MinSagongMD,PhDDepartmentofOphthalmology,YeungnamUniversityCollegeofMedicine

170Hyunchung-ro,Nam-gu,Daegu,42415,SouthKoreaTel:82-53-620-3443,Fax:82-53-626-5936,E-mail:msagong@ynu.ac.kr

ü  Significant correlation between VEGF and Ang-1, Ang-2, MCP-1, IL-8, IL-6, PIGF. ü  Significant correlation between PIGF and Ang-1, Ang-2, MCP-1, IL-8, IL-6, VEGF. ü  IL-6 and IL-8 showed significant correlation with all other cytokines.

Introduction

Difference of aqueous cytokines according to extent and location of ischemia assessed by ultra-widefield fluorescein angiography in macular edema secondary to retinal vein occlusion

Min Sagong1 , Donghyoun Noh1 , Gahyung Ryu , Junyeop Lee1 , Jano van Hemert2 1 Department of Ophthalmology, Yeungnam University College of Medicine, Daegu, Republic of Korea; 2 Optos Plc, Dunfermline, United Kingdom

§  Retinal vein occlusion (RVO) •  Vascular damage by complex cellular & inflammatory reactions. •  Disturbed balance of cytokines in ocular fluid of RVO.

ü  Angiogenic & inflammatory factors including VEGF, VEGFR-2, ICAM-1, IL-6, IL-8, MCP-1, PDGF, and TNF-alpha in aqueous and vitreous fluid

§  Concentration of aqueous or vitreous cytokines •  Cytokine levels in aqueous humor are supposed to reflect levels in the vitreous. •  VEGF, IL-6, IL-8, and MCP-1 levels showed significant correlation with retinal thickness and nonperfusion

area. •  IL-12 was significantly higher in the group refractory to bevacizumab. •  VEGF, IL-8 are associated with the improvement in ME after vitrectomy.

§  Recent advances in UWF software enable the area and length of the lesions to be automatically calculated in mm2 by correcting the non-linear distortion.

Purpose

§  To investigate the extent and location of nonperfusion area (NP) associated with changes of aqueous cytokines in patients with macular edema (ME) secondary to retinal vein occlusion (RVO) to analyze their association with best corrected visual acuity (BCVA) and central macular thickness (CMT).

Methods

§  Prospective cross-sectional study §  Inclusion criteria

•  Treatment naïve patients with ME (CMT ≥ 300㎛) secondary to RVO (n=31) •  BRVO (n=20), Hemi-CRVO (n=4), CRVO (n=7)

•  Age-matched control subjects (n=9) §  Exclusion criteria

•  Any previous treatment, other evidence of maculopathy §  Measurement of angiogenic & inflammatory cytokines

•  Ang-1, Ang-2, MCP-1, IL-8, IL-6, PDGF-AA, PIGF, and VEGF-A in aqueous humor were measured using suspension array technology.

Conclusion

§  Angiogenic and inflammatory cytokines in aqueous were overexpressed in RVO patients and showed a distinct differences according to the location and extent of NP.

§  In acute phase of RVO, mid-periphery, which is predominantly involved with partial ischemia representing the blood/oxygen deficiency, contributed to the production of angiogenic cytokines.

§  Complete ischemia may be the results of increased cytokines. §  Clinically, anti-VEGF with targeted retinal photocoagulation for complete ischemia may not reduce tr

eatment burden for the patients with ME related to RVO.

References

§  Association of inflammatory factors with macular edema in branch retinal vein occlusion. Noma H et al. JAMA Ophthalmol. 2013

§  Relation of intraocular concentrations of inflammatory factors and improvement of macular edema after vitrectomy in branch retinal vein occlusion. Okunuki Y et al. Am J Ophthalmol. 2011

§  Area of peripheral retinal nonperfusion and treatment response in branch and central retinal vein occlusion. Singer M et al. Retina 2014

§  Assessment of accuracy and precision of quantification of ultra-widefield images. M Sagong et al. Ophthalmology 2015

§  Quantification of UWF FA images §  Using stereographic projection technique from the early (45 sec), middle (2 min 30 sec), and late (5 min) phases UWF FA.

Areas of hypofluorescence with dilation and irregular patterns of the capillary networks

ü Distribution of NP and ISI showed significant difference among the retinal zones. (P<0.001) ü  Total ischemic area was most extensive in MPA, and was in order of NPA, FPA, and PMA. ü  Partial ischemia was mainly distributed in posterior retina & mid-periphery and complete ischemia was pr

edominant around periphery during acute phase.

v  Table 2. Distribution of ischemic area according to retinal zones

Results

v  Table 1. Baseline demographics

v  Figure 1. Correlation of retinal thickness and cytokines & VA

v  Table 3. Correlation of ischemia and cytokines, VA & CMT

§  Definition of perfused status and four concentric retinal zones

Spherical trigonometry 3D mapping Stereographic projection

§  Ischemic index (ISI)

Peri-macular area (0.5~3 mm)

Near-peripheral area (3~10 mm)

Mid-peripheral area (10~15 mm)

Far-peripheral area (15 mm ~ normal perfusion boundary)

Continuous area of hypofluorescence with remaining precapillary arterioles and postcapillary venules dilated and tortuous

ISI calculated by dividing ischemic area by total visible retina.

ü  Aqueous levels of Ang-1, Ang-2, MCP-1, IL-8, IL-6, PIGF, and VEGF-A were significantly higher in RVO group than control group.

ü  Total and partial ischemia showed significant correlation with CMT, Ang-1, Ang-2, MCP-1, IL-8, IL-6, PIGF, and VEGF-A.

ü However, complete NP and ISI did not showed correlation with any other factors.

Rho=0.518 P=0.016

Rho=0.354 P=0.055

Rho=0.420 P=0.021

Rho=0.633 P<0.001

Complete ischemia Partial ischemia

v  Table 4. Correlation matrix of cytokines

ü CMT correlated with Ang-2, IL-8, and baseline BCVA. (P=0.016, P=0.021, P<0.001, respectively)