Retina

Retina Publications

Hong GJ, Koerner JC, Weinert MC, Stinnett SS, Freedman SF, Wallace DK, Riggins WJ, Gallaher KJ, Prakalapakorn GS. Quantitatively comparing weekly changes in retinal vascular characteristics of eyes eventually treated versus not treated for retinopathy of prematurity. J AAPOS 2021;Abstract
PURPOSE: To quantitatively compare retinal vascular characteristics over time in eyes eventually treated versus not treated for retinopathy of prematurity (ROP), using ROPtool analysis of narrow-field retinal images. METHODS: This longitudinal study used prospectively collected narrow-field retinal images of infants screened for ROP, prior to treatment, if needed. Images were analyzed using a methodology that combines quadrant-level measures from several images of the same eye. For the longitudinal analysis, one examination per postmenstrual age (PMA) was included per eye. We compared the following ROPtool indices and their change per week between eyes eventually treated versus not treated for ROP: tortuosity index (TI), dilation index (DI), sum of adjusted indices (SAI), and tortuosity-weighted plus (TWP). Analysis was performed on three levels: eye (mean value/eye), quadrant (highest quadrant value/eye), and blood vessel (highest blood vessel value/eye). RESULTS: Of 832 examinations (99 infants), 745 images (89.5%) had 3-4 quadrants analyzable by ROPtool. On the eye level, ROPtool indices differed between eyes eventually treated versus not treated at PMA of 33-35 and 37 weeks for TI, SAI, and TWP, and at PMA of 33-34 and 37 weeks for DI (P ≤ 0.0014), and change per week differed between eyes eventually treated versus not treated only for SAI at PMA of 32 weeks (P < 0.001). CONCLUSIONS: Quantitative analysis of retinal vascular characteristics using ROPtool can help predict eventual need for treatment for ROP as early as 32 weeks PMA. ROPtool index values were more useful than change in these indices to predict eyes that would eventually need treatment for ROP.
Arroyo JG, Seto B, Yamada K, Zeng K, Minturn R, Lemire CA. Rapid reduction of macular edema due to retinal vein occlusion with low-dose normobaric hyperoxia. Graefes Arch Clin Exp Ophthalmol 2021;Abstract
PURPOSE: We investigated the effects of a relatively inexpensive, non-invasive, short-term treatment with low-dose normobaric hyperoxia (NBH) on macular edema in patients with retinal vein occlusion (RVO). METHODS: Participants with macular edema associated with RVO were treated with 5 LPM of NBH via facemask (40% fraction of inspired oxygen, FIO2) for 3 h. Patients with non-fovea involving edema who elected to be observed returned for a second treatment 1 month later to test reproducibility. RESULTS: A 3-h session of NBH (n = 45) resulted in decreased maximum macular thickness (MMT) (mean 7.10%, t=9.63 P<.001) and central macular thickness (CMT) (mean 4.64%, t=6.90, P<.001) when compared to untreated eyes with RVO measured over the same period of time (n = 12) or their healthy fellow eye (n = 34; MMT:t=-9.60, P<.001;CMT: t=-6.72, P<.001). Patients who had a second NBH treatment 1 month later experienced a recurrence of their edema, but demonstrated a similar significant reduction in MMT and CMT after the second NBH treatment. CONCLUSIONS: Three-hour treatment with 40% FIO2 NBH results in a significant reduction in MMT and CMT. This study supports an ischemic mechanism for macular edema associated with retinal vein occlusion. TRANSLATIONAL RELEVANCE: Short-term low-dose normobaric hyperoxia is a simple, inexpensive, and ubiquitous treatment that may provide an alternate or adjunctive approach to treating macular edema in patients who are resistant to or cannot afford anti-VEGF medications.
Wu F, Goldenberg PC, Mukai S. Bilateral anterior segment dysgenesis and peripheral avascular retina with tractional retinal detachment in an infant with multiple congenital anomalies-hypotony-seizures syndrome 3. Ophthalmic Genet 2021;:1-4.Abstract
: Multiple congenital anomalies-hypotony-seizures syndrome 3 (MCAHS3) is a rare autosomal recessive disorder caused by mutations in the gene. encodes phosphatidylinositol-glycan biosynthesis class T, which plays a crucial role in protein anchoring to cell membranes. The clinical presentation of MCAHS3 is variable in expression and severity, but can be characterized by developmental delay, seizures, hypotonia, facial dysmorphism, and other abnormalities.: Case report.: We report unusual ocular findings including bilateral anterior segment dysgenesis, avascular retinal periphery, and tractional retinal detachment in a 1-month-old male infant with compound heterozygous mutations consistent with MCAHS3. Whole-exome sequencing did not detect any other genetic abnormalities.: This case expands the clinical spectrum of MCAHS3 to include anomalies in ocular anterior segment and retinal vascular development. Given the rarity and the genetic heterogeneity of MCAHS3, giving rise to varied non-ocular phenotypes, it is possible that milder intraocular phenotypes could have gone unrecognized in the past.
Vingopoulos F, Koulouri I, Miller JB, Vavvas DG. Anatomical and Functional Recovery Kinetics After Epiretinal Membrane Removal. Clin Ophthalmol 2021;15:175-181.Abstract
Purpose: To investigate the nature of anatomical and functional recovery kinetics after epiretinal membrane (ERM) removal. Methods: The records of 42 patients (45 eyes) with idiopathic ERM treated with pars plana vitrectomy and surgical peeling of the ERM performed by a single surgeon at Massachusetts Eye and Ear between 2012 and 2017 were retrospectively reviewed. Outcome measures included spectral domain optical coherence tomography-measured central macular thickness (CMT) pre-operatively and at post-operative day 1, week 1, months 1, 3, 6, 12 and 24 as well as best-corrected visual acuity (BCVA). Correlations between baseline or early values and final anatomical and functional outcomes were investigated. Results: Improvement in CMT was statistically significant after 1 week, 1, 3, 6, 12 and 24 months ( < 0.01). BCVA improvement was statistically significant after 1, 6, 12 and 24 months follow-up (<0.01). The improvement of BCVA and CMT with time was found to be logarithmic (R =0.96, R =0.84) suggesting that early (<30 days) post-operative functional and anatomical changes may be predictive of long-term outcomes. Preoperative BCVA and CMT revealed a weak positive correlation with the respective BCVA and CMT at 24 months (R=0.13 and R=0.16). When plotted as a percentage of the fellow normal eye CMT, first week proportional improvement in CMT from pre-operative baseline was found to be correlated with final CMT proportional decrease (R=0.72) suggesting that first week postoperative CMT could be predictive of final CMT. Conclusion: There is a logarithmic improvement in CMT and BCVA after ERM peel with BCVA improvement following the CMT improvement. Early (less than 30 days) post-operative anatomical changes can be predictive of long-term anatomical outcomes.
Wu DM, Ji X, Ivanchenko MV, Chung M, Piper M, Rana P, Wang SK, Xue Y, West E, Zhao SR, Xu H, Cicconet M, Xiong W, Cepko CL. Nrf2 overexpression rescues the RPE in mouse models of retinitis pigmentosa. JCI Insight 2021;6(2)Abstract
Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2-treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).
Yan Y, Ludwig CA, Liao YJ. Multimodal Imaging Features of Optic Disc Drusen. Am J Ophthalmol 2021;Abstract
PURPOSE: Identify key en face multimodal imaging features of optic disc drusen (ODD). DESIGN: Retrospective cross-sectional study. METHODS: . SETTING: Single academic center. PATIENT OR STUDY POPULATION: 786 patients (age 10-82 years) with diagnostic codes for ODD or the term "optic disc drusen" in clinical notes extracted using natural language processing. INTERVENTION OR OBSERVATION PROCEDURES: Color fundus image, green-light and blue-light fundus autofluorescence (FAF), near-infrared reflectance (NIR), and enhanced-depth imaging optical coherence tomography (EDI-OCT). MAIN OUTCOME MEASURES: Ophthalmic imaging characteristics and sensitivity of en face imaging compared with EDI-OCT. RESULTS: 38 (61 eyes) of 786 patients had high-quality EDI-OCT and en face multimodal imaging. Green-light FAF had the highest sensitivity (96.8%) and showed homogeneously hyperautofluorescence while blue-light FAF differentiated superficial and deep ODD by the heterogeneous brightness of FAF. Blue-light FAF (93.5%) and NIR (91.8%) were also sensitive and provided important features including the location, size, and depth of ODD and morphology of the optic disc and ODD-associated features such as horizontal hyperreflective lines and peripapillary hyperreflective ovoid mass-like structures (PHOMS), respectively. Color fundus imaging had the lowest sensitivity (82%). There was good inter-rater reliability for all en face imaging modalities (P < .0001 for all). CONCLUSIONS: Green-light FAF had the highest sensitivity in diagnosis of ODD, while blue-light FAF and NIR provided more information regarding the severity, location, depth, and size of ODD. In eyes that are negative on green-light FAF, EDI-OCT can be performed and provides the highest-resolution characterization of the entire optic disc to rule out ODD.
Hong EH, Shin YU, Bae GH, Choi Y, Ahn SJ, Sobrin L, Hong R, Kim I, Cho H. Nationwide incidence and treatment pattern of retinopathy of prematurity in South Korea using the 2007-2018 national health insurance claims data. Sci Rep 2021;11(1):1451.Abstract
The aim of this study is to investigate the nationwide incidence and treatment pattern of retinopathy of prematurity (ROP) in South Korea. Using the population-based National Health Insurance database (2007-2018), the nationwide incidence of ROP among premature infants with a gestational age (GA) < 37 weeks (GA < 28 weeks, GA28; 28 weeks ≤ GA < 37 weeks; GA28-37) and the percentage of ROP infants who underwent treatment [surgery (vitrectomy, encircling/buckling); retinal ablation (laser photocoagulation, cryotherapy)] were evaluated. We identified 141,964 premature infants, 42,300 of whom had ROP, with a nationwide incidence of 29.8%. The incidence of ROP in GA28 group was 4.3 times higher than in GA28-37 group (63.6% [2240/3522] vs 28.9% [40,060/138,442], p < 0.001). As for the 12-year trends, the incidence of ROP decreased from 39.5% (3308/8366) in 2007 to 23.5% (2943/12,539) in 2018. 3.0% of ROP infants underwent treatment (25.0% in GA28; 1.7% in GA28-37); 0.2% (84/42,300) and 2.9% (1214/42,300) underwent surgery and retinal ablation, respectively. The overall percentage of ROP infants who underwent treatment has decreased from 4.7% in 2007 to 1.8% in 2018. This first Korean nationwide epidemiological study of ROP revealed a decreased incidence of ROP and a decreased percentage of ROP infants undergoing conventional treatment during a 12-year period.
Iannaccone A, Brabbit E, Lopez-Miro C, Love Z, Griffiths V, Kedrov M, Haider NB. Interspecies Correlations between Human and Mouse -Associated Recessive Disease. J Clin Med 2021;10(3)Abstract
-associated recessive disease in humans is historically defined by congenital night blinding retinopathy, characterized by an initial increase in short-wavelength (S)-cone sensitivity and progressive loss of rod and cone function. The retinal degeneration 7 () murine model, harboring a recessive mutation in the mouse ortholog of , has been a well-studied disease model and recently evaluated as a therapeutic model for -associated retinal degenerations. This study aims to draw parallels between human and mouse -related disease through examination of spectral domain optical coherence tomography (SD-OCT) imaging between different stage of human disease and its murine counterpart. We propose that SD-OCT is a useful non-invasive diagnostic tool to compare human clinical dystrophy presentation with that of the mouse and make inference that may be of therapeutically relevance. Additionally, a longitudinal assessment of disease progression, utilizing available clinical data from our patients as well as extensive retrospective analysis of visual acuity data from published cases of human -related disease, was curated to identify further valuable correlates between human and mouse disease. Results of this study validate the slow progression of -associated disease in humans and the mice and identify SD-OCT characteristics in patients at or near the vascular arcades that correlate well with the whorls and rosettes that are seen also in the mouse and point to imaging features that appear to be associated with better preserved S-cone mediated retinal function. The correlation of histological findings between mice and human imaging provides a solid foundation for diagnostic use of pathophysiological and prognostic information to further define characteristics and a relevant timeline for therapeutic intervention in the field of -associated retinopathies.
Arranz-Romera A, Hernandez M, Checa-Casalengua P, Garcia-Layana A, Molina-Martinez IT, Recalde S, Young MJ, Tucker BA, Herrero-Vanrell R, Fernandez-Robredo P, Bravo-Osuna I. A Safe GDNF and GDNF/BDNF Controlled Delivery System Improves Migration in Human Retinal Pigment Epithelial Cells and Survival in Retinal Ganglion Cells: Potential Usefulness in Degenerative Retinal Pathologies. Pharmaceuticals (Basel) 2021;14(1)Abstract
We assessed the sustained delivery effect of poly (lactic-co-glycolic) acid (PLGA)/vitamin E (VitE) microspheres (MSs) loaded with glial cell-derived neurotrophic factor (GDNF) alone (GDNF-MSs) or combined with brain-derived neurotrophic factor (BDNF; GDNF/BDNF-MSs) on migration of the human adult retinal pigment epithelial cell-line-19 (ARPE-19) cells, primate choroidal endothelial (RF/6A) cells, and the survival of isolated mouse retinal ganglion cells (RGCs). The morphology of the MSs, particle size, and encapsulation efficiencies of the active substances were evaluated. In vitro release, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability, terminal deoxynucleotidyl transferase (TdT) deoxyuridine dUTP nick-end labelling (TUNEL) apoptosis, functional wound healing migration (ARPE-19; migration), and (RF/6A; angiogenesis) assays were conducted. The safety of MS intravitreal injection was assessed using hematoxylin and eosin, neuronal nuclei (NeuN) immunolabeling, and TUNEL assays, and RGC in vitro survival was analyzed. MSs delivered GDNF and co-delivered GDNF/BDNF in a sustained manner over 77 days. The BDNF/GDNF combination increased RPE cell migration, whereas no effect was observed on RF/6A. MSs did not alter cell viability, apoptosis was absent in vitro, and RGCs survived in vitro for seven weeks. In mice, retinal toxicity and apoptosis was absent in histologic sections. This delivery strategy could be useful as a potential co-therapy in retinal degenerations and glaucoma, in line with future personalized long-term intravitreal treatment as different amounts (doses) of microparticles can be administered according to patients' needs.
Armstrong GW, Kim LA, Vingopoulos F, Park J, Garg I, Kasetty M, Silverman RF, Zeng R, Douglas VP, Lopera F, Baena A, Giraldo M, Norton D, Cronin-Golomb A, Arboleda-Velasquez JF, Quiroz YT, Miller JB. Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms. JAMA Ophthalmol 2021;139(1):49-56.Abstract
Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease. Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired. Design, Setting, and Participants: A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020. Main Outcomes and Measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension. Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, β = -3.06; P = .007; outer inferior quadrant, β = -2.60; P = .02), outer plexiform layer (outer superior quadrant, β = -3.44; P = .03), and outer nuclear layer (central quadrant, β = -8.61; P = .03; inner nasal quadrant, β = -8.39; P = .04; inner temporal quadrant, β = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied. Conclusions and Relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.
Niu L, Fang Y, Yao X, Zhang Y, Wu J, Chen DF, Sun X. TNFα activates MAPK and Jak-Stat pathways to promote mouse Müller cell proliferation. Exp Eye Res 2021;202:108353.Abstract
Mouse Müller cells, considered as dormant retinal progenitors, often respond to retinal injury by undergoing reactive gliosis rather than displaying neural regenerative responses. Tumor necrosis factor alpha (TNFα) is a key cytokines induced after injury and implicated in mediating inflammatory and neural regenerative responses in zebrafish. To investigate the involvement of TNFα in mouse retinal injury, adult C57BL/6J mice were subjected to light damage for 14 consecutive days. TNFα was elevated in the retina of mice exposed to light damage, which induced Müller cell proliferation in vitro. Affymetrix microarray showed that, in Müller cells, TNFα induces up-regulation of inflammatory and proliferation-related genes, including NFKB2, leukemia inhibitory factor, interleukin-6, janus kinase (Jak) 1, Jak2, signal transducer and activator of transcription (Stat) 1, Stat2, mitogen-activated protein kinase (MAPK) 7, and MAP4K4 but down-regulation of neuroprogenitor genes, including Sox9, Ascl1, Wnt2 and Hes1. Blocking the Jak/Stat and MAPK pathways attenuated TNFα-induced Müller cell proliferation. These results suggest that TNFα may drive the proliferation and inflammatory response, rather than the neural regenerative potential, of mouse Müller cells.
Ambrosio L, Williams JS, Gutierrez A, Swanson EA, Munro RJ, Ferguson DR, Fulton AB, Akula JD. Carbonic anhydrase inhibition in X-linked retinoschisis: An eye on the photoreceptors. Exp Eye Res 2021;202:108344.Abstract
The retinoschisin protein is encoded on the short arm of the X-chromosome by RS1, is expressed abundantly in photoreceptor inner segments and in bipolar cells, and is secreted as an octamer that maintains the structural integrity of the retina. Mutations in RS1 lead to X-linked retinoschisis (XLRS), a disease characterized by the formation of cystic spaces between boys' retinal layers that frequently present in ophthalmoscopy as a "spoke-wheel" pattern on their maculae and by progressively worsening visual acuity (VA). There is no proven therapy for XLRS, but there is mixed evidence that carbonic anhydrase inhibitors (CAIs) produce multiple beneficial effects, including improved VA and decreased volume of cystic spaces. Consequently, linear mixed-effects (LME) models were used to evaluate the effects of CAI therapy on VA and central retinal thickness (CRT, a proxy for cystic cavity volume) in a review of 19 patients' records. The mechanism of action of action of CAIs is unclear but, given that misplaced retinoschisin might accumulate in the photoreceptors, it is possible-perhaps even likely-that CAIs act to benefit the function of photoreceptors and the neighboring retinal pigment epithelium by acidification of the extracellular milieu; patients on CAIs have among the most robust photoreceptor responses. Therefore, a small subset of five subjects were recruited for imaging on a custom multimodal adaptive optics retinal imager for inspection of their parafoveal cone photoreceptors. Those cones that were visible, which numbered far fewer than in controls, were enlarged, consistent with the retinoschisin accumulation hypothesis. Results of the LME modeling found that there is an initial benefit to both VA and CRT in CAI therapy, but these wane, in both cases, after roughly two years. That said, even a short beneficial effect of CAIs on the volume of the cystic spaces may give CAI therapy an important role as pretreatment before (or immediately following) administration of gene therapy.
Han H, Yang Y, Wu Z, Liu B, Dong L, Deng H, Tian J, Lei H. Capilliposide B blocks VEGF-induced angiogenesis in vitro in primary human retinal microvascular endothelial cells. Biomed Pharmacother 2021;133:110999.Abstract
Abnormal angiogenesis is associated with intraocular diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, and current therapies for these eye diseases are not satisfactory. The purpose of this study was to determine whether capilliposide B (CPS-B), a novel oleanane triterpenoid saponin derived from Lysimachia capillipes Hemsl, can inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis signaling events and cellular responses in primary human retinal microvascular endothelial cells (HRECs). Our study revealed that the capilliposide B IC for HRECs was 8.5 μM at 72 h and that 1 μM capilliposide B specifically inhibited VEGF-induced activation of VEGFR2 and its downstream signaling enzymes Akt and Erk. In addition, we discovered that this chemical effectively blocked VEGF-stimulated proliferation, migration and tube formation of the HRECs, suggesting that capilliposide B is a promising prophylactic for angiogenesis-associated diseases such as proliferative diabetic retinopathy.

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