Manzo Taguchi

Changes in subfoveal choroidal thickness associated with uveitis activity in patients with Behçet's disease

Aims To evaluate the efficacy of measuring subfoveal choroidal thickness in monitoring uveitis activity before and after treatment with infliximab in patients with Behçets disease (BD)-associated uveitis. Methods Thirteen patients with BD (23 eyes) were selected for this retrospective observational case study. Subfoveal choroidal thickness was measured during active and remission phases of uveitis by enhanced depth imaging–spectral domain optical coherence tomography (EDI-OCT). In five patients (10 eyes), choroidal thickness was assessed at weeks 0, 2, 6 and 14 after the initiation of infliximab treatment. Results Accompanied by excessive dye leakage from choroidal vessels on indocyanine green angiography, dilation of choroidal vessels was observed in the active phase of uveitis by EDI-OCT and the choroidal thickness was significantly greater than that in the remission phase. Treatment with infliximab significantly reduced the choroidal thickness from week 2 after the first infusion, and the reduced choroidal thickness was maintained thereafter. No correlation was found between choroidal thickness and best corrected visual acuity converted to logarithm of the minimum angle of resolution, but choroidal thickness correlated significantly with anterior and posterior ocular inflammation scores. Conclusions This study indicates that measurement of subfoveal choroidal thickness by EDI-OCT is useful for evaluating the activity of uveitis and the therapeutic efficacy in patients with BD.

Elevated Levels of Cytokines Associated with Th2 and Th17 Cells in Vitreous Fluid of Proliferative Diabetic Retinopathy Patients

Macrophages are involved in low-grade inflammation in diabetes, and play pathogenic roles in proliferative diabetic retinopathy (PDR) by producing proinflammatory cytokines. T cells as well as other cells are also activated by proinflammatory cytokines, and infiltration into the vitreous of patients with PDR has been shown. In this study, we measured helper T (Th) cell-related cytokines in the vitreous of PDR patients to define the characteristics of Th-mediated immune responses associated with PDR. The study group consisted of 25 type 2 diabetic patients (25 eyes) with PDR. The control group consisted of 27 patients with epiretinal membrane (ERM), 26 patients with idiopathic macular hole (MH), and 26 patients with uveitis associated with sarcoidosis. Vitreous fluid was obtained at the beginning of vitrectomy, and centrifuging for cellular removals was not performed. Serum was also collected from PDR patients. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble sCD40L, and TNFα in the vitreous and serum samples were measured. Both percent detectable and levels of IL-4, IL-6, IL-17A, IL-21, IL-22, and TNFα in the vitreous were significantly higher than those in the serum in PDR patients. Vitreous levels of these cytokines and IL-31 were significantly higher in PDR than in ERM or MH patients. Vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα in PDR patients were also significantly higher than those of sarcoidosis patients. In PDR patients, vitreous IL-17A level correlated significantly with vitreous levels of IL-22 and IL-31, and especially with IL-4 and TNFα. Although it is unclear whether these cytokines play facilitative roles or inhibitory roles for the progression of PDR, the present study indicated that Th2- and Th17-related immune responses are involved in the pathogenesis of PDR.

Prevalence and aetiology of ocular hypertension in acute and chronic uveitis

Aims To evaluate the prevalence and aetiology of intraocular hypertension (OHT) in granulomatous and non-granulomatous uveitis Methods Medical records of 304 consecutive patients (484 eyes) with uveitis who visited the National Defense Medical Collage Hospital between April 2010 and March 2013 were reviewed retrospectively. OHT irrelevant to glaucomatous changes in optic disc or visual field was investigated. Results OHT was found in 123 eyes (25.4%) of 93 uveitic patients (30.6%); 92% of the eyes had open-angle OHT, 45.6% of which was steroid-induced. The prevalence of OHT was 100% (8/8) in Posner–Schlossman syndrome, 50.0% (10/20) in varicella zoster virus-associated iridocyclitis, 45% (9/20) in scleritis, 34.1% (15/44) in Vogt–Koyanagi–Harada disease, 32.1% (18/56) in Behçets disease (BD), 23.1% (6/26) in acute anterior uveitis, and 20.2% (19/94) in sarcoidosis. Pupillary block was observed only in non-granulomatous uveitis, but not in granulomatous uveitis. Seventy percent of OHT in granulomatous uveitis cases was inflammation-induced, while 76.7% in non-granulomatous uveitis cases was steroid-induced. Conclusions OHT in non-granulomatous uveitis was mainly steroid-induced open-angle OHT with some cases of angle-closure OHT caused by pupillary block, while that in granulomatous uveitis was mostly inflammation-induced open-angle OHT with no pupillary block-related angle-closure OHT.

Association between aqueous humor and vitreous fluid levels of Th17 cell-related cytokines in patients with proliferative diabetic retinopathy

Inflammation is known to be involved in the progression of diabetic retinopathy. We have recently reported that vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα are higher than the respective serum levels in proliferative diabetic retinopathy (PDR) patients, and that vitreous levels of these cytokines are higher in PDR than in other non-inflammatory vitreoretinal diseases or uveitis associated with sarcoidosis. In the present study, we investigated inflammatory cytokines including Th17 cell-related cytokines in aqueous humor samples obtained from eyes with PDR, and analyzed the association between the aqueous humor and vitreous fluid levels of individual cytokines. The study group consisted of 31 consecutive type 2 diabetic patients with PDR who underwent cataract surgery and vitrectomy for vitreous hemorrhage and/or tractional retinal detachment. Undiluted aqueous humor was collected during cataract surgery, and then vitreous fluid was obtained using a 25G vitreous cutter inserted into the mid-vitreous cavity at the beginning of vitrectomy. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα levels in the aqueous humor and vitreous fluid were measured using a beads-array system. Although IL-17A was detected in the aqueous humor of eyes with PDR and the level correlated with IL-17A level in the vitreous fluid, both percent detectable and level of IL-17A in the aqueous humor were significantly lower than those in the vitreous fluid. Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFα levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFα level. The present study demonstrated that IL-17A level and detectable rate in the aqueous humor of patients with PDR are markedly lower than those in the vitreous fluid and aqueous IL-17A does not correlate with vitreous levels of other cytokines, and hence should not be used as a surrogate for IL-17A in the vitreous fluid.

Evaluation of Efficacy and Safety of Latanoprost/Timolol versus Travoprost/Timolol Fixed Combinations for Ocular Hypertension Associated with Uveitis

ABSTRACT Purpose: To compare latanoprost/timolol (LT) versus travoprost/timolol (TT) fixed combinations for ocular hypertension (OHT) associated with uveitis. Methods: Thirty-six patients (55 eyes) who were treated with LT (28 eyes) or TT (27 eyes) for OHT associated with uveitis were reviewed retrospectively. Intraocular pressure (IOP) and inflammation scores at the initiation of treatment and at the last visit during therapy were analyzed. Results: Although IOP was reduced significantly in both LT and TT groups, the reduction rate was significantly greater with TT group than with LT. The differences in the reduction of IOP between the groups remained significant when the cases were classified into inflammation-induced OHT and steroid-induced OHT. Inflammation score was not exacerbated by LT or TT treatment. Conclusions: Both LT and TT are safe and effective for the treatment of OHT associated with uveitis and greater IOP reduction may be achieved by TT than by LT treatment.

Bilateral orbital inflammation following intravesical bacille Calmette-Guérin immunotherapy for bladder cancer.

Administration of intravesical bacille Calmette–Guérin (BCG) is a widely used and effective adjunctive immunotherapy for non-muscle invasive bladder cancer. Although complications following BCG immunotherapy are reported, most—such as cystitis—are local [1]. Although there are several reports of ophthalmic complications [2, 3], no specific orbital complications are reported. Here we describe an unusual case of bilateral orbital inflammation after BCG immunotherapy.

Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension.

Ocular hypertension (OHT) caused by inflammation or corticosteroid treatment is a common complication of uveitis. Ripasudil hydrochloride hydrate (K-115) is reportedly efficacious for lowering intraocular pressure (IOP). We retrospectively compared the IOP-lowering effect of K-115 for inflammatory and corticosteroid-induced OHT associated with uveitis. Thirty-six consecutive eyes of 27 patients with uveitis-associated OHT (20 and 16 eyes with inflammation- and corticosteroid-induced OHT, respectively) were treated with K-115 with or without other anti-glaucoma agents. In the inflammation-induced OHT, mean IOP and aqueous flare significantly decreased (P < 0.001 and P = 0.035, respectively), changing from 26.4 ± 7.5 mmHg and 28.1 ± 15.0 photon counts per millisecond (pc/ms) at the initial assessment to 17.9 ± 5.4 mmHg and 17.1 ± 10.7 pc/ms at the last visit, respectively. In the corticosteroid-induced OHT, mean IOP significantly decreased (P = 0.0005), changing from 26.7 ± 7.8 mmHg and 18.7 ± 11.2 pc/ms to 18.6 ± 8.8 mmHg and 22.6 ± 15.3 pc/ms, respectively; conversely, aqueous flare remained unchanged. In the inflammation-induced OHT, K-115 was more efficacious in the eyes with higher IOP. Neither remarkable adverse effects nor exacerbation of uveitis were observed in the eyes of either group during the observation period. K-115 decreased IOP in both inflammation- and corticosteroid-induced OHT associated with uveitis and played a synergistic role in reducing ocular inflammation in uveitis treatment.

Association of High-Mobility Group Box-1 With Th Cell-Related Cytokines in the Vitreous of Ocular Sarcoidosis Patients.

Purpose High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding nuclear protein released from necrotic cells, which is also secreted by activated leukocytes and acts as a primary proinflammatory cytokine. In this study, we compared vitreous HMGB1 levels in ocular sarcoidosis with those in noninflammatory vitreoretinal diseases and evaluated its association with Th cell-related and proinflammatory cytokines. Methods The study group consisted of 24 patients with ocular sarcoidosis. The control group consisted of 27 patients with proliferative diabetic retinopathy (PDR) and 24 with idiopathic epiretinal membrane (ERM). Vitreous fluid samples were obtained at the beginning of vitrectomy. Vitreous levels of HMGB1 and IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα were measured. Results High-mobility group box-1 was detected in the vitreous of 23 of 24 patients (95.8%) with ocular sarcoidosis. Mean vitreous level of HMGB1 was the highest in the sarcoidosis group, followed by the PDR and ERM groups, with significant differences between the three groups. In the sarcoidosis group, vitreous levels of IL-6, IL-10, IL-31, IFN-γ, sCD40L, and TNFα were significantly higher than those in the idiopathic ERM group, and IFN-γ and sCD40L were significantly higher than those in the PDR group. Vitreous HMGB-1 level correlated significantly with IL-10, IFN-γ, and sCD40L levels but not with IL-6, IL-17, IL-31, or TNFα levels. Conclusions The vitreous level of HMGB1 is elevated in ocular sarcoidosis and is associated with vitreous levels of Th1- and regulatory T-related cytokines, but not with proinflammatory or Th17-related cytokines.

Protective effects of dexamethasone on hypoxia-induced retinal edema in a mouse model

ABSTRACT Hypoxia‐induced retinal edema primarily induced by vascular lesion is seen in various conditions such as diabetic retinopathy (DR) and retinal vein occlusion (RVO). The edematous changes in these conditions occur mainly in intermediate and deep layers of retina as a result of disruption of the inner blood‐retinal barrier (iBRB). However, the effect of direct and acute hypoxia on iBRB remains to be elucidated. To investigate direct and acute hypoxia‐induced changes in retina, especially in astrocytes/Müller cells that are involved in the maintenance of retinal structure and function, we developed an adult mouse model of hypoxia‐induced retinal edema by 24‐h exposure in a 6% oxygen environment. Immunohistochemical staining of glial fibrillary acidic protein (GFAP) was enhanced mainly in the superficial layer of the hypoxic retina, corresponding to edematous change. Electron microscopic observation of the hypoxic retina showed vacuole formation in astrocyte/Müller cell foot processes around capillaries in the superficial layer, while no abnormal findings in the perivascular areas were found in intermediate and deep layers. Increase in vascular leakage quantified by Evans blue dye and tight junction breakdown detected by electron‐dense tracer were observed in the hypoxia group. In the hypoxic retina, microglia was activated and relative gene expressions of pro‐inflammatory cytokines were significantly upregulated. Dexamethasone suppressed these hypoxia‐induced pathological reactions. Thus, unlike DR and RVO that induce iBRB breakdown in deeper retinal layers, atmospheric hypoxia induced iBRB disruption with subsequent edematous change mainly in the superficial layer of the retina, and that dexamethasone prevented these pathological changes. In this mouse model, direct and acute hypoxia induces retinal edema in the superficial layer of the retina with morphological changes of astrocytes/Müller cells, and is potentially useful for ophthalmic research in the field related to retinal hypoxia and its treatment. HighlightsAdult mouse model of hypoxia‐induced retinal edema was established.Hypoxia induced retinal vascular leakage and astrocyte swelling in superficial layer.Pro‐inflammatory cytokines were up‐regulated by hypoxia in retina.Dexamethasone prevented up‐regulation of the cytokines and suppressed retinal edema.

Age-related differences in the clinical features of ocular sarcoidosis

The distribution of age at diagnosis in ocular sarcoidosis has shifted towards the older age groups in developed countries. In systemic sarcoidosis, age-related differences in the clinical presentation, which reflect the therapeutic strategies, was reported. We retrospectively compared 100 consecutive patients from April 2010 to March 2016 who were initially diagnosed with ocular sarcoidosis by International Workshop on Ocular Sarcoidosis criteria. They were classified into elder (>65 years: 50 patients) and younger (≤65 years: 50 patients) groups by the age at diagnosis of uveitis associated with sarcoidosis. All patients received ophthalmic examination to assess the presence of seven intraocular signs and 4 laboratory parameters. Significantly fewer ocular signs (2.8 ± 1.5 and 3.6 ± 1.5; P = 0.0034) and abnormal laboratory results (1.5 ± 1.2 and 2.0 ± 1.2; P = 0.023) were detected in the elder group than in the younger group; statistical differences were found between the groups regarding the frequencies of mutton-fat keratic precipitates (40% and 64%; P = 0.012), vitreous opacities (60% and 78%; P = 0.0059), bilateral inflammation (64% and 80%; P = 0.012), and bilateral hilar lymphadenopathy between the groups (52% and 78%; P < 0.001). Multiple linear regression analysis showed negative correlations between age and number of detected ocular signs (r = −0.36, P < 0.001) and laboratory results (r = −0.20, P = 0.023). The characteristic ocular signs and abnormal laboratory results had a lower frequency in the elder patients compared with the younger patients. Probable or possible ocular sarcoidosis by the international criteria should increase with increased life expectancy in developed countries.