Clinical Practice Update: Management of Infectious Endophthalmitis After Intravitreal Anti-VEGF Injection.

Although infectious endophthalmitis after intravitreal antivascular endothelial growth factor injections is rare, it is the most feared and potentially devastating complication of this procedure. There is no high-level evidence to provide definitive guidance on the management of endophthalmitis occurring after intravitreal injection (IVI). This clinical practice update reviews the published literature regarding post-IVI endophthalmitis and highlights areas in which further research is needed to better guide its management.

Prepapillary vascular loop-a new classification.

BACKGROUND/OBJECTIVES: To analyze the ophthalmic characteristics of congenital prepapillary vascular loop (PVL) and to propose a new morphologic classification dividing the loops into six types. SUBJECTS/METHODS: Collaborative multinational multicentre retrospective study of PVL cases. RESULTS: There was a total of 49 cases (61 eyes), 37 unilateral (75.5%) and 12 bilateral (24.5%), 32 arterial type (65.3%) and 18 venous type (36.7%) (one patient had either kind in each eye). The mean number of loops per eye was 2.7 (range, 1-7). The loops were asymptomatic in 42 cases (85.7%). Other findings included: the presence of cilioretinal artery (14 cases), retinal vascular tortuosity (26 cases), amaurosis fugax (1 case), branch retinal artery occlusion (1 case) and vitreous haemorrhage (3 cases). Six morphologic loop types could be discerned based on elevation (flat vs. elevated), shape (figure of 8 or corkscrew with hyaline sheath), number (multiple or single), location (central or peripheral), lumen size (arterial vs. arteriolar) and presence of vascular tortuosity or vitreous traction. CONCLUSIONS: PVL are usually asymptomatic and can be divided into six morphologic types with different pathogenesis during early embryogenesis.

Spontaneous Closure of a Macular Hole in Macular Telangiectasia Type 2.

Purpose: Spontaneous closure of a macular hole in macular telangiectasia type 2 (MacTel) with vision improvement is described. Methods: A case report is presented. Results: A 71-year-old man presented with a 1-week history of distorted vision in his left eye. Left visual acuity (LVA) was 20/80. Optical coherence tomography showed an almost full-thickness left macular hole with an intact internal limiting membrane drape. Small inner retinal cavitations were present at the right macula; multimodal imaging confirmed MacTel. Managed conservatively, at 5 months the patient's LVA had improved to 20/60, the defect was no longer full thickness, and the external limiting membrane had reconstituted. At the right macula, the inner cavitations grew and outer cavitations developed, but the external limiting membrane remained intact. At 32 months, right VA was 20/20 and LVA was 20/40. Conclusions: This case of MacTel with spontaneous closure of a macular hole was associated with an overlying internal limiting membrane drape.

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.

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.

Effect of Ranibizumab and Aflibercept on Best-Corrected Visual Acuity in Treat-and-Extend for Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial.

Importance: To our knowledge, this is the first randomized clinical trial to compare visual outcomes and injection loads between ranibizumab and aflibercept using an identical treat-and-extend (TE) regimen for neovascular age-related macular degeneration (nAMD). Objective: To report the results of the preplanned 12-month interim analysis of 2 predefined secondary efficacy end points of a randomized clinical trial. Design, Setting, and Participants: The Comparison of Ranibizumab and Aflibercept for the Development of Geographic Atrophy in (Wet) AMD Patients (RIVAL) trial was conducted in 24 sites in Australia and included 281 treatment-naive eyes from 281 participants with active choroidal neovascularization secondary to nAMD and a visual acuity letter score of 23 or greater who were recruited between April 11, 2014, and October 31, 2015. A preplanned interim analysis was performed at month 12. Best-corrected visual acuity (BCVA) assessors and the central reading center, which determined treatment intervals, were masked to treatment assignments. Interventions: Participants were randomized (1:1) to receive intravitreal injections of 0.5 mg of ranibizumab or 2.0 mg of aflibercept. After receiving 3 initial monthly injections, participants entered the TE phase. Main Outcomes and Measures: Mean change in BCVA and the number of injections from baseline to month 12. Results: Of 281 participants, 148 (52.7%) were women and the mean (SD) age was 77.7 (8.1) years. The baseline mean BCVA letter score (approximate Snellen equivalent) was 65.3 (20/50) in the ranibizumab arm and 65.1 (20/50) in the aflibercept arm. One hundred twenty-seven ranibizumab participants (90.1%) and 121 aflibercept participants (88.3%) completed month 12 with a mean (SD [Snellen equivalent]) BCVA letter score of 72.9 (15.5 [20/32]) and 70.5 (14.6 [20/40]), respectively. The mean change in BCVA letter scores from baseline to month 12 was 7.2 (95% CI, 5.5-8.9) for ranibizumab and 4.9 (95% CI, 3.1-6.6) for aflibercept (letter score difference, 2.3; 95% CI, -0.1 to 4.7; P = .06). The mean number of injections from baseline to month 12 was 9.7 in both the ranibizumab (SD, 2.8) and aflibercept (SD, 2.6) arms with a rate ratio of 1.00 (95% CI, 1.0-1.1; P = .86). Conclusions and Relevance: Our findings suggest that neither aflibercept nor ranibizumab for nAMD are superior to the other regarding the average visual acuity gains and number of injections during 1 year in a TE regimen. Further follow-up to 2 years may determine if advantages of one over the other can be identified. Trial Registration: Clinicaltrials.Gov identifier: NCT02130024.

Early Pars Plana Vitrectomy for Treatment of Acute Infective Endophthalmitis.

PURPOSE: To evaluate the efficacy and safety of early pars plana vitrectomy (PPV) for the treatment of acute infective endophthalmitis, and identify prognostic factors for better visual outcome. DESIGN: Retrospective cohort study. METHODS: Consecutive patients who underwent early PPV within 72 hours of presentation for the treatment of acute infective bacterial endophthalmitis and presented to a large tertiary referral center in New South Wales, Australia, between January 2009 and December 2013 were included. Changes in best-corrected visual acuity (VA) from baseline to 1 year were examined. RESULTS: A total of 64 patients were included. The inciting events were cataract surgery (53%), intravitreal injection (36%), trabeculectomy (3%), and endogenous (3%). The mean VA improved from 3.1 logMAR (hand motion) at baseline to 1.02 (approximately 20/200) at 1 year, with 42% achieving final VA equal to or better than 0.477 logMAR (20/60) following early PPV. Positive prognostic factors were negative microbial cultures (P < 0.01) and etiology of post-cataract surgery (P < 0.01). In multivariable analyses adjusting for age and prognostic factors, patients with baseline VA of light perception and hand motion achieved greater visual gains than those with counting fingers, with gains of logMAR of -2.68, -2.09, and -0.85, respectively (P < 0.0001). CONCLUSIONS: Most patients who undergo early PPV experience substantial VA improvement. Negative microbial cultures and endophthalmitis after cataract surgery were associated with better final visual outcome. Patients with presenting VA of light perception or hand motion achieved higher visual gains than those with counting fingers, suggesting the possibility that early PPV may be beneficial in both groups.

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.

Dual roles of different redox forms of complement factor H in protecting against age related macular degeneration.

Complement Factor H (CFH) is an important inhibitor of the alternate complement pathway in Bruch's membrane (BM), located between the choriocapillaris and the retinal pigment epithelium. Furthermore dysfunction of its activity as occurs with certain polymorphisms is associated with an increased risk of age related macular degeneration (AMD). The retina is a site of high generation of reactive oxygen species (ROS) and dysfunction of redox homeostasis in this milieu also contributes to AMD pathogenesis. In this study we wanted to explore if CFH exists in distinct redox forms and whether these species have unique protective biological functions. CFH can be reduced by the naturally occurring thioredoxin - 1 in CFH domains 1-4, 17-20. We found a duality of function between the oxidised and reduced forms of CFH. The oxidised form was more efficient in binding to C3b and lipid peroxidation by-products that are known to accumulate in the retinae and activate the alternate complement pathway. Oxidised CFH enhances Factor I mediated cleavage of C3 and C3b whereas the reduced form loses this activity. In the setting of oxidative stress (hydrogen peroxide)-mediated death of human retinal pigment epithelial cells as can occur in AMD, the free thiol form of CFH offers a protective function compared to the oxidised form. We found for the first time using a novel ELISA system we have developed for free thiol CFH, that both redox forms of CFH are found in the human plasma. Furthermore there is a distinct ratio of these redox forms in plasma depending if an individual has early or late AMD, with individuals with early AMD having higher levels of the free thiol form compared to late AMD.

Idiopathic full thickness macular hole in a 10-year-old girl.

BACKGROUND: Macular holes in children are generally associated with trauma. CASE PRESENTATION: We report the first case of an idiopathic full thickness macular hole in a 10-year-old girl. 23-gauge transconjunctival pars plana vitrectomy, induction of a posterior vitreous detachment, ILM blue-assisted internal limiting membrane peel, fluid-air exchange and air-26% sulfur hexafluoride (SF6) exchange was performed with subsequent macular hole closure. CONCLUSION: This is the first reported case of an idiopathic full thickness macular hole in a child. Treatment with pars plana vitrectomy with peeling of the ILM resulted in significant anatomic and functional improvement.

Topical antibiotics and intravitreal injections.

There is increasing evidence that topical antibiotics, given before and/or after intravitreal injections, are ineffective in preventing endophthalmitis and are possibly harmful. In addition to the lack of efficacy and increased development of resistant organisms, the use of topical antibiotics adds significantly to the cost of delivering intravitreal therapy. Despite this, in many countries, it is still common practice to use pre- and/or postinjection topical antibiotics. This review outlines the general principles of effective antibiotic prophylaxis, and the evidence regarding topical antibiotic use as a prophylactic measure for endophthalmitis following intravitreal injections. A key distinguishing feature of intravitreal injections from most other invasive procedures is the fact that they are often repeated on multiple occasions to the same eye. Given the lack of evidence to support topical antibiotics as an effective method of prophylaxis for postinjection endophthalmitis, it appears that more widespread education of ophthalmologists is required to avoid continued inappropriate use. Revision of drug labels in some jurisdictions, and amendment of local/professional society guidelines, may be required to assist in achieving this goal. Emphasis should be placed on antisepsis and aseptic technique, which are the major proven methods of endophthalmitis prevention, rather than antibiotics.

TWO YEAR OUTCOMES OF "TREAT AND EXTEND" INTRAVITREAL THERAPY USING AFLIBERCEPT PREFERENTIALLY FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To report 24-month outcomes of a treat and extend (T&E) regimen using aflibercept in eyes with neovascular age-related macular degeneration. METHODS: This was a database observational study that included treatment-naive eyes with neovascular age-related macular degeneration tracked by the Fight Retinal Blindness! outcome registry completing 24 months of sole monotherapy with aflibercept treatment under a T&E regimen between November 1, 2012 and January 31, 2014. Locally weighted scatterplot smoothing curves were used to display visual acuity outcomes. Main outcome measures were change in visual acuity at 24 months and number of injections and visits during the study period. RESULTS: The study population, identified by reviewing the database, consisted of 136 eyes from 123 patients completing 24 months of follow-up on aflibercept. Mean (SD) age was 77.2 (7.0) years, 59% were female. Mean visual acuity increased from 61.4 (∼20/60; SD 17.4) letters at baseline to 67.4 (∼20/45; SD 17.7) letters at 24 months (+6.0 letters [95% confidence interval: 3.3-8.5]; P < 0.001). From baseline to 24 months, the proportion of eyes with visual acuity ≥70 letters (20/40) increased (40%-58%, P < 0.001) and the proportion of eyes with visual acuity ≤35 letters (20/200) remained the same (10%; P = 0.547). Ninety-eight per cent of eyes starting with visual acuity ≥70 letters (20/40) were able to maintain this up to 24 months. From the first to the second year of treatment, the mean number of injections (7.8 [2.1] vs. 5.7 [2.6]; P < 0.001) and visits (8.7 [1.7] vs. 6.5 [2.4]; P < 0.001) decreased for eyes completing 24 months of treatment. When data from 60 eligible eyes that did not complete 2 years follow-up, along with 14 eyes that switched to ranibizumab, were included using last observation carried forward, the mean change in visual acuity from baseline was +5.6 letters (95% confidence interval: 3.3-7.7). CONCLUSION: These data indicate that eyes treated with aflibercept, as a sole therapy, in routine clinical practice with a T&E regimen can achieve good visual outcomes while decreasing the burden of treatments and clinic visits.

PERIPAPILLARY PACHYCHOROID SYNDROME.

PURPOSE: To describe the features of peripapillary pachychoroid syndrome (PPS), a novel pachychoroid disease spectrum (PDS) entity. METHODS: Medical records of 31 eyes (16 patients) with choroidal thickening associated with intraretinal and/or subretinal fluid in the nasal macula extending from the disk were reviewed (patients with PPS). Choroidal thickness was compared with 2 age-matched cohorts: typical PDS (17 eyes with central serous chorioretinopathy or pachychoroid neovasculopathy) and 19 normal eyes. RESULTS: The patients with PPS were 81% men aged 71 ± 7 years. Peripapillary pachychoroid syndrome eyes displayed thicker nasal versus temporal macular choroids, unlike PDS eyes with thicker temporal macular choroids (P < 0.0001). Peripapillary intraretinal and/or subretinal fluid was often overlying dilated Haller layer vessels (pachyvessels). Fundus autofluorescence and fluorescein angiography illustrated peripapillary pigmentary mottling without focal leakage. Most PPS eyes (70%) exhibited other PDS findings including serous pigment epithelial detachment or gravitational tracks. Indocyanine green angiography illustrated dilated peripapillary pachyvessels and choroidal hyperpermeability. The disk was usually crowded, with edema noted in 4/31 (13%) eyes and mild late fluorescein disk leakage identified in half of the cases. Choroidal folds (77%), short axial lengths (39% less than 23 mm), and hyperopia (86%) were common. CONCLUSION: Peripapillary pachychoroid syndrome is a distinct PDS variant, in which peripapillary choroidal thickening is associated with nasal macular intraretinal and/or subretinal fluid and occasional disk edema. Recognition of PPS is important to distinguish it from disorders with overlapping features such as posterior uveitis and neuro-ophthalmologic conditions.

Outcomes of Eyes with Failed Primary Surgery for Idiopathic Macular Hole.

PURPOSE: To describe the anatomic and visual outcomes of eyes undergoing reoperation after failed primary surgery for idiopathic macular hole. DESIGN: Prospective registry study. PARTICIPANTS: One hundred three patients who had undergone failed macular hole surgery. METHODS: Unclosed idiopathic macular holes were identified from a large national prospective registry run by the Australian and New Zealand Society of Retinal Specialists. Unclosed idiopathic macular holes were defined as idiopathic macular holes that underwent vitrectomy surgery for the first time, but were never observed to close in the postoperative period. Surgeons were contacted to submit retrospectively details of subsequent management and long-term outcome of these eyes. MAIN OUTCOME MEASURES: Macular hole closure; visual acuity (VA) change relative to baseline at 3, 12, and 24 months; and hole size at all time points. RESULTS: One hundred three patients with failed macular hole surgery were identified, among whom 53 underwent reoperation, 49 did not, and 1 was lost to follow-up. Macular hole closure was achieved in 45 of 53 patients (85%) undergoing revision surgery. Mean change in VA from baseline in eyes undergoing revision surgery versus eyes that did not was +2.8 letters versus -1.9 letters at 3 months (P = 0.278), +8.2 letters versus -1.9 letters at 12 months (P = 0.167), and +18.3 letters versus -3.4 letters at 24 months (P = 0.022). Thirty-six percent of eyes with reoperated holes showed improved VA of 15 letters or more at 3 months after operation, increasing to 48% at 12 months and 65% at 2 years. Before revision surgery, mean macular hole size was observed to increase from 483 µm to 562 µm after failed primary surgery (P = 0.046). CONCLUSIONS: In eyes undergoing revision surgery, reoperation for unclosed macular holes was significantly better than observation, although these visual gains took some time to occur. The surgical success rate was lower than that for primary idiopathic macular hole. The selection criteria for revision surgery need to be defined.

The Visual Outcomes of Macular Hole Surgery: A Registry-Based Study by the Australian and New Zealand Society of Retinal Specialists.

PURPOSE: To present the visual and safety outcomes of surgery for primary idiopathic macular holes including predictors of visual acuity and the impact of combined phacovitrectomy surgery. 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, and details of surgical intervention were collected. Primary follow-up data were collected at 3 months postoperatively or before revision surgery, and surgeons were also asked to submit data at 12 and 24 months postoperatively. MAIN OUTCOME MEASURES: Visual acuity improvement ≥15 letters and ≥0 letters, change in mean visual acuity, visual acuity ≥70 letters (20/40), retinal detachment, and endophthalmitis. RESULTS: A total of 2455 eyes of 2366 patients were included in the study, and hole closure was achieved in 95.6% of eyes with a single procedure. Mean baseline vision was 48.3 letters. The proportion of successful eyes improving ≥15 letters at 3, 12, and 24 months was 59.1%, 69.4%, and 68.2%, respectively. The mean improvement in acuity at 3, 12, and 24 months was 16.0, 19.2, and 23.6 letters, and 92.4%, 93.4%, and 95.8% improved ≥0 letters at 3, 12, and 24 months, respectively. Eyes receiving SF6 gas had better visual acuities at all time points postoperatively (adjusted effect 3.4, 3.1, and 4.6 letters better at 3, 12, and 24 months vs. longer-acting gas, respectively). Combined phacovitrectomy in phakic eyes was associated with better corrected visual acuity postoperatively (vs. vitrectomy surgery alone), a difference that vanished when eyes went on to have subsequent cataract surgery. The rate of retinal detachment postoperatively was 1.3%, and the odds of detachment were greater in eyes receiving longer-acting gases versus SF6 gas (adjusted odds ratio, 2.2; 95% confidence interval, 1.04-4.77; P = 0.039). There were no reported cases of endophthalmitis. CONCLUSIONS: Macular hole surgery substantially improved acuity in approximately two thirds of patients and was seldom associated with loss of vision. SF6 gas was associated with better visual outcomes, an effect that warrants further study.

Nitration of tyrosines in complement factor H domains alters its immunological activity and mediates a pathogenic role in age related macular degeneration.

Nitrosative stress has been implicated in the pathogenesis of age related macular degeneration (AMD). Tyrosine nitration is a unique type of post translational modification that occurs in the setting of inflammation and nitrosative stress. To date, the significance and functional implications of tyrosine nitration of complement factor H (CFH), a key complement regulator in the eye has not been explored, and is examined in this study in the context of AMD pathogenesis.Sections of eyes from deceased individuals with AMD (n = 5) demonstrated the presence of immunoreactive nitrotyrosine CFH. We purified nitrated CFH from retinae from 2 AMD patients. Mass spectrometry of CFH isolated from AMD eyes revealed nitrated residues in domains critical for binding to heparan sulphate glycosaminoglycans (GAGs), lipid peroxidation by-products and complement (C) 3b.Functional studies revealed that nitrated CFH did not bind to lipid peroxidation products, nor to the GAG of perlecan nor to C3b. There was loss of cofactor activity for Factor I mediated cleavage of C3b with nitrated CFH compared to non-nitrated CFH. CFH inhibits, but nitrated CFH significantly potentiates, the secretion of the pro-inflammatory and angiogenic cytokine IL-8 from monocytes that have been stimulated with lipid peroxidation by-products. AMD patients (n = 30) and controls (n = 30) were used to measure plasma nitrated CFH using a novel ELISA. AMD patients had significantly elevated nitrated CFH levels compared to controls (p = 0.0117). These findings strongly suggest that nitrated CFH contributes to AMD progression, and is a target for therapeutic intervention.

Bullous Variant of Central Serous Chorioretinopathy: Expansion of Phenotypic Features Using Multimethod Imaging.

PURPOSE: To define the phenotypic characteristics of the bullous variant of central serous chorioretinopathy (CSC) using multimethod imaging. DESIGN: Retrospective, observational case series. PARTICIPANTS: Twenty-one eyes of 14 patients with bullous retinal detachment resulting from CSC (bullous CSC group) and 122 eyes of 84 patients with chronic CSC without bullous retinal detachment (nonbullous CSC group). METHODS: We performed a retrospective review of clinical and multimethod imaging data of patients who sought treatment from the authors with bullous retinal detachment resulting from CSC between January 2010 and November 2015. Multimethod imaging comprised color photography, fluorescein angiography, fundus autofluorescence, and high-resolution optical coherence tomography. Consecutive cases of chronic CSC without bullous retinal detachment, seen during the same period, comprised a comparative group. MAIN OUTCOME MEASURES: Qualitative and quantitative characteristics of the choroid, retinal pigment epithelium, and retina were compared between the 2 groups. RESULTS: Mean age of the bullous CSC group was 53.8 years. There was no difference in age, visual acuity, corticosteroid use, or the proportion of white patients and men between the 2 groups (all P > 0.132). Peripheral nonperfusion occurred only in eyes with bullous retinal detachment (38% of cases). Retinal pigment epithelial tears were seen in 95% of eyes in the bullous group and none of the eyes in the nonbullous CSC group. The bullous CSC group demonstrated a greater number of pigment epithelial detachments (PEDs) and more eyes demonstrated PEDs with internal hyperreflectivity (both P < 0.016). Mean subfoveal choroidal thickness in the bullous CSC group (463.1±83.1 µm) was not different compared with that of the nonbullous CSC group (400.6±100.6 µm; P = 0.993). More eyes in the bullous CSC group demonstrated hyperreflectivity around large choroidal vessels and at the level of the choriocapillaris on OCT (P < 0.001). Retinal folds and subretinal fibrin were identified in a greater proportion of eyes in the bullous CSC group (both P < 0.001). CONCLUSIONS: Bullous retinal detachment is a rare manifestation of chronic CSC and is characterized by a unique constellation of phenotypic and multimethod imaging features.

Effects of switching from ranibizumab to aflibercept in eyes with exudative age-related macular degeneration.

AIMS: To examine 12-month outcomes of eyes switching from intravitreal ranibizumab to aflibercept for neovascular age-related macular degeneration (nAMD). METHODS: Database observational study of eyes with nAMD tracked by the Fight Retinal Blindness outcome registry that received ranibizumab for at least 12 months before switching to aflibercept and followed for at least 12 months after the switch. Visual acuity (VA) recorded at 12 months after the switch was analysed using locally weighted scatterplot smoothing curves. Lesion activity was graded according to a prospectively identified definition. Main outcomes were change in VA and treatment intervals 12 months after the treatment switch. Secondary outcomes included change in activity grading, effect of duration of treatment before switching and analysis of eyes that switched back. RESULTS: A total of 384 eyes switched from ranibizumab to aflibercept after a mean duration of 39.8 months on the original treatment. The mean VA did not change from the time of switching treatment (63.4, SD 15.9 logarithm of the minimum angle of resolution letters) to 12 months later (63.3, SD 16.7). While 10% of eyes gained 10 or more letters 12 months after the switch, 13% lost the same amount. The mean number of injections decreased by around one injection in the 12 months after switching (p<0.001), with a decrease in the proportion of choroidal neovascular membrane lesions that were graded as active. Eyes that had been treated for the longest time (49 or more months) before switching had worse vision at the point of switch but neither change in VA nor treatment interval was different between groups. The small proportion (6.9%) of eyes that switched back again to ranibizumab had already lost a mean of 5.2 letters from the first switch to the switch back and continued to lose vision at a similar rate for at least 6 months. CONCLUSIONS: The mean VA of eyes that switched treatments from ranibizumab to aflibercept was not different 12 months later. There was a modest increase in treatment intervals and a somewhat greater proportion of eyes that were graded as inactive after the switch.