Intravitreal injections during COVID-19 outbreak: Real-world experience from an Italian tertiary referral center
Eur J Ophthalmol. 2020 Sep 24;1120672120962032.
Adriano Carnevali, Giuseppe Giannaccare, Valentina Gatti, Gianfranco Scuteri, Giorgio Randazzo, Vincenzo Scorcia
PMID: 32967465 DOI: 10.1177/1120672120962032
We report our experience during COVID-19 outbreak for intravitreal injections in patients with maculopathy. We proposed a treatment priority levels and timings; the "High" priority level includes all monocular patients; the "Moderate" is assigned to all patients with an active macular neovascularization; the patients affected by diabetic macular edema or retinal vein occlusion belong to the "Low" class. This organization allowed us to treat the most urgent patients although the injections performed had a 91.7% drop compared to the same period of 2019.
Clinical Experience in the Administration of Intravitreal Injection Therapy at a Tertiary University Hospital in Jordan During the COVID-19 Lockdown
Clin Ophthalmol. 2020 Aug 24;14:2473-2480
Omar A Saleh, Hisham Jammal, Noor Alqudah, Asem Alqudah, Nakhleh Abu-Yaghi
PMID: 32943831 PMCID: PMC7468368 DOI: 10.2147/OPTH.S269179
Purpose: To describe the clinical experience with the delivery of intravitreal injection therapy to patients with various indications at a tertiary university hospital during the COVID-19 lockdown in Jordan.
Methods: This is a retrospective observational study of patients who received intravitreal injections between April 12th and May 9th, 2020, a period during the national COVID-19 lockdown (March 16th to June 6th, 2020). Special medical and logistic arrangements, priority and visual risk assessment and strict infection control precautions were implemented. Demographics, diagnosis, intravitreal injection history, medical history, ophthalmic examinations and optical coherence tomography data were collected and analyzed.
Results: Intravitreal injections were successfully administered to 132 patients with diabetic retinopathy, age-related macular degeneration and retinal vein occlusion. All logistic and transmission control measures were followed by the medical staff and patients with no incidents. No new exposures or COVID-19 positive cases were traced to our location or time of therapy. No complications related to the injections were recorded. The mean period of delay due to the lockdown from the original scheduled appointment was six weeks. Mean visual acuity significantly decreased from 20/55 before the lockdown to 20/70 after the lockdown, and mean central macular thickness significantly increased from 329 to 370 μ.
Conclusion: The administration of intravitreal injection therapy during the COVID-19 lockdown under special safety precautions was feasible and successful. Resumption of the essential therapies and medical services during periods of pandemic restrictions while adhering to strict transmission control measures is encouraged.
DIAGNOSIS & IMAGING
Development of Deep Learning Models to Predict Best-Corrected Visual Acuity from Optical Coherence Tomography
Transl Vis Sci Technol. 2020 Sep 9;9(2):51.
Michael G Kawczynski, Thomas Bengtsson, Jian Dai, J Jill Hopkins, Simon S Gao, Jeffrey R Willis
PMID: 32974088 PMCID: PMC7488630 DOI: 10.1167/tvst.9.2.51
Purpose: To develop deep learning (DL) models to predict best-corrected visual acuity (BCVA) from optical coherence tomography (OCT) images from patients with neovascular age-related macular degeneration (nAMD).
Methods: Retrospective analysis of OCT images and associated BCVA measurements from the phase 3 HARBOR trial (NCT00891735). DL regression models were developed to predict BCVA at the concurrent visit and 12 months from baseline using OCT images. Binary classification models were developed to predict BCVA of Snellen equivalent of <20/40, <20/60, and ≤20/200 at the concurrent visit and 12 months from baseline.
Results: The regression model to predict BCVA at the concurrent visit had R2 = 0.67 (root-mean-square error [RMSE] = 8.60) in study eyes and R2 = 0.84 (RMSE = 9.01) in fellow eyes. The best classification model to predict BCVA at the concurrent visit had an area under the receiver operating characteristic curve (AUC) of 0.92 in study eyes and 0.98 in fellow eyes. The regression model to predict BCVA at month 12 using baseline OCT had R2 = 0.33 (RMSE = 14.16) in study eyes and R2 = 0.75 (RMSE = 11.27) in fellow eyes. The best classification model to predict BCVA at month 12 had AUC = 0.84 in study eyes and AUC = 0.96 in fellow eyes.
Conclusions: DL shows promise in predicting BCVA from OCTs in nAMD. Further research should elucidate the utility of models in clinical settings.
Translational relevance: DL models predicting BCVA could be used to enhance understanding of structure-function relationships and develop more efficient clinical trials.
Prediction of age-related macular degeneration disease using a sequential deep learning approach on longitudinal SD-OCT imaging biomarkers
Sci Rep. 2020 Sep 22;10(1):15434.
Imon Banerjee, Luis de Sisternes, Joelle A Hallak, Theodore Leng, Aaron Osborne, Philip J Rosenfeld, Giovanni Gregori, Mary Durbin, Daniel Rubin
PMID: 32963300 DOI: 10.1038/s41598-020-72359-y
We propose a hybrid sequential prediction model called "Deep Sequence", integrating radiomics-engineered imaging features, demographic, and visual factors, with a recursive neural network (RNN) model in the same platform to predict the risk of exudation within a future time-frame in non-exudative AMD eyes. The proposed model provides scores associated with risk of exudation in the short term (within 3 months) and long term (within 21 months), handling challenges related to variability of OCT scan characteristics and the size of the training cohort. We used a retrospective clinical trial dataset that includes 671 AMD fellow eyes with 13,954 observations before any signs of exudation for training and validation in a tenfold cross validation setting. Deep Sequence achieved high performance for the prediction of exudation within 3 months (0.96 ± 0.02 AUCROC) and within 21 months (0.97 ± 0.02 AUCROC) on cross-validation. Training the proposed model on this clinical trial dataset and testing it on an external real-world clinical dataset showed high performance for the prediction within 3-months (0.82 AUCROC) but a clear decrease in performance for the prediction within 21-months (0.68 AUCROC). While performance differences at longer time intervals may be derived from dataset differences, we believe that the high performance and generalizability achieved in short-term predictions may have a high clinical impact allowing for optimal patient follow-up, adding the possibility of more frequent, detailed screening and tailored treatments for those patients with imminent risk of exudation.
Longitudinal Changes of Macular Curvature in Patients with Retinitis Pigmentosa
Transl Vis Sci Technol. 2020 Sep 10;9(10):11.
Monika Meinert, Shinji Ueno, Shiori Komori, Yoshito Koyanagi, Akira Sayo, Sten Andreasson, Taro Kominami, Yasuki Ito, Hiroko Terasaki
PMID: 32974083 PMCID: PMC7488647 DOI: 10.1167/tvst.9.10.11
Purpose: To investigate the longitudinal changes of the macular curvature in eyes with retinitis pigmentosa (RP) and to determine the factors associated with the changes.
Methods: We reviewed the medical charts of 107 RP patients, for whom the axial length of their right eyes ranged from 21.5 to 26.0 mm and who had had been followed by spectral-domain optical coherence tomography (OCT). The OCT images at the initial and the most recent examinations were compared. The mean curvature of Bruch's membrane within 6 mm of the central macula obtained from the OCT images was evaluated as the mean macular curvature index (MMCI). Changes in the MMCI and their relationships with other clinical factors, including the ellipsoid zone (EZ) width, were assessed.
Results: The MMCI decreased significantly in the vertical OCT images, from -15.47 × 10-5 µm-1 to -16.36 × 10-5 µm-1 (P = 0.008) during the mean observation period of 3.4 ± 1.4 years (mean ± SD). This indicated that the macular shape became more concave. The change to a steeper shape was more prominent in eyes with less photoreceptor degeneration and for which the EZ width was preserved at >2000 µm. In three eyes, the MMCI increased markedly by >5 × 10-5 µm-1, and this was accompanied by absorption of the macular edema.
Conclusions: The macular curvature in RP eyes becomes more concave in eyes with preserved EZ width.
Translational relevance: Longitudinal changes of the macular curvature in RP should be considered in future therapies, such as the implantation of the retinal prosthesis.
Characteristics of the inner retinal layer in the fellow eyes of patients with unilateral exudative age-related macular degeneration
PLoS One. 2020 Sep 23;15(9):e0239555.
Seong Eun Lee, Hyung Bin Lim, Yong Il Shin, Cheon Kuk Ryu, Woo Hyuk Lee, Jung-Yeul Kim
PMID: 32966311 DOI: 10.1371/journal.pone.0239555
Objective: To investigate the thicknesses of the ganglion cell-inner plexiform layer (GC-IPL) and retinal nerve fiber layer (RNFL) of the fellow eyes of patients with unilateral exudative age-related macular degeneration (AMD).
Methods: A total of 107 patients with unilateral exudative AMD [34 of typical choroidal neovascularization (tCNV), Group A; 73 of polypoidal choroidal vasculopathy (PCV), Group B] and 73 normal control eyes (Group C) were included. Drusen and subretinal drusenoid deposits were assessed in all participants using fundus photography, autofluorescence, and optical coherence tomography (OCT). The GC-IPL and RNFL thicknesses were measured using Cirrus HD-OCT and compared among groups. Linear regression analyses were used to evaluate the factors associated with GC-IPL thicknesses.
Results: The average GC-IPL thicknesses of Groups A, B, and C were 77.09 ± 3.87, 80.10 ± 6.61, and 80.88 ± 6.50 μm, respectively (p = 0.022). Sectoral GC-IPLs and central macular thicknesses (CMTs) were significantly different among groups (all, p <0.05), whereas none of the RNFL parameters differed significantly (all, p >0.05). Multivariate linear regression analyses revealed that age (p <0.001), CMT (p <0.001), and tCNV (p = 0.013) were significantly associated with average GC-IPL thickness, and the rate of reduction of GC-IPL thickness with increasing age in the fellow eyes of tCNV patients was higher than those in the PCV and control groups.
Conclusions: Unilateral tCNV patients exhibited statistically significant reduction of the GC-IPL thickness in the fellow eyes, compared to values of the fellow eyes of unilateral PCV patients or control patients. RNFL values trended to be lower but did not reach statistical significance.
A method to characterize compensatory oculomotor strategies following simulated central vision loss
J Vis. 2020 Sep 2;20(9):15.
Marcello Maniglia, Kristina M Visscher, Aaron R Seitz
PMID: 32965480 DOI: 10.1167/jov.20.9.15
Loss of central vision can be partially compensated by increased use of peripheral vision. For example, patients experiencing central vision loss due to disease (macular degeneration) or healthy participants trained with simulated central vision loss, tend to develop eccentric fixation spots for reading or other visual tasks. In both patients and in simulated conditions, there are substantial individual variations in the effective use of the periphery. The factors driving these individual differences are still unclear. Although early approaches have described some dimensions of these strategies, the field is still in its initial stages and important elements are often conflated when examining gaze patterns. Here, we propose a systematic approach to characterize oculomotor strategies in cases of central vision loss that distinguishes different components: saccadic re-referencing, saccadic precision, first saccade landing dispersion, fixation stability, latency of target acquisition, and percentage of trials that are useful. We tested this approach in healthy individuals trained with a gaze-contingent display obstructing the central 10 degrees of the visual field. The use of simulated scotoma helps overcome known challenges in clinical research, from recruitment and compliance to the diverse extent and nature of the visual loss. Importantly, this approach offers the ability to examine oculomotor strategies as they develop in controlled settings where viewing conditions are similar across participants. Results show substantial differences in characteristics of peripheral looking strategies, both across trials and individuals. This more complete characterization of peripheral looking strategies can help us understand individual differences in rehabilitation after central vision loss.
Early Ophthalmic Changes in Macula Does Not Correlate with Visual Function
Clin Ophthalmol. 2020 Sep 3;14:2571-2576.
Divya Narayanan, Garrick Wallstrom, John Rodriguez, Donna Welch, Matthew Chapin, Paul Arrigg, Rajkumar Patil, Mark Abelson
PMID: 32943838 PMCID: PMC7478363 DOI: 10.2147/OPTH.S260787
Purpose: Early detection and treatment of age-related macular degeneration require a clear understanding of the early progress of the disease. The purpose of this study was to investigate whether minimal macular ophthalmoscopic changes corresponded to changes in visual function.
Methods: Color macular photos from a group of older subjects who were classified as grade 0 on AREDS simplified grading were further evaluated by a retinal specialist using 5x magnification for possible minimal macular anomalies. Group 0-A (N = 15) were defined as subjects with no visible macular anomalies while Group 0-B (N = 19) comprised subjects for whom minimal macular mottling, pigment changes or very small drusen (< 63 µm) were observed in the study eye. All subjects had best VA of 20/25 or better and had no evidence of other retinal diseases in the study eye. All subjects underwent a series of visual function tests such as standard ETDRS VA, low luminance ETDRS VA, Pelli-Robson contrast sensitivity, variable contrast flicker (VCF) sensitivity, and reading speed (words per minute, wpm) using both MNRead and low luminance reading on a tablet.
Results: There was no significant difference between the mean age between the two groups (74.8 ± 5.2 years for 0-A vs 74.5 ± 4.4 for 0-B, p = 0.82). None of the visual function tests identified any significant difference between the two groups. Mean ETDRS VA was 0.0 ± 0.11 for 0-A subjects and 0.08 ± 0.12 for 0-B (p = 0.063). Mean Pelli-Robson log contrast sensitivity was 1.75 ± 0.29 for 0-A and 1.78 ± 0.17 for the 0-B group (p = 0.73). VCF threshold was 0.47 ± 0.25 for 0-A and 0.43 ± 0.22 for 0-B (p = 0.64). Reading speed using MNRead was 214 ± 47.4 wpm for 0-A and 210 ± 64.7 for 0-B (p = 0.85). Low luminance tablet reading speed was 137 ± 71.8 wpm for 0-A and 151 ± 39.4 (0-B) (p = 0.49).
Conclusion: A panel of psychophysical tests did not demonstrate significant differences between subjects with and without minimal macular changes.
Retinal Pigment Epithelial and Outer Retinal Atrophy in Age-Related Macular Degeneration: Correlation with Macular Function
J Clin Med. 2020 Sep 15;9(9):E2973.
Maria C Savastano, Benedetto Falsini, Grazia M Cozzupoli, Alfonso Savastano, Gloria Gambini, Umberto De Vico, Angelo M Minnella, Giorgio Placidi, Marco Piccardi, Stanislao Rizzo
PMID: 32942540 DOI: 10.3390/jcm9092973
The purpose of this study was to investigate the relationship between the retinal pigment epithelium (RPE) and outer retina changes, expressed in terms of sub-RPE illumination (SRI) on optical-coherence tomography (OCT), and central retinal function, measured by visual acuity and focal electroretinogram (fERG), in patients with non-exudative age-related macular degeneration (neAMD). In this retrospective study, 29 eyes of 29 patients affected by early (24.14%), intermediate (41.38%), and advanced (34.48%) neAMD were evaluated. All enrolled eyes were studied with OCT to measure the total area of SRI, by using an automated standardized algorithm. Visual acuity and fERG were assessed. The area of SRI was negatively correlated with fERG amplitude (r ≤ -0.4, p ≤ 0.02) and best-corrected visual acuity (BCVA) (r ≤ 0.4, p ≤ 0.04). Our results indicate that the severity of retinal pigment epithelium and outer retina atrophy (RORA), indirectly quantified through the detection of SRI areas by commercial OCT algorithms, is correlated with central retinal dysfunction, as determined by visual acuity and fERG, supporting the combined use of structural exams and functional tests as valid tools to detect the extent of RPE and photoreceptors' disruption.
Plasma Biomarkers of Reticular Pseudodrusen and the Risk of Progression to Advanced Age-Related Macular Degeneration
Transl Vis Sci Technol. 2020 Sep 11;9(10):12.
Anne M Lynch, Brandie D Wagner, Alan G Palestine, Nebojsa Janjic, Jennifer L Patnaik, Marc T Mathias, Frank S Siringo, Naresh Mandava
PMID: 32974084 PMCID: PMC7488626 DOI: 10.1167/tvst.9.10.12
Purpose: To determine, using an aptamer-based technology in patients with intermediate age-related macular degeneration (AMD), (1) if there is a difference in plasma levels of 4979 proteins in patients with and without reticular pseudodrusen (RPD), and (2) if plasma levels of proteins are related to time to conversion to advanced AMD.
Methods: Patients with intermediate AMD and RPD were identified from an AMD registry. Relative concentrations of each protein were log (base 2) transformed and compared between patients with and without RPD using linear regression. A Cox proportional hazards survival model was fit to each aptamer to quantify associations with time to conversion. A pathway analysis was conducted in converters versus non-converters using the Reactome database.
Results: Of the 109 intermediate AMD patients, 39 had bilateral RPD (36%). Two proteins, TCL1A and CNDP1, were lower in patients in the intermediate AMD group with RPD. Twenty-one patients converted to advanced AMD with a median time to conversion of 25.2 months (range, 2.3-48.5 months) and median follow-up time in non-converters of 26.4 months (range, 0.03-49.7 months). Several proteins (lysozyme C, TFF3, RNAS6, and SAP3) distinguished patients who converted from those who did not convert to advanced AMD. The top conversion pathways included tumor necrosis factors bind their physiological receptors, digestion and absorption, signaling by activin, and signaling by TGF-β family members.
Conclusions: We identified a protein signature related to RPD, as well as to conversion to advanced AMD. The pathway analysis suggests that dysfunction of critical systemic pathways may have links to conversion to advanced AMD.
Translational relevance: Biomarkers identified in plasma likely reflect systemic alterations in protein expression in patients with intermediate AMD.
Visual Impairment, Eye Disease, and the 3-year Incidence of Depressive Symptoms: The Canadian Longitudinal Study on Aging
Ophthalmic Epidemiol. 2020 Sep 24;1-9.
Alyssa Grant, Marie-Josée Aubin, Ralf Buhrmann, Marie-Jeanne Kergoat, Ellen E Freeman
PMID: 32970494 DOI: 10.1080/09286586.2020.1823425
Purpose: Our goal was to explore the longitudinal association between vision-related variables and incident depressive symptoms in a community-dwelling sample of older adults and to examine whether sex, education, or hearing loss act as effect modifiers.
Methods: A 3-year prospective cohort study was performed using data from the Canadian Longitudinal Study on Aging consisting of 30,097 individuals aged 45-85 years. Visual acuity was evaluated with habitual distance correction using an illuminated Early Treatment of Diabetic Retinopathy Study chart. Visual impairment was defined as binocular presenting visual acuity worse than 20/40. Incident depressive symptoms was defined using a cut-off score of 10 or greater on the Center for Epidemiologic Studies Depression scale. Participants were asked if they had ever had a physician diagnosis of age-related macular degeneration (AMD), glaucoma, or cataract. Multivariable Poisson regression was used.
Results: Of 22,558 participants without depressive symptoms at baseline, 7.7% developed depressive symptoms within 3 years. Cataract was associated with incident depressive symptoms (relative risk = 1.20, 95% confidence interval 1.05, 1.37) after adjusting for age, sex, income, education, partner status, smoking, level of comorbidity, hearing loss, and province. Visual impairment, AMD, and glaucoma were not associated with incident depressive symptoms. No effect modification was detected.
Conclusions: Our longitudinal data confirm that the risk of depressive symptoms is higher in those who report ever having a cataract. Further research should confirm this and interventions should be considered.
Association of age-related macular degeneration on fracture risks among osteoporosis population: a nationwide population-based cohort study
BMJ Open. 2020 Sep 17;10(9):e037028.
Chi Chin Sun, Ting-Shuo Huang, Tsai-Sheng Fu, Chia-Yi Lee, Bing-Yu Chen, Fang-Ping Chen
PMID: 32948557 DOI: 10.1136/bmjopen-2020-037028
Objectives: Visual impairment is an important risk factor for fracture in the elderly population. Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment in elderly people. This study was conducted to explore the relationship between AMD and incident fractures in patients with osteoporosis (OS).
Design: Retrospective analysis of Taiwan's National Health Insurance Research Database (NHIRD).
Setting: A multicenter study conducted in Taiwan.
Participants and controls: The current study used the NHIRD in Taiwan between 1996 and 2011. A total of 13 584 and 54 336 patients with OS were enrolled in the AMD group and the non-AMD group, respectively.
Intervention: Patients with OS were included from the Taiwan's NHIRD after exclusion, and each patient with AMD was matched for age, sex and comorbidities to four patients with non-AMD OS, who served as the control group. A Cox proportional hazard model was used for the multivariable analysis.
Primary outcome measures: Transitions for OS to spine fracture, OS to hip fracture, OS to humero-radio-ulnar fracture and OS to death.
Results: The risks of spine and hip fractures were significantly higher in the AMD group (HR=1.09, 95% CI=1.04 to 1.15, p<0.001; HR=1.18; 95% CI=1.08 to 1.30, p=0.001, respectively) than in the non-AMD group. The incidence of humero-radio-ulnar fracture between AMD and non-AMD individuals was similar (HR=0.98; 95% CI=0.90 to 1.06; p=0.599). However, the risk of death was higher in patients with OS with older age, male sex and all types of comorbidity (p<0.05), except for hyperthyroidism (p=0.200).
Conclusion: Patients with OS with AMD had a greater risk of spine and hip fractures than did patients without AMD.
Cell Types of the Human Retina and Its Organoids at Single-Cell Resolution
Cell. 2020 Sep 17;182(6):1623-1640.e34.
Cameron S Cowan, Magdalena Renner, Martina De Gennaro, Brigitte Gross-Scherf, David Goldblum, Yanyan Hou, Martin Munz, Tiago M Rodrigues, Jacek Krol, Tamas Szikra, Rachel Cuttat, Annick Waldt, Panagiotis Papasaikas, Roland Diggelmann, Claudia P Patino-Alvarez, Patricia Galliker, Stefan E Spirig, Dinko Pavlinic, Nadine Gerber-Hollbach, Sven Schuierer, Aldin Srdanovic, Marton Balogh, Riccardo Panero, Akos Kusnyerik, Arnold Szabo, Michael B Stadler, Selim Orgül, Simone Picelli, Pascal W Hasler, Andreas Hierlemann, Hendrik P N Scholl, Guglielmo Roma, Florian Nigsch, Botond Roska
PMID: 32946783 DOI: 10.1016/j.cell.2020.08.013
Human organoids recapitulating the cell-type diversity and function of their target organ are valuable for basic and translational research. We developed light-sensitive human retinal organoids with multiple nuclear and synaptic layers and functional synapses. We sequenced the RNA of 285,441 single cells from these organoids at seven developmental time points and from the periphery, fovea, pigment epithelium and choroid of light-responsive adult human retinas, and performed histochemistry. Cell types in organoids matured in vitro to a stable "developed" state at a rate similar to human retina development in vivo. Transcriptomes of organoid cell types converged toward the transcriptomes of adult peripheral retinal cell types. Expression of disease-associated genes was cell-type-specific in adult retina, and cell-type specificity was retained in organoids. We implicate unexpected cell types in diseases such as macular degeneration. This resource identifies cellular targets for studying disease mechanisms in organoids and for targeted repair in human retinas.
Embryonic stem cell microenvironment enhances proliferation of human retinal pigment epithelium cells by activating the PI3K signaling pathway
Stem Cell Res Ther. 2020 Sep 23;11(1):411.
Jiahui Liu, Liu Yang, Xiaoran Wang, Shoubi Wang, Zheqian Huang, Chaoyang Li, Ying Liu, Yaqi Cheng, Chengxiu Liu, Zhichong Wang
PMID: 32967731 DOI: 10.1186/s13287-020-01923-0
Background: Retinal pigment epithelium (RPE) replacement has been proposed as an efficacious treatment for age-related macular degeneration (AMD), which is the primary cause of vision loss in the elderly worldwide. The embryonic stem cell (ESC) microenvironment has been demonstrated to enable mature cells to gain a powerful proliferative ability and even enhance the stem/progenitor phenotype via activation of the phosphoinositide 3-kinase (PI3K) signaling pathway. As the PI3K signaling pathway plays a pivotal role in proliferation and homeostasis of RPE, we hypothesize that the stemness and proliferative capability of RPE can be enhanced by the ESC microenvironment via activation of the PI3K signaling pathway.
Methods: To investigate whether the ESC microenvironment improves the stem cell phenotype and proliferation properties of human RPE (hRPE) cells by regulating the PI3K signaling pathway, primary hRPE cells were cocultured with either ESCs or human corneal epithelial cells (CECs) for 72 h, after which their proliferation, apoptosis, cell cycle progression, and colony formation were assayed to evaluate changes in their biological characteristics. Gene expression was detected by real-time PCR and protein levels were determined by western blotting or immunofluorescence. LY294002, an antagonist of the PI3K signaling pathway, was used to further confirm the mechanism involved.
Results: In comparison to hRPE cells cultured alone, hRPE cells cocultured with ESCs had an increased proliferative capacity, reduced apoptotic rate, and higher colony-forming efficiency. The expression of the stem cell-associated marker KLF4 and the differentiation marker CRALBP increased and decreased, respectively, in hRPE cells isolated from the ESC coculture. Furthermore, PI3K pathway-related genes were significantly upregulated in hRPE cells after exposure to ESCs. LY294002 reversed the pro-proliferative effect of ESCs on hRPE cells. In contrast, CECs did not share the ability of ESCs to influence the biological behavior and gene expression of hRPE cells.
Conclusions: Our findings indicate that the ESC microenvironment enhances stemness and proliferation of hRPE cells, partially via activation of the PI3K signaling pathway. This study may have a significant impact and clinical implication on cell therapy in regenerative medicine, specifically for age-related macular degeneration.
Stepwise differentiation and functional characterization of human induced pluripotent stem cell-derived choroidal endothelial cells
Stem Cell Res Ther. 2020 Sep 23;11(1):409.
Kelly Mulfaul, Joseph C Giacalone, Andrew P Voigt, Megan J Riker, Dalyz Ochoa, Ian C Han, Edwin M Stone, Robert F Mullins, Budd A Tucker
PMID: 32967716 DOI: 10.1186/s13287-020-01903-4
Background: Endothelial cells (ECs) are essential regulators of the vasculature, lining arteries, veins, and capillary beds. While all ECs share a number of structural and molecular features, heterogeneity exists depending on their resident tissue. ECs lining the choriocapillaris in the human eye are lost early in the pathogenesis of age-related macular degeneration (AMD), a common and devastating form of vision loss. In order to study the mechanisms leading to choroidal endothelial cell (CEC) loss and to develop reagents for repairing the choroid, a reproducible in vitro model, which closely mimic CECs, is needed. While a number of protocols have been published to direct induced pluripotent stem cells (iPSCs) into ECs, the goal of this study was to develop methods to differentiate iPSCs into ECs resembling those found in the human choriocapillaris specifically.
Methods: We transduced human iPSCs with a CDH5p-GFP-ZEO lentiviral vector and selected for transduced iPSCs using blasticidin. We generated embryoid bodies (EBs) from expanded iPSC colonies and transitioned from mTESR™1 to EC media. One day post-EB formation, we induced mesoderm fate commitment via addition of BMP-4, activin A, and FGF-2. On day 5, EBs were adhered to Matrigel-coated plates in EC media containing vascular endothelial cell growth factor (VEGF) and connective tissue growth factor (CTGF) to promote CEC differentiation. On day 14, we selected for CECs using either zeocin resistance or anti-CD31 MACS beads. We expanded CECs post-selection and performed immunocytochemical analysis of CD31, carbonic anhydrase IV (CA4), and RGCC; tube formation assays; and transmission electron microscopy to access vascular function.
Results: We report a detailed protocol whereby we direct iPSC differentiation toward mesoderm and utilize CTGF to specify CECs. The CDH5p-GFP-ZEO lentiviral vector facilitated the selection of iPSC-derived ECs that label with antibodies directed against CD31, CA4, and RGCC; form vascular tubes in vitro; and migrate into empty choroidal vessels. CECs selected using either antibiotic selection or CD31 MACS beads showed similar characteristics, thereby making this protocol easily reproducible with or without lentiviral vectors.
Conclusion: ECs generated following this protocol exhibit functional and biochemical characteristics of CECs. This protocol will be useful for developing in vitro models toward understanding the mechanisms of CEC loss early in AMD.
NUTRITION & LIFESTYLE
Dietary Patterns, Carbohydrates, and Age-Related Eye Diseases
Nutrients. 2020 Sep 18;12(9):E2862.
Sarah G Francisco, Kelsey M Smith, Gemma Aragonès, Elizabeth A Whitcomb, Jasper Weinberg, Xuedi Wang, Eloy Bejarano, Allen Taylor, Sheldon Rowan
PMID: 32962100 DOI: 10.3390/nu12092862
Over a third of older adults in the U.S. experience significant vision loss, which decreases independence and is a biomarker of decreased health span. As the global aging population is expanding, it is imperative to uncover strategies to increase health span and reduce the economic burden of this age-related disease. While there are some treatments available for age-related vision loss, such as surgical removal of cataracts, many causes of vision loss, such as dry age-related macular degeneration (AMD), remain poorly understood and no treatments are currently available. Therefore, it is necessary to better understand the factors that contribute to disease progression for age-related vision loss and to uncover methods for disease prevention. One such factor is the effect of diet on ocular diseases. There are many reviews regarding micronutrients and their effect on eye health. Here, we discuss the impact of dietary patterns on the incidence and progression of age-related eye diseases, namely AMD, cataracts, diabetic retinopathy, and glaucoma. Then, we focus on the specific role of dietary carbohydrates, first by outlining the physiological effects of carbohydrates on the body and then how these changes translate into eye and age-related ocular diseases. Finally, we discuss future directions of nutrition research as it relates to aging and vision loss, with a discussion of caloric restriction, intermittent fasting, drug interventions, and emerging randomized clinical trials. This is a rich field with the capacity to improve life quality for millions of people so they may live with clear vision for longer and avoid the high cost of vision-saving surgeries.
Potential Therapeutic Benefit of NAD + Supplementation for Glaucoma and Age-Related Macular Degeneration
Nutrients. 2020 Sep 19;12(9):E2871.
Gloria Cimaglia, Marcela Votruba, James E Morgan, Helder André, Pete A Williams
PMID: 32961812 DOI: 10.3390/nu12092871
Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegenerative in their pathology of the retina and as such many of the events that trigger cell dysfunction, degeneration, and eventual loss are due to mitochondrial dysfunction, inflammation, and oxidative stress. Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions.
The role of reactive oxygen species in the pathogenesis and treatment of retinal diseases
Exp Eye Res. 2020 Sep 21;108255.
Thomas Cw Chan, Jennifer L Wilkinson Berka, Devy Deliyanti, Damien Hunter, Adrian Fung, Gerald Liew, Andrew White
PMID: 32971094 DOI: 10.1016/j.exer.2020.108255
Reactive oxygen species (ROS) normally play an important physiological role in health regulating cellular processes and signal transduction. The amount of ROS is usually kept in fine balance with the generation of ROS largely being offset by the body's antioxidants. A tipping of this balance has increasingly been recognised as a contributor to human disease. The retina, as a result of its cellular anatomy and physical location, is a potent generator of ROS that has been linked to several major retinal diseases. This review will provide a summary of the role of oxidative stress in the pathogenesis of diabetic retinopathy, age-related macular degeneration, myopia, retinal vein occlusion, retinitis pigmentosa and retinopathy of prematurity. Therapies aimed at controlling oxidative stress in these diseases are also examined.
Cerebral Modifications and Visual Pathway Reorganization in Maculopathy: A Systematic Review
Front Neurosci. 2020 Aug 21;14:755.
Raffaele Nuzzi, Laura Dallorto, Alessio Vitale
PMID: 32973424 PMCID: PMC7472840 DOI: 10.3389/fnins.2020.00755
Background: Macular degeneration (MD) is one of the most frequent causes of visual deficit, resulting in alterations affecting not only the retina but also the entire visual pathway up to the brain areas. This would seem related not just to signal deprivation but also to a compensatory neuronal reorganization, having significant implications in terms of potential rehabilitation of the patient and therapeutic perspectives.
Objective: This paper aimed to outline, by analyzing the existing literature, the current understanding of brain structural and functional changes detected with neuroimaging techniques in subjects affected by juvenile and age-related maculopathy.
Methods: Articles using various typologies of central nervous system (CNS) imaging in at least six patients affected by juvenile or age-related maculopathy were considered. A total of 142 were initially screened. Non-pertinent articles and duplicates were rejected. Finally, 19 articles, including 649 patients, were identified.
Results: In these sources, both structural and functional modifications were found in MD subjects' CNS. Changes in visual cortex gray matter volume were observed in both age-related MD (AMD) and juvenile MD (JMD); in particular, an involvement of not only its posterior part but also the anterior one suggests further causes besides an input-deprivation mechanism only. White matter degeneration was also found, more severe in JMD than in AMD. Moreover, functional analysis revealed differences in cortical activation patterns between MD and controls, suggesting neuronal circuit reorganization. Interestingly, attention and oculomotor training allowed better visual performances and correlated to a stronger cortical activation, even of the area normally receiving inputs from lesioned macula.
Conclusion: In MD, structural and functional changes in cerebral circuits and visual pathway can happen, involving both cerebral volume and activation patterns. These modifications, possibly due to neuronal plasticity (already observed and described for several brain areas), can allow patients to compensate for macular damage and gives therapeutic perspectives which could be achievable through an association between oculomotor training and biochemical stimulation of neuronal plasticity.
Oxidative Stress as a Therapeutic Target for the Prevention and Treatment of Early Age-related Macular Degeneration
Surv Ophthalmol. 2020 Sep 19;S0039-6257(20)30132-6.
Sayena Jabbehdari, James T Handa
PMID: 32961209 DOI: 10.1016/j.survophthal.2020.09.002
Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss among older adults in developed countries. It is a chronic, multifactorial, and progressive disease with the development of painless, central vision loss. Retinal pigment epithelial cell dysfunction is a core change in AMD that results from aging and the accumulated effects of genetic and environmental factors that, in part, is both caused by and leads to oxidative stress. In this review, we describe the role of oxidative stress, the cytoprotective oxidative stress pathways, and the impact of oxidative stress on critical cellular processes involved in AMD pathobiology. We also offer targeted therapy that may define how antioxidant therapy can either prevent or improve specific stages of AMD.
Comparative efficacy and safety of anti-vascular endothelial growth factor regimens for neovascular age-related macular degeneration: systematic review and Bayesian network meta-analysis
Ther Adv Chronic Dis. 2020 Sep 4;11:2040622320953349.
Lu Ye, Zhao Jiaqi, Wang Jianchao, Feng Zhaohui, Yao Liang, Zhang Xiaohui
PMID: 32953000 PMCID: PMC7475790 DOI: 10.1177/2040622320953349
Background: As a debilitating neurodegenerative disease, neovascular age-related macular degeneration (nAMD) accounts for more than 90% of severe visual loss or legal blindness among AMD patients. Anti-vascular endothelial growth factor (VEGF) had been applied widely in nAMD treatment. To date, debate regarding efficacy and safety still exists among different anti-VEGF regimens as management of nAMD. To provide substantial evidence for clinical nAMD treatment, this study ranks the priority of anti-VEGF regimens via Bayesian network meta-analysis (NMA), comparing data collected from randomized controlled trials (RCTs).
Methods: We searched PubMed Central, MEDLINE Ovid, Embase Ovid, ISRCTN, ICTRP and ClinicalTrials. gov from a database established until 1 April 2019 systematically for anti-VEGF regimens. Bayesian NMA with random-effect was conducted to compare efficacy and safety and rank priority of anti-VEGF regimens. The primary efficacy and safety outcomes were the proportion of patients gaining 15 or more letters, and the incidence of arterial thromboembolic (ATC) events. The effect measure is the standard mean difference (SMD), or the odds ratio (OR) with their 95% confidence interval (CI). The study protocol is registered with PROSPERO, number CRD42019132243.
Results: We obtained 6467 citations and identified 29 RCTs including 13,596 participants; 86% of these trials were low risk or of uncertain risk bias. In NMA, ORs compared with sham injection for the proportion of patients gaining 15 or more letters (12,699 participants from 23 trials) ranged from 4.05 [95% Bayesian credible interval (CrI) 1.62-10.11] for ranibizumab quarterly regimen to 8.57 (95% CrI 4.66-15.73) for a ranibizumab treat-and-extend regimen. No difference was found between sham injection and anti-VEGF regimens for ATC events (11,500 participants from 18 trials). Results for the primary outcome did not substantially change in sensitivity analyses after removing studies at high risk of bias and small sample size (n < 100), respectively.
Conclusion: The treat-and-extend regimen of ranibizumab and aflibercept are the preferred anti-VEGF regimens for nAMD. Bevacizumab treat-and-extend regimens need more head-to-head comparisons with other regimens or sham injection for advanced application. The treat-and-extend regimen proved to be the most effective regimen for each anti-VEGF drug in the NMA. Pegaptanib every 6 weeks and Conbercept quarterly are unable to satisfy the best corrected visual acuity (BCVA) improvement requirement of nAMD patients.
"Glaucomatous fields" after monthly intravitreal injections: Normal tension glaucoma or a mimicker?
Am J Ophthalmol Case Rep. 2020 Aug 25;20:100904.
Saumya M Shah, Cheryl L Khanna, Justin Yamanuha, Sophie J Bakri
PMID: 32964169 PMCID: PMC7490721 DOI: 10.1016/j.ajoc.2020.100904
Purpose: Anti-vascular endothelial growth factor (VEGF) injections, while used to effectively treat numerous retinal vascular conditions, can be associated with transient and prolonged ocular hypertension. There is minimal literature detailing the development of normal-tension glaucoma (NTG) following intravitreal anti-VEGF injections.
Observations: A 38-year-old Caucasian male with no medical or ocular history was diagnosed with an inferior HRVO with macular edema in the left eye. The patient received a total of eleven monthly intravitreal aflibercept injections over one year, with maintenance of stable vision and intraocular pressure (IOP) throughout the treatment period and during follow-up. Nine months after the last aflibercept injection, cup-to-disc asymmetry, inferior thinning of retinal nerve fiber layer (RNFL), and reduced superior visual field was evident in the left eye. Clinically, the patient was consistent with normal tension glaucoma and thus, the patient was started on daily timolol drops; however, the role of the glaucomatous findings being secondary to repeated injection-related IOP elevations is possible.
Conclusions and importance: While the clinical features based on visual fields and RNFL thinning with unmedicated normotensive IOP may suggest NTG in a patient, this clinical presentation may be a masquerader of NTG with the etiology of the glaucoma optic neuropathy caused by cumulative impact of transient IOP elevations secondary to intravitreal injections.
Non-arteritic anterior ischemic optic neuropathy after intravitreal aflibercept for age-related macular degeneration
Retin Cases Brief Rep. 2020 Sep 18.
Andrew B Paxton, Panos G Christakis, Jonathan A Micieli
PMID: 32969978 DOI: 10.1097/ICB.0000000000001053
Purpose: To report a case of non-arteritic anterior ischemic optic neuropathy (NAION) after intravitreal injection in a patient with a history of fellow-eye NAION.
Methods: Observational case report.
Results: An 82-year-old woman with a history of fellow eye NAION developed an inferior visual field defect 1 day after an intravitreal aflibercept injection for neovascular age-related macular degeneration (AMD). She was found to have optic disc edema and an inferior altitudinal defect, consistent with NAION. The mechanism may have involved compromised perfusion to the optic nerve head related to elevated intraocular pressure or vasoconstriction due to anti-vascular endothelial growth factor activity.
Conclusions: NAION is a rare complication of intravitreal injection and may be related to post-injection elevation in IOP. Monitoring of IOP post-injection with low-threshold for pre-injection aqueous suppression or post-injection anterior chamber paracentesis for persistently elevated IOP is recommended in patients with a history of NAION.