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Michael Singer,1 Mimi Liu,2 Patricio G Schlottmann,3 Arshad M Khanani,4 Miranda Hemphill,5 Lauren Hill,5 Lisa Tuomi,5 Zdenka Haskova5 1Medical Center Ophthalmology Associates, San Antonio, TX, USA; 2Colorado Retina Associates, Denver, CO, USA; 3Organizacion Medica de Investigacion, Buenos Aires, Argentina; 4Sierra Eye Associates, Reno, NV, USA; 5Genentech, Inc., South San Francisco, CA, USACorrespondence: Michael SingerMedical Center Ophthalmology Associates, 9157 Huebner Road, San Antonio, TX 78240, USATel +1 210 269 3754Fax +1 210 558 7679Email msinger11@me.comPurpose: To investigate the predictors of early diabetic retinopathy (DR) improvement in the RIDE/RISE (NCT00473382/NCT00473330) clinical trials.Patients and Methods: In RIDE/RISE, adult patients with vision loss due to diabetic macular edema (DME) were randomized to monthly intravitreal ranibizumab 0.3 or 0.5 mg (n=502 total) or sham (n=257). DR severity was graded (using the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale). In this post hoc analysis of RIDE/RISE, eyes with baseline DR score ≥ 35 were evaluated for ≥ 2-step improvements, and eyes with baseline DR score ≥ 43 were evaluated for ≥ 3-step improvements. The characteristics associated with ≥ 2- or ≥ 3-step DR improvement at months 3 or 6 were assessed using univariate and/or multivariable analyses.Results: The percentage of eyes with a ≥ 2- or ≥ 3-step DR improvement was 20.1% and 3.7% at month 3 and 31.2% and 5.8% at month 6. Odds of ≥ 2-step DR improvement at months 3 or 6 were significantly greater in eyes with moderately severe to severe nonproliferative DR (NPDR) at baseline versus less severe or more severe DR (both P< 0.0001). At month 6, odds of ≥ 2-step DR improvement were significantly greater in eyes with no DME at month 3 (P=0.008). Most patients with ≥ 3-step DR improvement at months 3 or 6 had proliferative DR (PDR) at baseline (83.3% and 66.7%).Conclusion: The strongest predictors of DR response to ranibizumab at month 6 were baseline DR severity and DME quiescence at month 3. Eyes with the most robust early improvements had moderately severe or severe NPDR or PDR at baseline.Keywords: diabetic retinopathy, ranibizumab, anti-VEGF, diabetic macular edema, post hoc

Axonal loss is thought to be the predominant cause of disability in progressive multiple sclerosis (MS). The retinal nerve fibre layer (RNFL) is composed largely of unmyelinated axons of retinal ganglion cells, and is accessible to study with optical coherence tomography (OCT), giving a measure of axonal loss. OCT measures of the RNFL thickness (RNFLT) and macular volume were studied in 23 patients with primary progressive multiple sclerosis (primary progressive MS) (13 male; 10 female; mean age 52 years; median EDSS 6.0; mean disease duration 11 years), and 27 patients with secondary progressive multiple sclerosis (secondary progressive MS) (8 male; 19 female; mean age 50 years; median EDSS 6; mean disease duration 22 years). Of the patients with secondary progressive MS, 14 had clinical history of optic neuritis (ON) in a single eye; the remaining patients had not had ON. Twenty healthy controls (11 male; 9 female; mean age 46 years) had RNFLT and macular volume studied. Of the patients' eyes not previously affected by ON, both the mean RNFL thickness and macular volume were reduced when compared with control values. The mean RNFL thickness and macular volume were significantly reduced in secondary progressive MS, but not in primary progressive MS when compared with control RNFL thickness and macular volume. RNFL loss was most evident in the temporal quadrant, where significant reduction was seen in primary progressive MS versus controls and in secondary versus primary progressive MS. There were significant correlations of decreased RNFLT and macular volume with measures of visual acuity, low contrast visual acuity and visual field mean deviation in the MS patients. There are significant global reductions in RNFLT and macular volume in the eyes of secondary progressive MS patients not previously affected by ON, but not in primary progressive MS patients, compared with controls. This may indicate a difference in the extent of the pathological processes that cause axonal loss in the retina, and by inference the optic nerve, in secondary progressive MS and primary progressive MS. [ABSTRACT FROM AUTHOR]

An abstract of the article "An Investigation of the Retinal Nerve Fibre Layer in Progressive Multiple Sclerosis," by A. P. D. Henderson, P. G. Schlottmann, and G. T. Plant is presented.

Purpose: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion., Design: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192)., Participants: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO., Methods: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks., Main Outcome Measures: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug., Results: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 μm [95.03% CI, -316.4 to -306.4 μm] and -304.4 μm [95.03% CI, -309.3 to -299.4 μm]) and COMINO (-461.6 μm [95.03% CI, -471.4 to -451.9 μm] and -448.8 μm [95.03% CI, -458.6 to -439.0 μm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively)., Conclusions: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME)., Design: Randomized, double-masked, noninferiority phase 3 trials., Participants: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME., Methods: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change., Main Outcome Measures: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100., Results: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept., Conclusions: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To characterize the largest cohort of individuals with retinol dehydrogenase 12 (RDH12)-retinal dystrophy to date, and the first one from South America., Design: Retrospective multicenter international study., Subjects: Seventy-eight patients (66 families) with an inherited retinal dystrophy and biallelic variants in RDH12., Methods: Review of clinical notes, ophthalmic images, and molecular diagnosis., Main Outcome Measures: Visual function, retinal imaging, and characteristics were evaluated and correlated., Results: Thirty-seven individuals self-identified as Latino (51%) and 34 as White (47%). Sixty-nine individuals (88%) had Leber congenital amaurosis (LCA)/early-onset severe retinal dystrophy. Macular and midperipheral atrophy were seen in all patients from 3 years of age. A novel retinal finding was a hyperautofluorescent ring in 2 young children with LCA. Thirty-nine patients (50%) had subsequent visits, with mean follow-up of 6.8 ± 7.3 (range, 0-29) years. Eight variants (21%) were previously unreported, and the most frequent variant was c.295C>A, p.Leu99Ile, present in 52 alleles of 32 probands. Individuals with LCA homozygous for p.Leu99Ile (31%) had a later age of onset, a slower rate of best-corrected visual acuity decrease, the largest percentage of patients with mild visual impairment, and were predicted to reach legal blindness at an older age than the rest of the cohort., Conclusions: By describing the largest molecularly confirmed cohort to date, improved understanding of disease progression was possible. Our detailed characterization aims to support research and the development of novel therapies that may have the potential to reduce or prevent vision loss in individuals with RDH12-associated retinal dystrophy., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To present the clinical characteristics, retinal features, natural history, and genetics of ADGRV1-Usher syndrome (USH)., Design: Multicenter international retrospective cohort study., Methods: Clinical notes, hearing loss history, multimodal retinal imaging, and molecular diagnosis were reviewed. Thirty patients (28 families) with USH type 2 and disease-causing variants in ADGRV1 were identified. Visual function, retinal imaging, and genetics were evaluated and correlated, with retinal features also compared with those of the commonest cause of USH type 2, USH2A-USH., Results: The mean age at the first visit was 38.6 ± 12.0 years (range: 19-74 years), and the mean follow-up time was 9.0 ± 7.7 years. Hearing loss was reported in the first decade of life by all patients, 3 (10%) described progressive loss, and 93% had moderate-severe impairment. Visual symptom onset was at 17.0 ± 7.7 years of age (range: 6-32 years), with 13 patients noticing problems before the age of 16. At baseline, 90% of patients had no or mild visual impairment. The most frequent retinal features were a hyperautofluorescent ring at the posterior pole (70%), perimacular patches of decreased autofluorescence (59%), and mild-moderate peripheral bone-spicule-like deposits (63%). Twenty-six (53%) variants were previously unreported, 19 families (68%) had double-null genotypes, and 9 were not-double-null. Longitudinal analysis showed significant differences between baseline and follow-up central macular thickness (-1.25 µm/y), outer nuclear layer thickness (-1.19 µm/y), and ellipsoid zone width (-40.9 µm/y). The rate of visual acuity decline was 0.02 LogMAR (1 letter)/y, and the rate of constriction of the hyperautofluorescent ring was 0.23 mm 2 /y., Conclusions: ADGRV1-USH is characterized by early-onset, usually non-progressive, mild-to-severe hearing loss and generally good central vision until late adulthood. Perimacular atrophic patches and relatively retained ellipsoid zone and central macular thickness in later adulthood are more often seen in ADGRV1-USH than in USH2A-USH., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study corresponds to the first large-scale genetic analysis of inherited eye diseases (IED) in Argentina and describes the comprehensive genetic profile of a large cohort of patients. Medical records of 22 ophthalmology and genetics services throughout 13 Argentinian provinces were analyzed retrospectively. Patients with a clinical diagnosis of an ophthalmic genetic disease and a history of genetic testing were included. Medical, ophthalmological and family history was collected. A total of 773 patients from 637 families were included, with 98% having inherited retinal disease. The most common phenotype was retinitis pigmentosa (RP, 62%). Causative variants were detected in 379 (59%) patients. USH2A, RPGR, and ABCA4 were the most common disease-associated genes. USH2A was the most frequent gene associated with RP, RDH12 early-onset severe retinal dystrophy, ABCA4 Stargardt disease, PROM1 cone-rod dystrophy, and BEST1 macular dystrophy. The most frequent variants were RPGR c.1345 C > T, p.(Arg449*) and USH2A c.15089 C > A, p.(Ser5030*). The study revealed 156/448 (35%) previously unreported pathogenic/likely pathogenic variants and 8 possible founder mutations. We present the genetic landscape of IED in Argentina and the largest cohort in South America. This data will serve as a reference for future genetic studies, aid diagnosis, inform counseling, and assist in addressing the largely unmet need for clinical trials to be conducted in the region., (© 2023. The Author(s).)

Background: To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody., Methods: YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593)., Findings: 3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%])., Interpretation: Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema., Funding: F Hoffmann-La Roche., Competing Interests: Declaration of interests CCW reports research support from Adverum, Aerie, Aldeyra, Alimera, Allergan, Amgen, Apellis, AsclepiX, Bayer, Boehringer Ingelheim, Chengdu Kanghong, Clearside, Gemini, Genentech, Graybug Vision, Gyroscope, Ionis, iRenix Medical, Iveric Bio, Kodiak, Lowy Medical Research Institute, Neurotech, NGM Bio, Novartis, Oxurion, RecensMedical, Regeneron, Regenxbio, Roche, SamChunDang Pharm, Samsung Bioepis, Taiwan Liposome Company, and Xbrane BioPharma, outside the submitted work. CCW reports consulting fees from Adverum, Aerie, Aerpio, Allergan, Allgenesis, Apellis, Arrowhead, Bausch and Lomb, Bayer, Bionic Vision Technologies, Chengdu Kanghong, Clearside, EyePoint, Genentech, Gyroscope, Iveric Bio, Janssen, Kato, Kodiak, Long Bridge Medical, NGM Bio, Novartis, OccuRx, Ocular Therapeutix, ONL Therapeutics, Opthea, Oxurion, Palatin, PolyPhotonix, RecensMedical, Regeneron, Regenxbio, Roche, Santen, Surrozen, Takeda, Verana Health, and Vitranu, outside the submitted work. CCW reports other personal fees from Regeneron, stock or stock options from ONL Therapeutics, PolyPhotonix, RecensMedical, and Visgenx, and has served on advisory boards for Kato, outside the submitted work. CCW has served as a board member of the American Society of Retina Specialists and the Vit-Buckle Society, outside the submitted work. FA is an employee of Genentech. APA was an employee of Genentech during the course of this study and reports stock or stock options from Roche. KB was an employee of Genentech during the course of this study and is a current employee of Roche Products (Ireland). DAE reports research support from Alkahest, AsclepiX, Bayer, Chengdu Kanghong, EyePoint, Gemini, Genentech, Gyroscope, Ionis, Iveric Bio, Kodiak, Mylan, NGM Bio, Novartis, Ocular Therapeutix, Opthea, RecensMedical, Regeneron, and Regenxbio, outside the submitted work. DAE reports consulting fees from Alimera, Allergan, Apellis, Bausch and Lomb, Dutch Ophthalmic, EyePoint, Genentech, Gyroscope, Iveric Bio, KKR, Kodiak, Notal Vision, Novartis, RecensMedical, Regeneron, and Regenxbio, outside the submitted work. DAE reports other personal fees from Allergan, Apellis, Bayer, Dutch Ophthalmic, EyePoint, Genentech, and Novartis; stock or stock options from Boston Image Reading Center, Clearside, Hemera, and Network Eye; and has served on advisory boards for Genentech, Iveric Bio, and RecensMedical, outside the submitted work. DAE has served as a board member of the Florida Society of Ophthalmology, outside the submitted work. ZH is an employee of Genentech, and reports stock or stock options from Genentech. HL is an employee of Genentech, reports personal fees and stock or stock options from Roche/Genentech, and is a coauthor on patent application WO202123804 involving the PTI algorithm. AL reports research support from Notal Vision and Novartis, and consulting fees from Allergan, Bayer, Beyeonics Surgical, and Syneos Health, outside the submitted work. SM is an employee of Genentech, and reports stock or stock options from Genentech. IAP reports consulting and other personal fees from Allergan, Bayer, Novartis, and Roche, and has served on advisory boards for Bayer, Novartis, and Roche, outside the submitted work. TS reports research support from Bayer, Chugai, Novartis, Santen, and Senju; consulting and other personal fees from Bayer, Novartis, and Senju; and has served on advisory boards for Bayer, Novartis, and Roche, outside the submitted work. PGS reports personal fees and has served on advisory boards for Roche, outside the submitted work. DS is an employee of Roche Products, reports personal fees and stock or stock options from Roche, and is a coauthor on patent application WO202123804 involving the PTI algorithm. JKS reports research support from Boehringer Ingelheim, Jaeb Center for Health Research, Juvenile Diabetes Research Foundation, KalVista, Novartis, Optovue, and Physical Sciences; personal fees from Merck, Novartis, and Novo Nordisk; and equipment loans from Adaptive Sensory Technology, Boston Micromachines, and Optovue, outside the submitted work. JAW reports research support from Adverum, Alimera, Bayer, Clover Therapeutics, Genentech, Iveric Bio, Kodiak, Lowy Medical Research Institute, NIH National Eye Institute, Neurotech, Opthea, and Regeneron, and consulting fees from Genentech, outside the submitted work. JRW is an employee of Genentech, reports stock or stock options from Genentech, and is a coauthor on patent application WO202123804 involving the PTI algorithm. RT reports consulting and personal fees and has served on advisory boards for AbbVie, Alcon, Allergan, Apellis, Bayer, Chengdu Kanghong, Genentech, Iveric Bio, Novartis, Oculis, Roche, and Thea, and reports equipment from Zeiss, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To provide a concise overview for ophthalmologists and practicing retina specialists of available clinical evidence of manipulating the angiopoietin/tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains (Tie) pathway and its potential as a therapeutic target in retinal vascular diseases., Methods: A literature search for articles on the angiopoietin/Tie pathway and molecules targeting this pathway that have reached Phase 2 or 3 trials was undertaken on PubMed, Association for Research in Vision and Ophthalmology meeting abstracts (2014-2019), and ClinicalTrials.gov databases. Additional information on identified pipeline drugs was obtained from publicly available information on company websites., Results: The PubMed and Association for Research in Vision and Ophthalmology meeting abstract search yielded 462 results, of which 251 publications not relevant to the scope of the review were excluded. Of the 141 trials related to the angiopoietin/Tie pathway on ClinicalTrials.gov, seven trials focusing on diseases covered in this review were selected. Vision/anatomic outcomes from key clinical trials on molecules targeting the angiopoietin/Tie pathway in patients with retinal vascular diseases are discussed., Conclusion: Initial clinical evidence suggests a potential benefit of targeting the angiopoietin/Tie pathway and vascular endothelial growth factor-A over anti-vascular endothelial growth factor-A monotherapy alone, in part due to of the synergistic nature of the pathways., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Opthalmic Communications Society, Inc.)

South America comprises of heterogeneous topographies, populations, and health care systems. Therefore, it is not surprising to see differences among the countries regarding expertise, education, and practices of ophthalmic genetics for patients with rare eye diseases. Nevertheless, common challenges such as limited genetics training in medical schools and among ophthalmologists, scarcity of diagnostic tools for phenotyping, and expensive genetic testing not covered by the public healthcare systems, are seen in all of them. Here, we provide a detailed report of the current status of ophthalmic genetics, described by the personal views of local ophthalmologists from Brazil, Colombia, Argentina, and Chile. By reporting our strengths and weaknesses as a region, we intend to highlight the need for guidelines on how to manage these patients aligned with public health policies. Our region contributes to research worldwide, with thousands of well diagnosed patients from a number of unique and genetically diverse populations. The constant expansion of ophthalmic genetics and molecular diagnostics requires us to join forces to collaborate across South America and with other countries to improve access to next-generation diagnostics and ultimately improve patient care., (© 2020 Wiley Periodicals LLC.)

Aim: To determine the efficacy of switching to ranibizumab in patients with diabetic macular oedema refractory to treatment with bevacizumab, and to evaluate the outcomes when switching back to bevacizumab., Methods: A prospective study was conducted that included 43 eyes of 31 patients refractory to previous bevacizumab treatment. The patients were switched to ranibizumab, and optical coherence tomography was performed one month post-injection. Patients showing improvement (>10% reduction in central sub-field thickness) were switched back to bevacizumab, and optical coherence tomography was performed one month post-switch back., Results: The 34 eyes switched to ranibizumab showed a statistically significant improvement in mean best corrected visual acuity from 0.67±0.39 logMAR to a mean of 0.55±0.36 logMAR (P<.05). In addition, there was a statistically significant decrease in central subfield thickness (CST) from a mean of 475.3±122.8 to a mean of 417.3±109.1 (P<.05). In the 21 eyes that were switched back to bevacizumab, there was no significant difference either in the change in CST or in the change in best corrected visual acuity post-switch back., Conclusion: Switching to ranibizumab in patients improves both the best corrected visual acuity and CST in diabetic patients refractory to previous bevacizumab treatment. This effect is pronounced in patients with increased CST prior to the switch. Switching back to bevacizumab adds no further improvement., (Copyright © 2018 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: This review aimed to determine the optimal management of retinal pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration (nAMD) based on review of available evidence in the literature., Methods: A comprehensive literature review evaluates previous retrospective and prospective studies that assessed the treatment of PEDs in nAMD., Results: Studies illustrated that anti-vascular endothelial growth factor (VEGF) therapy can be effective in eyes with PED secondary to nAMD. Similar visual outcomes are associated with different anti-VEGF treatments. Higher anti-VEGF doses may improve anatomical response, without correlation with vision improvement. Fibrovascular PEDs may be difficult to treat, but even these eyes can gain vision with anti-VEGF therapy. A retinal pigment epithelial tear may develop in 15% to 20% of eyes with PEDs after anti-VEGF therapy, especially in PEDs greater than 500 µm to 600 µm in height; however, vision may stabilize with continued therapy. Atrophy may complicate eyes with PED and nAMD after anti-VEGF therapy, especially in association with complete PED resolution., Conclusion: Available literature suggests that anti-VEGF therapy is safe and efficacious for PED and nAMD. Treatment should focus on vision gains rather than PED resolution because there is no apparent correlation between anatomical and functional improvement in most eyes with PED and nAMD.

Age-related macular degeneration (AMD) is considered one of the main causes of severe vision loss in older adults. The neovascular form (nAMD) is an advanced stage, which is responsible for the most severe vision loss. Vascular endothelial growth factor (VEGF) is at present the main factor that leads to the development of a neovascular membrane and the increased leakage from the membrane to the retina. At present, anti-VEGF therapy is the only treatment that achieves vision gains in many patients and halts progression in most of them. VEGF blockade can be achieved with several molecules and various treatment regimens, which have been studied with excellent results. Unfortunately, real-world data has shown to be far less efficacious than clinical trials. This gap between clinical trials and real-world results is an unmet medical need that supports the necessity of new treatment modalities for nAMD. Of the various treatments being studied, anti-VEGFs of higher efficacy and longer durability are those more advanced in their development. Brolucizumab and abicipar pegol are 2 new anti-VEGF drugs that had positive results in phase 2 studies and are being tested in phase 3 trials at present. Other promising therapies are antiangiopoietin 2 molecules, which are in phase 2 development. At earlier stages of development but with promising results are squalamine, anti-VEGF-C and -D, and gene therapy. The future will give retina specialists a broad armamentarium with which patients may achieve high visual gains for the long term with a low treatment burden., (Copyright 2017 Asia-Pacific Academy of Ophthalmology.)

Background: Raised intraocular pressure is a risk factor for glaucoma. One treatment option is glaucoma drainage surgery (trabeculectomy). Antimetabolites are used during surgery to reduce postoperative scarring during wound healing. Two agents in common use are mitomycin C (MMC) and 5-Fluorouracil (5-FU)., Objectives: To assess the effects of MMC compared to 5-FU as an antimetabolite adjunct in trabeculectomy surgery., Search Methods: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2015 Issue 9), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to October 2015), EMBASE (January 1980 to October 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to October 2015), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 October 2015., Selection Criteria: We included randomised controlled trials where wound healing had been modified with MMC compared to 5-FU., Data Collection and Analysis: Two review authors independently selected trials and collected data. The primary outcome was failure of a functioning trabeculectomy one year after surgery. Secondary outcomes included mean intraocular pressure at one year. We considered three subgroups: high risk of trabeculectomy failure (people with previous glaucoma surgery, extracapsular cataract surgery, African origin and people with secondary glaucoma or congenital glaucoma); medium risk of trabeculectomy failure (people undergoing trabeculectomy with extracapsular cataract surgery) and low risk of trabeculectomy failure (people who have received no previous surgical eye intervention)., Main Results: We identified 11 trials that enrolled 687 eyes of 679 participants. The studies were conducted in the United States, Europe, Asia and Africa. Five studies enrolled participants at low risk of trabeculectomy failure, five studies enrolled participants at high risk of failure, and one study enrolled people with both high and low risk of failure. None of the included trials enrolled participants with combined trabeculectomy/cataract surgery.We considered one study to be at low risk of bias in all domains, six studies to be at high risk of bias in one or more domains, and the remaining four studies to be at an unclear risk of bias in all domains.The risk of failure of trabeculectomy at one year after surgery was less in those participants who received MMC compared to those who received 5-FU, however the confidence intervals were wide and are compatible with no effect (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.30 to 1.00; studies = 11; I(2) = 40%). There was no evidence for any difference between groups at high and low risk of failure (test for subgroup differences P = 0.69).On average, people treated with MMC had lower intraocular pressure at one year (mean difference (MD) -3.05 mmHg, 95% CI -4.60 to -1.50), but the studies were inconsistent (I(2) = 52%). The size of the effect was greater in the high-risk group (MD -4.18 mmHg, 95% CI -6.73 to -1.64) compared to the low-risk group (MD -1.72 mmHg, 95% CI -3.28 to -0.16), but again the test for interaction was not statistically significant (P = 0.11).Similar proportions of eyes treated with MMC lost 2 or more lines of visual acuity one year after surgery compared to 5-FU, but the confidence intervals were wide (RR 1.05, 95% CI 0.54 to 2.06).Adverse events occurred relatively rarely, and estimates of effect were generally imprecise. There was some evidence for less epitheliopathy in the MMC group (RR 0.23, 95% CI 0.11 to 0.47) and less hyphaema in the MMC group (RR 0.62, 95% CI 0.42 to 0.91).None of the studies reported quality of life.Overall, we graded the quality of the evidence as low largely because of risk of bias in the included studies and imprecision in the estimate of effect., Authors' Conclusions: We found low-quality evidence that MMC may be more effective in achieving long-term lower intraocular pressure than 5-FU. Further comparative research on MMC and 5-FU is needed to enhance reliability and validity of the results shown in this review. Furthermore, the development of new agents that control postoperative scar tissue formation without side effects would be valuable and is justified by the results of this review.

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: OR(A allele) = 9.87, P = 2.13 × 10(-217); non-Japanese: OR(A allele) = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Purpose: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of ranibizumab in diabetic macular edema (DME)., Design: Phase III, randomized, multicenter, double-masked, 3-year trials, sham injection-controlled for 2 years., Participants: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320 Snellen equivalent, and central foveal thickness (CFT) ≥ 275 μm on optical coherence tomography., Methods: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as necessary., Main Outcome Measures: The proportion of patients gaining ≥15 Early Treatment Diabetic Retinopathy Study letters in BCVA from baseline at month 24., Results: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month 36; the proportions of patients who gained ≥15 letters from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained through month 36. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters). Per-injection rates of endophthalmitis remained low over time (∼0.06% per injection). The incidence of serious adverse events potentially related to systemic vascular endothelial growth factor inhibition was 19.7% in patients who received 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group., Conclusions: The strong VA gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to result in the same extent of VA improvement observed in patients originally randomized to ranibizumab. Ocular and systemic safety was generally consistent with the results seen at month 24., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: Acute optic neuritis due to an inflammatory demyelinating lesion of the optic nerve is often seen in association with multiple sclerosis. Although functional recovery usually follows the acute episode of visual loss, persistent visual deficits are common and are probably due to axonal loss. The mechanisms of axonal loss and early features that predict it are not well defined. We investigated clinical, electrophysiological, and imaging measures at presentation and after 3 months as potential markers of axonal loss following optic neuritis., Methods: We followed 21 patients after their first attack of acute unilateral optic neuritis for up to 18 months. Axonal loss was inferred from optical coherence tomography measures of retinal nerve fiber layer (RNFL) thickness at least 6 months following the episode. Visual function, visual evoked potential, and optic nerve magnetic resonance imaging measures obtained during the acute episode and 3 months later were investigated for their association with later axonal loss., Results: After multivariate analysis, prolonged visual evoked potential latency and impaired color vision, at baseline and after 3 months, were significantly and independently associated with RNFL thinning. Low-contrast acuity measures exhibited significant univariate associations with RNFL thinning., Interpretation: The association of RNFL loss with a prolonged visual evoked potential (VEP) latency suggests that acute and persistent demyelination is associated with increased vulnerability of axons. VEP latency and visual function tests that capture optic nerve function, such as color and contrast, may help identify subjects with a higher risk for axonal loss who are thus more suitable for experimental neuroprotection trials., (Copyright © 2011 American Neurological Association.)

Optical coherence tomography (OCT) is widely used in the assessment of retinal nerve fibre layer thickness (RNFLT) in glaucoma. Images are typically acquired with a circular scan around the optic nerve head. Accurate registration of OCT scans is essential for measurement reproducibility and longitudinal examination. This study developed and evaluated a special image registration algorithm to align the location of the OCT scan circles to the vessel features in the retina using probabilistic modelling that was optimised by an expectation-maximization algorithm. Evaluation of the method on 18 patients undergoing large number of scans indicated improved data acquisition and better reproducibility of measured RNFLT when scanning circles were closely matched. The proposed method enables clinicians to consider the RNFLT measurement and its scan circle location on the retina in tandem, reducing RNFLT measurement variability and assisting detection of real change of RNFLT in the longitudinal assessment of glaucoma.

Aims: To evaluate and compare the accuracy of scanning laser polarimetry with variable corneal compensation (GDx-VCC) and optical coherence tomography (OCT) for detecting glaucomatous damage observed in retinal nerve fibre layer (RNFL) monochromatic photographs from ocular hypertensive (OHT) individuals with normal visual fields., Methods: A total of 181 eyes from 181 patients with intraocular pressure >22 mm Hg were enrolled in a cross-sectional, hospital clinic-based study. All patients underwent full ophthalmological examination, standard automated perimetry, red-free digital RNFL photographs, and RNFL imaging with Stratus OCT and GDx-VCC. Subjects were divided into two groups according to observations from RNFL photographs: 128 OHT subjects without and 53 OHT subjects with RNFL defects. Receiver operating characteristic (ROC) curves plotted for the RNFL parameters were compared between OCT and GDx-VCC., Results: The OCT parameter with the highest diagnostic accuracy for detecting early RNFL defects was average thickness, and for the GDx-VCC was temporal-superior-nasal-inferior-temporal average, with areas under the ROC curve of 0.785 and 0.758, respectively (all AUCs p<0.001)., Conclusion: OCT and GDx have similar diagnostic accuracy for identifying early defects detected by RNFL monochromatic photography in OHT patients.

Spectral-domain optical coherence tomography (SD-OCT) provides volumetric images of retinal structures with unprecedented detail. Accurate segmentation algorithms and feature quantification in these images, however, are needed to realize the full potential of SD-OCT. The fully automated segmentation algorithm, FloatingCanvas, serves this purpose and performs a volumetric segmentation of retinal tissue layers in three-dimensional image volume acquired around the optic nerve head without requiring any pre-processing. The reconstructed layers are analyzed to extract features such as blood vessels and retinal nerve fibre layer thickness. Findings from images obtained with the RTVue-100 SD-OCT (Optovue, Fremont, CA, USA) indicate that FloatingCanvas is computationally efficient and is robust to the noise and low contrast in the images. The FloatingCanvas segmentation demonstrated good agreement with the human manual grading. The retinal nerve fibre layer thickness maps obtained with this method are clinically realistic and highly reproducible compared with time-domain StratusOCT(TM).

Purpose: To develop and validate a method of predicting visual function from retinal nerve fiber layer (RNFL) structure in glaucoma., Methods: RNFL thickness (RNFLT) measurements from scanning laser polarimetry (SLP) and visual field (VF) sensitivity from standard automated perimetry were made available for 535 eyes from three centers. In a training dataset, structure-function relationships were characterized by using linear regression and a type of neural network: radial basis function customized under a Bayesian framework (BRBF). These two models were used in a test dataset to (1) predict sensitivity at individual VF locations from RNFLT measurements and (2) predict the spatial relationship between VF locations and positions at a peripapillary RNFLT measurement annulus. Predicted spatial relationships were compared with a published anatomic structure-function map., Results: Compared with linear regression, BRBF yielded a nearly twofold improvement (P < 0.001; paired t-test) in performance of predicting VF sensitivity in the test dataset (mean absolute prediction error of 2.9 dB [SD 3.7] versus 4.9 dB [SD 4.0]). The predicted spatial structure-function relationship showed better agreement (P < 0.001; paired t-test) with anatomic prior knowledge when the BRBF was compared with the linear regression (median absolute angular difference of 15° vs. 62°)., Conclusions: The BRBF generates clinically useful relationships that relate topographical maps of RNFL measurement to VF locations and allows the VF sensitivity to be predicted from structural measurements. This method may allow clinicians to evaluate structural and functional measures in the same domain. It could also be generalized to use other structural measures.

Background: Several studies with optical coherence tomography (OCT) have demonstrated thinning of the retinal nerve fiber layer (RNFL) in patients with optic neuritis and multiple sclerosis. Similar studies have not been performed with scanning laser polarimetry (SLP), which relies on different physical phenomena. This study was designed to use SLP to measure axonal loss following a single episode of optic neuritis and to determine if there is a relationship between the degree of axonal loss and the degree of residual visual dysfunction., Methods: Twenty-five patients with a single episode of optic neuritis and 15 control subjects were studied with SLP using the GDxVCC device to determine RNFL thickness in relation to visual acuity, visual fields, color vision, visual evoked potentials (VEPs), and previously published OCT data., Results: SLP detected significant RNFL thinning in affected eyes compared to clinically unaffected fellow eyes in patients and in control eyes (P < 0.001). Reduced RNFL thickness was associated with significantly worse logMAR visual acuity, visual field mean deviation, and color vision. RNFL thinning correlated with reduced whole visual field and central visual field measures and VEP amplitudes. Superior and inferior quadrant RNFL thinning was related to corresponding regional visual field loss. There was a scaling factor between SLP and OCT RNFL measurements but only modest agreement., Conclusions: SLP detected functionally relevant axonal loss in eyes affected by optic neuritis. There was a scaling factor between RNFL measurements obtained with SLP and OCT but only modest agreement. Care should therefore be taken when comparing RNFL data from studies using these different devices.

Following an episode of optic neuritis, thinning of the retinal nerve fibre layer, which indicates axonal loss, is observed using optical coherence tomography. The longitudinal course of the retinal changes has not been well characterized. We performed a serial optical coherence tomography study in patients presenting with optic neuritis in order to define the temporal evolution of retinal nerve fibre layer changes and to estimate sample sizes for proof-of-concept trials of neuroprotection using retinal nerve fibre layer loss as the outcome measure. Twenty-three patients (7 male, 16 female, mean age 31 years) with acute clinically isolated unilateral optic neuritis were recruited to undergo optical coherence tomography, visual assessments and visual evoked potentials at presentation (median 16 days from onset of visual loss) and after 3, 6, 12 and 18 months. Compared with the clinically unaffected fellow eye, the retinal nerve fibre layer thickness of the affected eye was significantly increased at presentation and significantly reduced at all later time points. The evolution of retinal nerve fibre layer changes in the affected eye fitted well with an exponential model, with thinning appearing a mean of 1.6 months from symptom onset and the rate of ongoing retinal nerve fibre layer loss decreasing thereafter. At presentation, increased retinal nerve fibre layer thickness was associated with impaired visual acuity and prolonged visual evoked potential latency. Visual function after 12 months was not related to the extent of acute retinal nerve fibre layer swelling but was significantly associated with the extent of concurrent retinal nerve fibre layer loss. Sample size calculations for placebo-controlled trials of acute neuroprotection indicated that the numbers needed after 6 months of follow up are smaller than those after 3 months and similar to those after 12 months of follow-up. Study power was greater when investigating differences between clinically unaffected and affected eyes rather than retinal nerve fibre layer thickness of the affected eye alone. Inflammation in the optic nerve and impaired axonal transport (implied by retinal nerve fibre layer swelling) are associated with visual dysfunction and demyelination (long visual evoked potential latency) during acute optic neuritis. Retinal nerve fibre layer thinning is usually evident within 3 months. Optical coherence tomography-measured retinal nerve fibre layer loss after 6 months is a suitable outcome measure for proof-of-concept trials of acute neuroprotection in optic neuritis.

Thinning of the retinal nerve fiber layer (RNFL) of clinically unaffected eyes is seen in patients with multiple sclerosis (MS). It is uncertain when this thinning occurs, and whether ongoing RNFL loss can be measured over time with optical coherence tomography (OCT). Using time-domain OCT, we studied 34 patients with progressive MS (16 primary progressive MS, 18 secondary progressive; 14 male; 20 female; mean age at study entry 51 years; median EDSS 6; mean disease duration at study entry 12 years) on two occasions with a median interval of 575 (range 411-895) days apart. Eighteen healthy controls (10 male; eight female; mean age at study entry 46 years) were also studied twice, with a median interval of 656 days (range 398-890). Compared to controls, the patients had significant decreases in the RNFL thickness and macular volume of their clinically unaffected eyes at study entry. No significant decrease in RNFL thickness was observed between baseline and follow-up in either patients or controls. Macular volume declined significantly in patients and controls, but there was no difference in this change between the two groups. The study findings suggest that time domain OCT detects little disease-related ongoing loss of retinal axons in progressive forms of MS and has limited use for monitoring potential neuroprotective therapies at this stage of disease. Further studies are needed using higher-resolution OCT systems and in larger groups of patients, to elucidate the timing and mechanism of RNFL loss that is observed in clinically unaffected nerves in MS.

Purpose: The purpose of this study was to correlate the ultrastructural morphology of epiretinal tissue with optical coherence tomography and to investigate the effects of trypan blue staining on epiretinal membrane (ERM) ultrastructure and clinical outcome., Methods: A prospective, case-comparative study. Consecutive patients were recruited and underwent vitrectomy and ERM peeling with 0.15% trypan blue; these patients were compared with a control group peeled without stain. Optical coherence tomography was performed preoperatively and at 10 days and 3 months postoperatively. Data were collected prospectively to include Snellen visual acuity and surgical ERM characteristics. Epiretinal tissue was examined using transmission electron microscopy., Results: Thirty-seven patients underwent ERM surgery, and 34 had complete data, of which 18 had peeling of unstained and 16 had peeling of stained ERM. Staining resulted in a significantly greater postoperative reduction in macular thickness compared with the unstained group. There was no significant difference in the visual outcome and no ultrastructural evidence of alteration of the cleavage plane in cases in which trypan blue was used., Conclusion: There was no clinical or ultrastructural evidence of toxicity in peeling with trypan blue.

Purpose: The purpose of this study was to correlate the ultrastructural morphology of epiretinal and retinal tissue with optical coherence tomography assessment and to investigate the effects of trypan blue staining on internal limiting membrane (ILM) tissue., Methods: This was a prospective case-comparative study. Consecutive patients were recruited and underwent ILM peel with 0.5 mL of 0.15% trypan blue, and these were compared with a nonrandomized control group (unstained ILM). Patients underwent optical coherence tomography scanning preoperatively and postoperatively at 1.5 and 3 months. Data were collected prospectively to include Snellen visual acuity, macular hole, and operative characteristics. Internal limiting membrane was examined by transmission electron microscopy., Results: Sixty-four patients underwent macular hole surgery, and complete data were available on 49 patients (17 control subjects and 32 patients who had peeling of stained ILM). Trypan blue staining significantly improved ease and completeness of ILM removal. There was no significant difference in vision, optical coherence tomography characteristics, or macular hole closure rate at 3 months between stained and unstained groups. There was no ultrastructural evidence of alteration of the plane of ILM separation in cases in which trypan blue was used., Conclusion: Trypan blue stain from these data seems to improve the ease and completeness of the ILM peeling (assessed clinically) and does not show any signs of toxicity.

Objective: To examine the repeatability and reproducibility of intraocular pressure (IOP) measurements obtained with the Goldmann applanation tonometer (GAT), the Pascal dynamic contour tonometer (DCT; Swiss Microtechnology AG, Port, Switzerland), and the Reichert Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Buffalo, NY). A secondary objective was to assess agreement between the devices., Design: Evaluation of technology., Participants: One hundred participants; a mixture of glaucoma suspects, patients, and control volunteers., Methods: The IOP measurements were obtained with the GAT, DCT, and ORA by 2 of 3 experienced clinicians. Keratometry (CC) measurements were made using the IOLMaster (Carl Zeiss Meditech, AG, Jena, Germany). Three ORA corneal compensated IOP (IOPcc) measurements were obtained before the instillation of anesthesia, after which 2 GAT IOP and 3 DCT IOP measurements were obtained in a randomized order. Central corneal thickness (CCT) was measured using an ultrasound pachymeter. The average ORA corneal response factor (CRF) and the average DCT ocular pulse amplitude (OPA) were determined. Intraobserver variability was calculated by the repeatability coefficient. Interobserver variability (measurement reproducibility) and device agreement were calculated by Bland-Altman analysis (mean difference [bias] and 95% limits of agreement [LoA]). The effect of corneal characteristics (CC, CCT, and CRF) on the IOP measurement differences between tonometers also was determined., Main Outcome Measures: Repeatability and reproducibility of the GAT, DCT, and ORA IOPcc and agreement between tonometers., Results: The repeatability coefficients for GAT, DCT, and ORA were 2.2, 2.3, and 4.3 mmHg, respectively. The intraobserver variability of ORA measurements was shown to be significantly associated with OPA and to a lesser degree with the quality of ORA waveform scans. The interobserver bias (95% LoA) was -0.8 (+/-3.9) mmHg for GAT -0.2 (+/-2.8) mmHg for DCT and -0.3 (+/-3.9) mmHg for ORA IOPcc. On average, GAT under-read both DCT and ORA IOP measurements by approximately 2 mmHg. The IOP measurement differences were better predicted by CRF than CCT., Conclusions: The DCT shows excellent measurement precision, displaying the best repeatability and reproducibility of the 3 tonometers. Corneal stiffness, as defined using CRF, was associated significantly with agreement between devices. The IOP measurements with each device are not interchangeable., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the phenotypic and biochemical characteristics of the p.E139K missense variant in tissue inhibitor of metalloproteinase 3 (TIMP3) associated with Sorsby fundus dystrophy (SFD)., Methods: The coding regions and adjacent intronic sequence of TIMP3 were amplified by polymerase chain reaction and then analyzed by bidirectional sequencing. Allele-specific PCR was used to determine the minimum allele frequency of the mutant allele in ethnically matched controls. Clinical examination and imaging of affected individuals with color fundus photography, scanning laser ophthalmoscope (fundal autofluorescence), and optical coherence tomography was performed. A mutant construct of the TIMP3 protein was created and expressed in human retinal pigment epithelium (ARPE19) cells, which were then assayed for oligomerization and intrinsic matrix metalloproteinase (MMP) inhibitory activity., Results: Three affected individuals from a family of Welsh origin each harbored one allele of the TIMP3 missense variant c.415 G>A, (p.E139K), which was not identified in 534 ethnically matched control chromosomes and thus presumed pathogenic. The mutant protein was shown to dimerize in culture cells and retain its MMP inhibitory activity. Retinal examination was variable between eyes of affected individuals and between family members. Drusen-like deposits were common to all three affected individuals and yellow subretinal deposits, exudative maculopathy, and geographic atrophy were also observed. Optical coherence tomography (OCT) images of affected individuals demonstrated hyperreflectivity of the RPE-photoreceptor-choroid complex., Conclusions: The TIMP3 p.E139K mutation is another cause of SFD. It is the second TIMP3 sequence variant reported that does not affect the number of cysteine residues in the mutant protein yet dimerizes in vitro. The clinical presentation of this family is in keeping with previous clinical reports of this disorder.

Aims: To assess the impact of valdecoxib on the incidence of macular edema, after scleral buckling surgery., Methods: Prospective randomized double masked placebo controlled study. Patients undergoing scleral buckle surgery over 18 months were recruited and randomized to receive either oral valdecoxib or placebo. Patients also received two doses of either parecoxib (pro-drug of valdecoxib) intravenously 40 mg 6 hourly day one postoperative or identical placebo injection Patients underwent retinal examination, optical coherence tomography and retinal thickness analyzer scan of the macula preoperatively, and at 2 and 6 weeks postoperatively. Outcome measures were the incidence of macular edema, retinal thickness, visual acuity, contrast sensitivity and presence of persistent subretinal fluid., Results: Interim analysis was performed with 116 patients were recruited, 58 to each treatment arm. The incidence of macular edema in all patients was 5% at visit 1 and 2.2% at visit 2 postoperatively. This incidence was much lower than the expected incidence used in the power calculation to determine study size. It was therefore apparent that a much larger study population would be required to test for an effect and that this was not achievable within the study time period. The study was therefore terminated early. There was no evidence of a difference between COX 2 inhibitor and placebo groups in the incidence of edema, retinal thickness or visual outcome. The presence of residual subretinal fluid at the macula was significantly reduced by COX 2 inhibitor treatment., Conclusions: The rate of cystoid macular edema after scleral buckling surgery is low and is not influenced by prophylactic use of valdecoxib. The rate of residual subretinal fluid was reduced by COX 2 inhibitor treatment. Enhanced antiinflammatory therapy has the potential to improve outcomes in scleral buckling surgery.

Axonal loss is thought to be the predominant cause of disability in progressive multiple sclerosis (MS). The retinal nerve fibre layer (RNFL) is composed largely of unmyelinated axons of retinal ganglion cells, and is accessible to study with optical coherence tomography (OCT), giving a measure of axonal loss. OCT measures of the RNFL thickness (RNFLT) and macular volume were studied in 23 patients with primary progressive multiple sclerosis (primary progressive MS) (13 male; 10 female; mean age 52 years; median EDSS 6.0; mean disease duration 11 years), and 27 patients with secondary progressive multiple sclerosis (secondary progressive MS) (8 male; 19 female; mean age 50 years; median EDSS 6; mean disease duration 22 years). Of the patients with secondary progressive MS, 14 had clinical history of optic neuritis (ON) in a single eye; the remaining patients had not had ON. Twenty healthy controls (11 male; 9 female; mean age 46 years) had RNFLT and macular volume studied. Of the patients' eyes not previously affected by ON, both the mean RNFL thickness and macular volume were reduced when compared with control values. The mean RNFL thickness and macular volume were significantly reduced in secondary progressive MS, but not in primary progressive MS when compared with control RNFL thickness and macular volume. RNFL loss was most evident in the temporal quadrant, where significant reduction was seen in primary progressive MS versus controls and in secondary versus primary progressive MS. There were significant correlations of decreased RNFLT and macular volume with measures of visual acuity, low contrast visual acuity and visual field mean deviation in the MS patients. There are significant global reductions in RNFLT and macular volume in the eyes of secondary progressive MS patients not previously affected by ON, but not in primary progressive MS patients, compared with controls. This may indicate a difference in the extent of the pathological processes that cause axonal loss in the retina, and by inference the optic nerve, in secondary progressive MS and primary progressive MS.

Aim: To report on the agreement of macular hole size as measured using optical coherence tomography (OCT), Topcon digital photography, and surgeon estimate on clinical examination., Methods: Observational cohort series of patients who underwent macular hole surgery over an 18-month period. Patients had OCT scan and digital fundus photographs preoperatively. At operation the surgeon estimated the size of macular hole. The agreement between methods was assessed using the technique described by Bland and Altman., Results: There was good repeatability of photographic and OCT assessment and no evidence of systematic bias between repeated macular hole measurement by digital photography (P=0.36) or by OCT (P=0.58). There was evidence of systematic bias between photographic and surgeon measurements (P<0.001), and between OCT and surgeon (P<0.001) with photographic and OCT assessment being greater. There was also evidence of bias between OCT and photographic measurements with photographic measurement tending to be greater than the OCT measurement for smaller holes and lower for larger holes (P=0.02)., Conclusions: OCT and Topcon digital photography have good repeatability for measurement of macular hole size. Both these methods measured larger hole sizes compared to surgeon estimate. Digital photography and OCT methods did not agree.

Magnetization transfer imaging is an MRI technique that provides quantitative information about in vivo tissue integrity, including myelin and axonal content, and is expressed as the magnetization transfer ratio (MTR). The optic neuritis lesion can model the MS lesion in vivo and permits use of non-invasive markers of optic nerve myelination (visual evoked potential [VEP] latency) and retinal neuroaxonal loss (optical coherence tomography [OCT]) to provide further information about the in vivo substrates of optic nerve MTR. Twenty-five patients with optic neuritis were studied using an optic nerve MTR sequence, quantitative visual function testing, VEPs and OCT, along with 15 controls. MTR was reduced in affected nerves compared to both clinically unaffected nerves from patients and control nerves (P < 0.001). Whole-nerve MTR correlated modestly with central-field VEP latency but more strongly when lesion-only MTR was measured, when a modest correlation with whole-field VEP latency emerged. OCT-quantified retinal neuroaxonal loss also correlated with MTR. In conclusion, markers of optic nerve myelination and axonal loss both correlate with optic nerve MTR. Because axonal loss following optic neuritis also results in myelin loss, the relative contributions of the two pathological conditions to the MTR measures cannot be estimated from this study.

Purpose: To present the detailed ocular phenotype of a subject with Gorlin syndrome (GS) (basal cell nevus syndrome; OMIM 109400) and to undertake mutation screening of the gene Patched (PTCH)., Design: Interventional case report., Methods: Clinical examination, color fundus photography, fundus autofluorescence imaging, optical coherence tomography (OCT), detailed electrophysiological assessment, and mutation screening of PTCH. The protocol of the study was approved by the local Ethics Committee and informed consent was obtained., Results: A 34-year-old man with findings consistent with GS was identified. Ophthalmoscopy and OCT identified bilateral epiretinal membranes (ERMs). Fundus autofluorescence (AF) imaging and electrophysiological testing [full-field electroretinogram (ERG), pattern ERG, and electrooculogram] were normal. Mutation screening identified a novel nonsense mutation in PTCH (c.1136C > G; p.Ser383X), the gene associated with GS., Conclusions: We present a case of bilateral ERM in GS with a molecular genetic diagnosis. We also document data supporting the lack of focal or generalized retinal dysfunction.

Objective: To define the incidence, pattern, duration, and clinical consequences of persistent localized submacular fluid after scleral buckle surgery for retinal detachment (RD)., Design: Prospective observational cohort series., Participants: Ninety-eight patients were identified and recruited to the study., Methods: Patients aged > or =18 years undergoing scleral buckle surgery for uncomplicated primary RD over an 18-month period were recruited. All patients underwent clinical examination and optical coherence tomography (OCT) scan of the macula preoperatively and at 6 weeks postoperatively. Those patients who had an abnormality on OCT 6 weeks after surgery underwent follow-up with repeat of the study investigations at 3, 6, 9, 12, and 18 months after surgery until the abnormality resolved. If no abnormality was seen at the 6-week examination, no further investigation was undertaken., Main Outcome Measure: Presence of submacular fluid on OCT 6 weeks after surgery. Other outcome measures were duration of persistent fluid and associations with poor visual outcome, type, or duration of detachment., Results: Of the 98 patients recruited into the study, 54 (55%) had subretinal fluid (SRF) on OCT 6 weeks after surgery. We identified 3 patterns of submacular fluid: confluent fluid, a single discrete bleb of fluid, and multiple blebs of fluid. Fluid was associated with delayed visual recovery. Of those with SRF, 78% had persistent fluid at 6 months; resolution of fluid took a median of 10 months and was associated with an improvement in vision., Conclusions: Optical coherence tomography is a useful noninvasive diagnostic method that can detect SRF not seen on clinical examination. Persistent SRF 6 weeks after scleral buckle surgery occurs in approximately half of patients, may persist for many months, and can cause delayed visual recovery.

Aims: To investigate optic nerve head topography in patients with optic neuritis compared to controls using the Heidelberg retina tomograph-II (HRT-II) and to determine if detected changes are related to visual function and electrophysiology., Methods: 25 patients with a previous single episode of unilateral optic neuritis and 15 controls were studied with HRT-II, visual evoked potentials, and pattern electroretinogram. Patients also had testing of visual acuity, visual field, and colour vision., Results: In affected eyes compared to fellow eyes, there was reduction of both the mean retinal nerve fibre layer (RNFL) thickness at the disc edge (p = 0.009) and the neuroretinal rim volume (p = 0.04). In affected eyes compared to control eyes, the three dimensional optic cup shape measure was increased (p = 0.01), indicative of an abnormal cup shape. There were no other significant differences in HRT-II measures. Within patient interocular difference correlation was used to investigate the functional relevance of these changes and demonstrated associations between RNFL thickness change and changes in visual acuity, visual field, and colour vision. Colour vision change was also associated with change in neuroretinal rim volume., Conclusions: HRT detects functionally relevant changes in RNFL thickness and neuroretinal rim volume between eyes affected by optic neuritis and unaffected fellow eyes.

Aim: To devise a quantative method for the measurement of the extent of macular subretinal fluid using optical coherence tomography (OCT), and to assess the interobserver and intraobserver agreement for this grading system., Methods: Observational cohort series. Patients were a cohort who underwent retinal detachment surgery over an 18-month period. All patients had OCT scan at 6 weeks after surgery. The scans were graded by two independent observers experienced in OCT interpretation and each grader was masked to the others findings. Observer 1 then regraded the scans on a later day masked to his previous findings. The interobserver and intraobserver agreement was assessed using weighted Kappa (Kw) statistics., Results: In all, 116 patients were analysed. Both the intraobserver and interobserver agreement was very high, with Kw being 0.9631 and 0.9070, respectively., Conclusions: The grading system for assessment of the extent of macular subretinal fluid using OCT appears to have very good reproducibility and repeatability. We propose that this grading system would be clinically useful when applied to pathologies visible on OCT scan of the macula.

Objective: To define the incidence, duration, and clinical associations of persistent localized submacular fluid after pars plana vitrectomy (PPV) retinal detachment surgery., Design: Observational cohort series., Participants: One hundred patients were identified and recruited into the study., Methods: Patients aged 18 years and older who had undergone PPV and gas as a primary procedure for rhegmatogenous retinal detachment and postoperative follow-up were recruited from February through August 2004. All patients underwent clinical examination, optical coherence tomography (OCT) scan of the macula, and retinal thickness analysis scan of the macula. Those patients in whom an abnormality was seen on OCT at 6 weeks after surgery underwent follow-up with repeat of the study investigations at 3, 6, 9, 12, and 18 months after surgery until the abnormality resolved. If no abnormality was seen at the 6-week examination, no further investigation was undertaken. Demographic data, including detachment characteristics, were collected retrospectively from the patient case notes., Main Outcome Measures: The principle outcome measure was the presence of subretinal fluid (SRF) on OCT at 6 weeks after surgery. Other outcome measures included duration of persistent fluid and association with visual outcome and type and duration of detachment., Results: One hundred patients were recruited; 15 of these had SRF on OCT performed at 6 weeks after surgery. Subretinal fluid was associated with significantly worse visual acuity (VA) at 6 weeks (P = 0.033, Wilcoxon rank-sum); those with SRF had a median VA of 0.4, and those with no SRF had a median VA of 0.3. The fluid took a median of 5.5 months to resolve. Seven patients had combined PPV and scleral buckle surgery; none of these had fluid at 6 weeks., Conclusions: Optical coherence tomography is a useful noninvasive diagnostic method that can detect SRF not appreciated on clinical examination. Persistent SRF after PPV and gas surgery occurred in 15% of patients in this study and was still present in 53% of these at 6 months. The presence of SRF at 6 weeks after surgery was associated with a poorer visual outcome at this time point.

Magnetic resonance imaging (MRI) measures of brain atrophy are often considered to be a marker of axonal loss in multiple sclerosis (MS) but evidence is limited. Optic neuritis is a common manifestation of MS and results in optic nerve atrophy. Retinal nerve fibre layer (RNFL) imaging is a non-invasive way of detecting axonal loss following optic neuritis. We hypothesise that if the optic nerve atrophy that develops following optic neuritis is contributed to by axonal loss, it will correlate with thinning of the RNFL. Twenty-five patients were studied at least 1 year after a single unilateral attack of optic neuritis without recurrence, with a selection bias towards incomplete recovery. They had MR quantification of optic nerve cross-sectional area and optic nerve lesion length, as well as optical coherence tomography (OCT) measurement of mean RNFL thickness and macular volume, quantitative visual testing, and visual evoked potentials (VEPs). Fifteen controls were also studied. Significant optic nerve atrophy (mean decrease 30% versus controls), RNFL thinning (mean decrease 33% versus controls), and macular volume loss occurred in patients' affected eyes when compared with patients' unaffected eyes and healthy controls. The optic nerve atrophy was correlated with the RNFL thinning, macular volume loss, visual acuity, visual field mean deviation, and whole field VEP amplitude but not latency. These findings suggest that axonal loss contributes to optic nerve atrophy following a single attack of optic neuritis. By inference, axonal loss due to other post-inflammatory brain lesions is likely to contribute to the global MRI measure of brain atrophy in multiple sclerosis.

Objective: To use optical coherence tomography to assess the in vivo pathologic findings associated with incomplete visual recovery in patients who have undergone anatomically successful surgery to treat proliferative vitreoretinopathy., Methods: Eligible patients were recruited in vitreoretinal outpatient clinics between April 1, 2002, and July 31, 2003. Patients were included who had undergone anatomically successful vitreoretinal surgery to treat proliferative vitreoretinopathy and, at least 3 months after surgery, had postoperative vision worse than expected (< or =6/12) with no identifiable cause at clinical examination. Patients underwent optical coherence tomography, stereo fundus fluorescein angiography was performed in a cohort of patients, and angiographic findings were compared with those on the optical coherence tomograms. Relevant clinical data were collected retrospectively from patient case notes., Results: A total of 35 patients were recruited. Optical coherence tomograms revealed cystoid macular edema in 23 patients (66%) but did not identify any other specific intraretinal disease. Location of edema (outer or inner retina), determined with stereo fundus fluorescein angiography and optical coherence tomography, correlated well., Conclusions: Optical coherence tomography is a useful diagnostic tool for assessing poor postoperative visual acuity and can reveal disease undetected at clinical examination. Cystoid macular edema is a common finding on optical coherence tomograms in eyes with incomplete visual recovery after anatomically successful surgery to treat proliferative vitreoretinopathy.

Purpose: To evaluate the strength and pattern of the relationship between visual field (VF) sensitivity and retinal nerve fiber layer (RNFL) thickness measurements by scanning laser polarimetry (SLP)., Methods: Fifty-four eyes of 54 normal subjects (age, 42 +/- 15 years; VF mean deviation [MD], -0.69 +/- 1.01 dB) and 51 eyes of 51 glaucoma patients (age, 66 +/- 14 years; VF MD, -6.92 +/- 5.43 dB) were imaged with an SLP using fixed corneal compensation (FCC) and variable corneal compensation (VCC). VF sensitivity was recorded in the dB and the 1/L scales. Linear and logarithmic relationships were sought globally and in six VF sectors. Relationships of VF and RNFL thickness with age were sought in normal subjects., Results: Both VF sensitivity and RNFL thickness declined with age (as determined by the regression slope): -0.13% (P = 0.0005) and -0.64% (P = 0.0001) per year for dB and 1/L VF sensitivity, respectively, and -0.25% (P = 0.003) per year for VCC RNFL thickness. FCC RNFL thickness was not statistically significantly related to age. The relationship of VF sensitivity to VCC global (R(2) = 0.49) and sectoral (R(2) = 0.00-0.47) RNFL thickness was greater than for FCC global (R(2) = 0.12) and sectoral (R(2) = 0.00-0.21) RNFL thickness. Relationships were curvilinear with the dB scale, with logarithmic regression of dB VF sensitivity against RNFL thickness being significantly better than linear regression. Logarithmic regression of 1/L VF sensitivity against RNFL thickness was no better than linear regression for all sectors. There was no relationship between VF sensitivity and RNFL thickness in the temporal peripapillary RNFL sector., Conclusions: The strength of the structure/function relationships compare well with previous reports in the literature. The relationships were curvilinear with the dB scale and linear with the 1/L scale, and were much stronger with VCC than with FCC RNFL thickness measurements.