Novel Findings of Retinal and Choroidal Features Utilizing Optical Coherence Tomography Angiography Analysis in Patients With Autoimmune Posterior Uveitis

Purpose: To analyze the quantitative parameters acquired by optical coherence tomography angiography (OCTA) in patients with autoimmune posterior uveitis.Methods: OCTA images of 65 eyes affected with uveitis and 65 normal control (NC) eyes were obtained. The central macular thickness (CMT), retinal thicknesses, foveal avascular zone (FAZ) area, foveal density 300 μm (FD300), and vascular density (VD) were compared among acute uveitic eyes, chronic uveitic eyes, and NC eyes. VDs were evaluated in the choriocapillaris, outer retina, optic disk, whole and parafovea superficial capillary plexus (SCP), and whole and parafovea deep capillary plexus (DCP). Correlation analysis was used to analyze the relationship between LogMAR best-corrected visual acuity (BCVA) and quantitative parameters from OCTA.Results: Compared with NC eyes, the CMT and retinal thicknesses were increased significantly in eyes with uveitis (p < 0.05, respectively). No significant difference was observed in the FAZ area. FD300, VDs in the optic disk, SCP, and DCP both in whole image and parafovea, choriocapillaris were significantly decreased in uveitis eyes (p < 0.05, respectively) compared with NC eyes, only the acute group had decreased VD of the outer retina and choriocapillaris compared with the NC group (p < 0.05). Moreover, quantitative parameters of OCTA showed a significant correlation with LogMAR BCVA in the patients with uveitis. Whole VD DCP was the best predictive factor for BCVA in the patients with uveitis.Conclusion: Quantitative measurement by OCTA is a promising strategy for objective assessment of autoimmune posterior uveitis.

Enriched environment and visual stimuli protect the retinal pigment epithelium and photoreceptors in a mouse model of non-exudative age-related macular degeneration

Non-exudative age-related macular degeneration (NE-AMD), the main cause of blindness in people above 50 years old, lacks effective treatments at the moment. We have developed a new NE-AMD model through unilateral superior cervical ganglionectomy (SCGx), which elicits the disease main features in C57Bl/6J mice. The involvement of oxidative stress in the damage induced by NE-AMD to the retinal pigment epithelium (RPE) and outer retina has been strongly supported by evidence. We analysed the effect of enriched environment (EE) and visual stimulation (VS) in the RPE/outer retina damage within experimental NE-AMD. Exposure to EE starting 48 h post-SCGx, which had no effect on the choriocapillaris ubiquitous thickness increase, protected visual functions, prevented the thickness increase of the Bruch’s membrane, and the loss of the melanin of the RPE, number of melanosomes, and retinoid isomerohydrolase (RPE65) immunoreactivity, as well as the ultrastructural damage of the RPE and photoreceptors, exclusively circumscribed to the central temporal (but not nasal) region, induced by experimental NE-AMD. EE also prevented the increase in outer retina/RPE oxidative stress markers and decrease in mitochondrial mass at 6 weeks post-SCGx. Moreover, EE increased RPE and retinal brain-derived neurotrophic factor (BDNF) levels, particularly in Müller cells. When EE exposure was delayed (dEE), starting at 4 weeks post-SCGx, it restored visual functions, reversed the RPE melanin content and RPE65-immunoreactivity decrease. Exposing animals to VS protected visual functions and prevented the decrease in RPE melanin content and RPE65 immunoreactivity. These findings suggest that EE housing and VS could become an NE-AMD promising therapeutic strategy.

Wnt1-Cre mediated deletion of BMP7 suggests a role for neural crest-derived BMP7 in retina development and function

Neural crest (NC) contributes to various structures of the eye including cornea, ciliary body and retina. The association of NC-derived cells with hyaloid vessels in the form of pericytes is established. Similarly, persistence of NC-derived cells in the inner retina layer of the mature retina has been suggested. To date, no specific function has been attributed to them. NC-derived Bone morphogenetic protein 7 (BMP7) controls neurogenic properties in the brain and regulates glia differentiation. Here, we assessed the role of NC-derived BMP7 in the adult retina. BMP7 expression was determined using Bmp7LacZ reporter mice. BMP7 was expressed in GCL, IPL, OPL, and photoreceptors in P0, P14 and P30 retinas. Lineage tracing confirmed the presence of NC-derived cells in the GCL, INL, and ONL. Some but not all cells associated with vasculature. To test the function of NC-derived Bmp7, Bmp7fl/flWnt1cre (Bmp7ncko) mice were assessed by histological and functional methods. Loss of NC-derived cells in the GCL and INL and mild structural abnormalities were observed in the Bmp7ncko retina. Electroretinography revealed reduced a wave under photopic conditions and b wave under both scotopic and photopic conditions. The neuronal circuitry in the inner retina appeared affected, evidenced by decreased Calbindin in the GCL, IPL and INL. In the outer retina, S-opsin was increased. BMP7 expression in the mutant retina was strongly decreased at birth, but increased expression from cells other than NC was observed in the adult retina. This was associated with an increase in IBA1, suggestive that loss of NC-derived BMP7 predisposes to development of gliosis-like changes in the adult retina. Overall, our data reveal an important contribution of NC-derived BMP7 for the development and function of the inner and outer retina.

Multimodal imaging supporting the pathophysiology of white dot syndromes

White dot syndromes (WDS) represent a heterogeneous group of inflammatory diseases, primarily affecting the outer retina, choriocapillaris and choroid. Recent advances in the field of ocular imaging and development of new technologies, including optical coherence tomography angiography (OCT-A), have allowed a better characterization of the morphology of these conditions. This review will analyse the WDS from an imaging-based perspective, providing a better understanding of the pathophysiology underlying these disorders.

Retinal Vascular Response to Hyperoxia in Patients with Diabetes Mellitus without Diabetic Retinopathy

Purpose. To evaluate the retinal vascular response to hyperoxia in patients with diabetes at the preclinical stage of diabetic retinopathy (DR) and to quantify the changes in comparison with normal subjects using optical coherence tomography angiography (OCTA). Methods. In this prospective study, 40 eyes of 20 participants comprising 10 diabetic patients with no diabetic retinopathy (NDR) and 10 normal subjects were recruited. OCTA images were acquired in the resting position and were repeated after a hyperoxic challenge using a nasal mask connected to a reservoir bag supplying 100% oxygen at the rate of 15 L per minute for 5 minutes. The changes of mean parafoveal vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), the foveal avascular zone (FAZ) size, and the outer retina flow index were compared between two conditions in each group and between the two study groups. The statistical significance of differences in the means was evaluated using Student’s t-test for unpaired samples with consideration of the generalized estimating equations (GEE) for intereye correlation. Results. At baseline, the mean parafoveal VD of SCP and DCP were significantly lower in the NDR participants compared to the healthy subjects (P < 0.001 and P = 0.006, respectively). After induction of the hyperoxic challenge in healthy participants, mean parafoveal VD reduced at both the SCP and DCP, but reached a statistical significance only in DCP (P = 0.006). However, following induction of hyperoxic challenge in patients with NDR, no significant decline was noticed in mean parafoveal VD of SCP and DCP. The degree of change in mean parafoveal VD of DCP was statistically significantly more pronounced in healthy subjects compared to the NDR group (P = 0.034). The change in FAZ size and the outer retina flow index were comparable between the two study groups. Conclusion. Retinal capillary layers responded differently to hyperoxia-induced challenge, and in normal subjects, the autoregulatory mechanism was mostly effective in the parafoveal DCP. Retinal vascular reactivity was impaired in SCP and DCP at the preclinical stage of DR. OCTA as a noninvasive modality was able to quantify the retinal vascular response to the hyperoxic challenge.

Quantitative effect of subretinal fluid and intraretinal edema on visual acuity in uveitic cystoid macular edema

Background The effect of subretinal fluid (SRF) in uveitic cystoid macular edema (CME) is not fully understood. This study evaluates the quantitative effect of SRF and intraretinal thickness on visual acuity in eyes with uveitic CME. We separately measured SRF and intraretinal area on Optical Coherence Tomography (OCT) to determine the associations of each component with visual acuity and response to treatment. Main text Medical records were reviewed of patients with CME presenting to the University of Colorado uveitis clinic from January 2012 to May 2019. All available OCTs were reviewed to classify eyes as either having only CME or CME with SRF. Intraretinal area was manually measured using Image J along the central 1-mm section of B-scan OCT spanning from the internal limiting membrane to the outer most portion of the outer retina including both cysts and retinal tissue. SRF cross-sectional area was measured spanning from the outermost portion of the outer retina to retinal pigment epithelium. Response to treatment was assessed one to four months after presentation. Eyes with CME secondary to structural or non-inflammatory causes were excluded. Forty-seven (50.5%) eyes had CME alone and 46 (49.5%) eyes had SRF with CME. Measured SRF cross-sectional area was not associated (p = 0.21) with LogMAR at presentation. Conversely, intraretinal area was strongly correlated with visual acuity in eyes with SRF (p < 0.001) and without SRF (p < 0.001). Following treatment, there was a significant decrease in intraretinal area for both groups (p < 0.001), with a larger decrease in the SRF group compared to the non-SRF group (p = 0.001). Similarly, logMAR improved in both groups (p = 0.008 for SRF eyes and p = 0.005 for non-SRF eyes), but the change was more prominent in the SRF group (p = 0.06). Conclusions There was no direct association observed between the amount of SRF and visual acuity. In contrast, increased intraretinal area was significantly associated with decreased visual acuity. This relationship between intraretinal thickening and visual acuity may explain differences observed in response to treatment between SRF and non-SRF eyes, with a larger decrease in the intraretinal cross-sectional area in SRF eyes associated with a greater improvement in logMAR visual acuity.

Co-Injection of Sulfotyrosine Facilitates Retinal Uptake of Hyaluronic Acid Nanospheres Following Intravitreal Injection

Gene and drug delivery to the retina is a critical therapeutic goal. While the majority of inherited forms of retinal degeneration affect the outer retina, specifically the photoreceptors and retinal pigment epithelium, effective targeted delivery to this region requires invasive subretinal delivery. Our goal in this work was to evaluate two innovative approaches for increasing both the persistence of delivered nanospheres and their penetration into the outer retina while using the much less invasive intravitreal delivery method. We formulated novel hyaluronic acid nanospheres (HA-NS, 250 nm and 500 nm in diameter) conjugated to fluorescent reporters and delivered them intravitreally to the adult Balb/C mouse retina. They exhibited persistence in the vitreous and along the inner limiting membrane (ILM) for up to 30 days (longest timepoint examined) but little retinal penetration. We thus evaluated the ability of the small molecule, sulfotyrosine, to disrupt the ILM, and found that 3.2 µg/µL sulfotyrosine led to significant improvement in delivery to the outer retina following intravitreal injections without causing retinal inflammation, degeneration, or loss of function. Co-delivery of sulfotyrosine and HA-NS led to robust improvements in penetration of HA-NS into the retina and accumulation along the interface between the photoreceptors and the retinal pigment epithelium. These exciting findings suggest that sulfotyrosine and HA-NS may be an effective strategy for outer retinal targeting after intravitreal injection.

Two Novel Disease-Causing Variants in the PDE6C Gene Underlying Achromatopsia

We report the clinical phenotype and genetic findings of two variants in PDE6C underlying achromatopsia (ACHM). Four patients with the variant c.1670G&#x3e;A in exon 13 of the PDE6C gene were identified. Additionally, one had compound heterozygous genotype, with two variants in the <i>PDE6C</i> gene, a variant of c.2192G&#x3e;A in exon 18 and c.1670G&#x3e;A in exon 13. All patients presented the symptomatic triad of decreased visual acuity, severe photophobia, and colour vision disturbances. SD-OCT showed an absence of the ellipsoid zone, creating an optically empty cavity at the fovea in three patients. The patient with the compound heterozygous genotype presented a more severe subfoveal outer retina atrophy. ERG recordings showed extinguished responses under photopic and 30-Hz flicker stimulation, with a normal rod response. We identified two new variants in the <i>PDE6C</i> gene that leads to ACHM.