Prognostic factors of first-onset optic neuritis based on diagnostic criteria and antibody status: a multicentre analysis of 427 eyes.

BACKGROUND: Optic neuritis (ON) prognosis is influenced by various factors including attack severity, underlying aetiologies, treatments and consequences of previous episodes. This study, conducted on a large cohort of first ON episodes, aimed to identify unique prognostic factors for each ON subtype, while excluding any potential influence from pre-existing sequelae. METHODS: Patients experiencing their first ON episodes, with complete aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing, and clinical data for applying multiple sclerosis (MS) diagnostic criteria, were enrolled. 427 eyes from 355 patients from 10 hospitals were categorised into four subgroups: neuromyelitis optica with AQP4 IgG (NMOSD-ON), MOG antibody-associated disease (MOGAD-ON), ON in MS (MS-ON) or idiopathic ON (ION). Prognostic factors linked to complete recovery (regaining 20/20 visual acuity (VA)) or moderate recovery (regaining 20/40 VA) were assessed through multivariable Cox regression analysis. RESULTS: VA at nadir emerged as a robust prognostic factor for both complete and moderate recovery, spanning all ON subtypes. Early intravenous methylprednisolone (IVMP) was associated with enhanced complete recovery in NMOSD-ON and MOGAD-ON, but not in MS-ON or ION. Interestingly, in NMOSD-ON, even a slight IVMP delay in IVMP by >3 days had a significant negative impact, whereas a moderate delay up to 7-9 days was permissible in MOGAD-ON. Female sex predicted poor recovery in MOGAD-ON, while older age hindered moderate recovery in NMOSD-ON and ION. CONCLUSION: This comprehensive multicentre analysis on first-onset ON unveils subtype-specific prognostic factors. These insights will assist tailored treatment strategies and patient counselling for ON.

How is eyeball growth associated with optic nerve head shape and glaucoma? The Lamina cribrosa/Bruch's membrane opening offset theory.

The optic nerve head (ONH) is a complex structure wherein the axons of the retinal ganglion cells extrude from the eyeball through three openings: 1) the Bruch's membrane opening (BMO) in the retinal layer, 2) the anterior scleral canal opening in the anterior scleral layer, and 3) the lamina cribrosa (LC). Eyeball expansion during growth induces an offset among openings, since the expansion affects the inner retinal and outer scleral layers differently: the posterior polar retinal structure is preserved by the preferential growth in the equatorial region, whereas no such regional difference is observed in the scleral layer. The various modes and extents of eyeball expansion result in diverse directionality and amount of offset among openings, which causes diverse ONH morphology in adults, especially in myopia. In this review, we summarize the ONH changes that occur during myopic axial elongation. These changes were observed prospectively in our previous studies, wherein LC shift and subsequent offset from the BMO center could be predicted by tracing the central retinal vascular trunk position. This offset induces the formation of γ-zone parapapillary atrophy or externally oblique border tissue. As a presumptive site of glaucomatous damage, the LC/BMO offset may render the LC pores in the opposite direction more vulnerable. To support such speculation, we also summarize the relationship between LC/BMO offset and glaucomatous damage. Indeed, LC/BMO offset is not only the cause of diverse ONH morphology in adults, but is also, potentially, an important clinical marker for assessment of glaucoma.

Relationship between Three-Dimensional Magnetic Resonance Imaging Eyeball Shape and Optic Nerve Head Morphology.

PURPOSE: To determine if the 3-dimensional (3D) eyeball shape is associated with the positions of the central retinal vascular trunk (CRVT) and the externally oblique border (EOB) in the optic nerve head (ONH). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Fifty-six subjects (112 eyes) with a diagnosis of glaucoma or glaucoma suspect. METHODS: The eyeball shape on 3D magnetic resonance imaging (MRI) scans was classified according to the dimension of the longest diameter: axial dimension (prolate sphere), group 1; horizontal dimension (horizontally oblate sphere), group 2; and vertical dimension (vertically oblate sphere), group 3. The deviation of the CRVT, as a surrogate of lamina cribrosa (LC) shift, was measured from the center of the Bruch's membrane opening (BMO) demarcated by OCT imaging, with the horizontal midline as 0° and the superior location as a positive value. The angular location of the longest EOB was also measured. MAIN OUTCOME MEASURE: Positions of CRVT and EOB according to the 3D eyeball shape. RESULTS: Among 112 eyes, 54 (48%) had a prolate shape (group 1), 23 (21%) had a horizontally oblate shape (group 2), and 35 (31%) had a vertically oblate shape (group 3). The angular deviation of the CRVT differed among the groups: to the nasal side in group 1, to the temporal side in group 2, and along the vertical meridian in group 3. In cases of asymmetric eyeball shape, the CRVT was deviated toward the undergrown side from the overgrown side, regardless of grouping. The angular location of the longest EOB was in the direction opposite to the CRVT position (P < 0.001). A generalized estimating equation analysis revealed that the temporal location of the CRVT was associated with older age (P = 0.001), nasal location of the longest EOB (P < 0.001), and oblate shape of the eyeball (P < 0.001, group 2; P = 0.007, group 3). CONCLUSIONS: The position of the CRVT and EOB were associated with the 3D eyeball shape. Considering that infant ONH morphology is highly uniform, various modes of eyeball expansion during growth can result in diverse directionalities of offset between the LC and the BMO in adults.

Visual fatigue induced by watching virtual reality device and the effect of anisometropia.

The effect of small anisometropia on visual fatigue when using virtual reality (VR) devices was investigated. Participants (n = 34) visited three times. In the first visit, VR exposure (10 min) was conducted with the full correction of the refractive error of both eyes. Experimental anisometropia was induced by adding a + 1.0 dioptre spherical lens either on the dominant eyes in the second visit or on the non-dominant eyes in the third visit. At each visit, the participants played a predetermined video game using a head-mounted display VR for 10 min. Visual fatigue was assessed before and after playing VR game using the Virtual Reality Symptom Questionnaire (VRSQ) and high-frequency component of accommodative microfluctuation. Results showed that watching VR induced significant increase of VRSQ score, significant decrease in the maximum accommodation power and objective increase in visual fatigue. Experimental anisometropia induction either on the dominant or non-dominant eyes did not aggravate visual fatigue. Practitioner summary: Mild differences in refractive error (up to 1.0 dioptre) between both eyes do not significantly increase ocular fatigue by viewing virtual reality device (10 min). The impact of small anisometropia may be limited in developing a virtual reality device. Abbreviations: VR: virtual reality; VRSQ: virtual reality symptom questionnaire; HMD: head-mounted display; HFC: high-frequency component.

Sustained Nitric Oxide-Providing Small Molecule and Precise Release Behavior Study for Glaucoma Treatment.

Incidence ofglaucoma, a severe disease leading to irreversible loss of vision, is increasing with global aging populations. Lowering intraocular pressure (IOP) is the only proven treatment method for glaucoma. Nitric oxide (NO) is an emerging material targeting the conventional outflow pathway by relaxing the trabecular meshwork (TM). However, there is little understanding on the NO level effective in IOP lowering without toxicity. Here, we report a novel long-term NO-releasing polydiazeniumdiolate (NOP) that enables lowering IOP via the conventional outflow pathway. NOP is composed of carbon-bound polydiazeniumdiolate, a stable NO donor moiety. NO release was monitored with accurate parameters by real-time detection of gas and analysis of the accumulated release profile. Based on the NO release information, the selected safe level of NOP exhibited effective TM relaxation and a potential IOP lowering effect in vivo without side effects. This work provides new insights into nitric oxide release behavior that should be considered for glaucoma treatment.

Case report: what gives the myopic tilted disc an oval appearance?

BACKGROUND: Myopic tilted disc, observed as an oval disc, has been alleged to be a funduscopic en-face manifestation of excessive optic nerve head (ONH) sloping or tilting. Here, we report the case of a myopic child showing a developing oval disc in fundus photos during axial elongation, but without progressive tilting in spectral-domain optical coherence tomography (SD-OCT) images. CASE PRESENTATION: By merging B-scan SD-OCT images of the ONH and macula, the curvature of the posterior pole, including both the fovea and ONH, was reconstructed and compared before and after 2 years of axial elongation. Despite the marked increase of disc ovality, the posterior polar curvature was rarely changed. The preponderance of optic disc change was induced by the shift of the temporal disc margin in the nasal direction. This shifting alone imitated an increase of tilt angle but one that was still far smaller than the required degree of tilt for ONH-tilt-based disc ovality. To clarify, we calculated the required extent of axial elongation to obtain a substantial degree of ONH tilt when considering the adjacency of the fovea and the ONH. Without a focal increase of posterior polar curvature, which is to say posterior staphyloma, such change is not possible until the axial length increases extraordinarily. CONCLUSION: The most prominent change in the development of myopic tilted disc, which change gives it an oval appearance and imitates a tilt when measured, is actually not a tilt but rather a shift of the temporal disc margin.

Longitudinal Changes of Optic Nerve Head and Peripapillary Structure during Childhood Myopia Progression on OCT: Boramae Myopia Cohort Study Report 1.

PURPOSE: To delineate longitudinal changes in the optic nerve head (ONH) and peripapillary structure during myopia progression in childhood using spectral-domain (SD) OCT and to explore the factors associated with myopic ONH and peripapillary changes. DESIGN: Prospective cohort study. PARTICIPANTS: Twenty-three healthy children with myopia (46 eyes). METHODS: The participants underwent fundus photography, SD OCT, and axial length (AXL) measurements every 6 months for 2 years. Based on the morphologic changes of the ONH and ß-zone parapapillary atrophy (PPA), eyes were classified as group A (ONH unchanged without ß-zone PPA; 11 eyes), group B (ONH changed without ß-zone PPA at baseline; 10 eyes), group C (ONH changed with ß-zone PPA at baseline; 15 eyes), and group D (ONH unchanged with ß-zone PPA; 10 eyes). The configuration of the border tissue (BT) at the temporal margin of the ONH was assessed, and the ONH parameters, including Bruch's membrane opening distance (BMOD), border length (BL), and BT angle (BTA), were measured on horizontal SD OCT scans. MAIN OUTCOME MEASURES: Changes in ONH parameters and associated factors. RESULTS: Group B showed the greatest AXL increase per year (group B > group C > group A = group D; P < 0.001). During the follow-up periods, the BT configuration initially was changed from internally oblique to externally oblique (group B) and was stretched, resulting in optic disc ovality and γ-zone PPA development (group C). In group C, BL was increased significantly nasally and BTA was decreased significantly, whereas BMOD remained stable (P < 0.001, P < 0.001, and P = 0.100, respectively). In the multivariate analysis using the generalized linear mixed-effect model, the changes of BL and BTA were associated with axial elongation (P = 0.028 and P = 0.010, respectively). CONCLUSIONS: Development of myopic optic disc and γ-zone PPA during myopia progression was delineated using SD OCT images. During the ONH and peripapillary changes, the BL was increased nasally and the BTA was decreased, whereas the BMOD remained relatively stable. The association of axial elongation with ONH and peripapillary tissue changes may facilitate understanding of the relationship between myopia and glaucoma.

Positional Change of Optic Nerve Head Vasculature during Axial Elongation as Evidence of Lamina Cribrosa Shifting: Boramae Myopia Cohort Study Report 2.

PURPOSE: To investigate the positional change of central retinal vasculature and vascular trunk to deduce the change in the lamina cribrosa (LC) during axial elongation. DESIGN: Prospective cohort study. PARTICIPANTS: Twenty-three healthy myopic children (46 eyes). METHODS: Participants had undergone a full ophthalmologic examination and axial length measurement every 6 months for 2 years. Using spectral-domain OCT, circle scans centered around the optic disc in the glaucoma progression analysis mode, which enabled capturing of the same positions throughout the entire study period, and enhanced depth imaging of the deep optic nerve head complex were performed. Infrared imaging of the circle scans was used to measure the changes in the angles between the first and final visits. The angle between the major superior and inferior retinal arteries was measured along the circle scan twice: from the center of the circle scan and from the central retinal vascular trunk, respectively. The positional change of the retinal vascular trunk also was measured. MAIN OUTCOME MEASURES: Change in vascular angle and position of vascular trunk with axial elongation and associated factors. RESULTS: The vascular angle measured from the center of the circle scan did not change (P = 0.247), whereas the angle measured from the central retinal arterial trunk decreased with axial elongation (P < 0.001). A generalized estimating equation analysis revealed that the factors associated with angle decrease were axial elongation (P = 0.004) and vascular trunk dragging (P < 0.001). The extent of vascular trunk dragging was associated with axial elongation (P < 0.001) and increased border length with marginal significance (P = 0.053), but the extent of dragging could not be explained fully by their combination. The major directionality of dragging was mostly to the nasal side of the optic disc, with large variations among participants. CONCLUSIONS: During axial elongation, the retinal vasculature at the posterior pole was unchanged, whereas the position of the central vascular trunk was dragged nasally. Because the central retinal vascular trunk is embedded in the LC, its dragging indicates nasal shifting of the LC, which could explain the vulnerability of myopic eyes to glaucomatous optic neuropathy.

The effect of Vaccinium uliginosum extract on tablet computer-induced asthenopia: randomized placebo-controlled study.

BACKGROUND: To investigate the alleviation effect of Vaccinium uliginosum extract (DA9301) on tablet computer-induced asthenopia. METHODS: This was a randomized, placebo-controlled, double-blind and parallel study (Trial registration number: 2013-95). A total 60 volunteers were randomized into DA9301 (n = 30) and control (n = 30) groups. The DA9301 group received DA9301 oral pill (1000 mg/day) for 4 weeks and the control group received placebo. Asthenopia was evaluated by administering a questionnaire containing 10 questions (responses were scored on a scales of 0-6; total score: 60) regarding ocular symptoms before (baseline) and 4 weeks after receiving pills (DA9301 or placebo). The participants completed the questionnaire before and after tablet computer (iPad Air, Apple Inc.) watching at each visit. The change in total asthenopia score (TAS) was calculated and compared between the groups RESULTS: TAS increased significantly after tablet computer watching at baseline in DA9301 group. (from 20.35 to 23.88; p = 0.031) However, after receiving DA9301 for 4 weeks, TAS remained stable after tablet computer watching. In the control group, TAS changes induced by tablet computer watching were not significant both at baseline and at 4 weeks after receiving placebo. Further analysis revealed the scores for "tired eyes" (p = 0.001), "sore/aching eyes" (p = 0.038), "irritated eyes" (p = 0.010), "watery eyes" (p = 0.005), "dry eyes" (p = 0.003), "eye strain" (p = 0.006), "blurred vision" (p = 0.034), and "visual discomfort" (p = 0.018) significantly improved in the DA9301 group. CONCLUSIONS: We found that oral intake of DA9301 (1000 mg/day for 4 weeks) was effective in alleviating asthenopia symptoms induced by tablet computer watching. TRIAL REGISTRATION: The study is registered at www.clinicaltrials.gov (registration number: NCT02641470, date of registration December 30, 2015).

Optic nerve head factors associated with initial central visual field defect in primary open-angle glaucoma.

We investigated optic nerve head factors associated with initial parafoveal scotoma (IPFS) in primary open-angle glaucoma. Eighty (80) patients with an IPFS and 84 patients with an initial nasal step (INS) were compared. Central retinal vascular trunk (CRVT) deviation from the Bruch's membrane opening (BMO) center was measured as a surrogate of lamina cribrosa (LC)/BMO offset, and its obliqueness was defined as the absolute value of angular deviation from the fovea-BMO axis. Proximity of retinal nerve fiber layer defect (RNFLD) was defined as the angular deviation of the inner RNFLD margin from the fovea-BMO axis. Microvasculature dropout (MvD) was defined as a focal sectoral capillary dropout with no visible microvascular network identified in the choroidal layer. Factors associated with IPFS, as compared with INS, were assessed using logistic regression analyses and conditional inference tree analysis. The IPFS group had more oblique CRVT offset (P < 0.001), RNFLD closer to the fovea (P < 0.001), more MvD (P < 0.001), and more LC defects (P < 0.001) compared to the INS group. In logistic regression analyses, obliqueness of CRVT offset (P = 0.002), RNFLD proximity (P < 0.001), and MvD (P = 0.001) were significant factors influencing the presence of IPFS. Conditional inference tree analysis showed that RNFLD closer to the fovea (P < 0.001) in the upper level, more oblique CRVT offset (P = 0.013) and presence of MvD (P = 0.001) in the lower level were associated with the probability of having IPFS. IPFS was associated with closer RNFLD location to the fovea when assessed from the BMO. Oblique LC/BMO offset may not only mask RNFLD proximity to the fovea due to a deviated funduscopic disc appearance, but also potentiate IPFS via focal LC defect and MvD.

Association between eyeball asymmetry and offset of openings in optic nerve head canal assessed by posterior polar eyeball topography.

We investigated three-dimensional (3D) eyeball protrusion and its association with the offset between the lamina cribrosa (LC) and Bruch's membrane opening (BMO). 3D-MRI scans were taken from 93 subjects (186 eyes). An ellipsoid was fitted along the posterior 2/3 contour of each eyeball. Eyeball asymmetry with focal bulging was determined by the existence of an adjacent outward protrusion/reciprocal inward depression pair, and the angular deviation of the outermost protruded point (OPP) was measured from the nasal side of the fovea-BMO axis. The LC/BMO offset was evaluated by measuring the central retinal vascular trunk (CRVT) location from the BMO center: (1) the angular deviation and (2) the offset index as the ratio between the CRVT-BMO center distance and the BMO radius in the same direction. Seventy-nine eyes (42%) were classified as having eyeball asymmetry, which had a more superior LC/BMO offset (P < 0.001) and a larger offset index (P = 0.002). In those eyes, the angular deviation of the OPP showed a significant correlation with that of the LC/BMO offset (r = -0.724, P < 0.001), as did protrusion depth with the offset index (r = 0.291, P = 0.009). The presence of eyeball asymmetry was associated with superior LC/BMO offset (P = 0.004) and larger offset index (P = 0.009). Superior LC/BMO offset was associated with older age (P < 0.001), shorter axial length (P < 0.001) and inferior location of OPP (P < 0.001). The location and extent of focal bulging were closely associated with those of LC/BMO offset. This indicates that focal bulging during expansion might be associated with diverse directionality of LC/BMO offset.

Hemisphere opposite to central retinal vascular trunk deviation is earlier affected by glaucomatous damage in primary angle-closure glaucoma.

PURPOSE: The purpose of the study was to investigate whether the position of the central retinal vascular trunk (CRVT), as a surrogate for lamina cribrosa (LC) offset, is associated with the dominant hemisphere of visual field defect in primary angle-closure glaucoma (PACG) eyes. METHODS: Central retinal vascular trunk deviation was measured from Bruch's membrane opening (BMO) centre, which was delineated by OCT imaging, using the horizontal midline as a reference. The dominant hemisphere developing visual field defect was defined as three connected abnormal points (having a p-value < 5% probability of being normal) appearing in only one hemisphere or each point of the hemisphere having a statistically worse value compared with its mirrored point in the opposite hemisphere on pattern deviation plots. RESULTS: One hundred five (80%) of 132 eyes with PACG had dominant hemisphere of visual field defect initially: 70 eyes (67%) in the superior and 35 eyes (33%) in the inferior hemisphere. The CRVT was located superiorly in the dominant superior visual field defect group (p < 0.001). A logistic regression analysis revealed that superior deviation of the CRVT was the only factor associated with dominant superior visual field defect (p < 0.001). Externally oblique border (EOB) presence was associated with larger BMO (p = 0.005) and angular deviation of CRVT (p = 0.002). CONCLUSIONS: Central retinal vascular trunk deviation was associated with the dominant hemisphere of visual field defect in PACG eyes. This finding implies that the LC position relative to the BMO centre (LC/BMO offset) may incur structural vulnerability in the optic nerve head of PACG eyes.

Change of peripapillary retinal nerve fiber layer and choroidal thickness during 4-year myopic progress: Boramae Myopia Cohort Study Report 4.

AIMS: To investigate the longitudinal changes of peripapillary retinal nerve fibre layer (RNFL) and choroidal thickness during myopic axial elongation. METHODS: Peripapillary RNFL and choroidal thickness were prospectively evaluated by spectral-domain optical coherence tomography (SD-OCT) in 46 eyes of 23 myopic children over the course of 4 years. Using serial OCT images acquired based on a fixed scan circle in the glaucoma progression analysis mode, general and sectoral RNFL thicknesses were acquired at the same position and the angular location of the peak was measured. The peripapillary choroidal thickness likewise was measured at eight positions in serial OCT images. RESULTS: The mean age at the baseline was 9.6±1.7 years. The mean axial length increased from 24.80±1.28 mm to 25.64±1.35 mm. The global peripapillary RNFL thickness was 98.54±12.06 µm at baseline. The global and sectoral RNFL thicknesses did not change during the 4 years. The angular location of RNFL peaks was also stable and was located in the superotemporal (64.18±10.85°) and inferotemporal (293.98±11.62°) sectors. The global peripapillary choroidal thickness was 145.40±28.67 µm at the baseline. The global and sectoral choroidal thicknesses did not change during the 4 years. CONCLUSIONS: The peripapillary RNFL and choroidal thicknesses as well as the locations of the RNFL peaks had been preserved, during the 4-year follow-up on myopic children, when traced and measured from the same location.

Optic disc change with incipient myopia of childhood.

PURPOSE: To describe progressive tilting of the optic nerve head (ONH) and development/enlargement of parapapillary atrophy (PPA) observed in children with incipient myopia and to investigate factors associated with such changes. DESIGN: Retrospective, observational study. PARTICIPANTS: This study included 118 eyes of 118 Korean children who were assessed by serial disc photography at intervals of 1 year or more. METHODS: All disc photographs were reviewed by 2 experienced ophthalmologists, and eyes were classified into 2 groups with respect to the change in the ONH appearance and development/enlargement of ß-zone PPA: (1) ONH/PPA changed group and (2) ONH/PPA unchanged group. To quantify the ONH/PPA changes, the ratio of the horizontal to vertical disc diameter (HVDR) and the ratio of the maximum PPA width to vertical disc diameter (PVDR) were measured. Factors associated with ONH/PPA changes were evaluated using logistic regression analysis. Refractive errors were measured with cycloplegic refraction. MAIN OUTCOME MEASURES: Morphologic changes of the ONH/PPA as observed in serial disc photographs and its association with myopic shift. RESULTS: Mean subject age and refractive error at the time of initial fundus examination were 7.3 ± 3.7 years (range, 1-17 years) and -0.9 ± 1.9 diopters (range, -5.9 to +3.0 diopters), respectively. Mean follow-up period was 38.1 ± 19.6 months (range, 12-88 months). Fifty-one eyes (43%) were classified as the ONH/PPA change group. In the ONH/PPA change group, HVDR decreased from the initial value of 0.92 ± 0.08 to the final value of 0.86 ± 0.11, and the PVDR increased from the initial value of 0.08 ± 0.07 to the final value of 0.20 ± 0.11. The ONH/PPA changes were most remarkable in subjects between 7 and 9 years of age (odds ratio [OR] = 6.698; 95% confidence interval [CI], 2.296-19.546) and were associated with greater myopic shift during the follow-up period (OR = 0.483; 95% CI, 0.345-0.676). CONCLUSIONS: We demonstrate progressive tilting of the ONH, which was observed with development/enlargement of PPA in children who exhibited myopic shift. These findings suggest that tilted disc, as well as PPA, may be an acquired feature in myopic eyes, arising from scleral stretching. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Nitric oxide attenuated transforming growth factor-ß induced myofibroblast differentiation of human keratocytes.

Nitric oxide (NO) has the potential to modulate myofibroblast differentiation. In this study, we investigated the effect of exogenous NO on the myofibroblast differentiation of human keratocytes using sodium nitrite as a NO donor. Myofibroblasts were induced by exposing resting keratocytes to transforming growth factor (TGF)-ß1. N-cadherin and α-smooth muscle actin (αSMA) were used as myofibroblast markers. Both resting keratocytes and -stimulated keratocytes were exposed to various concentrations of sodium nitrite (1 µM to 1000 mM) for 24 to 72 h. Exposure to sodium nitrite did not alter keratocytes' viability up to a 10 mM concentration for 72 h. However, significant cytotoxicity was observed in higher concentrations of sodium nitrite (over 100 mM). The expression of αSMA and N-cadherin was significantly increased in keratocytes by TGF-ß1 stimulation after 72 h incubation. The addition of sodium nitrite (1 mM) to TGF-ß1-stimulated keratocytes significantly decreased αSMA and N cadherin expression. Smad3 phosphorylation decreased after sodium nitrite (1 mM) exposure in TGF-ß1-stimulated keratocytes. The effect of NO was reversed when NO scavenger, 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) was added in the culture medium. Application of sodium nitrite resulted in significant decrease of corneal opacity when measured at 2 weeks after the chemical burn in the mouse. These results verified the potential therapeutic effect of NO to decrease myofibroblast differentiation of human keratocytes and corneal opacity after injury.

Evaluation of moxifloxacin-induced cytotoxicity on human corneal endothelial cells.

Moxifloxacin hydrochloride (MXF) is widely used for the prevention of bacterial endophthalmitis after intraocular surgeries. However, the safety issue of intracameral injection of MXF for human corneal endothelial cells (HCECs) is still debatable. In this study, we investigated concentration-dependent cytotoxicity (0.05-1 mg/ml) of MXF for immortalized HCECs (B4G12 cell) and the underlying mechanism. Reactive oxygen generation (ROS) and cell viability after MXF exposure was measured. Flow cytometric analysis and TUNEL assay was used to detect apoptotic HCECs after MXF exposure. Ultrastructure of damaged HCECs by MXF was imaged by transmission electron microscope. Western blot analysis and caspase 2, 3 and 8 analysis were used to reveal the underlying mechanism of MXF induced damage in HCECs. We found that MXF induced dose-dependent cytotoxicity in HCECs. MXF exposure increased ROS generation and induced autophagy in HCECs. Increased LDH release represented the cellular membrane damage by MXF. In addition, caspases activation, Bax/Bcl-xL-dependent apoptosis pathway and apoptosis inducing factor nuclear translocation were all involved in MXF induced HCECs' damage, especially after exposure to high dose of MXF (0.5 and 1.0 mg/ml). These findings suggest that MXF toxicity on HCECs should be thoroughly considered by ophthalmologists when intracameral injection of MXF is planned.

Offset of openings in optic nerve head canal at level of Bruch's membrane, anterior sclera, and lamina cribrosa.

We compared the central retinal vascular trunk (CRVT) position, as a surrogate of lamina cribrosa (LC) offset, with the anterior scleral opening (ASCO) offset from the Bruch's membrane opening (BMO). Based on the BMO-centered radial scans, the BMO and ASCO margins were demarcated, and each center was determined as the center of the best-fitted ellipse for each margin. The ASCO/BMO offset was defined as the offset between each center. Angular deviations and the extent of ASCO and CRVT offsets from the BMO center were compared directly. Incomplete demarcation of ASCO was found in 20%, which was associated with a larger BMO area and a larger ASCO offset from the BMO. The angular deviation of ASCO offset was associated with that of CRVT offset and that of the longest externally oblique border. The ASCO offset was smaller than the CRVT offset, and, unlike the CRVT offset, it was rarely deviated to the inferior side. The complete ASCO margin might not be demarcatable when determined on BMO-centered radial scans in the presence of an offset. Also, the ASCO, which reflects only the superficial scleral layer, might not reflect the LC position, because the LC might be shifted further from the ASCO.

Central retinal vascular trunk deviation in unilateral normal-tension glaucoma.

PURPOSE: To investigate whether the position of the central retinal vascular trunk (CRVT), as a surrogate of lamina cribrosa (LC) offset, was associated with the presence of glaucoma in normal-tension glaucoma (NTG) patients. METHODS: The position of the CRVT was measured as the deviation from the center of the Bruch's membrane opening (BMO), as delineated by spectral-domain optical coherence tomography imaging. The offset index was calculated as the distance of the CRVT from the BMO center relative to that of the BMO margin. The angular deviation of CRVT was measured with the horizontal nasal midline as 0° and the superior location as a positive value. The offset index and angular deviation were compared between glaucoma and fellow control eyes within individuals. RESULTS: NTG eyes had higher baseline intraocular pressure (P = 0.001), a larger ß-zone parapapillary atrophy area (P = 0.013), and a larger offset index (P<0.001). In a generalized linear mixed-effects model, larger offset index was the only risk factor of NTG diagnosis (OR = 31.625, P<0.001). A generalized estimating equation regression model revealed that the offset index was larger in the NTG eyes than in the control eyes for all ranges of axial length, while it was the smallest for the axial length of 23.4 mm (all P<0.001). CONCLUSIONS: The offset index was larger in the unilateral NTG eyes, which fact is suggestive of the potential role of LC/BMO offset as a loco-regional susceptibility factor.

Effects of Nonporous Silica Nanoparticles on Human Trabecular Meshwork Cells.

PRECIS: Silica nanoparticles (SiNPs), which are potential drug carriers for glaucoma treatment, may induce mild dose-dependent cytotoxicity but not so severe as to compromise a mammalian target of rapamycin (mTOR) pathway in immortalized trabecular meshwork (TM) cells. PURPOSE: Nanoparticle-based ophthalmic drug delivery is a promising field of drug development. In this study, we evaluated the effect of nonporous SiNPs on human TM cells. METHODS: TM cells were exposed to different concentrations (0 to 100 µg/mL) of SiNPs (50, 100, and 150 nm) for up to 48 hours. Transmission electron microscopy confirmed the intracellular distribution of SiNPs. Cellular viability assay, reactive oxygen species generation, autophagy, and activation of the mTOR pathway were evaluated. Histologic analysis of the TM structure was performed after intracameral injection of SiNPs (0.05 mL of 200 µg/mL concentration) in rabbits. RESULTS: SiNPs were taken up by TM cells and localized in the cytoplasm. Neither nuclear entry nor mitochondrial damage was observed. SiNPs induced a mild but dose-dependent increase of lactate dehydrogenase. However, neither increase of intracellular reactive oxygen species levels nor apoptosis was observed after SiNPs exposure. Significant coactivation of autophagy and the mTOR pathway were observed with exposure to SiNPs. Aqueous plexus structure was well maintained without inflammation in rabbits after SiNPs exposure. CONCLUSIONS: SiNPs induce mild and dose-dependent cytotoxicity in TM cells. However, the toxicity level is not enough to compromise the mTOR pathway of TM cells and histologic structure of the aqueous plexus tissue.

Development of a novel hyaluronic acid membrane for the treatment of ocular surface diseases.

Ocular surface diseases (OSD) can cause serious visual deterioration and discomfort. Commercial artificial tear solution containing hyaluronic acid (HA) show excellent biocompatibility and unique viscoelastic characteristics. Here, we developed a novel HA membrane (HAM) by chemical crosslinking using 1,4-butanediol diglycidyl ether for the effective treatment of OSDs. The main purpose of HAMs is to provide sustained release of HA to modulate the wound healing response in OSDs. The safety and efficacy of HAMs were investigated using primary cultured human corneal epithelial cells and various OSD rabbit models. In the dry state, the HAM is firm, transparent, and easy to manipulate. When hydrated, it swells rapidly with high water retention and over 90% transmission of visible light. Human corneal epithelial cells and rabbit eyes showed no toxic response to HAM. Addition of HAMs to the culture medium enhanced human corneal epithelial cell viability and expression of cell proliferation markers. Investigation of HAM wound healing efficacy using mechanical or chemical corneal trauma and conjunctival surgery in rabbits revealed that application of HAMs to the ocular surface enhanced healing of corneal epithelium and reduced corneal limbal vascularization, opacity and conjunctival fibrosis. The therapeutic potential of HAMs in various OSDs was successfully demonstrated.