Fundus autofluorescence (FAF) is a widely utilized method of imaging the retina. It provides a quick and noninvasive method to assess the health of the photoreceptor and retinal pigment epithelium. FAF enables topographic mapping of the metabolic profile of the retina, allowing for disease detection, prognosis, and guidance for the management of a variety of retinal and choroidal diseases. Short-wavelength autofluorescence is the most widely used and studied method of FAF, though advanced techniques such as near-infrared autofluorescence may further expand the clinical utilities of FAF.

Purpose: To describe ultra-widefield fluorescein angiographic (UWF-FA) features of patients with retinitis pigmentosa (RP) and to compare the findings with those of controls without inherited retinal degeneration. Methods: Patients with RP who underwent ultra-widefield FA between 2017 and 2024 at an academic center were included. Age-matched controls without inherited retinal degeneration or vascular disease were also included. Arteriovenous transit times relative to choroidal flush and angiographic features were documented. Central and peripheral retinal vessels were defined based on distance from the fovea. Patients with RP with complete peripheral atrophy were excluded from peripheral analysis. Student t test was used for comparisons. Results: In total, 30 eyes from 15 patients with RP and 28 eyes from 14 control participants were analyzed. The groups were similar in age and sex distribution. Central retinal transit times were comparable between groups; however, patients with RP demonstrated significantly prolonged laminar flow during the arteriovenous phase (8.1 ± 2.4 vs 5.5 ± 1.2 seconds, P = .001) and delayed peripheral venous filling (28.6 ± 2.7 vs 17.7 ± 1.4 seconds, P < .001). Common angiographic features in RP included peripheral vascular dropout (93%), bone-spicule-associated blocking (87%), granular staining or window defects (73%), central hypofluorescence (67%), and ring-like hyperfluorescence (53%). Conclusions: Patients with RP demonstrate significant peripheral vascular dropout and delayed venous filling on ultra-widefield FA, along with distinct angiographic patterns that may aid in interpretation.

OBJECTIVE:To evaluate the long-term impact of social determinants of health on diabetic retinopathy (DR) incidence, complications, and management in patients with type 2 diabetes mellitus (T2DM), with emphasis on disparities among treatment-adherent individuals and demographic subgroups. METHODS:We conducted a retrospective cohort study using TriNetX, a national electronic health records network spanning 70 U.S. healthcare organisations. Adults diagnosed with T2DM were categorised into socially deprived and non-deprived cohorts based on ICD-10 codes related to housing instability, food insecurity, and financial hardship. Propensity score matching balanced cohorts on demographics, comorbidities, laboratory values, medications, and ophthalmic care utilisation. Outcomes included incident DR, sight-threatening complications, ophthalmic treatment and diagnostics, and documented treatment nonadherence. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS:Matched cohorts included 62,786 socially deprived and 62,786 non-deprived patients (mean age, 54 years; 42% female; 49% White, 27% Black, 14% Hispanic). Over a 10-year follow-up, social deprivation was associated with increased risk of DR (HR 1.40, 95% CI 1.34-1.47) and sight-threatening complications, including blindness. Documented nonadherence was significantly increased in the socially deprived cohort (HR 3.57, 95% CI 3.47-3.68). Among patients without documented nonadherence, social deprivation was associated with increased DR risk (HR 1.44, 95% CI 1.35-1.54) and treatment utilisation. Disparities were most pronounced in males, Hispanic individuals, and adults aged 18-39. CONCLUSIONS:Social deprivation, regardless of documented treatment adherence, increased DR incidence and complications. Targeted interventions are needed to address persistent disparities and reduce DR burden.

Objective:Retinitis pigmentosa (RP) is the most common inherited retinal disease and a major cause of irreversible vision loss. The purpose of this study was to assess peripheral retinal vessels in RP. Design:A cross-sectional study. Subjects:Patients with RP and age-matched controls. Methods:Using ultra-widefield fundus images, the retina was divided into 3 zones: posterior, midperiphery, and far periphery. To evaluate vascularity of the retina, the vessels were counted at the border of posterior and midperipheral zones (Z1/2) and the border of midperipheral and far peripheral zones (Z2/3). Main Outcome Measures:Vessel counts at Z1/2 and Z2/3. Results:One hundred eighty-one eyes of 107 RP patients and 130 eyes of 84 controls were included. In the RP group, the median vessel counts at Z1/2 and Z2/3 were 8 and 3, respectively. These were strikingly lower than the control group with the median vessels of 42 and 43.5 at Z1/2 (P < 0.001) and Z2/3 (P < 0.001), respectively. Twenty-two percent of RP eyes were entirely avascular in the far periphery, and 7% were avascular in the midperiphery and far periphery. Only 5% of RP eyes had >25 vessels at Z2/3. There were significantly fewer vessels in the temporal retina at both Z1/2 (P = 0.01) and Z2/3 (P < 0.001) in RP eyes. Furthermore, eyes with visual acuity of 20/200 or worse had significantly fewer vessels at Z1/2 (P < 0.001) and Z2/3 (P < 0.001). There were no significant differences in the number of vessels at Z1/2 and 2/3 between the right and left eyes of RP patients with both eyes included in the study. Conclusions:This study provides compelling evidence of substantial symmetrical peripheral retinal vascular loss in RP. This finding may aid in clinical diagnosis of the disease and have significant therapeutic implications. Financial Disclosures:The author(s) have no proprietary or commercial interest in any materials discussed in this article.

This study describes worldwide gene therapy clinical trials aimed at treating inherited retinal diseases (IRD). The information was collected through 15 different international registries including clinicaltrials.gov . There have been 101 gene therapy clinical trials targeting IRD up until the end of 2022. Seventy-seven trials employed gene augmentation using viral vectors; other approaches included inhibitory RNA (9), encapsulated cell technology (6), systemic approach (1), and observational trials (8). The most common clinical trial phase was phase 1/2 (46), followed by phase 3 (12). One trial led to an FDA-approved treatment. Sixty-nine trials were conducted in a single country, and 32 trials were multinational; The USA had the highest share in both categories. Retinitis pigmentosa was the most common disease targeted (39), followed by RPE65-mediated retinal dystrophy (13), Leber hereditary optic neuropathy (13), choroideremia (10 and achromatopsia (8), Leber congenital amaurosis (4), X-linked retinoschisis (4), Stargardt disease (4), Bietti's crystalline dystrophy (2), autosomal dominant optic atrophy (1), and Gyrate atrophy (1). For gene augmentation trials, adeno-associated virus was the most commonly used viral vector (70 trials-90%).

Purpose: Stargardt disease is an inherited form of retinal degeneration characterized by early-onset central vision loss. This report describes the long-term retinal histologic characteristics of a patient with Stargardt disease after human embryonic stem cell-derived retinal pigment epithelium (hESC-RPE) transplantation. Methods: Eyes were obtained postmortem from an 80-year-old legally blind male patient with Stargardt disease. The patient had previously undergone hESC-RPE transplantation of his left eye, and the right eye (untransplanted) served as a control. Fluorescence lifetime imaging microscopy was used to study retinal structure and metabolic activity. Staining of the retina for lipofuscin was performed using the Armed Forces Institute of Pathology method. Results: Metabolic analysis showed that the macular area had more oxidative phosphorylation relative to the mid-peripheral retina, in both the transplanted and untransplanted eye. Melanin-laden RPE cells were detected in the transplanted eye, which correlated with a pigment band present on fundus images post-hESC-RPE transplantation. Conclusions: This case description illustrates the long-term survival of subretinal hESC-RPE cells post-transplantation in a patient with Stargardt disease.

The Argus II retinal prosthesis restores visual perception to late blind individuals. It has been shown that structural changes occur in the brain due to late-onset blindness, including cortical thinning in visual cortical regions. Following vision restoration, it is not yet known whether visual regions are reinvigorated and regain a normal cortical thickness or retain the diminished thickness from blindness. We evaluated the cortical thicknesses of 10 Argus II participants, 10 blind participants, and 13 sighted participants. The Argus II patients on average had a thicker left cuneus cortex and lateral occipital cortex relative to the blind patients. The duration of the Argus II use significantly partially correlated with thicker visual cortical regions in the left hemisphere. Furthermore, in the 2 case studies (scanned before and after implantation), the patient with longer device use (44.5 months) had an increase in the cortical thickness of visual regions, whereas the shorter-using patient did not (6.5 months). Overall, the Argus II participants’ cortical thickness was on average significantly rejuvenated in 2 higher visual regions, and participants using the implant for a longer duration had thicker visual regions. This research raises the possibility of structural plasticity reversing visual cortical atrophy in vision restoration participants.

Background/Objectives: Gene therapy’s emergence has made molecular diagnosis for inherited retinal diseases clinically significant. Free genetic testing panels have improved testing access in clinical practice, yet the interpretation of results, especially variants of unknown significance (VUS), remains challenging and requires expertise. This study shares our experience in utilizing sponsored IRD panel tests by Invitae and Blueprint Genetics (BG), reporting their positivity rates, and comparing their reclassification of variants through amendments. Methods: This retrospective study analyzed genetic test reports from patients who underwent testing via Invitae or BG panels. A positive test was determined if there was a pathogenic mutation in an autosomal dominant gene, two pathogenic mutations in an autosomal recessive gene, or a pathogenic mutation in an X-linked gene in a male patient. Results: The testing positivity rates were 34.9% for Invitae (n = 109) and 42.1% for BG (n = 107). Invitae had more pathogenic variants per report (0.87 vs. 0.58 variants, p = 0.0038) and issued more amendments than BG (0.54 vs. 0.03 amendments; p < 0.01). Of the Invitae variant classification changes, 66.2% switched a VUS to benign. In the BG group, 75% of variant reclassifications changed a VUS to pathogenic. As a result of the Invitae amendments, 88% did not change the overall report result. Conclusions: While free-of-charge genetic testing panels offer valuable insights for diagnosing IRD, limitations such as low diagnostic yield and variant classification discrepancies persist between Invitae and BG. VUS should not be considered pathogenic in the clinical decision-making process. Careful interpretation of genetic testing is required.

Fluorescence lifetime imaging microscopy (FLIM) is a technique that analyzes the metabolic state of tissues based on the spatial distribution of fluorescence lifetimes of certain interacting molecules. We used multiphoton FLIM to study the metabolic state of developing C57BL6/J and rd10 retinas based on the fluorescence lifetimes of free versus bound nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate (NAD(P)H), with free NAD(P)H percentages suggesting increased glycolysis and bound NAD(P)H percentages indicating oxidative phosphorylation. The mice were sacrificed and enucleated at various time points throughout their first 3 months of life. The isolated eyecups were fixed, sectioned using a polyacrylamide gel embedding technique, and then analyzed with FLIM. The results suggested that in both C57BL6/J mice and rd10 mice, oxidative phosphorylation initially decreased and then increased, plateauing over time. This trend, however, was accelerated in rd10 mice, with its turning point occurring at p10 versus the p30 turning point in C57BL6/J mice. There was also a noticeable difference in oxidative phosphorylation rates between the outer and inner retinas in both strains, with greater oxidative phosphorylation present in the latter. A greater understanding of rd10 and WT metabolic changes during retinal development may provide deeper insights into retinal degeneration and facilitate the development of future treatments.

The intricate network of cells and processes that govern retinal health has long been a subject of fascination and intensive study within the scientific community [...]

Tuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage, Mycobacterium tuberculosis resides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can lead to a multisystemic diseases because M. tuberculosis invades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing poor visual outcomes of OTB patients. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in the protection from the antibiotic effects, making them an anatomical niche for invading M. tuberculosis . RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosed M. tuberculosis bacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosed M. tuberculosis are largely unknown. Here, liquid chromatography mass spectrometry (LC-MS) metabolomics was used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormant M. tuberculosis bacilli and enhance the antibiotic tolerance. The results have led to propose a novel therapeutic option to synthetically kill the dormant M. tuberculosis inside the RPE cells by modulating the phenotypic state of M. tuberculosis , thus laying the foundation for a new, innovative regimen for treating OTB. Importance:Understanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection with M. tuberculosis and mycobacterial dormancy is crucial to identify new therapeutic methods to cure OTB. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug tolerant state, thereby blunting the efficacy of anti-TB chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that intracellular environment within RPE cells is enriched with greater level of oxidative stress. The antibiotic tolerance of intracellular M. tuberculosis within RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.

The Argus II retinal prosthesis restores low-resolution visual perception to late blind patients. It has been shown that structural changes occur in the brain due to late-onset blindness, including cortical thinning in visual regions of the brain. Following vision restoration, it is not yet known whether these visual regions are reinvigorated and regain a normal cortical thickness or retain the diminished thickness from blindness. We evaluated the cortical thicknesses and subcortical volumes of Argus II patients (N=6), blind patients (N=10), and sighted participants (N=4) with a Siemens 3T MRI scanner (64-channel head coil) at USC. Age-matched sighted controls (N=6) from the Lifespan Human Connectome Project Aging (HCP-A) database were also included (Siemens 3T MRI scanner with a 32-channel head coil). We compared the cortical thicknesses of the occipital lobe regions delineated by the Desikan-Killiany atlas between the participant groups. The visual regions in the two sighted participant groups (USC and HCP-A) did not show a significant difference in cortical thickness, and therefore are included in one sighted group. The blind patients were shown to have a reduced cortical thickness in the left Cuneus Cortex, the left Lingual Gyrus, and the left Lateral Occipital Cortex, and a reduced volume of the right Lateral Geniculate Nucleus (LGN) relative to the sighted controls. The Argus II patients had a reduced cortical thickness in the left Lingual Gyrus, and a reduced volume in the right LGN relative to the sighted controls. However, the Argus II patients had a thicker left Lateral Occipital Cortex relative to the blind patients. Overall, the Argus II patients did not show a reversal of the blindness-driven thinning of grey matter in early visual regions. However, Argus II patients’ cortical thickness was rejuvenated in one higher visual region.

(1) Background: mfERG testing is used to study the function of cone photoreceptors in the central retina. Various filters including "smoothing" (Smooth) and "adaptive data filtering" (Adapt) are used to simplify raw data. This study will seek to characterize the effect of data modification on raw patient data. (2) Methods: This was a retrospective study of patients with mfERG results at our institution. For each patient, raw mfERG data without filtering, with smooth level 4 modifier applied, and with adapt level 4 applied were collected and compared. (4) Conclusions: In all patients, smoothing and adaptive filter modifiers create statistically significant differences in both P1 latency and P1 amplitude values when compared to raw data. The impacts of these filters demonstrated in this study should impact physicians' decision making when interpreting mfERG results.

Human studies have established that short periods of dark adaptation can induce outer retinal thinning and various band intensity changes that can be detected with Optical Coherence Tomography (OCT). Similar findings were observed in mice, including a positive correlation between the degree of outer retinal changes and dark adaptation duration. We decided to assess potential retinal structural changes following prolonged dark adaptation in humans. 40 healthy subjects without any ocular diseases participated in this study. For each subject, one eye was covered for dark adaptation for four hours, and the other eye was left uncovered as a control. Before and after the dark adaptation period, both eyes were assessed with OCT. Using the Heidelberg Spectralis system, basic statistical functions, and qualitative and quantitative analysis, we were able to compare retinal layer thicknesses and band intensities between covered (dark adapted) versus uncovered (control) eyes. Prolonged dark adaptation did not induce any significant thickness, volume, or intensity changes in the outer retina or in the inner or overall retina. These observations thus alter our current understanding of the mechanisms underlying dark adaptation's neuroprotective effects in preventing blindness and require further study.