Visual Outcomes during the Maintenance Phase of Treat-and-Extend Therapy for Age-Related Macular Degeneration.

PURPOSE: To present the treatment patterns, disease activity, and visual outcomes of eyes in the maintenance phase of a treat-and-extend regimen for neovascular age-related macular degeneration (nAMD). To compare the maintenance phase behavior of eyes with a shorter induction phase (≤3 injections) with those requiring a longer induction phase (>3 injections). DESIGN: Database observational study. PARTICIPANTS: Eyes with nAMD receiving anti-vascular endothelial growth factor (VEGF) treatment using a treat-and-extend protocol. Persistently active eyes were excluded, as were eyes with <12 months follow-up during the maintenance phase. METHODS: Clinical information from a large prospective international voluntary registry of nAMD was analyzed. The maintenance phase was defined as starting at the first clinician-reported grading of lesion inactivity. MAIN OUTCOME MEASURES: For analyses by eye: treatment interval at first reactivation; time to first reactivation; and visual acuity change during the study period. For analyses by visit: choroidal neovascular membrane activity graded by the treating physician; time since previous injection; and visual acuity loss since previous injection (>0 letters and ≥15 letters). RESULTS: The mean change in visual acuity during the maintenance phase was +1.0 letters at 12 months -0.6 letters at 24 months and -1.5 at 36 months. Median treatment interval increased from 35 days at study entry to 63 days at 12 months and was 60 days at 36 months. 38.5% of eyes remained inactive at all observed visits during the maintenance phase (minimum 1 year follow-up, mean 945 days). The most common treatment interval at first reactivation was 8 weeks. Treatment intervals beyond 12 weeks seemed to be associated with increased risk of disease reactivation, with risk of reactivation reaching 37.4% at treatment intervals of ≥20 weeks. Eyes with a longer induction phase had worse visual outcomes in the maintenance phase, and earlier and more-frequent disease reactivation, although they received injections less frequently. CONCLUSIONS: The detailed behavior of eyes in the maintenance phase of treat-and-extend management for nAMD is presented. Visual acuity was well maintained during the study period. The most common interval at which reactivation first occurred was 8 weeks. Longer duration of induction phase was associated with worse visual acuity outcomes and earlier disease reactivation, perhaps because of undertreatment.

TECHNIQUE OF LASER CHORIORETINAL ANASTOMOSIS CREATION IN CENTRAL RETINAL VEIN OCCLUSION AND SUCCESS RATE WITH A NEW PHOTOCOAGULATOR SYSTEM.

PURPOSE: To evaluate the success rate of laser chorioretinal anastomosis (L-CRA) creation with a new laser photocoagulator system capable of 5 watts (W) power in patients with central retinal vein occlusion (CRVO). METHODS: Patients with a treatment-naive CRVO were enrolled as part of an ongoing trial combining L-CRAs with anti-vascular endothelial growth factor treatment. RESULTS: Thirty-three patients were treated with an L-CRA developing in 29 (88%). Mean power was 2.7 W and mean time for development was 1.8 months. Each patient had two potential sites created. Eighteen patients developed 2 L-CRAs and the remaining 11 patients, one each. Of the 66 potential sites, successful L-CRAs developed at 47 sites (71%). Additional Nd:YAG laser applications were used in 39% of sites. Mean follow-up was 23 months and no significant complications were seen. CONCLUSION: An L-CRA as a means of permanently bypassing the obstruction to venous outflow in CRVO may become more relevant as not all patients respond well to intravitreal therapy. The limitation to this technique in the past has been lack of availability of a laser system with the power necessary to create the L-CRA. The success rate with the new system has improved to 88% representing a significant improvement over our original success rate of 33%.

Time to initial clinician-reported inactivation of neovascular age-related macular degeneration treated primarily with ranibizumab.

PURPOSE: To characterize in more detail routine treatment patterns of intravitreal ranibizumab for neovascular age-related macular degeneration (nAMD), we analyzed the length of time and the number of injections required until lesions with choroidal neovascularization (CNV) were first graded inactive. DESIGN: Database observational study. PARTICIPANTS: Treatment-naïve eyes receiving predominantly ranibizumab for nAMD in routine clinical practice that were tracked in the Fight Retinal Blindness! observational registry. METHODS: Eyes treated with ranibizumab were followed until CNV was first reported to be "inactive" (i.e., absence of intraretinal fluid and hemorrhages). MAIN OUTCOME MEASURES: The length of time until lesion inactivation occurred and the number of injections required. RESULTS: A total of 1096 eyes (65.8% from women) were included in the study. The median number of weeks until a lesion was graded as inactive after beginning treatment was 15 weeks. One to 3 injections were sufficient to inactivate the lesion in 61.1% of eyes. A mean change in visual acuity of +5.5 logarithm of the minimum angle of resolution letters (95% confidence interval, 4.8-6.3) was found from treatment initiation to the time that eyes were reported as inactive. In eyes with a mean treatment frequency less than every 5.3 weeks, a median of only 3 injections (mean=3.7) were required before lesions with CNV were graded as inactive, but if the mean treatment interval extended beyond 5.3 weeks, the median number of injections required increased sharply to 6 injections (mean, 7 injections). Occult lesions became inactive more slowly than classic lesions. CONCLUSIONS: Most lesions with CNV became inactive with 3 injections of ranibizumab, but a small proportion remained active for more than 12 months. Injection frequency and lesion type were the main factors that predicted the time and number of injections required to render lesions inactive.

Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration.

PURPOSE: To report 24-month outcomes of anti-vascular endothelial growth factor (VEGF) therapy for treatment-naïve eyes with neovascular age-related macular degeneration (nAMD) using a treat and extend treatment regimen in routine clinical practice. DESIGN: Database observational study. PARTICIPANTS: We included treatment-naïve eyes receiving predominantly ranibizumab for nAMD in routine clinical practice treated using a treat and extend regimen that were tracked in the Fight Retinal Blindness observational registry. METHODS: A cohort of eyes treated by practitioners using exclusively a treat and extend regimen was extracted from the Fight Retinal Blindness observational registry. MAIN OUTCOME MEASURES: Change in visual acuity (VA) over 2 years and number of injections and visits. RESULTS: Data from 1198 eyes from 1011 patients receiving anti-VEGF therapy using a treat and extend regimen for treatment-naïve nAMD between January 2007 and December 2012 and with 24-month follow-up were included in the analysis. Mean VA increased by +5.3 logarithm of the minimum angle of resolution letters from 56.5 letters (20/80+1) at initial visit to 61.8 (20/60+2) letters at 24 months. Mean VA gains improved and number of injections increased with successive years from +2.7 letters for eyes commencing in 2007 after a mean of 9.7 injections in 2 years, to +7.8 letters for eyes commencing in 2012 after a mean of 14.2 injections over 2 years. The proportion of eyes with VA >20/40 increased from 27% when starting treatment to 45% after 24 months; the proportion with vision of <20/200 remained unchanged (13% initial, 11% at 24 months). Of the included eyes, 90.5% avoided a vision loss of ≥15 letters. There was an overall mean of 13.0 injections over the 24 months, 7.5 injections in the first year and 5.5 in the second year, with a mean of 14.8 clinic visits. CONCLUSIONS: These data indicate that eyes managed in routine clinical practice with a treat and extend regimen can achieve good visual outcomes while decreasing the burden of treatments and clinic visits.

Long-Term Outcomes of Treatment of Neovascular Age-Related Macular Degeneration: Data from an Observational Study.

PURPOSE: To analyze the long-term outcomes of eyes with neovascular age-related macular degeneration (AMD) starting treatment with vascular endothelial growth factor (VEGF) inhibitors at least 5 years earlier. DESIGN: Database observational study. PARTICIPANTS: Treatment-naïve eyes with neovascular AMD tracked by the Fight Retinal Blindness outcome registry that received at least 1 anti-VEGF injection. METHODS: Locally weighted scatterplot smoothing curves were used to display visual acuity (VA) results. MAIN OUTCOME MEASURES: Change in mean VA and number of injections and visits from baseline up to 7 years after initiating treatment. RESULTS: The mean follow-up time of all 1212 identified eyes was 53.5 months, and 549 (45%) continued attending after 60 months. Mean VA improved from 55.1 to 61.4 letters after 6 months and remained above the mean presenting VA for approximately 6 years. After 7 years, mean VA was 2.6 letters lower than baseline for the 131 eyes still being followed; 40% had VA ≥70 (20/40) letters, and 18% had VA ≤35 letters (20/200). Of those with 20/40 VA before treatment, 40% had lost it after 7 years. Geographic atrophy affecting the fovea was thought to be the cause of a ≥10-letter loss after 6.5 years in 37% of a subset of such eyes that were retrospectively analyzed. A median of 6 injections and 9 visits were recorded over the first 12 months, and then 5 treatments and 7 to 9 visits per annum thereafter through 7 years. Treatment was discontinued for 663 eyes (53%) within the first 5 years. Despite initial gains in vision, the mean VA of these eyes had deteriorated to baseline or worse around the time treatment was discontinued. The rate of serious adverse events was low. CONCLUSIONS: Good long-term outcomes of VEGF inhibition for neovascular AMD were found in this study. These results may be better than other reports because more injections were given to our patients, possibly associated with a greater incentive for the physician to treat. Further studies to determine how to maximize the proportion of eyes that retain the initial VA gains of anti-VEGF are warranted.

The effect of central retinal venous pressure in patients with central retinal vein occlusion and a high mean area of nonperfusion.

PURPOSE: To evaluate the effect of central venous pressure (CVP) on visual outcomes and retinal ischemic consequences in patients with central retinal vein occlusion (CRVO). DESIGN: Prospective, single-center cohort study. PARTICIPANTS: Eighty-eight patients with CRVO and a high overall mean area (21.6 disc areas) of capillary nonperfusion (CNP) who were followed for 18 months before the availability of intravitreal therapy and who were offered standard care of the time. METHODS: Patients were evaluated at baseline and at 3, 8, and 18 months. At each study visit, measurements of CVP, best-corrected visual acuity (BCVA), area of CNP, retinal fluorescein transit time (FTT), and an evaluation for rubeosis iridis were performed. MAIN OUTCOME MEASURES: Evaluation of the effect of different levels of CVP on BCVA, retinal blood flow, and the development of retinal ischemia and rubeosis iridis. RESULTS: Mean BCVA was significantly higher in patients with lower CVP at all time points (P<0.0001). The area of CNP increased significantly with higher levels of CVP and progressed with time. The development of rubeosis iridis was significantly associated with CVP at all time points and was present in 5.6%, 27.9%, and 88.9% of those with low, moderate, and high CVP levels, respectively (P<0.0001), at the 18-month conclusion. Retinal blood flow as measured by FTT was reduced with higher levels of CVP. Spontaneous lowering of CVP had beneficial effects on BCVA, although this diminished with time. CONCLUSIONS: Eyes with increased CVP after more severe CRVO demonstrate significantly reduced vision, reduced retinal blood flow, a higher incidence of rubeosis iridis, and larger areas of CNP that correlate with the degree of CVP elevation.

A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: the BEVORDEX study.

OBJECTIVE: To report the 12-month results of the first head-to-head comparison of a dexamethasone implant (Ozurdex; Allergan, Inc., Irvine, CA) versus bevacizumab (Avastin; Genentech, South San Francisco, CA) for center-involving diabetic macular edema (DME). DESIGN: Phase 2, prospective, multicenter, randomized, single-masked clinical trial (clinicaltrials.gov identifier NCT01298076). PARTICIPANTS: We enrolled 88 eyes of 61 patients with center-involving DME. METHODS: Forty-two eyes were randomized to receive bevacizumab every 4 weeks and 46 eyes were randomized to receive a dexamethasone implant every 16 weeks, both pro re nata. Results were analyzed using linear regression with generalized estimation equation methods to account for between-eye correlation. MAIN OUTCOME MEASURES: The primary outcome was the proportion of eyes that improved vision by 10 logarithm of minimum angle of resolution letters. Secondary outcomes included mean change in best-corrected visual acuity (BCVA), change in central macular thickness (CMT), injection frequency, and adverse events. Patient-reported outcomes were measured using the Impact of Vision Impairment (IVI) questionnaire. RESULTS: Improvement in BCVA of 10 or more letters was found in 17 of 42 eyes (40%) treated with bevacizumab compared with 19 of 46 dexamethasone implant-treated eyes (41%; P = 0.83). None of the 42 bevacizumab eyes lost 10 letters or more, whereas 5 of 46 (11%) dexamethasone implant eyes did, mostly because of cataract. Mean CMT decreased by 122 µm for bevacizumab eyes and by 187 µm for dexamethasone implant eyes (P = 0.015). Bevacizumab-treated eyes received a mean of 8.6 injections compared with 2.7 injections for dexamethasone implant eyes. Significant improvement in IVI scores occurred for both treatment groups. CONCLUSIONS: Dexamethasone implant achieved similar rates of visual acuity improvement compared with bevacizumab for DME, with superior anatomic outcomes and fewer injections. Both treatments were associated with improvement in visual quality-of-life scores. However, more dexamethasone implant-treated eyes lost vision, mainly because of cataract.

Comparison of outcomes from a phase 3 study of age-related macular degeneration with a matched, observational cohort.

OBJECTIVE: To compare outcomes of intravitreal therapy from an observational study cohort with those of participants receiving treatment in the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab (MARINA) for the treatment of neovascular age-related macular degeneration (wet AMD). DESIGN: Database observational study. Participants in the observational cohort were chosen to match demographic features and entry criteria of the treatment group from MARINA. Outcomes over 12 months were compared. PARTICIPANTS: Eight hundred twenty-one anti-vascular endothelial growth factor (anti-VEGF)-naïve eyes treated with ranibizumab with 12 months or more of follow-up were included in the total Fight Retinal Blindness! (FRB-All) cohort, whereas a subset of this cohort of 401 eyes who were matched to the MARINA treatment group were included as the FRB-MARINA cohort. INTERVENTION: Intravitreal ranibizumab therapy of 0.5 mg for wet AMD. METHODS: Visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) letters and treatments given were recorded continuously and anonymously in an electronic database for 12 months. Locally weighted scatterplot smoothing (LOESS) regression was used to plot change in visual acuity data over the course of 12 months for both the FRB-All cohort and the FRB-MARINA cohort, whereas results from the MARINA trial were taken from the published study report. MAIN OUTCOME MEASURES: Change in VA in logMAR letters over 12 months, treatment, and visit intensity. RESULTS: Mean visual acuity improvement after 12 months in FRB-MARINA (+5.5 letters) was similar to that of the 0.5-mg group from MARINA (+7.2 letters). Improvement in FRB-ALL was slightly less (+4.9 letters). Mean treatment effect compared with the MARINA control group was similar for the MARINA treated group (+17.6 letters) and the FRB-MARINA cohort (+15.9 letters). A mean of 7.3 injections in 12 months was received by the observational cohorts. CONCLUSIONS: Similarity of mean VA improvement in the matched observational cohort with that of the phase 3 clinical trial suggests that these results can be achieved in real-world clinical practice with a modified treatment regimen.