All

Fan BJ, Bailey JC, Igo RP, Kang JH, Boumenna T, Brilliant MH, Budenz DL, Fingert JH, Gaasterland T, Gaasterland D, Hauser MA, Kraft P, Lee RK, Lichter PR, Liu Y, Moroi SE, Myers JS, Pericak-Vance MA, Realini A, Rhee DJ, Richards JE, Ritch R, Schuman JS, Scott WK, Singh K, Sit AJ, Vollrath D, Weinreb RN, Wollstein G, Zack DJ, Haines JL, Pasquale LR, Wiggs JL. Association of a Primary Open-Angle Glaucoma Genetic Risk Score With Earlier Age at Diagnosis. JAMA Ophthalmol 2019;Abstract
Importance: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations. Objective: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis. Design, Setting, and Participants: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018. Main Outcomes and Measures: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression. Results: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4). Conclusions and Relevance: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.
Douglas KA, Douglas VP, Cestari DM. Neuro-ophthalmic manifestations of the phakomatoses. Curr Opin Ophthalmol 2019;30(6):434-442.Abstract
PURPOSE OF REVIEW: The phakomatoses are a group of inherited disorders with variable clinical manifestations that are characterized by brain, cutaneous, ocular and other distinct lesions in multiple organs. Correctly recognizing the neuro-ophthalmic signs and symptoms can lead to early diagnosis and treatment. The group is composed of neurofibromatosis (type 1 and 2), tuberous sclerosis complex, von Hippel-Lindau, ataxia-telangiectasia and Sturge-Weber syndromes. However, more than 60 syndromes have been described in the medical literature. This review provides an update on the diagnosis and management of phakomatoses with a focus on their clinical neuro-ophthalmic manifestations. RECENT FINDINGS: Phakomatoses are a group of inherited syndromes with variable clinical manifestations that are characterized by brain, cutaneous, ocular and other distinct lesions in multiple organs. Recent advances in diagnostic and treatment options that have contributed to prompt recognition and management of these disorders are discussed with an emphasis on the beneficial effects on vision. SUMMARY: Phakomatoses, also known as neuro-oculo-cutaneous syndromes, are inherited disorders with characteristic lesions in multiple organs. Because of their frequent ocular involvement thorough ophthalmologic and neuro-ophthalmic evaluation is critical in this patient population in order to prevent vision loss and life-threatening complications that are often associated with these disorders.
Crotty GF, Chwalisz BK. Ocular motor manifestations of movement disorders. Curr Opin Ophthalmol 2019;30(6):443-448.Abstract
PURPOSE OF REVIEW: Impaired eye movements are frequently seen in ophthalmic and neurologic clinical practice, especially in individuals with movement disorders. Identification of the abnormal movement can aid initial diagnosis and improve understanding of the underlying disease pathophysiology. The present article reviews the ocular motor manifestations and recent research on them in common movement disorders. RECENT FINDINGS: Ocular motor manifestations and their pathophysiologic correlates are being defined. In particular, study of eye movements can help clarify the changing clinicopathologic spectrum of atypical parkinsonian disorders. The pathophysiology and natural history of blepharospasm are being elucidated. Recent research focuses on high-resolution imaging and other technological advances to improve the sensitivity of the ocular motility exam. Eye movements are being studied as biomarkers for diagnosis and progression in clinical care and trials. SUMMARY: The current review summarizes ocular motor manifestations in common movement disorders, and presents recent research investigating their cause and treatment.
Rico-Sánchez L, Garzón I, González-Andrades M, Ruíz-García A, Punzano M, Lizana-Moreno A, Muñoz-Ávila JI, Sánchez-Quevedo MDC, Martínez-Atienza J, Lopez-Navas L, Sanchez-Pernaute R, Oruezabal RI, Medialdea S, Gonzalez-Gallardo MDC, Carmona G, Sanbonmatsu-Gámez S, Perez M, Jimenez P, Cuende N, Campos A, Alaminos M. Successful development and clinical translation of a novel anterior lamellar artificial cornea. J Tissue Eng Regen Med 2019;13(12):2142-2154.Abstract
Blindness due to corneal diseases is a common pathology affecting up to 23 million individuals worldwide. The tissue-engineered anterior human cornea, which is currently being tested in a Phase I/II clinical trial to treat severe corneal trophic ulcers with preliminary good feasibility and safety results. This bioartificial cornea is based on a nanostructured fibrin-agarose biomaterial containing human allogeneic stromal keratocytes and cornea epithelial cells, mimicking the human native anterior cornea in terms of optical, mechanical, and biological behavior. This product is manufactured as a clinical-grade tissue engineering product, fulfilling European requirements and regulations. The clinical translation process included several phases: an initial in vitro and in vivo preclinical research plan, including preclinical advice from the Spanish Medicines Agency followed by additional preclinical development, the adaptation of the biofabrication protocols to a good manufacturing practice manufacturing process, including all quality controls required, and the design of an advanced therapy clinical trial. The experimental development and successful translation of advanced therapy medicinal products for clinical application has to overcome many obstacles, especially when undertaken by academia or SMEs. We expect that our experience and research strategy may help future researchers to efficiently transfer their preclinical results into the clinical settings.
Sharif R, Khaled ML, McKay TB, Liu Y, Karamichos D. Transcriptional profiling of corneal stromal cells derived from patients with keratoconus. Sci Rep 2019;9(1):12567.Abstract
Keratoconus (KC) is a multi-factorial corneal ectasia with unknown etiology affecting approximately 1:2000 people worldwide. Dysregulated gene expression, using RNA-Seq technology, have been reported in KC corneal tissue. However, the differential expression of genes, in KC corneal stromal cells have been widely ignored. We utilized mRNA-Seq to analyze gene expression in primary human corneal stromal cells derived from five non-Keratoconus healthy (HCF) and four Keratoconus (HKC) donors. Selected genes were further validated using real time PCR (RT-PCR). We have identified 423 differentially expressed genes with 187 down- and 236 up-regulated in KC-affected corneal stromal cells. Gene ontology analysis using WebGestalt indicates the enrichment of genes involved in cell migration, extracellular matrix, adherens junction, and MAPK signaling. Our protein-protein interaction network analysis identified several network seeds, such as EGFR, NEDD4, SNTA1, LGALS3BP, HSPB1, SDC2, MME, and HIF1A. Our work provides an otherwise unknown information on the transcriptional changes in HKCs, and reveals critical mechanisms of the cellular compartment. It also highlights the importance of human-based in vitro studies on a disease that currently lacks strong biomarkers and animal models.
Yong JJ, Hatch KM. Corneal Cross-Linking: An Effective Treatment Option for Pellucid Marginal Degeneration. Semin Ophthalmol 2019;:1-6.Abstract
: This is the first review article examining literature specific to the use of corneal cross-linking (CXL) to treat pellucid marginal degeneration (PMD). : CXL appears to be an effective treatment that may halt the progression of PMD to stabilize vision. This could postpone or eliminate the need for corneal transplantation in the management of these patients. Furthermore, combining CXL with keratorefractive surgery in a single procedure has been shown to be safe and successful in improving vision in PMD patients. : The data reported in literature is limited at this time, consisting mostly of retrospective studies with short term follow up. Further research is needed to evaluate refractive effects of combined CXL and excimer laser procedures.
Lundgren P, Hellgren G, Pivodic A, Sävman K, Smith LEH, Hellström A. Erythropoietin serum levels, versus anaemia as risk factors for severe retinopathy of prematurity. Pediatr Res 2019;86(2):276-282.Abstract
BACKGROUND: Preterm infants with anaemia are treated with recombinant human erythropoietin (rhEPO). It is debated whether rhEPO treatment is a risk factor for retinopathy of prematurity (ROP). We evaluated longitudinal EPO and haemoglobin levels, blood transfusions and neonatal morbidities as risk factors for severe ROP. METHOD: This prospective study included 78 Swedish infants, born <28 weeks gestational age (GA), screened for ROP. We tested serum EPO levels on postnatal days 1, 7, 14 and 28 and at postmenstrual ages 32, 36 and 40 weeks. Haemoglobin levels and blood transfusions were recorded during postnatal weeks 1-4. Anaemia was defined as haemoglobin ≤110 g/L. RESULTS: During postnatal week 1, infants with severe ROP requiring treatment (28%) more frequently developed anaemia (42.9% versus 8.0%, P = 0.003) and had higher mean EPO levels (postnatal day 7: 14.2 versus 10.8 mIU/mL, P = 0.003) compared to infants with no or less severe ROP not requiring treatment. In multivariable analyses, GA and anaemia during week 1 remained significant risk factors, but elevated EPO level postnatal day 7 was no longer significant. CONCLUSIONS: Among infants born <28 weeks GA, anaemia during week 1 was a significant risk factor for severe ROP requiring treatment but not elevated EPO levels.
Liu Y, Jassim F, Braaf B, Khoueir Z, Poon LY-C, Ben-David GS, Papadogeorgou G, Tsikata E, Simavli H, Que C, Lee R, Shieh E, Vakoc BJ, Bouma BE, de Boer JF, Chen TC. Diagnostic Capability of 3D Peripapillary Retinal Volume for Glaucoma Using Optical Coherence Tomography Customized Software. J Glaucoma 2019;28(8):708-717.Abstract
PRéCIS:: The diagnostic capability of peripapillary retinal volume is similar to peripapillary retinal nerve fiber layer thickness for diagnosing glaucoma, but with fewer artifacts. PURPOSE: To compare the diagnostic capability of 3-dimensional peripapillary retinal volume (RV) versus 2-dimensional peripapillary retinal nerve fiber layer (RNFL) thickness for open-angle glaucoma. PATIENTS AND METHODS: A retrospective cross-sectional analysis was conducted. A total of 180 subjects (113 open-angle glaucoma, 67 normal participants) had spectral domain optical coherence tomography volume scans and RNFL thickness measurements. Peripapillary RV values were calculated using a custom-designed program with 4 circumpapillary annuli (CA): CA1 had circle diameters of 2.5 and 3.5 mm; CA2, 3 and 4 mm; CA3, 3.5 and 4.5 mm; and CA4, 4 and 5 mm. Area under the receiver operating characteristic curves were calculated for global, quadrant, and octant regions for RV (CA1 to CA4) and RNFL thickness. Pair-wise comparisons were conducted. Artifacts rates were determined. RESULTS: Mean age was 62.7±15.4 years, and 47.8% (86/180) were male. Among RV measurements, best diagnostic performances were for the smallest 2 annuli for inferior RV (CA1: 0.964, CA2: 0.955). Of the 4 annuli, CA1 had the highest diagnostic performance. Of specific regions, the inferior RV quadrant had the highest performance across CA1 to CA4. Peripapillary RV had similar diagnostic capability compared with RNFL thickness (P>0.05). The artifact rate per B-scan for RV was 6.0%, which was significantly lower compared with 2-dimensional RNFL thickness in the same patient population (32.2%, P<0.0001). CONCLUSIONS: The diagnostic capability of RV is similar to RNFL thickness for perimetric open-angle glaucoma, but RV had fewer artifacts compared with RNFL thickness.
Costela FM, Woods RL. A free database of eye movements watching "Hollywood" videoclips. Data Brief 2019;25:103991.Abstract
The provided database of tracked eye movements was collected using an infra-red, video-camera Eyelink 1000 system, from 95 participants as they viewed 'Hollywood' video clips. There are 206 clips of 30-s and eleven clips of 30-min for a total viewing time of about 60 hours. The database also provides the raw 30-s video clip files, a short preview of the 30-min clips, and subjective ratings of the content of the videos for each in categories: (1) genre; (2) importance of human faces; (3) importance of human figures; (4) importance of man-made objects; (5) importance of nature; (6) auditory information; (7) lighting; and (8) environment type. Precise timing of the scene cuts within the clips and the democratic gaze scanpath position (center of interest) per frame are provided. At this time, this eye-movement dataset has the widest age range (22-85 years) and is the third largest (in recorded video viewing time) of those that have been made available to the research community. The data-acquisition procedures are described, along with participant demographics, summaries of some common eye-movement statistics, and highlights of research topics in which the database was used. The dataset is freely available in the Open Science Framework repository (link in the manuscript) and can be used without restriction for educational and research purposes, providing that this paper is cited in any published work.
Zhu Z, Ellwein LB, Wang SK, Zhao J, He M. Meeting the need for corrective spectacles in visually impaired Chinese school children: the potential of ready-made spectacles. Br J Ophthalmol 2019;103(8):1106-1111.Abstract
PURPOSE: To assess the potential of ready-made (spherical) spectacles (RMS) in meeting the need for refractive correction in visually impaired children in China. METHODS: Eligible children aged 5-17 years were identified from the three study sites in China. Distance visual acuity was measured with a retroilluminated logarithm of the minimum angle of resolution chart with tumbling E optotypes. Cycloplegic autorefraction was performed on all children using a handheld autorefractor. If uncorrected visual acuity (UCVA) was ≤20/40 in either eye, best corrected visual acuity was measured with subjective refractive error. RESULTS : A total of 13 702 children were enumerated from the three studies, with 12 334 (90.0%) having both reliable visual acuity measurements and successful cycloplegia. Among the 12 334 study children, the prevalence of UCVA ≤20/40 in the better seeing eye was 16.4% (95% CI 15.0% to 17.8%), with 91.1% (1843) of these improving by ≥3 lines of visual acuity with refractive correction. Prevalence was 12.7% (95% CI 11.5% to 13.9%) for UCVA 20/50 with 97.4% (1521) improving by ≥3 lines, and 9.38% (95% CI 8.39% to 19.4%) for UCVA ≤20/63 with 98.4% (1138) improving by ≥3 lines. Depending on the severity of visual impairment, 62.8%-64.0% of children could be accommodated with RMS if not correcting for astigmatism of ≤0.75 dioptres and anisometropia of ≤0.50 spherical equivalent dioptres. Approximately 87% of children could be accommodated with RMS if astigmatism and anisometropia limits were increased to ≤1.25 and ≤1.50 dioptres, respectively. CONCLUSIONS: RMS could substantially alleviate visual morbidity in two-thirds or more of visually impaired schoolchildren in China. This cost-effective approach to refractive correction might also be useful in low/middle-income countries with poor access to optometric services.
Chekuri A, Zientara-Rytter K, Soto-Hermida A, Borooah S, Voronchikhina M, Biswas P, Kumar V, Goodsell D, Hayward C, Shaw P, Stanton C, Garland D, Subramani S, Ayyagari R. Late-onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1. Aging Cell 2019;18(6):e13011.Abstract
Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular degeneration characterized by the formation of sub-retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L-ORD results from mutations in the C1q-tumor necrosis factor-5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L-ORD pathology, we used a human cDNA library yeast two-hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM-Ch) from wild-type (Wt), heterozygous S163R Ctrp5 mutation knock-in (Ctrp5 ), and homozygous knock-in (Ctrp5 ) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C-terminal PDZ-binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R-CTRP5 protein also binds to HTRA1 but is resistant to HTRA1-mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM-Ch of Ctrp5 and Ctrp5 mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L-ORD pathology.

Pages