Kazuaki Nishijima

Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vitrectomy

SummaryWe retrospectively investigated the relationship between the appearance of IS/OS line on OCT images and visual acuity after resolution of DME by vitrectomy. Postoperative visual acuity of eyes with complete IS/OS after resolution of DME was significantly better than that without complete IS/OS, though macular edema was completely resolved in both groups.PurposeTo evaluate the correlation between photoreceptor layer status following resolution of diabetic macular edema (DME) by pars plana vitrectomy (PPV) and final visual acuity (VA).MethodsWe retrospectively studied a series of 69 eyes from 58 patients with DME who were treated with PPV. Of the 69 eyes, 37 that were examined by optical coherence tomography (OCT) for at least 6xa0months and that showed a final macular thickness of less than 250xa0µm were included in this study. We assessed the integrity of the photoreceptor inner and outer segments (IS/OS) line in the fovea, using OCT in relation to their VA and other characteristics.ResultsThere were no differences in initial VA or in foveal thickness between eyes with or without complete IS/OS at final observation. However, final VA without complete IS/OS was significantly poorer (Pu2009=u20090.004). VA had improved by more than 2 lines in eight of ten eyes with complete IS/OS and in ten of 27 eyes without complete IS/OS; the groups differed significantly with regard to this percentage (Pu2009=u20090.03).ConclusionsThe postoperative photoreceptor status of the fovea is closely related to the final VA after resolution of DME by PPV.

Association Between Hyperreflective Foci in the Outer Retina, Status of Photoreceptor Layer, and Visual Acuity in Diabetic Macular Edema

PURPOSEnTo determine if hyperreflective foci in the outer retina are associated with photoreceptor integrity and the logarithm of minimal angle of resolution (logMAR) visual acuity (VA) in patients with diabetic macular edema (DME).nnnDESIGNnRetrospective, observational, cross-sectional study.nnnMETHODSnPatients (n=76; 108 eyes) with clinically relevant macular edema and no serous retinal detachment were analyzed retrospectively. Spectral-domain optical coherence tomography (SD-OCT) images were obtained for all patients. We investigated the relationship between the hyperreflective foci in the outer retinal layers of the external limiting membrane (ELM) at the fovea and the photoreceptor integrity and VA.nnnRESULTSnSD-OCT showed that 58 eyes (53.7%) had hyperreflective foci in the outer retinal layers, and 107 eyes (99.1%) had hyperreflective foci in the inner retinal layers. The logMAR VA was significantly (P<.0001) worse in eyes with hyperreflective foci in the outer retinal layers than in eyes without them (0.463±0.382 vs 0.127±0.206, respectively). Disruption of the ELM line on OCT was significantly (P<.0001, for both comparisons) associated with both hyperreflective foci in the outer retinal layers and poor logMAR VA. Disruption of the junction of the inner and outer segment line (IS/OS) also was related to hyperreflective foci in the outer retinal layers and poor logMAR VA (P<.0001 for both comparisons).nnnCONCLUSIONSnThe presence of hyperreflective foci in the outer retina is closely associated with a disrupted ELM and IS/OS line on SD-OCT images and decreased VA in DME.

Simvastatin Inhibits Leukocyte Accumulation and Vascular Permeability in the Retinas of Rats with Streptozotocin-Induced Diabetes

Leukocytes play important roles in the pathogenesis of diabetic retinopathy. Recently, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors have been reported to exert various effects in addition to their lipid-lowering ability. We investigated the effects of simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, on leukocyte-induced diabetic changes in retinas. Diabetes was induced in Long-Evans rats with streptozotocin, and simvastatin administration was begun immediately after the induction of diabetes. Two weeks of treatment with simvastatin suppressed significantly the number of leukocytes adhering to retinal vessel endothelium and the number of leukocytes accumulated in the retinal tissue by 72.9% and 41.0%, respectively (P < 0.01). The expression of intercellular adhesion molecule-1 (ICAM-1) and the CD18 (the common beta-chain of ICAM-1 ligands) were both suppressed with simvastatin. The amount of vascular endothelial growth factor in the retina was attenuated in the simvastatin-treated group. To evaluate the effects of simvastatin on leukocyte-induced endothelial cell damage, vascular permeability in the retina was measured with fluorescein-labeled dextran. Treatment with simvastatin markedly reduced retinal permeability (P = 0.014). This suggests that simvastatin attenuates leukocyte-endothelial cell interactions and subsequent blood-retinal barrier breakdown via suppression of vascular endothelial growth factor-induced ICAM-1 expression in the diabetic retina. Simvastatin may thus be useful in the prevention of diabetic retinopathy.

Pitavastatin prevents NMDA‐induced retinal ganglion cell death by suppressing leukocyte recruitment

Excitotoxicity is a major cause of retinal ganglion cell (RGC) death during ischemic diseases such as vessel occlusion and diabetic retinopathy. However, the underlying mechanisms are not well understood. Statins, inhibitors of the HMG‐CoA reductase, have neuroprotective effects in addition to their original role in lowering cholesterol. We hypothesize that pitavastatin, a recently introduced potent statin, is protective against N‐methyl‐d‐aspartic acid (NMDA)‐induced RGC death. Pitavastatin, administered by gavage, abolished NMDA‐induced loss of RGCs. To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin, we investigated its impact on inflammation. NMDA increased the expression of interleukin‐1β and TNF‐α, and endothelial adhesion molecules, including ICAM‐1, and induced leukocyte accumulation in the retinal vessels. Pitavastatin significantly reduced NMDA‐induced leukocyte accumulation and up‐regulation of endothelial adhesion molecules, whereas cytokine expression was unaffected. Systemic blockade of ICAM‐1 in wild‐type mice or absence of CD18 in gene‐deficient (CD18–/–) mice significantly suppressed NMDA‐induced leukocyte accumulation and RGC death. These findings suggest a novel and causative role for inflammatory leukocyte recruitment in NMDA‐induced excitotoxicity. Furthermore, we show the novel neuroprotective effect of statins against excitotoxicity‐induced RGC death. Statins or other anti‐inflammatory agents may thus have therapeutic benefits in excitotoxicity‐associated neuronal diseases through blockade of leukocyte recruitment.

Optical Coherence Tomographic Reflectivity of Photoreceptors beneath Cystoid Spaces in Diabetic Macular Edema

PURPOSEnTo investigate the relationship between the cystoid spaces in the outer plexiform layer (OPL) and the characteristics of the photoreceptors beneath the cystoid spaces in patients with diabetic macular edema (DME).nnnMETHODSnIn this observational cross-sectional study, 123 eyes of 96 consecutive patients with clinically significant macular edema were retrospectively reviewed. The characteristics of the photoreceptors on optical coherence tomography (OCT) images represented by the external limiting membrane (ELM) and the junction between inner and outer segments (IS/OS), and their association with the overlying cystoid spaces were investigated.nnnRESULTSnThe areas beneath the cystoid spaces in the OPL had a longer transverse length of disrupted or faint IS/OS and disrupted ELM lines than those without cystoid spaces (P < 0.001, P < 0.001, and P = 0.009). The IS/OS lines beneath the cystoid spaces had higher reflectivity than those in areas without cystoid spaces (P < 0.001). Enlarged cystoid spaces extending from the inner nuclear layer to the OPL were associated with disrupted IS/OS or ELM but not faint IS/OS (P < 0.001, P < 0.001, and P = 0.467). The transverse length of disrupted IS/OS at the fovea was correlated with the logarithm of the minimum angle of resolution (logMAR) more than the association between foveal thickness and logMAR (r = 0.49, P < 0.001 vs. r = 0.28, P = 0.002). The ELM descended to the RPE more frequently in eyes with single-lobulated fluorescein pooling in the foveal avascular zone than those with multi-lobulated pooling (P < 0.001).nnnCONCLUSIONSnOCT showed that the cystoid spaces in the OPL were accompanied by photoreceptor damage beneath the cystoid spaces in DME.

Optical Coherence Tomographic Evaluation of Foveal Hard Exudates in Patients with Diabetic Maculopathy Accompanying Macular Detachment

OBJECTIVEnTo study morphologic changes of serous retinal detachment (SRD) and hyperreflective dots, which have been reported to be precursors of hard exudates, detectable in SRD using optical coherence tomography (OCT) to assess whether or not the OCT findings are correlated with the subfoveal deposition of hard exudates in patients with diabetic macular edema (DME) accompanied by SRD.nnnDESIGNnRetrospective chart review.nnnPARTICIPANTSnTwenty-eight eyes of 19 patients with DME accompanied by SRD.nnnMETHODSnWe imaged SRD and the hyperreflective dots in SRD using spectral domain OCT (SD-OCT). The number and distribution of the hyperreflective dots in SRD were evaluated before the initial treatment at our hospital for DME accompanied by SRD. Based on a difference in the SD-OCT findings, the study eyes were divided into 2 groups: eyes with a few dots and those with many dots. We studied the clinical course of these 2 groups to assess whether or not the findings of SRD and hyperreflective dots on the SD-OCT images were correlated with deposition of hard exudates in the subfoveal space during follow-up.nnnMAIN OUTCOME MEASURESnCorrelation of the SD-OCT findings of SRD and hyperreflective dots with deposition of hard exudates in the subfovea of patients with DME accompanied by SRD.nnnRESULTSnSubfoveal deposition of hard exudates was seen in 11 of the 28 eyes at the final examination. Before initial treatment at our hospital, 14 eyes had a few hyperreflective dots SRD and 14 eyes had many hyperreflective dots. Whereas no deposition of hard exudates in the subfoveal space was seen in the former eyes, it was seen in 11 of the latter 14 eyes (P < 0.0001). In addition, using SD-OCT, we found discontinuity of the outer border of detached neurosensory retina in 9 of the 28 eyes. Of these 9 eyes, 1 was in the group with few hyperreflective dots and eight were in the group with many hyperreflective dots (P = .0046).nnnCONCLUSIONSnIn patients with DME accompanied by SRD, SD-OCT revealed that hyperreflective dots may be associated with the subfoveal deposition of hard exudates during follow-up.

Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema.

OBJECTIVEnTo study the association between pathomorphology at the foveal center delineated by spectral domain optical coherence tomography (SD-OCT) and vascular changes around the fovea in fluorescein angiography (FA) in patients with diabetic macular edema (DME).nnnDESIGNnRetrospective, observational, cross-sectional study.nnnPARTICIPANTSnConsecutive series of 86 eyes from 72 patients with clinically significant macular edema (CSME) on which SD-OCT and FA were performed on the same day.nnnMETHODSnFluorescein angiography using HRA2 (Heidelberg Engineering, Heidelberg, Germany) and SD-OCT images using Spectralis OCT (Heidelberg Engineering) were obtained for all patients. Microaneurysms (MAs) in the perifoveal capillary network (PCN) and foveal avascular zone (FAZ) in the FA images were quantified. The pathomorphology at the foveal center was evaluated in OCT images. We then investigated the association between pathologic perifoveal capillaries in FA and the neuroglial morphology in OCT.nnnMAIN OUTCOME MEASURESnThe relationship between pathologic changes in perifoveal capillaries in FA and foveal pathomorphology in OCT.nnnRESULTSnAccording to the foveal morphology in OCT images, 44 eyes presented foveal cystoid spaces (cystoid macular edema [CME]), 25 eyes had serous retinal detachment (SRD) at the foveal center, and 17 eyes had foveal thickening without cystoid spaces or retinal detachment (retinal swelling). After 3 eyes with ischemic maculopathy were excluded, the relationship was evaluated. The number of MAs in the PCN was significantly greater in eyes with CME (3.20 ± 1.76) than in eyes with SRD (0.40 ± 1.04; P < 0.01) or retinal swelling (0.47 ± 0.72; P < 0.01). In addition, the FAZ in the eyes with CME (0.553 ± 0.323 mm(2)) was significantly larger than that of the eyes with SRD (0.302 ± 0.245 mm(2); P < 0.01) or retinal swelling (0.268 ± 0.142 mm(2); P < 0.01). These associations were found in eyes with thickened posterior hyaloid membranes.nnnCONCLUSIONSnThe eyes with cystoid spaces at the foveal center delineated by OCT had more MAs in the PCN and larger FAZ in FA images.

Optical Coherence Tomographic Characteristics of Microaneurysms in Diabetic Retinopathy

PURPOSEnTo characterize microaneurysms in diabetic retinopathy (DR) depicted by spectral-domain optical coherence tomography (SD-OCT).nnnDESIGNnRetrospective, observational case series.nnnMETHODSnWe surveyed a consecutive series of 76 eyes from 60 patients with DR (22 mild nonproliferative diabetic retinopathy [NPDR]; 43 moderate NPDR; 9 severe NPDR; 2 proliferative diabetic retinopathy [PDR]) who underwent Spectralis OCT, fluorescein angiography (FA), and color fundus photography on the same day. The microaneurysms on OCT were oval and well demarcated at the points where those on color fundus photographs and FA were delineated. The characteristics of microaneurysms were evaluated.nnnRESULTSnBased on the status of the capsular structure shown in the sectional images of OCT (called ring sign), we classified 147 microaneurysms depicted by all of SD-OCT, FA, and color fundus photographs in 76 eyes: 28 with complete ring sign, 54 with incomplete one, and 65 with no structure. Microaneurysms with no ring sign had hyperreflective spots in the lumen and were accompanied by nearby cystoid spaces more frequently than other types (P = .033 and P = .007). Thirteen of 75 microaneurysms with nearby cystoid spaces protruded into the cystoid spaces, and 11 of those 13 microaneurysms presented with no ring sign. Microaneurysms resided mainly in the inner nuclear layer (INL) (80.3%), and 65 of such microaneurysms (55.1%) were accompanied by nearby cystoid spaces.nnnCONCLUSIONSnSD-OCT delineated the capsular structure, hyperreflective spots, and location of microaneurysms, and microaneurysms with the ring sign were positively correlated with nearby cystoid spaces and protrusion into the cystoid spaces.

SDF-1/CXCR4 Contributes to the Activation of Tip Cells and Microglia in Retinal Angiogenesis

PURPOSE. Although stromal cell-derived factor (SDF)-1 contributes to angiogenesis, its effects on sprouting angiogenesis remain ill defined. The authors investigated how SDF-1 and its receptor, CXCR4, influence neovascular sprouting. METHODS. In vivo retinal vascular development was evaluated and ex vivo retinal angiogenesis induced by vascular endothelial growth factor (VEGF). Time-sequential observation was followed by the quantification of movements in neovascular sprouts and microglia. Real-time PCR was performed for the measurement of mRNA levels. RESULTS. Neutralizing antibodies against SDF-1 or an antagonist of CXCR4, AMD3100, reduced the radius of the vascularized area in retinal vascular development. These inhibitions disturbed the filopodial extensions in tip cells and proliferation in stalk cells, reduced the number of microglia, and decreased the mRNA levels of KDR/Flk-1, UNC5B, and PDGFB, which are abundantly expressed in tip cells. In ex vivo experiments, VEGF induced SDF-1 mRNA expression, and the inhibition of SDF-1/CXCR4 decreased the number of VEGF-induced neovascular sprouts. The authors further evaluated the kinetics of sprouts using time-lapse imaging and found that SDF-1/CXCR4 contributes to the elongation of neovascular sprouts and to the extension and retraction of leading edges. The movements of resident microglia after VEGF treatment were also reduced by SDF-1/CXCR4 inhibition. Interestingly, microglial depletion decreased VEGF-induced neovascular sprouts with the partial effects of SDF-1/CXCR4 blockade. CONCLUSIONS. SDF-1/CXCR4 promotes retinal angiogenesis by both tip cell activation and the indirect angiogenic effects of microglia.

In Vivo Evaluation of Retinal Injury After Transient Ischemia in Hypertensive Rats

Abstract—A number of studies have suggested that hypertension affects the pathogenesis of inflammatory reactions in various organs. The objective of this study was to evaluate the effects of hypertension on leukocyte–endothelial interactions after transient retinal ischemia. Transient retinal ischemia was induced for 60 minutes in spontaneously hypertensive rats (SHR) and in age-matched normotensive Wistar-Kyoto rats (WKY). At 4, 12, 24, 48, and 72 hours after reperfusion, flat-mount retinas were prepared to evaluate the density of leukocytes that had been accumulated in the retina. Intercellular adhesion molecule-1 (ICAM-1) mRNA expression was studied by semiquantitative polymerase chain reaction and ICAM-1 protein levels were studied by enzyme-linked immunosorbent assay. At 14 days after reperfusion, the retinal damage and the effect of superoxide dismutase on the damage were evaluated histologically. In SHR, the number of accumulated leukocytes peaked at 48 hours after reperfusion, and it was upregulated to 5.2-fold, as compared with that of WKY (P <0.001). ICAM-1 mRNA expression and ICAM-1 protein levels were increased significantly in the ischemia-reperfused retina in SHR compared with WKY (P <0.05). Histological examination demonstrated marked increase in the retinal ischemia/reperfusion damage in SHR (P <0.01) and a significant amelioration of the damage by treatment with superoxide dismutase in SHR (P <0.05). Oxidative stress may thus be an important mechanism for the deterioration seen in ischemia/reperfusion injury in the SHR retina.