Thinning Of Outer Nuclear Layer Research Articles

Integrating Machine Learning and Traditional Survival Analysis to Identify Key Predictors of Foveal Involvement in Geographic Atrophy.

The purpose of this study was to investigate the incidence of foveal involvement in geographic atrophy (GA) secondary to age-related macular degeneration (AMD), using machine learning to assess the importance of risk factors. Retrospective, longitudinal cohort study. Patients diagnosed with foveal-sparing GA, having GA size ≥ 0.049mm² and follow-up ≥ 6months, were included. Baseline GA area, distance from the fovea, and perilesional patterns were measured using fundus autofluorescence. Optical coherence tomography assessed foveal involvement, structural biomarkers, and outer retinal layers thickness. Onset of foveal involvement was recorded. Foveal survival rates were estimated using Kaplan-Meier curves. Hazard ratios (HRs) were assessed with mixed model Cox regression. Variable Importance (VIMP) was ranked with Random Survival Forests (RSF), with higher scores indicating greater predictive significance. One hundred sixty-seven eyes (115 patients, average age = 75.8 ± 9.47years) with mean follow-up of 50 ± 29months, were included in this study. Median foveal survival time was 45months (95% confidence interval [CI] = 38-55). Incidences of foveal involvement were 26% at 24months and 67% at 60months. Risk factors were GA proximity to the fovea (HR = 0.97 per 10-µm increase, 95% CI = 0.96-0.98), worse baseline visual acuity (HR = 1.37 per 0.1 LogMAR increase, 95% CI = 1.21-1.53), and thinner outer nuclear layer (HR = 0.59 per 10-µm increase, 95% CI = 0.46-0.74). RSF analysis confirmed these as main predictors (VIMP = 16.7, P = 0.002; VIMP = 6.2, P = 0.003; and VIMP = 3.4, P = 0.01). Lesser baseline GA area (HR = 1.09 per 1-mm2 increase, 95% CI = 1.01-1.16) and presence of a double layer sign (HR = 0.42, 95% CI = 0.20-0.88) were protective but less influential. This study identifies anatomic and functional factors impacting the risk of foveal involvement in GA. These findings may help identify at-risk patients, enabling tailored preventive strategies.

Directional Optical Coherence Tomography Imaging of Macular Pathology.

To survey the impact of directional reflectivity on structures within optical coherence tomography (OCT) images in retinal pathology. Sets of commercial OCT images taken from multiple pupil positions were analyzed. These Directional OCT (D-OCT) sets revealed directionally reflective structures within the retina. After ensuring sufficient image quality, resulting hybrid and composite images were characterized by assessing the Henle Fiber Layer (HFL), Outer Nuclear Layer (ONL), Ellipsoid Zone (EZ), and Interdigitation Zone (IZ). Additionally, hybrid images were reviewed for novel directionally reflective pathological features. Cross-sectional D-OCT image sets were obtained in 75 eyes of 58 subjects having a broad range of retinal pathologies. All cases showed improved visualization of the ONL/Henle fiber layer interface, and ONL thinning was therefore more apparent in several cases. The EZ and IZ also demonstrated attenuation where a geometric impact of underlying pathology affected their orientation. Misdirected photoreceptors were also noted as a consistent direction-dependent change in EZ reflectivity between regions of normal and absent EZ. D-OCT enhances the understanding of retinal anatomy and pathology. This optical contrast yields more accurate identification of retinal structures and possible imaging biomarkers for photoreceptor-related pathology.

Altered Outer Retinal Structure, Electrophysiology and Visual Perception in Parkinson's Disease.

Visual biomarkers of Parkinson's disease (PD) are attractive as the retina is an outpouching of the brain. Although inner retinal neurodegeneration in PD is well-established this has overlap with other neurodegenerative diseases and thus outer retinal (photoreceptor) measures warrant further investigation. To examine in a cross-sectional study whether clinically implementable measures targeting outer retinal function and structure can differentiate PD from healthy ageing and whether these are sensitive to intraday levodopa (L-DOPA) dosing. Centre-surround perceptual contrast suppression, macular visual field sensitivity, colour discrimination, light-adapted electroretinography and optical coherence tomography (OCT) were tested in PD participants (n = 16) and controls (n = 21). Electroretinography and OCT were conducted before and after midday L-DOPA in PD participants, or repeated after ∼2 hours in controls. PD participants had decreased center-surround contrast suppression (p < 0.01), reduced macular visual field sensitivity (p < 0.05), color vision impairment (p < 0.01) photoreceptor dysfunction (a-wave, p < 0.01) and photoreceptor neurodegeneration (outer nuclear layer thinning, p < 0.05), relative to controls. Effect size comparison between inner and outer retinal parameters showed that photoreceptor metrics were similarly robust in differentiating the PD group from age-matched controls as inner retinal changes. Electroretinography and OCT were unaffected by L-DOPA treatment or time. We show that outer retinal outcomes of photoreceptoral dysfunction (decreased cone function and impaired color vision) and degeneration (i.e., outer nuclear layer thinning) were equivalent to inner retinal metrics at differentiating PD from healthy age-matched adults. These findings suggest outer retinal metrics may serve as useful biomarkers for PD.

Association of acute macular neuroretinopathy with acute optic neuritis following COVID-19 infection

Acute optic neuritis is characterized by thinning of the inner retinal layers on optical coherence tomography. Acute macular neuroretinopathy is an outer retinal disorder that leads to thinning of the outer nuclear layer. A 34-year-old woman experienced decreased bilateral visual acuity 1 day following the coronavirus disease 2019 infection. Brain magnetic resonance imaging and demyelination testing revealed mild-to-moderate uneven enhancement of bilateral optic nerve segments, with anti-mog antibody reactivity. Hormone therapy was initiated, which led to outer nuclear layer thinning, completion of the ellipsoid zone, and an absent chimeric zone. The patient’s vision had been fully restored at her 1-year follow-up.

Iron overload and chelation modulates bisretinoid levels in the retina

AimIron dysregulation in conjunction with other disease processes may exacerbate retinal degeneration. We employed models of iron overload and iron chelation to explore the interactions between iron-catalyzed oxidation and photoreactive bisretinoid lipofuscin.MethodsThe mice were injected intravitreally with ferric ammonium citrate (FAC) or were treated using the iron chelator deferiprone (DFP) from birth to 2 months of age. Short-wavelength fundus autofluorescence (SW-AF) and spectral-domain optical coherence tomography (SD-OCT) scans were acquired. The bisretinoid levels were quantified using ultra performance liquid chromatography (UPLC) and in vivo through quantitative fundus autofluorescence (qAF). In histologic sections, the photoreceptor cell viability was assessed by measuring the thickness of the outer nuclear layer (ONL).ResultsThe levels of bisretinoids, all-trans-retinal dimers, and A2PE were significantly increased in the FAC-injected eyes of C57BL/6J mice. Seven days after FAC injection, hyperautofluorescent foci were visible in fundus autofluorescence (488 nm) images, and in SD-OCT scans, aberrant hyperreflectivity was present in the outer retina and ONL thinning was observed. In FAC-injected Abca4–/– mice with pronounced RPE bisretinoid lipofuscin accumulation, the hyperautofluorescent puncta were more abundant than in the wild-type mice, and the extent of ONL thinning was greater. Conversely, the intravitreal injection of FAC in Mertk–/– mice led to a more modest increase in A2PE after 2 days. In contrast to the effect of iron accumulation, chelation with DFP resulted in significantly increased levels of A2E and A2-GPE and qAF due to the reduced iron-catalyzed oxidation of bisretinoids. In Mertk–/– mice, the A2E level was significantly lower and the ONL area was smaller than in DFP-treated mice. DFP chelation did not impair the visual cycle in BALB/cJ mice.ConclusionIron accumulation was associated with progressive impairment in photoreceptor cells that was associated with the increased formation of a bisretinoid species known to form in photoreceptor outer segments as a precursor to A2E. Additionally, disease features such as the development of hyperautofluorescence puncta in fundus AF images, hyperreflectivity in the outer retina of SD-OCT scans, and ONL thinning were more pronounced when iron was delivered to Abca4–/– mice with a greater propensity for bisretinoid formation. Higher bisretinoid levels and enhanced qAF are indicative of lesser bisretinoid loss due to oxidation.

Acute Macular Neuroretinopathy after SARS-CoV-2 Infection: An Analysis of Clinical and Multimodal Imaging Characteristics.

This study aimed to analyze clinical and multimodal imaging characteristics of acute macular neuroretinopathy (AMN) post-recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Retrospective observational study. Medical records and multimodal imaging of 12 AMN eyes of eight patients (six female and two male) with recent SARS-CoV-2 infection were retrospectively analyzed. Four patients (50%) presented with bilateral AMN. Fundus ophthalmoscopy revealed a reddish-brown lesion around the macula, and two eyes had cotton-wool spots at the posterior pole. Three eyes showed mild hypo-autofluorescence. All FFA images (7 eyes) showed no abnormal signs. On OCT scans, all eyes showed outer nuclear layer (ONL) thinning, 8 eyes (66.7%) showed ONL hyperreflectivity, 5 eyes (41.7%) showed outer plexiform layer (OPL) hyperreflectivity, 8 eyes (66.7%) showed interdigitation zone (IZ) disruption, 11 eyes (91.6%) showed ellipsoid zone (EZ) disruption, 2 eyes (16.7%) showed cotton-wool spots and inner plexiform layer (IPL) hyperreflectivity, 1 eye (8.3%) had intraretinal cyst and 1 eye (8.3%) had inner nuclear layer (INL) thinning. Persistent scotoma, ONL hyperreflectivity and IZ/EZ disruption as well as recovery of OPL hyperreflectivity were reported after follow-up in three cases. AMN post-SARS-CoV-2 mostly affected young females and could present unilaterally or bilaterally. Dark lesions on IR reflectance and outer retinal hyperreflectivity on OCT are useful in diagnosing AMN. OPL/ONL hyperreflectivity on OCT could disappear after follow-up, but ONL thinning and IZ/EZ could persist.

CRX haploinsufficiency compromises photoreceptor precursor translocation and differentiation in human retinal organoids

BackgroundThe CRX-associated autosomal dominant retinopathies suggest a possible pathogenic mechanism of gene haploinsufficiency. However, based on reported human patient cases and studies with mouse models, it is hard to confirm the specific weight of haploinsufficiency in pathogenesis due to the interspecies gaps between gene expression and function.MethodsWe created monoallelic CRX by replacing one allele with tdTomato in human embryonic stem cells (hESCs) and subsequently dissect pathogenesis in hESCs-derived retinal organoids. We used transcriptome and immunofluorescence analyses to dissect phenotypic differences between CRX-monoallelic knockout and control wildtype organoids. For location analysis of CRX+ cells, a CRX-expression-tracing system was constructed in control hESCs. We implemented long-term live-cell imaging to describe the translocation of CRX+ cells between two groups in early organoid differentiation. The expression pattern of these dynamic differences was validated using RNA-seq and immunofluorescence assays.ResultsWe identified delayed differentiation of outer nuclear layer (ONL) stratification along with thinner ONL, serious loss of photoreceptor outer segments, as well as downregulated expression of gene for phototransduction and inner/outer segment formation. By live-cell imaging and immunostaining, we observed the overtension of actomyosin network and the arrested translocation of monoallelic CRX+ cells in the early stage of retinal differentiation.ConclusionsWe confirmed that gene haploinsufficiency is the mechanism for the dominant pathogenicity of CRX and discovered that CRX regulated postmitotic photoreceptor precursor translocation in addition to its specification of photoreceptor cell fates during human retinal development. These findings revealed a new underlying mechanism of CRX dominant pathogenesis and provided a new clue for the treatment of CRX-associated human retinopathies.

PolySialic acid-nanoparticles inhibit macrophage mediated inflammation through Siglec agonism: a potential treatment for age related macular degeneration.

Age-related macular degeneration (AMD) is a chronic, progressive retinal disease characterized by an inflammatory response mediated by activated macrophages and microglia infiltrating the inner layer of the retina. In this study, we demonstrate that inhibition of macrophages through Siglec binding in the AMD eye can generate therapeutically useful effects. We show that Siglecs-7, -9 and -11 are upregulated in AMD associated M0 and M1 macrophages, and that these can be selectively targeted using polysialic acid (PolySia)-nanoparticles (NPs) to control dampen AMD-associated inflammation. In vitro studies showed that PolySia-NPs bind to macrophages through human Siglecs-7, -9, -11 as well as murine ortholog Siglec-E. Following treatment with PolySia-NPs, we observed that the PolySia-NPs bound and agonized the macrophage Siglecs resulting in a significant decrease in the secretion of IL-6, IL-1β, TNF-α and VEGF, and an increased secretion of IL-10. In vivo intravitreal (IVT) injection of PolySia-NPs was found to be well-tolerated and safe making it effective in preventing thinning of the retinal outer nuclear layer (ONL), inhibiting macrophage infiltration, and restoring electrophysiological retinal function in a model of bright light-induced retinal degeneration. In a clinically validated, laser-induced choroidal neovascularization (CNV) model of exudative AMD, PolySia-NPs reduced the size of neovascular lesions with associated reduction in macrophages. The PolySia-NPs described herein are therefore a promising therapeutic strategy for repolarizing pro-inflammatory macrophages to a more anti-inflammatory, non-angiogenic phenotype, which play a key role in the pathophysiology of non-exudative AMD.

Pathophysiology of Secondary Macular Hole in Rhegmatogenous Retinal Detachment.

To describe the pathophysiology of secondary macular hole (MH) in rhegmatogenous retinal detachment (RRD). A retrospective cohort of 360 consecutive primary fovea-off RRDs presenting to St. Michael's Hospital, Toronto, from January 2012 to September 2022 were included. Preoperative OCT was assessed for bacillary layer detachment (BALAD) abnormalities. Histological sections of normal eyes were assessed to inform OCT interpretations. Primary outcome measure was the progression of BALAD to full-thickness MH (FTMH). Of the 360 patients, 22.5% (n = 81) had BALAD abnormalities at presentation. Eight percent (29/360) had associated MH, of which 79.3% (23/29) were a BALAD-lamellar hole and 20.7% (6/29) were FTMH. After reattachment, 62% of MHs persisted (18/29), of which 83% (15/18) had BALAD-lamellar holes that subsequently progressed to FTMH in a mean of 8.1 ± 3.2 days. BALAD-lamellar holes had significantly worse postoperative visual acuity (P < 0.001) when compared with other BALAD abnormalities (58/81) or with the rest of the cohort (279/360). OCT spectrum from BALAD to FTMH includes (1) cleavage planes extending from Henle fiber layer into the BALAD; (2) central outer nuclear layer thinning; (3) Müller cell cone loss with tissue remnants at the foveal walls; (4) retinal tissue operculum close to BALAD-MH; and (5) progressive thinning or degradation of the posterior band of BALAD-lamellar hole leading to FTMH. Histological specimens identified foveal regions of low mechanical stability. BALAD plays a crucial role in the pathophysiology of MH in RRDs, which forms owing to sequential changes in four critical areas: RPE-photoreceptor interface, myoid zone, Henle fiber layer, and Müller cell cone with surrounding tissue. Timely management of fovea-off RRD with BALAD may be prudent to avoid the progression to BALAD-lamellar hole, subsequent FTMH, and worse functional outcomes.

PREVALENCE AND MORPHOLOGIC BIOMARKERS OF METAMORPHOPSIA IN EYES WITH "RESOLVED" CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.

To assess relationships between demographics, clinical characteristics, and optical coherence tomography characteristics with persistence of metamorphopsia after resolution of subretinal fluid in eyes with chronic central serous chorioretinopathy. One-hundred participants with "resolved" (absence of subretinal fluid) chronic central serous chorioretinopathy were retrospectively analyzed. Patients underwent a complete ophthalmologic evaluation, including assessment of the presence of metamorphopsia. At the study visit, optical coherence tomography scans were reviewed for qualitative and quantitative features. Sixty-six of 100 patients (66.0%) complained of metamorphopsia. Both the foveal and parafoveal ganglion cell complex thicknesses were thinner in central serous chorioretinopathy eyes with metamorphopsia (35.1 ± 10.6 µ m and 82.0 ± 18.1 µ m vs. 40.7 ± 11.8 µ m and 93.1 ± 13.5 µ m, P = 0.030 and P < 0.0001). In the foveal region, the outer plexiform layer and outer nuclear layer thicknesses were thinner in patients with metamorphopsia (24.6 ± 8.5 µ m and 63.1 ± 20.9 µ m vs. 29.1 ± 8.7 and 76.2 ± 18.2 µ m, P = 0.016 and P = 0.005). The ellipsoid zone band was more frequently discontinued in eyes with metamorphopsia (56.1% vs. 35.3%, P = 0.039). Multivariate stepwise linear regression analysis demonstrated that the strongest associations with the presence of metamorphopsia were with parafoveal ganglion cell complex thickness ( P = 0.004), foveal outer nuclear layer thickness ( P = 0.010), and number of previous recurrences of subretinal fluid accumulation ( P = 0.017). The time interval from the last subretinal fluid resolution was not associated with the presence of metamorphopsia. In "resolved" central serous chorioretinopathy, clinical aspects (i.e., number of previous recurrences) and structural changes (i.e., ganglion cell complex and outer nuclear layer thinning) are associated with metamorphopsia after subretinal fluid resolution.

Intravitreal Administration of Retinal Organoids-Derived Exosomes Alleviates Photoreceptor Degeneration in Royal College of Surgeons Rats by Targeting the Mitogen-Activated Protein Kinase Pathway.

Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.

Retinal Responses to Visual Stimuli in Interphotoreceptor Retinoid Binding-Protein Knock-Out Mice.

Interphotoreceptor retinoid-binding protein (IRBP) is an abundant glycoprotein in the subretinal space bound by the photoreceptor (PR) outer segments and the processes of the retinal pigmented epithelium (RPE). IRBP binds retinoids, including 11-cis-retinal and all-trans-retinol. In this study, visual function for demanding visual tasks was assessed in IRBP knock-out (KO) mice. Surprisingly, IRBP KO mice showed no differences in scotopic critical flicker frequency (CFF) compared to wildtype (WT). However, they did have lower photopic CFF than WT. IRBP KO mice had reduced scotopic and photopic acuity and contrast sensitivity compared to WT. IRBP KO mice had a significant reduction in outer nuclear layer (ONL) thickness, PR outer and inner segment, and full retinal thickness (FRT) compared to WT. There were fewer cones in IRBP KO mice. Overall, these results confirm substantial loss of rods and significant loss of cones within 30 days. Absence of IRBP resulted in cone circuit damage, reducing photopic flicker, contrast sensitivity, and spatial frequency sensitivity. The c-wave was reduced and accelerated in response to bright steps of light. This result also suggests altered retinal pigment epithelium activity. There appears to be a compensatory mechanism such as higher synaptic gain between PRs and bipolar cells since the loss of the b-wave did not linearly follow the loss of rods, or the a-wave. Scotopic CFF is normal despite thinning of ONL and reduced scotopic electroretinogram (ERG) in IRBP KO mice, suggesting either a redundancy or plasticity in circuits detecting (encoding) scotopic flicker at threshold even with substantial rod loss.

Clinical and Genetic Findings in Korean Patients with Choroideremia.

We share and analyze the clinical presentations and genotypes of Korean male patients and female carriers who visited our clinic. Six male patients and three female carriers with comprehensive ophthalmic examinations and next-generation sequencing were included. Detailed clinical features were identified using visual field (VF) test and multimodal imaging including color fundus photography, fundus autofluorescence (FAF), optical coherence tomography (OCT). Six male patients were diagnosed with choroideremia at the median age of 25 years. Before genetic testing, three (50.0%) patients were clinically diagnosed with choroideremia, while the other three (50.0%) patients with retinitis pigmentosa (RP). Patients showed different types of hemizygous CHM mutation, including two nonsense mutations (c.715C>T, p.Arg239Ter; c.799C>T, p.Arg267Ter), two frameshift mutations (c.1584_1587del, p.Val529HisfsTer7; c.403_404delGA, p.Asp135PhefsTer9), one splicing mutation (c.1511-28_1511-2del), and one exon duplication (2-9). The latter three mutations are novel findings. Two female carriers showed exon duplication (2-9) and the other one female carrier showed nonsense mutations (c.715C>T, p.Arg239Ter) in heterozygote form. Fundus showed diffuse yellow-whitish scleral reflex and granular pigmented lesions. FAF showed multiple patchy hypofluorescence lesions, sparing macula. OCT showed thinning of outer nuclear layer, ellipsoid zone, RPE layer, choroid thickness, interlaminar bridges (ILBs), outer retinal tubulations (ORTs), and microcysts in the inner nuclear layer. VF showed ring scotoma pattern with small amount of remaining central field. Asymptomatic female carriers showed variable fundus findings and mild changes in OCT. A detailed description of the genotypes with three novel mutations and phenotypes of six choroideremia patients and three CHM mutation female carriers are presented.

Modeling rod and cone photoreceptor cell survival in vivo using optical coherence tomography

Many retinal diseases involve the loss of light-sensing photoreceptor cells (rods and cones) over time. The severity and distribution of photoreceptor loss varies widely across diseases and affected individuals, so characterizing the degree and pattern of photoreceptor loss can clarify pathophysiology and prognosis. Currently, in vivo visualization of individual photoreceptors requires technology such as adaptive optics, which has numerous limitations and is not widely used. By contrast, optical coherence tomography (OCT) is nearly ubiquitous in daily clinical practice given its ease of image acquisition and detailed visualization of retinal structure. However, OCT cannot resolve individual photoreceptors, and no OCT-based method exists to distinguish between the loss of rods versus cones. Here, we present a computational model that quantitatively estimates rod versus cone photoreceptor loss from OCT. Using histologic data of human photoreceptor topography, we constructed an OCT-based reference model to simulate outer nuclear layer thinning caused by differential loss of rods and cones. The model was able to estimate rod and cone loss using in vivo OCT data from patients with Stargardt disease and healthy controls. Our model provides a powerful new tool to quantify photoreceptor loss using OCT data alone, with potentially broad applications for research and clinical care.

Retinal photoreceptor layer thickness has disease specificity and distinguishes predicted FTLD-Tau from biomarker-determined Alzheimer's disease

While Alzheimer's disease (AD) is associated with inner retina thinning (retinal nerve fiber layer and ganglion cell layer), we have observed photoreceptor outer nuclear layer (ONL) thinning in patients with frontotemporal lobar degeneration tauopathy (FTLD-Tau) compared to normal controls. We hypothesized that ONL thinning may distinguish FTLD-Tau from patients with biomarker evidence of AD neuropathologic change (ADNC) and will correlate with FTLD-Tau disease severity.Predicted FTLD-Tau (pFTLD-Tau; n = 21; 33 eyes) and predicted ADNC (pADNC; n = 24; 46 eyes) patients were consecutively enrolled, underwent optical coherence tomography macula imaging, and disease was categorized (pFTLD-Tau vs. pADNC) with cerebrospinal fluid biomarkers, genetic testing, and autopsy data when available. Adjusting for age, sex, and race, pFTLD-Tau patients had a thinner ONL compared to pADNC, while retinal nerve fiber layer and ganglion cell layer were not significantly different. Reduced ONL thickness correlated with worse performance on Folstein Mini-Mental State Examination and clinical dementia rating plus frontotemporal dementia sum of boxes for pFTLD-Tau but not pADNC. Photoreceptor ONL thickness may serve as an important noninvasive diagnostic marker that distinguishes FTLD-Tau from AD neuropathologic change.

Transducin-Deficient Rod Photoreceptors Evaluated With Optical Coherence Tomography and Oxygen Consumption Rate Energy Biomarkers.

To test the hypothesis that rod energy biomarkers in light and dark are similar in mice without functional rod transducin (Gnat1rd17). Gnat1rd17 and wildtype (WT) mice were studied in canonically low energy demand (light) and high energy demand (dark) conditions. We measured rod inner segment ellipsoid zone (ISez) profile shape, external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness, and magnitude of a hyporeflective band (HB) intensity dip located between photoreceptor tips and apical RPE; antioxidants were given in a subset of mice. Oxygen consumption rate (OCR) and visual performance indexes were also measured. The lower energy demand expected in light-adapted wildtype retinas was associated with an elongated ISez, thicker ELM-RPE, and higher HB magnitude, and lower OCR compared to high energy demand conditions in the dark. Gnat1rd17 mice showed a wildtype-like ISez profile shape at 20 minutes of light that became rounder at 60 minutes; at both times, ELM-RPE was smaller than wildtype values, and the HB magnitude was unmeasurable. OCR was higher than in the dark. Light-adapted Gnat1rd17 mice biomarkers were unaffected by anti-oxidants. Gnat1rd17 mice showed modest outer nuclear layer thinning and no reduction in visual performance indexes. Light-stimulated changes in all biomarkers in WT mice are consistent with the established light-induced decrease in net energy demand. In contrast, biomarker changes in Gnat1rd17 mice raise the possibility that light increases net energy demand in the absence of rod phototransduction.

Pigment epithelium and choroid changes in pachychoroid pigment epitheliopathy: A descriptive study

AbstractPurpose: To describe characteristic elementary lesions of retinal pigment epithelium and choroidal vascular parameters determined by swept source optical coherence tomography (SS‐OCT) and OCT‐angiography (OCT‐A) in eyes with pachychoroid pigment epitheliopathy.Methods: Twenty‐seven patients with retinal pigment epithelium (RPE) abnormalities associated to pachychoroid features, with no history or findings indicative of subretinal fluid or soft drusen were evaluated. All eyes underwent comprehensive ophthalmic examination, fundus photography, SS‐OCT and OCT‐A. After binarization of B‐scan images with ImageJ Software, the choroidal vascularity index (CVI), the choroidal vascularity proportion (CVP) and flow voids area were calculated.Results: A total of 27 eyes of 23 patients, 19 of whom were male (70.37%), with a mean age of 59.11 ± 12.76 years were enrolled in this study. We detected six different types of RPE lesions: focal disruption in ellipsoid and interdigitation zones in 18 eyes (66.66%), RPE elevation with microbreak appearance in 12 eyes (44.44%), RPE thickening in 10 eyes (37.03%), small pigment epithelium detachment in seven eyes (25.92%), RPE spike in five eyes (18.51%) and outer nuclear layer thinning in five eyes (18.51%). The subfoveal choroidal thickness (SFCT) was 399, 78 ± 88, 13 μm. The mean inner choroidal thickness was 87.18 ± 36.67 μm. The CVI was 65.28 ± 3.35%. The CVP was 59.10 ± 0.58% in the choriocapillaris and 59.69 ± 1.42% in the Haller layer. The total choriocapillaris flow void area was 39.87 ± 1.21%.Conclusions: SS‐OCT and OCT‐A are valuable diagnostic tools to characterize pigment epithelium and choroidal changes in PPE eyes.

Retinal Vascular Plexuses Are Unequally Affected in Canine Inherited Retinal Degenerations.

To characterize the progression of vascular changes that occur in each retinal plexus, in three canine models of inherited retinal degeneration. In this retrospective cohort study, we examined the retinal imaging records of 44 dogs from a research colony that had undergone optical coherence tomography angiography (OCTA) imaging. Animals enrolled included crd2/NPHP5 and xlpra2/RPGR mutant dogs imaged at different stages of photoreceptor loss, as well as RHOT4R/+ dogs after acute light-induced rod degeneration. Also included were normal controls imaged at similar ages. OCT angiograms of the superficial vascular plexus combined with the intermediate capillary plexus (SVP + ICP), and the deep capillary plexus (DCP) were analyzed using the AngioTool software to calculate vessel density and other vascular parameters. A reduction in vessel density was seen over time in both the SVP + ICP and DCP in all mutant dogs but was more pronounced in the DCP. Scans were subclassified based on outer nuclear layer (ONL) thinning compared to age-matched normal controls. When ONL loss was 0% to 50%, vessel density in the DCP was significantly lower than in age-matched controls. In all cases, when ONL loss exceeded 87.5%, vessel density in the SVP + ICP was significantly reduced as well. In the acute light-induced rod degeneration model, the vascular regression changes were observed mainly in the DCP. Vessel density reduction in dogs undergoing retinal degeneration is first detected by OCTA in the DCP, and only at later stages in the SVP + ICP.

Visual function and retinal changes after voretigene neparvovec treatment in children with biallelic RPE65-related inherited retinal dystrophy

To report quantitative retinal changes assessed by spectral-domain optical coherence tomography (SD-OCT) in children treated with voretigene neparvovec (VN) at a single center in Italy. Retrospective review of six consecutive pediatric patients with biallelic RPE65-related dystrophy treated bilaterally with VN. SD-OCT scans were analyzed to extract Early Treatment Diabetic Retinopathy Study (ETDRS) thickness maps of the whole retina and the outer nuclear layer (ONL). Changes in visual function were assessed by best-corrected visual acuity (BCVA) and retinal morphology at Days 30/45 and 180. BCVA significantly improved at Day 30/45 and 6 months (both P < 0.001). Central foveal retinal thickness and central foveal ONL thickness tended to increase (6.4 ± 19.2 µm; P = 0.080 and 3.42 ± 7.68 µm; P = 0.091, respectively). ONL thickness of the internal ETDRS-ring significantly increased at day 30/45 (4.7 ± 8.4 µm; P < 0.001) and day 180 (5.0 ± 5.7 µm; P = 0.009). Intra-operative foveal detachment was not associated with a higher function gain in terms of BCVA, but with a mild thinning of foveal ONL after treatment. The improvement of BCVA and thickening of the ONL layer suggest that improvement of visual acuity could be related to partial recovery of retinal morphology in the perifoveal ring.

Short-term progression of optic disc and macular changes in optic nerve head drusen

PurposeTo quantify in patients with optic nerve head drusen (ONHD)changes after 1-year observation in: (i) optic disc and (ii) macular optical coherence tomography (OCT) parameters and (iii) the effect of age at enrolment in the study.DesignProspective, cross-sectional observational study using Spectral Domain-OCT (Copernicus; OPTOPOL Technology S.A., Zawiercie, Poland) imaging was carried out in 35 patients with ONHD (age–42.8 ± 19.9 years; males = 15; females = 20) at baseline and after 12 months follow-up.ResultsPatients with ONHD had significant thinning of the surface nerve fibre layer in the central (p = 0.03), superior (p = 0.05) and inferior (p = 0.04) areas; mean ppRNFL thinning (p = 0.0 4) and ppRNFL thinning in the nasal segment (p = 0.028). Retinal thinning in the central (p = 0.001), inner (p = 0.01) and outer (p = 0.002) temporal, outer superior (p = 0.03) and inferior (p = 0.02) areas; borderline ganglion cell layer thinning (p = 0.051) and outer nuclear layer (p = 0.03) thinning in the central retina and outer segment layer thinning nasally (p = 0.01) between the first and the second visit in macula. Correlation of the difference in optic disc and macular parameters with the age at enrolment did not reveal any significance.ConclusionsStatistically detectable thinning of the optic nerve and macula structures occurred already after 12 months. The proximity of optic nerve changes to the vascular arcades can possibly be explained by involvement of retinal vessels in the pathophysiology of ONHD.