Kentaro Semba

Diurnal variations in luminal and stromal areas of choroid in normal eyes

Aims To determine the diurnal variations of the luminal and stromal areas of the choroid in normal eyes. Methods This was a prospective observational study of 38 eyes of 38 normal subjects. The blood pressure, heart rate, intraocular pressure and enhanced depth imaging optical coherence tomographic (EDI-OCT) images were recorded every 3 hours between 6:00 and 21:00 hours. The horizontal EDI-OCT images of the subfoveal choroid were converted to binary images. The central choroidal thickness (CCT), total cross-sectional choroidal area, the luminal areas, stromal areas and the ratio of luminal area to total choroidal area (L/C ratio) were determined. Results There were significant diurnal variations in the CCT, total choroidal area, luminal area and L/C ratio with the maximum values at 6:00 hours and the minimum values at 15:00 hours (p<0.001 for the CCT, p=0.011 for the total choroidal area, p<0.001 for the luminal area and p=0.014 for the L/C ratio). There was no significant variation in the stromal area (p=0.216). The range of fluctuation in the CCT was significantly correlated with that in the luminal area and the total choroidal area (p<0.001). However, there was no significant correlation between the fluctuation range in the CCT and that in the stromal area (p=0.095). There was no statistical relationship between the systemic parameters and the choroidal parameters. Conclusions The changes in the luminal area are most likely responsible for the diurnal change in the CCT and subfoveal choroidal area. Trial registration number UMIN000019060, Pre-results.

Changes of choroidal structure after corticosteroid treatment in eyes with Vogt–Koyanagi–Harada disease

Aims To report the changes of the choroidal structure in the enhanced depth imaging optical coherence tomographic (EDI-OCT) images after high-dose corticosteroid treatment for acute Vogt–Koyanagi–Harada (VKH) disease. Methods Retrospective, observational case series. Thirty-four eyes of 17 patients with acute VKH disease were examined by EDI-OCT before, and 1, 4 and 52 weeks after the treatment. The EDI-OCT images were binarised by ImageJ, a publicly accessible software. The luminal, stromal and total choroidal areas and ratio of luminal/stromal area (L/S ratio) were measured in the subfoveal choroid of 1500 µm width. The area of the peripapillary atrophy (PPA) was measured in the fundus photographs at 1 and 52 weeks. For statistical analyses, a generalised estimating equation method was used to eliminate the effect of within-subject intereye correlations. Results Before treatment, the EDI-OCT images could not be binarised because of poor image quality in most of the cases. After treatment, the luminal, stromal and total choroidal areas were significantly decreased during the follow-up period (all p<0.05). The L/S ratio significantly fluctuated over time (p=0.0201), and was significantly lower at 4 weeks than at 1 week (p=0.0158). The L/S ratio at 1 week was significantly correlated with increase in the PPA area, subsequent chronic recurrences and total dose of corticosteroid (p<0.0001, p=0.0006, p=0.0037, respectively). Conclusions The L/S ratio measured by binarisation of EDI-OCT images was predictive factor for the progression of PPA, subsequent chronic recurrences and total dose of corticosteroid, and may serve as a marker for degree of choroidal inflammation in the VKH disease.

Brimonidine suppresses loss of retinal neurons and visual function in a murine model of optic neuritis.

Optic neuritis is inflammation of the optic nerve and is strongly associated with multiple sclerosis (MS), an inflammatory demyelinating syndrome of the central nervous system. It leads to retinal ganglion cell (RGC) death and can cause severe vision loss. Brimonidine (BMD) is a selective α2-adrenergic receptor agonist that is used clinically for the treatment of glaucoma. BMD lowers intraocular pressure, but recent evidence suggests that its therapeutic efficacy may also mediate through mechanisms independent of modulation of intraocular pressure. In this study, we examined the effects of topical administration of BMD on retinal degeneration during optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE was induced with MOG35-55 in C57BL/6J mice and BMD eyedrops were applied daily. In the EAE retina, the number of RGCs was significantly decreased and this effect was suppressed with BMD treatment. Consistent with histological analyses, the visual impairment observed in EAE mice was inhibited with BMD treatment, indicating the functional significance of the neuroprotective effect of BMD. Furthermore, BMD increased the expression level of basic fibroblast growth factor in the EAE retina, particularly in Müller glial cells and RGCs. Our findings suggest that topical administration of BMD may be available for RGC protection during optic neuritis, as well as for glaucoma.

Changes in Choroidal Structures in Eyes with Chronic Central Serous Chorioretinopathy after Half-Dose Photodynamic Therapy

Purpose To determine the structural changes in the choroid after half-dose photodynamic therapy (hPDT) in eyes with chronic central serous chorioretinopathy (CSC). Methods This was a retrospective interventional study of 29 eyes of 29 patients who underwent hPDT for chronic CSC with serous retinal detachment (SRD) and were followed for ≥3 months. Enhanced depth imaging optical coherence tomographic (EDI-OCT) images of the subfoveal choroid were converted to binary images. The central choroidal thickness (CCT), the cross sectional subfoveal choroidal area, the hyporeflective and hyperreflective areas of the inner, outer, and whole choroid were determined at the baseline, and at 1, 3, and 12 months after the hPDT. Results The SRDs were resolved in 26 (89.7%) eyes at 3 months after the hPDT. The mean CCT (P = 0.001), the total choroidal area (P = 0.001), and the hypo-reflective area (P = 0.003) of the whole choroid were significantly decreased from the baseline at 3 months. The hyperreflective area of whole choroid was not significantly changed during the study period (P = 0.083). The hyperreflective but not the hyporeflective area of the inner choroid was significantly decreased at 3 months (P = 0.001, P = 1.000, respectively). The hyporeflective but not the hyperreflective area of the outer choroid was significantly decreased at 3 months (P = 0.001, P = 1.000, respectively). Conclusions The hyperreflective area of the inner choroid and hyporeflective area of the outer choroid were significantly decreased after hPDT for chronic CSC. Because the hyperreflective and hyporeflective area correspond to the choroidal stroma and vessels, respectively, the decreased CCT and subfoveal choroidal area after hPDT may be attributed to a decrease in the exudative changes in the inner choroidal stroma and the reduction of the dilation of the outer choroidal vessels.

Dock3 overexpression and p38 MAPK inhibition synergistically stimulate neuroprotection and axon regeneration after optic nerve injury

The dedicator of cytokinesis 3 (Dock3) is an atypical guanine nucleotide exchange factor that is predominantly expressed in the CNS. Dock3 exerts neuroprotective effects and stimulates optic nerve regeneration. The p38 mitogen-activated protein kinase acts downstream of apoptosis signal-regulating kinase 1 (ASK1) signaling and plays an important role in neural cell death. We assessed a therapeutic efficacy of Dock3 stimulation and p38 inhibition in retinal degeneration induced by optic nerve injury (ONI). In vivo retinal imaging using optical coherence tomography revealed that ONI-induced retinal degeneration was ameliorated in SB203580 (a p38 inhibitor)-treated WT mice and PBS-treated Dock3 overexpressing (Dock3 Tg) mice, and SB203580 further stimulated retinal protection in Dock3 Tg mice. In addition, SB203580 increased the number of regenerating axons after ONI in both WT and Dock3 Tg mice. ONI-induced phosphorylation of ASK1, p38 and the N-methyl-d-aspartate receptor 2B subunit were suppressed in the retina of Dock3 Tg mice. Inhibition of the ASK1 pathway in Dock3 Tg mice suggests that Dock3 may have an antioxidant-like property. These results indicate that overexpression of Dock3 and pharmacological interruption of p38 have synergistic effects for both neuroprotection and axon regeneration, thus combined application may be beneficial for the treatment of ONI.

Choroidal Structure in Children with Anisohypermetropic Amblyopia Determined by Binarization of Optical Coherence Tomographic Images

Purpose To compare the choroidal structure of the subfoveal area in the eyes of children with anisohypermetropic amblyopia to that of the fellow eyes and to age-matched controls using a binarization method of the images obtained by enhanced depth imaging optical coherence tomography (EDI-OCT). Methods This study was performed at Nara Medical University Hospital, Tokushima University Hospital, and Kagoshima University Hospital, Japan. Forty amblyopic eyes with anisohypermetropic amblyopia and their fellow eyes (5.9 ± 2.1 years, mean ± standard deviation), and 103 age-matched controls (6.7 ± 2.4 years) were studied. The control eyes were divided into myopic, emmetropic, and hyperopic eyes. The total choroidal area, luminal area and stromal area of the subfoveal choroid were measured by the binarization method. The luminal/stromal ratio and the axial length of the amblyopic eyes were compared to that of the control eyes. Results The total choroidal area in the amblyopic eyes was significantly larger than that of the fellow eyes (P = 0.005). The luminal/stromal ratio was significantly larger in the amblyopic eyes than that of the fellow eyes (P<0.001) and the control hyperopic eyes (P<0.001). There was a significant negative correlation between the luminal/stromal ratio and the axial length in the control eyes (r = -0.30, P = 0.001), but no significant correlation was found in the amblyopic eyes. Conclusions The choroidal structure of the amblyopic eyes was different from that of the fellow and the control hyperopic eyes. The choroidal changes are related to amblyopia.

Expression of promyelocytic leukemia protein and vascular endothelial growth factor in aqueous humor and vitreous fluid in patients with proliferative diabetic retinopathy

AIMS To examine the expression of promyelocytic leukemia protein (PML) in the eye of proliferative diabetic retinopathy (PDR) patients. METHODS PML mRNA levels were measured in proliferative membranes from 12 PDR patients and idiopathic epiretinal membranes from 5 control patients by quantitative RT-PCR. Protein levels of PML and vascular endothelial growth factor (VEGF) in aqueous humor and vitreous fluid samples from 34 PDR patients and 38 control patients were determined using ELISA. RESULTS The PML mRNA expression levels in membrane samples, and the PML protein concentrations in aqueous humor and vitreous fluid samples were significantly lower in PDR patients than control patients. We observed a statistically significant inverse correlation between the concentrations of PML and VEGF in the aqueous humor and vitreous fluid of PDR patients. CONCLUSION PML may be a good candidate as a diagnostic marker and a therapeutic agent for PDR.

Expression of intraocular peroxisome proliferator-activated receptor gamma in patients with proliferative diabetic retinopathy

AIMS To determine whether peroxisome proliferator-activated receptor gamma (PPARγ), which is recognized as a component of the exosomes circulating in plasma, is expressed intraocularly in patients with proliferative diabetic retinopathy (PDR). METHODS The concentrations of PPARγ and vascular endothelial growth factor (VEGF) in the aqueous humor and vitreous of 50 eyes with PDR and 38 control eyes were determined by ELISA. The levels of the mRNA and protein of PPARγ were determined in proliferative membranes from 12 PDR and 5 control eyes by quantitative RT-PCR and immunohistochemical analyses. RESULTS PPARγ was detected in the culture media of human umbilical vein endothelial cells indicating that PPARγ can be released into the extracellular fluid. The PPARγ concentrations in the aqueous humor and vitreous fluid were significantly higher in PDR patients than in controls (P<0.0005). There was a significant positive correlation between the PPARγ and VEGF concentrations (P<0.0005). The level of PPARγ increased as the clinical stage advanced. The expressions of the mRNA and protein of PPARγ were higher in the membranes of PDR than those of controls. Anti-VEGF therapy significantly reduced the VEGF concentration (P<0.0001) but not the PPARγ concentration. CONCLUSIONS PPARγ may play an important role in the pathogenesis of PDR.

Effect of optical correction on subfoveal choroidal thickness in children with anisohypermetropic amblyopia

The purpose of this study was to determine the effect of optical correction on the best-corrected visual acuity (BCVA) and subfoveal choroidal thickness (CT) in the eyes of children with anisohypermetropic amblyopia. Twenty-four anisohypermetropic amblyopic eyes and their fellow eyes of 24 patients and twenty-three eyes of 23 age-matched control children were studied. After one year of optical correction, the BCVA in the anisohypermetropic amblyopic eyes was significantly improved. Before the treatment, the mean subfoveal CT in the amblyopic eyes was 351.9 ± 59.4 μm which was significantly thicker than that of control eyes at 302.4 ± 63.2 μm. After the treatment, the amount of change in the subfoveal CT in the amblyopic and fellow eyes was greater than that in the control eyes. The amblyopic and fellow eyes with thicker choroids had a greater thinning of the choroid whereas eyes with thinner choroids had a greater thickening of the choroid. We conclude that wearing corrective lenses improves the visual acuity, and induces changes of the subfoveal CT in eyes with anisohypermetropic amblyopia.

Prepapillary Vascular Loops Complicated by Suspected Macroaneurysm Rupture

We present a case of prepapillary vascular loops complicated by a suspected macroaneurysm rupture which was treated with intravitreal bevacizumab (IVB). A 62-year-old woman presented with decreased vision and myodesopsia in her left eye. Her best-corrected visual acuity (BCVA) was 0.6 in the left eye. Fundus examination disclosed an elevated, round, and reddish lesion, retinal hemorrhage at the superior aspect of the optic disc, retinal opacification along the superior branch retinal artery, and a small vitreous hemorrhage. Optical coherence tomography showed a serous retinal detachment, and indocyanine green angiography demonstrated prepapillary vascular loops and a hypofluorescent area with hyperfluorescent margins. These findings suggested the presence of a macroaneurysm. No filling of the dye in the aneurysm-like dilatation suggested a blockage of the lumen with a thrombus which might be associated with a branch retinal artery occlusion (BRAO). A diagnosis of prepapillary vascular loops complicated by a suspected macroaneurysm rupture and BRAO was made. Because of a persistent serous retinal detachment, IVB was performed. One month later, the BCVA improved to 1.0. Fundus examination disclosed an organized yellowish-white macroaneurysm and resolution of the serous retinal detachment. We recommend careful monitoring of patients with prepapillary vascular loops because of complications such as macroaneurysm rupture and BRAO.