Hirokuni Kitamei

Clinical features of intraocular inflammation in Hokkaido, Japan

Purpose:  We aimed to investigate the clinical features of intraocular inflammation/uveitis in Hokkaido, Japan.

Results of 2 years of treatment with as-needed ranibizumab reinjection for polypoidal choroidal vasculopathy

Purpose To investigate the 2-year outcomes of three monthly intravitreal ranibizumab injections followed by as-needed reinjections to treat polypoidal choroidal vasculopathy (PCV). Methods Seventy-five consecutive eyes with naïve symptomatic PCV with 2 years of follow-up after treatment were studied prospectively. Results The mean (±SD) numbers of injections were 4.2±1.3 that included three monthly injections in the loading phase and 1.6±1.7 during years 1 and 2, respectively (mean 2-year total, 5.6±1.9). The baseline logarithm of the minimum angle of resolution visual acuity (VA) was 0.59±0.51 that improved significantly (p=0.001 for both comparisons) to 0.37±0.33 and 0.41±0.40 at 1 and 2 years, respectively, after the first injection. Although no significant difference was found between years 1 and 2 after the first injection, the VA tended to decrease slightly during year 2. The improved foveal thickness was maintained during year 2. Thirty (40%) eyes and 19 (25%) eyes, respectively, at years 1 and 2 after the first injection had no polypoidal lesions on indocyanine green angiography. A branching vascular network (BVN) remained in all eyes 2 years after the first injection and tended to increase in size during year 2. Conclusions The 2-year outcomes showed significant VA and foveal thickness improvements in eyes with PCV. During year 2, the magnitude of the improvement was lower compared with year 1. An as-needed reinjection schedule might not prevent polypoidal lesions or BVNs from regrowing. Further investigations should establish a treatment strategy for PCV.

Osteopontin Aggravates Experimental Autoimmune Uveoretinitis in Mice

Human endogenous uveitis is a common sight-threatening intraocular inflammatory disease and has been studied extensively using a murine model of experimental autoimmune uveoretinitis (EAU). It is possibly mediated by Th1 immune responses. In the present study, we investigated the role of osteopontin (OPN), a protein with pleiotropic functions that contributes to the development of Th1 cell-mediated immunity. Accompanying EAU progression, OPN was elevated in wild-type (WT) mice that had been immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide 1–20. OPN-deficient (OPN−/−) mice showed milder EAU progression in clinical and histopathological scores compared with those of WT mice. The T cells from hIRBP-immunized OPN−/− mice exhibited reduced Ag-specific proliferation and proinflammatory cytokine (TNF-α and IFN-γ) production compared with those of WT T cells. When hIRBP-immunized WT mice were administered M5 Ab reacting to SLAYGLR sequence, a cryptic binding site to integrins within OPN, EAU development was significantly ameliorated. T cells from hIRBP-immunized WT mice showed significantly reduced proliferative responses and proinflammatory cytokine production upon stimulation with hIRBP peptide in the presence of M5 Ab in the culture. Our present results demonstrate that OPN may represent a novel therapeutic target to control uveoretinitis.

Amelioration of experimental autoimmune uveoretinitis (EAU) with an inhibitor of nuclear factor-κB (NF-κB), pyrrolidine dithiocarbamate

Experimental autoimmune uveoretinitis (EAU) is a T helper type 1 cell‐mediated autoimmune disease, which serves as a model of human chronic uveitis. In this model, cells of a monocyte/macrophage lineage and retinal antigen (Ag)‐specific T cells infiltrate into the retina and cause inflammatory lesion, where proinflammatory cytokines and various stimuli activate a transcriptional factor, nuclear factor‐κB (NF‐κB), which modulates inflammation and enhances immune responses. In the present study, the therapeutic effect of administration of a NF‐κB inhibitor, pyrrolidine dithiocarbamate (PDTC), was examined in a murine EAU model. It was shown that PDTC ameliorated the clinical symptoms of EAU mice and significantly reduced the histopathological score compared with those in untreated mice. mRNA expressions of tumor necrosis factor α and interleukin‐1β were suppressed in eyes of PDTC‐treated EAU mice. However, when T cells from PDTC‐treated EAU mice, Ag‐presenting cells (APC), and the retinal Ag peptides were cocultured, these T cells showed the same level of proliferation as those from control mice. Furthermore, addition of PDTC in the culture of T cells from EAU mice, Ag, and APC completely abrogated the T cell‐proliferative response and cytokine production. Pretreatment of Ag‐primed T cells or APC with PDTC in vitro also reduced these responses. These results indicate that the inhibitory effect of PDTC is attributed mainly to the suppression of effector‐phase responses including inflammation but not to the inhibition of T cell priming. Regulation of NF‐κB pathway in the lesion could be a novel target for the successful control of uveoretinitis.

Two-year outcomes of intravitreal bevacizumab therapy for macular oedema secondary to branch retinal vein occlusion

Aim To determine the 2-year outcomes of intravitreal bevacizumab (IVB) injections in eyes with macular oedema (ME) following branch retinal vein occlusion (BRVO). Methods Of 105 consecutive eyes (105 treatment-naïve patients) with ME following BRVO, 89 eyes were followed for 2 years after the first injection. During the 2-year follow-up period, patients were examined at least every 3 months and received an IVB injection (1.25 mg/0.05 mL) if they met prespecified retreatment criteria. Rescue grid laser was permitted based on the findings of the Branch Vein Occlusion Study. Results The baseline logarithm of the minimum angle of resolution visual acuity (VA) was 0.64±0.24 (mean±SD), which significantly (p=0.001) improved 1 month after the first injection to 0.39±0.22. One year after the first injection, VA improved significantly (p=0.001) to 0.33±0.21 and remained 0.34±0.21 until 2 years after the first injection (p=0.001). The changes in foveal thickness were correlated with those of VA during the 2-year follow-up period with a mean of 3.8±1.5 injections (including the first injection). Conclusions This relatively large case series study showed favourable 2-year outcomes using bevacizumab to treat ME following BRVO. Bevacizumab provides substantial long-term benefits in the treatment of ME following BRVO.

Prognostic factors of 2-year outcomes of ranibizumab therapy for polypoidal choroidal vasculopathy

Purpose To determine predictors of 2-year outcomes after three, monthly, intravitreal ranibizumab (IVR) injections followed by as-needed injections for treatment-naive polypoidal choroidal vasculopathy (PCV). Methods This trial included 85 Japanese patients with symptomatic treatment-naive PCV who received one 0.5 mg IVR injection monthly for 3 months followed by as-needed retreatments. PCV with subfoveal leakage on fluorescein angiography with or without actual choroidal neovascularisation were included. Analyses evaluated independent baseline predictors of better and improved visual acuity (VA) and need for fewer reinjections 2 years after the first injection. Results After the three monthly injections, 1.3±1.4 and 1.5±2.0 (mean±SD) as-needed injections were administered during years 1 and 2, respectively. The baseline logarithm of the minimum angle of resolution, VA (0.60±0.49) improved significantly (p=0.001) (0.41±0.47) 2 years after the first injection. Younger patients’ eyes with a better baseline VA and no cluster of grape-like polypoidal lesions were significant independent predictors of better VA 2 years after treatment. No baseline factors predicted fewer ranibizumab reinjections during 2 years. At 2 years, resolution of polypoidal lesions 1 month after the three monthly injections did not affect VA and number of reinjections during 2 years. Conclusions Patient age, baseline VA and clusters of grape-like polypoidal lesions predicted VA outcomes 2 years after treatment with IVR for PCV.

Retinal Angiography and Optical Coherence Tomography Disclose Focal Optic Disc Vascular Leakage and Lipid-rich Fluid Accumulation Within the Retina in a Patient With Leber Idiopathic Stellate Neuroretinitis

A 52-year-old woman with clinical features of Leber idiopathic stellate neuroretinitis (LISN) underwent retinal fluorescein and indocyanine green angiography that revealed lipid-containing fluid leakage from a single arteriole in the superficial nerve fiber layer of the optic disc. The fluid expanded gradually into the upper half of the optic disc and the adjacent peripapillary retina. Optical coherence tomography (OCT) demonstrated fluid accumulation in two separate subretinal spaces and in the outer nuclear-plexiform layer, which extended from the optic disc margin to the fovea. These angiographic and OCT findings support the hypothesis that LISN develops from focally increased permeability of an optic disc surface arteriole from which lipid-rich fluid flows through the outer nuclear-plexiform layer space to pool in these retinal areas.

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA.

Osteopontin (OPN) is elevated during the progression of experimental autoimmune uveoretinitis (EAU) in C57BL/6 (B6) mice. Furthermore, EAU symptoms are ameliorated in OPN knockout mice or in B6 mice treated with anti-OPN antibody (M5). Recently, OPN has been shown to promote the Th1 response not only in the extracellular space as a secretory protein but also in cytosol as a signaling component. Thus, we attempted to reduce OPN in both compartments by using a small interfering RNA (siRNA) targeting the OPN coding sequence (OPN-siRNA). EAU was induced in B6 mice by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1-20. The OPN- or control-siRNA was administered with hydrodynamic methods 24 h before and simultaneously with immunization (prevention regimen). When plasma OPN levels were quantified following siRNA administration with the prevention regimen, the level in the OPN-siRNA-treated group was significantly lower than that in the control-siRNA-treated group. Accordingly, the clinical and histopathological scores of EAU were significantly reduced in B6 mice when siRNA caused OPN blockade. Furthermore, TNF-alpha, IFN-gamma, IL-2, GM-CSF and IL-17 levels in the culture supernatants were markedly suppressed in the OPN-siRNA-treated group, whereas the proliferative responses of T lymphocytes from regional lymph nodes against immunogenic peptides was not significantly reduced. On the other hand, the protection was not significant if the mice received the OPN-siRNA treatment on day 7 and day 8 after immunization when the clinical symptoms appeared overt (reversal regimen). Our results suggest that OPN blockade with OPN-siRNA can be an alternative choice for the usage of anti-OPN antibody and controlling uveoretinitis in the preventive regimen.

Relation between changes in foveal choroidal thickness and 1-year results of ranibizumab therapy for polypoidal choroidal vasculopathy

Aim To determine a correlation between changes in the subfoveal choroidal thickness and outcomes 1 year after ranibizumab therapy for polypoidal choroidal vasculopathy (PCV). Methods We prospectively studied 89 consecutive eyes with treatment-naïve symptomatic PCV and 1 year of follow-up after treatment. The choroidal thickness was measured monthly by optical coherence tomography using enhanced-depth imaging and the correlation between the changes in the choroidal thickness and outcomes 1 year after treatment was analysed. Results 86 eyes followed for 1 year were ultimately analysed. The mean logarithm of the minimum angle of resolution visual acuity (0.33±0.35) 1 year after the first injection significantly (p=0.001) improved compared to baseline (0.42±0.37). The mean choroidal and foveal retinal thicknesses decreased significantly (p=0.001 for both comparisons) from 271 and 347 μm to 212 and 203 μm, respectively. The amplitude of the change in the subfoveal choroidal thickness during the 1-year follow-up in eyes in which the polypoidal lesions resolved 1 year after the first injection (89±94 μm) was significantly (p=0.022) greater than in eyes in which the polypoidal lesions remained (45±109 μm). Conclusions The subfoveal choroidal thickness decreased during ranibizumab therapy, which was associated with resolved polypoidal lesions and foveal retinal thickness, and may be associated with PCV activity.

Retinal neovascularization during treatment with IGF-1 for insulin resistance syndrome

BackgroundLeprechaunism is a rare congenital syndrome and the most severe form of insulin resistance syndrome, with mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) is currently applicable to the treatment for insulin resistance syndrome by its insulin-like effect. Although IGF-1 is thought to promote tissue proliferation and neovascularization, it is uncertain how it acts on the development of diabetic retinopathy.MethodsInterventional case report.ResultsA 12-year-old girl with leprechaunism has been treated with IGF-1 since she was 6 months old. She presented with neovascular glaucoma in the left eye, but with no serious changes in the right fundus except for tortuosity and dilatation of retinal veins. Thereafter, retinal neovascularization in the right eye developed in 6 months to form a loop-shaped vascular network in the vitreous cavity despite panretinal photocoagulation.ConclusionsCharacteristics of retinal neovascularization and clinical course suggest that IGF-1 treatment was closely associated with the development of diabetic retinopathy in this case.