Publications by authors named "Benjamin Wolff"

38 Publications

Association between anatomical and clinical outcomes of neovascular age-related macular degeneration treated with anti-VEGF.

Retina 2020 Dec 14;Publish Ahead of Print. Epub 2020 Dec 14.

The University of Sydney, Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, Sydney, NSW, Australia Department of Ophthalmology, Miguel Servet University Hospital, Zaragoza, Spain Department of Ophthalmology, Dijon University Hospital, Dijon, France Maison Rouge, Ophthalmologic Centre, Strasbourg, France Mater Private Hospital, Dublin, Ireland University Hospital Zurich, University of Zurich, Department of Ophthalmology Zurich, Switzerland.

Purpose: Assess the relationship between subretinal fluid (SRFL), intraretinal fluid (IRFL), and visual outcomes of neovascular age-related degeneration (nAMD) in routine clinical practice.

Methods: Treatment-naive eyes enrolled in the Fight Retinal Blindness! registry after Jan-2017 were identified. Lesion activity was graded at each visit as inactive, active not SRFL only (A-NSRFL only), or active SRFL only (A-SRFL only). Eyes were grouped based on initial activity: 1) initially A-NSRFL only or 2) initially A-SRFL only, and their predominant activity status over 12 months: 1) mostly inactive, 2) mostly A-NSRFL only or 3) mostly A-SRFL only.

Results: 703 eyes were eligible for analysis. Initially A-NSRFL only had similar adjusted mean 12-month VA change to initially A-SRFL eyes (5.7 vs. 6.9 letters; P=0.165) but their final VA was worse (62.5 vs. 67.5 letters at 12 months; P=0.003). Adjusted mean 12-month VA change between the predominant activity groups was significantly different (P=0.005), with mostly inactive (7.6 letters) and mostly A-SRFL only (7.5 letters) eyes gaining more than mostly A-NSRFL only eyes (3.6 letters).

Conclusions: Eyes with SRFL only had similar outcomes at 1 year to eyes that were mostly inactive. Intraretinal fluid was associated with worse visual outcomes, highlighting the importance of distinguishing between IRFL and SRFL when managing nAMD.
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http://dx.doi.org/10.1097/IAE.0000000000003061DOI Listing
December 2020

Acute syphilitic posterior placoid chorioretinopathy presenting as atypical multiple evanescent white dot syndrome.

Eur J Ophthalmol 2020 Sep 2:1120672120957589. Epub 2020 Sep 2.

Fondation Ophtalmologique Adolphe de Rothschild, Service du Professeur Sahel, Paris, France.

Background: This paper reports the case of a young man who presented with syphilis masquerading as multiple evanescent white dots syndrome (MEWDS), which turned out to be an acute syphilitic posterior placoid chorioretinopathy (ASPPC) during follow-up.

Case Presentation: A 59-year-old healthy male consulted for a three days' history of visual impairment in both eyes. On multimodal imaging, he was diagnosed as MEWDS. Fundus fluorescein angiography (FFA) showed early peripheral bilateral granular hyperfluorescence that correlated with the yellow-white dots found on fundus exam. Indocyanine green angiography (ICGA) depicted hypofluorescent dots on late phase. Spectral-domain optical coherence tomography (SD-OCT) revealed numerous inner retinal highly reflective deposits in the outer nuclear layer and disruption of the ellipsoid zone. After initial improvement, he presented again for a sudden visual loss at 3 weeks. FFA, ICGA and SD-OCT demonstrated the same but more numerous and outer lesions suggesting an ASPPC. A full inflammatory work-up revealed highly positive titers of rapid plasma regain (RPR) and fluorescent treponemal antibody absorption (FTA-Abs), suggesting a syphilis infection. The ophthalmological manifestations dramatically improved after the patient was admitted for high-dose intravenous penicillin G 24 million per day for 2 weeks.

Conclusion: This is the first case that reports an ocular syphilitic infection masquerading as MEWDS at presentation and that turns to be an ASPPC. Syphilis serology should be routinely done in every case of atypical MEWDS especially when unusually presented in a young healthy man, with bilateral involvement and a bad clinical evolution.
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http://dx.doi.org/10.1177/1120672120957589DOI Listing
September 2020

Intraocular Pressure Changes and Vascular Endothelial Growth Factor Inhibitor Use in Various Retinal Diseases: Long-Term Outcomes in Routine Clinical Practice: Data from the Fight Retinal Blindness! Registry.

Ophthalmol Retina 2020 09 20;4(9):861-870. Epub 2020 Jun 20.

Save Sight Institute, Discipline of Ophthalmology, Sydney Medical School, The University of Sydney, Sydney, Australia.

Purpose: To report long-term changes in intraocular pressure (IOP) in eyes receiving vascular endothelial growth factor (VEGF) inhibitors for various retinal conditions over 12 and 24 months in routine clinical practice.

Design: Retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness!

Project:

Participants: Treatment-naïve eyes receiving monotherapy with VEGF inhibitors (ranibizumab [0.5 mg], aflibercept [2 mg], or bevacizumab [1 mg]) with at least 3 injections from December 2013 through December 31, 2018, and at least 12 months of follow-up.

Methods: Intraocular pressure was measured at each clinical visit for all eyes as part of routine practice.

Main Outcome Measures: The primary outcome was the mean change in IOP (in millimeters of mercury) at 12 months. The following secondary IOP outcome measures were investigated at 12 and 24 months: (1) mean change in IOP from baseline and (2) proportion of clinically significant IOP increase defined as an elevation of at least 6 mmHg to an IOP of more than 21 mmHg at any point during the follow-up.

Results: We identified 3429 treatment-naïve eyes (395 receiving bevacizumab, 1138 receiving aflibercept, and 1896 receiving ranibizumab) with complete IOP data from 3032 patients with 12 months of follow-up data, of which 2125 (62%) had 24 months of follow-up data. The overall mean IOP change was -0.5 mmHg (95% confidence interval CI, -0.6 to -0.3 mmHg) at 12 months and -0.4 mmHg (95% CI, -0.6 to -0.3 mmHg) at 24 months, whereas the proportions of clinically significant IOP increases were 5.6% and 8.8%, respectively. A lower mean IOP change and fewer IOP elevations at 12 and 24 months was observed in eyes receiving aflibercept than in those receiving bevacizumab and ranibizumab (P ≤ 0.01 for both comparisons at each time point and outcome). Eyes with pre-existing glaucoma demonstrated more IOP increases over 12 and 24 months (odds ratio [OR], 2.2 [95% CI, 1.2-3.8; P = 0.012] and 2.1 [95% CI, 1.1-3.8; P = 0.025], respectively).

Conclusions: Mean IOP did not change significantly from baseline to 12 and 24 months in eyes receiving VEGF inhibitors, whereas clinically significant IOP elevations occurred in a small proportion of eyes. Aflibercept was associated with fewer clinically significant IOP elevations, whereas eyes with pre-existing glaucoma were at a higher risk.
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http://dx.doi.org/10.1016/j.oret.2020.06.020DOI Listing
September 2020

Hypomethylating Agent Azacitidine Is Effective in Treating Brain Metastasis Triple-Negative Breast Cancer Through Regulation of DNA Methylation of Keratin 18 Gene.

Transl Oncol 2020 Jun 11;13(6):100775. Epub 2020 May 11.

Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, 400 Lee Street North, Lewisburg, WV. Electronic address:

Breast cancer patients presenting with symptomatic brain metastases have poor prognosis, and current chemotherapeutic agents are largely ineffective. In this study, we evaluated the hypomethylating agent azacitidine (AZA) for its potential as a novel therapeutic in preclinical models of brain metastasis of breast cancer. We used the parental triple-negative breast cancer MDA-MB-231 (231) cells and their brain colonizing counterpart (231Br) to ascertain phenotypic differences in response to AZA. We observed that 231Br cells have higher metastatic potential compared to 231 cells. With regard to therapeutic value, the AZA IC value in 231Br cells is significantly lower than that in parental cells (P < .01). AZA treatment increased apoptosis and inhibited the Wnt signaling transduction pathway, angiogenesis, and cell metastatic capacity to a significantly higher extent in the 231Br line. AZA treatment in mice with experimental brain metastases significantly reduced tumor burden (P = .0112) and increased survival (P = .0026) compared to vehicle. Lastly, we observed a decreased expression of keratin 18 (an epithelial maker) in 231Br cells due to hypermethylation, elucidating a potential mechanism of action of AZA in treating brain metastases from breast cancer.
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http://dx.doi.org/10.1016/j.tranon.2020.100775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225776PMC
June 2020

Ten-year outcomes of anti-vascular endothelial growth factor treatment for neovascular age-related macular disease: A single-centre French study.

Clin Exp Ophthalmol 2020 07 16;48(5):636-643. Epub 2020 Mar 16.

The Save Sight Institute, Sydney Medical School, The University of Sydney, Sydney, Australia.

Importance: Long-term data of intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors are lacking.

Background: This study aims to assess visual and anatomic outcomes of eyes with neovascular age-related macular degeneration (nAMD) after 10 years of anti-VEGF therapy.

Design: Retrospective analysis of data from a prospectively designed database.

Participants: One hundred and sixteen eyes with nAMD (94 participants) that started anti-VEGF therapy at least 10 years earlier.

Methods: Eyes were tracked by the Fight Retinal Blindness! registry.

Main Outcome Measures: Mean change in visual acuity at 10 years vs baseline. Visual acuity was assessed by the number of letters read on a logarithm of the minimum angle of resolution chart.

Results: Eyes received a median of 27.5 injections over 10 years. Mean visual acuity was 57.5 letters (SD 17.5) at baseline. It increased slightly at 1 year, then dropped steadily by 18 letters (95% CI: 13.7; 22.3) at 10 years. Overall, 10% of eyes gained ≥10 letters, 64% lost ≥10 letters and 23% remained stable (±5 letters from baseline). Geographic atrophy and subretinal fibrosis were found in 93% and 71%, respectively, after 10 years, both mostly affecting the centre of the fovea. Pre-treated eyes (47.5%) had significantly worse visual acuity than treatment-naïve eyes at baseline and during follow-up and were significantly more likely to have atrophy and fibrosis.

Conclusions And Relevance: Despite short-term stabilization, long-term visual outcomes of nAMD eyes under anti-VEGF therapy may be poor. Development of atrophy and fibrosis, resulting from the natural progression of the disease, may partly explain this evolution.
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http://dx.doi.org/10.1111/ceo.13742DOI Listing
July 2020

Synthesis and structure activity relationship of 1, 3-benzo-thiazine-2-thiones as selective HDAC8 inhibitors.

Eur J Med Chem 2019 Dec 7;184:111756. Epub 2019 Oct 7.

Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Haardtring 100, 64295, Darmstadt, Germany. Electronic address:

Human histone deacetylase 8 (HDAC8) is a highly promising target for neuroblastoma and other types of cancer. Several HDAC inhibitors are approved for the treatment of special cancer subtypes or are evaluated in clinical trials. By far the most drugs or drug candidates contain a hydroxamate group that chelates the catalytic zinc ion within HDACs. Most hydroxamate inhibitors are more or less unselective, although there are considerable exceptions demonstrating the general feasibility to develop at least HDAC isoenzyme selective inhibitors. In addition, hydroxamates have recently come under discussion regarding their potential for mutagenicity. Recently, PD-404,182 was discovered as a selective and potent non-hydroxamate inhibitor of HDAC8. However, this active compound turned out to be decomposed in the presence of glutathion (GSH). Here, we describe the synthesis of significantly improved analogs of PD-404,182 that demonstrate both, great selectivity for HDAC8 and also chemical stability in the presence of GSH. The compounds are characterized with respect to structure-activity relationship, binding mode and target engagement in neuroblastoma cells by combining biochemical and biophysical methods with chemoinformatics.
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http://dx.doi.org/10.1016/j.ejmech.2019.111756DOI Listing
December 2019

Morphological Predictive Features on Spectral-Domain Optical Coherence Tomography for Visual Outcomes in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab.

Biomed Res Int 2018 26;2018:7438083. Epub 2018 Jun 26.

Rothschild Ophthalmological Foundation, 25 rue Manin, 75940 Paris Cedex 19, France.

Purpose: To identify spectral-domain optical coherence tomography (SD-OCT) predictive morphological features for the outcome of Ranibizumab therapy for neovascular age-related macular degeneration (AMD).

Methods: This is a retrospective multicentric study that involved 64 eyes with naïve AMD. Patients who received three monthly intravitreal injections of Ranibizumab were stratified into (1) "responders" [≥ 5 letters gain on Early Treatment Diabetic Retinopathy Study (ETDRS) scale] and (2) "nonresponders" (< 5 letters gain). Best-corrected visual acuity (BCVA) and SD-OCT morphological features were compared at baseline and one month after three consecutive injections of Ranibizumab. Univariate and multivariate analyses were carried out to correlate these morphological features with the change in BCVA.

Results: Among the 64 patients enrolled, 40 (62.5%) were "responders" and 24 (37.5%) "nonresponders". Age, sex, and BCVA were comparable between both groups. A multivariate correlational analysis found that subfoveal choroidal thickness (SFCT) and the presence of pigment epithelial detachment (PED) > 250 m at baseline were two independent prognostic indicators of final BCVA. No other SD-OCT morphological studied features seem to affect final BCVA after Ranibizumab treatment.

Conclusion: SFCT and the presence of PED > 250 m are two significant biomarkers that may predict improvement after Ranibizumab therapy for AMD. These markers may guide ophthalmologists' treatment decision under financial constraints and limited time.
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http://dx.doi.org/10.1155/2018/7438083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038676PMC
January 2019

Aflibercept Treatment in Polypoidal Choroidal Vasculopathy: Results of a Prospective Study in a Caucasian Population.

Ophthalmologica 2018 25;240(4):208-212. Epub 2018 May 25.

Adolphe de Rothschild Foundation, CIC Department, Paris, France.

Introduction: Polypoidal choroidal vasculopathy (PCV) is a choroidal pathology characterized by frequent occurrences of subretinal hemorrhages and resistance to monotherapies such as ranibizumab or bevacizumab intravitreal injections (IVT). The purpose of this study is to evaluate both the anatomical and functional efficacy of aflibercept IVT as a monotherapy in PCV in a Caucasian population.

Methods: We conducted a prospective multicenter study in either treatment-naïve patients with PCV or PVC patients who had not been treated with anti-VEGF within the previous 3 months or with photodynamic therapy (PDT) within the previous 6 months. All patients had been treated with 3 initial monthly loading doses of aflibercept followed by a Q8 regimen for 28 weeks in total. All patients underwent a complete ophthalmic examination including the measurement of best-corrected visual acuity (BCVA) before each IVT and after 28 weeks as well as an optical coherent tomography (OCT) of the macula. At baseline and 28 weeks, the polypoidal dilations were analyzed with indocyanine green angiography.

Results: Thirty-four eyes of 34 patients were included in this study. All patients were followed for 28 weeks and received 5 aflibercept IVT. The mean baseline BCVA was 55 letters. After 28 weeks, significant +13 letters in BCVA and a regression of exudative signs on OCT in all patients were observed. In 62% of the cases, polyp disappearance was observed on indocyanine green angiography.

Discussion: In this study on a Caucasian population, we showed that aflibercept as a monotherapy provided both a significant visual gain and the regression of polypoidal dilations. Aflibercept use in monotherapy may contribute to reduce the hemorrhagic risk and atrophy linked to PDT.
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http://dx.doi.org/10.1159/000488808DOI Listing
January 2019

Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients.

Sci Rep 2018 05 1;8(1):6840. Epub 2018 May 1.

Department of Ophtalmology, Amiens University Hospital, Paris, France.

EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.10) was lower in Provence-Côte d'Azur with a Mediterranean diet (1.9/1.10), and higher in regions with intensive farming or industrialized activities (5 to 20/1.10). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina.
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http://dx.doi.org/10.1038/s41598-018-25003-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931512PMC
May 2018

Dark and white lesions observed in central serous chorioretinopathy on optical coherence tomography angiography.

Eur J Ophthalmol 2018 Jul 19;28(4):446-453. Epub 2018 Mar 19.

4 Rothschild Ophthalmologic Foundation, Paris, France.

Purpose: To describe abnormal dark (hyposignal) and white (hypersignal) lesions observed on optical coherence tomography angiography in central serous chorioretinopathy.

Methods: Prospective, multicenter, and descriptive study including patients with active or quiescent central serous chorioretinopathy. All patients had undergone a complete ophthalmic examination.

Results: Abnormal dark lesions were detected as "dark spots" and "dark areas" on optical coherence tomography angiography. A "dark spot" could correspond to six different abnormalities: pigment epithelium detachment, subretinal deposit, "Lucency" within surrounding subretinal fibrin, choroidal cavitation, choroidal excavation, and choroidal fluid. A "dark area" could be related to a serous retinal detachment or choriocapillary compression. Abnormal white lesions were also detected: A "white spot" could correspond with the leaking point on fluorescein angiography or with hyper-reflective dots; A "white filamentous pattern" at the Brüch's membrane level corresponded to abnormal choroidal neovascular vessels.

Conclusion: A semiology is described using optical coherence tomography angiography in central serous chorioretinopathy as abnormal dark and white lesions. Multimodal imaging is mandatory in addition to optical coherence tomography angiography to diagnose non-neovascular retinal and choroidal central serous chorioretinopathy lesions. However, optical coherence tomography angiography alone is helpful in detecting choroidal neovascular membrane in central serous chorioretinopathy.
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http://dx.doi.org/10.1177/1120672118758401DOI Listing
July 2018

Perfluorinated hydroxamic acids are potent and selective inhibitors of HDAC-like enzymes from Pseudomonas aeruginosa.

Bioorg Med Chem Lett 2017 04 21;27(7):1508-1512. Epub 2017 Feb 21.

Department of Chemical Engineering and Biotechnology, University of Applied Sciences, Haardtring 100, 64295 Darmstadt, Germany. Electronic address:

A series of perfluorinated SAHA (PFSAHA) was prepared and profiled against a panel of human and bacterial members of the Histone deacetylase (HDAC) family. Some of the active substances show nanomolar inhibitory activity and several hundred fold selectivity for the HDAC like enzyme PA3774 from P. aeruginosa. The extraordinary selectivity against human HDACs results from the distinct oligomeric state of PA3774 which consists of two head-to-head dimers. The binding pocket is defined by the surface of both opposite monomers confining the access of ligands to the active site. In addition, the aromatic cap group of PFSAHA undergoes an edge-to-face aromatic interaction with phenylalanine from the opposite monomer.
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http://dx.doi.org/10.1016/j.bmcl.2017.02.050DOI Listing
April 2017

Multimodal imaging findings in 'hyper-early' stage MEWDS.

Br J Ophthalmol 2017 10 15;101(10):1381-1385. Epub 2017 Feb 15.

Fondation Ophtalmologique Adolphe de Rothschild (FOR), 25 rue Manin, Paris Cedex 19, Île-de-France, France.

Objective: To describe a new stage of multiple evanescent white dot syndrome (MEWDS), occurring at a very early phase of the disease.

Methods: Retrospective analysis of clinical, angiographic and tomographic findings in four patients with 'hyper-early' stage MEWDS.

Results: In four patients seen within 1 week of the onset of symptoms, fundus analysis revealed macular granity and the classic yellow-white dots, some having no corresponding hyperautofluorescent pattern. Spectral-domain optical coherence tomography (SD-OCT) showed central foveal disruption of the ellipsoid zone (EZ) and interdigitation layer with a hyper-reflective dome-shaped lesion. In two patients, fluorescein angiography (FA) revealed an intermediate hypofluorescent perimacular halo, whereas late indocyanine green angiography (ICGA) showed a hyperfluorescent halo as well as the classic MEWDS features. After a few days, the EZ disruption appeared complete on OCT and fundus autofluorescence (FAF) in all patients. Visual acuity, OCT and FAF findings had fully recovered within 3 months.

Conclusions: We have shown a new feature of MEWDS on FAF, OCT, FA and ICGA, corresponding to a very early stage of the disease.
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http://dx.doi.org/10.1136/bjophthalmol-2016-309175DOI Listing
October 2017

[Age-related macular degeneration diagnosis].

Rev Prat 2017 01;67(1):92-95

Service d'ophtalmologie, hôpital de la Croix-Rousse, Lyon, France.

Age-related macular degeneration diagnosis. Age-related macular degeneration (AMD) is a progressive degeneration of the central area of the retina that allows detailed vision. This area called the macula is responsible for the discrimination of high spatial frequencies (reading), color vision and central visual field. The loss of visual acuity secondary to the occurrence of AMD causes a significant impairment for the patient quality of life. From an early form, causing no or little visual harm to patients, AMD can progress to 2 late forms: atrophic form, which progresses slowly, and exudative or neovascular form of more rapid evolution. It seems important to achieve early detection of this disease in order to promote management that will fight against its progression. The use of multimodal imaging can meet these screening criteria and perform personalized follow-up of AMD patients.
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January 2017

Pachychoroid neovasculopathy: aspect on optical coherence tomography angiography.

Acta Ophthalmol 2017 Jun 6;95(4):421-427. Epub 2016 Sep 6.

Italian Macula Center, Rome, Italy.

Purpose: To describe and interpret the features of pachychoroid neovasculopathy (PNV) using optical coherence tomography angiography (OCTA) technique.

Methods: This is an observational case series of patients who presented with PNV. Best-corrected visual acuity (BCVA), anterior segment examination, dilated funduscopic examination, infrared and autofluorescence fundus images and spectral-domain optical coherence tomography (SD-OCT; B-scan, 'en-face' and OCTA) were carried out for all patients. Choroid thickness was measured using enhanced depth imaging (EDI) mode. Colour fundus photographs, fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were not performed systematically. Optical coherence tomography angiography (OCTA) features of PNV are described and interpreted.

Results: Five eyes of five patients with a mean age of 62.2 years (range, 53-73 years) presenting with PNV were analysed. They all presented pachychoroid pigment epitheliopathy (PPE) with choroidal thickening and dilated choroidal vessels as seen with EDI-OCT. Fluorescein angiography (FFA) was performed in three patients showing multiple areas of retinal pigment epithelium atrophy and fundus lesions suggestive of chronic central serous chorioretinopathy. Indocyanine green angiography (ICGA) in one patient confirmed the presence of large choroidal veins and choroidal hyperpermeability seen beneath the area of the neovascular tissue. Two eyes had the appearance of polypoidal structures within the neovascular tissue, with the characteristic aspect of the polypoidal lesions on B-scan and 'en-face'. Optical coherence tomography angiography (OCTA) showed the appearance of tangled filamentous vascular network in all eyes.

Conclusion: Optical coherence tomography angiography (OCTA) is a safe, highly sensitive and specific examination for the detection of type 1 neovascularization associated with PPE. Features are characteristic of tangled filamentous vessels overlying a focal area of thickened choroid.
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http://dx.doi.org/10.1111/aos.13221DOI Listing
June 2017

Martinique Crinkled Retinal Pigment Epitheliopathy: Clinical Stages and Pathophysiologic Insights.

Ophthalmology 2016 10 26;123(10):2196-204. Epub 2016 Jul 26.

Institute for Neurosciences of Montpellier U1051, University of Montpellier - University Hospital, Genetics of Sensory Diseases, Montpellier, France. Electronic address:

Purpose: To reappraise the autosomal dominant Martinique crinkled retinal pigment epitheliopathy (MCRPE) in light of the knowledge of its associated mutated gene mitogen-activated protein kinase-activated protein kinase 3 (MAPKAPK3), an actor in the p38 mitogen-activated protein kinase pathway.

Design: Clinical and molecular study.

Participants: A total of 45 patients from 3 generations belonging to a family originating from Martinique with an autosomal dominant MCRPE were examined.

Methods: Best-corrected visual acuity, fundus photographs, and spectral-domain optical coherence tomography (SD OCT) of all clinically affected patients and carriers for the causal mutation were reviewed at the initial visit and 4 years later for 10 of them. Histologic retinal lesions of Mapkapk3(-/-) mice were compared with those of the human disease.

Main Outcome Measures: The MCRPE natural history in view of MAPKAPK3 function and Mapkapk3(-/-) mouse retinal lesions.

Results: Eighteen patients had the c.518T>C mutation. One heterozygous woman aged 20 years was asymptomatic with normal fundus and SD OCT (stage 0). All c.518T>C heterozygous patients older than 30 years of age had the characteristic dried-out soil fundus pattern (stages 1 and 2). Complications (stage 3) were observed in 7 cases, including polypoidal choroidal vasculopathy (PCV) and macular fibrosis or atrophy. One patient was homozygous and had a form with severe Bruch's membrane (BM) thickening and macular exudation with a dried-out soil pattern in the peripheral retina. The oldest heterozygous patient, who was legally blind, had peripheral nummular pigmentary changes (stage 4). After 4 years, visual acuity was unchanged in 6 of 10 patients. The dried-out soil elementary lesions radically enlarged in patients with a preferential macular extension and confluence. These findings are in line with the progressive thickening of BM noted with age in the mouse model. During follow-up, there was no occurrence of PCV.

Conclusions: MCRPE is an autosomal dominant, fully penetrant retinal dystrophy with a preclinical stage, an onset after the age of 30 years, and a preserved visual acuity until occurrence of macular complications. The natural history of MCRPE is in relation to the role of MAPKAPK3 in BM modeling, vascular endothelial growth factor activity, retinal pigment epithelial responses to aging, and oxidative stress.
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http://dx.doi.org/10.1016/j.ophtha.2016.06.028DOI Listing
October 2016

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial.

Ophthalmology 2016 09 16;123(9):1865-73. Epub 2016 Jun 16.

Eye Clinic, Hôpital Intercommunal, Créteil, France.

Purpose: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years.

Design: A national matched case-control study.

Participants: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415).

Methods: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression.

Main Outcome Measures: Extensive macular atrophy with pseudodrusen status (cases vs. controls).

Results: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP.

Conclusions: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.
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http://dx.doi.org/10.1016/j.ophtha.2016.05.018DOI Listing
September 2016

Effectiveness and safety of dexamethasone implants for postsurgical macular oedema including Irvine-Gass syndrome: the EPISODIC-2 study.

Br J Ophthalmol 2017 03 17;101(3):333-341. Epub 2016 May 17.

Department of Ophthalmology, Croix-Rousse University Hospital, Hospices Civils de Lyon, University of Lyon I, Lyon, France.

Aim: To assess the effectiveness of intravitreal dexamethasone implants for treating postsurgical macular oedema (PSMO) including Irvine-Gass syndrome and determining the predictive factors of treatment response.

Methods: Descriptive, observational, retrospective, consecutive, uncontrolled, multicentre, national case series. One hundred patients were included between April 2011 and June 2014, with a minimum of 1-year follow-up. Patients received dexamethasone implant 0.7 mg at baseline. Clinical characteristics, best-corrected visual acuity (BCVA), central subfield macular thickness (CSMT) and intraocular pressure were measured at each visit. The main outcome measure was the change in BCVA (Early Treatment of Diabetic Retinopathy Study (ETDRS) letters: L). An analysis of predictive factors of treatment response is also provided.

Results: Mean improvement in BCVA was 9.6 (±10.6) L at month 6 and 10.3 (±10.7) L at month 12 (p<0.001). The proportion of eyes with gains in BCVA of 15 or more letters was 32.5% and 37.5% at months 6 and 12, respectively. The mean reduction in CSMT was 135.2 and 160.9 µm at months 6 and 12, respectively (p<0.001). Thirty-seven per cent of patients did not need a second injection after the first injection during follow-up. The presence of at least one PSMO risk factor decreases the probability of a gain in visual acuity (VA) ≥10 L (p=0.006). Initial VA ≤50 L at baseline and non-naïve status decrease the probability of having only one injection during follow-up (p=0.044).

Conclusions: The significant gain in BCVA from baseline achieved at month 6 was maintained at month 12 after intravitreal injection of dexamethasone implant. Naïve status seems to be a good predictive factor of treatment response.
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http://dx.doi.org/10.1136/bjophthalmol-2016-308544DOI Listing
March 2017

Inner Retinal Refractile Lesions in Type 1 Neurofibromatosis.

Retina 2016 Apr;36(4):e25-6

*XV-XX Ophthalmology National Center, Paris, France; †Ophthalmology Center, Pantin, Paris, France; and ‡Ophthalmology Center for Imaging and Laser, Paris, France.

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http://dx.doi.org/10.1097/IAE.0000000000000822DOI Listing
April 2016

Retinal arterial macroaneurysms: clinical, angiographic, and tomographic description and therapeutic management of a series of 14 cases.

Eur J Ophthalmol 2016 Jan-Feb;26(1):36-43. Epub 2015 Jul 2.

From Fondation Ophtalmologique Adolphe de Rothschild, Paris - France.

Purpose: To describe clinical, angiographic, and tomographic features and the therapeutic management of patients with retinal arterial macroaneurysm (RAM).

Methods: Retrospective analysis of patients diagnosed with RAM between January 2011 and September 2014 in Professor Sahel's Department of Ophthalmology, Rothschild Foundation. Retinal arterial macroaneurysms were classified as hemorrhagic, exudative, or quiescent. Patient demographics and comorbidities were recorded. All patients underwent complete ophthalmologic examination including initial and final visual acuity (Early Treatment Diabetic Retinopathy Study chart), slit-lamp biomicroscopy, fundus examination, color and autofluorescence fundus imaging, fluorescein and indocyanine green angiography, and spectral-domain optical coherence tomography. Treatments were recorded.

Results: Fourteen RAMs of 14 patients were included: 9 hemorrhagic and 5 exudative. The most severe clinical picture was associated with the hemorrhagic form. Exudative cases had a progressive onset and a better visual prognosis. Direct laser photocoagulation was performed in 4 cases, anti-vascular endothelial growth factor (VEGF) intravitreal injection in 4 cases, combined treatment (YAG laser + argon laser + anti-VEGF intravitreal injection) in 1 case, and 5 cases received no treatment.

Conclusions: Retinal arterial macroaneurysm management should be specialized and rapid. Multimodal imaging should be performed for classifying it, assessing its prognosis and determining the most suitable treatment.
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http://dx.doi.org/10.5301/ejo.5000641DOI Listing
April 2016

"En face" optical coherence tomography imaging in type 2 idiopathic macular telangiectasia.

Retina 2014 Oct;34(10):2072-8

*Rothschild Ophthalmologic Foundation, Paris, France; †Kleber Retinal Center, Lyon, France; and ‡Lariboisiere Hospital, Paris, France.

Purpose: To comprehensively evaluate the retinal and choroidal changes in eyes with Type 2 idiopathic macular telangiectasia using "en face" and B-scan spectral domain optical coherence tomography (OCT), and to compare their respective contributions to this evaluation.

Methods: Eyes with a diagnosis of proliferative or nonproliferative Type 2 macular telangiectasia were prospectively studied. All patients underwent an extensive ophthalmologic examination including biomicroscopic fundus examination, color photography, fundus autofluorescence, fluorescein angiography, B-scan and en face spectral domain OCT.

Results: Twenty eyes of 10 patients were included in this study. En face OCT C-scans and conventional B-scans were both able to show inner crystalline deposits (15%), retinal capillary anomalies (100%), intraretinal cysts (80%), hyperreflective spots in the outer nuclear layer (100%) and external limiting membrane (80%), hyperplastic pigment plaques (30%), intraretinal neovascularization (20%), photoreceptor loss (100%), and choroidal cavitations (30%). En face OCT C-scans provided more information than B-scans on intraretinal neovascularization, photoreceptor loss, and choroidal cavitations. Also, en face OCT C-scans provided better visualization of the retinal vessels and telangiectasia than fluorescein angiography.

Conclusion: En face OCT is a noninvasive and reproducible technique that helps to better assess and follow up retinal and choroidal processes in Type 2 macular telangiectasia.
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http://dx.doi.org/10.1097/IAE.0000000000000208DOI Listing
October 2014

"En-face" spectral-domain optical coherence tomography findings in multiple evanescent white dot syndrome.

J Ophthalmol 2014 22;2014:928028. Epub 2014 Apr 22.

Professor Sahel Department, Rothschild Ophthalmologic Foundation, 25 rue Manin, 75019 Paris, France ; Kleber Retinal Center, 50 Cours Franklin Roosevelt, 69006 Lyon, France ; Monticelli Paradis Retinal Center, 88 rue du Commandant Rolland, 13008 Marseille, France.

Purpose. The recent use of "en-face" enhanced-depth imaging spectral-domain optical coherence tomography (EDI SD-OCT) helps distinguish the retinal layers involved in the physiopathology of multiple evanescent white dot syndrome (MEWDS). Methods. Four patients presenting with MEWDS underwent a comprehensive ocular examination including C-scan ("en-face") EDI SD-OCT at the initial visit and during follow-up. Results. C-scans combined with the other multimodal imaging enabled the visualization of retinal damage. Acute lesions appeared as diffuse and focal disruptions occurring in the ellipsoid and interdigitation zones. The match between autofluorescence imaging, indocyanine green angiography, and "en-face" OCT helped identify the acute microstructural damages in the outer retina further than the choroid. Follow-up using "en-face" EDI-OCT revealed progressive and complete recovery of the central outer retinal layers. Conclusion. "En-face" EDI SD-OCT identified the site of initial damage in MEWDS as the photoreceptors and the interdigitation layers rather than the choroid. Moreover, "en-face" OCT is helpful in the follow-up of these lesions by being able to show the recovery of the outer retinal layers.
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http://dx.doi.org/10.1155/2014/928028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016932PMC
May 2014

Microcystic changes in the retinal internal nuclear layer associated with optic atrophy: a prospective study.

J Ophthalmol 2014 23;2014:395189. Epub 2014 Feb 23.

Rothschild Ophthalmologic Foundation, Professor Sahel Department, 25 rue Manin, 75019 Paris, France.

Purpose. This study aimed at assessing the prevalence of pathologies presenting retinal inner nuclear layer (RINL) microcystic perimacular changes associated with optic nerve atrophy (OA). The charts of patients presenting a significant defect of the Retinal Nerve Fiber Layer (RNFL) were included prospectively in this study. Patients were classified according to the etiology of the RNFL defect. Two hundred and one eyes of 138 patients were enrolled in this analysis. Retinal images obtained showed the typical hyporeflective perifoveal crescent-shaped lesion composed of small round hyporeflective microcysts confined to the RINL in 35.3% of the eyes. Those findings were found in 75% of eyes presenting hereditary OA, 50% of eyes presenting ischemic optic neuritis, 50% of eyes with drusen of the optic nerve (ON), 44.4% of eyes presenting a compressive OA, 32% of eyes presenting inflammatory optic neuropathy from multiple sclerosis, 18.5% of eyes presenting OA from undetermined origin, and 17.6% of eyes having primary open-angle glaucoma. This study demonstrates that microcystic changes in RINL are not specific to a disease but are found in OA of various etiologies. Moreover, their incidence was found to be dependent upon the cause of OA, with the highest incidence occurring in genetic OA.
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http://dx.doi.org/10.1155/2014/395189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3950921PMC
April 2014

A case of neurosyphilis revealed by acute exudative polymorphous vitelliform maculopathy.

Ophthalmic Surg Lasers Imaging Retina 2014 Apr 4;45 Online:e29-31. Epub 2014 Apr 4.

The authors report the case of a healthy 56-year-old man presenting with bilateral vision loss. Clinical features were consistent with the diagnosis of acute exudative polymorphous vitelliform maculopathy (AEPVM). The patient returned 10 days later with bilateral anterior granulomatous uveitis, and the inflammatory work-up revealed treponemal antibodies in the serum and spinal fluid, consistent with a diagnosis of active neurosyphilis. The patient received standard treatment for neurosyphilis with intravenous penicillin G. Two months later, the intraocular inflammation had resolved, but the resolution of the vitelliform lesions was more gradual. An immune process could be a plausible explanation for these clinical findings. Clinicians should be aware that syphilis can produce AEPVM.
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http://dx.doi.org/10.3928/23258160-20140331-06DOI Listing
April 2014

Association of reticular pseudodrusen and early onset drusen.

ISRN Ophthalmol 2013 16;2013:273085. Epub 2013 May 16.

Department of Ophthalmology, Croix-Rousse University Hospital, 103 Grande rue de la Croix Rousse, 69317 Lyon Cedex 04, France.

Purpose. To report an association between reticular pseudodrusen, located above the retinal pigment epithelium (RPE), and Early Onset Drusen (EOD) as described using Spectral-Domain Optical Coherence Tomography (SD-OCT). Methods. Eight patients (16 eyes) with EOD were examined. EOD were classified into three entities called Large Colloid Drusen (LCD), Malattia Leventinese (ML), and Cuticular Drusen (CD). Best-corrected visual acuity, fundus examination, color fundus photographs, fundus autofluorescence (FAF), fluorescein angiography (FA), indocyanine green angiography (ICGA), and SD-OCT were performed in all study patients. Results. Four patients had LCD, 2 had ML, and 2 had CD. Reticular pseudodrusen were observed with SD-OCT in all study patients; all these patients had hyperreflective lesions above and below the RPE. Conclusion. Early Onset Drusen appear to be associated with reticular pseudodrusen. SD-OCT is helpful in distinguishing the location of the deposits that are above and below the RPE in EOD. Further studies are needed to understand the role of reticular pseudodrusen in the pathophysiology of EOD.
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http://dx.doi.org/10.1155/2013/273085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914185PMC
February 2014

Outer retinal tubulations in serpinginous choroiditis.

Graefes Arch Clin Exp Ophthalmol 2013 Nov 10;251(11):2657-8. Epub 2013 Jul 10.

Ophthalmology Service, Fondation Ophtalmologique Adolphe de Rothschild, 25 rue Manin, 75019, Paris, France,

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http://dx.doi.org/10.1007/s00417-013-2414-4DOI Listing
November 2013

Retinal and choroidal changes observed with 'En face' enhanced-depth imaging OCT in central serous chorioretinopathy.

Br J Ophthalmol 2013 Sep 3;97(9):1181-6. Epub 2013 Jul 3.

Department of Vitreo-Retinal Surgery, Rothschild Ophthalmologic Foundation, Paris, France.

Aims: To describe retinal and choroidal changes in acute and quiescent central serous chorioretinopathy (CSC) observed with 'En face' spectral domain optical coherence tomography (SD OCT) combined with enhanced-depth imaging (EDI).

Methods: A prospective and descriptive study at the Rothschild Ophthalmologic Foundation (Paris, France) between September 2011 and February 2012. Eyes with a clinical diagnosis of CSC were examined using SD OCT with EDI, fluorescein and indocyanine green angiography. 3D reconstruction of 197 transverse sections with SD OCT, spaced of 30 μ, provided a virtual macular brick through which 496 sections in the coronal plane resulted in a C-scan or En face OCT image.

Results: 23 of 29 eyes (79%) had serous retinal detachment (all active CSC) and 22 had pigment epithelial detachment (75%). Pigment epithelial hyperplasia was visualised in nine eyes (31%). Posterior cystoid retinal degenerations were present in five eyes (17%). The mean choroidal thickness was 491.5 μ. In 11 eyes (38%), En face OCT showed multiple hyper reflective points located at the level of the choriocapillary layer and choroidal cavitations were found in two patients.

Conclusions: En face OCT imaging using SD OCT is an easy, reproducible, non-invasive and effective tool to understand choroidal changes in acute and quiescent CSCR. It provides complementary morphological information, describes new semiological entities and might substitute other exams in the future.
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http://dx.doi.org/10.1136/bjophthalmol-2012-302974DOI Listing
September 2013

Retinal inner nuclear layer microcystic changes in optic nerve atrophy: a novel spectral-domain OCT finding.

Retina 2013 Nov-Dec;33(10):2133-8

*Rothschild Ophthalmologic Foundation, Paris, France; and †Centre Ophtalmologique Rabelais, Lyon, France.

Purpose: Optic atrophy constitutes the final stage in the evolution of optic neuropathy. The aim of this study was to describe the presence of macular microcystic changes or pseudocysts in patients with advanced optic atrophy.

Methods: The medical records of 24 patients who had retinal pseudocysts in association with optic atrophy have been analyzed. All patients underwent a complete neuro-ophthalmologic assessment; peripapillary retinal nerve fiber layer thickness and macular screening with spectral-domain optical coherence tomography and optical coherence tomography "en face" imaging analysis were also performed.

Results: A total of 36 eyes were included in the study. Patients' mean age was 37 years. The major cause of optic atrophy was glaucoma (12 cases). The retinal pseudocysts were observed as hyporeflective lesions in the internal nuclear layer. Infrared images revealed a hyporeflective circular or semilunar shape corresponding to the location of the pseudocysts in all cases. In eyes with pseudocysts, mean thickness of the peripapillary retinal nerve fiber layer was statistically significantly less than that of fellow eyes (P = 0.0003), whereas macular thickness was statistically significantly higher compared with fellow eyes (P < 0.005).

Conclusion: The presence of pseudocystic lesions always associated with severe optic nerve fiber loss is reported. The reason why pseudocystic lesions develop within the retina is not well understood. They might constitute the translation of degeneration of Muller cells in severe optic nerve fiber loss. Recognizing these pseudocysts is crucial because they may be confused with cystoid macular edema. Their prognostic value and role in the therapeutic process need to be further evaluated with prospective studies and molecular experiments in vivo.
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http://dx.doi.org/10.1097/IAE.0b013e31828e68d0DOI Listing
March 2014

B-scan and "en-face" spectral-domain optical coherence tomography imaging for the diagnosis and followup of acute retinal pigment epitheliitis.

Case Rep Med 2013 18;2013:260237. Epub 2013 Feb 18.

Department of Ophthalmology Croix-Rousse University Hospital and Hospices Civils de Lyon, University of Medicine Lyon 1, 103 Grande Rue de la Croix-Rousse, 69317 Lyon Cedex 04, France.

Purpose. To report B-scan and "En-face" spectral-domain optical coherence tomography (SD-OCT) findings in acute retinal pigment epitheliitis (ARPE). Methods. Two patients (3 eyes) with ARPE were examined. Fluorescein and indocyanine green (ICGA) angiography, B-scan, and "En-face" SD-OCT were performed in each patient at initial and follow-up visits. Results. Both patients presented with acute onset of blurred vision, and one with bilateral involvement. B-can OCT revealed disruption of the macular retinal pigment epithelial (RPE) inner band layer and photoreceptors' inner and outer segment (IS-OS) junction. Hyperreflective dots were observed in the outer nuclear layer (ONL) above the RPE/IS-OS disruption. Just around these hyperreflective dots, slight thickening of the hyperreflective IS/OS junction was observed. During the late phase, indocyanine green angiography (ICGA) showed a macular cockade-like hyperfluorescent halo. "En-face" OCT showed the same cockade-like appearance with a hyporeflective center and a hyperreflective border matching the pattern observed on ICGA. At followup, as vision improved without treatment, B-scan OCT demonstrated progressive resolution of the hyperreflective and disrupted lesions; "en-face" OCT also showed disappearance of the macular cockade-like halo with a transient discrete hyperreflective macular star at the RPE level in one eye. Conclusion. "En-face" OCT associated with B-scan SD-OCT analysis appears to be very helpful in the diagnosis and followup of ARPE. The pathophysiology of ARPE remains complex and still poorly understood. These techniques help define the location and extent of structural damage occurring in this disease.
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http://dx.doi.org/10.1155/2013/260237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3588221PMC
March 2013

Photocoagulation therapy of leaking archer's type 2 retinal arteriovenous communication.

Retin Cases Brief Rep 2013 ;7(1):95-7

*Department of Ophthalmology, Fondation Ophtalmologique Adolphe de Rothschild †Department of Ophthalmology, Centre National d'Ophtalmologie des XV-XX ‡Centre Ophtalmologique d'Imagerie et de Laser, Paris, France.

Purpose: Type 2 retinal arteriovenous communication is characterized by direct arteriovenous communication without an intervening arteriolar or capillary segment. It may be complicated by extravascular exudation. The successful results of low-intensity argon laser photocoagulation in two cases are reported.

Methods: Case report of two patients.

Results: Both cases were associated with a serous macular detachment, showing evidence of vascular leakage. Argon laser photocoagulation was performed. Visual improvement was observed in both cases, with disappearance of vascular leakage.

Conclusion: Type 2 arteriovenous communications lead to increased arterial flow through a low-resistance vein. The resulting high intraluminal pressure may explain the observed vascular ectasia and consequent fluid leakage. Spontaneous regression may occur. Nevertheless, direct argon laser photocoagulation may be considered a therapeutic option and lead to visual improvement.
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http://dx.doi.org/10.1097/ICB.0b013e31826f0927DOI Listing
January 2015