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Purpose: To evaluate postoperative pain level using a supplemental peribulbar injection at the conclusion of retinal surgery., Design: Prospective, parallel-assigned, single-masked, randomized clinical trial., Participants: Fifty-eight patients undergoing scleral buckle, vitrectomy, or combined surgery., Methods: In a single academic institutional practice, 58 patients undergoing scleral buckle, vitrectomy, or combined surgery were enrolled. Exclusion criteria included those with a risk for glaucoma, a pre-existing chronic pain disorder, among others. Patients were assigned randomly to receive a postoperative peribulbar formulation of either bupivacaine, triamcinolone acetonide, and cefazolin (group A) or bupivacaine, balanced salt solution, and cefazolin (group B). The postoperative pain score and ocular motility were assessed by a masked observer on the first postoperative day., Main Outcome Measures: The primary outcome measure was the postoperative pain score. Secondary outcome measures included oral analgesic use, ocular motility, and intraocular pressure (IOP)., Results: The mean pain scores were 2.8±2.9 for group A and 3.8±2.6 for group B (P = 0.095). Pain was absent in 28% of group A patients versus 14% of group B patients (P = 0.11). Group A required less narcotic pain medication (hydroxycodone: group A, 0.7±3 mg vs. group B, 3±6 mg; P = 0.05; oxycodone: group A, 7±7 mg vs. 9±13 mg; P = 0.2) than group B. Motility was full in group B and limited in group A (P ≤ 0.001), with no differences in mean IOP measurements at any point after surgery., Conclusions: We did not demonstrate a statistically significant reduction in mean postoperative pain scores. However, patients in group A required less hydroxycodone use and had greater akinesia, suggesting prolonged neural blockade., (Copyright © 2017 American Academy of Ophthalmology. All rights reserved.)

Contradictory data have been presented regarding the implication of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in age-related macular degeneration (AMD), the leading cause of vision loss in the Western world. Recognizing that antibody specificity may explain this discrepancy and in line with recent National Institutes of Health (NIH) guidelines requiring authentication of key biological resources, the specificity of anti-NLRP3 antibodies was assessed to elucidate whether non-immune RPE cells express NLRP3. Using validated resources, NLRP3 was not detected in human primary or human established RPE cell lines under multiple inflammasome-priming conditions, including purported NLRP3 stimuli in RPE such as DICER1 deletion and Alu RNA transfection. Furthermore, NLRP3 was below detection limits in ex vivo macular RPE from AMD patients, as well as in human induced pluripotent stem cell (hiPSC)-derived RPE from patients with overactive NLRP3 syndrome (Chronic infantile neurologic cutaneous and articulate, CINCA syndrome). Evidence presented in this study provides new data regarding the interpretation of published results reporting NLRP3 expression and upregulation in RPE and addresses the role that this inflammasome plays in AMD pathogenesis.

Purpose: We hypothesized that the elastic nature of the choroid leads to tissue contraction following a full-thickness, sharp incision. Furthermore, we sought to quantify, measure, and compare tissue contraction in ex vivo porcine globes and human globes of various ages using predetermined variables., Method: A full-thickness, ex vivo choroidal incision was performed in either pig ( n = 97) or human ( n = 30) specimens. Variables included trephine diameter (1.5, 2.0, or 2.5 mm) versus a straight surgical blade, and temperature (1.7 °-4.4° vs. 36.6°F). Central centripetal and surround centrifugal tissue contractions were measured. Mean percentage tissue contraction was assessed as a ratio of trephine diameter to final tissue contraction measured immediately following each incision using a standardized device., Results: For trephination in pig specimens, centripetal contraction ranged from 38% to 50% with a mean of 44%. Centrifugal contraction was approximately 15%. Human choroidal contraction was 39% and 15%, respectively, with a statistically significant inverse relationship to age ( R 2 = 0.35, P ≤ 0.01). Asymmetric contraction was noted when incisions were closer to choroidal attachment sites to the sclera, such as near vortex ampullae. Linear incisions resulted in contraction that correlated with incision length ( R 2 = 0.35, P ≤ 0.001)., Conclusions: A full-thickness choroidal incision results in significant tissue contraction. For circular incisions, the centripetal contraction approaches 50% of the original incision size. For linear incisions, the contraction corresponds directly with incision length. In human specimens, there is less contraction with advancing age., Translational Relevance: Our findings have clinical relevance for choroidal biopsy, traumatic injury, and choroidal translocation surgery.

Purpose: To refine the Minnesota Grading System (MGS) using definitions from the Age-Related Eye Disease Studies (AREDS) into a nine-step grading scale (MGS-9)., Methods: A nine-step grading scale descriptive analysis using three key phenotypic features (total drusen area, increased, and decreased pigmentation) of human eyebank eyes that were graded according to definitions from the AREDS criteria in order to harmonize studies of disease progression for research involving human tissue. From 2005 through February 2017, we have analyzed 1159 human eyes, procured from two eyebanks. Each macula was imaged using high-resolution, stereoscopic color fundus photography with both direct- and transillumination. Fundus images were digitally overlaid with a grading template and triangulated for foveal centration., Results: We documented and stratified risk for each globe by applying the AREDS nine-step grading scale to the key clinical features from the MGS-9. We found a good distribution within the MGS categories (1-9) with few level eight globes. Eyes were processed within 12.1 ± 6.3, hours from the time of death through imaging, dissection, and freezing or fixation. Applying the MGS-9 to 331 pairs (662 eyes were simultaneously graded), 84% were within one-grading step and 93% within two steps of the fellow eye. We also document reticular pseudodrusen, basal laminar drusen, and pattern dystrophy., Conclusions: The MGS nine-step grading scale enables researchers using human tissue to refine the risk assessment of donor tissue. This analysis will harmonize results among researchers when grading human tissue using MGS criteria. Most importantly, the MGS-9 links directly to the known risk for progression from the AREDS.

Purpose: To compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model., Methods: Forty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit μg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study., Results: In 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 ± 20 μm) versus controls (180 ± 20 μm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 ± 43 μm) compared to SC pazopanib (478 ± 105 μm; P = 0.018). The mean lesion size in hI-con1-treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells., Conclusions: Intravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans.

Purpose: To describe an economic (Ec) model for estimating the impact of screening and treatment for retinopathy of prematurity (ROP)., Design: EcROP is a cost-effectiveness, cost-utility, and cost-benefit analysis., Methods: We surveyed caregivers of 52 children at schools for the blind or pediatric eye clinics in Atlanta, Georgia and 43 in Mexico City. A decision analytic model with sensitivity analysis determined the incremental cost-effectiveness (primary outcome) and incremental monetary benefit (secondary outcome) of an ideal (100% screening) national ROP program as compared to estimates of current practice. Direct costs included screening and treatment expenditures. Indirect costs estimated lost productivity of caretaker(s) and blind individuals as determined by face-to-face surveys. Utility and effectiveness were measured in quality-adjusted life years and benefit in US dollars. EcROP includes a sensitivity analysis to assesses the incremental cost-effectiveness and societal impact of ROP screening and treatment within a country or economic region. Estimates are based on evidence-based clinical data and region-specific economic data acquired from direct field survey., Results: In both Mexico and the United States, an ideal national ROP screening and treatment program was highly cost-saving. The incremental net benefit of an ideal ROP program over current practice is $5556 per child ($206 574 333 annually) and $3628 per child ($205 906 959 annually) in Mexico and the United States, respectively., Conclusion: EcROP demonstrates that ROP screening and treatment is highly beneficial for quality of life, cost saving, and cost-effectiveness in the United States and Mexico. EcROP can be applied to any country or region to provide data for informed allocation of limited health care resources., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Unlabelled: COMPREHENSIVE ADULT MEDICAL EYE EVALUATION® PREFERRED PRACTICE PATTERN®, Guidelines: Evidence-based update of the Comprehensive Adult Medical Eye Evaluation Preferred Practice Pattern® (PPP) guidelines, discussing the rationale and components of an ophthalmic evaluation for adult patients with and without risk factors., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Local drug delivery to the posterior segment, particularly the macula, represents a significant challenge. In this chapter, we review current challenges, barriers and limitations. Due to the local drug delivery to the retina and macula, systemic side effects are limited. In this chapter, we also discuss the historical approaches, key aspects of ideal drug delivery systems, the use of animal models to study pharmacokinetics, and the principles of transscleral, suprachoroidal and gas phase drug delivery., (© 2016 S. Karger AG, Basel.)

Unlabelled: IDIOPATHIC EPIRETINAL MEMBRANE AND VITREOMACULAR TRACTION PREFERRED PRACTICE PATTERN®, Guidelines: New evidence-based Idiopathic Epiretinal Membrane and Vitreomacular Traction Preferred Practice Pattern® (PPP) guidelines, describing recommendations for the diagnosis, treatment, and management of patients., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Unlabelled: RETINAL VEIN OCCLUSIONS PREFERRED PRACTICE PATTERN®, Guidelines: New evidence-based Retinal Vein Occlusions Preferred Practice Pattern® (PPP) guidelines, discussing the prognosis and risk factors of retinal vein occlusions and the treatment options., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: We compared smartphone fundus photography, nonmydriatic fundus photography, and 7-field mydriatic fundus photography for their abilities to detect and grade diabetic retinopathy (DR)., Design: This was a prospective, comparative study of 3 photography modalities., Participants: Diabetic patients (n = 300) were recruited at the ophthalmology clinic of a tertiary diabetes care center in Chennai, India., Methods: Patients underwent photography by all 3 modalities, and photographs were evaluated by 2 retina specialists., Main Outcome Measures: The sensitivity and specificity in the detection of DR for both smartphone and nonmydriatic photography were determined by comparison with the standard method, 7-field mydriatic fundus photography., Results: The sensitivity and specificity of smartphone fundus photography, compared with 7-field mydriatic fundus photography, for the detection of any DR were 50% (95% confidence interval [CI], 43-56) and 94% (95% CI, 92-97), respectively, and of nonmydriatic fundus photography were 81% (95% CI, 75-86) and 94% (95% CI, 92-96%), respectively. The sensitivity and specificity of smartphone fundus photography for the detection of vision-threatening DR were 59% (95% CI, 46-72) and 100% (95% CI, 99-100), respectively, and of nonmydriatic fundus photography were 54% (95% CI, 40-67) and 99% (95% CI, 98-100), respectively., Conclusions: Smartphone and nonmydriatic fundus photography are each able to detect DR and sight-threatening disease. However, the nonmydriatic camera is more sensitive at detecting DR than the smartphone. At this time, the benefits of the smartphone (connectivity, portability, and reduced cost) are not offset by the lack of sufficient sensitivity for detection of DR in most clinical circumstances., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine whether the neurosteroid progesterone, shown to have protective effects in animal models of traumatic brain injury, stroke, and spinal cord injury, is also protective in ocular ischemia animal models., Methods: Progesterone treatment was tested in two ocular ischemia models in rats: a rodent anterior ischemic optic neuropathy (rAION) model, which induces permanent monocular optic nerve stroke, and the middle cerebral artery occlusion (MCAO) model, which causes transient ischemia in both the retina and brain due to an intraluminal filament that blocks the ophthalmic and middle cerebral arteries. Visual function and retinal histology were assessed to determine whether progesterone attenuated retinal injury in these models. Additionally, behavioral testing and 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining in brains were used to compare progesterone's neuroprotective effects in both retina and brain using the MCAO model., Results: Progesterone treatment showed no effect on visual evoked potential (VEP) reduction and retinal ganglion cell loss in the permanent rAION model. In the transient MCAO model, progesterone treatment reduced (1) electroretinogram (ERG) deficits, (2) MCAO-induced upregulation of glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), and (3) retinal ganglion cell loss. As expected, progesterone treatment also had significant protective effects in behavioral tests and a reduction in infarct size in the brain., Conclusions: Progesterone treatment showed protective effects in the retina following MCAO but not rAION injury, which may result from mechanistic differences with injury type and the therapeutic action of progesterone.

Purpose: To describe a series of chorioretinal folds (CRFs) representing a clinical sign that may be associated with multiple systemic, orbital, and ophthalmologic disorders. We report the associations with systemic disease and describe 3 stages of a CRF-related maculopathy., Design: Observational, retrospective case series., Methods: We reviewed 57 affected eyes from 40 patients with the clinical sign of CRF from 1 of 2 academic institutions. A careful review of the medical histories and systemic diagnostic evaluations were conducted. Imaging studies were conducted., Results: The mean age at diagnosis was 64 ± 17 years. Most eyes (n = 18) were hyperopic (+2.60 ± +2.90 diopters). There were 20 patients (50%) with some form of autoimmune disorder. Overall, the mean presenting visual acuity was 20/50, declining slightly to 20/60 over 19 ± 30 months. Ten eyes had stage 3 CRF-related maculopathy, more common in older individuals with more chronic CRFs. Four stage 3 eyes had associated choroidal neovascularization, and these eyes had 20/60 presenting visual acuity that decreased to 20/100 over approximately 1.5 years. Stage 3 eyes without choroidal neovascularization had a mean presenting visual acuity of 20/40 that decreased to 20/65 over 2.1 years., Conclusions: CRFs are associated with numerous ophthalmic and systemic disorders. A careful medical history and evaluation are essential. We describe 3 stages of a unique CRF-related maculopathy. Stage 3 resembles occult choroidal neovascularization, occurs primarily in older individuals with chronic CRFs, and is accompanied by a slow deterioration in central acuity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.

Purpose: To report results of aflibercept therapy in eyes with neovascular age-related macular degeneration previously treated with bevacizumab, ranibizumab, or both., Design: Retrospective, interventional, noncomparative, consecutive case series., Methods: Ninety-six eyes from 85 patients with neovascular age-related macular degeneration who previously had received bevacizumab, ranibizumab, or both were treated with aflibercept monthly for 3 months followed by a fourth injection within 2 months. Outcomes were determined 4 ± 1 months after the first aflibercept dose and included: proportion of patients gaining or losing 2 lines or more of best-corrected visual acuity, proportion remaining within a gain or loss of 1 line, mean change in logarithm of the minimal angle of resolution visual acuity, mean change in central foveal thickness, mean change in macular cube volume, and qualitative anatomic response as assessed by spectral-domain optical coherence tomography., Results: At baseline, 82 (85%) eyes had signs of active exudation despite a mean of 17 previous anti-vascular endothelial growth factor injections. At final visit, 82 (85%) remained stable within a gain or loss of 1 line, 7 (7%) gained 2 lines or more, and 7 (7%) lost 2 lines or more of best-corrected visual acuity. Mean logarithm of the minimal angle of resolution visual acuity showed minimal change 0.02 (range, -0.46 to 0.70; P = .14). Mean central foveal thickness decreased -18 μm (range, -242 to 198 μm; P = .06). Mean macular volume decreased -0.27 mm(3) (95% confidence interval, -0.4 to -0.1 mm(3); P = .004). On qualitative analysis, 4 (5%) eyes had complete resolution of exudative fluid, 40 (49%) showed partial resolution, 26 (32%) remained unchanged, and 12 (14%) showed worsened exudative fluid., Conclusions: Aflibercept seems to be an effective alternative for neovascular age-related macular degeneration patients previously treated with bevacizumab, ranibizumab, or both at 4 months of follow-up. Most treated eyes demonstrated stable visual acuity and anatomic improvements by spectral-domain optical coherence tomography., (Published by Elsevier Inc.)

Purpose: To assess the effect of air versus fluid tamponade on the intraocular migration of india ink particles through nonsutured transconjunctival 23-gauge sclerotomies in living porcine eyes., Methods: Both eyes (n = 20) underwent 3-port, transconjunctival, 23-gauge vitrectomy. An angled trocar insertion technique was used in all cases. In each animal, one eye underwent a partial fluid-air exchange at the conclusion of the vitrectomy, yielding an air fill of approximately 80% (n = 10), whereas the other was left fluid filled (n = 10). After removal of the instruments and trocar cannulae, india ink was applied to the ocular surface. Animals were allowed to partially recover from anesthesia and resume normal blinking behavior. Animals were then reanesthetized, euthanized, and enucleated. Histopathologic examination was performed in a masked fashion. The presence and location of ink was noted for each identified sclerotomy., Results: Ink was identified on the ocular surface in 18 of 20 eyes. Sclerotomy wounds were identified in 16 of 20 eyes. Ink penetration was seen in 2 of 16 sclerotomy wounds, 1 in an air-filled globe and 1 in a fluid-filled globe. In both eyes, the ink was identified along the outer one third of the wound. There was no penetration of ink along the inner two thirds of the sclerotomy wound or in the posterior segment of any eyes., Conclusion: In an experimental, in vivo, porcine model, india ink migration into angled transconjunctival sclerotomy incisions was minimal, regardless of the use of an 80% fluid-air exchange at the conclusion of the case.

Purpose: To define surveillance approaches and metrics to capture the burden of vision health disparities and to identify properties of a surveillance system to guide public health interventions., Design: Expert panel., Methods: Analysis of relevant literature and deliberations of expert panel., Results: The panel identified that the purpose of vision surveillance was to link data to public health interventions. Panel members noted the importance of assessing vision through self-reported and performance-based measures. Defined populations should be included in a surveillance system to assess disparities in utilization of eye care and vision loss. The panel suggested that ophthalmic/vision measures should be sustained in national surveys and suggested that a vision surveillance system should be forged among federal agencies., Conclusions: Employing the 6 outlined strategies would improve vision surveillance and help reach the vision-related objectives of Healthy People 2020., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To determine the cost-effectiveness of laser treatment for retinopathy of prematurity (ROP) in Lima, Peru., Design: A cost-of-illness study (in US dollars) to determine the direct cost of treatment, the indirect lifetime cost of blindness, and the quality-adjusted life years., Methods: The direct cost of ROP-related treatment was determined by reviewing data retrospectively from a social security sector hospital. The indirect cost was determined using national economic data of Peru published by the Central Information Agency (CIA), including the per capita gross domestic product, the sex-adjusted income distribution, and years spent in the work force. Indirect costs per child that were avoided by treatment were calculated using the known natural history of ROP vs evidence-based treatment., Results: For ROP-related neonatal blindness in Peru, we estimate the total indirect cost saving at $197,753 per child and the direct cost of laser treatment at $2496 per child. The societal lifetime cost saving per child is estimated at $195,257. The mean annual income per educated adult in Peru is $8000 and treating 1 child is equivalent to employing 24 educated Peruvians per year. The generational cost savings for society is approximately $516 million, or the equivalent of 64,500 educated Peruvian work years., Conclusions: The societal burden of blindness far exceeds the costs of treatment per child. Proper screening and treatment of ROP prevents blindness and leads to substantial cost savings for society. Public health policy in Peru and other middle-income countries should consider financial impact when allocating healthcare resources., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Ocular manifestations of Lyme disease are uncommon. There has not been a documented case of serous retinal detachment and chorioretinal folds because of Lyme disease that have resolved after only antibiotic treatment., Methods (case Report): A 69-year-old white man with a history of recent tick bites presented with a gradual decrease in visual acuity in the left eye. Initial visual acuity was 3/200 in the left eye. Examination revealed an inferior, serous, macula-off retinal detachment. Chorioretinal folds were also noted. Lyme screening antibody test (enzyme-linked immunosorbent assay) was positive and a confirmatory Western blot was immunoglobulin M negative and immunoglobulin G positive., Results: Oral amoxicillin (500 mg 3 times daily for 2 weeks) was given followed by intravenous ceftriaxone (2 g daily for 4 weeks). After two weeks of ceftriaxone, fundus examination and ultrasonography showed complete reattachment of the macula and periphery, and only mild residual chorioretinal folds remained on fluorescein angiogram., Conclusion: We suggest that Borrelia burgdorferi infection led to choroidal inflammation with secondary chorioretinal folds and a serous retinal detachment, which resolved with antibiotic therapy alone. This supports the suspicion of an intraocular infection, perhaps involving the choroid, as opposed to a secondary autoimmune reaction.

Objective: To describe the clinical features and imaging characteristics in unilateral acute idiopathic maculopathy., Methods: Retrospective review of 4 patients with a diagnosis of unilateral acute idiopathic maculopathy. Clinical characteristics (age, symptoms, Snellen visual acuity, and funduscopic features) and images from spectral-domain optical coherence tomography, fundus autofluorescence, fluorescein angiography, and indocyanine green angiography were analyzed., Results: The median (range) age at presentation was 31 (27-52) years. The median (range) interval between symptom onset and presentation was 4 (1-20) weeks. Associated systemic findings included a viral prodrome (50%), orchitis (50%), hand-foot-mouth disease (25%), and positive coxsackievirus titers (50%). The median (range) visual acuity at initial examination was 20/400 (20/70 to 1/400), which improved to 20/30 (20/20 to 20/60) at final follow-up. The median (range) follow-up time was 8 (8-13) weeks. Early in the disease course, the central macula developed irregular, circular areas of white-gray discoloration. Following recovery, the macula had a stippled retinal pigment epithelium characterized by rarefaction and hyperplasia. Fluorescein angiography demonstrated irregular early hyperfluorescence and late subretinal hyperfluorescence. Spectral-domain optical coherence tomography showed a partially reversible disruption of the outer photoreceptor layer. Fundus autofluorescence initially revealed stippled autofluorescence that eventually became more hypoautofluorescent. Indocyanine green angiography showed "moth-eaten"-appearing choroidal vasculature, suggestive of choroidal inflammation., Conclusions: The imaging characteristics highlight the structural changes during the active and resolution phases of unilateral acute idiopathic maculopathy. The visual recovery correlates with structural changes and suggests that the pathogenesis involves inflammation of the inner choroid, retinal pigment epithelium, and outer photoreceptor complex that is partially reversible.

Purpose: To provide a perspective on the impact of the Comparison of Age-related Macular Degeneration Treatments Trial (CATT) on future clinical practices., Design: Interpretation of trial outcomes relative to clinical use of neovascular age-related macular degeneration (AMD) treatments, assessment of the influence of study design and execution on results, and review of unanalyzed safety data in the online supplement., Methods: Expert opinion., Results: The CATT study supports the selection of either ranibizumab or bevacizumab for treatment of AMD based on factors other than efficacy, such as cost, because monthly administration of bevacizumab was noninferior to the reference treatment of monthly ranibizumab in improving visual acuity at 1 year. Visual acuity results for bevacizumab as needed were inconclusive for noninferiority relative to monthly administration of either drug. The secondary outcome of decrease in thickness at the foveal center as measured by time-domain optical coherence tomography significantly favored the monthly ranibizumab group vs the bevacizumab-as-needed group but is more difficult to interpret as it did not correlate with visual acuity and is less appropriate for a noninferiority design. Bevacizumab groups had a statistically higher observed risk of serious adverse events; however, scrutiny of the online supplements shows similar numbers of cardiac and neurologic events in bevacizumab and ranibizumab users. Information regarding fellow eye treatment with anti-VEGF agents was not given., Conclusions: CATT provides the first level I evidence for bevacizumab in a large number of patients with neovascular AMD. The trial supports use of either drug as primary therapy and suggests that modification of monthly dosing regimens is feasible. A difference in cardiovascular safety between the 2 drugs was not apparent on inspection of the supplementary safety data., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Macrophages can be polarized to exhibit either pro-inflammatory M1 or pro-angiogenic M2 phenotypes, but have high phenotypic plasticity. This pilot study investigated macrophage polarization in the macular retina and choroid of age-related macular degeneration (AMD) and non-AMD subjects, as well as in AMD choroidal neovascular membranes (CNVM). All specimens were evaluated for routine histopathology. Quantitative real-time polymerase chain reaction for representative M1 (CXCL11) and M2 (CCL22) transcripts were performed on macular choroidal trephines (MCT) of 19 AMD and nine non-AMD eye bank eyes, on the microdissected macular retinal cells from the archived slides of five geographic atrophic AMD, five exudative/neovascular AMD, and eight normal autopsied eyes, and on microdissected inflammatory cells from two surgically removed CNVM that did not respond to anti-vascular endothelial growth factor (VEGF) therapy. High M2-chemokine transcript and a low ratio of M1 to M2 chemokine transcript were found in aging non-AMD MCT. Advanced AMD maculae had a higher M1 to M2 chemokine transcript ratio compared to normal autopsied eyes. Macrophages in the two CNVM of patients unresponsive to anti-VEGF therapy were polarized toward either M1 or M2 phenotypes. The number of M2 macrophages was increased compared to M1 macrophages in normal aging eyes. A pathological shift of macrophage polarization may play a potential role in AMD pathogenesis., (© 2011 US Government. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.)

Purpose: To compare the pharmacokinetics and tissue response between intravitreal and microcannulation injections into the suprachoroidal space using bevacizumab., Methods: Sixty-two pigs were studied. Either a pars plana intravitreal bevacizumab or a viscoelastic-enhanced microcannula suprachoroidal injection was performed with either 1.25 mg (group 1) or 3 mg (group 2). In group 1, six animals were euthanatized at 0.5, 7, 30, 60, 90, and 120 days after injection (n = 36). In group 2, six animals were euthanatized at 0.5, 7, 14, and 32 days (n = 24). Eyes were enucleated, dissected, and snap-frozen, or they were fixed for histology. Analysis of drug tissue levels was performed at two separate laboratories using masked specimens., Results: Both laboratories were confirmatory. Intravitreal bevacizumab pharmacokinetics demonstrated a gradual decline in tissue levels over 30 to 60 days in both groups 1 and 2. In addition, suprachoroidal bevacizumab tissue levels declined rapidly and were not measurable at or beyond 7 days. Vitreitis and granulomatous vasculitis were noted in 7 of 30 intravitreal injection eyes. Immunohistology suggested a distinctive drug distribution., Conclusions: Direct intravitreal injection of bevacizumab has a more sustained pharmacologic profile than does a similar dose delivered to the suprachoroidal space. Intravitreal injections distributed more to the inner retina, whereas suprachoroidal delivery occurred primarily at the choroid, retinal pigment epithelium, and photoreceptor outer segments. Sustained release formulation of larger biological molecules should be considered to optimize suprachoroidal delivery. Inflammation from injections is granulomatous, seen only with intravitreal injections, and may result from either an altered immune response or a dose-related effect.

Purpose: To describe a novel method for placement of a sulcus-fixated, sutured posterior chamber intraocular lens (sf-SPC-IOL) using endoscopic guidance during pars plana vitrectomy surgery., Design: A retrospective case-series by a single surgeon in both pediatric and adult patients undergoing sf-SPC-IOL in the setting of posterior segment surgery., Methods: Seventy-four eyes of 71 patients had pars plana vitrectomy and placement of an sf-SPC-IOL in an academic, outpatient setting. Preoperative diagnosis included trauma (42%), subluxated lenses with no capsular support (24%), uveitis (15%), congenital cataract (11%), Marfan syndrome or ectopia lentis (6%), and other (2%). Fifty-one adults and 20 children (<18 years of age) were reviewed from cases performed from 1999 through 2007. The sf-SPC-IOL sutures were placed using endoscopic visualization of ab interno scleral fixation., Results: The mean follow-up time was nearly 3 years (3 months to 9 years) and most patients experienced an improvement in visual function. Many eyes had advanced posterior segment disorders. Only 2 broken sutures occurred, both attributable to repeat trauma. Advantages of this technique include: excellent visualization and haptic localization, optimal lens centration, buried knots, broad scleral imbrication, and minimal vitreous- and hemorrhage-related complications. Disadvantages include the learning curve, increased operative time, long-term suture stability issues, and limited availability of intraocular endoscopes., Conclusions: Endoscopic-guided sf-SPC-IOL using this approach, in the setting of posterior segment disease, is a reasonable option for visual rehabilitation in both pediatric and adult patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To describe the clinical courses of patients who received intravitreal injections of highly concentrated amphotericin B deoxycholate for suspected fungal endophthalmitis., Methods: Retrospective medical record review of 3 cases of intraocular toxicity from highly concentrated amphotericin B., Results: The first patient developed posttraumatic endophthalmitis and received an undiluted dose (500 μg) of amphotericin B. He developed severe intraocular inflammation and required a pars plana lensectomy, vitrectomy, and scleral buckle after developing a cataract and retinal detachment. Six years later, his visual acuity stabilized at 20/30. The second patient developed endogenous endophthalmitis and was treated with 5 intravitreal injections of amphotericin B and underwent 3 surgical procedures. The surgeon later discovered that the patient had received 55 μg of amphotericin B during the second injection. Three months after the injection, the patient's visual acuity was 20/60. The third patient developed chronic postoperative endophthalmitis following cataract extraction. He received 160 μg of amphotericin B and was immediately treated with a vitreous washout. Two years later, his visual acuity improved to 20/30. The vitreous culture results were negative in each case. A key finding was that the amphotericin B solution appeared to be yellow instead of nearly colorless., Conclusions: We present 3 cases of intraocular toxicity from highly concentrated amphotericin B. In every case, the overly concentrated amphotericin B solution was yellow in color. Although severe noninfectious panophthalmitis resulted in every case, the visual acuity outcomes were good. Physicians should examine the color of amphotericin B solution prior to intraocular administration. If the solution appears to be yellow, the medication should not be injected.

Purpose: Increasing evidence suggests a central role for mitochondrial (mt) dysfunction in age-related macular degeneration (AMD). Previous proteomic data from the retinal pigment epithelium (RPE) revealed significant changes to mt proteins, suggesting potential functional defects and damage to mitochondrial DNA (mtDNA) with AMD progression. The present study tests the hypothesis that mtDNA damage increases with aging and AMD., Methods: Genomic DNA was isolated from the macular region of human donor RPE graded for stages of AMD (Minnesota Grading System [MGS] 1-4). Region-specific mtDNA damage with normal aging was evaluated in 45 control subjects (ages 34-88 years, MGS 1) and AMD-associated damage in diseased subjects (n = 46), compared with that in age-matched control subjects (n = 26). Lesions per 10 kb per genome in the mtDNA and nuclear DNA were measured with long-extension polymerase chain reaction (LX PCR). The level of deleted mtDNA in each donor was measured with quantitative real-time PCR (qPCR)., Results: With aging, an increase in mtDNA damage was observed only in the common deletion region of the mt genome. In contrast, with AMD, mtDNA lesions increased significantly in all regions of the mt genome beyond levels found in age-matched control subjects. mtDNA accumulated more lesions than did two nuclear genes, with total damage of the mt genome estimated to be eight times higher., Conclusions: Collectively, the data indicate that mtDNA is preferentially damaged with AMD progression. These results suggest a potential link between mt dysfunction due to increased mtDNA lesions and AMD.

The purpose of this study was to quantify how the elastic modulus of the ex vivo iris changes following stimulation by pilocarpine (PILO), phenylephrine (PE), and tropicamide (TROP). Irides (n = 20) were dissected from porcine eyes within 4 h post-mortem and tested uniaxially. Either the entire iris or sector thereof was used. The samples were stretched up to 40% Green strain. The radial modulus was calculated from the linear portion of the stress-strain curve, and the azimuthal modulus was fitted to a model treating the iris as a collection of circular elastic bands. One of the three drugs (n = 6 or 7) of interest was added (80 microg/ml) to the bath surrounding the tissue, and the test was repeated. Changes in pupil diameter of free-floating samples and isometric force of mounted samples confirmed that the tissue was responsive to the drugs. The untreated iris modulus for cut sections in radial extension was 4.0 +/- 0.9 kPa (mean +/- s.d., n = 20), and treated iris modulus was 7.7 +/- 2.0 kPa (PILO, n = 7), 6.9 +/- 2.2 kPa (PE, n = 6), and 8.4 +/- 1.7 kPa (TROP, n = 7). Intact irides (n = 10) gave similar trends but values approximately 25% higher, presumably due to support from the nominally unloaded tissue. The azimuthal modulus of the untreated iris was 2.97 +/- 1.3 kPa (n = 5), and that of the treated iris (PILO) was 5.34 +/- 2.1 kPa. Although PILO, PE, and TROP work by different mechanisms, all three had similar results - an increase of modulus by a factor of two. These results suggest that in most normal situations the iris remains compliant at all pupil diameters.

Aim: To compare current hydroxychloroquine retinopathy screening practices with the published 2002 American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPP)., Methods: A multiple-choice survey was distributed to 105 ophthalmologists to assess current screening practices and knowledge of patient risk factors. Results were compared with the PPP guidelines. A cost analysis of the PPP and survey paradigms was conducted., Results: Sixty-seven (64%) of 105 surveys were completed. The majority (90%) of physicians screen for hydroxychloroquine retinopathy with either central automated threshold perimetry or Amsler grid as recommended by the PPP. Most survey respondents could not correctly identify the evidence-based risk factors. The majority screen more frequently than recommended: 87% screen high-risk patients and 94% screen low-risk patients more frequently than recommended in the PPP. The increased screening frequency of low-risk patients translates into an excess of $44 million in the first 5 years of therapy. If all patients were screened using exact PPP paradigm, savings could exceed $150 million every 10 years., Conclusions: Ophthalmologists currently screen for hydroxychloroquine retinopathy correctly; however, their lack of familiarity with evidence-based guidelines may result in excessive follow-up. Increasing awareness and implementation of the PPP could potentially reduce hydroxychloroquine retinopathy screening costs significantly.

Objective: To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking, and serum cholesterol., Design: Clinic-based and population-based case control study., Participants: A total of 805 AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study, Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank., Methods: DNA samples were genotyped for polymorphisms of rs11200638 in HtrA1 promoter and rs380390 in CFH. HtrA1 protein in ocular tissue was measured. Interactions of the HtrA1 risk allele with the CFH risk variant, smoking status, and cholesterol were assessed., Main Outcome Measures: AMD was evaluated by retinal specialists, and AMD subtypes (geographic atrophy and neovascularization) were determined., Results: Strong associations of the HtrA1 risk allele (A) with AMD were present in all sample sets. A similar magnitude of association was observed for central geographic atrophy and neovascular AMD. The combination of the HtrA1 and CFH risk alleles increased AMD susceptibility, as did the combination of the HtrA1 risk allele with smoking. No combined effect of HtrA1 risk allele and cholesterol level was found. Enhanced expression of HtrA1 protein was detected in retina with AMD., Conclusions: Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA1 was combined with either CFH risk alleles or history of smoking.

Purpose: Age-related macular degeneration (AMD) is the leading cause of vision loss in individuals over the age of 65. Histopathological changes become evident in the retinal pigment epithelium (RPE), a monolayer that provides metabolic support for the overlying photoreceptors, even at the earliest stages of AMD that precede vision loss. In a previous global RPE proteome analysis, changes were identified in the content of several mitochondrial proteins associated with AMD. In this study, the subproteome of mitochondria isolated from human donor RPE graded with the Minnesota Grading System (MGS) was analyzed., Methods: Human donor eye bank eyes were categorized into one of four progressive stages (MGS 1-4) based on the clinical features of AMD. After dissection of the RPE, mitochondrial proteins were isolated and separated by two-dimensional gel electrophoresis based on their charge and mass. Protein spot densities were compared between the four MGS stages. Peptides from spots that changed significantly with MGS stage were extracted and analyzed by using mass spectrometry to identify the protein., Results: Western blot analyses verified that mitochondria were consistently enriched between MGS stages. The densities of eight spots increased or decreased significantly as a function of MGS stage. These spots were identified as the alpha-, beta-, and delta-ATP synthase subunits, subunit VIb of the cytochrome c oxidase complex, mitofilin, mtHsp70, and the mitochondrial translation factor Tu., Conclusions: The results are consistent with the hypothesis that mitochondrial dysfunction is associated with AMD and further suggest specific pathophysiological mechanisms involving altered mitochondrial translation, import of nuclear-encoded proteins, and ATP synthase activity.

Aims/hypothesis: Diabetic retinopathy is the most common complication of diabetes and a leading cause of blindness among working-age adults. Anatomical and functional changes occur in the retina and retinal pigment epithelium (RPE) prior to clinical symptoms of the disease. However, the molecular mechanisms responsible for these early changes, particularly in the RPE, remain unclear. To begin defining the molecular changes associated with pre-retinopathic diabetes, we conducted a comparative proteomics study of human donor RPE., Methods: The RPE was dissected from diabetic human donor eyes with no clinically apparent diabetic retinopathy (n=6) and from eyes of age-matched control donors (n=17). Soluble proteins were separated based upon their mass and charge using two-dimensional (2-D) gel electrophoresis. Protein spots were visualised with a fluorescent dye and spot densities were compared between diabetic and control gels. Proteins from spots with significant disease-related changes in density were identified using mass spectrometry., Results: Analysis of 325 spots on 2-D gels identified 31 spots that were either up- or downregulated relative to those from age-matched control donors. The protein identity of 18 spots was determined by mass spectrometry. A majority of altered proteins belonged to two major functional groups, metabolism and chaperones, while other affected categories included protein degradation, synthesis and transport, oxidoreductases, cytoskeletal structure and retinoid metabolism., Conclusions/interpretation: Changes identified in the RPE proteome of pre-retinopathic diabetic donor eyes compared with age-matched controls suggest specific cellular alterations that may contribute to diabetic retinopathy. Defining the pre-retinopathic changes affecting the RPE could provide important insight into the molecular events that lead to this disease.

Purpose: To establish a grading system of eye bank eyes using fundus autofluorescence (FAF) and identify a methodology that correlates FAF to age-related macular degeneration (AMD) with clinical correlation to the Age-Related Eye Disease Study (AREDS)., Methods: Two hundred sixty-two eye bank eyes were evaluated using a standardized analysis of FAF. Measurements were taken with the confocal scanning laser ophthalmoscope (cSLO). First, high-resolution, digital, stereoscopic, color images were obtained and graded according to AREDS criteria. With the neurosensory retina removed, mean FAF values were obtained from cSLO images using software analysis that excludes areas of atrophy and other artifact, generating an FAF value from a grading template. Age and AMD grade were compared to FAF values. An internal fluorescence reference standard was tested., Results: Standardization of the cSLO machine demonstrated that reliable data could be acquired after a 1-hour warm-up. Images obtained prior to 1 hour had falsely elevated levels of FAF. In this initial analysis, there was no statistical correlation of age to mean FAF. There was a statistically significant decrease in FAF from AREDS grade 1, 2 to 3, 4 (P < .0001). An internal fluorescent standard may serve as a quantitative reference., Conclusions: The Minnesota Grading System (MGS) of FAF (MGS-FAF) establishes a standardized methodology for grading eye bank tissue to quantify FAF compounds in the retinal pigment epithelium and correlate these findings to the AREDS. Future studies could then correlate specific FAF to the aging process, histopathology AMD phenotypes, and other maculopathies, as well as to analyze the biochemistry of autofluorescent fluorophores.

Purpose: To describe a method of drug delivery to the retina via aerosolized nanoparticles in the gas phase during the gas-exchange stage of vitrectomy in a porcine model., Methods: An ultrasonically atomized and dried sodium fluorescein aerosol was produced with a concentration of 12 ng/mL and a mass median particle size of 407 nm. Eighteen porcine eyes were randomly divided into six groups and subjected to standard three-port pars plana vitrectomy. After the air-fluid exchange and during the gas exchange, the eyes were exposed to the aerosol, either as a steady flow through the chamber (3.6 microg/min) or as a single fill (50 ng) at three exposure times (three eyes/time point)., Results: The flow-through delivery mode provided a relatively uniform deposition of aerosol on the inner surface of the retina, and longer delivery time led to an increase in the quantity deposited, with greater than 40 ng total deposition by 10 minutes. The single-fill method had uniform deposition but lower total delivery, approximately 10 ng by 60 minutes. Modeling of the data suggests that deposition in the flow-through mode is successful if the vitreous chamber contents are well mixed. The single-fill delivery was described by diffusion in a quiescent state., Conclusions: This study demonstrates a novel method of drug delivery to the posterior pole by using aerosolized nanoparticles that may be used in the gas phase of vitrectomy. Therapeutic applications include antimetabolites for modulation of proliferative vitreoretinopathy, antimicrobial agents for endophthalmitis, antiangiogenic compounds for vasoproliferative disorders, corticosteroid delivery, and other pharmacotherapies directed at the retina and choroid.

Purpose: Oxidative damage to proteins, lipids, and DNA has been suggested to be a mechanism for age-related macular degeneration (AMD). The retina is particularly susceptible to lipid peroxidation due to high concentrations of easily oxidized polyunsaturated fatty acids in the presence of abundant oxygen. One of the most toxic products of lipid peroxidation, 4-hydroxy-2-nonenal (HNE), can modify and inactivate proteins. The hypothesis was that 4-HNE-modified proteins would accumulate and serve as a marker for progressive stages of AMD., Methods: Proteins containing HNE adducts were identified in both the macular and peripheral regions during four progressive stages of AMD. The proteins were resolved by two-dimensional (2-D) gel electrophoresis before detection of HNE-adducted proteins. Modified proteins were identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/MS). The total content of HNE adducts was compared using a slot blot immunoassay. One-dimensional Western blot analysis was used to measure levels of proteins involved in HNE detoxification., Results: Nineteen proteins that were consistently modified regardless of stage of AMD or retinal region were identified. These proteins are involved in two main functions: energy production and stress response. No change in total HNE-adducted protein was observed between regions or stages. Modest increases in content of proteins involved in HNE detoxification were observed., Conclusions: Consistently modified proteins indicate preferred protein targets for oxidation by HNE. HNE-modified proteins were not different between regions or stages, suggesting that pathways for detoxification of HNE or removal of damaged proteins are adequate. Consistent levels of HNE-modified proteins suggest that HNE is not a sensitive retinal biomarker for AMD.