Tomoko Hasegawa

Microvascular Density in Glaucomatous Eyes With Hemifield Visual Field Defects: An Optical Coherence Tomography Angiography Study

PURPOSEnTo investigate microcirculation of peripapillary retina and optic disc in eyes with primary open-angle glaucoma (POAG) and hemifield visual field (VF) defects.nnnDESIGNnProspective observational case series with normal comparison group.nnnMETHODSnSixty eyes with POAG (41 with superior and 19 with inferior hemifield VF defects) and 21 normal eyes were included in this study. Optical coherence tomography (OCT) angiography was used to acquire 3xa0× 3-mm optic disc cubes, and circumpapillary retinal nerve fiber layer thickness was also measured using OCT. Vessel densities in the peripapillary superficial retina and whole-signal-mode optic discxa0were individually analyzed based on the sectorial division.nnnRESULTSnThe peripapillary vessel densities were significantly reduced at the corresponding location of the VF defects in both non-highly myopic (P < .001, Pxa0= .006) and highly myopic glaucomatous eyes (P < .001, Pxa0= .005) compared with the normal eyes. Vessel densities of the optic discs were significantly reduced at locations corresponding to the VF defects in eyes without high myopia but with inferior hemifield VF defects (Pxa0= .006), but not in the other eyes. The vessel densities in the peripapillary retina were significantly associated with visual field total deviation values at their corresponding sides. The choroidal microvascular reduction in the peripapillary area extended to the α-peripapillary atrophy (PPA) as well as β-PPA zones.nnnCONCLUSIONSnMicrovascular reduction was associated with VF defects in a region-specific manner: significantly and partially in the peripapillary retina and optic disc, respectively.

Microstructure of Peripapillary Atrophy and Subsequent Visual Field Progression in Treated Primary Open-Angle Glaucoma

PURPOSEnTo investigate the relationship between the microstructure of β-zone peripapillary atrophy (PPA) and the subsequent visual field (VF) progression in eyes with primary open-angle glaucoma (POAG), including highly myopic eyes.nnnDESIGNnRetrospective cohort study.nnnPARTICIPANTSnA total of 129 patients with POAG who had been followed up for a minimum of 2 years and had undergone at least 5 reliable standard automated perimetry tests after spectral-domain (SD) optical coherence tomography (OCT) examination.nnnMETHODSnβ-Zone PPA was evaluated from 3 SD OCT scans centered on the optic disc. Upper and lower scans were defined as scans at 30° above and below the horizontal scan, respectively. From 3 scans of each eye, β-zone PPA was classified as PPA(+BM) or PPA(-BM) on the basis of the presence or absence of Bruchs membrane (BM), respectively. Eyes were classified into 3 groups according to the horizontal scan images: group A (only PPA(+BM)), group B (both PPA(+BM) and PPA(-BM)), and group C (only PPA(-BM)). Factors associated with the subsequent mean deviation (MD) slope after OCT examination were analyzed, and the hemifield total deviation (TD) slope was assessed in eyes with unilateral hemifield VF defects in the corresponding direction.nnnMAIN OUTCOME MEASURESnSubsequent MD slope after OCT examination.nnnRESULTSnThe VF progression in group A was faster than in group C (P = 0.004). A larger PPA(+BM) width was associated with a faster MD slope in all eyes (P < 0.001) and highly myopic eyes (P < 0.001) and with a faster TD slope in eyes with superior or inferior hemifield VF defects in the corresponding direction (P = 0.002 and P = 0.035, respectively). A larger PPA(-BM) was correlated with a slower MD slope in all eyes (P = 0.030 and P = 0.034) but not in highly myopic eyes.nnnCONCLUSIONSnThere were significant differences in VF progression according to the microstructure of the β-zone PPA in eyes with POAG. The PPA(+BM) width may be an important risk factor for VF progression in POAG, including high myopia, and the PPA(-BM) width may have a protective effect for VF progression in this subtype of POAG.

Lamina Cribrosa Defects and Optic Disc Morphology in Primary Open Angle Glaucoma with High Myopia

Purpose To investigate whether lamina cribrosa (LC) defects are associated with optic disc morphology in primary open angle glaucoma (POAG) eyes with high myopia. Methods A total of 129 POAG patients and 55 age-matched control subjects with high myopia were evaluated. Three-dimensional scan images obtained by swept source optical coherence tomography were used to detect LC defects. Radial B-scans and infrared images obtained by spectral domain optical coherence tomography were used to measure β-peripapillary atrophy (PPA) lengths with and without Bruchs membrane (BM) (temporal, nasal, superior, and inferior), tilt angle (vertical and horizontal), and disc diameter (transverse and longitudinal). Peripapillary intrachoroidal cavitations (PICCs), disc area, ovality index, and cyclotorsion of the optic disc were analyzed as well. Results LC defects were found in 70 of 129 (54.2%) POAG eyes and 1 of 55 (1.8%) control eyes (P<0.001). Age, sex, spherical equivalent, axial length, intraocular pressure, and central corneal thickness were not significantly different among POAG eyes with LC defects, POAG eyes without LC defects, and control eyes. Temporal PPA lengths without BM in all three groups correlated significantly with vertical and horizontal tilt angles, although no PPA length with BM correlated significantly with any tilt angle. PICCs were detected more frequently in POAG eyes with LC defects than those without LC defects (Pu200a=u200a0.01) and control eyes (Pu200a=u200a0.02). POAG eyes with LC defects showed a smaller ovality index (Pu200a=u200a0.004), longer temporal PPA without BM (P<0.001), and larger vertical/horizontal tilt angles (vertical, P<0.001; horizontal, Pu200a=u200a0.01), and transverse diameter (Pu200a=u200a0.01). In multivariate analysis for the presence of LC defects, presence of POAG (P<0.001) and vertical tilt angle (P<0.001) were identified as significant. Conclusions The presence of LC defects was associated with myopic optic disc morphology in POAG eyes with high myopia.

Microcystic inner nuclear layer changes and retinal nerve fiber layer defects in eyes with glaucoma

Objective To examine microcystic inner nuclear layer (INL) changes in glaucomatous eyes and to determine associated factors. Design Retrospective, cross-sectional, observational study. Methods Two hundred seventeen eyes of 133 patients with primary open angle glaucoma (POAG), 41 eyes of 32 patients with preperimetric glaucoma and 181 normal eyes of 117 subjects were ultimately included. Microcystic INL lesions were examined with infrared fundus images and with 19 vertical spectral domain optical coherence tomography (SD-OCT) images in the macular area. Results Microcystic INL changes were observed in 6.0% of eyes with POAG, but none of the normal eyes or eyes with preperimetric glaucoma showed microcystic INL changes. The proportion of eyes with advanced glaucoma was significantly larger (P = 0.013) in eyes with microcystic lesions than without. The visual field mean deviation (MD) slope was also significantly worse (P = 0.027) in eyes with microcystic lesions. No significant differences were observed in age, sex, refraction, axial length, intraocular pressure, or MD value between eyes with and without microcystic INL lesions. In several cases, microcystic INL lesions occurred along with glaucomatous visual field progression. The retinal nerve fiber layer (RNFL) thickness (P = 0.013) and ganglion cell layer (GCL) + inner plexiform layer thickness (P = 0.023) were significantly lower in areas with microcystic lesions than without. The INL was also significantly thicker (P = 0.002) in areas with microcystic lesions. Conclusions Microcystic INL lesions in glaucomatous eyes are closely associated with RNFL and GCL thinning and correlated with worse MD slope. These INL lesions may indicate focal and progressive damage in glaucoma.

Neuroprotective effects of VCP modulators in mouse models of glaucoma

Glaucoma is a major cause of adult blindness due to gradual death of retinal ganglion cells. Currently, no therapeutics are available for the protection of these cells from the cell death. We have recently succeeded in synthesizing novel compounds, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption by specifically inhibiting the ATPase activities of VCP, a major ATPase in the cell, and we have shown that KUSs could mitigate the disease progression of rd10, a mouse model of retinitis pigmentosa, without any apparent side effects. Here we show that KUSs (e.g. KUS121 and KUS187) can prevent antimycin- and oligomycin-induced ATP depletion, endoplasmic reticulum (ER) stress, and cell death in neuronally differentiated PC12 cells. Furthermore, KUSs manifest significant efficacies on several mouse models of glaucoma. KUS administration prevented or mitigated ER stress and subsequent apoptotic cell death of retinal ganglion cells in an acute injury mouse model of retinal ganglion cell loss, which was induced with N-methyl-D-aspartate. In a mouse model of glaucoma with high intraocular pressure, KUSs prevented the typical glaucoma pathologies, i.e. enlargement of optic disc cupping and thinning of the retinal nerve fiber layer. KUSs also preserved visual functions in GLAST knockout mice, a mouse model for chronic retinal ganglion cell loss. We propose “ATP maintenance” via inhibition of ATPase activities of VCP as a promising new neuroprotective strategy for currently incurable eye diseases, such as glaucoma.

Longitudinal change in choroidal thickness after trabeculectomy in primary open-angle glaucoma patients

PurposeTo investigate longitudinal changes in intraocular pressure (IOP), axial length (AL), and choroidal thickness (ChT) in primary open-angle glaucoma (POAG) eyes after trabeculectomy and to evaluate the parameters that might influence those changes.MethodsIn this prospective observational study, we recruited 28 patients with POAG (28 eyes) scheduled for trabeculectomy. The average macular ChTs and foveal retinal thicknesses along 6-mm segments centered on the fovea were examined preoperatively and postoperatively (at 1, 3, and 6xa0months) using swept-source optical coherence tomography. The IOP, AL, and mean deviation (MD) of standard automated perimetry (SAP) were also analyzed as independent variables.ResultsResults from 16 patients were included in the final analysis. A significant increase in ChT with respect to the preoperative value was observed at every postoperative stage (1xa0month, Pxa0<xa00.001; 3xa0months, Pxa0<xa00.001; 6xa0months, Pxa0=xa00.011), whereas the retinal thickness showed no significant change over the study period. The ChT increase and IOP reduction were sustained throughout the 6-month period without further significant changes. Stepwise multivariate analyses showed significant correlations between the percentage decrease in IOP and the percentage increase in ChT at 1 and 6xa0months postoperatively. The percentage increase in ChT was also significantly correlated with a better MD of the SAP at 1xa0month (βxa0=xa00.01; Pxa0=xa00.009).ConclusionsThe ChT increase following trabeculectomy was sustained at 1, 3, and 6xa0months postoperatively. The percentage increase in ChT was significantly correlated with the percentage change in IOP and (more weakly) with better SAP MD values.

Changes in morphology and visual function over time in mouse models of retinal degeneration: an SD-OCT, histology, and electroretinography study

PurposeTo examine the long-term natural course of retinal degeneration in rd10 and rd12 mice using serial spectral-domain optical coherence tomography (SD-OCT), electroretinography/electroretinograms (ERGs), and histological analysis.MethodsPhotoreceptor layer thickness and the ability to visualize photoreceptor ellipsoid zones were analyzed using SD-OCT images, and these images were compared with hematoxylin and eosin-stained sections and electron microscopy images. The a- and b-wave amplitudes of the ERGs were analyzed.ResultsIn rd10 mice, the photoreceptor layer thickness rapidly decreased, and the photoreceptor ellipsoid zone was visible on SD-OCT images in 89xa0and 43 % of eyes of 21 and 33-day-old mice, respectively. In rd12 mice, the photoreceptor layer gradually thinned, and the ellipsoid zone remained visible in 92xa0% of eyes at 19xa0months. Electron microscopy revealed that photoreceptor degeneration had occurred on the inner side of the outer nuclear layer in 21-day-old rd10 and 7-month-old rd12 mice, possibly due to autophagy mechanisms. Scotopic ERGs of rd10 mice showed a diminished response at 21xa0days; at 33 days, no response was detectable. In rd12 mice, scotopic ERGs were undetectable at 28xa0days (stimulus intensity 3.0xa0cds/m2). Photopic ERGs were nearly undetectable in 28-day-old rd10 mice, but a small b-wave was still recordable in 13-month-old rd12 mice.ConclusionsOur results demonstrate that visual function deteriorated with photoreceptor degeneration within 1xa0month in rd10 mice. In rd12 mice, however, the process of visual function deterioration and photoreceptor degeneration was still in progress at 13xa0months of age.

Evaluation of Photoreceptors in Bietti Crystalline Dystrophy with CYP4V2 Mutations Using Adaptive Optics Scanning Laser Ophthalmoscopy

PURPOSEnTo evaluate photoreceptors in Bietti crystalline dystrophy patients with CYP4V2 mutations using high-resolution images of the macula obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO).nnnDESIGNnProspective observational case series with comparison to healthy controls.nnnMETHODSnSeven eyes of 7 Bietti crystalline dystrophy patients with CYP4V2 mutations and 12 normal eyes of 12 age- and axial length-matched healthy volunteers were studied. All participants underwent ophthalmologic examinations and AO-SLO assessments. All patients underwent spectral-domain optical coherence tomography, fundus autofluorescence, Humphrey field analysis, and electroretinography. AO-SLO images were analyzed 0.5 mm and 1.0 mm from the center of the fovea in the superior, inferior, nasal, and temporal quadrants.nnnRESULTSnMean ± standard deviation cone density (cells/mm(2)) 0.5 mm from the center of the fovea was 17,209 ± 2276 in patients and 20 493 ± 2758 in controls, which was statistically different (P = .001); however, mean cone density 1.0 mm from the center of the fovea was 15 685 ± 2302 in patients and 15 705 ± 1848 in controls, which was not statistically different (P = .20). There was no correlation between cone density and mean deviation measured using a Humphrey field analysis or visual acuity in patients.nnnCONCLUSIONSnIn Bietti crystalline dystrophy patients with CYP4V2 mutations, cone density remained for visual dysfunction by evaluation using high-resolution AO-SLO. These findings support the theory that disorder of the retinal pigment epithelium and the photoreceptors in the patients are the primary and secondary pathologic changes, respectively. This is consistent with results from previous basic studies.

Clustering of Combined 24-2 and 10-2 Visual Field Grids and Their Relationship With Circumpapillary Retinal Nerve Fiber Layer Thickness.

PURPOSEnThe purpose of this study was to cluster the test points of the combined 24-2 and 10-2 visual fields (VFs) and circumpapillary retinal nerve fiber layer thickness (cpRNFLT) sectors using explanatory factor analyses (EFAs). The correlations between the VF clusters and cpRNFLT clusters were determined, and a new function-structure relationship map was determined.nnnMETHODSnTwo hundred fifty-four eyes of 166 subjects (13 normal eyes and 241 eyes with glaucoma) were studied retrospectively. All eyes had an axial length <27 mm and had undergone 24-2 and 10-2 VF tests using the Swedish Interactive Threshold Algorithm (SITA-standard) and cpRNFLT examinations by spectral domain optical coherence tomography within a 3-month period. Explanatory factor analysis was performed to group the 116 test points of the combined 24-2/10-2 VF test grids into a smaller number of VF clusters. Another EFA was performed to cluster the 24 cpRNFLT sectors. The correlations between the VF clusters and the cpRNFLT clusters were evaluated by Pearsons correlation analysis.nnnRESULTSnThe combined 24-2/10-2 VF test grids were grouped into seven VF clusters by EFA. Another EFA grouped the cpRNFLT sectors into 11 clusters. The correlation coefficients between the corresponding VF and cpRNFLT clusters ranged from 0.304 (P < 1 × 10-6) to 0.794 (P < 2.2 × 10-16).nnnCONCLUSIONSnExplanatory factor analysis revealed detailed patterns of glaucomatous VF defects and glaucomatous cpRNFL thinning. Their significant correlations indicate that they have common latent factors that might be derived from a developing pattern of glaucomatous optic neuropathy. These findings support the function-structure relationship theory in glaucoma.

Comparison of Longitudinal Changes in Functional and Structural Measures for Evaluating Progression of Glaucomatous Optic Neuropathy.

PURPOSEnWe compared longitudinal changes in functional and structural measures in eyes with glaucomatous optic neuropathy.nnnMETHODSnCircumpapillary retinal nerve fiber layer thickness (cpRNFL) and macular ganglion cell complex thickness (mGCC) were measured using spectral-domain optical coherence tomography (SD-OCT; RTVue). The Spectralis HRA+OCT instrument also was used to measure cpRNFL, and Heidelberg retina tomography II (HRT) and standard automated perimetry (SAP) were performed. Assessments were performed every 3 months over several years. Linear mixed modeling was used to evaluate the rate of change in each measure.nnnRESULTSnTotals of 1406 RTVue, 1366 Spectralis, 1245 HRT, and 1392 SAP measurements were analyzed. Average baseline SAP mean deviation (MD) was -6.24 ± 5.46 dB. Linear mixed modeling revealed that SAP MD changed by -0.23 dB/y (95% confidence interval [CI], -0.34 to -0.12 dB/y). Significant negative trends also were detected in cpRNFL (RTVue, -0.41 μm/y [95% CI, -0.67 to -0.16 μm/y]; Spectralis, -1.36 μm/y [95% CI, -1.65 to -1.07 μm/y]; and mGCC (RTVue, -0.47 μm/y [95% CI, -0.64 to -0.30 μm/y]). Disc rim area remained constant over time (HRT, -0.01 mm2/y [95% CI, -0.03 to 0.01 mm2/y]). The SAP MD, RTVue mGCC, and Spectralis cpRNFL showed the fastest changes in the inferior retina (superior visual field), while RTVue cpRNFL changed the fastest in the superior retina.nnnCONCLUSIONSnFunctional (SAP) and structural (SD-OCT) testing can detect longitudinal changes of glaucomatous optic neuropathy, but in different ways.