Takashi Katome

Inhibition of ASK1-p38 pathway prevents neural cell death following optic nerve injury

Optic nerve injury (ONI) induces retinal ganglion cell (RGC) death and optic nerve atrophy that lead to visual loss. Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase (MAPK) kinase kinase and has an important role in stress-induced RGC apoptosis. In this study, we found that ONI-induced p38 activation and RGC loss were suppressed in ASK1-deficient mice. Sequential in vivo retinal imaging revealed that post-ONI treatment with a p38 inhibitor into the eyeball was effective for RGC protection. ONI-induced monocyte chemotactic protein-1 production in RGCs and microglial accumulation around RGCs were suppressed in ASK1-deficient mice. In addition, the productions of tumor necrosis factor and inducible nitric oxide synthase in microglia were decreased when the ASK1-p38 pathway was blocked. These results suggest that ASK1 activation in both neural and glial cells is involved in neural cell death, and that pharmacological interruption of ASK1-p38 pathways could be beneficial in the treatment of ONI.

Macular Choroidal Thickness and Volume in Healthy Pediatric Individuals Measured by Swept-Source Optical Coherence Tomography

PURPOSE We evaluated the choroidal thickness and volume in healthy pediatric individuals by swept-source optical coherence tomography (SS-OCT) and compared the findings to those of adults. METHODS We examined 100 eyes of 100 healthy pediatric volunteers (3-15 years) and 83 eyes of 83 healthy adult volunteers (24-87 years) by SS-OCT with a tunable long wavelength laser source. The three-dimensional raster scan protocol was used to construct a choroidal thickness map. When the built-in software delineated an erroneous chorioscleral border in the B-scan images, manual segmentation was used. RESULTS The central choroidal thickness and volume within a 1.0-mm circle were significantly larger in the children (260.4 ± 57.2 μm, 0.205 ± 0.045 mm(3)) than in the adults (206.1 ± 72.5 μm, 0.160 ± 0.056 mm(3), both P < 0.0001). In the children, the mean choroidal thickness of the nasal area was significantly thinner than that of all other areas (P < 0.005). Pediatric choroidal thinning with increasing age in the central area was faster than that in the outer areas. Stepwise regression analysis showed that the axial length and body mass index had the highest correlation with the choroidal thickness (R(2) = 0.313, P < 0.0001). CONCLUSIONS The macular choroidal thickness and volume in the pediatric individuals were significantly larger than those in the adults. The pediatric choroidal thinning with increasing age is more rapid in the central area. Pediatric choroidal thickness is associated with several systemic or ocular parameters, especially the axial length and body mass index. These differences should be remembered when the choroidal thickness is evaluated in pediatric patients with retinochoroidal diseases.

Photoreceptor Impairment and Restoration on Optical Coherence Tomographic Image

With recent development of spectral-domain optical coherence tomography (SD-OCT), the pathological changes of retina can be observed in much greater detail. SD-OCT clearly delineates three highly reflective lines in the outer retina, which are external limiting membrane (ELM), photoreceptor inner and outer segment (IS/OS) junction, and cone outer segment tips (COST) in order from inside. These lines can serve as hallmarks for the evaluation of photoreceptor condition. In retinitis pigmentosa (RP) leading to photoreceptor degeneration, the ELM, IS/OS, and COST lines are shortened with the progression of the disease. In addition, shortening of the ELM, IS/OS and COST lines is significantly associated with each other. The line length is longest in the ELM, followed by the IS/OS, and COST, suggesting that retinal layer becomes disorganized first at the COST, followed by the IS/OS and finally the ELM. This finding is consistent with the previous report that the earliest histopathological change in RP is a shortening of the photoreceptor outer segments. On the other hand, retinal layer becomes restored first at the ELM, followed by the IS/OS and finally the COST after macular hole surgery. There may be a directionality of photoreceptor impairment or restoration on optical coherence tomographic image.

Two cases of focal choroidal excavation detected by spectral-domain optical coherence tomography.

Purpose: To report the clinical findings of 2 patients with focal choroidal excavation in the macula detected by spectral-domain optical coherence tomography (SD-OCT). Methods: Three eyes of 2 patients with a focal macular choroidal excavation detected by SD-OCT were studied. The eyes were examined by fundus autofluorescence (FAF), fluorescein angiography, fundus-related microperimetry, and multifocal electroretinography (mfERG). Results: In spite of a complaint of metamorphopsia, the visual acuity was normal in 2 eyes. SD-OCT demonstrated a choroidal excavation in the macula but the foveal contour was normal in 3 eyes. The excavation involved the outer retinal layers up to the external limiting membrane in all eyes, and a type 2 secondary choroidal neovascularization (CNV) developed in 1 of the 3 eyes. There were areas of hypoautofluorescence in the FAF images, and areas of decreased retinal sensitivity determined by microperimetry. These areas corresponded to the choroidal excavation in all eyes. The P1 amplitudes of the mfERGs were decreased in the fovea of 1 eye without a CNV. Conclusions: The choroidal excavation remained stable for 3 years in 2 eyes, a secondary CNV developed in 1 eye during the course of the disease. More cases and longer follow-up periods will be necessary to determine the etiology, clinical course, and visual prognosis of eyes with a choroidal excavation.

Swept-source optical coherence tomography identifies connection between vitreous cavity and retrobulbar subarachnoid space in patient with optic disc pit

Swept-source optical coherence tomography identifies connection between vitreous cavity and retrobulbar subarachnoid space in patient with optic disc pit

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.

QUANTITATIVE ANALYSIS OF CYSTOID MACULAR EDEMA USING SCANNING LASER OPHTHALMOSCOPE IN MODIFIED DARK-FIELD IMAGING

Purpose: To quantitatively analyze cystoid macular edema (CME) using scanning laser ophthalmoscope in the modified dark-field imaging. Methods: We studied 37 eyes with CME associated with different diseases before and after treatment. The CME area was measured with the modified dark-field imaging and fluorescein angiography. The best-corrected visual acuity, mean deviation and macular sensitivity measured by Humphrey automated perimetry, and foveal thickness and macular volume determined by optical coherence tomography were investigated. Results: The CME area could be clearly outlined in 50% with the fluorescein angiography and in 100% with the modified dark-field imaging (P < 0.0001). The CME area calculated using the modified dark-field imaging was significantly correlated with that using the fluorescein angiography (P = 0.0001). Before treatment, the CME area calculated using the modified dark-field imaging was significantly correlated with only the macular volume (P = 0.0230). Three months after treatment, decrease in the CME area was significantly correlated with improvement in the best-corrected visual acuity, mean deviation, macular sensitivity, foveal thickness, and macular volume (P < 0.05 for all). Conclusion: Our findings indicate that scanning laser ophthalmoscope in the modified dark-field imaging can measure the CME area and is useful in analyzing CME quantitatively. The findings can also be used to evaluate the effectiveness of treatment.

Swept-source optical coherence tomographic findings in morning glory syndrome.

Swept-source optical coherence tomography (SSOCT) uses a wavelength swept laser as the light source. Swept-source optical coherence tomography can achieve much less roll-off in sensitivity with depth compared with spectral-domain optical coherence tomography. In addition, current SS-OCT device uses a longer center wavelength (1050 nm). Thus, evaluations of posterior structures are possible using SSOCT. We describe a patient of morning glory syndrome in whom suspected retrobulbar subarachnoid space (SAS) around optic nerve was clearly delineated using SS-OCT. A 68-year-old woman with morning glory syndrome and retinal detachment (Figure 1) underwent vitrectomy. After surgery, SS-OCT (DRI OCT-1; Topcon, Tokyo, Japan) clearly delineated suspected SAS and its direct communication with vitreous cavity (Figures 2–4).

Aggressive retinal astrocytoma associated with tuberous sclerosis.

We report the case of a patient with an aggressive retinal astrocytoma accompanied with macular edema and neovascular vessels, who was initially treated with intravitreal bevacizumab injections. A 24-year-old male presented to our clinic complaining of visual disturbance in his right eye. At 8 years of age, he had been diagnosed as having tuberous sclerosis complex. Fundus examination demonstrated a retinal tumor accompanied with marked neovascular vessels on the surface, retinal hemorrhage, and macular edema. After six monthly intravitreal bevacizumab injections, fundus examination demonstrated marked regression of the macular edema and neovascular vessels. Two months later, a vitreous hemorrhage developed which necessitated pars plana vitrectomy. After additional intravitreal bevacizumab injection for preventing intraoperative bleeding, vitrectomy with endophotocoagulation for the tumor was performed. The vitreous sample was obtained during vitrectomy, and we measured the vascular endothelial growth factor concentration by enzyme-linked immunosorbent assay. The surgically removed epiretinal neovascular membrane and biopsied retinal tumor expressed vascular endothelial growth factor, although several intravitreal bevacizumab injections led to a vitreous vascular endothelial growth factor concentration of undetectable levels. The clinical course and immunohistochemical analyses indicate that intravitreal bevacizumab monotherapy may have been insufficient to treat the aggressive retinal astrocytoma with macular edema and that laser photocoagulation or photodynamic therapy for the tumor should be considered following intravitreal bevacizumab injection in such cases.

Optical Coherence Tomography Reveals New Insights into the Accommodation Mechanism.

Purpose. To evaluate the movement of the anterior and posterior lens poles during naturally stimulated accommodation in children using anterior segment optical coherence tomography (OCT). Methods. This is a prospective, observational, noncomparative case series including 18 eyes of nine children. Analysis of the anterior segment in the accommodated and unaccommodated state (with cycloplegia) was done using anterior segment OCT. The main outcome measures were the position of the anterior and posterior lens poles (in relation to the cornea) and lens thickness (LT). Results. A Statistically significant forward movement of the anterior lens pole and backward movement of the posterior lens pole with an increase in LT were found during accommodation (P < 0.001). There was no significant difference between the degree of movement of the anterior lens pole and the posterior lens pole during accommodation (P = 0.944). Conclusions. Anterior segment OCT provides a rapid noncontact method for studying accommodation in children. The backward movement of the posterior lens pole during accommodation nearly equals the forward movement of its anterior pole. These data minimize the theoretical hydraulic effect of the vitreous during accommodation, adding more support to the capsular theory of Helmholtz.