Clinical relevance of fibrin membranous structures in the intra-photoreceptor outer segment separation on spectral domain optical coherence tomography (SD-OCT) in initial-onset acute Vogt-Koyanagi-Harada disease.

PURPOSE: The purpose of the study was to investigate clinical relevance of fibrin membranous structure (FMS) in the photoreceptor outer segments on spectral-domain optical coherence tomography (SD-OCT) in untreated initial-onset acute Vogt-Koyanagi-Harada (VKH) disease. METHODS: Clinical charts of 39 patients (78 eyes) diagnosed with initial-onset VKH disease were retrospectively reviewed. Age, gender, period from the onset of symptoms to first visit, visual acuity (VA), intraocular pressure (IOP), anterior chamber cells, serous retinal detachment (SRD), SD-OCT findings, as well as fluorescein (FA), and indocyanine green angiography (ICGA) were collected. RESULTS: FMS was observed in 24 out of 39 VKH patients in either eye (61.5%). VKH patients with FMS (FMS group) were significantly younger and had the shorter period from the onset of symptoms to the first visit compared with those without FMS (non-FMS group). Mean logMAR VA and proportion of pooling of dye, mean central retinal thickness (CRT) were significantly higher in FMS group than in non-FMS group. In contrast, hyperfluorescence of the optic disc on FA was more in non-FMS group than in FMS group. Significant positive correlations between CRT and logMAR VA or IOP were only observed in the FMS group. Total amount of corticosteroids was significantly greater in FMS group than in non-FMS group. However, there were no significant differences in LogMAR VA and IOP between two groups at 6 months after treatment initiation. CONCLUSION: FMS on SD-OCT is a critical feature observed in the early stage of initial-onset acute VKH disease, which is more common in younger patients and is related to the disease activity.

Epidemiology and characteristics of common forms of anterior uveitis at initial presentation in a tertiary facility in Japan.

PURPOSE: To elucidate detailed epidemiological profile of common types of anterior uveitis (AU) in real-world clinical setting of a tertiary facility in Japan, and to evaluate the characteristic clinical findings at initial presentation. STUDY DESIGN: Retrospective cohort study. METHODS: Clinical charts of 275 patients (335 eyes) aged 52.5 ± 19.1 years were reviewed retrospectively. Herpetic AU was diagnosed by multiplex polymerase chain reaction tests using aqueous humor. Time of uveitis onset, gender, laterality, disease course since the initial onset of AU, visual acuity (VA) and intraocular pressure (IOP) at first visit, and definitive diagnosis were collected from clinical charts. RESULTS: Acute AU (AAU) was the most common (21.8%) form of AU; followed by herpetic AU (20.7%) comprising Herpes Simplex Virus (HSV) (8.0%), Varicella Zoster Virus (VZV) (9.1%) and cytomegalo virus (CMV) (3.6%); scleritis (13.5%); diabetic iritis (7.6%), and Posner-Schlossman syndrome (5.5%). Unilateral AU constituted 78.2%, and VA less than 20/30 accounted for 31.2%. Of all the eyes, 16.1% had an IOP higher than 20 mmHg, out of which 37.0% had herpetic AU, followed by scleritis in 25.9%, and Posner-Schlossman syndrome (PSS) in 11.1%. AU patients over 60 years of age were 40.4%, in which 34.2% had herpetic AU, followed by scleritis in 14.4% and AAU in 13.5%. Herpetic AU patients were significantly older and had higher IOP compared with AAU patients. CONCLUSION: The most frequent AU was AAU, followed by herpetic AU. Herpetic AU patients were older and had higher intraocular pressure than AAU patients, although VA was equally impaired in both groups.

Osteopontin-induced vascular hyperpermeability through tight junction disruption in diabetic retina.

Diabetic retinopathy is a major cause of blindness in developed countries, and is characterized by deterioration of barrier function causing vascular hyperpermeability and retinal edema. Vascular endothelial growth factor (VEGF) is a major mediator of diabetic macular edema. Although anti-VEGF drugs are the first-line treatment for diabetic macular edema, some cases are refractory to anti-VEGF therapy. Osteopontin (OPN) is a phosphoglycoprotein with diverse functions and expressed in various cells and tissues. Elevated OPN level has been implicated in diabetic retinopathy, but whether OPN is involved in hyperpermeability remains unclear. Using streptozotocin-induced diabetic mice (STZ mice) and human retinal endothelial cells (HRECs), we tested the hypothesis that up-regulated OPN causes tight junction disruption, leading to vascular hyperpermeability. The serum and retinal OPN concentrations were elevated in STZ mice compared to controls. Intravitreal injection of anti-OPN neutralizing antibody (anti-OPN Ab) suppressed vascular hyperpermeability and prevented decreases in claudin-5 and ZO-1 gene expression levels in the retina of STZ mice. Immunohistochemical staining of retinal vessels in STZ mice revealed claudin-5 immunoreactivity with punctate distribution and attenuated ZO-1 immunoreactivity, and these changes were prevented by anti-OPN Ab. Intravitreal injection of anti-OPN Ab did not change VEGF gene expression or protein concentration in retina of STZ mice. In an in vitro study, HRECs were exposed to normal glucose or high glucose with or without OPN for 48 h, and barrier function was evaluated by transendothelial electrical resistance and Evans blue permeation. Barrier function deteriorated under high glucose condition, and was further exacerbated by the addition of OPN. Immunofluorescence localization of claudin-5 and ZO-1 demonstrated punctate appearance with discontinuous junction in HRECs exposed to high glucose and OPN. There were no changes in VEGF and VEGF receptor-2 expression levels in HRECs by exposure to OPN. Our results suggest that OPN induces tight junction disruption and vascular hyperpermeability under diabetic conditions. Targeting OPN may be an effective approach to manage diabetic retinopathy.

Cytomegalovirus Retinitis with Hypopyon Similar to Bacterial Endophthalmitis in a Patient with non-Hodgkin's Lymphoma.

PURPOSE: To report a case of cytomegalovirus retinitis (CMVR) with hypopyon and intense ocular inflammation. CASE REPORT: An 81-year-old female was referred to our hospital with a suspicion of postoperative endophthalmitis in the left eye. She had been treated with etoposide and prednisolone for non-Hodgkin's lymphoma. Examination revealed mutton-fat keratic precipitates and numerous infiltrating cells in the anterior chamber with hypopyon. The fundus was invisible due to intense vitreous opacity. Systemic and topical administration of antibiotics was started, and vitrectomy was performed. However, the ocular symptoms did not respond to treatment. Vitrectomy was repeated twice, but severe endophthalmitis findings recurred soon after surgery. Finally, a comprehensive viral PCR test using the intraocular fluid detected CMV with 3.34 × 109 copies/ml, leading to a diagnosis of CMV retinitis. CONCLUSIONS: If the causative agent is not identified in endophthalmitis that develops in immunosuppressive patients, CMV may also be considered as the possible cause.

Inflammatory Factors of Macular Atrophy in Eyes With Neovascular Age-Related Macular Degeneration Treated With Aflibercept.

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment. Methods: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured. Results: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1ß, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1ß, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1ß were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1ß (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group. Conclusion: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy.

Retinal changes in mice spontaneously developing diabetes by Th17-cell deviation.

Elevated level of interleukin (IL)-17, predominantly produced by T helper (Th) 17 cells, has been implicated in diabetic retinopathy (DR), but it remains unclear whether IL-17 is involved in the pathogenesis of DR. Ins2Akita (Akita) mice spontaneously develop diabetes, and show early pathophysiological changes in diabetic complications. On the other hand, interferon-γ knock out (GKO) mice exhibit high differentiation and activation of Th2 and Th17 cells as a result of Th1 cell inhibition. In this study, Ins2Akita IFN-γ-deficient (Akita-GKO) mice were established by crossbreeding Akita mice with GKO mice, and Th17-mediated immune responses on DR were investigated. Blood glucose levels (BGL) of Akita mice and Akita-GKO mice were significantly higher than those of age-matched wild type (WT) or GKO mice, and there was no significant difference in BGL between Akita and Akita-GKO mice. Relative mRNA expression of ROR-γt that is a transcriptional factor of Th17 cells but not GATA-3 that is for Th2 cells was significantly upregulated only in Akita-GKO mice compared with WT mice, and the proportions of IL-17 and IL-22-producing splenic CD4+ cells were significantly higher in Akita-GKO mice than in wild type (WT), Akita, or GKO mice. In the retina, mRNA expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) were increased in Akita-GKO mice more than in Akita or GKO mice, and statistically significant differences were observed between Akita-GKO mice and WT mice. Leukostasis in retinal vessels and ocular level of VEGF protein increased significantly in Akita-GKO mice compared with the other groups. Edematous change in the retinal surface layer, retinal exudative lesions depicted as areas of hyperfluorescence in fluorescein angiography (FA), and vascular basement membrane thickening in all layers of the retina were also observed in Akita-GKO mice at 9-week-old but not in age-matched Akita or GKO mice. These results suggested that Th17 cell-mediated immune responses might be involved in promotion of functional and morphological changes in the retina of mice spontaneously developing diabetes.

Clinical characteristics and visual outcomes of work-related open globe injuries in Japanese patients.

PURPOSE: To investigate the clinical characteristics and visual outcomes of patients with work-related open globe injuries (OGIs) and compare them with patients with non-work-related OGIs. DESIGN: Retrospective, observational, multicentre, case-control study. METHODS: A total of 374 patients with work-related OGIs and 170 patients with non-work-related OGIs who presented to hospitals that belong to the Japan-Clinical Research of Study group from 2005 to 2015 were included in this study. Clinical data including age, sex, initial and final visual acuity, type of open globe injury, lens status, zone of injury, wound length, and presence of proliferative vitreoretinopathy, retinal detachment, expulsive haemorrhage, and endophthalmitis were recorded. MAIN OUTCOME MEASURES: Visual acuity. Results Work-related OGIs were associated with younger age, male sex, better initial and final visual acuity, more laceration, smaller wounds, presence of retinal detachment, and expulsive haemorrhage, compared with non-work-related OGIs. Multiple regression analysis revealed that final visual acuity is significantly associated with initial visual acuity, wound length, and the presence of proliferative vitreoretinopathy in work-related OGIs. CONCLUSIONS: Work-related OGIs showed better visual outcomes than other OGIs. Initial visual acuity, wound length, and the presence of proliferative vitreoretinopathy are predictors of visual outcomes in patients with work-related OGIs.

Identification of Underlying Inflammation in Vogt-Koyanagi-Harada Disease with Sunset Glow Fundus by Multiple Analyses.

PURPOSE: To evaluate underlying subclinical ocular inflammation in Vogt-Koyanagi-Harada (VKH) disease with sunset glow fundus (SGF) by multiple analyses. STUDY DESIGN: Retrospective observational study. METHODS: Clinical records of 34 eyes of 17 VKH patients with SGF in whom laser flare photometry (LFP), enhanced depth imaging optical coherence tomography (EDI-OCT), and indocyanine green angiography (ICGA) were performed on the same day were reviewed. The mean age was 57.3 ± 16.3 years, and the mean duration from the initial onset of uveitis was 47.1 ± 22.1 months. Flare counts, ICGA scores, and subfoveal choroidal thickness (SFCT) were compared between eyes. RESULTS: Although clinical ocular inflammation was observed only in 4 eyes (11.8%), inflammatory signs were observed in 23 out of 34 eyes by LFP (67.6%), in 27 eyes by ICGA (79.4%), and in 10 eyes by SFCT (29.4%). Active inflammatory signs detected by ICGA were observed in 77.8% by LFP and in 25.9% by SFCT. The strength of agreement (Cohen's kappa coefficient) between positive ICGA score and positive flare score was 0.406 (95% CI: 0.076-0.7359, P < 0.01), but there was no association between positive ICGA score and increased SFCT. In addition, positive flare count was the significant prognostic factor of positive ICGA score with odds ratio 11.7. CONCLUSIONS: Subclinical ocular inflammation signs were detected in most VKH patients with SGF by ICGA and a substantial proportion of which were also detected by LFP, whereas SFCT was less sensitive to detect subclinical inflammation.

Clinical preferences and trends of anti-vascular endothelial growth factor treatments for diabetic macular edema in Japan.

AIMS/INTRODUCTION: To determine the current clinical preferences of anti-vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan. MATERIALS AND METHODS: This was a descriptive cross-sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists. RESULTS: The results showed that 81.2% preferred intravitreal injections of anti-VEGF antibodies as the first-line therapy. The most important indicators for beginning anti-VEGF therapy were: the best-corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti-VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub-Tenon steroid injection were preferred. The contraindications for anti-VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti-VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately. CONCLUSIONS: Our results present the current clinical preferences of anti-VEGF treatment for DME in Japan. The best-corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti-VEGF treatment as first-line therapy and prefer the 1 + pro re nata regimen.

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.

Clinical characteristics and outcomes of fall-related open globe injuries in Japan.

PURPOSE: To investigate the clinical characteristics and visual outcomes in patients with fall-related open globe injuries and to evaluate differences between fall-related and non-fall-related open globe injuries in Japan. METHODS: A retrospective review of patients with open globe injury who presented to Japan-Clinical Research of Study (J-CREST) hospitals between 2005 and 2015 was enrolled. Clinical information including age, sex, initial visual acuity, final visual acuity, type of injury, status of the crystalline lens, zone of injury, wound length, presence of retinal detachment, proliferative vitreoretinopathy, expulsive hemorrhage, and endophthalmitis was recorded. RESULTS: A total of 374 eyes were enrolled, of which 120 (32.1%) suffered from fall-related injury with average age of 73.7 ± 15.9 years (range, 11-101 years). A majority of patients were female (55.8%). Of 120 patients with fall-related injury, 109 (90.8%) presented with rupture and 11 (9.2%) with laceration. A multiple regression analysis revealed that final visual acuity was significantly associated with initial visual acuity (r = 0.99, P < 0.001). Compared to non-fall-related open globe injuries, fall-related open globe injuries were associated with elderly age, female sex, poorer initial and final visual acuity, rupture, absence of the lens, larger wound size, retinal detachment, expulsive hemorrhage, and absence of endophthalmitis (P < 0.01). CONCLUSIONS: Fall-related open globe injuries were more frequent in elderly female and accompanied by larger wound lengths and severer ocular complications. Visual outcomes in patients with fall-related open globe injuries were related to initial visual acuity.

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-1ß, 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.

Reconstitution of disrupted photoreceptor layer in uveitis associated with Behçet's disease by infliximab treatment.

BACKGROUND: Behçet's disease (BD)-associated uveitis causes retinal damage leading to severe visual disturbance. The early morphological changes in the retina are revealed by disappearance or disruption of the external limiting membrane (ELM), inner segment ellipsoid zone (EZ) and cone interdigitation zone (CIZ) in the outer retina shown on spectral domain-optical coherence tomography (SD-OCT). However, it is unknown whether these changes in the retina are reversible in BD-associated uveitis. CASE PRESENTATION: A 38-year-old man was referred to our hospital with 5 years history of panuveitis in both eyes. Recurrent oral ulcer, folliculitis, and genital ulcer were noted as systemic complications. Moderate cell infiltration into the anterior chamber, and diffuse vitritis were observed in both eyes, and best corrective visual acuity (BCVA) was 20/60 in the right and 20/200 in the left eye. Fluorescein angiography (FA) showed severe dye leakage from extensive retinal vessels in both eyes. Spectral domain-optical coherence tomography (SD-OCT) revealed retinal cysts and disruption of the external limiting membrane (ELM), inner segment ellipsoid zone (EZ) and cone interdigitation zone (CIZ) in the macular region of both eyes. BD was diagnosed based on the ocular features and systemic lesions, and infliximab therapy was initiated for the severe visual disturbance. After treatment with infliximab, foveal excavation was first recovered with disappearance of retinal cysts, and then ELM and EZ were gradually reconstituted on SD-OCT. Finally, CIZ became distinguishable after 24 months of infliximab therapy. BCVA was recovered to 20/25 in both eyes, and ocular inflammatory attack did not recur after the initiation of infliximab therapy. CONCLUSION: Disruption of ELM, EZ, and CIZ shown on SD-OCT in BD-associated uveitis could be reconstituted by continuous infliximab treatment, which leaded to the improvement of visual acuity.

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 Behçet's 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.