Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL.

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.

Adaptive optics ophthalmoscopy: a systematic review of vascular biomarkers.

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.

Unsupervised Approaches for the Segmentation of Dry ARMD Lesions in Eye Fundus cSLO Images.

Age-related macular degeneration (ARMD), a major cause of sight impairment for elderly people, is still not well understood despite intensive research. Measuring the size of the lesions in the fundus is the main biomarker of the severity of the disease and as such is widely used in clinical trials yet only relies on manual segmentation. Artificial intelligence, in particular automatic image analysis based on neural networks, has a major role to play in better understanding the disease, by analyzing the intrinsic optical properties of dry ARMD lesions from patient images. In this paper, we propose a comparison of automatic segmentation methods (classical computer vision method, machine learning method and deep learning method) in an unsupervised context applied on cSLO IR images. Among the methods compared, we propose an adaptation of a fully convolutional network, called W-net, as an efficient method for the segmentation of ARMD lesions. Unlike supervised segmentation methods, our algorithm does not require annotated data which are very difficult to obtain in this application. Our method was tested on a dataset of 328 images and has shown to reach higher quality results than other compared unsupervised methods with a F1 score of 0.87, while having a more stable model, even though in some specific cases, texture/edges-based methods can produce relevant results.

Normalization of series of fundus images to monitor the geographic atrophy growth in dry age-related macular degeneration.

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

ATTENUATION OUTER RETINAL BANDS ON OPTICAL COHERENCE TOMOGRAPHY FOLLOWING MACULAR EDEMA: A Possible Manifestation of Photoreceptor Misalignment.

PURPOSE: Macular edema is a common retinal disease which may leave important anatomical and functional sequelaes. Directional fundus imaging consists of comparing on- and off-axis images to reveal angle-dependent reflectance properties of fundus structures, which may be related to misaligned photoreceptors. Here, we analyzed directional optical coherence tomography (OCT) and flood-illumination adaptive optics ophthalmoscopy images to detect evidence of misaligned photoreceptors following macular edema. METHODS: Transversal, observational study. Nine patients having recovered a normal macular profile after macular edema due to retinal vein occlusion were included. For each patient, a reference OCT scan (i.e., with the incident beam normal to the fovea) was acquired, and off-axis scans were then acquired by laterally shifting the entry pupil. In addition, in four of these eyes, directional adaptive optics ophthalmoscopy documented the directional variations of cone metrics. RESULTS: Included patients comprised two women and seven men (age range, 19-76 years). Reference OCT scans showed patchy attenuation of the cone outer segment tips and to a lesser extent of the inner segment/outer segment lines in all, but two eyes; these. Increased intensity of the cone outer segment tips and inner segment/outer segment lines could be observed on off-axis scans. Accordingly, fusion images showed 66% average reduction of the length of cone outer segment tips attenuation. In two cases, although reference scans showed continuity of outer bands, focal attenuation was evidenced in off-axis images. Directional adaptive optics ophthalmoscopy imaging showed a strong directional variability of cone counts in these areas, ranging from near absence to roughly two-third of reference values. In each case, directional variations of cone counts paralleled those of the reflectance of outer bands. CONCLUSION: After macular edema, focal attenuations of the inner segment/outer segment and of the cone outer segment tips lines may be present on OCT. These areas may show a strong directional variability by both OCT and adaptive optics ophthalmoscopy, suggesting that misaligned photoreceptor outer segments contribute to such features. The evaluation of outer retinal damage following macular edema should therefore take into account the optical Stiles-Crawford effect to disambiguate missing from misaligned cones.

IGF-1 is an independent predictor of retinal arterioles remodeling in subjects with uncontrolled acromegaly.

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 increased growth hormone levels. No in vivo study has evaluated the consequences of acromegaly on the retinal microvasculature. OBJECTIVE: The aim of this study was to identify in vivo the presence of morphological alterations of retinal arterioles in subjects with acromegaly. PATIENTS AND METHODS: Single-center retrospective study of a cohort of 60 subjects with acromegaly, matched to 60 controls, who were referred for adaptive optics camera (AOC) from 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 diameter (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 retinal arteriolar remodeling. These results provide new perspectives to better stratify cardiovascular risk and consequently optimize treatment in acromegaly.

Analyzing Age-Related Macular Degeneration Progression in Patients with Geographic Atrophy Using Joint Autoencoders for Unsupervised Change Detection.

Age-Related Macular Degeneration (ARMD) is a progressive eye disease that slowly causes patients to go blind. For several years now, it has been an important research field to try to understand how the disease progresses and find effective medical treatments. Researchers have been mostly interested in studying the evolution of the lesions using different techniques ranging from manual annotation to mathematical models of the disease. However, artificial intelligence for ARMD image analysis has become one of the main research focuses to study the progression of the disease, as accurate manual annotation of its evolution has proved difficult using traditional methods even for experienced practicians. In this paper, we propose a deep learning architecture that can detect changes in the eye fundus images and assess the progression of the disease. Our method is based on joint autoencoders and is fully unsupervised. Our algorithm has been applied to pairs of images from different eye fundus images time series of 24 ARMD patients. Our method has been shown to be quite effective when compared with other methods from the literature, including non-neural network based algorithms that still are the current standard to follow the disease progression and change detection methods from other fields.

High-Resolution Imaging of Retinal Vasculitis by Flood Illumination Adaptive Optics Ophthalmoscopy: A Follow-up Study.

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.

Highlighting Directional Reflectance Properties of Retinal Substructures From D-OCT Images.

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.

Adaptive optics ophthalmoscopy: Application to age-related macular degeneration and vascular diseases.

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.

DIRECTIONAL VARIABILITY OF FUNDUS REFLECTANCE IN ACUTE MACULAR NEURORETINOPATHY: EVIDENCE FOR A CONTRIBUTION OF THE STILES-CRAWFORD EFFECT.

PURPOSE: To document directional reflectivity of fundus lesions in a case of acute macular neuroretinopathy. METHODS: Case report. Clinical and imaging data from a patient with acute macular neuroretinopathy were reviewed. Imaging comprised infrared scanning laser ophthalmoscopy, optical coherence tomography and flood-illumination adaptive optics images acquired through different entry pupils in the cardinal directions (approximately 2° eccentricity). RESULTS: The patient reported acute bilateral paracentral scotoma revealing dark, wedge-shaped macular plaques which by optical coherence tomography were associated with focal loss of the visibility of the cone outer segment tip and inner/outer segment lines. Comparing scanning laser ophthalmoscopy images taken at different entry points in the pupil showed that macular plaques varied from hyporeflectance to isoreflectance. Cone counts by flood-illumination adaptive optics within plaques and optical coherence tomography features of the cone outer segment tip showed also a strong directional variability, peaking at near-normal values. Within each modality, fusion images showed that directional variability covered most of macular plaques. CONCLUSION: The characteristic fundus abnormalities of acute macular neuroretinopathy may show a strong directional variability. Our findings suggest that the Stiles-Crawford effect may be an important factor in signs and symptoms of acute macular neuroretinopathy.

Effects of age, blood pressure and antihypertensive treatments on retinal arterioles remodeling assessed by adaptive optics.

BACKGROUND: In humans, adaptive optics camera enables precise large-scale noninvasive retinal microcirculation evaluation to assess ageing, blood pressure and antihypertensive treatments respective roles on retinal arterioles anatomy. METHOD: We used adaptive optics camera rtx1 (Imagine-Eyes, Orsay, France) to measure wall thickness, internal diameter and to calculate wall-to-lumen ratio (WLR) and wall cross-sectional area of retinal arterioles. This assessment was repeated within a short period in two subgroups of hypertensive individuals without or with a drug-induced blood pressure drop. RESULTS: In 1000 individuals, mean wall thickness, lumen diameter and WLR were 23.2 ±â€Š3.9, 78.0 ±â€Š10.9 and 0.300 ±â€Š0.054 µm, respectively. Blood pressure and age both independently increased WLR by thickening arterial wall. In opposite, hypertension narrowed lumen in younger as compared to older individuals (73.2 ±â€Š9.0 vs. 81.7 ±â€Š10.2 µm; P < 0.001), whereas age exerted no influence on lumen diameter. Short-term blood pressure drop (-29.3 ±â€Š17.3/-14.4 ±â€Š10.0 mmHg) induced a WLR decrease (-6.0 ±â€Š8.0%) because of lumen dilatation (+4.4 ±â€Š5.9%) without wall thickness changes. By contrast, no modifications were observed in individuals with stable blood pressure. In treated and controlled hypertensives under monotherapy WLR normalization was observed because of combined wall decrease and lumen dilatation independently of antihypertensive pharmacological classes. In multivariate analysis, hypertension drug regimen was not an independent predictor of any retinal anatomical indices. Retinal arteriolar remodeling comprised blood pressure and age-driven wall thickening as well as blood pressure-triggered lumen narrowing in younger individuals. CONCLUSION: Remodeling reversal observed in controlled hypertensives seems to include short-term functional and long-term structural changes.

Functional and high-resolution retinal imaging monitoring photoreceptor damage in acute macular neuroretinopathy.

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.

The Negative Cone Mosaic: A New Manifestation of the Optical Stiles-Crawford Effect in Normal Eyes.

PURPOSE: The purpose of this study was to describe a previously unreported manifestation of the optical Stiles-Crawford effect (oSCE) in normal eyes. METHODS: In a cohort of 50 normal subjects, the directional reflectance of cones in the retinal periphery was explored by flood-illuminated adaptive optics (FIAO) and optical coherence tomography (OCT). RESULTS: In 32 eyes (64%), off-axis FIAO images of the retinal periphery (∼15-20° from the fovea) showed variably sized patches of hyporeflective dots (called here negative mosaic) coexisting with hyperreflective (positive) cones. In nine cases, shifting the entry pupil toward the optical axis restored the positive cone mosaic, with a point-by-point correspondence between positive and negative mosaics. Rods remained hyperreflective around negative and positive cones. These changes were paralleled by changes of the OCT reflectance of the cone outer segment tips and, to a lesser extent, of the inner/outer segment limit. CONCLUSIONS: By en face FIAO imaging of the retina, the contrast of cones over rods may be strongly dependent on the entry pupil to such an extent that their reflectance is lower than that of rods. We hypothesized that the negative cone mosaic aspect results from the differential Stiles-Crawford effect of cones and rods. Cone reflectance by en face FIAO parallels the reflectance from the cone outer segment tip line and to a lesser extent of the inner/outer segment limit by OCT. Taking this into account, the oSCE is of importance for the interpretation of high-resolution images of photoreceptors. (ClinicalTrials.gov number, NCT01546181.)

Venous Nicking Without Arteriovenous Contact: The Role of the Arteriolar Microenvironment in Arteriovenous Nickings.

IMPORTANCE: Arteriovenous nickings (AVNs) in the retina are the cause of retinal vein occlusions and are also surrogates of cerebrovascular aging. The prevalent mechanistic model of AVNs stating that arteries crush veins remains somewhat unchallenged despite the lack of evidence other than fundus photographs. Here, we observed that venous nicking may be observed in the absence of physical contact with an arteriole. OBSERVATIONS: This observational study, conducted from January 2013 to September 2014, included 7 patients showing remodeling of a venous segment close to a retinal arteriole without arteriovenous overlap were imaged by adaptive optics imaging. Affected venous segments showed a variable association of nicking, narrowing, deviation, and opacification. Venous segments were deviated toward the arterioles in 6 of the 7 cases. The degree of venous narrowing ranged from 40% to 77%, while at these sites, the width of the intervascular space ranged from 16 µm to 42 µm. Similar features were identified in typical AVNs. CONCLUSIONS AND RELEVANCE: Arteriovenous nickings do not necessarily involve an arteriovenous compression. Instead, the topology of venous changes suggests a retractile process originating in the intervascular space. These findings have important implications for the understanding of retinal vein occlusions and of cerebrovascular aging.

Morphometric analysis of small arteries in the human retina using adaptive optics imaging: relationship with blood pressure and focal vascular changes.

OBJECTIVES: The wall-to-lumen ratio (WLR) of retinal arteries is a recognized surrogate of end-organ damage due to aging and/or arterial hypertension. However, parietal morphometry remains difficult to assess in vivo. Recently, it was shown that adaptive optics retinal imaging can resolve parietal structures of retinal arterioles in humans in vivo. Here, using adaptive optics retinal imaging, we investigated the variations of parietal thickness of small retinal arteries with blood pressure and focal vascular damage. METHODS: Adaptive optics imaging of the superotemporal retinal artery was done in 49 treatment-naive individuals [mean age (±SD) 44.9 years (±14); mean systolic pressure 132  mmHg (±22)]. Semi-automated segmentation allowed extracting parietal thickness and lumen diameter. In a distinct cohort, adaptive optics images of arteriovenous nicking (AVN; n = 12) and focal arteriolar narrowing (FAN; n = 10) were also analyzed qualitatively and quantitatively. RESULTS: In the cohort of treatment-naive individuals, by multiple regression taking into account age, body mass index, mean, systolic, diastolic and pulse blood pressure, the WLR was found positively correlated to mean blood pressure and age which in combination accounted for 43% of the variability of WLR. In the cohort of patients with focal vascular damage, neither FANs or AVNs showed evidence of parietal growth; instead, at sites of FANs, decreased outer diameter suggestive of vasoconstriction was consistently found, while at sites of AVNs venous narrowing could be seen in the absence of arteriovenous contact. CONCLUSION: High resolution imaging of retinal vessels by adaptive optics allows quantitative microvascular phenotyping, which may contribute to a better understanding and management of hypertensive retinopathy.

Foveal shape and structure in a normal population.

PURPOSE: The shape of the human fovea presents important but still poorly characterized variations. In this study, the variability of the shape and structure of normal foveae were examined. METHODS: In a group of 110 eyes of 57 healthy adults, the shape and structure of the fovea were analyzed by automated segmentation of retinal layer on high-resolution optical coherence tomography scans. In an additional group of 10 normal eyes of 10 patients undergoing fluorescein angiography, the size of the foveal avascular zone (FAZ) was correlated to foveal shape. RESULTS: From the thickest to the thinnest fovea, there was a structural continuum ranging from a shallow pit with continuity of the inner nuclear layer (INL) over the center (seven eyes; 6.7%), to a complete separation of inner layers overlying a flat and thinner central outer nuclear layer (ONL; eight eyes; 7.3%). Central foveal thickness correlated inversely to the degree of inner layer separation and to the surface of the FAZ. CONCLUSIONS: Foveal structure strongly correlates with its neurovascular organization. The findings support a developmental model in which the size of the FAZ determines the extent of centrifugal migration of inner retinal layers, which counteracts in some way the centripetal packing of cone photoreceptors.