Tear fluid cytokine analysis: a non-invasive approach for assessing retinopathy of prematurity severity.

PURPOSE: To determine whether there is a significant association between inflammatory cytokines in the tear fluid and the severity of Retinopathy of Prematurity (ROP). STUDY DESIGN: Retrospective cohort study. METHODS: The cytokine levels in tear fluids were determined in 34 eyes with ROP and 18 eyes without ROP. There were 15 eyes with severe ROP requiring treatment and 19 eyes with mild ROP not requiring treatment. For severe ROP eyes, tear fluids were collected before treatment. RESULTS: Significantly higher levels of CCL2 and vascular endothelial growth factor (VEGF) were detected in eyes with severe ROP compared to eyes with mild ROP and no ROP. When assessed for cytokine levels that discriminate each disease group, CCL2 showed a significant odds ratio of 1.76 for severity change (/quintile, P = 0.032, after adjusting for birth weight). Correlation analysis showed that birth weight correlated with IL-1α levels, and decreased weight gain increased IFN-γ levels. We next determined tear fluid cytokines which discriminate severe ROP using receiver operating characteristics' analysis. We found that combination of higher CCL2 levels, higher VEGF levels, and lower IFN-γ levels in the tear fluid had a stronger predictive value for severe ROP (area under curve, 0.85). CONCLUSION: The levels of CCL2, VEGF, and IFN-γ in tear fluid may serve as useful biomarkers for assessing the severity of ROP.

Profiling miRNAs in tear extracellular vesicles: a pilot study with implications for diagnosis of ocular diseases.

PURPOSE: To estimate the roles of extracellular vesicles (EVs) in tears and to determine whether their profiles are associated with the type of ocular disease. STUDY DESIGN: Cross-sectional study. METHODS: Tear EVs were extracted from 14 healthy participants and from 21 patients with retinal diseases (age-related macular degeneration [AMD] or diabetic macular edema [DME]). The surface marker expression of tear EVs was examined, and microRNAs (miRNAs) were extracted and profiled by use of real-time PCR array. The stability of the expression of the miRNAs was determined, and their functions were assessed by network analyses. Classification accuracy was evaluated by use of a random forest classifier and k-fold cross-validation. RESULTS: The miRNAs that were highly expressed in tear EVs were miR-323-3p, miR-548a-3p, and miR-516a-5p. The most stably expressed miRNAs independent of diseases were miR-520h and miR-146b-3p. The primary networks of the highly stably expressed endogenous miRNAs were annotated as regulation of organismal injury and abnormalities. The highly expressed miRNAs for severe retinal disease were miR-151-5p for AMD and miR-422a for DME, suggesting potential roles of tear EVs in liquid biopsy. Nine miRNAs (miR-25, miR-30d, miR-125b, miR-132, miR-150, miR-184, miR-342-3p, miR-378, and miR-518b) were identified as distinguishing individuals with AMD from healthy individuals with a classification accuracy of 91.9%. CONCLUSIONS: The finding that tear EVs contain characteristic miRNA species indicates that they may help in maintaining homeostasis and serve as a potential tool for disease diagnosis.

Association of IL-4 with pachychoroid neovasculopathy.

The purpose of this study was to identify the inflammatory cytokines that were associated with pachychoroid neovasculopathy (PNV). Seventy-five eyes of 75 patients with PNV, 145 eyes of 145 patients with neovascular age-related macular degeneration without pachyvessels, and 150 eyes of 150 normal subjects were examined for the levels of intraocular cytokines. In eyes with PNV, the levels of IL-1α, IL-1ß, IL-2, IL-4, IL-10, and VEGF were significantly higher than that of the controls. Logistic regression analysis showed that the highest association with the pachyvessels was found for IL-4, IL-2, and IL-1α. In eyes with PNV, the levels of IL-4, IL-2, IL-5, IL-13, IL-1α, and IL-1ß were significantly higher in eyes with both increased choroidal thickness and choroidal vessel diameter. The strongest correlation with the choroidal thickness and vessel diameter was observed for IL-4. In PNV eyes with polypoidal lesions, the levels of IL-4, IL-17, and TNFß were significantly correlated with the number of polypoidal lesions. Of these cytokines, IL-4 was especially associated with the thickness of the choroidal vessels and the formation of polypoidal lesions. We conclude that IL-4 is most likely involved in establishing the clinical characteristics of PNV and polypoidal vascular remodeling.

Antiviral cytotoxic T lymphocyte responses for long term prognosis of corneal infection by cytomegalovirus in immunocompetent subjects.

Ocular cytomegalovirus (CMV) infections in immunocompetent individuals are rare, but its activation can cause chronic and relapsing inflammation in anterior segment of the eye resulting in loss of corneal clarity and glaucoma. Fifty five patients with anterior segment CMV infection were assessed for their clinical characteristics, and CMV corneal endotheliitis was found to cause significant loss of corneal endothelial cells. The disease duration with recurrences was significantly correlated with the maximum intraocular level of CMV DNA. To examine why CMV is activated in healthy immunocompetent individuals and causing corneal endothelial cell damage, assays of cytotoxic T cells (CTLs) which directly target infected corneal endothelial cells were performed for 9 HLA-matched CMV corneal endotheliitis patients (HLA-A*2402). When the cell loss was analyzed for associations with CTL responses, CMV-induced endothelial cell damage was mitigated by pp65-specific CTL induction. The recurrence-free time was also prolonged by pp65-specific CTL induction (hazard ratio (HR): 0.93, P = 0.01). In contrast, IE1-specific CTL was associated with endothelial cell damage and reduced the time for corneal transplantation (HR: 1.6, P = 0.003) and glaucoma surgery (HR: 1.5, P = 0.001). Collectively, induction of pp65-specific CTL was associated with improved visual prognosis. However, IE1-specific CTL without proper induction of pp65-specific CTL can cause pathological damage leading to the need of surgical interventions.

Bilateral diffuse anterior scleritis after unilateral cataract surgery: A case report.

Surgically induced scleritis (SIS) is a rare complication after a variety of ocular surgeries. Majority of the patients had had two or more surgical procedures before the onset of SIS. We report a patient who developed bilateral diffuse scleritis after unilateral cataract surgery. A 64-year-old man presented with red eye and tenderness in the right eye. An uneventful cataract surgery had been conducted in the right eye 5 months earlier. He had lost vision in the left eye 25 years ago, and there had been no ocular symptoms in both the eyes for the previous 20 years. Scleritis of the right eye appeared 5 months after cataract surgery, and scleritis of the left eye developed three months later. No previous reports referred to the possibility that the right eye surgery could induce scleritis in the left eye. Our case implies that surgical trauma in one eye can induce scleritis in both the eyes with a history of severe inflammation.

Role of IL-4 in bone marrow driven dysregulated angiogenesis and age-related macular degeneration.

Age-associated sterile inflammation can cause dysregulated choroidal neovascularization (CNV) as age-related macular degeneration (AMD). Intraocular fluid screening of 234 AMD patients identified high levels of IL-4. The purpose of this study was to determine the functional role of IL-4 in CNV formation using murine CNV model. Our results indicate that the IL-4/IL-4 receptors (IL4Rs) controlled tube formation and global proangiogenic responses of bone marrow cells. CCR2+ bone marrow cells were recruited to form very early CNV lesions. IL-4 rapidly induces CCL2, which enhances recruitment of CCR2+ bone marrow cells. This in vivo communication, like quorum-sensing, was followed by the induction of IL-4 by the bone marrow cells during the formation of mature CNVs. For CNV development, IL-4 in bone marrow cells are critically required, and IL-4 directly promotes CNV formation mainly by IL-4R. The IL-4/IL-4Rα axis contributes to pathological angiogenesis through communications with bone marrow cells leading to retinal degeneration.

Subtenon triamcinolone injection for postoperative cystoid macular edema associated with tafluprost.

PURPOSE: We report the successful treatment of a case of cystoid macular edema (CME) associated with topical tafluprost, which was accompanied by serous retinal detachment (SRD). CASE: A 78-year-old woman underwent intraocular lens suture surgery, including anterior vitreous cutting, for crystalline lens dislocation in the right eye. Tafluprost was initiated 12 weeks after surgery. Intraocular pressure (IOP) was controlled at 10-14 mmHg. Visual acuity remained at 20/40-30/40. However, the patient complained of blurred vision (20/200) 9 months after surgery. CME accompanied by SRD was identified by optical coherence tomography (OCT) and treated with subtenon triamcinolone injection. Visual acuity rapidly increased to 20/50, and the volume of SRD decreased in a few days. Discontinuation of tafluprost and initiation of diclofenac eye drops improved visual acuity to 20/40 and resulted in improved OCT findings within a few weeks. Three months after injection, tafluprost was resumed along with diclofenac. No recurrence of CME occurred over the following 3 months, and IOP was controlled at 10-15 mmHg. CONCLUSION: SRD is considered to be a symptom of treatment-resistant CME, which may lead to poor visual acuity after recovery. In such cases, subtenon triamcinolone injection should be strongly considered at an early stage.

Successful treatment of prostaglandin-induced cystoid macular edema with subtenon triamcinolone.

PURPOSE: Cystoid macular edema (CME) is associated with the use of prostaglandin eye drops after cataract surgery. The study aim was to report on the treatment of two CME patients with subtenon triamcinolone injections. METHODS: Case one was a 70-year-old woman who underwent uneventful cataract surgery. Travoprost was administrated at 10 weeks after surgery, and CME occurred at 13 weeks after surgery. Case two was an 85-year-old man who underwent intraocular lens extraction and an intraocular lens suture operation. Latanoprost was readministered after the surgery. The patient complained of blurred vision 3 years later. RESULTS: For both cases, discontinuation of the prostaglandin eye drops, subsequent initiation of treatment with diclofenac eye drops, and subtenon injection of triamcinolone was followed by the rapid disappearance of the CME. After the CME had disappeared for 3 months, the prostaglandin eye drops were resumed. Diclofenac was added in case two. No CME recurrence was seen in either case over 2 years. CONCLUSION: Subtenon triamcinolone injection can be effective for CME associated with prostaglandin eye liquid after cataract surgery. Prostaglandin eye liquid that causes CME is not necessarily precluded for future use if administered under careful observation.