Publications by authors named "Kohji Nishida"

475 Publications

CTLA-2 Alpha Is a Potent Inhibitor of Angiogenesis in Murine Ocular Tissue.

Antioxidants (Basel) 2021 Mar 15;10(3). Epub 2021 Mar 15.

Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka 565-0871, Japan.

Cytotoxic T lymphocyte antigen-2 (CTLA-2) alpha has been reported to suppress the activities of cathepsin L (Cath L), which is deeply involved in angiogenesis. Therefore, we assessed whether CTLA-2 alpha plays a role in angiogenesis in ocular tissue. To establish models of corneal inflammation and experimental choroidal neovascularization (CNV), male C57BL/6J mice ( = 5) underwent corneal suture placement or laser-induced CNV, respectively. Mice were then injected with recombinant CTLA-2 alpha (1 µg) into the peritoneal cavity at day 0 and every 2 days after operation. In vitro experiments were performed to assess the inflammatory response by measuring TNF-alpha secretion in peritoneal cavity exudate cells (PECs) or the proliferation of mouse vascular endothelial cells (mVECs). CTLA-2 alpha treatment dramatically suppressed corneal angiogenesis, as well as laser-induced CNV. Moreover, CTLA-2 alpha inhibited the proliferation of mVECs in vitro, while CTLA-2 alpha abolishment was able to rescue proliferation. However, CTLA-2 alpha could not suppress cytokine secretion from inflammatory cells such as PECs. In summary, CTLA-2 alpha was able to suppress angiogenesis by suppressing endothelial cell proliferation. Further studies are needed to investigate its usefulness as a new antiangiogenic treatment for a variety of conditions, including age-related macular degeneration.
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http://dx.doi.org/10.3390/antiox10030456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000157PMC
March 2021

Rubicon regulates A2E-induced autophagy impairment in the retinal pigment epithelium implicated in the pathology of age-related macular degeneration.

Biochem Biophys Res Commun 2021 Apr 16;551:148-154. Epub 2021 Mar 16.

Department of Ocular Immunology and Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan. Electronic address:

Waste product deposition and light stress in the retinal pigment epithelium (RPE) are crucial factors in the pathogenesis of various retinal degenerative diseases, including age-related macular degeneration (AMD), a leading cause of vision loss in elderly individuals worldwide. Given that autophagy in the RPE suppresses waste accumulation, determining the molecular mechanism by which autophagy is compromised in degeneration is necessary. Using polarized human RPE sheets, we found that bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E), a major toxic fluorophore of lipofuscin, causes significant impairment of autophagy and the simultaneous upregulation of Rubicon, a negative regulator of autophagy. Importantly, this impairment was reversed in Rubicon-specific siRNA-treated RPE sheets. In a retinal functional analysis using electroretinograms (ERGs), mice with the RPE-specific deletion of Rubicon showed no significant differences from control cre-expressing mice but presented partially but significantly enhanced amplitudes compared with Atg7 knockout mice. We also found that an inflammatory reaction in the retina in response to chronic blue light irradiation was alleviated in mice with the RPE-specific deletion of Rubicon. In summary, we propose that upregulating basal autophagy by targeting Rubicon is beneficial for protecting the RPE from functional damage with ageing and the inflammatory reaction caused by light-induced cellular stress.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.148DOI Listing
April 2021

Flow pattern and perforating vessels in three different phases of myopic choroidal neovascularization seen by swept-source optical coherence tomography angiography.

Graefes Arch Clin Exp Ophthalmol 2021 Mar 9. Epub 2021 Mar 9.

Department of Ophthalmology, Osaka University Medical School, 2-2 Yamadaoka, 565-0871, Suita, Osaka, Japan.

Purpose: To compare the choroidal neovascularization (CNV) flow patterns and the relationship between perforating vessels (PVs) and CNV in the three different stages of networks in myopic CNV (mCNV) using swept-source optical coherence tomography angiography (SS-OCTA).

Methods: This retrospective study included 28 eyes with mCNV that was divided into three phases (active, scar, and atrophic) and observed by SS-OCTA. SS-OCTA findings, with special focus on the relationship between the PVs and CNV, were compared among the three phases.

Results: Overall, the CNV signal was detected in 31 of the 34 areas of CNV (91%); in the active, scar, and atrophic phases, respectively, CNV signals were detected in eight of eight areas of CNV (100%), 10 of 11 areas of CNV (91%), and 13 of 15 areas of CNV (86%). Two signal patterns were observed in each phase, i.e., dense and loop; in the atrophic phase, seven eyes were unclassifiable. The ratio between the dense and loop patterns did not differ significantly among the phases. In 30 of 34 areas of CNV for which clear images were obtained, the PVs and CNV were connected directly or indirectly in 19 area of CNV, and in five areas of CNV, trunk-like vessels were connected to the PVs within the CNV. The numbers of foveal or parafoveal CNVs accompanied by PVs were significantly (p=0.0048) greater than those of the extrafoveal CNV.

Conclusions: OCTA provides detailed observation of mCNV and the relationship between CNV and PVs. Although the CNV signal pattern does not differ depending on the degree of atrophy, there are cases in which only the trunk-like vessels connect to the PVs within the CNV in the atrophic phase without CNV flow signal.
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http://dx.doi.org/10.1007/s00417-021-05134-yDOI Listing
March 2021

Simultaneous bilateral choroidal neovascularization associated with infective endocarditis: A case report.

Am J Ophthalmol Case Rep 2021 Jun 18;22:101037. Epub 2021 Feb 18.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan.

Purpose: To report a case of simultaneous bilateral choroidal neovascularization (CNV) associated with infective endocarditis.

Observations: A 35-year-old man presented with acute visual impairment 14 days after cardiac surgery for acute infective endocarditis caused by methicillin-susceptible . Fundus photography, fluorescein angiography, optical coherence tomography (OCT), and OCT angiography confirmed the presence of a single CNV area in the right eye and three CNV areas in the left eye. Treatment with intravitreal aflibercept resulted in an improvement in the visual acuity in both eyes.

Conclusion And Importance: The findings from this case highlight the importance of monitoring visual symptoms in patients with infective endocarditis. CNV can result in vision loss when it involves the macula; therefore, prompt diagnosis is important. Intravitreal anti-vascular endothelial growth factor injection can be an effective treatment in such cases. To the best of our knowledge, this is the first report of simultaneous bilateral CNV associated with infective endocarditis.
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http://dx.doi.org/10.1016/j.ajoc.2021.101037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910410PMC
June 2021

Efficacy and safety of 0.01% atropine for prevention of childhood myopia in a 2-year randomized placebo-controlled study.

Jpn J Ophthalmol 2021 Feb 14. Epub 2021 Feb 14.

Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, Kyoto, 602-0841, Japan.

Purpose: Atropine eye drops prevent the progression of myopia, but their use has not been tested in the Japanese schoolchildren population. Here, we evaluate the efficacy and safety of 0.01% atropine eye drops for myopia control in Japanese children.

Study Design: Multicenter (7 university hospitals), randomized, double-masked, placebo-controlled trial.

Methods: Participants were 171 Japanese schoolchildren aged 6 to 12 years, with progressive myopia, spherical equivalence (SE) of -1.00 to -6.00 diopters (D), and astigmatism of ≤1.5 D. They were randomized to receive either 0.01% atropine (n=85) or placebo (n=86) eye drops once nightly OU for 24 months. Primary and secondary efficacy endpoints were changes in SE and axial length (AL), respectively, from baseline to month 24.

Results: Data from 168 subjects were analyzed. At month 24, compliance was similar in both groups (atropine: 83.3%; placebo: 85.7%). The least squares mean change in SE and AL from baseline were, respectively, -1.26 D (95% confidence interval [CI]: -1.35, -1.17) and 0.63 mm (0.59, 0.67) for atropine and -1.48 D (- 1.57, -1.39) and 0.77 mm (0.73, 0.81) for placebo. Inter-group differences were 0.22 D (95% CI: 0.09, 0.35; P < 0.001) for SE and - 0.14 mm (-0.20, -0.08; P < 0.001) for AL. Three patients experienced mild allergic conjunctivitis side effects, with no inter-group difference in incidence (atropine: 2.4%; 2/84 patients; placebo: 1.4%; 1/84 patients).

Conclusion: With good compliance, 0.01% atropine is effective and safe for preventing the progression of childhood myopia.
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http://dx.doi.org/10.1007/s10384-021-00822-yDOI Listing
February 2021

Efficacy and safety of 5-fluorouracil in infrared monitor guided bleb revision.

BMC Ophthalmol 2021 Feb 8;21(1):75. Epub 2021 Feb 8.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Room E7, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Purpose: Infrared monitor-guided bleb revision (IRGBR), an alternative needling system, visualizes anterior-segment tissues around the bleb not visible during needle revision after trabeculectomy. This study determined the safety and efficiency of 5-fluorouracil (5-FU) as an adjunctive anti-metabolite in IRGBR.

Methods: We retrospectively analyzed 43 consecutive eyes (40 patients; 14 eyes, primary open-angle; 29 eyes, secondary glaucoma) treated with IRGBR for failing filtering blebs. The patients were divided into two groups. The first one had IRGBR without adjunctive 5-FU subconjunctival injection, and the second one had IRGBR with 5-FU. We performed Kaplan-Meier survival analysis using log-rank tests after 2 years of follow-up and Cox proportional hazards regression model to analyze the dependence of the survival time on predictor variables. Two failure criteria were defined as the need for additional surgery for intraocular pressure (IOP) reduction and the IOP at two consecutive follow-up visits based on definition 1, IOP ≧22 mmHg and definition 2, IOP ≧17 mmHg.

Results: Thirty eyes (29 cases) underwent IRGBR with subconjunctival 5-FU injection (group A in the second term) and 13 eyes (11 cases) without 5-FU (group B in the first term). The success rates 24 months after IRGBR were 73.3 and 23.1%, respectively, in groups A and B based on the definition 1 failure and 56.7 and 7.7% based on the definition 2 failure. Complications included transient bleb leaks (group A, 3 eyes; group B, none) and choroidal detachment (group A, 1 eye; group B, none). No use of 5-FU and IOPs ≧10 mmHg 1 week after IRGBR were significant risk factors.

Conclusions: Adjunctive 5-FU in IRGBR achieved a better success rate for failing trabeculectomy blebs.
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http://dx.doi.org/10.1186/s12886-021-01843-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869480PMC
February 2021

Generation of functional conjunctival epithelium, including goblet cells, from human iPSCs.

Cell Rep 2021 Feb;34(5):108715

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address:

The conjunctival epithelium, which covers the sclera (the white of the eye) and lines the inside of the eyelids, is essential for mucin secretion and the establishment of a healthy tear film. Here, we describe human conjunctival development in a self-formed ectodermal autonomous multi-zone (SEAM) of cells that were derived from human-induced pluripotent stem cells (hiPSCs) and mimic whole-eye development. Our data indicate that epidermal growth factor (EGF) drives the generation of cells with a conjunctival epithelial lineage. We also show that individual conjunctival cells can be sorted and reconstituted by cultivation into a functional conjunctival epithelium that includes mucin-producing goblet cells. Keratinocyte growth factor (KGF), moreover, is necessary for the maturation of hiPSC-derived conjunctival epithelium-particularly the goblet cells-indicating key complementary roles of EGF and KGF in directing the differentiation and maturation, respectively, of the human conjunctival epithelium.
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http://dx.doi.org/10.1016/j.celrep.2021.108715DOI Listing
February 2021

Chondroitin Sulfate as a Potential Modulator of the Stem Cell Niche in Cornea.

Front Cell Dev Biol 2020 12;8:567358. Epub 2021 Jan 12.

Structural Biophysics Group, School of Optometry and Vision Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom.

Chondroitin sulfate (CS) is an important component of the extracellular matrix in multiple biological tissues. In cornea, the CS glycosaminoglycan (GAG) exists in hybrid form, whereby some of the repeating disaccharides are dermatan sulfate (DS). These CS/DS GAGs in cornea, through their presence on the proteoglycans, decorin and biglycan, help control collagen fibrillogenesis and organization. CS also acts as a regulatory ligand for a spectrum of signaling molecules, including morphogens, cytokines, chemokines, and enzymes during corneal growth and development. There is a growing body of evidence that precise expression of CS or CS/DS with specific sulfation motifs helps define the local extracellular compartment that contributes to maintenance of the stem cell phenotype. Indeed, recent evidence shows that CS sulfation motifs recognized by antibodies 4C3, 7D4, and 3B3 identify stem cell populations and their niches, along with activated progenitor cells and transitional areas of tissue development in the fetal human elbow. Various sulfation motifs identified by some CS antibodies are also specifically located in the limbal region at the edge of the mature cornea, which is widely accepted to represent the corneal epithelial stem cell niche. Emerging data also implicate developmental changes in the distribution of CS during corneal morphogenesis. This article will reflect upon the potential roles of CS and CS/DS in maintenance of the stem cell niche in cornea, and will contemplate the possible involvement of CS in the generation of eye-like tissues from human iPS (induced pluripotent stem) cells.
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http://dx.doi.org/10.3389/fcell.2020.567358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835413PMC
January 2021

Optimizing correction of coma aberration in keratoconus with a novel soft contact lens.

Cont Lens Anterior Eye 2021 Jan 10:101405. Epub 2021 Jan 10.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan. Electronic address:

Purpose: To report on a second-generation prototype contact lens (modified lens) with enhanced optics to correct coma aberration and compare its performance with that of the prototype contact lens (conventional lens) used to optimise correction of coma aberration in keratoconus (KC).

Methods: Both lenses were designed as a set of standardised soft contact lenses (SCLs) with asymmetric powers along the posterior surface. The modified lens differs from the conventional lens in that the optical zone is decentred superiorly by 0.7 mm. The on-eye performance was compared between the SCLs and no-lens wearing in terms of manifest refraction, corrected distance visual acuity (CDVA), ocular aberrations, subjective quality of vision, and on-eye lens position relative to the pupil.

Results: Thirty-four KC eyes were included. SCLs significantly decreased coma aberration compared to no-lens wear (none, 0.68 ± 0.27 μm; conventional lens, 0.37 ± 0.28 μm; modified lens, 0.19 ± 0.15 μm; P < 0.001), with the reduction in coma aberration being significantly greater with the modified lens than with the conventional lens (P = 0.018). No significant difference in manifest refraction or CDVA was found among the three conditions. Quality of vision was significantly better with the modified lens than with no SCL wear (P < 0.05) but no differences were found between the SCLs. The on-eye optical center position relative to the pupil was closer to the pupil centre using the modified lens than the conventional lens (P < 0.001).

Conclusion: Optimisation of the location of the optical zone in a standardised asymmetric SCL improves correction of coma aberrations and on-eye optical centration.
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http://dx.doi.org/10.1016/j.clae.2020.12.071DOI Listing
January 2021

Optical Quality in Keratoconus Is Associated With Corneal Biomechanics.

Cornea 2020 Dec 16;Publish Ahead of Print. Epub 2020 Dec 16.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan; Department of Innovative Visual Science, Osaka University Graduate School of Medicine, Osaka, Japan; Seed Co, Ltd, Tokyo, Japan; Instituto de Olhos Renato Ambrósio/Visare Personal Laser, and Department of Ophthalmology, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Brazil; and Life and Medical Science Frontier Research Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University Graduate School of Medicine, Osaka, Japan.

Purpose: To evaluate the correlations between corneal biomechanical indices from dynamic Scheimpflug assessment and optical quality assessed as higher-order aberrations (HOAs) using a Hartmann-Shack ocular wavefront sensor in patients with keratoconus (KC).

Methods: In this prospective, observational case series, the eyes with KC or KC suspect (KCS) from Osaka University Hospital, Osaka, Japan, were analyzed. Corneal biomechanical assessment was performed using Corvis ST (Oculus Optikgeräte GmbH, Wetzlar, Germany), and ocular wavefront aberrations were measured using the KR-1W (Topcon Corp, Tokyo, Japan). Correlations between the biomechanical indices and ocular HOAs were assessed. Corneal biomechanical indices included the deformation amplitude ratio within 2 mm, integrated radius, stiffness parameter at the first applanation, and the linear Corvis Biomechanical Index. Wavefront data of the central 4-mm region were expanded up to the sixth order of Zernike polynomials. The magnitudes of trefoil, coma, tetrafoil, secondary astigmatism, and spherical aberration were calculated by Zernike vector analysis and then used as ocular HOA parameters along with total HOAs.

Results: Thirty-four KC eyes and 37 KCS eyes were included. KC eyes showed significant correlations between ocular HOAs and biomechanics, whereas there were few significant correlations in KCS eyes. In KC eyes, deformation amplitude ratio within 2 mm, integrated radius, and Corvis Biomechanical Index beta showed stronger correlations with coma among the wavefront parameters.

Conclusions: Corneal biomechanical indices correlated with ocular HOAs in patients with KC. In particular, there was a strong association with the increase in coma caused by inferosuperior asymmetry of the shape of the cornea in patients with KC.
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http://dx.doi.org/10.1097/ICO.0000000000002631DOI Listing
December 2020

Structural En Face OCT Angiography Image of Avulsed Retinal Vessels and Vitreal Neovascularization.

Ophthalmol Retina 2020 Dec;4(12):1157

Department of Ophthalmology, Osaka University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.1016/j.oret.2020.05.010DOI Listing
December 2020

New severity grading system for Fuchs endothelial corneal dystrophy using anterior segment optical coherence tomography.

Acta Ophthalmol 2020 Nov 30. Epub 2020 Nov 30.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Purpose: To report a new severity grading system for Fuchs endothelial corneal dystrophy (FECD) using anterior segment optical coherence tomography (AS-OCT).

Methods: This observational case series included 75 eyes of 43 patients with FECD and 33 eyes of 33 healthy subjects. Pachymetry and posterior elevation maps were used to determine the AS-OCT-based grading scores. FECD severity was graded from 0-3 as follows: 0, normal; 1, guttae only; 2, stromal oedema; and 3, epithelial and stromal oedema. We further investigated the central corneal thickness (CCT), thinnest corneal thickness (TCT), anterior and posterior best-fit spheres (BFS), and the distance between the central cornea and the thinnest point.

Results: Thirty-three eyes were graded as 0, four as 1, thirteen as 2, fourteen as 3, twenty-nine as 4, eleven as 5 and four as 6 by the modified Krachmer grade. Thirty-three, 41, 30 and 4 eyes were graded as 0, 1, 2 and 3, respectively, by the AS-OCT-based grading system. The inter-observer agreement was 100% for the AS-OCT-based grading system. The CCT, TCT, posterior BFS, and distance between the central cornea and thinnest point were significantly different between AS-OCT-based grades (p = 0.0001, 0.0001, 0.0036 and 0.0001, respectively). Anterior BFS was not significantly different with the AS-OCT-based grades (p = 0.1184).

Conclusion: We devised a new severity grading using only objective evaluation and quantitatively demonstrated corneal thickening, predominant flattening of the posterior corneal surface compared with the anterior surface, and displacement of the thinnest point away from the central cornea with FECD progression.
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http://dx.doi.org/10.1111/aos.14690DOI Listing
November 2020

The generation of fluorometholone nanocrystal eye drops, their metabolization to dihydrofluorometholone and penetration into rabbit eyes.

Int J Pharm 2021 Jan 13;592:120067. Epub 2020 Nov 13.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Fluorometholone is a widely used anti-inflammatory ophthalmic formulation, which elicits a lower ocular hypertensive response than other glucocorticoid medications. This serves to mitigate against the risk of steroid-induced glaucoma. Based on the hypothesis that an improved corneal permeability can increase the bioavailability of a drug, we sought to obtain fluorometholone in suspension with a small particle size. Accordingly, we describe the formulation of fluorometholone nanocrystal eye drops, which have a mean particle size of 201.2 ± 14.1 nm (standard deviation (s.d.)) when measured by dynamic light scattering. Scanning electron microscopy further indicates that fluorometholone nanocrystals are predominantly rectangular in shape. Fluorometholone microcrystals, on the other hand, with a mean particle size of 9.24 ± 4.51 µm (s.d.), tend to have a rod-like morphology. Powder x-ray diffraction revealed that fluorometholone microcrystal and nanocrystal formulations have the same crystal structure, with the main diffraction peaks at 2θ = 10.4 and 15.3°. The nanocrystal formulation was found to be stable, long-term, when stored at 10 °C for up to 6-months. High pressure liquid chromatography (HPLC) of the aqueous humor of rabbit eyes 15-240 mins after the in vivo application of fluorometholone eye drops to the ocular surface revealed that the molecule had been converted to 20α-dihydrofluorometholone (with no evidence of a 20β-dihydrofluorometholone fraction), and that penetration was 2-6 fold higher and longer lasting with the nanocrystal, rather than the microcrystal, formulation. In current study we show how newly generated fluorometholone nanocrystals when administered as eye drops enter the anterior chamber of the eye and become metabolized to dihydrofluorometholone.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120067DOI Listing
January 2021

Corneal tomographic changes during corneal rigid gas-permeable contact lens wear in keratoconic eyes.

Br J Ophthalmol 2020 Nov 10. Epub 2020 Nov 10.

Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Background/aims: We aimed to investigate the refractive changes in the posterior corneal surface in keratoconus (KC) associated with wearing spherical corneal rigid gas-permeable contact lenses (corneal GPs) with apical touch or three-point touch fitting and the effect of spherical corneal GPs on corneal biomechanics.

Methods: Patients with KC wearing corneal GPs every day without facing complications were enrolled as a single group. Corneal tomographic data were obtained using a three-dimensional anterior segment optical coherence tomography from the same eye with and without corneal GPs. Dioptric data from the central 3-mm zone of the posterior corneal surface were decomposed into spherical, regular astigmatism, asymmetry and higher-order irregularity components using Fourier harmonic analysis. The corneal biomechanical indices were deformation amplitude ratio within 2 mm, integrated radius, stiffness parameter at first applanation and linear Corvis Biomechanical Index. Correlations between the difference in Fourier indices with and without corneal GPs and the corneal biomechanical parameters were analysed.

Results: Thirty-two eyes of 32 patients with KC were enrolled. Spherical, regular astigmatism and asymmetry components were significantly smaller with corneal GP wear than without the wear (all p<0.001). All biomechanical indices were significantly correlated with the difference in the spherical components with and without corneal GPs.

Conclusion: Corneal biomechanical properties of KC were correlated with posterior corneal surface flattening induced by wearing corneal GPs on the spherical components. This effect is greater in biomechanically weaker corneas.
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http://dx.doi.org/10.1136/bjophthalmol-2020-317057DOI Listing
November 2020

Comparison of semicircular and bent tips regarding regional differences in oscillation amplitude under various torsional power settings.

J Cataract Refract Surg 2020 Oct;46(10):1381-1386

From the Department of Ophthalmology (Noguchi, Baba, Maeda, Oie, Nishida), Graduate School of Medicine, Osaka University, Suita, Department of Ophthalmology (Noguchi, Nakakura, Tabuchi), Saneikai Tsukazaki Hospital, Himeji, Integrated Frontier Research for Medical Science Division (Nishida), Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Japan.

Purpose: To analyze the difference between the behavior of semicircular (balanced) and bent (mini) tips at 20 incremental torsional power settings.

Setting: Tsukazaki Hospital, Himeji, Japan.

Design: Experimental study.

Methods: Using an ultra-high-speed video camera HPV-X2, the 2 tips during torsional oscillation were recorded, comparing tip behavior at power settings from 5% to 100% by tracking points 1 to 5 (tip end and at 1325, 2650, 3975, and 5035 μm from the tip end).

Results: Both tips increased their amplitude widths, drawing an S-curve at all points as the torsional power setting was increased, reaching their upper limits from 70% to 90% torsional power. At all 20 power settings, both tips showed significantly different amplitudes (all P < .01), and the difference of the amplitude increased as the power setting increased. Although, at points 1 and 3, the balanced tip amplitude was nearly 1.5 times larger than the mini tip amplitude, the amplitude difference was 10 μm or less at points 2 and 4. At point 5, the mini tip amplitude was at least 3 times more than the balanced tip amplitude.

Conclusions: The amplitude does not increase proportionally and varies markedly with the tip shape on reaching the upper limit, suggesting that a higher power setting might not contribute greatly to nuclear fragmentation. The balanced tip might cause greater damage to surrounding tissues if it is inserted at approximately 3 mm from the wound site. To obtain maximum shaft stability using the balanced tip, it is important to insert at least 5 mm.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000258DOI Listing
October 2020

Fourier Analysis on Regular and Irregular Astigmatism of Anterior and Posterior Corneal Surfaces in Fuchs Endothelial Corneal Dystrophy.

Am J Ophthalmol 2021 03 8;223:33-41. Epub 2020 Oct 8.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Purpose: To conduct Fourier analysis on regular and irregular astigmatism of the anterior and posterior corneal surfaces using anterior segment optical coherence tomography in patients with Fuchs endothelial corneal dystrophy (FECD) DESIGN: Observational case series.

Methods: This study included 75 eyes of 43 FECD patients and 34 eyes of 34 healthy subjects in Osaka University Hospital. Corneal dioptric data from the central 6-mm zone of the anterior and posterior corneal surface were expanded into spherical, regular astigmatism, asymmetry, and higher-order irregularity components using Fourier analysis. We analyzed the association between each component and modified Krachmer grade.

Results: There were significant differences in regular astigmatism, asymmetry, and higher-order irregularity components of the anterior corneal surface, and spherical, regular astigmatism, asymmetry, and higher-order irregularity components of the posterior corneal surface among modified Krachmer grades (P = .036, <.001, <.001, <.001, <.001, <.001, and <.001, respectively). Asymmetry component of the anterior and posterior corneal surfaces gradually increased with FECD progression. Higher-order irregularity components of the anterior and posterior corneal surfaces drastically increased in Grade 6. Many eyes had an axis of 0°-180° for the asymmetry component of the anterior surface and 180°-360° for that of the posterior surface.

Conclusion: Patients with severe FECD had a larger amount of asymmetry and higher-order irregularity components of the anterior and posterior corneal surfaces. Patients with FECD up to Grade 5 were characterized by anterior and posterior flattening in the inferior cornea, and those with Grade 6 showed irregularity in the anterior and posterior corneal surfaces.
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http://dx.doi.org/10.1016/j.ajo.2020.09.045DOI Listing
March 2021

Corneal Opacity Induced by Light in a Mouse Model of Gelatinous Drop-Like Corneal Dystrophy.

Am J Pathol 2020 12 1;190(12):2330-2342. Epub 2020 Oct 1.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.

Gelatinous drop-like corneal dystrophy (GDLD) is a severe inherited corneal dystrophy characterized by subepithelial corneal amyloid deposition. We had previously succeeded in identifying the responsible gene, TACSTD2, and subsequently found that the epithelial barrier function is significantly decreased. As with GDLD patients, the knockout mice showed severe loss of tight junction, progressive opacity, and neovascularization in the cornea. We devised an easy method to confirm the loss of the corneal barrier function even before corneal opacity is observed. Furthermore, by using knockout mice, we were able to verify clinical findings, such as the wound healing delay and light-induced acceleration of the disease. This mouse model should prove to be a highly useful tool for investigating the pathology of GDLD and for developing new therapies.
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http://dx.doi.org/10.1016/j.ajpath.2020.08.017DOI Listing
December 2020

Comparison of ocular surface squamous neoplasia and pterygium using anterior segment optical coherence tomography angiography.

Am J Ophthalmol Case Rep 2020 Dec 27;20:100902. Epub 2020 Aug 27.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Japan.

Purpose: To compare ocular surface squamous neoplasia (OSSN) and pterygium using anterior segment optical coherence tomography angiography (AS-OCTA).

Observations: Flow patterns of conjunctival vessels in patients with OSSN and pterygium were investigated using AS-OCTA. In case 1, slit-lamp examination of a 72-year-old woman revealed an elevated lesion with increased permeability of fluorescein in the inferior nasal conjunctiva of her left eye. AS-OCTA showed markedly meandering large blood vessels in both the superficial and deep layers. Histopathological evaluation of the conjunctival biopsy indicated conjunctival intraepithelial neoplasia. Case 2 was that of a 79-year-old man with a history of three conjunctival tumor excisions. Slit-lamp examination showed an elevated lesion with hyperpermeability of fluorescein in the nasal conjunctiva of his left eye. AS-OCTA revealed increased meandering vasculature in both the superficial and deep layers. Histopathological investigation concluded that the diagnosis was squamous cell carcinoma. Case 3 involved a 61-year-old man with a pterygium. Slit-lamp examination showed typical findings of an elevated nasal lesion accompanied by a head that appeared triangular with a blunt apex. AS-OCTA revealed increased straight vasculature in the superficial layer and an avascular area in the deep layer of the pterygium head.

Conclusions And Importance: AS-OCTA revealed abnormal "zigzag vessel patterns" in both the superficial and deep layers denoting meandering vessels in the patients with OSSN. In the patient with the pterygium, it showed "straight vessel patterns" signifying unbending stretched vessels in the superficial layer and an avascular zone in the deep layer of the pterygium head. These findings may be useful for the differential diagnosis of OSSN and pterygium.
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http://dx.doi.org/10.1016/j.ajoc.2020.100902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502819PMC
December 2020

Complete Visual Recovery From Severe Outer Retinitis After Tonsillitis.

J Neuroophthalmol 2020 Sep 11. Epub 2020 Sep 11.

Department of Ophthalmology (RK, KM, NH, KN), Osaka University Graduate School of Medicine, Osaka, Japan; Department of Ophthalmology (KK), Kindai University Faculty of Medicine, Osaka-Sayama City, Japan; Osaka University Graduate School of Frontier Biosciences (TF), Osaka, Japan; and Integrated Frontier Research for Medical Science Division (KN), Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan.

Background: To report a case of severe acute bilateral outer retinitis after tonsillitis and rapid morphologic and functional recovery after steroid treatment.

Methods: Observational case report.

Results: A 26-year-old woman with acute bilateral blurred vision that developed after tonsillitis underwent spectral-domain optical coherence tomography (SD-OCT) that showed photoreceptor outer segment damage. Full-field electroretinography (ERG) and multifocal ERG were nonrecordable. The patient had a remarkable anatomic and functional recovery in response to steroid treatment; however, partial damage remained around the macula on SD-OCT, and an adaptive optics imaging system showed damaged cone photoreceptors.

Conclusions: Prednisolone is an effective treatment for a disease that is believed to be due to suspicious involvement of the autoimmune system. Even severe outer retinitis can recover completely with rapid diagnosis and treatment.
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http://dx.doi.org/10.1097/WNO.0000000000001073DOI Listing
September 2020

Safety and efficacy of brilliant blue g250 (BBG) for lens capsular staining: a phase III physician-initiated multicenter clinical trial.

Jpn J Ophthalmol 2020 Sep 18;64(5):455-461. Epub 2020 Aug 18.

Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.

Purpose: To evaluate the safety and efficacy of BBG (Brilliant Blue G250) for lens capsular staining during cataract surgery with continuous curvilinear capsulorhexis.

Study Design: Prospective clinical study.

Methods: This clinical trial enrolled 30 eyes of 30 patients who underwent cataract surgery with BBG (0.25 mg/mL Brilliant Blue G250) for capsular staining. Visualization of the lens capsule and the ease of capsulorhexis with BBG staining were evaluated in five grades (grade 0 to 4) by the Independent Data Monitoring Committee and the surgeons. The safety of BBG was also evaluated in terms of ocular and systemic tolerance for 7 days after surgery.

Results: The use of BBG improved visualization of the lens capsule and complete capsulorhexis was performed in all patients. The major endpoint (Independent Data Monitoring Committee evaluation) showed that use of BBG improved visualization of the lens capsule and the ease of capsulorhexis (grades 2 to 4); the committee's grading results were similar to those of the surgeons. Frequent complications observed in more than two eyes were conjunctival injection, corneal edema and intraocular pressure elevation. No severe complications were observed in ocular and systemic evaluations.

Conclusion: BBG staining contributed to improved visualization of the lens capsule and aided in the completion of capsulorhexis during cataract surgery. The use of BBG for capsular staining also exhibited favorable safety results.
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http://dx.doi.org/10.1007/s10384-020-00763-yDOI Listing
September 2020

Development of an Infrared Monitor-Guided Bleb Revision Procedure.

Case Rep Ophthalmol 2020 May-Aug;11(2):234-241. Epub 2020 Jun 25.

Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Suita, Japan.

The needle revision procedure to address failing filtering blebs is a blind technique that might easily damage the scleral flap, conjunctiva, and choroid. We propose a new surgical procedure, infrared monitor-guided bleb revision, to perform bleb revision minimally invasively and effectively, and demonstrate the procedure in a patient. We developed the guided procedure with the infrared monitor to observe the bleb interior with greater contrast. Under the monitor, we dissect the hard fibrotic tissue with a bleb knife and, if necessary, remove adhesions using a needle and vitreous forceps. Finally, 5-fluorouracil is injected into the subconjunctiva. We have performed bleb revisions safely with clear visualization of the scleral flap using an infrared light. In the current case, the patient had good intraocular pressure control for about 1 year. The new infrared monitor-guided bleb revision procedure facilitates successful bleb revisions without damage to the underlying structures.
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http://dx.doi.org/10.1159/000508606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383186PMC
June 2020

Novel mutation identified in Leber congenital amaurosis - a case report.

BMC Ophthalmol 2020 Jul 31;20(1):313. Epub 2020 Jul 31.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Leber congenital amaurosis (LCA) is the earliest onset and the most severe form of all inherited retinal degenerative disorders, characterized by blindness, or severe visual impairment from birth, and typically exhibits clinical and genetic heterogeneity. Recently, 14 causative genes of LCA were reported. We performed whole-exome sequencing (WES) for Japanese siblings, and identified a novel homozygous nonsense mutation in the RPGR-interacting protein 1 (RPGRIP1) gene. We also report their follow-up data over 27 years.

Case Presentation: Patient 1 is a 37-year-old male. In 1992, his eye position indicated orthophoria, however, horizontal nystagmus was evident, and he complained of photophobia. His best corrected decimal visual acuity (BCVA) was 0.2 (S + 6.5/C-3.5/170°) OD and 0.1 (S + 6.0/C-2.5/10°) OS. Fundus examination revealed bisymmetrical inferior focal retinal pigment epithelium (RPE) mottling. Bright-flash electroretinogram (ERG) revealed a subnormal pattern, while 30 Hz flicker ERG was non-recordable in both eyes. At his final visit in 2019, his BCVA was 0.09 (S + 3.5/C-3.5/180°) OD and 0.09 (S + 3.0/C-4.0/10°) OS. Patient 2, a 34-year-old female, is the sibling of patient 1. In 1992, her BCVA was 0.05 (S + 6.0) OD and 0.06 (S + 5.0) OS. She was in a chin-up position during visual acuity testing. Horizontal nystagmus was evident, and she also complained of photophobia. Bright-flash ERG was severely attenuated, and 30 Hz flicker ERG was non-recordable in both eyes. At her final visit in 2019, her BCVA was 0.02 (uncorrectable) OD and 0.03 (uncorrectable) OS. There were no other patients with LCA in their family and their parents were non-consanguineous. WES revealed a homozygous, consecutive, two-nucleotide variation in the RPGRIP1 gene (NM_020366: exon15:c.G2294A and c.C2295A, p.C765X), resulting in a premature stop codon. We interpreted this variation as a novel pathogenic mutation of RPGRIP1 that contributes to LCA6 development.

Conclusions: Herein, we report a novel nonsense mutation of RPGRIP1 in two patients with LCA6 and present their long-term follow-up data. These clinical data linked to genotypes provide important information for the development of new treatments, such as gene therapy, as well as for genetic counseling.
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http://dx.doi.org/10.1186/s12886-020-01577-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393846PMC
July 2020

HLA-Matched Allogeneic iPS Cells-Derived RPE Transplantation for Macular Degeneration.

J Clin Med 2020 Jul 13;9(7). Epub 2020 Jul 13.

Department of Ophthalmology and Kobe City Eye Hospital, Kobe 650-0047, Japan.

Immune attacks are key issues for cell transplantation. To assess the safety and the immune reactions after iPS cells-derived retinal pigment epithelium (iPS-RPE) transplantation, we transplanted HLA homozygote iPS-RPE cells established at an iPS bank in HLA-matched patients with exudative age-related macular degeneration. In addition, local steroids without immunosuppressive medications were administered. We monitored immune rejections by routine ocular examinations as well as by lymphocytes-graft cells immune reaction (LGIR) tests using graft RPE and the patient's blood cells. In all five of the cases that underwent iPS-RPE transplantation, the presence of graft cells was indicated by clumps or an area of increased pigmentation at 6 months, which became stable with no further abnormal growth in the graft during the 1-year observation period. Adverse events observed included corneal erosion, epiretinal membrane, retinal edema due to epiretinal membrane, elevated intraocular pressure, endophthalmitis, and mild immune rejection in the eye. In the one case exhibiting positive LGIR tests along with a slight fluid recurrence, we administrated local steroid therapy that subsequently resolved the suspected immune attacks. Although the cell delivery strategy must be further optimized, the present results suggest that it is possible to achieve stable survival and safety of iPS-RPE cell transplantation for a year.
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http://dx.doi.org/10.3390/jcm9072217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408794PMC
July 2020

Assessment of a self-assembling peptide gel, SPG-178, in providing a clear operative field for trabeculectomy surgery for glaucoma in an animal model.

Sci Rep 2020 07 9;10(1):11326. Epub 2020 Jul 9.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan.

The presence of blood during ophthalmic surgery is problematic, as it can obstruct a surgeon's view of the operative field. This is particularly true when performing trabeculectomy surgery to enhance ocular fluid outflow and reduce intraocular pressure as a treatment for glaucoma, one of the most common vision loss conditions worldwide. In this study, we investigated the performance of a transparent, self-assembling peptide gel (SPG-178) and its ability to maintain visibility during trabeculectomy surgery. Unlike the hyaluronic acid gel commonly used in ophthalmic surgery, SPG-178 did not permit the ingress of blood into the gel itself. Rather, it forced blood to flow peripherally to the gel. Moreover, if bleeding occurred under the SPG-178 gel, perfusion with saline was able to effectively flush the blood away along the interface between the SPG-178 and the ocular tissue (in this case scleral) to clear the surgical field of view. In experimental trabeculectomy surgeries with mitomycin C used as an adjuvant, there were no differences in the postoperative recovery of intraocular pressure or bleb morphology with or without the use of SPG-178. SPG-178, therefore, when used in a gel formulation, represents a new material for use in intraocular surgery to ensure a clear operative field with likely beneficial treatment outcomes.
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http://dx.doi.org/10.1038/s41598-020-68171-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347556PMC
July 2020

Ocular surface ectoderm instigated by WNT inhibition and BMP4.

Stem Cell Res 2020 07 1;46:101868. Epub 2020 Jun 1.

Department of Ophthalmology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan; Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka 565-0871, Japan.

We sought to elucidate how and when the ocular surface ectoderm commits to its differentiation into the corneal epithelium in eye development from human induced pluripotent stem cells (hiPSCs) under the influence of WNT signaling and the actions of BMP4. These signals are key drivers ocular surface ectodermal cell fate determination. It was discovered that secreted frizzled related protein-2 (SFRP2) and Dickkopf1 (DKK1), which are expressed in neural ectoderm, are both influential in the differentiation of hiPSCs, where they act as canonical WNT antagonists. BMP4, moreover, was found to simultaneously initiate non-neural ectodermal differentiation into a corneal epithelial lineage. Combined treatment of hiPSCs with exogenous BMP4 aligned to WNT inhibition for the initial four days of differentiation increased the ocular surface ectodermal cell population and induced a corneal epithelial phenotype. Specification of a surface ectodermal lineage and its fate is thus determined by a fine balance of BMP4 exposure and WNT inhibition in the very earliest stages of human eye development.
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http://dx.doi.org/10.1016/j.scr.2020.101868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347012PMC
July 2020

Quantitative Analysis of the Association Between Follow-Up Duration and Severity of Limbal Stem Cell Deficiency or Visual Acuity in Aniridia.

Invest Ophthalmol Vis Sci 2020 06;61(6):57

,.

Purpose: This study aimed to quantitatively analyze the association between follow-up duration and the severity of limbal stem cell deficiency (LSCD) or visual acuity in patients with aniridia.

Methods: A total of 52 eyes of 27 patients with aniridia were enrolled at Osaka University Hospital. Medical records were retrospectively reviewed to obtain information on the severity of LSCD and corrected distance visual acuity (CDVA). LSCD severity was based on a modified severity grading scale. We used an ordered logistic regression model to examine the association between follow-up duration and LSCD severity, and a linear regression model with a generalized linear mixed model for the association between follow-up duration and visual acuity.

Results: The mean follow-up duration was 5.2 ± 6.3 years. The mean age at the last follow-up visit was 40.5 ± 18.9 years. The mean CDVA was 1.52 ± 1.09 logMAR. At the last follow-up, 1 examined eye (1.9%) was categorized as stage 0, 7 (13.5%) as Ia, 9 (17.3%) as Ib, 5 (9.6%) as Ic, 2 (3.8%) as IIb, 12 (23.1%) as IIc, and 11 (21.2%) as III. Five eyes (9.6%) were unclassifiable. There was a significant association between follow-up duration and LSCD severity (odds ratio per +1 year, 1.41; P < 0.001). CDVA significantly decreased as follow-up duration increased. Each increase of 1 year in the follow-up duration was associated with a mean difference of +0.021 logMAR (95% confidence interval [CI] 0.01-0.03; P < 0.001).

Conclusion: We quantitatively demonstrate that LSCD severity and visual impairment significantly progress as follow-up duration increases.
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http://dx.doi.org/10.1167/iovs.61.6.57DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415892PMC
June 2020

Effect of peripapillary tilt direction and magnitude on central visual field defects in primary open-angle glaucoma with high myopia.

Jpn J Ophthalmol 2020 Jul 22;64(4):414-422. Epub 2020 Jun 22.

Department of Ophthalmology E7, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Purpose: To evaluate the relationship between peripapillary tilt and visual field (VF) defects in glaucomatous eyes with axial myopia.

Study Design: Retrospective cross-sectional study.

Patients And Methods: One hundred four eyes of 104 patients with primary open-angle glaucoma (POAG) with myopia were included (52 eyes with high myopia [HM], 26.5 mm ≤ axial length [AL] < 30.0 mm; and 52 eyes without HM, 24.0 mm < AL < 26.5 mm). The direction and magnitude of the peripapillary tilt were evaluated using optical coherence tomography. The eyes were divided into 12 groups according to the tilt directions defined by clock-hour sectors in a clockwise direction in the right eyes and in a counterclockwise direction in the left eyes. The mean deviation (MD) and central VF (CVF) values, ie, the mean threshold values of 4 paracentral points within 5 degrees of the Swedish Interactive Threshold Algorithm 30-2 test, were evaluated.

Results: The direction of the tilt was toward sector 9 (47.1%) and sector 8 (34.6%). The MD and CVF values were significantly worse (P = 0.013 and P = 0.019, respectively) in the sector 9 group than in the sector 8 group. Furthermore, the smaller peripapillary tilt magnitude in the sector 9 group was negatively correlated (P = 0.0019) with the CVF but not with the MD (P = 0.1) among the POAG eyes with HM. In contrast, the ovality index in the sector 9 group was not significantly correlated with the MD (P = 0.4) or the CVF (P = 0.36).

Conclusion: A smaller temporal peripapillary tilt correlated with CVF defects in POAG eyes with HM. The peripapillary tilt direction and magnitude affect the CVF defect in POAG eyes with HM.
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http://dx.doi.org/10.1007/s10384-020-00747-yDOI Listing
July 2020