Role of inflammation in a rat model of radiation retinopathy.

Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive microvasculopathy, ischemia and macular edema, ultimately leading to vision loss, neovascular glaucoma, and, in extreme cases, secondary enucleation. Intravitreal anti-VEGF agents, steroids and laser photocoagulation have limited effects on RR. The role of retinal inflammation and its contribution to the microvascular damage occurring in RR remain incompletely understood. To explore cellular and vascular events after irradiation, we analyzed their time course at 1 week, 1 month and 6 months after rat eyes received 45 Gy X-beam photons. Müller glial cells, astrocytes and microglia were rapidly activated, and these markers of retinal inflammation persisted for 6 months after irradiation. This was accompanied by early cell death in the outer retina, which persisted at later time points, leading to retinal thinning. A delayed loss of small retinal capillaries and retinal hypoxia were observed after 6 months, indicating inner blood‒retinal barrier (BRB) alteration but without cell death in the inner retina. Moreover, activated microglial cells invaded the entire retina and surrounded retinal vessels, suggesting the role of inflammation in vascular alteration and in retinal cell death. Radiation also triggered early and persistent invasion of the retinal pigment epithelium by microglia and macrophages, contributing to outer BRB disruption. This study highlights the role of progressive and long-lasting inflammatory mechanisms in RR development and demonstrates the relevance of this rat model to investigate human pathology.

Immunohistochemical characterisation of the immune landscape in primary uveal melanoma and liver metastases.

BACKGROUND: The immune landscape of uveal melanoma liver metastases (UMLM) has not been sufficiently studied. METHODS: Immune cell infiltrates (ICIs), PD-1 and PD-L1 were characterised in 62 UMLM and 28 primary uveal melanomas (PUM). ICI, PD-1 and PD-L1 were scored as: (1) % tumoral area occupied by tumour-infiltrating lymphocytes or macrophages (TILs, TIMs) and (2) % perTumoral (perT) area. ICIs and other variables including histopathologic growth patterns (HGPs), replacement and desmoplastic, of UMLM were analysed for their prognostic value. RESULTS: ICIs recognised by haematoxylin-eosin-saffron (HES) and IHC (e.g., T cells (CD3), B cells (CD20). Macrophages (CD68), (CD163), were primarily localised to the perT region in PUM and UMLM and were more conspicuous in UMLM. HES, CD3, CD4, FoxP3, CD8, CD20, PD-1 TILs were scant (<5%). TIMs were more frequent, particularly in UMLM than in PUM. Both CD68+ TIMs and HGPs remained significant on multivariate analysis, influencing overall (OS) and metastasis-specific overall survival (MSOS). CD68 + , CD163+ and CD20+ perT infiltrates in UMLM predicted increased OS and MSOS on univariate analysis. CONCLUSIONS: TILs and PD-L1 have no predictive value in PUM or UMLM. CD68+ and CD163+TIMs, CD20+ perT lymphocytes, and HGPs are important prognostic factors in UMLMs.

L1CAM and laminin vascular network: Association with the high-risk replacement histopathologic growth pattern in uveal melanoma liver metastases.

The replacement histopathologic growth pattern (rHGP) in melanoma liver metastases connotes an aggressive phenotype (vascular co-option; angiotropic extravascular migratory spread) and adverse prognosis. Herein, replacement and desmoplastic HGP (dHGP) were studied in uveal melanoma liver metastases (MUM). In particular, L1CAM and a "laminin vascular network" were detected at the advancing front of 14/20 cases (p = 0.014) and 16/20 cases (p = 6.4e-05) rHGPs, respectively, but both were absent in the dHGP (8/8 cases) (p = 0.014, and p = 6.3e-05, respectively). L1CAM highlighted progressive extension of angiotropic melanoma cells along sinusoidal vessels in a pericytic location (pericytic mimicry) into the hepatic parenchyma. An inverse relationship between L1CAM expression and melanin index (p = 0.012) suggested differentiation toward an amelanotic embryonic migratory phenotype in rHGP. Laminin labeled the basement membrane zone interposed between sinusoidal vascular channels and angiotropic melanoma cells at the advancing front. Other new findings: any percentage of rHGP and pure rHGP had a significant adverse effect on metastasis-specific overall survival (p = 0.038; p = 0.0064), as well as predominant rHGP (p = 0.0058). Pure rHGP also was associated with diminished metastasis-free survival relative to dHGP (p = 0.040), possibly having important implications for mechanisms of tumor spread. In conclusion, we report for the first time that L1CAM and a laminin vascular network are directly involved in this high-risk replacement phenotype. Further, this study provides more detailed information about the adverse prognostic effect of the rHGP in MUM.

CLINICAL FEATURES OF RETINAL METASTASES: New Cases Integrated in a Systematic Review of the Literature.

PURPOSE: To report a cohort of patients diagnosed with retinal metastases (RM), and to integrate these new cases in a systematic review of the literature, analyzing the clinical features and prognosis factors of patients with RM. METHODS: We conducted a retrospective multicenter study including patients with RM. We also performed a full literature review of all published cases with a diagnosis of RM. RESULTS: A total of six new cases were described on multimodal imaging. By combining the data from the literature and from our patients, we report the characteristics of a total of 69 patients. The most frequent primary tumor sites were cutaneous melanoma (36%), lung (23%), gastrointestinal tract (17%), and breast (12%). Multimodal imaging highlighted specific characteristics of RM. Fluorescein and indocyanine green angiography revealed early hypofluorescence followed by progressive filling of intrinsic dilated vessels. Optical coherence tomography demonstrated a hyperreflective intraretinal mass in all cases with or without subretinal fluid, hyperreflective intraretinal dots, or intraretinal fluid. Ultrasonography revealed a medium-high reflective dome-shaped tumor. Fifty-nine percent of the patients died during the follow-up with a mean survival time of 8.8 ± 8.7 months. CONCLUSION: We described here the clinical spectrum of RM and highlighted specific features of the disease.

Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.

Ocular Spiroplasma ixodetis in Newborns, France.

Cataract and uveitis are rare in newborns but potentially blinding. Three newborns with cataract and severe anterior uveitis underwent cataract surgery. Spiroplasma ixodetis was detected in lens aspirates using bacterial 16S-rRNA PCR and transmission electron microscopy. These findings, which suggest maternal-fetal infection, are consistent with previous experimental Spiroplasma-induced cataract and uveitis.

Levels of the oxidative stress biomarker malondialdehyde in tears of patients with central serous chorioretinopathy relate to disease activity.

Purpose: Central serous chorioretinopathy (CSCR) has been associated with oxidative stress-related risk factors. The objective of this study was to optimize an analytical method for evaluating the oxidative stress biomarker malondialdehyde (MDA) in human tears and determine its level in the tears of patients with CSCR. Methods: In this pilot study, tear samples were obtained from 34 healthy donors and 31 treatment-naïve CSCR male patients (eight with acute CSCR and 23 with chronic CSCR). Two analytical methods based on high-performance liquid chromatography followed by fluorescence detection were evaluated, with either 2-thiobarbituric derivative (TBA) or 2-aminoacridone (2-AA). Activity of CSCR was defined by the serous retinal detachment (SRD) height, which was measured by two independent observers on spectral-domain optical coherence tomography. Results: The 2-AA method showed higher sensitivity and precision compared to the TBA method. When the 2-AA method was applied to tears from healthy donors, the levels of MDA were statistically significantly higher in men compared to women (mean ± standard deviation, SD: 9,914 nM ± 6,126 versus 4,635 nM ± 1,173, p = 0.006). No difference was found in tear MDA levels between male patients with CSCR and age-matched control men (p = 0.17). However, MDA levels were statistically significantly higher in acute compared to chronic CSCR cases (mean ± SD: 12,295 nM ± 8,495 versus 6,790 ± 3,969 nM, p = 0.03). Additionally, there was a correlation between MDA levels and RPE leakage, quantified by the height of the serous retinal detachment (p = 0.02, r = 0.40). Conclusions: Levels of MDA in tears, measured with an optimized analytical method, correlate with RPE leakage in CSCR.

INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR TREATMENT AT 2-MONTH INTERVALS REDUCES FOVEAL AVASCULAR ZONE ENLARGEMENT AND VISION LOSS IN RADIATION MACULOPATHY: A Pilot Study.

PURPOSE: To evaluate, in eyes with radiation maculopathy, the effect of 2-month-interval anti-vascular endothelial growth factor therapy on best-corrected visual acuity and foveal avascular zone (FAZ) enlargement using optical coherence tomography angiography. METHODS: Consecutive treatment-naive patients with radiation maculopathy after proton beam irradiation for choroidal melanoma were retrospectively included. Clinical and optical coherence tomography angiography data at baseline and the 6-month visit were recorded. Two independent observers measured FAZ area manually on 3 × 3-mm optical coherence tomography angiography images of the superficial capillary plexus and deep capillary plexus. Patients were encouraged to follow strictly a 2-month-interval intravitreal anti-vascular endothelial growth factor treatment by either bevacizumab or ranibizumab. Findings were analyzed based on the adherence to the treatment scheme. RESULTS: According to the adherence to the bimonthly anti-vascular endothelial growth factor treatment protocol, patients were categorized into 3 groups: treatment protocol (n = 19, strict adherence), variable intervals (n = 11, intervals other than 2 months), and no treatment (n = 11). The estimated radiation dose to the foveola in each group was 49 ± 16, 46 ± 17, and 46 ± 18 cobalt gray equivalent, respectively (P = 0.85). For the entire cohort, best-corrected visual acuity loss (P < 0.02) and FAZ enlargement (P < 0.0001) were observed over 6 months. Best-corrected visual acuity loss was significantly less pronounced in the treatment-protocol group than in the variable-interval and no-treatment groups (P = 0.007 and P = 0.004). The FAZ enlargement was lower in the treatment-protocol group compared with the variable-interval group for both superficial capillary plexus (P = 0.029) and deep capillary plexus (P = 0.03), and to the no-treatment group for the deep capillary plexus only (P = 0.016). CONCLUSION: Decrease in best-corrected visual acuity and FAZ enlargement on optical coherence tomography angiography occurred over 6 months in eyes with radiation maculopathy and were significantly reduced under 2-month-interval anti-vascular endothelial growth factor therapy.

PATTERNS OF CHORIOCAPILLARIS FLOW SIGNAL VOIDS IN CENTRAL SEROUS CHORIORETINOPATHY: An Optical Coherence Tomography Angiography Study.

PURPOSE: To investigate choriocapillaris flow signal void distribution on optical coherence tomography (OCT) angiography in central serous chorioretinopathy (CSCR) and its correlation to choroidal vessel morphology. METHODS: Fifty-three CSCR eyes (48 patients) and 34 healthy control eyes were included, retrospectively. Exclusion criteria were refractive error >2D, previous laser or photodynamic therapy, low-quality OCT angiography, or excessive shadowing artifacts. Choriocapillaris OCT angiography scans were processed by local-threshold binarization to identify signal voids, and extract their cumulative area. The locations of the two largest voids in each eye were reported on the corresponding enhanced depth imaging OCT raster scan. Choriocapillaris thickness and diameter of underlying outer choroidal vessels were measured at the level of flow voids and of adjacent outer choroidal vessels, not colocalizing with voids. RESULTS: There were 22 acute, 16 recurrent, and 15 chronic CSCR eyes. Total flow void area was larger in CSCR than control eyes. In univariate analysis, the total flow void area on OCT angiography increased with age (P = 0.0002), duration since CSCR diagnosis (P = 0.004), extension of autofluorescence alterations (P = 0.016), and CSCR severity (P < 0.0001). In multivariate analysis, age (P = 0.014) and CSCR type (P = 0.046) influenced independently the total flow void area. On enhanced depth imaging OCT, outer choroidal vessel diameter was higher (P < 0.0001), and choriocapillaris was thinner (P < 0.0001) at flow voids compared with adjacent sites, independently from eccentricity from the fovea. CONCLUSION: Choriocapillaris flow voids colocalize with choriocapillaris thinning and deep choroidal vessel dilation in CSCR eyes. Age and CSCR severity influence choriocapillaris flow, a key contributor to CSCR pathophysiology and clinical expression.

YOUNGER AGE AT PRESENTATION IN CHILDREN WITH COATS DISEASE IS ASSOCIATED WITH MORE ADVANCED STAGE AND WORSE VISUAL PROGNOSIS: A Retrospective Study.

PURPOSE: To determine the age distribution of children with Coats disease and the impact of age at diagnosis on the visual prognosis. METHODS: Consecutive Coats disease cases aged 18 years or younger at diagnosis were retrospectively included. Clinical and imaging parameters were analyzed by comparative, correlation, survival, univariate, and multivariate statistics. RESULTS: Ninety-eight patients were included. At diagnosis, mean age was 5.4 years ± 4.3 years (1 month-18 years). Younger age at diagnosis was correlated with more severe disease stage (P < 0.0001, r = -0.52), which was confirmed by survival analysis (P < 0.0001). Comparative analysis was performed between patients younger and older than 4 years at diagnosis. Leukocoria or strabismus was more frequent at presentation in patients younger than 4 years (P < 0.0001). Areas of peripheral nonperfusion and peripheral telangiectasia were more extensive at presentation in younger than older patients (P = 0.0003 and P = 0.039). Foveal sparing at diagnosis was less frequent in younger than older patients (2% vs. 23%, P = 0.002). The incidence of structural complications or enucleation during follow-up (mean duration: 5.9 years ± 4.5 years) was higher, and last-recorded visual acuity was lower in younger than older patients (P = 0.001 and P = 0.0009). Final logarithm of the minimal angle of resolution visual acuity was negatively correlated with age at diagnosis (P = 0.001, Spearman r = -0.42). Multivariate analysis indicated that disease stage (P < 0.0001), but not age at diagnosis (P = 0.07), independently influenced the last-recorded visual acuity. CONCLUSION: Onset of Coats disease in children of younger age is associated with more severe manifestations, more advanced stage, and worse visual outcome. Age, correlated with disease stage, should be considered a prognostic marker in Coats disease.

RISK FACTORS FOR RECURRENCES OF CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To describe recurrence patterns and investigate candidate risk factors for recurrences of central serous chorioretinopathy. METHODS: In 46 patients with acute central serous chorioretinopathy and follow-up >12 months after first episode resolution, parameters influencing recurrences were retrospectively evaluated using a frailty Cox proportional hazard survival model. Covariates included baseline systemic findings: age, gender, corticosteroid use, stress, shift work, sleep disorder, depression, allergy, cardiovascular risk; baseline optical coherence tomography findings: subfoveal choroidal thickness, pigment epithelial detachment pattern (regular/bump/irregular), number of subretinal hyperreflective foci at leakage site; baseline angiographic findings: fluorescein leakage intensity (intense/moderate/subtle/absent), hyperpermeability pattern on indocyanine-green angiography (focal/multifocal); and episode-related findings: duration and treatment of previous episode. RESULTS: Twenty of 46 subjects (43%) presented ≥1 recurrences during a mean follow-up of 29.9 ± 9.5 months (range, 15-54 months). Follow-up duration did not differ between cases with or without recurrences (P = 0.3). Worse final visual acuity levels (logarithm of the minimal angle of resolution) were associated with a higher number of episodes during follow-up (P = 0.032, r = 0.28). In a univariate analysis, higher subfoveal choroidal thickness (P = 0.021), nonintense fluorescein leakage (= moderate/subtle/absent, P = 0.033), multiple subretinal hyperreflective foci (P = 0.026), and shift work (P < 0.0001) were significantly associated with recurrences, with a near-significant influence of irregular pigment epithelial detachment (P = 0.093). In a multivariate analysis, higher subfoveal choroidal thickness (P = 0.007), nonintense fluorescein leakage (P = 0.003) and shift work (P < 0.0001) remained significant and independent risk factors for recurrences. CONCLUSION: Multiple factors influence the risk of central serous chorioretinopathy recurrence. These findings may contribute to identify patients at higher risk, who could benefit from earlier or more intensive treatment.

CONCURRENT IDIOPATHIC MACULAR TELANGIECTASIA TYPE 2 AND CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To describe cases presenting with features of idiopathic macular telangiectasia (MacTel) Type 2 and central serous chorioretinopathy (CSC). METHODS: Databases from four tertiary retina centers were searched for cases copresenting CSC and MacTel Type 2. RESULTS: Five cases were identified (4 men, 1 woman; mean age: 67.2 years). Four patients were referred for chronic or nonresolving CSC, and the diagnosis of MacTel Type 2 was made based on multimodal imaging findings. One patient had advanced MacTel Type 2, and developed acute CSC. Regarding the MacTel Type 2 findings, all subjects presented perifoveal telangiectasia on fluorescein angiography, and four subjects showed intraretinal cavitations typical of MacTel Type 2 on optical coherence tomography, in one or both eyes. Regarding the CSC findings, fluorescein angiography identified focal or extended retinal pigment epithelium alteration in all eyes, and an active leakage in two eyes. Indocyanine green angiography showed choroidal vascular hyperpermeability in four subjects. On optical coherence tomography, pigment epithelial detachments were detected in five eyes (four subjects), and foveal detachments were present in five eyes (three subjects), which spontaneously resolved (two eyes), responded to photodynamic therapy (two eyes), or persisted (one eye). Mean choroidal thickness was 402 ± 99 µm. CONCLUSION: The codiagnosis of CSC and MacTel Type 2 should be considered in atypical presentations associating features from both disorders.

SUBFOVEAL NODULE IN COATS' DISEASE: Toward an Updated Classification Predicting Visual Prognosis.

PURPOSE: To determine the prevalence, clinical characteristics and nature of subfoveal nodules in Coats' disease and the associated impact on the long-term visual outcome. METHODS: Consecutive cases of Coats' disease with foveal exudation were retrospectively reviewed. The presence of a subfoveal nodule or macular fibrosis was recorded. Clinical characteristics, retinal imaging, and outcome were analyzed by comparative analysis. The histopathological description of an enucleated eye with subfoveal nodule was performed. RESULTS: Among 40 patients presenting unilateral Stage 2B or 3A1 Coats' disease, a subfoveal nodule was detected in 21 patients (52.5%). The median follow-up was 4.7 years. Nineteen patients (47.5%) did not present a subfoveal nodule. Three patients (15.8%) without subfoveal nodule and 21 patients (100%) with subfoveal nodule progressed to a macular fibrotic scar (P < 0.0001), and the mean time of macular fibrosis onset was 11.0 ± 2.6 months. Final visual acuity was significantly worse in patients who presented a subfoveal nodule at diagnosis (P = 0.01). Of 18 cases with subfoveal nodule who underwent fluorescein angiography, retinal-retinal anastomosis and neovascularization were detected in 13 (72.2%) and 2 eyes (11.1%), respectively. Histopathological analysis of a subfoveal nodule revealed an aggregate of proteinaceous material including fibrin, spindle cells, macrophages, and pigmented cells. CONCLUSION: The presence of a subfoveal nodule at presentation is a predictive factor for macular fibrosis development and worse visual outcome in patients with Coats' disease. These observations suggest an updated classification introducing two subcategories within Stage 2B: without subfoveal nodule (Stage 2B1) and with subfoveal nodule (Stage 2B2).

VOLUME-RENDERED ANGIOGRAPHIC AND STRUCTURAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY OF MACULAR TELANGIECTASIA TYPE 2.

PURPOSE: To evaluate multimodal imaging including volume-rendered angiographic and structural optical coherence tomography of macular telangiectasia Type 2 (MacTel2) for right-angle vein complexes, macular cavitations, and signs of deeper retinal vascular invasion. METHODS: Retrospective review of imaging performed in a community-based retinal referral center. The eyes were scanned using optical coherence tomography using split-spectrum amplitude-decorrelation techniques to derive flow information. These data were extracted and used to create volume-rendered images of the retinal vasculature with integrated structural information derived from the component optical coherence tomographic images. RESULTS: There were 24 eyes of 16 patients who had a mean age of 61.8 years. Right-angle veins seemed in association with vascular proliferation external to the deep vascular plexus. The origin of a right-angle vein was surrounded by a stellate arrangement of radiating retinal vessels apparently caused by contraction of surrounding tissue in the temporal macula. Cavitations were found in the fovea and varied in size and configuration from one examination to the next. Many smaller cavitations, called microcavitations, were seen in the surrounding macula. Vascular invasion occurred into the subretinal space. CONCLUSION: There are contractile features of the tissue in the temporal macula and the number, size, and temporal variations in the cavitations have not been in not mentioned in previous published descriptions of MacTel2. Vascular invasion of deeper layers occurred in the temporal macula through the outer nuclear layer. Volume-rendered angiographic and structural optical coherence tomography offers unprecedented ability to examine the vascular interrelationships their associations with cavitations in the macula.

ACUTE CENTRAL SEROUS CHORIORETINOPATHY: Factors Influencing Episode Duration.

PURPOSE: To evaluate the influence of clinical and multimodal imaging parameters on the duration of acute central serous chorioretinopathy (CSCR) episodes. METHODS: Consecutive patients with first, treatment-naïve central serous chorioretinopathy episodes presenting within 20 days of symptoms onset were prospectively included. They were reevaluated 15 days to 20 days later, followed by monthly evaluation for 6 months. Subfoveal choroidal thickness (SFCT), fluorescein leakage intensity on fluorescein angiography, elevation of retinal pigment epithelium (RPE) lesions at leakage sites, focal/multifocal pattern of indocyanine green angiography (ICGA) at baseline, time-dependent pattern of subretinal fluid (SRF) resorption on OCT using volume segmentation, history of corticosteroid intake and mean blood pressure were evaluated using univariate (Log rank test) and multivariate (Cox proportional hazard regression) survival analysis. RESULTS: Thirty-one patients were included (26 men, 5 women, mean age: 40.0 ± 8.9 years, range: 24-58), of which 26 (84%) had episode resolution by 6 months. Using univariate analysis, episode duration was longer in cases with subfoveal choroidal thickness ≥500 µm (P = 0.0002), retinal pigment epithelium elevation at leakage sites ≥50 µm (P = 0.033), and a peak in subretinal fluid observed during follow-up (P = 0.013), and there was a near-significant association of intense fluorescein leakage (P = 0.074) with longer episodes. Using multivariate analysis, subfoveal choroidal thickness ≥500 µm (P = 0.017), retinal pigment epithelium elevation at leakage sites ≥50 µm (P = 0.010) and patient age ≥40 years (P = 0.010) were significantly and independently associated to longer episodes. Indocyanine green angiography pattern, corticosteroid intake, and blood pressure did not influence episode duration. CONCLUSION: Older age, higher subfoveal choroidal thickness, and higher degree of retinal pigment epithelium alteration at leakage sites are independent factors of longer acute central serous chorioretinopathy episodes.

EFFICACY OF INTRAVITREAL AFLIBERCEPT IN MACULAR TELANGIECTASIA TYPE 1 IS LINKED TO THE OCULAR ANGIOGENIC PROFILE.

PURPOSE: To evaluate intravitreal aflibercept in macular telangiectasia Type 1 (MacTel 1) patients and measure their ocular angiogenic profile. METHODS: Eight subjects with MacTel 1 refractory to bevacizumab, ranibizumab, or laser therapy and switched to aflibercept were included. Best-corrected visual acuity, central macular thickness, and cystic areas quantified on optical coherence tomography B-scans were assessed during 12 months. Perifoveal capillary densities were measured on optical coherence tomography angiography. Aqueous humor was sampled from six patients and eight control subjects undergoing cataract extraction. Growth factors were quantified using a multiarray immunoassay. RESULTS: Over 12 months, patients received 6.6 ± 1.4 (range, 5-8) intravitreal aflibercept injections. Twelve months after switching to aflibercept, best-corrected visual acuity increased by ≥5 letters in 5 of 8 patients, compared with preaflibercept levels. Mean best-corrected visual acuity improved from 79.6 (∼20/50) to 88.0 (∼20/35) Early Treatment Diabetic Retinopathy Study letters (P = 0.042), and central macular thickness decreased from 434 ± 98 µm to 293 ± 59 µm (P = 0.014). Compared with control subjects, the profile of angiogenic factors in MacTel 1 eyes revealed no difference in vascular endothelial growth factor-A levels but significantly higher levels of placental growth factor (P = 0.029), soluble vascular endothelial growth factor receptor-1 (sFlt-1; P = 0.013), vascular endothelial growth factor-D (P = 0.050), and Tie-2 (P = 0.019). Placental growth factor levels inversely correlated with both superficial and deep capillary plexus densities on optical coherence tomography angiography (P = 0.03). CONCLUSION: The clinical response to aflibercept coupled to the angiogenic profile of MacTel 1 eyes support the implication of the placental growth factor/Flt-1 pathway in MacTel 1.

[Ophthalmology in 2016 : the advent of ocular biomarkers]. / Ophtalmologie. L' avénement des biomarqueurs oculaires.

Precision medicine is the future. In all fields of medicine, optimized therapy aims at identifying individuals at risks in order to prevent diseases, to identify specific molecular targets in a specific patient, at a specific time, to administer optimized treatment with less side effects. To achieve this ambitious aim, biomarkers, which should be specific and sensitive predictive indicators of diseases, or of response to treatment or of a state of evolution of the disease, must be identified. The eye offers an easy access organ to collect directly media or tissue, which can serve to identify such markers. This paper summarizes recent advances in the identification of ocular biomarkers of ocular diseases but also of brain diseases.

La médecine de précision est la médecine du futur. Demain, on ne traitera plus un symptôme ou une maladie, on saura identifier les individus à risque de développer une maladie pour la prévenir, on traitera avec précision, une phase spécifique de la maladie chez un individu en particulier. Réaliser une thérapie optimisée, plus ciblée, associée à moins d'effets non spécifiques est notre objectif. Pour parvenir à cet objectif, des biomarqueurs doivent être définis et validés. L'œil est un organe isolé du reste de l'organisme par l'existence de barrières et par son privilège immunologique mais c'est aussi une fenêtre ouverte sur le cerveau. Les tissus et milieux oculaires sont une source insoupçonnée d'informations que les chercheurs commencent à découvrir. Cet article fait le point sur la médecine de précision en ophtalmologie.

EXTRAMACULAR FIBROSIS IN COATS' DISEASE.

PURPOSE: To determine the rate, risk factors, and outcome of extramacular fibrosis in Coats' disease. METHODS: Consecutive cases from a single center were retrospectively reviewed. Clinical characteristics and treatments were analyzed by comparative, multivariate, and survival approaches. RESULTS: Among 69 patients with Coats' disease, 28 (40.6%) showed evidence of extramacular fibrosis (mean follow-up: 58.2 months). Mean time of fibrosis onset was 17.4 months. Extent of retinal exudation and rate of exudative retinal detachment at baseline were significantly higher in eyes that developed extramacular fibrosis compared with those that did not (P < 0.001). Similarly, these parameters showed significant differences using multivariate (P < 0.05) and survival analysis (P < 0.001). Extension of telangiectasia, number of cryotherapy, or laser sessions, and treatment by anti-vascular endothelial growth factor were not associated with extramacular fibrosis. Final visual acuity was worse in patients with extramacular fibrosis (P < 0.001). The rates of tractional retinal detachment and macular fibrosis were higher in patients with extramacular fibrosis (39%.0 vs. 0% and 60.7% vs. 19.5%, respectively, P < 0.001). CONCLUSION: Extramacular fibrosis led to a worse visual prognosis and was associated with the extension of retinal exudation and the presence of exudative retinal detachment at diagnosis. Treatment should target a quick resolution of exudation to limit its development.

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window.

Systemic adalimumab induces peripheral corneal infiltrates: a case report.

BACKGROUND: Tumor necrosis factor-alpha inhibitors are widely used agents in the treatment of immune disorders such as rheumatoid arthritis and inflammatory bowel disease. Despite their anti-inflammatory action, paradoxical drug-induced inflammatory events have been occasionally associated with the use of infliximab, etanercept, and in a lesser extent adalimumab. However, eye involvement is uncommon and anterior uveitis is the only reported ocular adverse manifestation. It can be induced by etanercept, but has also been described during adalimumab therapy. We present here the first report of recurrent peripheral corneal infiltrates following subcutaneous injections of adalimumab. CASE PRESENTATION: A 34 year-old Caucasian woman with Crohn's disease presented to the emergency department with bilateral red eyes and discomfort 36 hours after she received her bimonthly dose of subcutaneous adalimumab. Examination revealed bilateral peripheral corneal infiltrates with characteristic features of immune infiltrates. Symptoms and infiltrates regressed after topical corticosteroid therapy, but recurred after each adalimumab injection over the following weeks. CONCLUSION: Paradoxical immune reactions associated with tumor necrosis factor-alpha inhibitors may result either from hypersensitivity mechanisms, or from immune-complex deposition via anti-adalimumab antibodies. Both mechanisms could explain this newly described manifestation. Care should be taken to search for corneal infiltrates in the event of red eye symptoms during adalimumab therapy since they respond to topical corticosteroids and do not necessarily prompt the discontinuation of the immunosuppressive therapy.