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Proliferative diabetic retinopathy (PDR) is a vision-threatening complication of diabetes mellitus (DM). Systemic and intraocular factors are intricately related to PDR, and vitreous fluid (VF) cytokines are representative intraocular biomarkers. However, the associations between systemic factors and VF cytokines and their influence on PDR pathology are unclear. This study aimed to examine the correlation between systemic factors and VF cytokines and analyze their contributions to the pathology of PDR using multivariate analyses. We conducted a retrospective observational study on 26 PDR eyes of 25 patients with type 2 DM, and 30 eyes of 30 patients with idiopathic macular hole or epiretinal membrane as controls. Fifteen systemic and laboratory tests including blood pressure (BP) and body mass index (BMI), and 27 cytokines in VF were analyzed. BP and BMI correlated positively with VF levels of IL-6 and IP-10 in PDR patients, while no significant correlation was found between systemic factors and VF cytokines in controls. MCP-1 and VEGF-A in VF separately clustered with different systemic factors in controls, but these cytokines lost the property similarity with systemic factors and acquired property similarity with each other in PDR. Systemic factors contributed to only 10.4%, whereas VF cytokines contributed to 42.3% out of 52.7% variance of the whole PDR dataset. Our results suggest that intraocular factors play a major role in the pathology of PDR, whereas systemic factors may have limited effects, and that BP and BMI control in PDR could be useful interventions to improve intraocular immune condition.

BackgroundNeovascular 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.MethodsTwenty-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.ResultsTwo-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)-1β, 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-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β 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-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group.ConclusionSubstantial 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.

Neovascular age-related macular degeneration (nAMD) is a complex and multi-factorial disease, and low-grade inflammation is associated with pathogenesis of nAMD. Aqueous humor could reflect intraocular immune environments in various eye diseases. The research so far used aqueous humor samples and revealed that inflammation is involved in pathophysiology of nAMD, although immunological roles of cytokines were evaluated inadequately with aspect to individual effects. Here we used 27 kinds of cytokines covering general immunologic reactions, examined specific expression patterns of cytokines, and assessed relationships between inflammation and pathophysiology of nAMD by multivariate analyses. In nAMD eyes, principal component analysis showed that IL-7, MCP-1, MIP-1β and VEGF had high principal component loadings of over 0.6 in the first principal component constituting 32.6% of all variability of the data. In exploratory factor analysis, IL-6, MCP-1 and MIP-1β had high factor loadings (FL) of over 0.5 in Factor 1 constituting 32.6% of all variability, while VEGF had FL of over 1.0 in Factor 3 constituting 10.7% of all variability. In hierarchical cluster analysis, MCP-1 and VEGF were located in the cluster of first proximate mutual distance to central retinal thickness. These data could suggest that low-grade inflammation is a principal contributor in nAMD.

Objective Penicillium species are abundant, generally saprophytic, and widely distributed in the environment. On rare occasions, they cause endophthalmitis in immunocompromised patients or in immunocompetent patients with uncontrolled diabetic mellitus or immunosuppressive agents. We report a case of endophthalmitis caused by Penicillium species in an immunocompetent patient without any disorders. Case presentation A 67-year-old woman presented with ocular pain, hyperemia, and blurred vision in her right eye. She was in an immunocompetent condition and had received cataract surgery without complications 3 months ago. Severe cell infiltration and a clump of 3 mm diameter were found in the anterior chamber of the right eye, and there was no abnormality in the posterior segment. Serum β-d-glucan was not elevated; bacterial culture, histological analysis, and PCR using aqueous humor did not detect any pathogen (28S rDNA 2.4×102 copies/mL). However, because the clinical findings suggested fungal endophthalmitis, anti-fungal medication was initiated. The inflammation was gradually resolved with contraction of the clump; however, it recurred 47 days after the initiation by discontinuation of antifungal medication. Examination of culture identified Penicillium species in samples from both the anterior chamber and the vitreous. Conclusion Chronic postoperative endophthalmitis by Penicillium species can occur in an immunocompetent patient without any systemic diseases.

Age-related macular degeneration (AMD) is a cause of blindness in people older than 50 years. Accumulating evidence indicates the involvement of systemic and local inflammation in the pathogenesis and progression of AMD. Aflibercept is an anti-vascular endothelial growth factor (VEGF) inhibitor, and intravitreal injection of aflibercept (IVA) is the approved treatments of neovascular AMD (nAMD), but the effect on inflammatory response remains unclear. The aim of our study was to investigate the profiles of inflammatory cytokines in the aqueous humor of nAMD patients before and after initiation of IVA. In nAMD patients, IP-10 level was significantly higher and IL-6 level was significantly lower compared with those of cataract patients as controls. Logistic regression analysis identified IP-10 as a positive factor and IL-6 a negative factor associated with the pathogenesis of nAMD. In addition, IP-10 level correlated positively with the mean thickness of macula in the central 1-mm diameter circle. After initiation of IVA, IP-10 level was further elevated, and correlated negatively with VEGF level. These data suggest that IP-10 plays a critical role as an antiangiogenic factor and at the same time an inflammatory factor in the pathogenesis and pathophysiology of nAMD eyes at onset and after IVA initiation.

Purpose: To report a case of successful treatment with infliximab for Behcet disease (BD) during pregnancy. Design: A case report.Methods: A 30-year-old woman was diagnosed with BD at 12 weeks of pregnancy. Additional symptoms occurred, and infliximab at a dose of 5 mg/kg body weight was initiated at 18 weeks and repeated.Results: All symptoms improved, and a 3950-g infant was delivered uneventfully without any abnormality at 39 weeks. A few weeks after delivery, uveitis and systemic symptoms relapsed. Infliximab was reinitiated and all symptoms were resolved.Conclusions: Infliximab may be safe and effective for BD during pregnancy.

Purpose: To investigate whether the multifocal visual evoked potential (mVEP) is dependent on the electrode position, and to confirm the reproducibility of the mVEP. Methods: The mVEPs were recorded using the Veris III system with two different bipolar electrode settings. In Position 1, electrodes were placed at equal distances in vertical alignment 2 cm above and below the inion. In Position 2, the electrodes were placed in horizontal alignment at equal distances 2 cm to the left and right of the inion. Dartboard pattern stimulation was conducted. The mVEPs were repeatedly recorded from 4 volunteers, and mainly the second-order kernel response components were analyzed. Results: Although the reproducibility of mVEP was good in both Position 1 and Position 2, each waveform of the mVEP was drastically different between the two positions. This difference in the waveforms was clearly shown in the center and at the horizontal meridian. We also investigated the first-order kernel response components of the mVEPs. Several traces of the first-order kernel response components did not reveal flat traces. This point is also worthy of consideration. Conclusion: Responses from mVEPs are clearly dependent on the electrode position.

To extract the nonlinear component of the electroretinogram (ERG) from the posterior pole (pp) of the human ocular fundus and to evaluate the possibility of its clinical application, three types of stimulus modes – double-flash, single-flash, and delayed single-flash stimuli – were produced using a conventional electrophysiological system. A large hexagonal element was presented on a CRT monitor, and ppERGs were recorded from 14 normal eyes and 16 eyes of eight highly myopic patients. The nonlinear component of the ppERG was obtained by subtracting the single-flash ERG and delayed single-flash ERG responses from the double flash ERG response. Three peaks were commonly observed in the nonlinear component of ppERG, all of which were significantly depressed in patients with high myopia. ppERGs that can be obtained using a simple algorithm might be useful in clinical applications.

Purpose: It has been reported that the second-order kernel response components of multifocal electroretinograms (mERGs) reflect the electrical activity of the inner retinal layers. In this study, we have investigated whether the amplitudes of the second-order kernel response components correlate with the spatial distribution of human retinal ganglion cells. Methods: Multifocal electroretinograms were recorded using the Veris III™ system from 5 healthy subjects with different stimulus and recording parameters. The mERGs were analyzed using the Veris Science™ software programs. The stimuli consisted of densely arranged arrays of 103, 61, 37 or 19 hexagonal elements. Four minutes were required to record one set of mERG responses using 8 sessions, and 8 minutes using 16 sessions. The second-order kernel response components were extracted and analyzed using the Veris Science™ program. Results: The signal-to-noise ratio of the first-order kernel response components was improved considerably by the summation of the nine reproducible responses from the same subject but the second-order kernel response components were not. The summation of the nine reproducible responses was insufficient to identify an array of the second-order kernel response components. Both the first- and second-order kernel response components were larger when fewer hexagonal elements were used. There was no significant difference in the individual responses between the 4-minute and the 8-minute recordings. A response density analysis revealed a weak correlation between the amplitude distribution of the second-order kernel response components and the spatial distribution of human retinal ganglion cells. Conclusions: The distribution of the amplitudes of the second-order kernel response components of the mERGs elicited from normal subjects did not correlate with the distribution of human ganglion cells. This suggests that the theory that second-order kernel response components arise from the activity of retinal ganglion cells should be reconsidered.

Anisomyopia is the condition in which there is a difference in the myopic refractive errors of the two eyes. In most cases the ocular axial lengths are different in the two eyes. To elucidate clinical factors in anisomyopia, we examined refractive errors and axial length in 11 patients. Two patients had dense corneal opacity and one patient had an apparent familial history of anisomyopia. These findings show that monocular deprivation in childhood and hereditary factors are important in the etiology of anisomyopia.

PURPOSE. To compare the ocular hypotensive effect of travoprost plus timolol (TTFC) and latanoprost plus timolol fixed combinations (LTFC) in patients with normal-tension glaucoma (NTG). METHODS. A two-sequence 12-week, multicenter, prospective, randomized, single-blinded, crossover clinical trial examined 59 NTG patients. If both eyes were eligible, only one eye (chosen at random) was used for analytical purposes. After a 12-week run-in period with dorzolamide plus timolol fixed combination (DTFC), patients were randomized into one of the two crossover sequences of treatment for 12 weeks with TTFC or LTFC and were subsequently crossed over to the alternative treatment for a further 12 weeks. The primary endpoint was reduction in IOP after 12 weeks of each treatment sequence. The effect of treatment on IOP was assessed using a linear mixed model. RESULTS. ThemeanbaselineIOPwas14.8 63.3mmHg(95%confidenceinterval[CI],14.1‐15.3 mmHg)for treatmentwithDTFC.TheTTFCtreatmentperiodshowedconsistentlylower mean IOP compared with LTFC treatment period at all measurement time points. Mean reduction in IOPat 12weekswassignificantlygreater inthe TTFC group than intheLTFC group (� 2.4 62.3 mm Hg vs. � 1.1 6 2.3 mm Hg; P ¼ 0.021). No interaction between the drug and treatment sequence was detected. The effects of intraocular lens implantation and measurement time were also not significant. The tolerability profiles of both treatments were similar. CONCLUSIONS. The additional reduction in IOP was greater with TTFC than with LTFC, and their tolerability profiles were similar. (http://www.umin.ac.jp/ctr/ number, UMIN 000005974.)

Sight threatening ocular complications are rare in adult patients with dermatomyositis. We encountered a 52-year-old female with dermatomyositis who had severe visual disturbance and rapidly progressive intersitial pneumonia. She was admitted to our hospital because of skin erythema, general fatigue, mild fever, and severe bilateral visual disturbance. Rentinal hemorrhages, cotton wool spots, and macular edema were observed in her fundus at the first ophthalmic examination. A diagnosis of dermatomyositis was made because of the myogenic pattern of her electromyogram, elevation of serum creatine kinase, and skin lesions. Oral prednisolone treatment was started and the retinopathy was improved, but was complicated by acute interstitial pneumonia. The interstitial pneumonia was not respond to steroid pulse therapy with methylprednisolone, and the patient died of respiratory failure on the 47th day after the onset of visual symptoms. In adult dermatomyositis patients, the complication of severe retinopathy should be considered as a risk factor for rapid progress of interstitial pneumonia.