Clinical Manifestations and Outcomes of Tubercular Uveitis in Taiwan-A Ten-Year Multicenter Retrospective Study.

Background andObjectives: This 10-year multicenter retrospective study reviewed the clinical manifestations, diagnostic tests, and treatment modalities of tubercular uveitis (TBU), including direct infection and indirect immune-mediated hypersensitivity to mycobacterial antigens in Taiwan. Materials and Methods: This retrospective chart review of patients with TBU was conducted at 11 centers from 1 January 2008 to 31 December 2017. We used a multiple regression model to analyze which factors influenced best-corrected visual acuity (BCVA) improvement. Results: A total of 79 eyes from 51 patients were included in the study. The mean age was 48.9 ± 16.4 years. The mean change of LogMAR BCVA at last visit was -0.21 ± 0.45. Diagnostic tools used include chest X-ray, chest computed tomography, Mantoux test, interferon gamma release test (QuantiFERON-TB Gold test), intraocular fluid tuberculosis polymerase chain reaction, and bronchial alveolar lavage. The clinical manifestations included 48% posterior uveitis and 37% panuveitis. In the sample, 55% of the cases were bilateral and 45% unilateral. There was 60.76% retinal vasculitis, 35.44% choroiditis, 21.52% serpiginous-like choroiditis, 17.72% vitreous hemorrhage, 12.66% posterior synechiae, 6.33% retinal detachment, and 3.80% choroidal granuloma. Treatment modalities included rifampicin, isoniazid, pyrazinamide, ethambutol, oral steroid, posterior triamcinolone, non-steroidal anti-inflammatory drugs, vitrectomy, and immunosuppressants. BCVA improved in 53.2% of eyes and remained stable in 32.9% of eyes. In the final model of multiple regression, worse initial BCVA, pyrazinamide, and receiving vitrectomy predicted better BCVA improvement. Ethambutol was associated with worse visual outcomes. Seven eyes experienced recurrence. Conclusions: This is the largest 10-year multicenter retrospective study of TBU in Taiwan to date, demonstrating the distribution of clinical manifestations and clinical associations with better treatment outcomes. The study provides a comprehensive description of TBU phenotypes in Taiwan and highlights considerations for the design of further prospective studies to reliably assess the role of ATT and vitrectomy in patients with TBU.

Recommendation of using systemic anti-tumor necrosis factor-alpha for the treatment of noninfectious uveitis in Taiwan.

Noninfectious uveitis is a sight-threatening disease with an autoimmune or autoinflammatory basis. Systemic treatment is required if intraocular inflammation threatens a patient's vision or cannot be controlled locally and when it is associated with systemic rheumatic diseases. Corticosteroids and immunomodulatory chemotherapy are the conventional initial treatments. However, the various side effects of these therapies increase the burden on patients, not only physically but also mentally. Moreover, uncontrolled inflammation and poor visual outcomes have sometimes been recorded despite the combination of these medications or their high dosage. Antitumor necrosis factor-alpha (anti-TNF-α) and other biologic agents have been widely used to treat rheumatic diseases for >15 years. Randomized controlled clinical trials have demonstrated that anti-TNF-α can reduce and delay episodes of intraocular inflammation not only in patients with active uveitis but also in corticosteroid-dependent patients with inactive uveitis. The Taiwan Food and Drug Administration approved the use of adalimumab, an anti-TNF-α agent, for treating nonanterior noninfectious uveitis (NANIU) in 2017. This report provides a recommendation and a proposed stepladder approach for using anti-TNF-α agents to treat NANIU in Taiwan.

Effects of horizontal acceleration on human visual acuity and stereopsis.

The effect of horizontal acceleration on human visual acuity and stereopsis is demonstrated in this study. Twenty participants (mean age 22.6 years) were enrolled in the experiment. Acceleration from two different directions was performed at the Taiwan High-Speed Rail Laboratory. Gx and Gy (< and >0.1 g) were produced on an accelerating platform where the subjects stood. The visual acuity and stereopsis of the right eye were measured before and during the acceleration. Acceleration <0.1 g in the X- or Y-axis did not affect dynamic vision and stereopsis. Vision decreased (mean from 0.02 logMAR to 0.25 logMAR) and stereopsis declined significantly (mean from 40 s to 60.2 s of arc) when Gx > 0.1 g. Visual acuity worsened (mean from 0.02 logMAR to 0.19 logMAR) and poor stereopsis was noted (mean from 40 s to 50.2 s of arc) when Gy > 0.1 g. The effect of acceleration from the X-axis on the visual system was higher than that from the Y-axis. During acceleration, most subjects complained of ocular strain when reading. To our knowledge, this study is the first to report the exact levels of visual function loss during Gx and Gy.

Lapatinib and platinum-based chemotherapy ameliorate breast cancer with choroidal metastasis and restore visual acuity.

Involvement of the central nervous system in metastatic breast cancer is a particularly dismal occurrence because of its effects on mortality and quality of life. Development of choroidal metastasis in a breast cancer patient indicates poor prognosis and has become the major life-limiting problem. Various treatment modalities for choroidal metastasis have been applied with different efficacy. Here we describe a patient with HER2-overexpressing breast cancer and limited choroidal metastasis who responded to an HER2 tyrosine kinase inhibitor after failure of radiotherapy and chemotherapy. Her visual acuity was completely and durably restored after the targeted therapy. This case provides a unique treatment experience of breast cancer with choroidal metastasis.

Proteomic analysis and identification of aqueous humor proteins with a pathophysiological role in diabetic retinopathy.

Diabetic retinopathy (DR) can cause irreversible blindness and is the severest microvascular complication in the eyes of patients with diabetic mellitus (DM). The identification of susceptibility factors contributing to development of DR is helpful for identifying predisposed patients and improving treatment efficacy. Although proteomics analysis is useful for identifying protein markers related to diseases, it has never been used to explore DR-associated susceptibility factors in the aqueous humor (AH). To better understand the pathophysiology of DR and to identify DR-associated risk factors, a gel-based proteomics analysis was performed to compare AH protein profiles of DM patients with and without development of DR. MALDI-TOF MS was then performed to identify protein spots that were differentially expressed between the two groups and western blot analysis was used to validate the expressional change of protein demonstrated by proteomics. Our proteomics and bioinformatics analysis identified 11 proteins differentially expressed between DR and control groups. These proteins are linked to biological networks associated with nutrition transport, microstructure reorganization, angiogenesis, anti-oxidation, and neuroprotection. The data may provide potential AH biomarkers and susceptibility factors for predicting DR development, and provide an insight into the underlying pathophysiological mechanisms of DR. This article is part of a Special Issue entitled: Proteomics: The clinical link.

Ocular responses and visual performance after emergent acceleration stress.

PURPOSE: To evaluate visual function after emergent acceleration stress. METHODS: Sixteen subjects were enrolled in this study. Human ejection seat trainer was used to induce six times gravitational force in the head-to-toe (z-axis) direction (+6 Gz). Visual performance was evaluated using the visual chart and contrast sensitivity (CS) at indicated times. Ocular reactions were assessed with biomicroscopy and topographic mapping. RESULTS: Temporary visual acuity reduction (0.02 ± 0.05 vs. 0.18 ± 0.08 logMAR visual acuity [VA]; P < 0.05) and ocular reactions were observed after ejection. These reactions included changes in increasing anterior chamber depth (ACD; 3.18 ± 0.29 vs. 4.48 ± 0.32 mm; P < 0.05) and pupillary dilation (PD; 3.56 ± 0.72 vs. 5.64 ± 0.56 mm; P < 0.05). The ACD deepening continued at 15 minutes (4.37 ± 0.26 mm; P < 0.05), and PD persisted at 30 minutes after the gravitational stress (5.42 ± 0.54 mm, P < 0.05). CS decreased significantly at all spatial frequencies immediately after ejection. However, CS returned to the initial range at high spatial frequency by 30 minutes. CONCLUSIONS: Emergent acceleration force induces significant ocular responses and visual fluctuation. Prolonged ACD deepening (>15 minutes) and PD (>30 minutes) were noted, but cornea and refraction remain stable. CS at all spatial frequencies revealed remarkable reduction immediately after ejection, and recovered to baseline levels within 30 minutes only at high spatial frequency. Neuroretinal function may involve visual fluctuation after acceleration stress, because visual fluctuation corresponds with the characters of neuroretinal function. However, further studies are necessary.

Reactive arthritis following Streptococcus viridans urinary tract infection.

PURPOSE: To report a case with reactive arthritis (ReA) following Streptococcus viridans genitourinary infection. METHODS: Case report. DESIGN: Clinical findings and treatment are presented. The 28-year-old man visited the authors' hospital due to ciliary injection and hypopyon over left eye. On examination, Behcet-mimicking symptoms were observed, such as genital and oral ulcers and arthritis. Furthermore, S. viridans was found in the urethral discharge culture. Under the impression of ReA, which was triggered by S. viridans, NSAID and antibiotics were prescribed. Complete resolution of ocular and systemic symptoms was achieved after 2 months of treatment. CONCLUSIONS: Streptococcus viridans is potential microorganisms of ReA. Careful survey and prompt treatment is necessary.

Independent effects of the broccoli-derived compound sulforaphane on Ca²âº influx and apoptosis in Madin-Darby canine renal tubular cells.

This study explored whether sulforaphane changed basal [Ca²âº]i levels in suspended Madin-Darby canine kidney (MDCK) cells by using fura-2 as a Ca²âº-sensitive fluorescent dye. Sulforaphane at concentrations between 2.5-10 microM increased [Ca²âº]i in a concentration-dependent manner. This Ca²âº influx was inhibited by phospholipase A2 inhibitor aristolochic acid but not by Ca²âº channel blockers such as nifedipine, nimodipine, nicardipine, diltiazem, verapamil, econazole and SK&F96365. The Ca²âº signal was abolished by removing extracellular Ca²âº. In Ca²âº-free medium, pretreatment with sulforaphane did not alter the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin-induced Ca²âº release suggesting sulforaphane did not induce slow Ca²âº release from endoplasmic reticulum. At concentrations between 1 and 20 microM, sulforaphane induced concentration-dependent decrease in cell viability which was not affected by pre-chelation of cytosolic Ca²âº with BAPTA/AM. Flow cytometry data suggest that 20 (but not 5 and 10) microM sulforaphane induced significant increase in sub G1 phase indicating involvement of apoptosis. Collectively, in MDCK cells, sulforaphane induced [Ca²âº]i rises by causing Ca²âº entry through phospholipase A2-sensitive pathways without inducing Ca²âº release from the endoplasmic reticulum. Sulforaphane also induced Ca²âº-independent cell death that might involve apoptosis.

Suppression of experimental uveitis by a recombinant adeno-associated virus vector encoding interleukin-1 receptor antagonist.

PURPOSE: To evaluate the potential of gene therapy with a recombinant adeno-associated virus vector encoding the interleukin-1 receptor antagonist gene (rAAV-IL-1Ra) in the treatment of experimental uveitis. METHODS: The vitreal cavity of New Zealand white rabbits was injected with rAAV-IL-1Ra (4x10(7) infectious units), and the contralateral eye was injected with the same amount of rAAV-LacZ or PBS as a control. Transgene expression was evaluated by immunohistochemistry, ELISA, and RT-PCR. To evaluate the therapeutic potential of rAAV-IL-1Ra, experimental uveitis was induced by intravitreal injection of IL-1alpha at 10 and 100 days after rAAV-IL-1Ra administration. The effects of rAAV-IL-1Ra on experimental uveitis were investigated using histological and aqueous analysis. RESULTS: Following intravitreal injection of rAAV-IL-1Ra, transgene expression was found in various cell types of the ocular tissues, such as ciliary epithelial cells, retinal ganglion cells, and retinal pigment epithelial cells. RT-PCR and ELISA showed that the IL-1Ra transgene persisted in the rabbit eye for at least 100 days. Compared with the control eyes, the transgene expression ameliorated experimental uveitis at 10 and 100 days after a single administration of rAAV-IL-1Ra. CONCLUSIONS: Intravitreal administration of rAAV-IL-1Ra led to sustained human IL-1Ra transgene expression in rabbit eyes for 100 days. The transgene expression suppressed uveitis episodes at 10 and 100 days after rAAV-IL-1Ra injection. Long-term suppression of experimental uveitis could be achieved by gene therapy with rAAV-IL-1Ra.

Ocular responses and visual performance after high-acceleration force exposure.

PURPOSE: To evaluate ocular responses and visual performance after high-acceleration force exposure. METHODS: Fourteen men were enrolled in the study. A human centrifuge was used to induce nine times the acceleration force in the head-to-toe (z-axis) direction (+9 Gz force). Visual performance was evaluated using the ETDRS (Early Treatment of Diabetic Retinopathy Study) visual chart, and contrast sensitivity (CS) was examined before and after centrifugation. Ocular responses were assessed with biomicroscopy and topographic mapping after gravitational stress. RESULTS: Transient visual acuity reduction (0.02 +/- 0.04 logMar vs. 0.19 +/- 0.07 logMar VA; P < 0.05) and temporary ocular anterior segment reactions were observed immediately after centrifugation. These reactions included changes in corneal thickening (553.7 +/- 21.7 mum vs. 591.2 +/- 20.6 mum; P < 0.05), increasing anterior chamber depth (ACD; 3.19 +/- 0.26 mm vs. 4.53 +/- 0.34 mm; P < 0.05), and pupillary enlargement (3.54 +/- 0.73 mm vs. 5.76 +/- 0.61 mm; P < 0.05). The increase in ACD continued for 15 minutes after exposure to acceleration (3.19 +/- 0.26 mm vs. 4.39 +/- 0.27 mm; P < 0.05). Pupillary dilation was noted both 15 (3.54 +/- 0.73 mm vs. 5.56 +/- 0.67 mm; P < 0.05) and 30 (5.47 +/- 0.59 mm, P < 0.05) minutes after the gravitational stress. CS decreased significantly at low and medium spatial frequencies (1.5, 3, and 6 cyc/deg) and did not return to the baseline level by 30 minutes. CONCLUSIONS: High-acceleration force may induce transient visual acuity reduction and temporary corneal thickening. Prolonged increase in ACD and pupillary dilation were also observed. The decrease in CS persisted for 30 minutes after centrifugation. The mechanisms underlying these observations are not clear, because there are no previous reports on this topic. Further studies are needed.

Changes in visual function during the Coriolis illusion.

BACKGROUND: The Coriolis illusion produces spatial disorientation and is, therefore, dangerous for pilots. It is not known whether it also affects visual function (visual acuity and stereopsis). METHODS: There were 18 subjects (15 men and 3 women, mean age 24.7 yr) enrolled in the study. A spatial disorientation simulator was used to produce Coriolis stimulation. The visual acuity of the subjects was evaluated with the Rosenbaum Vision Card before and during Coriolis stimulation. Stereopsis was measured with the Titmus stereo test. Throughout the experiments, eyeball movements were observed on a television monitor. Electrooculography (EOG) and electroencephalography (EEG) were also documented. RESULTS: Before Coriolis stimulation, the visual acuity and stereopsis of all subjects were 20/20 and 40 s of arc, respectively. During the Coriolis illusion, the visual acuity of nine subjects (50%) remained 20/20, whereas the visual acuity of the others (50%) dropped by two lines. The stereopsis of most subjects (77.8%) decreased to 800 arc-seconds or less. Rhythmic nystagmus was observed, while EOG amplitudes were significantly elevated compared with those at baseline (9.41 +/- 0.26 microv2 and 8.45 +/- 0.36 microv2, respectively). EEG activity (frequency) was also greater than at baseline (13.15 +/- 0.84 Hz and 11.94 +/- 1.20 Hz, respectively; P < 0.05). CONCLUSIONS: During Coriolis stimulation, the visual acuity of the subjects remained stable, but their stereopsis was reduced. Further study is warranted.

Visual fields during acute exposure to a simulated altitude of 7620 m.

BACKGROUND: The hypoxia associated with sudden exposure to high altitude is known to impair vision and may thereby affect flight safety. However, no data were available regarding hypoxic effects on visual fields. The aim of this study was to evaluate black-and-white visual field sensitivity with acute hypoxia during acute exposure to a simulated altitude of 7620 m. METHODS: Subjects were 15 male pilots 26-39 yr of age. We measured arterial oxygen saturation (S(aO2)%) using transdermal pulse oximetry while the visual field was measured within a 30 degrees eccentricity in the right eye by computerized perimetry. The subject breathed 100% O2 for 30 min before and during chamber ascent, then removed his mask while measurements were performed. RESULTS: The S(aO2)% and visual field sensitivities (mean +/- SD) at ground level were 99.1 +/- 0.4% and 43.9 +/- 2.1 dB, respectively. During hypoxia, the S(aO2)% dropped to 64.0 +/- 5.4% within 3 min. Mean visual sensitivity was significantly reduced by 7.2 +/- 1.6 dB. Furthermore, peripheral sensitivity was slightly but significantly more diminished than central sensitivity. CONCLUSIONS: Severe acute hypoxia reduces central and moderate peripheral black-and-white vision by a factor of two with the strongest effect in the periphery.

Optic disc hemorrhages in a patient with hemophilia A.

To report a hemophilia patient complicated with optic disc hemorrhages. A 13-year-old boy presented to our emergency room with a black shadow in the left eye for 1 day. The best-corrected visual acuity was 6/6 in both eyes. Peripapillary retinal and subretinal hemorrhages were found in the left eye. Result of the laboratory examination showed an extremely low level of coagulation factor VIII (1.9%). Factor VIII concentrate was given for 8 weeks. A follow-up 3 months later showed absorption of the hemorrhages, black shadow diminished, and the vision was 6/6.

Inducible adeno-associated virus vector-delivered transgene expression in corneal endothelium.

PURPOSE: To investigate whether recombinant adeno-associated virus (rAAV) vector--mediated transgene expression is induced by inflammation in corneal endothelial cells in vivo. METHODS: The ocular anterior chamber of New Zealand White rabbits was injected with rAAV-LacZ (10(7) units of infection). Transient ocular anterior segment inflammation was induced by an intravitreal injection of lipopolysaccharide (LPS). The effect of inflammation on LacZ gene expression in corneal endothelial cells was evaluated by histochemical staining and reverse transcription-polymerase chain reaction (RT-PCR). The influence of rAAV on endothelial cell function was monitored by measuring corneal thickness. RESULTS: Inflammatory reaction peaked at 1 day after LPS treatment and, at the same time, most of the endothelial cells (91.3% plus minus 7.2%) showed prominent LacZ gene expression. The transgene expression gradually diminished to basal level (3.4% plus minus 2.1%) when the inflammation subsided at 15 days after LPS treatment. The diminished transgene expression was efficiently reactivated to a high level (86.1% plus minus 8.7%) by a second LPS injection 60 days later. Moreover, the transgene expression remained low for a long period (60 days) in the absence of LPS treatment, but was increased to high levels (87.3% plus minus 8.1%) 1 day after LPS treatment. Throughout the observation period, endothelial cell function remained intact. CONCLUSIONS: The rAAV vector can deliver genes into endothelial cells, and transgene expression is dramatically induced by inflammation. The rAAV-delivered transgene is stable and does not compromise endothelial cell function. Inducible rAAV-mediated transgene expression in corneal endothelial cells is a potential strategy in the treatment and prevention of ocular diseases.