Vasilikos I, Haas J, Teixeira GQ, Nothelfer J, Neidlinger-Wilke C, Wilke H-J, Seitz A, Vavvas DG, Zentner J, Beck J, Hubbe U, Mizaikoff B. Infrared attenuated total reflection spectroscopic surface analysis of bovine-tail intervertebral discs after UV-light-activated riboflavin-induced collagen crosslinking. J Biophotonics 2020;:e202000110.Abstract
The tensile strength of the intervertebral disc (IVD) is mainly maintained by collagen cross-links. Loss of collagen cross-linking combined with other age-related degenerative processes contributes to tissue weakening, biomechanical failure, disc herniation and pain. Exogenous collagen cross-linking has been identified as an effective therapeutic approach for restoring IVD tensile strength. The current state-of-the-art method to assess the extent of collagen cross-linking in tissues requires destructive procedures and high-performance liquid chromatography (HPLC). In this study, we investigated the utility of infrared attenuated total reflection (IR-ATR) spectroscopy as a non-destructive analytical strategy to rapidly evaluate the extent of UV-light-activated riboflavin (B2)-induced collagen crosslinking (UVA-CXL) in bovine IVD samples. Thirty five fresh bovine-tail IVD samples were equally divided into five treatment groups: (i) untreated, (ii) cell culture medium DMEM only, (iii) B2 only, (iv) UV-light only, and (v) UV-light-B2. A total of 674 measurements have been acquired, and were analyzed via partial least squares discriminant analysis. This classification scheme unambiguously identified individual classes with a sensitivity >91% and specificity >92%. The obtained results demonstrate that IR-ATR spectroscopy reliably differentiates between different treatment categories, and promises an excellent tool for potential in vivo, non-destructive, and real-time assessment of exogenous IVD crosslinking. This article is protected by copyright. All rights reserved.
Yan W, Peng Y-R, van Zyl T, Regev A, Shekhar K, Juric D, Sanes JR. Cell Atlas of The Human Fovea and Peripheral Retina. Sci Rep 2020;10(1):9802.Abstract
Most irreversible blindness results from retinal disease. To advance our understanding of the etiology of blinding diseases, we used single-cell RNA-sequencing (scRNA-seq) to analyze the transcriptomes of ~85,000 cells from the fovea and peripheral retina of seven adult human donors. Utilizing computational methods, we identified 58 cell types within 6 classes: photoreceptor, horizontal, bipolar, amacrine, retinal ganglion and non-neuronal cells. Nearly all types are shared between the two retinal regions, but there are notable differences in gene expression and proportions between foveal and peripheral cohorts of shared types. We then used the human retinal atlas to map expression of 636 genes implicated as causes of or risk factors for blinding diseases. Many are expressed in striking cell class-, type-, or region-specific patterns. Finally, we compared gene expression signatures of cell types between human and the cynomolgus macaque monkey, Macaca fascicularis. We show that over 90% of human types correspond transcriptomically to those previously identified in macaque, and that expression of disease-related genes is largely conserved between the two species. These results validate the use of the macaque for modeling blinding disease, and provide a foundation for investigating molecular mechanisms underlying visual processing.
Chwalisz BK, Douglas VP, Douglas KA, Martinez-Lage M, Kelly HR, Cestari DM. Episodic Visual Distortions and Stroke-Like Symptoms in a 56-Year-Old Man With Intravascular Lymphoma. J Neuroophthalmol 2020;40(2):265-270.Abstract
A healthy 56-year-old man presented with vision changes and left upper extremity motor and sensory changes. MRI of the brain without contrast was significant for multifocal areas of restricted diffusion in multiple vascular territories. Neuro-Ophthalmic evaluation revealed an inferonasal visual field defect in the left eye, thickened choroid on optical coherence tomography, and bilateral delayed arteriovenous and choroidal filling on fluorescein angiogram. Repeat MRI demonstrated interval enlargement of many of the same foci of abnormal diffusion-weighted imaging signal. Computed tomography of the abdomen and pelvis revealed 3 distinct lobulated retroperitoneal masses that were biopsied and found to be consistent with diffuse large B-cell lymphoma. Brain biopsy specimens showed intravascular lymphocytes, confirming a diagnosis of intravascular lymphoma (IVL). In this diagnostically challenging case, a link was established between the presence of multiple strokes (some of which showed slow evolution over time) and retinochoroidal hypoperfusion, which provided a critical clue to the ultimate diagnosis of IVL.
Li LH, Lee JC-Y, Leung HH, Lam WC, Fu Z, Lo ACY. Lutein Supplementation for Eye Diseases. Nutrients 2020;12(6)Abstract
Lutein is one of the few xanthophyll carotenoids that is found in high concentration in the macula of human retina. As synthesis of lutein within the human body is impossible, lutein can only be obtained from diet. It is a natural substance abundant in egg yolk and dark green leafy vegetables. Many basic and clinical studies have reported lutein's anti-oxidative and anti-inflammatory properties in the eye, suggesting its beneficial effects on protection and alleviation of ocular diseases such as age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, myopia, and cataract. Most importantly, lutein is categorized as Generally Regarded as Safe (GRAS), posing minimal side-effects upon long term consumption. In this review, we will discuss the chemical structure and properties of lutein as well as its application and safety as a nutritional supplement. Finally, the effects of lutein consumption on the aforementioned eye diseases will be reviewed.
Huckfeldt RM, Grigorian F, Place E, Comander JI, Vavvas D, Young LH, Yang P, Shurygina M, Pierce EA, Pennesi ME. Biallelic -associated retinal dystrophies: Expanding the mutational and clinical spectrum. Mol Vis 2020;26:423-433.Abstract
Purpose: To evaluate the phenotypic spectrum of autosomal recessive associated retinal dystrophies and assess genotypic associations. Methods: A retrospective multicenter study was performed of patients with biallelic -associated retinal dystrophies. Data including presenting symptoms and age, visual acuity, kinetic perimetry, full field electroretinogram, fundus examination, multimodal retinal imaging, and genotype were evaluated. Results: Nineteen eligible patients from 17 families were identified and ranged in age from 10 to 56 years at the most recent evaluation. Ten of the 21 unique variants identified were novel, and mutations within exon 2 accounted for nearly half of alleles across the cohort. Patients had clinical diagnoses of retinitis pigmentosa (13), cone-rod dystrophy (3), Leber congenital amaurosis (1), early-onset severe retinal dystrophy (1), and macular dystrophy (1). Macular atrophy was a common feature across the cohort. Symptom onset occurred between 4 and 30 years of age (mean 14.9 years, median 13 years), but there were clusters of onset age that correlated with the effects of mutations at a protein level. Patients with later-onset disease, including retinitis pigmentosa, had at least one missense variant in an exon 2 DCX domain. Conclusions: Biallelic mutations cause a broad spectrum of retinal disease. Exon 2 missense mutations are a significant contributor to disease and can be associated with a considerably later onset of retinitis pigmentosa than that typically associated with biallelic mutations.
Yang Y, Huang X, Ma G, Cui J, Matsubara JA, Kazlauskas A, Zhao J, Wang J, Lei H. PDGFRβ plays an essential role in patient vitreous-stimulated contraction of retinal pigment epithelial cells from epiretinal membranes. Exp Eye Res 2020;197:108116.Abstract
Platelet-derived growth factor (PDGF) is associated with clinical proliferative vitreoretinopathy (PVR), which is characterized by formation of sub- or epi-retinal membranes that consist of cells including retinal pigment epithelial (RPE) cells and extracellular matrix. RPE cells play an important role in PVR pathogenesis. Previous findings indicated that PDGF receptor (PDGFR)α was essential in experimental PVR induced by fibroblasts. In RPE cells derived from epiretinal membranes from patients with PVR (RPEMs), Akt was activated by PDGF-B but not PDGF-A, which suggested that PDGFRβ was the predominant PDGFR isoform expressed in RPEMs. Indeed, CRISPR/Cas9-mediated depletion of PDGFRβ in RPEMs attenuated patient vitreous-induced Akt activation and cellular responses intrinsic to PVR including cell proliferation, migration, and contraction. We conclude that PDGFRβ appears to be the PVR relevant PDGFR isoform in RPEMs.
Ung L, Wang Y, Vangel M, Davies EC, Gardiner M, Bispo PJM, Gilmore MS, Chodosh J. Validation of a Comprehensive Clinical Algorithm for the Assessment and Treatment of Microbial Keratitis. Am J Ophthalmol 2020;214:97-109.Abstract
PURPOSE: To validate a comprehensive clinical algorithm for the assessment and treatment of microbial keratitis (MK). DESIGN: Retrospective cohort study. METHODS: The "1, 2, 3 Rule" for the initial management of MK was conceived by Vital and associates in 2007 to inform the decision as to when to perform corneal cultures. The rule is invoked when any 1 of 3 clinical parameters is met: ≥1+ anterior chamber cells, ≥2 mm infiltrate, or infiltrate ≤3 mm distance from the corneal center. When the rule is met, we added the mandatory use of fortified topical antibiotics after cultures are obtained. We compared outcomes of cases presenting to Massachusetts Eye and Ear 2 years before (Group I, n = 665) and after (Group II, n = 767) algorithm implementation. The primary composite outcome was a vision-threatening complication, such as corneal perforation. RESULTS: At a median follow-up of 67.0 and 60.0 days, respectively, 172 patients experienced a vision-threatening complication (Group I, 12.9% vs Group II, 11.2%, P = .51). While the algorithm codified conventional management practice at either end of disease severity, the effect of algorithm-augmented care was best appreciated in patients with lesions satisfying only 1 criterion. In this group, there was an increase in the proportion of patients undergoing culture at presentation (54.6% vs 67.7%, P = .006), fortified antibiotic prescription (29.7% vs 53.9%, P < .001), and reduction in vision-threatening complications (9.7% vs 1.8%, P = .001). The proportion of patients who were not cultured at presentation but later required culturing decreased (13.4% vs 5.1%, P = .001), as did patients who did not meet any criteria but were nonetheless cultured (23.9% vs 8.5%, P < .001). Multiple logistic regression showed that all algorithm parameters were independently associated with outcome: ≥1+ anterior chamber cells (odds ratio [OR] 1.66, 95% confidence interval 1.09-2.52); ≥2 mm infiltrate (OR 4.74, 2.68-8.40); and ≤3 mm from corneal center (OR 2.82, 1.85-4.31), confirmed with comparison to a bootstrapped sample (n = 10,000). CONCLUSIONS: The implementation of this algorithm reduced vision-threatening complications for patients with lesions satisfying only 1 criterion, arguably the most difficult patients in whom to judge disease severity. Implementation also led to a decrease in patients receiving unnecessary care.
Soh YQ, Kocaba V, Weiss JS, Jurkunas UV, Kinoshita S, Aldave AJ, Mehta JS. Corneal dystrophies. Nat Rev Dis Primers 2020;6(1):46.Abstract
Corneal dystrophies are broadly defined as inherited disorders that affect any layer of the cornea and are usually progressive, bilateral conditions that do not have systemic effects. The 2015 International Classification of Corneal Dystrophies classifies corneal dystrophies into four classes: epithelial and subepithelial dystrophies, epithelial-stromal TGFBI dystrophies, stromal dystrophies and endothelial dystrophies. Whereas some corneal dystrophies may result in few or mild symptoms and morbidity throughout a patient's lifetime, others may progress and eventually result in substantial visual and ocular disturbances that require medical or surgical intervention. Corneal transplantation, either with full-thickness or partial-thickness donor tissue, may be indicated for patients with advanced corneal dystrophies. Although corneal transplantation techniques have improved considerably over the past two decades, these surgeries are still associated with postoperative risks of disease recurrence, graft failure and other complications that may result in blindness. In addition, a global shortage of cadaveric corneal graft tissue critically limits accessibility to corneal transplantation in some parts of the world. Ongoing advances in gene therapy, regenerative therapy and cell augmentation therapy may eventually result in the development of alternative, novel treatments for corneal dystrophies, which may substantially improve the quality of life of patients with these disorders.
Collett G, Elhusseiny AM, Scelfo C, Whitman MC, VanderVeen DK. Ocular injury via epinephrine auto-injector. J AAPOS 2020;Abstract
Intraocular injury by epinephrine auto-injector has been rarely reported. Toxic risk to the intraocular structures is suspected, but the evidence is inconclusive. We present the case of a 2-year-old girl who sustained an injury to her right eye by inadvertent epinephrine injection. Cataract surgery was performed to treat an increasingly opaque lens, and an intraocular lens was implanted. The visual outcome was good, with no retinal damage.
Elhusseiny AM, Jamerson EC, Menshawey R, Tam EK, El Sayed YM. Collector Channels: Role and Evaluation in Schlemm's Canal Surgery. Curr Eye Res 2020;45(10):1181-1187.Abstract
OBJECTIVES: 1) To elucidate the role of collector channels in the aqueous humor outflow pathway 2) To suggest anatomic and functional methods of imaging collector channels in-vitro and in-vivo and 3) To discuss the role of such imaging modalities in the surgical management of glaucoma. METHODS: A thorough literature search was conducted on databases for studies published in English regarding the available methods to determine the role of collecting channels in normal and glaucomatous patients and to assess their patency. RESULTS: Intraocular pressure (IOP) exists as a balance between aqueous humor production and aqueous humor outflow. Collector channels are an essential anatomical constituent of the distal portion of the conventional aqueous humor outflow pathway. There are different surgical options for glaucoma management and with the recent advances in Schlemm's canal-based surgeries, collector channel's patency became a key factor in determining the optimum management for the glaucomatous eye. The advent of anatomic imaging methods has improved the ability to visualize collector channel morphology in-vitro, including swept-source optical coherence tomography (SS-OCT), spectral domain optical coherence tomography (SD-OCT), micro-computed tomography (micro CT), new immunohistochemistry techniques and scanning electron microscopy. The recent advent of real-time assessment of collector channel patency (including evaluation of episcleral venous outflow, observation of episcleral venous fluid wave, and tracer studies utilizing fluorescein, indocyanine green, and trypan blue) has been validated by the aforementioned anatomic imaging modalities. CONCLUSIONS: New modalities of in-vitro and in-vivo studies of collector channels provide promise to aid in the assessment of collector channel patency and individualization of surgical management for glaucoma patients.
Cogné B, Latypova X, Senaratne LDS, Martin L, Koboldt DC, Kellaris G, Fievet L, Le Meur G, Caldari D, Debray D, Nizon M, Frengen E, Bowne SJ, Consortium L99, Cadena EL, Daiger SP, Bujakowska KM, Pierce EA, Gorin M, Katsanis N, Bézieau S, Petersen-Jones SM, Occelli LM, Lyons LA, Legeai-Mallet L, Sullivan LS, Davis EE, Isidor B. Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy. Am J Hum Genet 2020;106(6):893-904.Abstract
Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor.
Agarwal A, Agrawal R, Raje D, Testi I, Mahajan S, Gunasekeran DV, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. Twenty-four Month Outcomes in the Collaborative Ocular Tuberculosis Study (COTS)-1: Defining the "Cure" in Ocular Tuberculosis. Ocul Immunol Inflamm 2020;:1-9.Abstract
PURPOSE: To report the clinical findings, anatomical features, and treatment outcomes in subjects with ocular tuberculosis (OTB) at 24 months in the Collaborative Ocular Tuberculosis Study (COTS)-1. METHODS: Of the 945 subjects included in COTS-1, those who completed a 24-month follow-up after completion of treatment were included. The main outcome measure was a number of patients with treatment failure (TF). RESULTS: 228 subjects (120 males; mean age of 42.82 ± 14.73 years) were included. Most common phenotype of uveitis was posterior ( = 81; 35.53%), and panuveitis ( = 76; 33.33%). Fifty-two patients (22.81%) had TF. On univariable analysis, odds of high TF was observed with bilaterality (OR: 3.46, = .003), vitreous haze (OR: 2.14, = .018), and use of immunosuppressive therapies (OR: 5.45, = .003). However, only bilaterality was significant in the multiple regression model (OR: 2.84; = .02). CONCLUSIONS: Majority of subjects (>75%) achieved cure in the COTS-1 at 24-month follow-up. The concept of "cure" may be a valuable clinical endpoint in trials for OTB.
Valdes LM, Sobrin L. Uveitis Therapy: The Corticosteroid Options. Drugs 2020;80(8):765-773.Abstract
Uveitis is characterized by intraocular inflammation involving the uveal tract; its etiologies generally fall into two broad categories: autoimmune/inflammatory or infectious. Corticosteroids  are a powerful and important class of medications ubiquitous in the treatment of uveitis. They may be given systemically or locally, in the form of topical drops, periocular injection, intravitreal suspension, or intravitreal implant. This review describes each of the currently available corticosteroid treatment options for uveitis, including favorable and unfavorable characteristics of each as well as applicable clinical trials. The main advantage of corticosteroids as a whole is their ability to quickly and effectively control inflammation early on in the course of uveitis. However, they can have serious side effects, whether localized to the eye (such as cataract and elevated intraocular pressure) or systemic (such as osteonecrosis and adrenal insufficiency) and in the majority of cases of uveitis are not an appropriate option for long-term therapy.