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.

Severe macular complications in glaucoma: high-resolution multimodal imaging characteristics and review of the literature.

PURPOSE: To describe imaging characteristics of severe macular complications occurring in glaucoma and discuss available treatments. METHODS: Retrospective case series of glaucomatous patients with macular retinoschisis (MR) and/or serous retinal detachment (SRD). Patients underwent a complete ophthalmological examination and multimodal imaging including retinography, SD-OCT, fluorescein and indocyanine green angiography (FA & ICGA) and adaptive optics (AO). RESULTS: Ten eyes (8 patients) were included. Initial BCVA was 1.04 ± 1.12 logMAR and IOP was 24.0 ± 9.3mmHg. All eyes presented with MR while SRD was present in 5 eyes (5 patients), with a central macular thickness of 573 ± 152 µm. FA and ICGA allowed to exclude leakage in all cases. A focal lamina cribrosa defect (LCD) was found in four eyes (4 patients) using OCT, with AO providing en-face visualization of the defect in one eye. Outer retinal hole was present in 3 eyes (3 patients). No visual improvement or resolution of the macular retinoschisis was observed in eyes with medical or surgical IOP control (N = 9). Vitrectomy with internal membrane limiting peeling and gas tamponade was performed in one eye with good visual results. CONCLUSIONS: Multimodal high-resolution imaging is essential to diagnose severe macular complications associated with advanced glaucoma.

Long Term Time-Lapse Imaging of Geographic Atrophy: A Pilot Study.

Geographic atrophy (GA), the late stage of age-related macular degeneration, is a major cause of visual disability whose pathophysiology remains largely unknown. Modern fundus imaging and histology revealed the complexity of the cellular changes that accompanies atrophy. Documenting the activity of the disease in the margins of atrophy, where the transition from health to disease occurs, would contribute to a better understanding of the progression of GA. Time-lapse imaging facilitates the identification of structural continuities in changing environments. In this retrospective pilot study, we documented the long-term changes in atrophy margins by time-lapse imaging of infrared scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) images in 6 cases of GA covering a mean period of 32.8 months (range, 18-72). The mean interval between imaging sessions was 2.4 months (range, 1.4-3.8). By viewing time-lapse sequences we observed extensive changes in the pattern of marginal hyperreflective spots, which associated fragmentation, increase and/or disappearance. Over the entire span of the follow-up, the most striking changes were those affecting hyperreflective spots closest to margins of atrophy, on the non-atrophic side of the retina; a continuum between the successive positions of some of the hyperreflective spots was detected, both by SLO and OCT. This continuum in their successive positions resulted in a subjective impression of a centrifugal motion of hyperreflective spots ahead of atrophy progression. Such mobilization of hyperreflective spots was detected up to several hundred microns away from atrophic borders. Such process is likely to reflect the inflammatory and degenerative process underlying GA progression and hence deserves further investigations. These results highlight the interest of multimodal time-lapse imaging to document cell-scale dynamics during progression of GA. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT04128150 and NCT04129021.

A New Method for Visualizing Drusen and Their Progression in Flood-Illumination Adaptive Optics Ophthalmoscopy.

Purpose: Drusen are dynamic sub-RPE deposits that are risk factors for late-stage age-related macular degeneration (AMD). Here we show a new imaging method using flood-illumination adaptive optics (FIAO) that reveal drusen with high contrast and resolution. Methods: A fovea-centered 4° × 4° FIAO image and eight surrounding images with gaze displaced by ±2° vertically and horizontally were acquired. Clinical color fundus and spectral-domain optical coherence tomography were acquired for clinical grading and comparison. Custom software registered overlapping FIAO images and fused the data statistically to generate a fovea-centered 4° × 4° gaze-dependent image. Our dataset included 15 controls (aged 31-72) and 182 eyes from 104 AMD patients (aged 56-92), graded as either normal aging (n = 7), and early (n = 12), intermediate (n = 108) and late AMD (n = 42); 27 had subretinal drusenoid deposits (SDDs), and 83 were imaged longitudinally. Results: No gaze varying structures were detected in young eyes. In aging eyes with no evidence of age-related changes, putative drusen <20 µm in diameter were visible. Gaze-dependent images revealed more drusen and many smaller drusen than visible in color fundus images. Longitudinal images showed expansion and fusion of drusen. SDDs were lower contrast, and RPE atrophy did not yield a consistent signal. Conclusions: Gaze-dependent imaging in a commercially available FIAO fundus camera combined with image registration and postprocessing permits visualization of drusen and their progression with high contrast and resolution. Translational Relevance: This new technique offers promise as a robust and sensitive method to detect, map, quantify, and monitor the dynamics of drusen in aging and AMD.

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.

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.)

High-resolution imaging of gunn's dots.

BACKGROUND: In healthy fundi, glistening whitish dots (so-called Gunn's dots) can often be seen, especially in young subjects. They are commonly attributed to the reflectance of Müller cell's footplates. However, despite their potential interest as biomarkers of retinal diseases, Gunn's dots have received little attention in the scientific literature. METHODS: Scanning laser ophthalmoscope reflectance imaging and adaptive optics infrared flood imaging were performed in 18 healthy subjects (age range, 18-58 years) to analyze the localization, density, and shape of Gunn's dots. RESULTS: Gunn's dots were more easily observed in the midperipheral retina along temporal vessels, although in two subjects, they could be detected in the macula. The reflectance of Gunn's dots showed a strong directional variability, which paralleled that of the inner limiting membrane. The mean (±SD) diameter of Gunn's dots was 13.3 µm (±3.5). Their density peaked at ∼120 per square millimeter and decreased with age to become barely detectable after 50 years. CONCLUSION: Gunn's dots are highly anisotropic structures close to the inner limiting membrane. Their density, size, and age-related decline are closer to the characteristics of hyalocytes than those of Müller cells. Further studies are necessary to progress in the determination of their origin and interest as biomarkers of retinal diseases.

The normal age-corrected and reaction time-corrected isopter derived by semi-automated kinetic perimetry.

PURPOSE: To determine the increase in isopter extent, resulting from the measurement of, and correction for, individual reaction time (RT; the latency between stimulus presentation and individual patient response), derived under the standardized conditions of semi-automated kinetic perimetry (SKP), and to model the age- and RT-corrected normative isopter values for SKP applicable to any Goldmann stimulus combination. DESIGN: Cross-sectional observational study. PARTICIPANTS: Eighty-three healthy participants aged 10 to 80 years (11-12 participants per decade of age). METHODS: One eye of each participant underwent SKP using the Octopus 101 perimeter (Haag-Streit, Koeniz, Switzerland). Four Goldmann stimulus combinations, III4e at 25 degrees/second, III4e at 5 degrees/second, I3e at 5 degrees/second, and I2e at 2 degrees/second, were presented centripetally (i.e., in a direction toward the center of the bowl) along the 8 cardinal meridia in random order. The local kinetic threshold (LKT) for each stimulus combination along each meridian was corrected for the angular distance traveled during the individual geometric mean RT and was modeled in terms of the covariables stimulus size, stimulus luminance, meridian, and age, and then presented in terms of a graphical reference plot. MAIN OUTCOME MEASURES: The variation of the LKT with RT, stimulus combination, meridian, and age. RESULTS: The median of the individual geometric mean RTs initially decreased and then increased with increase in age and was greater for stimulus combinations producing small isopters compared with those generating large isopters. Reaction time-corrected LKTs were fitted optimally by a multiple regression model (R2 = 0.86). For large (> or =size III) and intense (4e) stimuli, RT-corrected LKTs were independent of age and mainly were influenced by instrument- and facial anatomy-related characteristics. Reaction time-corrected LKTs, particularly for small (< or = size II) stimuli, exhibited a clear age dependence above the age of 40 years particularly for reduced luminance stimuli (< or = 2e), with an approximate reduction in angular extent of 2 degrees per decade for the I1e stimulus. CONCLUSIONS: The development of a graphical reference plot with mean isopters and accompanying reference intervals for age- and RT-corrected SKP, applicable to any individual patient, should facilitate the evaluation of clinical data and the implementation of a computerized alternative to manual Goldmann kinetic perimetry.