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Background and Objective: Proliferative vitreoretinopathy (PVR) has been mitigated by intravitreal methotrexate (MTX) 400 μg/0.1 mL in several studies. Here, we evaluate the results from a lower dose of MTX, 200 μg/0.05 mL. Materials and Methods: We identified and reviewed records of patients with grade ≥C1 PVR who were treated with 200 μg/0.05 mL MTX injections: during PVR surgery and every 2 weeks thereafter. Results: Twenty-four eyes met inclusion criteria with a mean of 5.6 injections and follow-up ranging 6 to 56 months. The retina was reattached in 19 of 24 eyes (79%) after a single surgery and in 5 of 24 eyes (21%) after one additional PVR surgery. Visual acuity improved from baseline logMAR 1.63 to 0.97 at 12 months ( P < .001), with 5 of 20 achieving 20/60 or better and 16 of 20 achieving 20/200 or better. One eye developed a transient corneal abrasion that resolved within 1 week. Conclusion: Low-dose MTX (200 μg/0.05 mL) during and after PVR surgery resulted in good rates of retinal reattachment and visual acuity recovery. [ Ophthalmic Surg Lasers Imaging Retina 2023;54(3):139–146.]

En face retinal vessel maps generated from bedside optical coherence tomography (OCT) can show posterior pole vascular tortuosity and dilation (ie, plus/pre-plus disease). In this proof-of-concept study, we found that ROPtool could trace OCT-generated retinal vessel maps with high reliability and accuracy for detecting plus or pre-plus disease.

IMPORTANCE: Preterm infants are at risk for poor visual acuity (VA) outcomes, even without retinal problems on ophthalmoscopy. Infant retinal microanatomy may provide insight as to potential causes. OBJECTIVE: To evaluate the association between preterm infant retinal microanatomy and VA at 9 months’ corrected age. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational study took place from November 2016 and December 2019 at a single academic medical center and included preterm infants enrolled in Study of Eye Imaging in Preterm Infants (BabySTEPS). Infants were eligible for enrollment in BabySTEPS if they met criteria for retinopathy of prematurity (ROP) screening, were 35 weeks’ postmenstrual age or older at the time of first OCT imaging, and a parent or guardian provided written informed consent. Of 118 infants enrolled in BabySTEPS, 61 were included in this analysis. Data were analyzed from March to April 2021. EXPOSURES: Bedside optical coherence tomography (OCT) imaging at a mean (SD) 39.85 (0.79) weeks’ postmenstrual age and monocular grating VA measurement at 9 months’ corrected age. MAIN OUTCOMES AND MEASURES: Presence and severity of macular edema and presence of ellipsoid zone at the fovea measured by extracting semiautomated thicknesses of inner nuclear layer, inner retina, and total retina at the foveal center; choroid across foveal 1 mm; and retinal nerve fiber layer (RNFL) across the papillomacular bundle (PMB). Pearson correlation coefficients were calculated and 95% CIs were bootstrapped for the association between retinal layer thicknesses and continuous logMAR VA. Associations were analyzed between retinal microanatomy and normal (3.70 cycles/degree or greater) vs subnormal grating VA at 9 months’ corrected age using logistic regression and with logMAR VA using linear regression, adjusting for birth weight, gestational age, and ROP severity at the time of OCT imaging and accounting for intereye correlation using generalized estimating equations. RESULTS: The mean (SD; range) gestational age of included infants was 27.6 (2.8; 23.0-34.6) weeks, and mean (SD; range) birth weight was 958.2 (293.7; 480-1580) g. In 122 eyes of 61 infants, the correlations between retinal layer thicknesses and logMAR VA were as follows: r, 0.01 (95% CI, −0.07 to −0.27) for inner nuclear layer; r, 0.19 (95% CI, 0.01 to 0.35) for inner retina; r, 0.15 (95% CI, −0.02 to 0.31) for total retina; r, −0.22 (95% CI, −0.38 to −0.03) for choroid; and r, −0.27 (95% CI, −0.45 to 0.10) for RNFL across the PMB. In multivariable analysis, thinner RNFL across the PMB (regression coefficient, −0.05 per 10-μm increase in RNFL thickness; 95% CI, −0.10 to −0.01; P = .046) and prior ROP treatment (regression coefficient, 0.33 for ROP treatment; 95% CI, 0.11 to 0.56; P = .003) were independently associated with poorer 9-month logMAR VA. CONCLUSIONS AND RELEVANCE: In preterm infants, RNFL thinning across the PMB was associated with poorer 9-month VA, independent of birth weight, gestational age, need for ROP treatment, and macular microanatomy. Evaluation of RNFL thickness using OCT may help identify preterm infants at risk for poor vision outcomes.

IMPORTANCE: Early diagnosis of plus disease is critical in the management of retinopathy of prematurity (ROP). However, there is substantial interexpert disagreement in the diagnosis of plus disease based on vascular changes alone. Information derived from optical coherence tomography (OCT) may help characterize the severity of vascular and structural abnormalities in ROP. OBJECTIVE: To describe integrated visualization of 3-dimensional (3-D) data from investigational swept-source OCT optimized to delineate retinal vascular and microanatomical features in eyes with and without ROP. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, observational report of OCT was captured in the prospective Study of Eye Imaging in Preterm Infants (BabySTEPS) designed in July 2016 at the Duke Health Intensive Care Nursery. Between December 2018 and August 2019, 2 preterm infants born at 24 and 30 weeks’ gestation were enrolled, underwent ROP screening, and were imaged at those screening visits. Data at 36 weeks’ postmenstrual age were analyzed via this visualization developed between September 2020 and May 2021. MAIN OUTCOMES AND MEASURES: Superimposed en face retinal vascular shadow view (RVSV) montages and thickness maps were used along with OCT B-scans to evaluate retinal vasculature and cross-section in eyes with and without ROP. RESULTS: In the right eyes of 2 infants, 3-D data were integrated and visualized from investigational bedside OCT imaging at the posterior pole. In the infant who developed type 1 ROP, RVSV-OCT confirmed presence of dilated and tortuous posterior pole vessels, shunting, and incomplete perifoveal vascular development, resulting in a temporal notch of avascular retina in zone 1. The thickness map revealed irregular pockets of thickening and thinning, and integrated visualization outlined the demarcation between thicker vascularized retina and thinner avascular fovea and presence of extraretinal neovascularization overlying elevated vessels in the superior arcades. In the infant without ROP (stage 0), RVSV-OCT revealed no abnormal vascular findings at the posterior pole. The integrated visualization showed a dome-shaped retinal thickening at the fovea, which was confirmed as macular edema. CONCLUSIONS AND RELEVANCE: In 2 preterm infants in BabySTEPS, 3-D visualization of OCT findings during the ongoing ROP disease process demonstrated supplemental information about the retinal vasculature and microanatomy that can be useful to clinicians. These additional details provided by OCT could be integrated into future ROP screening methods with artificial intelligence–based analytics.

OBJECTIVE: To describe predominantly persistent subretinal fluid (SRF) in eyes receiving ranibizumab or bevacizumab for neovascular age-related macular degeneration and compare visual acuity (VA) to eyes with non-persistent SRF. DESIGN: Cohort within randomized clinical trial PARTICIPANTS: Comparison of Age-related Macular Degeneration Treatments Trials patients assigned to pro re nata (PRN) treatment. METHODS: Reading center graders evaluated optical coherence tomography scans at baseline and monthly follow-up visits for SRF. Predominantly persistent SRF through week 12 was defined as SRF at baseline, weeks 4, 8, and 12. Predominantly persistent SRF through 1 or 2 years was defined as SRF in ≥80% of visits by year 1 or year 2, respectively. Adjusted mean VA score and VA change from baseline were compared between eyes with predominantly persistent SRF and eyes non-persistent SRF over the same duration using linear regression models including baseline predictors of VA and predominantly persistent intraretinal fluid (IRF). PRIMARY OUTCOME MEASURES: Predominantly persistent SRF through year 1, adjusted VA score and VA change, and SRF thickness at the foveal center. RESULTS: Among 406 eyes with baseline SRF, SRF persisted in 108 (26.6%) through week 12, 94 (23.2%) through year 1, and 77 (19.0%) through year 2. Adjusted VA means (letters) at year 1 were similar between eyes with predominantly persistent vs. non-persistent SRF by week 12, (68.1 vs. 70.2; P=0.18), year 1 (67.6 vs. 70.2; P=0.11), and year 2 (71.4 vs. 70.9; P=0.78). Adjusted change in VA at year 1 means were similar between eyes with predominantly persistent vs. non-persistent SRF by week 12 (6.3 vs. 7.6; P=0.38), year 1 (5.5 vs. 7.8; P=0.14), and year 2 (8.1 vs. 7.7; P=0.78). Among eyes with predominantly persistent SRF through year 1, SRF was absent in the foveal center in 46 (48.9%), thickness was 1-200 μm in 48 (50.0%) and >200 μm in 1 (1.1%) at year 1. CONCLUSIONS: Eyes with predominantly persistent and non-persistent SRF through week 12, year 1, or year 2 had similar VA outcomes after adjustment for baseline covariates and persistent IRF. At the foveal center, predominantly persistent SRF was most commonly absent or present in small quantities.

Intraoperative optical coherence tomography (OCT) systems provide high-resolution, real-time visualization and/or guidance of microsurgical procedures. While the use of intraoperative OCT in ophthalmology has significantly improved qualitative visualization of surgical procedures inside the eye, new surgical techniques to deliver therapeutics have highlighted the lack of quantitative information available with current-generation intraoperative systems. Indirect viewing systems used for retinal surgeries introduce distortions into the resulting OCT images, making it particularly challenging to make calibrated quantitative measurements. Using an intraoperative OCT system based in part on the Leica Enfocus surgical microscope interface, we have devised novel measurement procedures, which allowed us to build optical and mathematical models to perform validation of quantitative measurements of intraocular structures for intraoperative OCT. These procedures optimize a complete optical model of the sample arm including the OCT scanner, viewing attachments, and the patient’s eye, thus obtaining the voxel pitch throughout an OCT volume and performing quantitative measurements of the dimensions of imaged objects within the operative field. We performed initial validation by measuring objects of known size in a controlled eye phantom as well as ex vivo porcine eyes. The technique was then extended to measure other objects and structures in ex vivo porcine eyes and in vivo human eyes.

OBJECTIVE: To report our ability to capture, grade reliably and analyze bedside macular optical coherence tomography (OCT) images from preterm infants and relate OCT findings to biological factors and retinopathy of prematurity (ROP) status at a single time window in the STudy of Eye imaging in Preterm infantS (BabySTEPS). DESIGN: Prospective observational study PARTICIPANTS: Preterm infants eligible for ROP screening, with parental consent for research and a 36±1 weeks postmenstrual age (PMA) visit. METHODS: We imaged both eyes of preterm infants with an investigational non-contact, handheld swept-source OCT at the time of clinical ROP examinations. Macular OCT features and layer thicknesses for untreated eyes of infants at 36±1 weeks PMA were compared to demographic data and clinical ROP examination performed by experts. Statistical analyses accounted for the use of both eyes of infants. MAIN OUTCOME MEASURES: Macular OCT features and layer thicknesses, gender, race/ethnicity, gestational age, birth weight, ROP stage, and plus disease. RESULTS: We captured macular OCT from 169 eyes (one eye excluded for prior ROP treatment) at 36±1 weeks PMA. The quality of OCT volumes was excellent in 33 eyes (19%), acceptable in 112 (67%), poor in 24 (14%) and unusable in 0 (0%). Macular edema was present in 60% of eyes and bilateral in 82% of infants with edema. At the fovea, retinal thickness and inner nuclear layer (INL) thickness increased with edema severity: 183±36μm and 51±27μm in mild edema (16% of eyes), 308±57μm and 163±53μm in moderate (25%) and 460±76μm and 280±83μm in severe (12%), respectively. With an increase in ROP stage from 0 to 2, the mean (standard deviation) retinal thickness at fovea increased from 227(124) to 297(99)μm, p

To identify precursors of macular atrophy (MA) and of fibrotic scar (FS) in eyes treated with anti-vascular endothelial growth factor through pixel-mapping analysis of baseline optical coherence tomography (OCT).Design: Cross-sectional analysis.Multicenter clinical trial.68 eyes from the Comparison of Age-Related Macular Degeneration Treatments Trials.Treatment with anti-vascular endothelial growth factor agents.The percentage of MA or FS pixels with each OCT feature at baseline, and the odds ratio for baseline pixels with an OCT feature to develop MA or FS.Retinal pigment epithelium atrophy and photoreceptor loss on OCT were highly predictive of MA at that location at years 2 and 5 (P.0001), but accounted for only 22.5% of the ensuing atrophy at year 2 and less at year 5. Among pixels of MA at year 2, 78% were preceded by thick drusen, 54% by subretinal macular neovascularization (MNV), and 22.5% by no detectable OCT features. MNV, subretinal hyperreflective material, pigment epithelial detachment, intraretinal fluid, and sub-retinal pigment epithelium fluid were predictive of FS at that location (P values.05). More than 75% of the pixels of FS at years 2 and 5 were preceded by pixels of baseline MNV.Most pixels of FS were preceded by components of neovascularization. Although one-quarter of MA was accounted for by pre-existing evidence of atrophy on OCT alone, the development of MA in areas of thick drusen, areas with and without subretinal MNV lesion, and areas without detectable OCT precursors argues that the development of MA is multifactorial and may follow, in part, a non-neovascular pathway.

To assess retinal nerve fiber layer (RNFL) thickness in preterm infants.Prospective observational study.We imaged 83 awake infants (159 eyes) at 36 ± 1 weeks postmenstrual age (defined as the time elapsed between the first day of the last maternal menstrual period and the time at imaging) using a handheld optical coherence tomography (OCT) system at the bedside. Blinded graders semi-automatically segmented RNFL in the papillomacular bundle (-15 to +15° relative to the fovea-optic nerve axis). We correlated RNFL thickness and 7 characteristics of interest (sex, race, ethnicity, gestational age, birth weight, stage of retinopathy at prematurity, and presence of pre-plus or plus disease) via univariable and multivariable regressions.RNFL was 3.4 μm thicker in the right eyes than in the left eyes (P.001). Among 7 characteristics, birth weight was the only independent predictor of RNFL thickness (P.001). A 250-g increase in birth weight was associated with 5.2 μm (95% confidence interval: 3.3-7.0) increase in RNFL thickness. Compared with very preterm infants, extremely preterm infants had thinner RNFL (58.0 ± 10.7 μm vs 63.4 ± 10.7 μm, P = .03), but the statistical significance disappeared after adjustment for birth weight (P = .25). RNFL thickness was 11.2 μm thinner in extremely low birth weight infants than in very low birth weight infants (55.5 ± 8.3 μm vs. 66.7 ± 10.2 μm; P.001). The difference remained statistically significant after adjustment for gestational age.Birth weight is a significant independent predictor of RNFL thickness near birth, implying that the retinal ganglion cells reserve is affected by intrauterine processes that affect birth weight.

Background/AimsThe optic nerve development during the critical postnatal weeks of preterm infants is unclear. We aimed to investigate the change of retinal nerve fibre layer (RNFL) in preterm infants.MethodsWe used an investigational handheld optical coherence tomography (OCT) system to serially image awake preterm infants between 30 and 60 weeks postmenstrual age (PMA) at the bedside. We assessed RNFL thickness in the papillomacular bundle and nasal macular ganglion cell layer+inner plexiform layer (GCL+IPL) thickness. We applied a segmented mixed model to analyse the change in the thickness of RNFL and GCL+IPL as a function of PMA.ResultsFrom 631 OCT imaging sessions of 101 infants (201 eyes), RNFL thickness followed a biphasic model between 30 and 60 weeks, with an estimated transition at 37.8 weeks PMA (95% CI: 37.0 to 38.6). RNFL thickness increased at 1.8 μm/week (95% CI: 1.6 to 2.1) before 37.8 weeks and decreased at −0.3 μm/week (95% CI: −0.5 to −0.2) afterwards. GCL+IPL thickness followed a similar biphasic model, in which the thickness increased at 2.9 μm/week (95% CI: 2.5 to 3.2) before 39.5 weeks PMA (95% CI: 38.8 to 40.1) and then decreased at −0.8 μm/week (95% CI: −0.9 to −0.6).ConclusionWe demonstrate the feasibility of monitoring RNFL and GCL+IPL thickness from OCT during the postnatal weeks of preterm infants. Thicknesses follow a biphasic model with a transition age at 37.8 and 39.5 weeks PMA, respectively. These findings may shed light on optic nerve development in preterm infants and assist future study designs.

BackgroundThe macular central 1 mm diameter zone is crucial to patients’ visual acuity, but the long-term natural history of central sparing in eyes with geographic atrophy (GA) is unknown.MethodsWe manually segmented GA in 210 eyes with GA involving central 1 mm diameter zone (mean follow-up=3.8 years) in the Age-Related Eye Disease Study. We measured the residual area in central 1 mm diameter zone and calculated central residual effective radius (CRER) as square root of (residual area/π). A linear mixed-effects model was used to model residual size over time. We added a horizontal translation factor to each data set to account for different durations of GA involving the central zone.ResultsThe decline rate of central residual area was associated with baseline residual area (p=0.008), but a transformation from central residual area to CRER eliminated this relationship (p=0.51). After the introduction of horizontal translation factors to each data set, CRER declined linearly over approximately 13 years (r2=0.80). The growth rate of total GA effective radius was 0.14 mm/year (95% CI 0.12 to 0.15), 3.7-fold higher than the decline rate of CRER (0.038 mm/year, 95% CI 0.034 to 0.042). The decline rate of CRER was 53.3% higher in eyes with than without advanced age-related macular degeneration in the fellow eyes at any visit (p=0.007).ConclusionsCRER in eyes with GA declined linearly over approximately 13 years and may serve as an anatomic endpoint in future clinical trials aiming to preserve the central zone.

Background: Multiple studies have described the utility of intraoperative spectral-domain OCT (SD-OCT) with two dimensional (2D) B-scan imaging in the management of numerous vitreoretinal disorders including macular holes, vitreomacular traction disorders, epiretinal membranes and retinal detachment. Some of these studies also described post-processing of the 2D B-scans to obtain 3D images. With the advancement of intraoperative OCT technology, live volumetric (4D, i.e. 3D over time) visualization of different anterior and posterior segment surgeries has been described in recent studies using intraoperative swept-source microscope-integrated OCT (SS-MIOCT). Our study aims to explore the potential utility of SS-MIOCT during vitrectomy for complications of proliferative diabetic retinopathy. Aim of the work: To evaluate the use of live volumetric (4D) intraoperative swept-source microscope-integrated OCT (SS-MIOCT) in vitrectomy for proliferative diabetic retinopathy (PDR) complications.Patient and Methods: In this prospective study, we analyzed a subgroup of cases with PDR complications that required vitrectomy and that were imaged by the research SS-MIOCT system. In near real time, images were displayed in stereo heads-up display facilitating intraoperative surgeon feedback. Postoperative review included scoring image quality, identifying different diabetic retinopathy (DR)-associated pathologies and reviewing the intraoperatively documented surgeon feedback.Results: Twenty eyes were included. Indications for vitrectomy were tractional retinal detachment (TRD, 16 eyes), combined tractional-rhegmatogenous retinal detachment (2 eyes) and vitreous hemorrhage (2 eyes). Useful, good quality 2D (B-scans) and 4D images were obtained in 16/20 eyes (80%). In these eyes, multiple DR pathologies could be imaged. SS-MIOCT provided surgical guidance, e.g. in identifying dissection planes under fibrovascular membranes, and in determining residual membranes and traction that would benefit from additional peeling. In 4/20 eyes (20%) acceptable images were captured, but they were not useful due to high TRD elevation which was challenging for imaging.Conclusion: SS-MIOCT can provide important guidance during surgery for PDR complications through intraoperative identification of different pathologies and facilitation of intraoperative decision making.

PURPOSE: To detect retinal features and abnormalities on optical coherence tomography (OCT) without pupil dilation and relate these to brain injury in infants with a clinical diagnosis of hypoxic ischemic encephalopathy (HIE). METHODS: Under an institutional review board approved protocol, we imaged eight infants without pharmacologic mydriasis, using handheld, non-contact spectral-domain (Leica Microsystems, IL) or investigational swept-source OCT at the bedside in an intensive care nursery, after birth (depending on primary clinical care team permission based on health status) and weekly until discharge. The newborn infant with HIE is neurologically unstable; therefore, pharmacologic mydriasis and stimulation with visible light for retinal examination are usually avoided. We analyzed images for retinal pathologies, central foveal thickness and retinal nerve fiber layer (RNFL) thickness at the papillomacular bundle and compared them to historical controls and published normative data, HIE clinical assessment, and abnormalities on brain magnetic resonance imaging (MRI). RESULTS: On OCT, three of eight infants had bilateral multiple small macular and perimacular cystoid spaces; two of these three infants also had pronounced retinal ganglion cell layer thinning and severe brain injury on MRI, and the third had bilateral paracentral acute middle maculopathy and mild brain injury on MRI. Other findings in HIE infant eyes included abnormally thin fovea and thin RNFL and markers of retinal immaturity such as absence of sub-foveal photoreceptor development and sub-foveal fluid. CONCLUSIONS: Bedside handheld OCT imaging within the first two weeks of life revealed retinal injury in infants with HIE-related brain injury. Future studies may determine the relationship between acute/subacute retinal abnormalities and brain injury severity and neurodevelopmental outcomes in HIE.

Objective To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. Design Multicenter, randomized clinical trial. Participants Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. Interventions At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. Main Outcome Measures Mean change in visual acuity. Results Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, −1.4 letters; 95% confidence interval [CI], −3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, −2.4 letters; 95% CI, −4.8 to −0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P P = 0.03) and a lower proportion without fluid (−19%; P P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07−1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). Conclusions Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Background/purpose Poretti-Boltshauser syndrome is a rare, nonprogressive neurologic syndrome with characteristic cerebellar cysts on neuroimaging due to mutations in LAMA1. The ophthalmic findings in Poretti-Boltshauser syndrome are not well described. Here, we report the ophthalmic findings from multimodal imaging and electrophysiology of a patient with genetically confirmed Poretti-Boltshauser syndrome. Methods A 3-year-old boy with confirmed mutations in LAMA1 underwent examination under anesthesia with electroretinography and multimodal imaging including fundus photography, fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography. Results Dilated fundus examination was notable for retinal vascular anomalies, including a large area of nonperfusion in the temporal macula with corresponding retinal thinning on optical coherence tomography. There was an absence of a distinct foveal avascular zone and decreased density of both the superficial and deep vascular plexuses in the macula on optical coherence tomography angiography. There was diffuse loss of choriocapillaris architecture and decreased choroidal thickness. Conclusion Patients with Poretti-Boltshauser syndrome may possess chorioretinal thinning and retinal vascular abnormalities appreciable on examination and multimodal imaging. These findings suggest a role for LAMA1 in retinal and choroidal vascular development.

To identify features correlating with drusenoid pigment epithelial detachment (DPED) progression in the Age-Related Eye Disease Study 2 Ancillary spectral-domain optical coherence tomography study cohort.In this retrospective analysis of a prospective longitudinal study, eyes with intermediate age-related macular degeneration and DPEDs were followed longitudinally with annual multimodal imaging.Thirty-one eyes of 25 participants (mean age 72.6 years) in the Age-Related Eye Disease Study 2 Ancillary spectral-domain OCT substudy (A2A study) had DPED identified in color fundus images. Spectral-domain optical coherence tomography inspection confirmed a subretinal pigment epithelium drusenoid elevation of ≥433 µm diameter in 25 eyes (80.6%). Twenty-four of these eyes were followed longitudinally (median 4.0 years), during which 7 eyes (29.2%) underwent DPED collapse (with 3/7 further progressing to geographic atrophy), 6 (25.0%) developing neovascular age-related macular degeneration, and 11 (45.8%) maintaining DPED persistence without late age-related macular degeneration. On Kaplan-Meier analysis, mean time to DPED collapse was 3.9 years. Both DPED collapse and progression to neovascular age-related macular degeneration were preceded by the presence of hyperreflective foci over the DPED.The natural history of DPED comprises collapse (sometimes followed by the development of atrophy), vascularization followed by exudation, or DPED persistence. Spectral-domain optical coherence tomography can confirm retinal pigment epithelial elevation caused by drusenoid accumulation and facilitate the identification of high-risk features that correlate with progression.

Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single cell-based RNA-seq of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not been previously compared to that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP; eNOS-/-; db/db mice and compared it to streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP; eNOS-/- mice utilizing Translating Ribosome Affinity Purification (TRAP) and RNA-seq. Over 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN compared to T1DN. TGF-β signaling pathway genes were upregulated while MAPK pathway genes were downregulated only in T2DN while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number diabetes-induced genes not previously been linked to podocyte injury were confirmed in both mouse and human DN. Differences and similarities in the podocyte translatome in T2DN and T1DN can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury.

Purpose To describe the ocular findings in a patient with glycogen storage disease II (Pompe disease). Methods Case report. Results A 14-year-old boy with Pompe disease was referred for evaluation of a retinal detachment in the left eye. Indirect ophthalmoscopy revealed bilateral fibrotic snowbanks and an inferior rhegmatogenous retinal detachment extending into the macula. Fluorescein angiography revealed mild diffuse perivascular leakage in both eyes. The retinal detachment was repaired with scleral buckling and cryotherapy. Workup for the etiology of the intermediate uveitis was unrevealing. Conclusion Enzyme replacement therapy has improved the survival of individuals with Pompe disease. With greater patient longevity, new ocular associations may continue to emerge. Whether intermediate uveitis is an ocular association of Pompe disease remains to be determined.

PURPOSE: To assess macular vasculature in healthy infants and children using OCT angiography (OCTA). DESIGN: Prospective cross-sectional study. PARTICIPANTS: One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks–17 years) treated at the Duke University Eye Center. METHODS: We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes. MAIN OUTCOME MEASURES: The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC. RESULTS: The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm(2); P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R(2) = 0.46; P < 0.001) but not gender (P >0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R(2) = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00). CONCLUSIONS: Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes.

Objective: Dopamine function is sensitive to toxin exposure. The environmental toxin polychlorinated biphenyl (PCB) alters dopamine physiology in several, harmful ways. Intermediary signals include thyroid hormones as PCB exposure alters thyroid function leading to changes in dopamine neurochemistry. To compare PCB and thyroid alterations directly, we exposed rats perinatally to either PCB (25 ppm) or thiouracil (THIO; 0.625%) from gestational day 1 to separation from the dam at postnatal day (PND) 25 and examined a set of tests sensitive to dopamine function. Methods: We measured behaviors including prepulse inhibition (PPI) of the acoustic startle response (ASR) in adulthood (60-90 PND) and ultrasonic vocalizations (USVs) during pup and adult periods. Dopamine levels in striatum were estimated using tyrosine hydroxylase immunohistochemistry and thyroid hormone levels were assayed in adulthood. Results: Animals exposed to thiouracil had significantly elevated startle response and impaired PPI relative to controls and PCB exposed animals. This group also had significant reductions in both USV emission during PPI and tyrosine hydroxylase staining within striatum. Conversely, PCB exposure during the perinatal period did not lead to alterations in gating or dopamine levels in adulthood. Similar to previous studies using perinatal exposure to PCB or THIO, thyroid hormone levels were unchanged (THIO group) relative to controls or actually increased (PCB group) by adulthood. Conclusion: The findings support an important role for thyroid function in dopamine-dependent behaviors. Results suggest PCB exposure leads to different outcomes in comparison to direct thyroid manipulations suggesting PCB exposure has distinct mechanisms of developmental hormone dysfunction and potential compensatory changes in response to endocrine disruption.

Purpose Measurements of the ganglion cell complex (GCC), comprising the retinal nerve fiber (RNFL), ganglion cell, and inner plexiform layers, can be correlated with vision loss caused by optic nerve disease. Handheld optical coherence tomography (HH-OCT) can be used with sedation in children who are not amenable to traditional imaging. We report GCC and RNFL measurements in normal children using HH-OCT. Design Prospective observational study of normal children ≤5 years of age. Methods Healthy, full-term children ≤5 years of age undergoing sedation or anesthesia were enrolled. Exclusion criteria included prematurity and pre-existing neurologic, genetic, metabolic, or intraocular pathology. Demographic data, axial length (Master-Vu Sonomed Escalon, Lake Success, New York, USA), and HH-OCT macular and optic nerve volume scans at 0° (Bioptigen, Inc., Morrisville, North Carolina, USA) were obtained. Retinal segmentation was completed with DOCTRAP software, creating average volume thickness maps. Results Sixty-seven children (67 eyes, 31 males ranging in age from 3.4–70.9 months) were enrolled. Average axial length was 21.2 ± 1.0 mm with mean spherical equivalent +1.49 ± 1.34 diopters (range −2.25 to 4.25). Average GCC volume for the total retina was 0.28 ± 0.04 mm3. Forty-seven of these eyes had RNFL analysis. Average RNFL thickness of the papillomacular bundle was 38.2 ± 9.5 μm. There was no correlation between GCC volume, RNFL thickness, patient age, or axial length. Conclusion Average GCC volume and RNFL thickness was stable from 6 months to 5 years of age. This study provides normative data for GCC and RNFL obtained by HH-OCT in healthy eyes of young children, to serve in evaluating those with optic neuropathies.

Purpose: Subretinal delivery of stem cells and gene therapy vectors hold great promise in clinical care. Delivery techniques are evolving. We investigate the utility of 4-dimensional (volumes over time) microscope-integrated optical coherence tomography (4D-MIOCT) to guide such maneuvers. Methods: This investigational 4D-MIOCT system displayed heads-up cross-sectional and stereoscopic volumetric views through the microscope oculars at 3.3–10 volumes/second. In enucleated porcine eyes, we evaluated novel information available to the surgeon during subretinal: 1) injection of fluid and cell suspensions, 2) retinotomy creation, 3) insertion of membranes with a retinal pigment epithelium (RPE) cell monolayer and 4) subretinal instrument maneuvers, all in postmortem porcine eyes. Results: Interactions between tools, membranes, retina and RPE were often not detectable on the conventional microscope view but were obvious with 4D-MIOCT. 4D-MIOCT visualization was essential to: monitor the extent of induced retinal detachment, guide the cannula tip and instrument maneuvers in the subretinal space, and identify efflux of cells into the vitreous cavity. This allowed adjustment by the surgeon to avoid complications—e.g. scissors scraping RPE. Conclusions: 4D-MIOCT is useful for continuous monitoring of model subretinal surgery and may help avoid technique-related complications. 4D-MIOCT can contribute to the advancement of subretinal delivery of therapies under development.

Ischemic stroke is a major cause of mortality and long-term disability with limited treatment options, and a greater understanding of the gene regulatory mechanisms underlying ischemic stroke-associated neuroinflammation is required for new therapies. To study ischemic stroke in vivo, mice were subjected to sustained ischemia by intraluminal filament-induced middle cerebral artery occlusion (MCAo) for 24 h without reperfusion or transient ischemia for 30 min followed by 23.5 h reperfusion, and brain miRNA and mRNA expression changes were quantified by TaqMan OpenArrays and gene (mRNA) expression arrays, respectively. Sustained ischemia resulted in 18 significantly altered miRNAs and 392 altered mRNAs in mouse brains compared to Sham controls; however, the transient ischemic condition was found to impact only 6 miRNAs and 126 mRNAs. miR-367-3p was found to be significantly decreased in brain homogenates with sustained ischemia. G protein-coupled receptor, family C, group 5, member A ( Gprc5a), a miR-367-3p target gene, was found to be significantly increased with sustained ischemia. In primary neurons, inhibition of endogenous miR-367-3p resulted in a significant increase in Gprc5a expression. Moreover, miR-367-3p was found to be co-expressed with GPRC5A in human neurons. Results suggest that loss of miR-367-3p suppression of GPRC5A may contribute to neuroinflammation associated with ischemic stroke.

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or “wet” form of AMD, no therapy is successful for the non-neovascular or “dry” form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy., No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

Purpose To describe changes in visual acuity (VA) and macular morphologic features at 5 years in eyes with nonfibrotic scar (NFS) identified at 1 year in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Design Prospective cohort study within a randomized clinical trial. Participants Participants in CATT. Methods Participants assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens were released from the clinical trial protocol after 2 years and recalled at 5 years. Nonfibrotic scar was identified on color images at year 1 as flat, small, well-circumscribed areas of pigmentation with varying degrees of central hypopigmentation without exposure of underlying choroidal vessels at the site of baseline choroidal neovascularization. Follow-up images were assessed for changes in and around NFS. Main Outcome Measures Pigmentation changes, VA, development of fibrotic scar (FS), nongeographic atrophy (NGA), geographic atrophy (GA), retinal fluid on OCT, and fluorescein leakage. Results Among 474 eyes with images obtained at 1, 2, and 5 years, 39 (8.2%) showed NFS at 1 year with a mean VA of 80 letters (Snellen equivalent, 20/25). Among these eyes, FS developed in 5% at 2 years and 28% at 5 years. Nongeographic atrophy was observed in 34%, 47%, and 65% of eyes at 1, 2, and 5 years, respectively. Geographic atrophy developed in 5% of eyes at 2 years and 21% at 5 years. Among eyes with NFS, FS, or no scar at 1 year, mean VA at 5 years was 73 letters (20/32), 48 letters (20/100), and 62 letters (20/63), respectively. At 5 years, NFS eyes demonstrated less GA, less intraretinal fluid, more subretinal fluid, and less subretinal pigment epithelium fluid (all P 0.50). The proportion of eyes with fluid on OCT also did not change (P = 0.36). Subretinal hyperreflective material disappeared by 5 years in 40% of eyes with NFS. Conclusions These results indicate that, on average, eyes with NFS after anti-VEGF treatment have good VA not only at 1 and 2 years, but also through 5 years.

Purpose: To identify best clinical practices for macular degeneration imaging. Methods: We reviewed best clinical practices for imaging patients with age-related macular degeneration. These recommendations are based on different levels of evidence (I-III). Results: The type of imaging needed depends to some degree on the clinical scenario: first visit vs follow-up visit vs poorly responsive patient. Conclusions: Imaging technologies that may be useful include optical coherence tomography, fundus photography, fundus autofluorescence imaging, fluorescein angiography, indocyanine green angiography, and optical coherence tomography angiography.

Treatment of severe retinopathy of prematurity (ROP) has evolved over the last decade. This article reviews recent clinical trials and experimental evidence that supports clinical outcomes and observations, including the efficacy of anti-vascular endothelial growth factor (VEGF) agents in reducing the vascular activity of severe ROP, and the mechanisms behind recurrent stage 3 ROP and plus disease in some infants treated with anti-VEGF agents. Also discussed will be current imaging modalities that link experimental models of ROP with longitudinal human studies and which provide exciting future opportunities to enhance the understanding of pathophysiology of ROP and improve treatments. [ Ophthalmic Surg Lasers Imaging Retina. 2019;50:228–234.]

BACKGROUND: The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization. METHODS: Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and using enhanced ray casting were converted to 3D volumes to which color filter were applied. RESULTS: Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stage 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF. CONCLUSIONS: The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.

Purpose To describe the clinical impact of subfoveal lucency (SFL) seen on OCT before and after treatment of vitreomacular traction (VMT) or symptomatic vitreomacular adhesion (VMA) without macular hole (MH) in the prospective phase 3 trials of ocriplasmin vitreolysis. Design Randomized double-blind placebo-controlled multicenter study. Participants Four hundred ninety-nine eyes with VMT or VMA without MH. Methods Eyes were randomized to either a single intravitreal injection of ocriplasmin or placebo treatment and were followed up for 6 months. Main Outcome Measures Eyes were analyzed for presence, dimensions, and course of SFL on OCT, release of VMT, and their effect on visual acuity (VA). Results Among eyes without baseline SFL, new SFL was more frequent after ocriplasmin than placebo at week 1 (23.1% vs. 6.54%; P = 0.0002) and week 2 (19.7% vs. 3.85%; P = 0.0001), but was similar in frequency by week 4 (8.37% vs. 7.69%; P = 0.83). Six-month VA for eyes demonstrating SFL after ocriplasmin during the first 2 weeks was comparable with those without SFL at any point in the study (P = 0.12). In placebo-treated eyes but not ocriplasmin-treated eyes, SFL was associated with worse VA at all visits. The increase in SFL width from baseline to week 2 was significantly greater with ocriplasmin than placebo (P = 0.029). Among ocriplasmin-treated eyes at month 6, those with SFL and VMT release had better VA than those with SFL and persistent adhesion (P = 0.037) and similar VA to those with persistent adhesion without SFL (P = 0.17). In the placebo group, those with baseline SFL showed low rates of spontaneous VMT release at month 6 compared with those without baseline SFL (3/21 eyes vs. 33/99 eyes; P = 0.045). Conclusions Compared with placebo, SFL occurred more frequently only in the initial weeks after treatment with ocriplasmin. When SFL developed after ocriplasmin administration, VA was not impacted at the 6-month visit. Persistent SFL in ocriplasmin-treated eyes at month 6 was associated with poorer vision if VMT had not released. Eyes with SFL at baseline had low rates of spontaneous VMT release and may need treatment.

Purpose To investigate the use of imaging modalities in the volumetric measurement of the subretinal space and examine the volume of subretinal blebs created by a subretinal drug delivery device utilizing microscope-integrated optical coherence tomography (MIOCT). Methods An MIOCT image-based volume measurement method was developed and assessed for accuracy and reproducibility by imaging ceramic spheres of known size that were surgically implanted into ex vivo porcine eyes. This method was then used to measure subretinal blebs created in 10 porcine eyes by injection of balanced salt solution utilizing a subretinal delivery device via a suprachoroidal cannula. Bleb volumes obtained from MIOCT were compared to the intended injection volume. Results Validation of image-based volume measurements of ceramic spheres showed accuracy to ±0.029 µL (5.6%) for objects imaged over the posterior pole and ±0.025 µL (4.8%) over peripheral retina. The mean expected injection volume from extraocular tests of the suprachoroidal cannula was 66.44 µL (σ = 2.4 µL). The mean injection volume as measured by the MIOCT imaging method was 54.8 µL (σ = 12.3 µL), or 82.48% of expected injection volume. Conclusions MIOCT can measure the volume of subretinal blebs with accuracy and precision. The novel suprachoroidal approach using a subretinal delivery device was able to deliver greater than 80% of expected injection volume into the subretinal space, as assessed by MIOCT. Translational relevance MIOCT provides a method for visualization, and analysis of images enables surgeons to quantify and evaluate the success of subretinal drug delivery via a suprachoroidal approach.

Background/aimsNeonatal insults from systemic diseases have been implicated in the pathway of impaired neurodevelopment in preterm infants. We aimed to investigate the associations between systemic health factors and retinal nerve fibre layer (RNFL) thickness in preterm infants.MethodsWe prospectively enrolled infants and imaged both eyes at 36±1 weeks postmenstrual age (PMA) using a hand-held optical coherence tomography system at the bedside in the Duke intensive care nurseries. We evaluated associations between RNFL thickness and 29 systemic health factors using univariable and multivariable regression models.Results83 infants with RNFL thickness measures were included in this study. Based on the multivariable model, RNFL thickness was positively associated with infant weight at imaging and was negatively associated with sepsis/necrotising enterocolitis (NEC). RNFL thickness was 10.4 µm (95% CI −15.9 to −4.9) lower in infants with than without sepsis/NEC in the univariable analysis (pConclusionsLow infant weight and sepsis/NEC were independently associated with thinner RNFL in preterm infants at 36 weeks PMA. To our knowledge, this study is the first to suggest that sepsis/NEC may affect retinal neurodevelopment. Future longitudinal studies are needed to investigate this relationship further.

Purpose To describe a case of a large, traumatic macular hole in a pediatric patient closed using an internal limiting membrane flap in combination with autologous plasma concentrate (APC). Methods Description of a surgical technique as performed in one patient. Results Successful macular hole closure and improvement in postoperative visual acuity were achieved in the patient in whom the technique was performed. Conclusion The combined use of APC with the internal limiting membrane flap is advantageous because the APC acts to hold the internal limiting membrane in proper position and promotes the proliferation of glial cells through the presence of growth factors. This technique may be particularly advantageous in chronic or recalcitrant holes particularly in the setting of trauma.

Purpose: This work aimed to examine the microvasculature of macular fibrosis in Coats disease. Methods: Three boys (aged 3, 4, and 6 years) with Coats disease (stages 2B to 3A2) and macular fibrotic nodules were imaged using optical coherence tomography angiography (OCTA) on the Spectralis spectral-domain OCT tabletop and investigational portable Spectralis Flex module (version 6.9, Heidelberg Engineering). Results: In 2 eyes, a neovascular complex was observed in the avascular slab on OCTA. This neovascular complex had vessels connected to diving vessels from the superficial vascular complex that traveled through the deep vascular complex to the avascular complex. In the third eye, no neovascular complex was observed on OCTA at presentation, but on subsequent examinations fluorescein leakage was observed and cross-sectional OCTA further confirmed the presence of angiographic flow in the nodule. Conclusions: OCTA demonstrates the presence of type 3 neovascularization in fibrotic nodules in Coats disease.