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Peiris TJ, El Rami HE, Sun JK.
CENTRAL SEROUS CHORIORETINOPATHY ASSOCIATED WITH STEROID ENEMA. Retin Cases Brief Rep 2021;15(1):15-17.
AbstractBACKGROUND/PURPOSE: To report a case of acute recurrent central serous chorioretinopathy that developed after a regimen of corticosteroid enemas and suppositories. METHODS: Observational case report. Fluorescein angiography and spectral domain optical coherence tomography. RESULTS: A 47-year-old male patient with ulcerative colitis managed through hydrocortisone enemas presented to clinic with a 1-day history of blurry vision of his left eye. Posterior segment examination revealed subretinal fluid in the superotemporal macula of the left eye extending centrally. After diagnosis of acute central serous chorioretinopathy, the patient was advised to taper steroid enemas and his visual symptoms and subretinal fluid resolved within the month. Seven years later, several months after using steroid suppositories for the first time since the original central serous chorioretinopathy episode, asymptomatic subretinal fluid accumulation with foveal sparing was found on routine ophthalmic examination. Three months later, most of this fluid had resolved with minimal residual subretinal fluid on clinical examination. CONCLUSION: Acute central serous chorioretinopathy may develop after corticosteroid enema or suppository use, a route of administration that has not been previously reported in association with the disease.
Peiris TJ, Indaram M, Koo E, Soul JS, Hunter DG.
Congenital muscular dystrophy-dystroglycanopathy, type A, featuring bilateral retinal dysplasia and vertical angle kappa. J AAPOS 2018;22(3):242-244.e1.
AbstractMuscular dystrophy-dystroglycanopathy type A (MDDGA3), one of a group of diseases collectively known as congenital muscular dystrophies, is an alpha-dystroglycanopathy with characteristic brain and ocular abnormalities. We report the case of a 9-month-old boy with developmental delay whose family sought evaluation for esotropia. Subsequent examination, imaging, and testing revealed significant motor and cognitive delay, marked weakness with appendicular spasticity, and a diffuse brain malformation. In addition, the patient had poor visual acuity, nystagmus, optic nerve hypoplasia, bilateral retinal dysplasia and retinal dragging with a large vertical angle kappa, and an avascular peripheral retina. Genetic testing revealed two known heterozygous mutations in the POMGnT1 gene confirming MDDGA3. He was treated with botulinum toxin injections for his strabismus and continues to be followed, with planned laser ablation of the peripheral avascular retina.
Peng Y-R, Shekhar K, Yan W, Herrmann D, Sappington A, Bryman GS, van Zyl T, Do MTH, Regev A, Sanes JR.
Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina. Cell 2019;176(5):1222-1237.e22.
AbstractHigh-acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible organisms lack a fovea, its specialized function and its dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >60 cell types match between the two regions but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved. In contrast, projection neuron types and programs diverge, despite exhibiting conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 7 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.
Pennock S, Kazlauskas A.
Vascular endothelial growth factor A competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses. Mol Cell Biol 2012;32(10):1955-66.
AbstractCertain platelet-derived growth factor (PDGF) isoforms are associated with proliferative vitreoretinopathy (PVR), a sight-threatening complication that develops in a subset of patients recovering from retinal reattachment surgery. Although these PDGF isoforms are abundant in the vitreous of patients and experimental animals with PVR, they make only a minor contribution to activating PDGF receptor α (PDGFRα) and driving experimental PVR. Rather, growth factors outside of the PDGF family are the primary (and indirect) agonists of PDGFRα. These observations beg the question of why vitreal PDGFs fail to activate PDGFRα. We report here that vitreous contains an inhibitor of PDGF-dependent activation of PDGFRα and that a major portion of this inhibitory activity is due to vascular endothelial cell growth factor A (VEGF-A). Furthermore, recombinant VEGF-A competitively blocks PDGF-dependent binding and activation of PDGFR, signaling events, and cellular responses. These findings unveil a previously unappreciated relationship between distant members of the PDGF/VEGF family that may contribute to pathogenesis of a blinding eye disease.
Pennock S, Kim D, Mukai S, Kuhnle M, Chun DW, Matsubara J, Cui J, Ma P, Maberley D, Samad A, Van Geest RJ, Oberstein SL, Schlingemann RO, Kazlauskas A.
Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease. Am J Pathol 2013;182(5):1659-70.
AbstractProliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non-PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti-VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions.
Perepelkina T, Kegeles E, Baranov PY.
Optimized conditions and use of synthetic matrix for retinal differentiation from pluripotent cells. Tissue Eng Part C Methods 2019;
AbstractPURPOSE: Since it was first introduced in 2011, three-dimensional "Sasai" method for retinal differentiation became a strategy of choice for retinal tissue and neuron production. It is based on the recapitulation of retinal development and requires several stages: aggregate formation, neuroectoderm induction, and eye field induction, followed by retinal maturation. In order to achieve the consistency of retinal differentiation needed for drug discovery and cell transplantation we have attempted to improve spheroid formation as well as approach xeno-free conditions. METHODS: In this study we compared the effect of cell culture plate shape and material, medium viscosity, lipid and bovine serum albumin concentrations on aggregate formation from mouse embryonic stem cells. We have also assessed the possibility of substituting Matrigel with the synthetic vitronectin-mimicking oligopeptide. RX-GFP mES cell line used for experiments. The dose-response of synthetic ECM has been assessed and quantified by live fluorescence microscopy, immunohistochemistry, flow cytometry and qPCR for early retinal development genes (Rx, Pax6, Lhx2, Sox2, Six6). RESULTS: The comparison of seeding conditions at 24hr. post seeding showed the dose-dependent effects of lipids (lipids concentration of 2% resulted in 100% efficiency of aggregate formation and significant increase in size to 532.8 ± 31.87um, p< 0.05); and viscosity (methylcellulose concentration of 0.06% in OV medium showed 100% efficiency and increase in aggregate size 532±19.23 um, p<0.01). The addition of synthetic matrix resulted in retinal differentiation (34.47% of RX as detected by flow cytometry compared to 33.8%, observed with Matrigel). The early retinal genes expression at day 7 was confirmed by qPCR. CONCLUSIONS: We present the optimized conditions for 3D retinal differentiation including the option of xeno-free extracellular matrix. These defined medium conditions significantly decrease the variability within and between batches and allow substantial scale up of retinal tissue and cell production for drug discovery, disease modeling and transplantation purposes.
Peterson SL, Li Y, Sun CJ, Wong KA, Leung KS, de Lima S, Hanovice NJ, Yuki K, Stevens B, Benowitz LI.
Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve. J Neurosci 2021;41(41):8508-8531.
AbstractAxon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries, and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on RGC survival. Local injections of C1q function-blocking antibody revealed that complement acts primarily within the optic nerve, not retina, to support regeneration. Moreover, C1q opsonizes and CR3+ microglia/monocytes phagocytose growth-inhibitory myelin debris after ONI, a likely mechanism through which complement and myeloid cells support axon regeneration. Collectively, these results indicate that local optic nerve complement-myeloid phagocytic signaling is required for CNS axon regrowth, emphasizing the axonal compartment and highlighting a beneficial neuroimmune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENT Despite the importance of achieving axon regeneration after CNS injury and the inevitability of inflammation after such injury, the contributions of complement and microglia to CNS axon regeneration are largely unknown. Whereas inflammation is commonly thought to exacerbate the effects of CNS injury, we find that complement proteins C1q and C3 and microglia/monocyte phagocytic complement receptor CR3 are each required for retinal ganglion cell axon regeneration through the injured mouse optic nerve. Also, whereas studies of optic nerve regeneration generally focus on the retina, we show that the regeneration-relevant role of complement and microglia/monocytes likely involves myelin phagocytosis within the optic nerve. Thus, our results point to the importance of the innate immune response for CNS repair.
Phadikar P, Saxena S, Ruia S, Lai TYY, Meyer CH, Eliott D.
The potential of spectral domain optical coherence tomography imaging based retinal biomarkers. Int J Retina Vitreous 2017;3:1.
AbstractBACKGROUND: Biomarker", a merged word of "biological marker", refers to a broad subcategory of medical signs that objectively indicate the state of health, and well-being of an individual. Biomarkers hold great promise for personalized medicine as information gained from diagnostic or progression markers can be used to tailor treatment to the individual for highly effective intervention in the disease process. Optical coherence tomography (OCT) has proved useful in identifying various biomarkers in ocular and systemic diseases. MAIN BODY: Spectral domain optical coherence tomography imaging-based biomarkers provide a valuable tool for detecting the earlier stages of the disease, tracking progression, and monitoring treatment response. The aim of this review article is to analyze various OCT based imaging biomarkers and their potential to be considered as surrogate endpoints for diabetic retinopathy, age related macular degeneration, retinitis pigmentosa and vitreomacular interface disorder. These OCT based surrogate markers have been classified as retinal structural alterations (macular central subfield thickness and cube average thickness); retinal ultrastructural alterations (disruption of external limiting membrane and ellipsoid zone, thinning of retinal nerve fiber layer and ganglion cell layer); intraretinal microangiopathic changes; choroidal surrogate endpoints; and vitreoretinal interface endpoints. CONCLUSION: OCT technology is changing very quickly and throughout this review there are some of the multiple possibilities that OCT based imaging biomarkers will be more useful in the near future for diagnosis, prognosticating disease progression and as endpoint in clinical trials.
Pivodic A, Johansson H, Smith LEH, Hård A-L, Löfqvist C, Yoder BA, Hartnett EM, Wu C, Bründer M-C, Lagrèze WA, Stahl A, Al-Hawasi A, Larsson E, Lundgren P, Gränse L, Sunnqvist B, Tornqvist K, Wallin A, Holmström G, Albertsson-Wikland K, Nilsson S, Hellström A.
Development and validation of a new clinical decision support tool to optimize screening for retinopathy of prematurity. Br J Ophthalmol 2022;106(11):1573-1580.
AbstractBACKGROUND/AIMS: Prematurely born infants undergo costly, stressful eye examinations to uncover the small fraction with retinopathy of prematurity (ROP) that needs treatment to prevent blindness. The aim was to develop a prediction tool (DIGIROP-Screen) with 100% sensitivity and high specificity to safely reduce screening of those infants not needing treatment. DIGIROP-Screen was compared with four other ROP models based on longitudinal weights. METHODS: Data, including infants born at 24-30 weeks of gestational age (GA), for DIGIROP-Screen development (DevGroup, N=6991) originate from the Swedish National Registry for ROP. Three international cohorts comprised the external validation groups (ValGroups, N=1241). Multivariable logistic regressions, over postnatal ages (PNAs) 6-14 weeks, were validated. Predictors were birth characteristics, status and age at first diagnosed ROP and essential interactions. RESULTS: ROP treatment was required in 287 (4.1%)/6991 infants in DevGroup and 49 (3.9%)/1241 in ValGroups. To allow 100% sensitivity in DevGroup, specificity at birth was 53.1% and cumulatively 60.5% at PNA 8 weeks. Applying the same cut-offs in ValGroups, specificities were similar (46.3% and 53.5%). One infant with severe malformations in ValGroups was incorrectly classified as not needing screening. For all other infants, at PNA 6-14 weeks, sensitivity was 100%. In other published models, sensitivity ranged from 88.5% to 100% and specificity ranged from 9.6% to 45.2%. CONCLUSIONS: DIGIROP-Screen, a clinical decision support tool using readily available birth and ROP screening data for infants born GA 24-30 weeks, in the European and North American populations tested can safely identify infants not needing ROP screening. DIGIROP-Screen had equal or higher sensitivity and specificity compared with other models. DIGIROP-Screen should be tested in any new cohort for validation and if not validated it can be modified using the same statistical approaches applied to a specific clinical setting.
Pivodic A, Nilsson S, Stahl A, Smith LEH, Hellström A.
Validation of the Retinopathy of Prematurity Activity Scale (ROP-ActS) using retrospective clinical data. Acta Ophthalmol 2021;99(2):201-206.
AbstractPURPOSE: The International Neonatal Consortium recently published a proposed retinopathy of prematurity (ROP) activity scale intended for use in clinical trials after validation. The aim of this study was to validate the ROP activity scale (ROP-ActS) in a ROP screened cohort with protocol based collected data by evaluating the ability of the ROP-Act scores to predict ROP treatment. In addition, we aimed to evaluate the scale's sensitivity characteristic of disease severity by studying association with gestational age (GA) in comparison with conventionally used ROP stage and zone. METHODS: A cohort of 535 preterm infants with 3324 ROP examinations with an end-point of ROP treatment or end of screening in Gothenburg, Sweden, was included. Median GA was 28.1 weeks, 47.5% were girls, and 74 (13.8%) infants were treated for ROP. The validation was performed by estimating probabilities for ROP treatment, and by applying logistic and linear regression. RESULTS: The original ROP-ActS was overall well-ordered with respect to ability to predict ROP treatment but could be improved by re-ordering score 3 (zone II stage 1) and 5 (zone III stage 3) based on our clinical cohort data. The modified ROP-ActS was superior to ROP stage and zone in the prediction analysis of ROP treatment. Modified ROP-ActS was more strongly related to GA than currently used ROP stage, but not zone. CONCLUSION: In the studied cohort, the modified ROP-ActS could better predict ROP treatment compared to ROP stage and zone. Retinopathy of Prematurity Activity Scale (ROP-ActS) had a superior sensitivity characteristic studied through association to GA than conventionally used ROP stage.
Pivodic A, Smith LEH, Hård A-L, Löfqvist C, Almeida AC, Al-Hawasi A, Larsson E, Lundgren P, Sunnqvist B, Tornqvist K, Wallin A, Holmstrom G, Gränse L.
Validation of DIGIROP models and decision support tool for prediction of treatment for retinopathy of prematurity on a contemporary Swedish cohort. Br J Ophthalmol 2023;107(8):1132-1138.
AbstractBACKGROUND/AIMS: Retinopathy of prematurity (ROP) is currently diagnosed through repeated eye examinations to find the low percentage of infants that fulfil treatment criteria to reduce vision loss. A prediction model for severe ROP requiring treatment that might sensitively and specifically identify infants that develop severe ROP, DIGIROP-Birth, was developed using birth characteristics. DIGIROP-Screen additionally incorporates first signs of ROP in different models over time. The aim was to validate DIGIROP-Birth, DIGIROP-Screen and their decision support tool on a contemporary Swedish cohort. METHODS: Data were retrieved from the Swedish national registry for ROP (2018-2019) and two Swedish regions (2020), including 1082 infants born at gestational age (GA) 24 to <31 weeks. The predictors were GA at birth, sex, standardised birth weight and age at the first sign of ROP. The outcome was ROP treatment. Sensitivity, specificity and area under the receiver operating characteristic curve (AUC) with 95% CI were described. RESULTS: For DIGIROP-Birth, the AUC was 0.93 (95% CI 0.90 to 0.95); for DIGIROP-Screen, it ranged between 0.93 and 0.97. The specificity was 49.9% (95% CI 46.7 to 53.0) and the sensitivity was 96.5% (95% CI 87.9 to 99.6) for the tool applied at birth. For DIGIROP-Screen, the cumulative specificity ranged between 50.0% and 78.7%. One infant with Beckwith-Wiedemann syndrome who fulfilled criteria for ROP treatment and had no missed/incomplete examinations was incorrectly flagged as not needing screening. CONCLUSIONS: DIGIROP-Birth and DIGIROP-Screen showed high predictive ability in a contemporary Swedish cohort. At birth, 50% of the infants born at 24 to <31 weeks of gestation were predicted to have low risk of severe ROP and could potentially be released from ROP screening examinations. All routinely screened treated infants, excluding those screened for clinical indications of severe illness, were correctly flagged as needing ROP screening.
Pivodic A, Holmström G, Smith LEH, Hård A-L, Löfqvist C, Al-Hawasi A, Larsson E, Lundgren P, Gränse L, Tornqvist K, Wallin A, Johansson H, Albertsson-Wikland K, Nilsson S, Hellström A.
Prognostic Value of Parenteral Nutrition Duration on Risk of Retinopathy of Prematurity: Development and Validation of the Revised DIGIROP Clinical Decision Support Tool. JAMA Ophthalmol 2023;141(8):716-724.
AbstractIMPORTANCE: The prognostic impact of parenteral nutrition duration (PND) on retinopathy of prematurity (ROP) is not well studied. Safe prediction models can help optimize ROP screening by effectively discriminating high-risk from low-risk infants. OBJECTIVE: To evaluate the prognostic value of PND on ROP; to update and validate the Digital ROP (DIGIROP) 2.0 birth into prescreen and screen prediction models to include all ROP-screened infants regardless of gestational age (GA) and incorporate PND; and to compare the DIGIROP model with the Weight, IGF-1, Neonatal, and ROP (WINROP) and Postnatal Growth and ROP (G-ROP) models. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study included 11 139 prematurely born infants from 2007 to 2020 from the Swedish National Registry for ROP. Extended Poisson and logistic models were applied. Data were analyzed from August 2022 to February 2023. MAIN OUTCOMES AND MEASURES: Any ROP and ROP requiring treatment were studied in relation to PND. ROP treatment was the outcome in DIGIROP models. Sensitivity, specificity, area under the receiver operating characteristic curve, and adjusted OR (aOR) with 95% CI were the main measures. Internal and external validations were performed. RESULTS: Of 11 139 screened infants, 5071 (45.5%) were girls, and the mean (SD) gestational age was 28.5 (2.4) weeks. ROP developed in 3179 infants (29%), treatment was given in 599 (5%), 7228 (65%) had PND less than 14 days, 2308 (21%) had PND for 14 days or more, and 1603 (14%) had unknown PND. PND was significantly correlated with ROP severity (Spearman r = 0.45; P < .001). Infants with 14 days or more of PND vs less than 14 days had faster progression from any ROP to ROP treatment (adjusted mean difference, -0.9 weeks; 95% CI, -1.5 to -0.3; P = .004). Infants with PND for 14 days or more vs less than 14 days had higher odds of any ROP (aOR, 1.84; 95% CI, 1.62-2.10; P < .001) and of severe ROP requiring treatment (aOR, 2.20; 95% CI, 1.73-2.80; P < .001). Among all 11 139 infants, the DIGIROP 2.0 models had 100% sensitivity (95% CI, 99.4-100). The specificity was 46.6% (95% CI, 45.6-47.5) for the prescreen model and 76.9% (95% CI, 76.1-77.7) for the screen model. G-ROP as well as the DIGIROP 2.0 prescreen and screen models showed 100% sensitivity on a validation subset (G-ROP: sensitivity, 100%; 95% CI, 93-100; DIGIROP prescreen: sensitivity, 100%; 95% CI, 93-100; DIGIROP screen: sensitivity, 100%; 95% CI, 93-100), whereas WINROP showed 89% sensitivity (95% CI, 77-96). Specificity for each prediction model was 29% (95% CI, 22-36) for G-ROP, 38% (95% CI, 32-46) for DIGIROP prescreen, 53% (95% CI, 46-60) for DIGIROP screen at 10 weeks, and 46% (95% CI, 39-53) for WINROP. CONCLUSION AND RELEVANCE: Based on more than 11 000 ROP-screened infants born in Sweden, PND of 14 days or more corresponded to a significantly higher risk of having any ROP and receiving ROP treatment. These findings provide evidence to support consideration of using the updated DIGIROP 2.0 models instead of the WINROP or G-ROP models in the management of ROP.
Pivodic A, Hård A-L, Löfqvist C, Smith LEH, Wu C, Bründer M-C, Lagrèze WA, Stahl A, Holmström G, Albertsson-Wikland K, Johansson H, Nilsson S, Hellström A.
Individual Risk Prediction for Sight-Threatening Retinopathy of Prematurity Using Birth Characteristics. JAMA Ophthalmol 2019;:1-9.
AbstractImportance: To prevent blindness, repeated infant eye examinations are performed to detect severe retinopathy of prematurity (ROP), yet only a small fraction of those screened need treatment. Early individual risk stratification would improve screening timing and efficiency and potentially reduce the risk of blindness. Objectives: To create and validate an easy-to-use prediction model using only birth characteristics and to describe a continuous hazard function for ROP treatment. Design, Setting, and Participants: In this retrospective cohort study, Swedish National Patient Registry data from infants screened for ROP (born between January 1, 2007, and August 7, 2018) were analyzed with Poisson regression for time-varying data (postnatal age, gestational age [GA], sex, birth weight, and important interactions) to develop an individualized predictive model for ROP treatment (called DIGIROP-Birth [Digital ROP]). The model was validated internally and externally (in US and European cohorts) and compared with 4 published prediction models. Main Outcomes and Measures: The study outcome was ROP treatment. The measures were estimated momentary and cumulative risks, hazard ratios with 95% CIs, area under the receiver operating characteristic curve (hereinafter referred to as AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Among 7609 infants (54.6% boys; mean [SD] GA, 28.1 [2.1] weeks; mean [SD] birth weight, 1119 [353] g), 442 (5.8%) were treated for ROP, including 142 (40.1%) treated of 354 born at less than 24 gestational weeks. Irrespective of GA, the risk for receiving ROP treatment increased during postnatal weeks 8 through 12 and decreased thereafter. Validations of DIGIROP-Birth for 24 to 30 weeks' GA showed high predictive ability for the model overall (AUC, 0.90 [95% CI, 0.89-0.92] for internal validation, 0.94 [95% CI, 0.90-0.98] for temporal validation, 0.87 [95% CI, 0.84-0.89] for US external validation, and 0.90 [95% CI, 0.85-0.95] for European external validation) by calendar periods and by race/ethnicity. The sensitivity, specificity, PPV, and NPV were numerically at least as high as those obtained from CHOP-ROP (Children's Hospital of Philadelphia-ROP), OMA-ROP (Omaha-ROP), WINROP (weight, insulinlike growth factor 1, neonatal, ROP), and CO-ROP (Colorado-ROP), models requiring more complex postnatal data. Conclusions and Relevance: This study validated an individualized prediction model for infants born at 24 to 30 weeks' GA, enabling early risk prediction of ROP treatment based on birth characteristics data. Postnatal age rather than postmenstrual age was a better predictive variable for the temporal risk of ROP treatment. The model is an accessible online application that appears to be generalizable and to have at least as good test statistics as other models requiring longitudinal neonatal data not always readily available to ophthalmologists.
Poon LY-C, Solá-Del Valle D, Turalba AV, Falkenstein IA, Horsley M, Kim JH, Song BJ, Takusagawa HL, Wang K, Chen TC.
The ISNT Rule: How Often Does It Apply to Disc Photographs and Retinal Nerve Fiber Layer Measurements in the Normal Population?. Am J Ophthalmol 2017;184:19-27.
AbstractPURPOSE: To determine what percentage of normal eyes follow the ISNT rule, and whether ISNT rule variants may be more generalizable to the normal population. DESIGN: Cross-sectional study. METHODS: Setting: Institutional setting. STUDY POPULATION: Total of 110 normal subjects. OBSERVATION PROCEDURES: Neuroretinal rim assessments from disc photographs and retinal nerve fiber layer (RNFL) thickness measurements from spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES: The percentages of subjects that obeyed the ISNT rule and its variants. RESULTS: The ISNT rule is only valid for 37.0% of disc photograph rim assessments and 43.8% of RNFL measurements. Deviation of the nasal sector from the expected ISNT pattern was a major cause for the ISNT rule not being obeyed for both rim and RNFL assessments. Specifically, 10.9% of subjects had wider nasal rims than the inferior rims, 29.4% had wider nasal rims than the superior rims, 14.7% had narrower nasal rims than the temporal rims, and 42.9% had thinner nasal RNFLs compared to the temporal quadrant. Exclusion of the nasal quadrant from the ISNT rule significantly increased the validity of ISNT variant rules, with 70.9% and 76.4% of disc photographs following the IST rule and the IS rule, respectively. Similarly, for RNFL thickness, 70.9% and 71.8% of patients followed the IST and IS rule, respectively. CONCLUSIONS: The ISNT rule is only valid for about a third of disc photographs and less than half of RNFL measurements in normal patients. ISNT rule variants, such as the IST and IS rule, may be considered, as they are valid in more than 70% of patients.
Prahst C, Ashrafzadeh P, Mead T, Figueiredo A, Chang K, Richardson D, Venkaraman L, Richards M, Russo AM, Harrington K, Ouarné M, Pena A, Chen DF, Claesson-Welsh L, Cho K-S, Franco CA, Bentley K.
Mouse retinal cell behaviour in space and time using light sheet fluorescence microscopy. Elife 2020;9
AbstractAs the general population ages, more people are affected by eye diseases, such as retinopathies. It is therefore critical to improve imaging of eye disease mouse models. Here, we demonstrate that 1) rapid, quantitative 3D and 4D (time lapse) imaging of cellular and subcellular processes in the mouse eye is feasible, with and without tissue clearing, using light-sheet fluorescent microscopy (LSFM); 2) flat-mounting retinas for confocal microscopy significantly distorts tissue morphology, confirmed by quantitative correlative LSFM-Confocal imaging of vessels; 3) LSFM readily reveals new features of even well-studied eye disease mouse models, such as the oxygen-induced retinopathy (OIR) model, including a previously unappreciated 'knotted' morphology to pathological vascular tufts, abnormal cell motility and altered filopodia dynamics when live-imaged. We conclude that quantitative 3D/4D LSFM imaging and analysis has the potential to advance our understanding of the eye, in particular pathological, neuro-vascular, degenerative processes.
Primo V, Graham M, Bigger-Allen AA, Chick JM, Ospina C, Quiroz YT, Manent J, Gygi SP, Lopera F, D'Amore PA, Arboleda-Velasquez JF.
Blood biomarkers in a mouse model of CADASIL. Brain Res 2016;1644:118-26.
AbstractMutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice.
Putera I, Ridwan AS, Dewi M, Cifuentes-González C, Rojas-Carabali W, Sitompul R, Edwar L, Susiyanti M, Aziza Y, Pavesio C, Chee S-P, Mahendradas P, Biswas J, Kempen JH, Gupta V, de-la-Torre A, Distia Nora RL, Agrawal R.
Antiviral treatment for acute retinal necrosis: A systematic review and meta-analysis. Surv Ophthalmol 2024;69(1):67-84.
AbstractAcute retinal necrosis is a progressive intraocular inflammatory syndrome characterized by diffuse necrotizing retinitis that can lead to a poor visual outcome, mainly from retinal detachment. The antiviral treatment approach for acute retinal necrosis varies as there are no established guidelines. We summarize the outcomes of acute retinal necrosis with available antiviral treatments. Electronic searches were conducted in PubMed/MEDLINE, EMBASE, Scopus, and Google Scholar for interventional and observational studies. Meta-analysis was performed to evaluate the pooled proportion of the predefined selected outcomes. This study was registered in PROSPERO (CRD42022320987). Thirty-four studies with a total of 963 participants and 1,090 eyes were included in the final analysis. The estimated varicella-zoster virus and herpes simplex virus polymerase chain reaction-positive cases were 63% (95% CI: 55-71%) and 35% (95% CI: 28-42%), respectively. The 3 main antiviral treatment approaches identified were oral antivirals alone, intravenous antivirals alone, and a combination of systemic (oral or intravenous) and intravitreal antivirals. The overall pooled estimated proportions of visual acuity improvement, recurrence, and retinal detachment were 37% (95% CI: 27-47%), 14% (95% CI: 8-21%), and 43% (95% CI: 38-50%), respectively. Patients treated with systemic and intravitreal antivirals showed a trend towards better visual outcomes than those treated with systemic antivirals (oral or intravenous) alone, even though this analysis was not statistically significant (test for subgroup differences P = 0.83).
