RESUMO
A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
Assuntos
Antígeno CD47/metabolismo , Cromossomos Humanos Par 10/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Degeneração Macular/genética , Osteopontina/metabolismo , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Sítios de Ligação/fisiologia , Células COS , Linhagem Celular , Chlorocebus aethiops , Olho/patologia , Predisposição Genética para Doença/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Humanos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Transdução de Sinais/genéticaRESUMO
INTRODUCTION: Central retinal vein occlusions are not well-known complications of SARS-CoV-2 infection. We describe a case of central retinal vein occlusion secondary to COVID-19, and a review of the literature was performed. HISTORY AND SIGNS: A 47-year-old woman with no underlying ocular or medical condition presented to the hospital complaining about sudden onset of multiple scotomas in her left eye. A COVID-19 infection was confirmed 2 days previously by a PCR test that was performed 2 days after the onset of symptoms. Medical history revealed no risk factors and no oral contraception. Her best-corrected visual acuity was 1.0 in the right eye and 0.04 in the left eye. Clinical exam showed a left relative afferent pupillary defect and a nasally localized papilledema on fundoscopy of the left eye. Multiple dot and blot hemorrhages were also present. Optical coherence tomography revealed cystoid macular edema and paracentral acute middle maculopathy. The results of the fluoresceine angiography were consistent with central retinal vein occlusion. Laboratory workup later revealed an elevated fibrinogen level, corresponding to the COVID-19-induced hypercoagulable state. No other prothrombotic conditions were found. The patient immediately received an intravitreal injection of Lucentis (ranibizumab) after diagnosis. Complete resolution of the retinal hemorrhages and papilledema was observed 1.5 months after treatment and the final visual acuity was 1.25 in the left eye. CONCLUSION: Coagulation abnormalities are frequently observed in infectious diseases such as COVID-19 infection and the resulting prothrombotic state can sometimes lead to retinal vascular complications, including central retinal vein occlusion, irrespective of the presence of other classical risk factors. The consideration of this information could help clinicians establish a prompt diagnosis and therefore appropriate treatment, which could hopefully lead to complete healing of retinal lesions.
Assuntos
COVID-19 , Papiledema , Oclusão da Veia Retiniana , Humanos , Feminino , Pessoa de Meia-Idade , Oclusão da Veia Retiniana/diagnóstico , Oclusão da Veia Retiniana/tratamento farmacológico , Oclusão da Veia Retiniana/etiologia , Papiledema/diagnóstico , Papiledema/tratamento farmacológico , Papiledema/etiologia , COVID-19/complicações , COVID-19/diagnóstico , SARS-CoV-2 , Ranibizumab , Injeções Intravítreas , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodos , Inibidores da Angiogênese/uso terapêuticoRESUMO
PURPOSE: To investigate the visual and anatomical impact of intravitreal injection treatment deferral because of the COVID-19 lockdown on patients affected by neovascular age-related macular degeneration. METHODS: We retrospectively reviewed 314 patients (394 eyes) who were scheduled to receive the impact of intravitreal injections during the Swiss lockdown. We compared patients who continued to receive scheduled impact of intravitreal treatment without clinical consultation (Group Continue ?C"; n = 215) and patients for whom the impact of intravitreal treatment was completely deferred (Group Stop, ?S"; n = 179). Functional and anatomical parameters were collected at four time points before and after the lockdown. RESULTS: In Group C, the visual acuity at baseline and after the lockdown did not differ significantly. In Group S, the visual acuity deteriorated significantly compared with baseline and then improved slightly after the resumption of treatment, but it did not recover to baseline values. The mean central subfield thickness remained stable in Group C, whereas it increased in Group S and then returned to prelockdown values after the resumption of treatment. CONCLUSION: An "injection-only" approach was effective in managing patients with neovascular age-related macular degeneration during the pandemic lockdown, whereas patients who deferred their scheduled treatment showed partially irreversible deterioration of visual function. We recommend treatment continuation in patients with neovascular age-related macular degeneration during a lockdown.
Assuntos
COVID-19 , Degeneração Macular , Degeneração Macular Exsudativa , Inibidores da Angiogênese/uso terapêutico , COVID-19/epidemiologia , Controle de Doenças Transmissíveis , Humanos , Injeções Intravítreas , Degeneração Macular/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Degeneração Macular Exsudativa/tratamento farmacológicoRESUMO
PURPOSE: To report the clinical features and treatment outcomes of patients with macular hole coexistent with rhegmatogenous retinal detachment surgically treated with pars plana vitrectomy and inverted internal limiting membrane flap technique. METHODS: Eleven consecutive patients with rhegmatogenous retinal detachment and macular hole who underwent vitrectomy and internal limiting membrane peeling with the inverted flap technique between December 2017 and February 2021 were retrospectively evaluated. The main outcome measures were retinal reattachment rate, macular hole closure rate, and postoperative best-corrected visual acuity. A nonsystematic literature review was performed to compare the study outcomes with those previously reported. RESULTS: The primary retinal reattachment rate was 90% (10/11) with one surgery and 100% with 2 surgical procedures. Macular hole closure was achieved in all patients (11/11). All patients showed an improvement in visual acuity at the final postoperative visit, and the mean postoperative best-corrected visual acuity was 0.60 ± 0.32 logarithm of the minimum angle of resolution (20/80 Snellen equivalent). CONCLUSION: Vitrectomy with the inverted internal limiting membrane flap technique achieved not only favorable anatomical retinal reattachment rates but also an encouraging recovery of central macular anatomy and visual function in patients with macular hole coexistent with rhegmatogenous retinal detachment.
Assuntos
Descolamento Retiniano , Perfurações Retinianas , Membrana Basal/cirurgia , Humanos , Descolamento Retiniano/complicações , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/cirurgia , Perfurações Retinianas/complicações , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/cirurgia , Estudos Retrospectivos , Tomografia de Coerência Óptica , Vitrectomia/métodosRESUMO
BACKGROUND AND OBJECTIVES: Brolucizumab is a novel anti-vascular endothelial growth factor (VEGF), whose efficacy has been shown in the Hawk and Harrier phase 3 clinical studies. The goal of the present case series is to report initial results of brolucizumab intravitreal injections (IVI) on type 3 neovascularization in neovascular age-related macular degeneration (nAMD), evaluated by optical coherence tomography angiography (OCTA). MATERIALS AND METHODS: This is a bicentric retrospective case series. Patients with newly diagnosed type 3 MNV treated with brolucizumab IVI and at least 6 months follow-up were enrolled. OCTA en face images and B-scans were analyzed for lesions at baseline, 1 month, 3 months, and 6 months. Whenever detectable, lesion area on outer retina and choriocapillaris layers was measured. RESULTS: Twelve eyes of 12 patients were included into the study. The most consistent OCTA sign at baseline was the presence of a vascular tuft in the outer retina (100%). The highest response was achieved at 3 months, with statistically significant decrease in lesion detection in the outer retina, in the choriocapillaris, and outer retinal lesion size. At 6 months, 58% of outer retinal lesions had disappeared. CONCLUSIONS: Brolucizumab IVI shows a good short-term efficacy for the treatment of type 3 neovascularizations. Further studies with greater number of patients and longer follow-up are warranted to confirm these findings.
Assuntos
Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular , Anticorpos Monoclonais Humanizados , Fatores de Crescimento Endotelial , Angiofluoresceinografia/métodos , Humanos , Injeções Intravítreas , Neovascularização Patológica , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Acuidade VisualRESUMO
PURPOSE: To evaluate 18 months' results of a strict anti-vascular endothelial growth factor protocol for radiation maculopathy following proton therapy in choroidal melanoma. METHODS: Retrospective, comparative, nonrandomized study of 74 radiation maculopathy patients presenting macular lipid deposits, hemorrhages, microaneurysms, cystoid edema, nerve layer infarction, telangiectasia, or capillary nonperfusion. The study group included 52 consecutive patients injected with intravitreal anti-vascular endothelial growth factors (bevacizumab/ranibizumab: 46/6) every two months for the first and every 3 months for the second year, with minimum 12 months' follow-up. The control group consisted of 22 patients having declined this treatment. Best-corrected visual acuity, spectral domain-optical coherence tomography and optical coherence tomography angiography were recorded at baseline, 6, 12, and 18 months. The foveal avascular zone and capillary density were measured at the superficial capillary plexus. RESULTS: Radiation maculopathy was diagnosed at 2 years (1.5-3.5) after proton therapy. Best-corrected visual acuity at baseline, 12 and 18 months improved in the study group from 0.45, 0.3 to 0.2 logarithm of the minimum angle of resolution, but decreased in the control group from 0.5, 0.9 to 1.0 logarithm of the minimum angle of resolution respectively (P < 0.001 at 12 months). Simultaneously, foveal avascular zone enlargement was less in the study (from 0.377, 0.665 to 0.744 mm2) than control group (from 0.436, 1.463 to 2.638 mm2) (P = 0.05 at 12 months). CMT (280 and 276 µm) and capillary density (37% and 38%, at baseline, respectively) did not evolve significantly different. CONCLUSION: Intravitreal anti-vascular endothelial growth factors, every 2 months for the first and every 3 months for the second year, slow down, over up to 18 months, vision loss and anatomical degradation in radiation maculopathy following proton therapy for choroidal melanoma.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Neoplasias da Coroide/radioterapia , Macula Lutea/efeitos da radiação , Melanoma/radioterapia , Microcirculação/efeitos dos fármacos , Terapia com Prótons/efeitos adversos , Doenças Retinianas/diagnóstico por imagem , Idoso , Bevacizumab/administração & dosagem , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Humanos , Injeções Intravítreas , Macula Lutea/diagnóstico por imagem , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Ranibizumab/administração & dosagem , Doenças Retinianas/diagnóstico , Doenças Retinianas/etiologia , Estudos Retrospectivos , Fatores de Tempo , Tomografia de Coerência Óptica , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade VisualRESUMO
We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis.
Assuntos
Diabetes Mellitus Tipo 2/genética , Retinopatia Diabética/genética , Edema Macular/genética , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Humor Aquoso/metabolismo , Diabetes Mellitus Tipo 2/patologia , Retinopatia Diabética/patologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Edema Macular/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: To evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV). METHODS: OLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab. RESULTS: The mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22-85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03-124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55-513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline < 10 letters (OR [95%CI]: 17.60 [1.39-222.75]) were the factors with the greatest effect on retreatment with ranibizumab. The mean (SD) BCVA gain from baseline to month 12 was 8.4 (12.8) letters (P < 0.0001). The mean (SD) number of injections was 2.41 (1.53); range 1-9. Ocular and non-ocular adverse events were reported in 41 (20.5%) and 30 (15.0%) patients, respectively. CONCLUSIONS: Individualized treatment with ranibizumab was effective in improving BCVA in patients with mCNV over 12 months. Both anatomical and functional variables had significant effects on causing retreatment. There were no new safety findings. TRIAL REGISTRATION: www.ClinicalTrials.Gov (NCT No: NCT02034006).
Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Miopia Degenerativa/tratamento farmacológico , Ranibizumab/uso terapêutico , Transtornos da Visão/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neovascularização de Coroide/complicações , Neovascularização de Coroide/fisiopatologia , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Miopia Degenerativa/etiologia , Miopia Degenerativa/fisiopatologia , Estudos Prospectivos , Retratamento , Líquido Sub-Retiniano , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologia , Acuidade Visual/fisiologia , Adulto JovemRESUMO
Technological advances in ophthalmology are becoming more and more important. New imaging instruments and software analysis allow ultra-wide field visualization of the retina non-invasively. This creates important clinical advantages for an aging population affected by chronic pathologies such as cataract, age related macular degeneration, and diabetic retinopathy. In particular, it will be possible to organize screening programs and an individualized approach and follow up of the patients. While new retinal implants are under development a new drug is now available for the treatment of corneal scars.
La technologie devient de plus en plus présente dans l'ophtalmologie. Les nouvelles modalités d'imagerie ainsi que les analyses automatisées permettent une visualisation de la rétine à haute résolution et à grand champ de façon non invasive. Les avantages du point de vue clinique pour la population qui vieillit et qui présente des pathologies chroniques (cataracte, dégénérescence maculaire liée à l'âge, rétinopathie diabétique) sont immédiats : organisation de dépistage et prise en charge individualisée des patients. Les développements des implants rétiniens progressent et un nouveau traitement pour les cicatrices cornéennes est désormais disponible.
Assuntos
Oftalmologia , Humanos , Processamento de Imagem Assistida por Computador , Oftalmologia/tendências , SoftwareRESUMO
Here we report novel mutations in ABCA4 with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of ABCA4 (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment (p = 0.002) and an earlier age of onset (p = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of ABCA4 underlying Stargardt disease.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Estudos de Associação Genética , Degeneração Macular/congênito , Transportadores de Cassetes de Ligação de ATP/sangue , Adolescente , Adulto , Códon sem Sentido , Estudos de Coortes , Simulação por Computador , Eletrorretinografia , Éxons , Feminino , França/epidemiologia , Heterozigoto , Humanos , Estudos Longitudinais , Degeneração Macular/sangue , Degeneração Macular/epidemiologia , Degeneração Macular/genética , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo , Doença de Stargardt , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To assess the safety and efficacy of E10030 (Fovista; Ophthotech, New York, NY), a platelet-derived growth factor (PDGF) antagonist, administered in combination with the anti-vascular endothelial growth factor (VEGF) agent ranibizumab (Lucentis; Roche, Basel, Switzerland) compared with ranibizumab monotherapy in patients with neovascular age-related macular degeneration (nAMD). DESIGN: Phase IIb global, multicenter, randomized, prospective, double-masked, controlled superiority trial. PARTICIPANTS: Four hundred forty-nine patients with treatment-naïve nAMD. METHODS: Participants were randomized in a 1:1:1 ratio to 1 of the following 3 intravitreal treatment groups: E10030 0.3 mg in combination with ranibizumab 0.5 mg, E10030 1.5 mg in combination with ranibizumab 0.5 mg, and sham in combination with ranibizumab 0.5 mg (anti-VEGF monotherapy). Drugs were administered monthly in each of the groups for a total duration of 24 weeks. MAIN OUTCOME MEASURES: The prespecified primary end point was the mean change in visual acuity (VA; Early Treatment Diabetic Retinopathy [ETDRS] letters) from baseline to 24 weeks. RESULTS: No significant safety issues were observed in any treatment group. The E10030 (1.5 mg) combination therapy regimen met the prespecified primary end point of superiority in mean VA gain compared with anti-VEGF monotherapy (10.6 compared with 6.5 ETDRS letters at week 24; P = 0.019). A dose-response relationship was evident at each measured time point commencing at 4 weeks. Visual acuity outcomes favored the E10030 1.5 mg combination therapy group regardless of baseline VA, lesion size, or central subfield thickness on optical coherence tomography. All clinically relevant treatment end points of visual benefit (≥15 ETDRS letter gain, final VA ≥20/40 or ≥20/25) and visual loss (≥1 ETDRS line loss, ≥2 ETDRS line loss, final VA ≤20/125 or ≤20/200) favored the E10030 1.5 mg combination group. CONCLUSIONS: In this phase IIb clinical trial, a 62% relative benefit from baseline was noted in the E10030 1.5 mg combination therapy group compared with the anti-VEGF monotherapy group. A favorable safety and efficacy profile of E10030 combination therapy for nAMD was evident across multiple clinically relevant end points. This highly powered study provides strong rationale for a confirmatory phase III clinical trial.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Aptâmeros de Nucleotídeos/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Ranibizumab/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravítreas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Acuidade VisualRESUMO
BACKGROUND: Although photodynamic therapy (PDT) has become the standard treatment for central serous chorioretinopathy (CSC), its mechanism of action remains unclear. It is assumed that PDT induces short-term choriocapillaris (CC) occlusion and long-term choroidal vascular remodeling. In this paper, we describe the short-term CC changes induced by Half-Dose PDT (HD-PDT) in chronic CSC using optical coherence tomography-angiography (OCTA). METHODS: This is a prospective interventional case series. Chronic CSC eyes underwent Spectral-Domain OCT, Fundus Autofluorescence, FA, ICGA (Heidelberg Spectralis, Heidelberg, Germany) and OCTA (RTVue XR Avanti with AngioVue; Optovue Inc., Fremont, CA, USA) before HD-PDT, with follow-up after one hour, one week, and one month. Vascular changes after PDT were analyzed within the CC layer. The CC vessel density was defined as the percentage of an area occupied by flow pixels, using Image J software to obtain measurements by applying a grey level threshold. All pixels with a grey level above the threshold were considered as indicators of blood flow. RESULTS: 20 eyes of 19 patients were included. At baseline the mean CC vessel density was 94.87 ± 2.32%. It significantly differed from the density at 1 week and 1 month (92.79 ± 3.16% and 95.55 ± 2.05%, p < 0.001, respectively), but not with values at 1 h (94.8 ± 2.28%, p = 0.516). CONCLUSIONS: CC vessel density was significantly reduced at 1 week as compared with baseline, suggesting a possible short-term effect of PDT on CC perfusion. After 1 month however, the CC vessel density was even higher than the baseline, probably due to a CC recovery. OCTA seems to be useful in the visualization of CC vessels and in confirming the mechanism of action of PDT treatment in eyes with chronic CSC.
Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Coriorretinopatia Serosa Central/diagnóstico por imagem , Corioide/diagnóstico por imagem , Fotoquimioterapia/efeitos adversos , Adulto , Idoso , Vasos Sanguíneos/efeitos da radiação , Coriorretinopatia Serosa Central/complicações , Coriorretinopatia Serosa Central/fisiopatologia , Coriorretinopatia Serosa Central/terapia , Corioide/irrigação sanguínea , Corioide/fisiopatologia , Feminino , Angiofluoresceinografia , Fundo de Olho , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica , Acuidade Visual/efeitos da radiaçãoRESUMO
Contrary to Alzheimer's disease (AD), the APOE2 allele increases and the APOE4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common APOE3 allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate in Cx3cr1-deficient mice due to the overexpression of APOE, interleukin-6, and CC chemokine ligand 2 (CCL2). We here show using targeted replacement mice expressing the human APOE isoforms (TRE2, TRE3, and TRE4) that MPs of TRE2 mice express increased levels of APOE, interleukin-6, and CCL2 and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of APOE-dependent subretinal inflammation in Cx3cr1(GFP/GFP) mice, the APOE4 allele led to diminished APOE and CCL2 levels and protected Cx3cr1(GFP/GFP) mice against harmful subretinal MP accumulation observed in Cx3cr1(GFP/GFP)TRE3 mice. Our study shows that pathogenic subretinal inflammation is APOE isoform-dependent and provides the rationale for the previously unexplained implication of the APOE2 isoform as a risk factor and the APOE4 isoform as a protective factor in AMD pathogenesis. SIGNIFICANCE STATEMENT: The understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human APOE isoform-defining sequences at the mouse APOE chromosomal location and express the human APOE isoforms. Our study is the first to show how APOE2 provokes and APOE4 inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of APOE in inflammation and inflammation in AMD.
Assuntos
Envelhecimento , Apolipoproteínas E/metabolismo , Regulação da Expressão Gênica/genética , Inflamação/etiologia , Degeneração Macular/complicações , Degeneração Macular/genética , Isoformas de Proteínas/metabolismo , Animais , Apolipoproteínas E/genética , Receptor 1 de Quimiocina CX3C , Proteínas de Ligação ao Cálcio/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas do Olho/genética , Feminino , Humanos , Inflamação/genética , Lasers/efeitos adversos , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/genética , Isoformas de Proteínas/genética , Receptores de Quimiocinas/genética , Retina/citologiaRESUMO
BACKGROUND: A macular hole is an anatomic opening in the retina that develops at the fovea. Macular holes can be seen in highly myopic eyes or following ocular trauma, but the great majority are idiopathic. Pars plana vitrectomy was introduced to treat full-thickness macular holes, which if left untreated have a poor prognosis since spontaneous closure and visual recovery are rare.Vitrectomy is a surgical technique involving the removal of the vitreous body that fills the eye. The surgeon inserts thin cannulas into the eyes through scleral incisions to relieve traction exerted by the vitreous or epiretinal membranes to the central retina and to induce glial tissue to bridge and close the hole. OBJECTIVES: The primary objective of this review was to examine the effects of vitrectomy for idiopathic macular hole on visual acuity. A secondary objective was to investigate anatomic effects on hole closure and other dimensions of visual function, as well as to report on adverse effects recorded in included studies. SEARCH METHODS: We searched the Cochrane Eyes and Vision Group Trials Register (4 March 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 2), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2015), EMBASE (January 1980 to March 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2015), the Web of Science Conference Proceedings Citation Index-Science (CPCI-S) (January 1980 to March 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 4 March 2015. SELECTION CRITERIA: We included randomised controlled trials comparing vitrectomy (with or without internal limiting membrane peeling) to no treatment (that is observation) for macular holes. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently extracted the data. We estimated best corrected visual acuity and macular hole closure at 6 to 12 months of follow-up. MAIN RESULTS: Three studies provided data on the comparison between vitrectomy and observation in eyes with macular hole and visual acuity less than 20/50. Two studies, conducted in the USA and published in 1996 and 1997, used a similar protocol and included participants with stage II macular hole (42 eyes randomised, 36 analysed, number of participants not reported) or participants with stage III/IV hole (129 eyes of 120 participants, 115 eyes in analyses). The third study, conducted in the UK and published in 2004, included 185 eyes of 174 participants with full-thickness macular hole (41 eyes with stage II holes and 74 eyes with stage III/IV holes in analyses). Studies were of good quality for randomisation and allocation concealment, whereas visual acuity measurement was unmasked.At 6 to 12 months, visual acuity was improved by about 1.5 Snellen lines (-0.16 logMAR, 95% confidence intervals -0.23 to -0.09 logMAR, 270 eyes, moderate-quality evidence). The chances of macular hole closure at 6 to 12 months were greatly increased using vitrectomy, yielding an odds ratio of 31.4 (95% confidence intervals 14.9 to 66.3, 265 eyes, high-quality evidence; raw sum data: 76% vitrectomy, 11% observation). Vitrectomy was beneficial both in smaller (stage II) and in larger (stage III/IV) macular holes.The largest study reported that cataract surgery was needed in about half of cases at two years after operation and that retinal detachment occurred in about 5% of operated eyes. AUTHORS' CONCLUSIONS: Vitrectomy is effective in improving visual acuity, resulting in a moderate visual gain, and in achieving hole closure in people with macular hole. However, these results may not apply to modern surgery due to technological improvements in vitrectomy techniques.
Assuntos
Perfurações Retinianas/cirurgia , Acuidade Visual , Vitrectomia/métodos , Extração de Catarata/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Descolamento Retiniano/epidemiologia , Vitrectomia/efeitos adversos , Conduta ExpectanteRESUMO
With the spread of the "omics" sciences, the approaches of systems biology can be considered as new paradigms of pharmacological research for discovery of novel targets and/or treatments for complex multifactorial diseases. Data from omics sciences can be used for the design of biologic networks, that in turn can be quantitatively analyzed to identify new pharmacological targets. In this review, we will introduce the concept of network pharmacology, particularly the application of this innovative approach in the field of ocular pharmacology, with a focus on retinal diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD) and glaucoma.
Assuntos
Retinopatia Diabética , Doenças Retinianas , Humanos , Farmacologia em Rede , Olho , Retinopatia Diabética/tratamento farmacológico , Descoberta de DrogasRESUMO
OBJECTIVES: The aim of this paper is to present two cases of severe idiopathic non-infectious paediatric panuveitis, unresponsive to traditional therapy, successfully treated with Adalimumab (HumiraTM, Abbott Pharmaceutical Inc.) in the long term. METHODS: The data of the two cases are presented and the literature is reviewed. RESULTS: At base line, case 1 had 0.2 in the RE and 0.5 in the LE, while case 2 had 0.5 and 0.4 in the RE and LE, respectively. The anterior chamber (AC) of case 1 had 3+ cells and 3+ flare in both eyes, as well as diffuse keratic precipitates (Kps). Case 2 presented 2+ cells and 3+ flare in both eyes, as well as tiny Kps in the inferior part of the endothelium. The Binocular Indirect Ophthalmoscopy (BIO) score was +2 in both eyes of case 1 and case 2 at first examination. After Adalimumab initiation, both patients presented a dramatic resolution of the ocular inflammation, as well as a rapid improvement of the BCVA. Case 1 had 0.8 and 1.0 in the RE and the LE, respectively, while case 2 presented 1.0 in both eyes. At the last visit, both patients presented a quiet uveitis and stable BCVA: case 1 had 0.8 and 1.0 in the RE and the LE, respectively, while case 2 presented 1.0 in both eyes. No side effects were recorded during this time. CONCLUSIONS: Adalimumab can be a promising drug for the therapy of severe, refractory paediatric uveitis, although further studies are needed on its application in uveitis.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Pan-Uveíte/tratamento farmacológico , Adalimumab , Adolescente , Criança , Feminino , Humanos , MasculinoRESUMO
PURPOSE: To describe a unique unilateral association between an iris stromal tumor and a macular focal choroidal excavation. CASE DESCRIPTION: A 40-year old patient presented with a small iris tumor associated with a unilateral macular lesion disclosed during a routine ophthalmologic examination. The patient was asymptomatic and visual function was not affected. After clinical and instrumental evaluation, a diagnosis of nonmelanocytic undefined stromal tumor of the iris associated with macular focal choroidal excavation was made. The size and shape of the two lesions remained stable during a 7-year follow-up and the patient did not develop other signs. CONCLUSION: The concurrent presence of a stromal iris tumor associated with focal choroidal excavation has never been reported. Further reports of this association are required in order to understand its exact pathogenesis.
Assuntos
Doenças da Coroide , Neoplasias da Íris , Humanos , Adulto , Doenças da Coroide/diagnóstico , Neoplasias da Íris/complicações , Neoplasias da Íris/diagnóstico , Neoplasias da Íris/patologia , Tomografia de Coerência Óptica , Angiofluoresceinografia , Corioide/patologiaRESUMO
Understanding the factors that influence the human perception of glare is necessary to properly address glare risks in buildings and achieve comfortable visual environments, especially in the workplace. Yet large inter-individual variabilities in glare perception remain unexplained and thus uncovered by the current empirical glare models. We hypothesize that this variability has an origin in the human retina, in particular in the density of macular pigments present in its central area, which varies between individuals. Macular pigments are known to absorb blue light and attenuate chromatic aberration, thus reducing light scatter. This study presents the outcomes of the first experiment ever conducted in a daylit office environment, in which glare sensitivity and macular pigment density were measured and compared for 110 young healthy individuals, along with other ocular parameters. The participants were exposed to different glare conditions induced by the sun filtered through either color-neutral or blue-colored glazing. In neutral daylight conditions with sun disc in the near periphery, neither macular pigment nor any other investigated ocular factors have an impact on discomfort glare perception whereas glare perception in conditions with the blue-colored sun disc in the near periphery was found to be correlated with macular pigment optical density.
Assuntos
Macula Lutea , Pigmento Macular , Humanos , Ofuscação , Pigmentos da Retina , Luz , Sensibilidades de ContrasteRESUMO
OBJECTIVE: We present a portable automatic kinetic perimeter based on a virtual reality (VR) headset device as an innovative and alternative solution for the screening of clinical visual fields. We compared the performances of our solution with a gold standard perimeter, validating the test on healthy subjects. METHODS: The system is composed of an Oculus Quest 2 VR headset with a clicker for participant response feedback. An Android app was designed in Unity to generate moving stimuli along vectors, following a standard Goldmann kinetic perimetry approach. Sensitivity thresholds are obtained by moving centripetally three different targets (V/4e, IV/1e, III/1e) along 24 or 12 vectors from an area of non-seeing to an area of seeing and then transmitted wirelessly to a PC. A Python real-time algorithm processes the incoming kinetic results and displays the hill of vision in a two-dimensional map (isopter). We involved 21 subjects (5 males and 16 females, age range 22-73 years) for a total of 42 eyes tested with our proposed solution, and results were compared with a Humphrey visual field analyzer to test reproducibility and efficacy. RESULTS: isopters generated with the Oculus headset were in good agreement with those acquired with a commercial device (Pearson's correlation values r > 0.83 for each target). CONCLUSIONS: we demonstrate the feasibility of VR kinetic perimetry by comparing performances between our system and a clinically used perimeter in healthy subjects. SIGNIFICANCE: proposed device leads the way for a portable and more accessible visual field test, overcoming challenges in current kinetic perimetry practices.
Assuntos
Realidade Virtual , Testes de Campo Visual , Cinética , Testes de Campo Visual/instrumentação , Testes de Campo Visual/métodos , Humanos , Masculino , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Dispositivos Eletrônicos Vestíveis , Reprodutibilidade dos Testes , Voluntários SaudáveisRESUMO
Anti-vascular endothelial growth factor (anti-VEGF) therapies have become the standard of care in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), resulting in a remarkable decrease in disease-related vision loss. However, the need for regular injections places a significant burden on patients, caregivers, and the healthcare system and improvements in vision may not be maintained long term. As a result of its drying potency and duration of action, brolucizumab, an intravitreal anti-VEGF therapy approved for the treatment of nAMD and DME, could decrease injection frequency for patients and provide an efficacious treatment; however, balancing its benefits and risks can be challenging. There have been reports of intraocular inflammation (IOI) in patients treated with brolucizumab, which, if left untreated, may result in severe vision loss. Recent evidence, however, indicates that early recognition of IOI and prompt and aggressive systemic corticosteroid treatment in response to posterior segment involvement can lead to favorable outcomes in these relatively rare but severe cases. A series of consensus meetings were conducted in 2022 between Swiss medical retina experts and diabetologists, discussing the current data for brolucizumab and exploring various challenges to its use, including the associated risk of IOI. The outcome is a collation of practical insights and guidance for ophthalmologists on the use of brolucizumab in patients with nAMD and DME, including patient selection and assessment, treatment regimen and monitoring, and the recognition and management of adverse events.