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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.
White TL, Deshpande N, Kumar V, Gauthier AG, Jurkunas UV. Cell cycle re-entry and arrest in G2/M phase induces senescence and fibrosis in Fuchs Endothelial Corneal Dystrophy. Free Radic Biol Med 2021;164:34-43.Abstract
Fuchs endothelial corneal dystrophy (FECD) is an age-related disease whereby progressive loss of corneal endothelial cells (CEnCs) leads to loss of vision. There is currently a lack of therapeutic interventions as the etiology of the disease is complex, with both genetic and environmental factors. In this study, we have provided further insights into the pathogenesis of the disease, showing a causal relationship between senescence and endothelial-mesenchymal transition (EMT) using in vitro and in vivo models. Ultraviolet A (UVA) light induced EMT and senescence in CEnCs. Senescent cells were arrested in G2/M phase of the cell cycle and responsible for the resulting profibrotic phenotype. Inhibiting ATR signaling and subsequently preventing G2/M arrest attenuated EMT. In vivo, UVA irradiation induced cell cycle re-entry in post mitotic CEnCs, resulting in senescence and fibrosis at 1- and 2-weeks post-UVA. Selectively eliminating senescent cells using the senolytic cocktail of dasatinib and quercetin attenuated UVA-induced fibrosis, highlighting the potential for a new therapeutic intervention for FECD.
Benedi-Garcia C, Vinas M, Dorronsoro C, Burns SA, Peli E, Marcos S. Vision is protected against blue defocus. Sci Rep 2021;11(1):352.Abstract
Due to chromatic aberration, blue images are defocused when the eye is focused to the middle of the visible spectrum, yet we normally are not aware of chromatic blur. The eye suffers from monochromatic aberrations which degrade the optical quality of all images projected on the retina. The combination of monochromatic and chromatic aberrations is not additive and these aberrations may interact to improve image quality. Using Adaptive Optics, we investigated the optical and visual effects of correcting monochromatic aberrations when viewing polychromatic grayscale, green, and blue images. Correcting the eye's monochromatic aberrations improved optical quality of the focused green images and degraded the optical quality of defocused blue images, particularly in eyes with higher amounts of monochromatic aberrations. Perceptual judgments of image quality tracked the optical findings, but the perceptual impact of the monochromatic aberrations correction was smaller than the optical predictions. The visual system appears to be adapted to the blur produced by the native monochromatic aberrations, and possibly to defocus in blue.
Hu Z, Cao J, Choi EY, Li Y. Progressive retinal vessel malformation in a premature infant with Sturge-Weber syndrome: a case report and a literature review of ocular manifestations in Sturge-Weber syndrome. BMC Ophthalmol 2021;21(1):56.Abstract
BACKGROUND: Sturge-Weber syndrome is a disorder marked by a distinctive facial capillary malformation, neurological abnormalities, and ocular abnormalities such as glaucoma and choroidal hemangioma. CASE PRESENTATION: We report a case of progressively formed retinal vessel malformation in a premature male infant with Sturge-Weber syndrome and retinopathy of prematurity, after treatment with intravitreal anti-vascular endothelial growth factor (VEGF). The baby was born at 30 weeks gestation with a nevus flammeus involving his left eyelids and maxillary area. On postmenstrual age week 39, he received intravitreal anti-VEGF. Diffuse choroidal hemangioma became evident at 40 weeks, with the classic "tomato catsup fundus" appearance. These clinical findings characterized Sturge-weber syndrome. He presented with posterior retinal vessel tortuosity and vein-to-vein anastomoses at 44 weeks. CONCLUSION: This is a rare case of documented progression of retinal vessel malformations in a patient with Sturge-Weber syndrome and retinopathy of prematurity.
Cubuk MO, Ucgul AY, Ozgur A, Ozulken K, Yuksel E. Topical cyclosporine a (0.05%) treatment in dry eye patients: a comparison study of Sjogren's syndrome versus non-Sjogren's syndrome. Int Ophthalmol 2021;41(4):1479-1485.Abstract
PURPOSE: To evaluate the clinical effect of topical cyclosporine A (CsA) (0.05%) on dry eye patients with Sjogren's syndrome (SS) and non-Sjogren's syndrome (NSS). METHOD: This retrospective comparative study includes the dry eye (DE) patients who were treated with topical CsA. DE patients were divided into two groups as follows: DE with Sjogren's syndrome (DE-SS) and DE with Non-Sjogren's syndrome (DE-NSS). Dry eye parameters were recorded at baseline and each visit. RESULTS: Schirmer's test 1 scores were 2.7 ± 0.5 mm at baseline and 3.5 ± 0.7 mm at 12th month in DE-SS, 2.9 ± 0.7 mm at baseline and 9.5 ± 0.7 mm in DE-NSS groups at 12th month. Mean ST score was higher in DE-NSS group than DE-SS group at sixth and 12th months of the treatment (both p = 0.001). Tear break-up time score showed a significant improvement in DE-NSS group, and it was lower in DE-NSS group than DE-SS group group at sixth and 12th months of the treatment (p = 0.044 and 0.027, respectively). Mean OSDI score was lower in DE-NSS group than DE-SS group at sixth and 12th months of the treatment (p = 0.030 and 0.032, respectively). CONCLUSION: Topical CsA seems to be more effective in the treatment of the DE-NSS.
Shroff S, Gu SZ, Vardhan S A, Mani I, Aziz K, P N, Datta D, Friedman DS. Screening first-degree relatives of glaucoma patients reveals barriers to participation. Br J Ophthalmol 2021;Abstract
PURPOSE: To report the results of a glaucoma screening campaign targeting first-degree relatives of glaucoma patients in South India. METHODS: 1598 glaucoma patients were contacted via letter or letter and phone call and asked to bring their siblings and children to a glaucoma screening. Participants underwent standardised eye examinations and completed questionnaires that assessed barriers to participation and awareness of glaucoma risk. Two-proportion z-tests were used to compare categorical data. Costs associated with the screening were recorded. RESULTS: 206 probands (12.9%) attended the screening along with 50 siblings and children. Probands were nearly twice as likely to attend if they had been contacted via both letter and phone call rather than letter only. Over half of probands reported that their relatives could not participate because they did not live in the region, and one-fifth reported that their relatives had other commitments. Fifty-eight per cent of the siblings and children who attended did not know that they were at increased risk for glaucoma due to their family history, and 32.0% did not know that the relative who had invited them to the screening had glaucoma. Thirteen siblings and children (26.0% of those who attended) were found to have findings concerning for glaucoma. The average cost per first-degree relative who was screened was INR2422 (£26). CONCLUSION: Participation in this glaucoma screening campaign was poor. The major barrier to participation was distance from the screening site and associated indirect costs. Better strategies for bringing first-degree relatives in for examinations are needed.
Yang S, Kam WR, Liu Y, Ding J, Li Y, Sullivan DA. Comparative influence of differentiation and proliferation on gene expression in human meibomian gland epithelial cells. Exp Eye Res 2021;205:108452.Abstract
We recently discovered that by changing environmental signals, differentiated immortalized human meibomian gland epithelial cells (IHMGECs) de-differentiate into proliferating cells. We also discovered that following exposure to appropriate stimuli, these proliferative cells re-differentiate into differentiated IHMGECs. We hypothesize that this plasticity of differentiated and proliferative IHMGECs is paralleled by very significant alterations in cellular gene expression. To begin to test this hypothesis, we compared the gene expression patterns of IHMGECs during differentiation and proliferation. IHMGECs were cultured for four days in either differentiating or proliferating media. After four days of culture, cells were processed for the analysis of gene expression by using Illumina BeadChips and bioinformatic software. Our study identified significant differences in the expression of more than 9200 genes in differentiated and proliferative IHMGECs. Differentiation was associated with significant increases in the expression of specific genes (e.g. S100 calcium binding protein P; 7,194,386-fold upregulation) and numerous ontologies (e.g. 83 biological process [bp] ontologies with ≥100 genes were upregulated), such as those related to development, transport and lysosomes. Proliferation also led to a significant rise in specific gene expressions (e.g. cathelicidin antimicrobial peptide; 859,100-fold upregulation) and many ontologies (115 biological process [bp] ontologies with ≥100 genes were upregulated), with most of the highly significant ontologies related to cell cycle (z scores > 13.9). Our findings demonstrate that gene expression in differentiated and proliferative IHMGECs is extremely different. These results may have significant implications for the regeneration of HMGECs and the reversal of MG dropout in MG dysfunction.
Jakobiec FA, Barrantes PC, Ma L, Mihm M. Epibulbar Proliferative Fasciitis, a Variant of Nodular Fasciitis: A Differential Diagnosis of Conditions With Focal or Diffuse Myxoid Stromas. Ophthalmic Plast Reconstr Surg 2021;Abstract
PURPOSE: To describe the clinical and pathologic features of a case of epibulbar proliferative fasciitis and to compare it with other focal or diffuse myxoid lesions. METHODS: A clinical, histopathologic, and immunohistochemical analysis was performed. The clinical history, photographic documentation, history, and referred slides were reanalyzed. Additional immunohistochemical stains were performed at our institution. RESULTS: A 68-year-old woman developed over a week a brightly vascularized and focally hemorrhagic placoid lesion on the temporal side of the OS. She had had earlier augmentation breast surgery that had been mistakenly initially reported to us to be for breast carcinoma. Hematoxylin- and eosin-stained reactions revealed microscopically a spindle cell lesion with an intact nonkeratinizing epithelium and a background myxoid stroma with prominent capillaries and a light dispersion of small T-cell lymphocytes. Most striking among the spindle cells were some widely separated large atypical cells. The atypical cells were cytokeratin positive, but an expansive panel of immunohistochemical stains for breast carcinoma was negative. The lesion was diagnosed as proliferative fasciitis and has not recurred after 1-year follow up. CONCLUSION: A rapidly evolving conjunctival lesion is unlikely to be a primary or metastatic carcinoma. In the current case, the large ganglioform or rhabdomyoblast-like cells displayed diffuse cytokeratin positivity, still consistent with a mesenchymal or connective tissue cell lineage. Cytokeratin expression has been a finding previously reported in connective tissue tumors and in lymphoma cells. While the current lesion clinically resembles a conventional nodular fasciitis, the presence of the large atypical cells can lead to the misdiagnosis of a sarcoma, which typically displays a much higher Ki-67 proliferation index in comparison with nodular/proliferative fasciitis.
Eguchi A, Inomata T, Nakamura M, Nagino K, Iwagami M, Sung J, Midorikawa-Inomata A, Okumura Y, Fujio K, Fujimoto K, Miura M, Akasaki Y, Shokirova H, Hirosawa K, Kuwahara M, Zhu J, Dana R, Murakami A, Kobayashi H. Heterogeneity of eye drop use among symptomatic dry eye individuals in Japan: large-scale crowdsourced research using DryEyeRhythm application. Jpn J Ophthalmol 2021;65(2):271-281.Abstract
PURPOSE: To determine eye drop type and usage frequency and investigate risk factors for no eye drop use in individuals with symptomatic dry eye (DE) in Japan. STUDY DESIGN: Crowdsourced observational study. METHODS: This study was conducted using the DryEyeRhythm smartphone application between November 2016 and September 2019. Data collected included the type and frequency of eye drop use, demographics, medical history, lifestyle, and self-reported symptoms. Symptomatic DE was defined as an Ocular Surface Disease Index total score of ≥ 13. Risk factors for no eye drop use were identified using multivariate logistic regression analyses. RESULTS: Among 2619 individuals with symptomatic DE, 1876 did not use eye drops. The most common eye drop type was artificial tears (53.4%), followed by hyaluronic acid 0.1% (33.1%) and diquafosol sodium 3% (18.7%). Risk factors (odds ratio [95% confidence interval]) for no eye drop use were age (0.97 [0.97-0.98]), body mass index (1.04 [1.01-1.07]), brain disease (0.38 [0.15-0.98]), collagen disease (0.30 [0.13-0.68]), mental illness other than depression and schizophrenia (0.65 [0.45-0.93]), cataract surgery (0.12 [0.02-0.59]), ophthalmic surgery other than cataract and laser-assisted in situ keratomileusis (0.55 [0.34-0.88]), current (0.47 [0.38-0.57]) or past (0.58 [0.43-0.77]) contact lens use, >8 h screen exposure time (1.38 [1.05-1.81]), <6 h (1.24 [1.01-1.52]) and >9 h (1.34 [1.04-1.72]) sleep time, and water intake (0.97 [0.94-0.98]). CONCLUSION: Many participants with symptomatic DE did not use optimized eye drop treatment and identified risk factors for no eye drop use. The DryEyeRhythm application may help improve DE treatment.
Winter A, Chwalisz B. MRI Characteristics of NMO, MOG and MS Related Optic Neuritis. Semin Ophthalmol 2021;:1-10.Abstract
Acute isolated optic neuritis can be the initial presentation of demyelinating inflammatory central nervous system disease related to multiple sclerosis (MS), neuromyelitis optica (NMO) or myelin oligodendrocyte glycoprotein antibody disease (MOG-AD). In addition to the well-characterized brain and spinal cord imaging features, important and characteristic differences in the radiologic appearance of the optic nerves in these disorders are being described, and magnetic resonance imaging (MRI) of the optic nerves is becoming an essential tool in the differential diagnosis of optic neuritis. Whereas typical demyelinating optic neuritis is a relatively mild and self-limited disease, atypical optic neuritis in NMO and MOG-AD is potentially much more vision-threatening and merits a different treatment approach. Thus, differentiation based on MRI features may be particularly important during the first attack of optic neuritis, when antibody status is not yet known. This review discusses the optic nerve imaging in the major demyelinating disorders with an emphasis on clinically relevant differences that can help clinicians assess and manage these important neuro-ophthalmic disorders. It also reviews the utility of optic nerve MRI as a prognostic indicator in acute optic neuritis.
Ebrahimiadib N, Maleki A, Fadakar K, Manhapra A, Ghassemi F, Foster SC. Vascular abnormalities in uveitis. Surv Ophthalmol 2021;66(4):653-667.Abstract
Inflammation can involve several ocular structures, including the sclera, retina, and uvea, and cause vascular changes in these tissues. Although retinal vasculitis is the most common finding associated with uveitis involving the posterior segment, other vascular abnormalities may be seen in the retina. These include capillary nonperfusion and ischemia, vascular occlusions, preretinal neovascularization, microaneurysms and macroaneurysms, and telangiectasia. Moreover, vasoproliferative tumors and subsequent coat-like response can develop secondary to uveitis. Fluorescein angiography is ideal for the investigation of retinal vascular leakage and neovascularization, while optical coherence tomography angiography can provide depth resolved images from the superficial and deep capillary plexus and can demonstrate vascular remodeling. Choroidal vascular abnormalities primarily develop in the choriocapillaris or in the choroidal stroma and can appear as flow void in optical coherence tomography angiography and filling defect and vascular leakage in indocyanine green angiography. Extensive choriocapillaris nonperfusion in the presence of choroidal inflammation can increase the risk of choroidal neovascular membrane development. Iris vascular changes may manifest as dilation of vessels in stroma due to inflammation or rubeosis that is usually from ischemia in retinal periphery secondary to chronic inflammation. More severe forms of scleral inflammation, such as necrotizing scleritis, are associated with vascular occlusion in the deep episcleral plexus, which can lead to necrosis of sclera layer and uveal exposure.
Gu P, Fan T, Wong SSC, Pan Z, Tai WL, Chung SK, Cheung CW. Central Endothelin-1 Confers Analgesia by Triggering Spinal Neuronal Histone Deacetylase 5 (HDAC5) Nuclear Exclusion in Peripheral Neuropathic Pain in Mice. J Pain 2021;22(4):454-471.Abstract
The rationale of spinal administration of endothelin-1(ET-1) mediated anti-nociceptive effect has not been elucidated. ET-1 is reported to promote nuclear effluxion of histone deacetylase 5 (HDAC5) in myocytes, and spinal HDAC5 is implicated in modulation of pain processing. In this study, we aimed to investigate whether central ET-1 plays an anti-nociceptive role by facilitating spinal HDAC5 nuclear shuttling under neuropathic pain. Here, we demonstrate that upregulating spinal ET-1 attenuated the nociception induced by partial sciatic nerve ligation surgery and this analgesic effect mediated by ET-1 was attenuated by intrathecal injection of endothelin A receptor selective inhibitor (BQ123) or by blocking the exportation of nuclear HDAC5 by adeno-associated viruses targeting neuronal HDAC5 (AVV-HDAC5 S259/498A Mutant). Notably, ET-1 administration increased spinal glutamate acid decarboxylases (GAD65/67) expression via initiating HDAC5 nuclear exportation and increased the acetylation of histone 3 at lysine 9 (Acetyl-H3K9) in the promotor regions of spinal Gad1 and Gad2 genes. This was reversed by blocking endothelin A receptor function or by inhibiting the spinal neuronal nuclear exportation of HDAC5. Therefore, inducing spinal GABAergic neuronal HDAC5 nuclear exportation may be a novel therapeutic approach for managing neuropathic pain. PERSPECTIVE: Neuropathic pain is intractable in a clinical setting, and epigenetic regulation is considered to contribute to this processing. Characterizing the anti-nociceptive effect of ET-1 and investigating the associated epigenetic mechanisms in animal models may lead to the development of new therapeutic strategies and targets for treating neuropathic pain.
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.
Davies E. Case Series: Novel Utilization of Rho-Kinase Inhibitor for the Treatment of Corneal Edema. Cornea 2021;40(1):116-120.Abstract
PURPOSE: To describe 3 cases of corneal clearance after the use of topical rho-kinase inhibitor, netarsudil, in the setting of endothelial cell dysfunction in comparison to one case without corneal clearance after the use of netarsudil. METHODS: Four patients presenting to a busy academic clinical corneal practice with visual complaints from corneal edema secondary to endothelial cell dysfunction were treated with topical netarsudil one drop daily in the affected eye. RESULTS: Corneal clearance was observed in 1) a case of peripheral corneal edema in the setting of iridocorneal endothelial syndrome after 4 weeks on netarsudil, 2) a case of corneal edema in the setting of early penetrating keratoplasty graft failure after 2-week use of netarsudil, and 3) a case of corneal edema in the setting of chronic penetrating keratoplasty graft failure after 4-week use of netarsudil. Corneal clearance was not observed in a case of corneal edema in the setting of pseudophakic bullous keratopathy from previous complicated intraocular lens exchange surgery with placement of an anterior chamber intraocular lens after the use of netarsudil for 12 weeks. CONCLUSIONS: Addition of topical rho-kinase inhibitor in the form of netarsudil can result in corneal clearance in a variety of certain cases of endothelial cell dysfunction, not previously documented in the literature.

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