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A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity. [ABSTRACT FROM AUTHOR]

Laser Doppler holography is a planar blood flow imaging technique recently introduced in ophthalmology to image human retinal and choroidal blood flow non-invasively. Here we present a digital method based on the Doppler spectrum asymmetry that reveals the local direction of blood flow with respect to the optical axis in out-of-plane vessels. This directional information is overlaid on standard grayscale blood flow images to depict flow moving towards the camera in red and flow moving away from the camera in blue, as in ultrasound color Doppler imaging. We show that thanks to the strong contribution of backscattering to the Doppler spectrum in out-of-plane vessels, the local axial direction of blood flow can be revealed with a high temporal resolution, which enables us to evidence pathological blood flow reversals. We also demonstrate the use of optical Doppler spectrograms to quantitatively monitor retinal blood flow reversals. [ABSTRACT FROM AUTHOR]

Adaptive optics (AO)-enhanced en face retinal imaging, termed here AO ophthalmoscopy (AOO) has reached a level of robustness which fuels its increasing use in research and clinical centers. Here we will review the contribution of clinical AOO to the understanding and monitoring of 1) age-related macular degeneration and 2) vascular diseases. The main contributions of AOO to the phenotyping of AMD are a better identification of drusen, a better delineation of the limits of atrophy, and the identification of novel features such as punctate hyperreflectivity and mobile melanin-containing clumps. Characterization of progression of atrophy is facilitated by time-lapse imaging. In vessels, AOO enables the observation and measurement of parietal structures and the observation of microscopic pathological features such as small hemorrhages and inflammatory cell accumulations. [ABSTRACT FROM AUTHOR]

PURPOSE: To explore the anatomic correlation of the retinal cone mosaic on adaptive optics images. DESIGN: Retrospective nonconsecutive observational case series. METHODS: A retrospective review of the multimodal imaging charts of 6 patients with focal alteration of the cone mosaic on adaptive optics was performed. Retinal diseases included acute posterior multifocal placoid pigment epitheliopathy (n = 1), hydroxychloroquine retinopathy (n = 1), and macular telangiectasia type 2 (n = 4). High-resolution retinal images were obtained using a flood-illumination adaptive optics camera. Images were recorded using standard imaging modalities: color and red-free fundus camera photography; infrared reflectance scanning laser ophthalmoscopy, fluorescein angiography, indocyanine green angiography, and spectral-domain optical coherence tomography (OCT) images. RESULTS: On OCT, in the marginal zone of the lesions, a disappearance of the interdigitation zone was observed, while the ellipsoid zone was preserved. Image recording demonstrated that such attenuation of the interdigitation zone co-localized with the disappearance of the cone mosaic on adaptive optics images. In 1 case, the restoration of the interdigitation zone paralleled that of the cone mosaic after a 2-month follow-up. CONCLUSION: Our results suggest that the interdigitation zone could contribute substantially to the reflectance of the cone photoreceptor mosaic. The absence of cones on adaptive optics images does not necessarily mean photoreceptor cell death. [ABSTRACT FROM AUTHOR]

The article presents the discussion on showing an increasing risk of retinal vein occlusion (RVO) among patients with diabetes initiating sodium–glucose cotransporter 2 inhibitors (SGLT2i) including severe polyuria and dehydration occuring on treatment initiation.

Abstract: Niemann–Pick type C (NPC) disease is an inherited lysosomal storage disease and caused by mutations in Npc1 or Npc2, which mediate cooperatively the egress of cholesterol from lysosomes. The disease entails progressive neurodegeneration, whose cause is poorly understood. Here, we report that Npc1 is distributed in distinct layers of the mouse retina and that its deficiency causes striking retinal degeneration in 2-month-old mice with signs of age-related maculopathies. This includes impaired visual function, accumulation of lipofuscin in the retinal pigment epithelium layer, degeneration of photoreceptor outer segments, disruption of synaptic layers and an increase in autophagy markers in the ganglion cell layer. Moreover, the lack of Npc1 results in the upregulation of proteins that mediate cellular cholesterol release in the retina. Our findings suggest that Npc1 is required for normal retinal function and that its absence may serve as model to study age-related degeneration of the retina. [Copyright &y& Elsevier]

Abstract: We evaluated fundus imaging using a modified confocal scanning laser ophthalmoscope (cSLO) in mice. Examinations were performed in conscious, untrained mice. The largest field of view measured 1520×1520μ, with a significant interindividual variability, itself correlated to biometric variability. The composite field of view extended up to the ora serrata. The reflectance imaging associated light reflection from nerve fiber bundles and vessel walls, and absorption by hemoglobin and melanin. Light absorption by the pigment epithelium indeed increased the contrast of the nerve fiber layer, but impaired viewing of the choroid. Due to the confocal mode, fluorescence angiograms with clear separation of retinal and choroidal fluorescence could be obtained even in albino mice. Micrometric-scale transverse resolution and several planes of optical sectioning within the retina were obtained. This permitted for instance tridimensional, subcellular viewing of gfp-expressing retinal microglial cells in CX3CR1 mice. We concluded that cSLO is a promising tool for noninvasive, multimodal intravital microscopy of the fundus in the mouse. [Copyright &y& Elsevier]

Purpose: To report in four patients with retinal vein occlusion the presence of biomicroscopically visible circulation in the minor arterial circle of the iris, preceding rubeosis iridis in two cases. Design: Retrospective observational case series. Methods: Four patients with ischemic type of central or hemi-central retinal vein occlusion seen at a single center. Results: Dilation of the minor arterial circle remnants with biomicroscopically visible circulation was observed in four eyes of four adult patients with severe retinal ischemia secondary to retinal vein occlusion and preceded the occurrence of anterior segment neovascularization in two cases. Conclusion: In patients with ischemic retinal vein occlusion, the clinical finding of a dilation of the minor arterial circle may indicate the necessity of a closer follow-up to make a timely decision on panretinal photocoagulation. [Copyright &y& Elsevier]

The purpose of this study was to analyse the dynamics of red blood cells (RBC) and white blood cells (WBC) in the retinal capillaries of C57BL/KS db/db mice, a genetic model of type 2 diabetes, and control mice, at different ages.Modified epifluorescence microscopy was used to analyse the capillary velocity of FITC-labeled RBC and rhodamine-labeled WBC in the retina. C57BL/KS db/db diabetic mice were compared to heterozygous non-diabetic mice at ages 8 and 18 weeks (n=6 in each group).At 8 weeks, when hyperglycemia begins in db/db mice, no significant difference was found between average RBC and WBC velocity of the 2 groups. At 18 weeks, RBC velocity was significantly higher in diabetic mice compared to controls (1·21±0·29 versus 1·08±0·28 mm sec−1 p=0·0003). No significant difference was found between WBC velocities (0·87±0·3 versus 0·85±0·3 mm sec−1) even when normalized by RBC velocity values. Temporal and spatial coefficients of variation were significantly higher for WBC than RBC velocities (p<0·0001) but were not significantly different in diabetic and control mice.Direct measurement of RBC velocity with this new method showed that it was higher in the retinal capillaries of diabetic than control mice after 10–12 weeks of hyperglycemia, but not at the onset of hyperglycemia. This suggests that enhanced RBC velocity is not an immediate effect of hyperglycemia but a consequence of persistent hyperglycemia. The above results are in line with the hypothesis that microvascular flow increases in diabetes, as one of the first microvascular alterations. In contrast, WBC velocity was not different in diabetic and control mice. [Copyright &y& Elsevier]

: PurposeTo investigate the possible persistence and characteristics of infrared fluorescence of the fundus for several months after surgery with intraocular injection of indocyanine green (ICG).: DesignInterventional, noncomparative, prospective case series.: ParticipantsSeventeen patients operated on in our department with ICG injection into the vitreous cavity, who gave prior informed consent.: MethodsAfter standard three-port pars plana vitrectomy and posterior vitreous detachment, 0.1 to 0.2 ml of an ICG solution at a concentration of 2.5 mg/ml was injected through a 5-μm sterile filter over the posterior pole and left in place for 3 minutes. The stained internal limiting membrane was then peeled off. Patients had postoperative infrared fundus photographs at each consultation in our department. Follow-up ranged from 1 to 7 months. Visual acuity and any unexpected event were also recorded.: Main outcome measuresPostoperative infrared fluorescence of the fundus.: ResultsThe day after surgery, no green ICG staining of the fundus was visible on biomicroscopy. However, infrared photography showed diffuse fluorescence of the fundus. At 1 and 3 postoperative months, infrared fundus photography showed an intensely fluorescent optic nerve disc. In patients with macular hole, the center of the macula also exhibited faint granular fluorescence. At 6 months postoperative or later, only the optic disc remained fluorescent, but the fluorescence was far less intense than at 3 months. Infrared photographs of the fellow eyes exhibited no fluorescence. Visual acuity improved or was unchanged compared with preoperative vision in 16 eyes and decreased by 1 line in 1 eye.: ConclusionsAfter intraoperative use of ICG for macular surgery, fluorescence of the optic disc and of the macular center after macular hole surgery persisted for months in all cases. ICG may accumulate in the macular pigment epithelium and optic nerve, raising the problem of the as yet unknown pharmacokinetics of ICG after intravitreous administration and of its long-term safety. [Copyright &y& Elsevier]

• Processing of series of fundus images for monitoring dry AMD, which had not yet been done. • The images of the series are processed jointly to correct illumination distortion. • The inter-image normalization allows the longitudinal study of atrophy progression. • Experiments on a dataset of 18 series manually segmented by a medical expert, to demonstrate the benefits of the proposed method. • Computation of colored maps highlighting the disease progression, of high interest for clinical interpretation. Age-related macular degeneration (ARMD) is a degenerative disease that affects the retina, and the leading cause of visual loss. In its dry form, the pathology is characterized by the progressive, centrifugal expansion of retinal lesions, called geographic atrophy (GA). In infrared eye fundus images, the GA appears as localized bright areas and its growth can be observed in series of images acquired at regular time intervals. However, illumination distortions between the images make impossible the direct comparison of intensities in order to study the GA progress. Here, we propose a new method to compensate for illumination distortion between images. We process all images of the series so that any two images have comparable gray levels. Our approach relies on an illumination/reflectance model. We first estimate the pixel-wise illumination ratio between any two images of the series, in a recursive way; then we correct each image against all the others, based on those estimates. The algorithm is applied on a sliding temporal window to cope with large changes in reflectance. We also propose morphological processing to suppress illumination artefacts. The corrected illumination function is homogeneous in the series, enabling the direct comparison of grey-levels intensities in each pixel, and so the detection of the GA growth between any two images. To demonstrate that, we present numerous experiments performed on a dataset of 18 series (328 images), manually segmented by an ophthalmologist. First, we show that the normalization preprocessing dramatically increases the contrast of the GA growth areas. Secondly, we apply segmentation algorithms derived from Otsu's thresholding to detect automatically the GA total growth and the GA progress between consecutive images. We demonstrate qualitatively and quantitatively that these algorithms, although fully automatic, unsupervised and basic, already lead to interesting segmentation results when applied to the normalized images. Colored maps representing the GA evolution can be derived from the segmentations. To our knowledge, the proposed method is the first one which corrects automatically and jointly the illumination inhomogeneity in a series of fundus images, regardless of the number of images, the size, shape and progression of lesion areas. This algorithm greatly facilitates the visual interpretation by the medical expert. It opens up the possibility of treating automatically each series as a whole (not just in pairs of images) to model the GA growth. [ABSTRACT FROM AUTHOR]

We explored by fundus photographs, OCT and adaptive optics ophthalmoscopy (AOO) the vessels of eyes after proton beam therapy for uveal melanoma in 10 eyes. We observed strong fluctuations of diameters in both arteries and veins, without significant changes in vascular wall thickness suggesting that vasoconstriction was involved in this process. Reduction of lumen diameter could be focal or diffuse, and could lead in some cases to branch retinal vein occlusion unrelated to arteriovenous crossings. The ensuing collateral circulation could lead to the development of TelCaps (capillary macroaneurysms), successfully treated by targeted laser in one case. Many areas of capillary closure followed a vascular perfusion or drainage scheme, suggesting that vasoconstriction played a role in the complex pattern of radiation retinopathy. This may provide the basis for therapeutic trials based on the modulation of vasomotricity. [ABSTRACT FROM AUTHOR]

Telangiectatic capillaries (TelCaps), also termed capillary macroaneurysms, are commonly observed in retinal vascular diseases and may cause chronic macular edema even if distally located. Their recognition is important since their targeted photocoagulation may be clinically beneficial. Diagnosis of TelCaps is facilitated by the use of indocyanine green angiography, particularly in its late frames, since they appear to be a correlation between ICG staining and the intensity of blood –retinal barrier breakdown. This is a crucial point, since TelCaps often escape fundus and OCT examination. As such, the identification of TelCaps may contribute to a reevaluation of chronic macular edema management. Here we will discuss this emerging concept, and its integration into management schemes of chronic macular edema, especially for diabetic macular edema. A randomized study is currently ongoing in France, aiming at investigating the potential of targeted photocoagulation to reduce the amount of intravitreal injections. [ABSTRACT FROM AUTHOR]

This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices. [ABSTRACT FROM AUTHOR]

Background: Macular edema (ME) results from hyperpermeability of retinal vessels, leading to chronic extravasation of plasma components into the retina and hence potentially severe visual acuity loss. Current standard of care consists in using intravitreal injections (IVI), which results in a significant medical and economic burden. During diabetic retinopathy (DR) or retinal vein occlusion (RVO), it has recently been shown that focal vascular anomalies (capillary macro-aneurysms, also termed TelCaps) for telangiectatic capillaries may play a central role in the onset, early recurrence, and/or persistence of ME. Since targeted photocoagulation of TelCaps may improve vision, identification, and photocoagulation of TelCaps, it may represent a way to improve management of ME. Objective: The Targeted Laser in (Diabetic) Macular Edema (TalaDME) study aims to evaluate whether ICG-guided targeted laser (IGTL), in association with standard of care by IVI, allows reducing the number of injections during the first year of treatment compared with IVI only, while remaining non-inferior for visual acuity. Methods: TalaDME is a French, multicentric, two-arms, randomized, sham laser-controlled, double-masked trial evaluating the effect of photocoagulation of TelCaps combined to IVI in patients with ME associated with TelCaps. Patients with vision loss related to center involved ME secondary to RVO or DR and presenting TelCaps are eligible. Two hundred and seventy eyes of 270 patients are randomized in a 1:1 ratio to standard care, i.e., IVI of anti-VEGF solely (control group) or combined with IGTL therapy (experimental group). Stratification is done on the cause of ME (i.e., RVO versus diabetes). Anti-VEGF IVI are administered to both groups monthly for 3 months (loading dose) and then with a pro re nata regimen with a monthly follow-up for 12 months. The primary endpoint will be the number of IVI and the change in visual acuity from baseline to 12 months. Secondary endpoints will be the changes in central macular thickness, impact on quality of life, cost of treatment, and incremental cost-utility ratio in each groups. Key safety: Rare but severe AE linked to the use of IVI and laser, and previously described, are expected. In the sham group, rescue laser photocoagulation may be administered by the unmasked investigator if deemed necessary at month 3. Discussion: The best management of ME associated with TelCaps is debated, and there have been no randomized study designed to answer this question. Given the fact that TelCaps may affect 30 to 60% of patients with chronic ME due to DR or RVO, a large number of patients could benefit from a specific management of TelCaps. TalaDME aims to establish the clinical and medico-economic benefits of additional targeted laser. The results of TalaDME may raise new recommendations for managing ME and impact healthcare costs. Trial registration: EudraCT: 2018-A00800-55/ NCT03751501. Registration date: Nov. 23, 2018. [ABSTRACT FROM AUTHOR]

The Retinal Pigment Epithelium (RPE) plays a prominent role in diseases such as age-related macular degeneration, but imaging individual RPE cells is challenging due to their high absorption and low autofluorescence emission. The RPE lies beneath the highly reflective photoreceptor layer (PR) and contains absorptive pigments, preventing direct backscattered light detection when the PR layer is intact. Here, we used near-infrared autofluorescence adaptive optics scanning laser ophthalmoscopy (NIRAF AOSLO) and transscleral flood imaging (TFI) in the same healthy eyes to cross-validate these approaches. Both methods revealed a consistent RPE mosaic pattern and appeared to reflect a distribution of fluorophores consistent with findings from histological studies. Interestingly, even in apparently healthy RPE, we observed dynamic changes over months, suggesting ongoing cellular activity or alterations in fluorophore distribution. These findings emphasize the value of NIRAF AOSLO and TFI in understanding RPE morphology and dynamics. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is invariably associated with the chronic accumulation of activated mononuclear phagocytes in the subretinal space. The mononuclear phagocytes are composed of microglial cells but also of monocyte-derived cells, which promote photoreceptor degeneration and choroidal neovascularization. Infiltrating blood monocytes can originate directly from bone marrow, but also from a splenic reservoir, where bone marrow monocytes develop into angiotensin II receptor (ATR1)+ splenic monocytes. The involvement of splenic monocytes in neurodegenerative diseases such as AMD is not well understood. Using acute inflammatory and well-phenotyped AMD models, we demonstrate that angiotensin II mobilizes ATR1+ splenic monocytes, which we show are defined by a transcriptional signature using single-cell RNA sequencing and differ functionally from bone marrow monocytes. Splenic monocytes participate in the chorio-retinal infiltration and their inhibition by ATR1 antagonist and splenectomy reduces the subretinal mononuclear phagocyte accumulation and pathological choroidal neovascularization formation. In aged AMD-risk ApoE2-expressing mice, a chronic AMD model, ATR1 antagonist and splenectomy also inhibit the chronic retinal inflammation and associated cone degeneration that characterizes these mice. Our observation of elevated levels of plasma angiotensin II in AMD patients, suggests that similar events take place in clinical disease and argue for the therapeutic potential of ATR1 antagonists to inhibit splenic monocytes for the treatment of blinding AMD. [ABSTRACT FROM AUTHOR]

Optical coherence tomography (OCT), which is routinely used in ophthalmology, enables transverse optical imaging of the retina and, hence, the identification of the different neuronal layers. Directional OCT (D-OCT) extends this technology by acquiring sets of images at different incidence angles of the light beam. In this way, reflectance properties of photoreceptor substructures are highlighted, enabling physicians to study their orientation, which is potentially an interesting biomarker for retinal diseases. Nevertheless, commercial OCT devices equipped to automate D-OCT acquisition do not yet exist, meaning that physicians manually deviate the light beam to acquire a set of D-OCT images sequentially. Therefore, the intensities in the stack of images are not directly comparable, and a normalization step is required before differential analysis. In this paper, we present advanced image processing methods to perform differential analysis of a set of D-OCT images and extract the angle-dependent retinal substructures. Our approach relies on a robust and accurate normalization algorithm followed by a classification that is spatially regularized. We also propose a robust color representation that facilitates interpretation of D-OCT data in general, by detecting and highlighting angle-dependent structures in healthy and diseased eyes. Experimental results show evidence of photoreceptor disarray in a variety of retinal diseases, demonstrating the potential medical interest of the approach. [ABSTRACT FROM AUTHOR]

We provide here a procedure enabling light sheet fluorescence microscopy (LSFM) of entire human eyes after iDISCO + -based clearing (ClearEye) and immunolabeling. Demonstrated here in four eyes, post-processing of LSFM stacks enables three-dimensional (3D) navigation and customized display, including en face viewing of the fundus similarly to clinical imaging, with resolution of retinal capillaries. This method overcomes several limitations of traditional histology of the eyes. Tracing of spatially complex structures such as anterior ciliary vessels and Schlemm's canal was achieved. We conclude that LSFM of immunolabeled human eyes after iDISCO + -based clearing is a powerful tool for 3D histology of large human ocular samples, including entire eyes, which will be useful in both anatomopathology and in research. A procedure is established to image the entire human eye with light sheet fluorescence microscopy. [ABSTRACT FROM AUTHOR]

Branch retinal vein occlusion (BRVO) is a frequent retinal vascular disease that may cause extensive microvascular remodeling leading to severe visual impairment. Little is known regarding the histology of non‐neovascular microvascular remodeling. Here, we examined by confocal microscopy the structure of retinal microvessels of a donor eye with longstanding BRVO. The post‐mortem retina of a 91‐year‐old woman that had superotemporal BRVO for 2 years was examined by confocal microscopy after anti‐collagen IV (collIV), alpha‐smooth muscle cell (αSMA), and anti‐von Willebrand factor (vWf) immunolabeling. In the retinal quadrant affected by BRVO, extensive vascular remodeling affected all vessels, from arterioles to venules, including the foveal avascular zone. Most affected vessels were either irregularly dilated or, on the opposite, reduced to micrometric‐size CollIV positive, vWf negative, nuclear‐staining negative strings. Telangiectatic capillaries of various sizes and shapes were seen, the largest one (233 μm) being located in the parafoveal area. Some telangiectatic capillaries had a thick, multilayered vWf‐ and CollIV‐positive wall, that often occluded the lumen. Other features included double‐channeled arterioles. The majority of microvascular abnormalities were devoid of nuclear staining, suggesting extensive loss of endothelial cells. We describe the spectrum of microvascular abnormalities upstream of a longstanding BRVO. This spectrum comprises a large parafoveal telangiectatic capillary corresponding to what has been previously clinically defined as TelCap. The absence of intraluminal nuclear staining in the majority of abnormal vessels raises the hypothesis that the loss of endothelial cells plays a crucial role in the development of the different manifestations of capillary remodeling. The presence of vWF in de‐endothelialized vessels suggests deposition of plasma, hence that they may remain perfused. Our work may help to understand the clinical imaging features of TelCaps. [ABSTRACT FROM AUTHOR]

Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid. Recent advances highlight how both genetic and environmental risk factors directly promote subretinal inflammation and tip the balance from a beneficial inflammation that helps control debris accumulation to detrimental chronic inflammation and destructive late AMD. Finally, we discuss how changes in life style or pharmacological intervention can help to break the vicious cycle of inflammation and degeneration, restore the immunosuppressive properties of the subretinal space, and reestablish homeostasis. [ABSTRACT FROM AUTHOR]

Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the "don't eat me" signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47−/−-mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression. [ABSTRACT FROM AUTHOR]

Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the "don't eat me" signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47−/−-mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression. [ABSTRACT FROM AUTHOR]

The ocular vasculature is critically involved in many blinding diseases and is also a popular research model for the exploration of developmental and pathological angiogenesis. The development of ocular vessels is a complex, finely orchestrated sequence of events, involving spatial and temporal coordination of hyaloid, choroidal and retinal networks. Comprehensive studies of the tridimensional dynamics of microvascular remodeling are limited by the fact that preserving the spatial disposition of ocular vascular networks is cumbersome using classical histological procedures. Here, we demonstrate that light-sheet fluorescence microscopy (LFSM) of cleared mouse eyes followed by extensive virtual dissection offers a solution to this problem. To the best of our knowledge, this is the first 3D quantification of the evolution of the hyaloid vasculature and of post-occlusive venous remodeling together with the characterization of spatial distribution of various cell populations in ocular compartments, including the vitreous. These techniques will prove interesting to obtain other insights in scientific questions addressing organ-wide cell interactions. An organic-solvent based clearing technique is used to visualize the vasculature in 3D using light sheet microscopy in retinal and hyaloid vessel development, and applied to branch retinal vein occlusion (BRVO) models. [ABSTRACT FROM AUTHOR]

Tubular structure tracking is a crucial task in the fields of computer vision and medical image analysis. The minimal paths-based approaches have exhibited their strong ability in tracing tubular structures, by which a tubular structure can be naturally modeled as a minimal geodesic path computed with a suitable geodesic metric. However, existing minimal paths-based tracing approaches still suffer from difficulties such as the shortcuts and short branches combination problems, especially when dealing with the images involving complicated tubular tree structures or background. In this paper, we introduce a new minimal paths-based model for minimally interactive tubular structure centerline extraction in conjunction with a perceptual grouping scheme. Basically, we take into account the prescribed tubular trajectories and curvature-penalized geodesic paths to seek suitable shortest paths. The proposed approach can benefit from the local smoothness prior on tubular structures and the global optimality of the used graph-based path searching scheme. Experimental results on both synthetic and real images prove that the proposed model indeed obtains outperformance comparing with the state-of-the-art minimal paths-based tubular structure tracing algorithms. [ABSTRACT FROM AUTHOR]

We present a compact multi-modal and multi-scale retinal imaging instrument with an angiographic functional extension for clinical use. The system integrates scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT) and OCT angiography (OCTA) imaging modalities and provides multi-scale fields of view. For high resolution, and high lateral resolution in particular, cellular imaging correction of aberrations by adaptive optics (AO) is employed. The entire instrument has a compact design and the scanning head is mounted on motorized translation stages that enable 3D self-alignment with respect to the subject's eye by tracking the pupil position. Retinal tracking, based on the information provided by SLO, is incorporated in the instrument to compensate for retinal motion during OCT imaging. The imaging capabilities of the multi-modal and multi-scale instrument were tested by imaging healthy volunteers and patients. [ABSTRACT FROM AUTHOR]

Retinal degenerative diseases lead to the blindness of millions of people around the world. In case of age-related macular degeneration (AMD), the atrophy of retinal pigment epithelium (RPE) precedes neural dystrophy. But as crucial as understanding both healthy and pathological RPE cell physiology is for those diseases, no current technique allows subcellular in vivo or in vitro live observation of this critical cell layer. To fill this gap, we propose dynamic full-field OCT (D-FFOCT) as a candidate for live observation of in vitro RPE phenotype. In this way, we monitored primary porcine and human stem cell-derived RPE cells in stress model conditions by performing scratch assays. In this study, we quantified wound healing parameters on the stressed RPE, and observed different cell phenotypes, displayed by the D-FFOCT signal. In order to decipher the subcellular contributions to these dynamic profiles, we performed immunohistochemistry to identify which organelles generate the signal and found mitochondria to be the main contributor to D-FFOCT contrast. Altogether, D-FFOCT appears to be an innovative method to follow degenerative disease evolution and could be an appreciated method in the future for live patient diagnostics and to direct treatment choice. Dynamic full-field optical coherence tomography (D-FFOCT) is used for live cell imaging of primary porcine retinal pigment epithelium (ppRPE) cultures and human induced pluripotent stem cell-derived RPE (hiRPE) cultures, allowing non-invasive realtime access to organelles and cytoskeleton dynamics in RPE cells. [ABSTRACT FROM AUTHOR]

Retinal vascular diseases are a leading cause for blindness and partial sight certifications. By applying adaptive optics (AO) to conventional imaging modalities, the microstructures of the retinal vasculature can be observed with high spatial resolution, hence offering a unique opportunity for the exploration of the human microcirculation. The objective of this systematic review is to describe the current state of retinal vascular biomarkers imaged by AO flood illumination ophthalmoscopy (FIO) and AO scanning laser ophthalmoscopy (SLO). A literature research was conducted in the PubMed and Scopus databases on July 9, 2020. From 217 screened studies, 42 were eligible for this review. All studies underwent a quality check regarding their content. A meta-analysis was performed for the biomarkers reported for the same pathology in at least three studies using the same modality. The most frequently studied vascular biomarkers were the inner diameter (ID), outer diameter (OD), parietal thickness (PT), wall cross-sectional area (WCSA), and wall-to-lumen ratio (WLR). The applicability of AO vascular biomarkers has been mostly explored in systemic hypertension using AO FIO and in diabetes using AO SLO. The result of the meta-analysis for hypertensive patients showed that WLR, PT, and ID were significantly different when compared to healthy controls, while WCSA was not (P < 0.001, P = 0.002, P < 0.001, and P = 0.070, respectively). The presented review shows that, although a substantial number of retinal vascular biomarkers have been explored in AO en face imaging, further clinical research and standardization of procedures is needed to validate such biomarkers for the longitudinal monitoring of arterial hypertension and other diseases. [ABSTRACT FROM AUTHOR]

To describe the application of OCT-A in various posterior uveitis disorders in our experience and to compare it with the available literature. Eighteen eyes with the diagnoses of multifocal choroiditis (MFC), multifocal placoid pigment epitheliopathy (APMPPE), multiple evanescent white dot syndrome (MEWDS), tuberculous serpiginous-like choroiditis (SLC), serpiginous choroiditis (SC), and birdshot chorioretinopathy (BSCR) were studied. We found flow void of the choriocapillaris in patients with APMPPE, SC, MFC, BSCR, and in SLC. In contrast, perfusion of the choriocapillaris seemed normal in patients with MEWDS. We confirmed that OCT-A contributes new information on the physiopathology of white dot syndromes and inflammatory chorioretinopathies, notably on whether or not the choriocapillaris is involved. Comparing the OCT-A features allowed us to suggest that both APMPPE and SLC might be part of the same spectrum of inflammatory disease with primary involvement at the level of the choriocapillaris and secondary RPE damage. [ABSTRACT FROM AUTHOR]

Human cone phototropism is a key mechanism underlying the Stiles-Crawford effect, a psychophysiological phenomenon according to which photoreceptor outer/inner segments are aligned along with the direction of incoming light. However, such photomechanical movements of photoreceptors remain elusive in mammals. We first show here that primate cone photoreceptors have a planar polarity organized radially around the optical center of the eye. This planar polarity, based on the structure of the cilium and calyceal processes, is highly reminiscent of the planar polarity of the hair cells and their kinocilium and stereocilia. Secondly, we observe under super-high resolution expansion microscopy the cytoskeleton and Usher proteins architecture in the photoreceptors, which appears to establish a mechanical continuity between the outer and inner segments. Taken together, these results suggest a comprehensive cellular mechanism consistent with an active phototropism of cones toward the optical center of the eye, and thus with the Stiles-Crawford effect. Verschueren et al. expand our understanding of the Stiles-Crawford effect in mammals by using super-high resolution expansion microscopy of the adult macaque eye. They show that cone photoreceptors have a planar polarity organized radially around the optical center of the eye and that Usher proteins establish a mechanical continuity between the outer and inner segments, which sheds light on the Stiles-Crawford effect in this species. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Neurovascular coupling (NVC) is the blood flow modulation in response to stimuli and has been extensively studied in the brain. Concerning the human retina, this behaviour has been only measured in the ipsilateral eye, where stimuli and observed effects involve the same eye. This work aims to set up the hardware to assess NVC in the contralateral eye and demonstrate its feasibility in edifying human retina‐retina or cortico‐retinal connections. Methods: Adaptive optics (AO) is a cutting‐edge technology in retinal fundus imaging, offering exceptional spatial resolution. The NVC effect was successfully assessed using the RTX1, an AO retinal camera capable of ipsilateral stimulation. The possible effects of contralateral stimulation can be readily assessed by providing RTX1 with an external flickering device. Furthermore, connecting the thread between previous fMRI results and photic stimulation in the ipsi‐ and contralateral retina can offer valuable information on uncharted interocular or brain‐retina neural pathways and lead to cost‐effective and non‐invasive biomarkers for neurodegenerative diseases or early brain vasculature impairment diagnosis. Results: Even though further optimization of flicker‐related parameters is necessary to investigate the contralateral NVC response, preliminary tests showed the successful integration of a fully operational contralateral stimulation prototype with the RTX1. The entire procedure has been documented, and all components have been thoroughly evaluated. Conclusions: These preliminary assessments precede a clinical study involving patients with type 1 Diabetes Mellitus and a control group of healthy individuals. It follows previous fMRI studies that showed impaired NVC in type 2 diabetic patients by measuring the BOLD (Blood Oxygen Level‐Dependent) response using block and event‐related optical stimuli. A comparative analysis of the findings aims to demonstrate the potential role of neurovascular uncoupling in the early pathogenesis of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Purpose: To monitor perivascular sheathing during the course of retinal vasculitis by flood illumination adaptive optics ophthalmoscopy (AOO). Methods: Perivenous sheathing and venous diameters were quantitatively analyzed by semi-automatic segmentation of AOO images in 12 eyes of treatment-naive patients with retinal vasculitis. Results: The width of venous sheathing ranged from 45 to 225 µm (mean 101.0 µm ± 54.3). In 10 cases, the underlying vein showed focal narrowing (mean ± SD 14% ± 10). Focal narrowing of arteries was also present in one eye. At presentation, width of sheathing and vessel diameters were not correlated with fluorescein leakage. During follow-up, 5 eyes showed an increase in vein diameter or resolution of narrowing and in 10 eyes a thinning of vascular sheathing was observed (p= .003). Conclusions: Perivenous sheathing may be quantitatively analyzed and monitored by AOO. AOO may therefore contribute to monitor vascular sheathing during posterior uveitis. [ABSTRACT FROM AUTHOR]

Retinal vascular diseases (RVD) have been identified as a major cause of blindness worldwide. These pathologies, including the wet form of age‐related macular degeneration, retinopathy of prematurity, and diabetic retinopathy are currently treated by intravitreal delivery of anti‐vascular endothelial growth factor (VEGF) agents. However, repeated intravitreal injections can lead to ocular complications and resistance to these treatments. Thus, there is a need to find new targeted therapies. Nucleolin regulates the endothelial cell (EC) activation and angiogenesis. In previous studies, we designed a pseudopeptide, N6L, that binds the nucleolin and blocks the tumor angiogenesis. In this study, the effect of N6L was investigated in two experimental models of retinopathies including oxygen‐induced retinopathy (OIR) and choroidal neovascularization (CNV). We found that in mouse OIR, intraperitoneal injection of N6L is delivered to activated ECs and induced a 50% reduction of pathological neovascularization. The anti‐angiogenic effect of N6L has been tested in CNV model in which the systemic injection of N6L induced a 33% reduction of angiogenesis. This effect is comparable to those obtained with VEGF‐trap, a standard of care drug for RVD. Interestingly, with preventive and curative treatments, neoangiogenesis is inhibited by 59%. Our results have potential interest in the development of new therapies targeting other molecules than VEGF for RVD. [ABSTRACT FROM AUTHOR]

Context: Cardiovascular disease is one of the main causes of morbidity in active acromegaly due to the increased prevalence of risk factors and arterial consequences of increas ed growth hormone levels. No in vivo study has evaluated the consequences of acromegaly on the retinal microva sculature. Objective: The aim of this study was to identify in vivo the presence of morphological alterations of retinal arteriole s in subjects with acromegaly. Patients and methods: Single-center retrospective study of a cohort of 60 subjects w ith acromegaly, matched to 60 controls, who were referred for adaptive optics camera (AOC) fr om September 2014 to December 2016. Of the subjects with acromegaly, 19 had an active disease (AD) and 41 a controlled disease (CD) based on the IGF1 ratio (IGF1r). Retinal arteriolar remodeling was previously assessed using adaptive optics camera (AOC) in order to measure wall-to-lumen ratio (WLR), wall thickness (WT), internal diamet er (ID) and wall cross sectional area (WCSA). Results: WLR was significantly higher in AD subjects compared to CD subjects and controls (AD: 0.311 ± 0.06, CD: 0.279 ± 0.04, controls: 0.281 ± 0.04, P = 0.031). A significant positive correlation was observed between WLR and IGF-1r (R2 = 0.215, P < 0.001), even after adjustment for gender, age, systolic blood pressure (SBP) and the presence of dopamine agonist treatment (R2 = 0.406, P < 0.001). Retinal arteriolar anatomical indices were comparable between CD and controls. Conclusion: Active acromegaly is associated with the presence of small ret inal arteriolar remodeling. These results provide new perspectives to better stratify cardiovascular risk and consequently optimize treatment in acromegaly. [ABSTRACT FROM AUTHOR]

Purpose: To image retinal blood vessels in patients with Waldenström's macroglobulinemia using optical coherence tomography (OCT). Methods: Retrospective case series examining fundus photographs and OCT scans of 16 eyes in eight patients with Waldenström's macroglobulinemia. Analyses included intravascular OCT reflectivity profiles and vessel diameters, and their relation to total immunoglobulin M (IgM) levels. Results: In six out of eight patients, cross‐sectional OCT scans of larger retinal vessels (diameter > 100 μm) showed normal intravascular reflectivity and retrovascular shadowing. In two patients with the highest total IgM > 60 g/l, altered intravascular reflectivity, distinct anterior and posterior vessel wall reflexes, and retrovascular hyposhadowing were seen. Normalization of the OCT reflectivity in these patients occurred after reduction of total IgM to < 17 g/l and was accompanied by decreasing venous tortuosity and disappearance of retinal haemorrhages and cotton wool spots. Conclusion: This study found that Waldenström's macroglobulinemia and total IgM > 60 g/l were associated with abnormal intravascular reflectivity and retrovascular shadowing on OCT. Awareness of these signs of hyperviscosity could potentially enable earlier detection of critical conditions in patients with Waldenström's macroglobulinemia and improve the assessment of severity and treatment effect. [ABSTRACT FROM AUTHOR]

We could establish five morphological patterns of AO that were repetitively observed in patients with RP using multimodal imaging on 174 patients with syndromic or non-syndromic RP (in most of the cases genetically confirmed). We like to report on typical morphological findings in Retinitis pigmentosa (RP), based on 3 years clinical experience with the adaptive optics (AO) in the Clinics for Hereditary Retinal Degenerations at the Center for Ophthalmology, Tuebingen. The unspecific atrophy on AO is characterized by dark patchy atrophic zones without clearly distinguishable cone mosaic and is often accompanied by epiretinal membranes, visible as folds on the epiretinal side, a frequent finding in RP patients. [Extracted from the article]

The HANAC syndrome is caused by mutations in the gene coding for collagen4a1, a major component of blood vessel basement membranes. Ocular symptoms include an increase in blood vessel tortuosity and occasional hemorrhages. To examine how vascular defects can affect neuronal function, we analyzed the retinal phenotype of a HANAC mouse model. Heterozygous mutant mice displayed both a thinning of the basement membrane in retinal blood vessels and in Bruch's membrane resulting in vascular leakage. Homozygous mice had additional vascular changes, including greater vessel coverage and tortuosity. This greater tortuosity was associated to higher expression levels of vascular endothelial growth factor (VEGF). These major changes to the blood vessels were correlated with photoreceptor dysfunction and degeneration. The neuronal damage was associated with reactive gliosis in astrocytes and Müller glial cells, and by the migration of microglial cells into the outer retina. This study illustrates how vascular changes can trigger neuronal degeneration in a new model of HANAC syndrome that can be used to further study dysfunctions of neurovascular coupling. Summary statement This study provides a phenotypic analysis of a novel mouse model of HANAC syndrome focusing on the retinal aspect. It recapitulates most of the aspects of the human disease and is therefore a great tool to study and to address this condition. [ABSTRACT FROM AUTHOR]

Adaptive optics is a relatively new field, yet it is spreading rapidly and allows new questions to be asked about how the visual system is organized. The editors of this feature issue have posed a series of question to scientists involved in using adaptive optics in vision science. The questions are focused on three main areas. In the first we investigate the use of adaptive optics for psychophysical measurements of visual system function and for improving the optics of the eye. In the second, we look at the applications and impact of adaptive optics on retinal imaging and its promise for basic and applied research. In the third, we explore how adaptive optics is being used to improve our understanding of the neurophysiology of the visual system. [ABSTRACT FROM AUTHOR]

Mutations of the COL4A1 gene, a major structural protein of vessels, may cause hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome. The vascular structure and function of patients with HANAC is poorly known. Here, we report a family with HANAC syndrome associated to a previously unreported mutation in COL4A1. The structure and function of retinal vessels were detailed by adaptive optics ophthalmoscopy (AOO) and optical coherence tomography (OCT) angiography. Clinical data from six affected individuals (43 to 72 years old) from a single family comprising two generations were collected. Imaging charts including conventional fundus imaging, OCT-angiography and AOO in static and dynamic (flicker) mode were reviewed. DNA sequencing was done in the proband. DNA sequencing of the proband revealed a heterozygous deletion of COL4A1 (NM_001845) at position 1120 in the intron 20 resulting in the loss of splicing donor site for exon 20 (c.1120 + 2_1120 + 8del heterozygote). Four patients had arterial hypertension, and three had kidney dysfunction, one of which under dialysis. By fundus examination, five had typical retinal arteriolar tortuosity with arteriolar loops. Wall-to-lumen ratio of arteries was within normal limits, that is, lower than expected for hypertensive patients. Several foci of arteriolar irregularities were noted in the two oldest patients. In three affected subjects, evaluation of the neurovascular coupling showed a higher flicker-induced vasodilation than a control population (6 % to 11 %; n < 5 %). Structural and dynamic analysis of retinal vessels in a HANAC family bearing a previously unreported intronic COL4 mutation was done. In addition to arteriolar tortuosity, we found reduced wall-to-lumen ratio, arteriolar irregularity and increased vasodilatory response to flicker light. These abnormalities were more marked in the oldest subjects. This abnormal flicker response affected also non-tortuous arteries, suggesting that microvascular dysfunction extends beyond tortuosity. Such explorations may help to better vascular dysfunction related to HANAC and hence better understand the mechanisms of end-organ damage. [ABSTRACT FROM AUTHOR]

• Irinotecan is a topoisomerase-I inhibitor widely used for gastrointestinal tumours. • Vision loss has never been reported after irinotecan infusion. • Irinotecan-induced retinopathy has never been reported so far. • This toxicity is characterised by a diffuse loss of photoreceptors' outer segments. • Further studies are required to better characterise irinotecan-induced retinopathy. [ABSTRACT FROM AUTHOR]

Purpose: Mutations of the COL4A1 gene may cause hereditary angiopathy with nephropathy, aneurysms and muscle cramps (HANAC) syndrome. The vascular structure and function of patients with HANAC is poorly known. Here, we report a family with HANAC syndrome associated to a previously unreported mutation in COL4A1. The structure and function of retinal vessels were detailed by adaptive optics ophthalmoscopy (AOO) and optical coherence tomography (OCT) angiography. Methods: Clinical data from six affected individuals from a single family over two generations were collected. Imaging charts including conventional fundus imaging, OCT‐angiography and AOO in static and dynamic (flicker) mode were reviewed. DNA sequencing was done in the proband. Results: DNA sequencing of the proband revealed a heterozygous deletion of COL4A1 (NM_001845) at position 1120 in the intron 20 resulting in the loss of splicing donor site for exon 20 (c.1120 + 2_1120 + 8del heterozygote). Four had arterial hypertension, and three had kidney dysfunction, one of which under dialysis. Examination of retinal vessels showed that all patients had retinal arteriolar tortuosity which peaked in precapillary arterioles but spared capillaries and veins. Wall‐to‐lumen ratio of arteries was within normal limits, that is, lower than expected for hypertensive patients. Several foci of arteriolar irregularities were noted I the oldest patients. In three affected subjects, evaluation of the neurovascular coupling showed a high flicker‐induced vasodilation (from 6% to 10.8%; n < 5%). Conclusions: Structural and dynamic analysis of retinal vessels in a HANAC family bearing a novel intronic COL4 mutation showed reduced parietal thickness, arteriolar irregularity and increased dilatory response to flicker light. This affected as well non tortuous arteries, suggesting that HANAC causes diffuse microvascular dysfunction. Our findings may help to better understand end‐organ damage related to HANAC. [ABSTRACT FROM AUTHOR]

Photo-transduction in cone segments (CS) is crucial for high acuity daytime vision. For ill-defined reasons, CS degenerate in retinitis pigmentosa (RP) and in the transitional zone (TZ) of atrophic zones (AZ), which characterize geographic atrophy (GA). Our experiments confirm the loss of cone segments (CS) in the TZ of patients with GA and show their association with subretinal CD14+mononuclear phagocyte (MP) infiltration that is also reported in RP. Using human and mouse MPs in vitro and inflammation-prone Cx3cr1GFP/GFP mice in vivo, we demonstrate that MP-derived IL-1β leads to severe CS degeneration. Our results strongly suggest that subretinal MP accumulation participates in the observed pathological photoreceptor changes in these diseases. Inhibiting subretinal MP accumulation or Il-1β might protect the CS and help preserve high acuity daytime vision in conditions characterized by subretinal inflammation, such as AMD and RP. [ABSTRACT FROM AUTHOR]

Background: To report functional and high-resolution retinal imaging abnormalities, including adaptive optics (AO) throughout the course of acute macular neuroretinopathy (AMNR). Methods: Two female patients (four eyes) with a diagnosis of AMNR were observed at the Clinical Investigation Center, CHNO des Quinze-Vingts, Paris, France. The patients underwent detailed ophthalmic examination including best-corrected visual acuity, slit-lamp examination, kinetic and static perimetry, full-field and multifocal electroretinogram, infrared reflectance, autofluorescence imaging and spectral-domain optical coherence tomography (SD-OCT) and AO fundus imaging at presentation and during follow-up. Results: Both cases showed concomitant loss of integrity of the outer retinal structures on SD-OCT, and marked abnormalities on AO imaging with disruption of the visibility of the cone mosaic. In the first case, photoreceptor damage was seen to progress during several weeks before healing. In both cases, there were persistent morphological abnormalities of photoreceptors 1 year after onset. Conclusion: This study further highlights the value of AO fundus imaging to facilitate detection, mapping, and monitoring of damage to the cone outer segments during AMNR. In particular, residual damage to the cone mosaic can be precisely documented. [ABSTRACT FROM AUTHOR]

Adaptive optics imaging of the retina has recently proven its capability to image micrometric structures such as blood vessels, involved in common ocular diseases. In this paper, we propose an approach for automatically segmenting the walls of retinal arteries in the images acquired with this technology. The walls are modeled as four curves approximately parallel to a previously detected reference line located near the vessel center (axial reflection). These curves are first initialized using a tracking procedure and then more accurately positioned using an active contour model embedding a parallelism constraint. We consider both healthy and pathological subjects in the same framework and show that the proposed method applies in all cases. Extensive experiments are also proposed, by analyzing the robustness of the axial reflections detection, the influence of the tracking parameters as well as the performance of the tracking and the active contour model. Noticeably, the results show a good robustness for detecting axial reflections and a moderate influence of the tracking parameters. Compared to a naive initialization, the active contour model coupled with the tracking also offers faster convergence and better accuracy while keeping an overall error smaller or very near the inter-physicians error. [ABSTRACT FROM AUTHOR]

In order to segment elongated structures, we propose a new approach for integrating an approximate parallelism constraint in deformable models. The proposed Parallel Double Snakes evolve simultaneously two contours, in order to minimize an energy functional which attracts these contours towards high image gradients and enforces the approximate parallelism between them by controlling their distance to a centerline under regularity constraints of this line. The proposed approach is applied on retina images, for segmenting retinal layers in optical coherence tomography images of pathological subjects (and it applies to healthy subjects as well). Results are evaluated by comparing with manual segmentations for three retinal layers, and provide a similarity index above 0.87, sensitivity between 0.85 and 0.93, and specificity between 0.84 and 0.94. These results are within the range of intra and inter-expert variability. Moreover, quantitative studies demonstrate that, in our application, our Parallel Double Snake (PDS) model outperforms other parametric active contour algorithms integrating parallelism information. [ABSTRACT FROM AUTHOR]

Aims: Branch retinal vein occlusion (BRVO) leads to extensive vascular remodeling and is important cause of visual impairment. Although the vascular morphological changes following experimental vein occlusion have been described in a variety of models using angiography, the underlying cellular events are ill defined. Methods and Results: We here show that laser-induced experimental BRVO in mice leads to a wave of TUNEL-positive endothelial cell (EC) apoptosis in the upstream vascular network associated with a transient edema and hemorrhages. Subsequently, we observe an induction of EC proliferation within the dilated vein and capillaries, detected by EdU incorporation, and the edema resolves. However, the pericytes of the upstream capillaries are severely reduced, which was associated with continuing EC apoptosis and proliferation. The vascular remodeling was associated with increased expression of TGFβ, TSP-1, but also FGF2 expression. Exposure of the experimental animals to hypoxia, when pericyte (PC) dropout had occurred, led to a dramatic increase in endothelial cell proliferation, confirming the vascular instability induced by the experimental BRVO. Conclusion: Experimental BRVO leads to acute endothelial cells apoptosis and increased permeability. Subsequently the upstream vascular network remains destabilized, characterized by pericyte dropout, un-physiologically high endothelial cells turnover and sensitivity to hypoxia. These early changes might pave the way for capillary loss and subsequent chronic ischemia and edema that characterize the late stage disease. [ABSTRACT FROM AUTHOR]

Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in lightinduced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the performance of a full-field optical coherence tomography (FF-OCT) system in the study of human donor and pathological corneas and assess its suitability for use in eye banks. Methods: Our study was carried out using an FF-OCT system developed for non-invasive imaging of tissue structures in depth with ultrahigh resolution (1 µm in all directions). Images were acquired from eight stored human donor corneas (either edematous or after deswelling) and five surgical specimens of corneas with various diseases (bullous keratopathy, lattice corneal dystrophy, stromal scar after keratitis, keratoconus and Fuchs dystrophy). They were compared with standard histology and pre-operative spectral domain OCT. Results: The FF-OCT device enabled a precise visualization of the cells and the different structures (epithelium, basement membrane, Bowman's layer, stroma, Descemet's membrane and endothelium) in normal corneas. Specific lesions in various corneal diseases could also be easily identified, such as corneal edema, epithelium and Bowman's layer irregularities, breaks, or scars (keratoconus), stromal opacities, deposits, fibrosis (stromal corneal scar, bullous keratopathy, lattice corneal dystrophy) and Descemet's membrane thickening and guttae (Fuchs dystrophy). FF-OCT image features were comparable to the details provided by conventional histology. Higher resolution could be demonstrated with FF-OCT when compared with spectral domain OCT. Conclusion: FF-OCT is a powerful non-invasive imaging tool that allows detailed study of corneal structures. Images correlate well with conventional histology. Further studies should evaluate the benefit of this technique as a complement to current assessment methods of human donor corneas. [ABSTRACT FROM AUTHOR]