OCT-Angiographic Findings in Intermediate Uveitis-related Refractory Macular Edema


 Objective : To assess the microvascular structure of macula in uveitic refractory macular edemaMethod:In a cross-sectional observational study fifty-five patients in all were assessed for macular microvascular structure using Optuve OCT angiography: 30 patients with intermediate uveitis-related refractory macular edema (RME group), and 25 patients with intermediate uveitis without macular edema (control group).Results:Superficial layer density in RME and control group were significantly different in whole image and parafovea (P=0.027 , P= 0.001), however there was no significant differences between the two groups in fovea superficial density (P=0.711).There was no significant difference in deep layer density between the two groups (P>0.05).Conclusion:The density of superficial vessels is lower in refractory macular edema. Micro-cystic changes in inner retina and ischemia can be the cause of alteration in superficial layer density in refractory macular edema.


Introduction
Cystoid macular edema (CME) is the main cause of permanent visual impairment in almost 40 to 50% of patients with uveitis [1] , and up to 80% in patients with intermediate uveitis. [2][3][4] Strong associations have been shown between the occurrence of CME and various speci c uveitis entities. Panuveitis showed the strongest association, with 66% of patients having CME, followed by intermediate uveitis at 60%, posterior uveitis at 34%, scleritis at 13%, and anterior uveitis at 11%. [1] The pathophysiology of uveitic CME is still undetermined. In short, the blood-retinal barrier integrity is responsible for keeping the environment of ocular neurons and photoreceptors stable. [5] The blood-retinal barrier is kept at two levels: an outer barrier consisting of tight junctions between the retinal pigment epithelium, and an inner barrier consisting of tight junctions between the endothelium of retinal vessels. [6] Various in ammatory mediators (prostaglandins, interleukins, interferon gamma, and tumor necrosis factor alpha) break down the blood retinal barrier, leading to an out ow of uid into and under the retinal tissue, resulting in extracellular edema. [7,8] . Swelling of Müller glial cells should also be presumed in the development of CME, including intracellular uid collection in the absence of vascular leakage, results in cysts formed by swollen and dying Müller cells. [9,10] Spectral domain optical coherence tomography angiography (SD-OCTA) is a unique imaging technology that employs the advances in OCT technology to make high-resolution angiographic displays of the retinal microvascular structure. [11][12][13] SD-OCTA permits both qualitative and quantitative evaluation of microvascular integrity in retinal vascular diseases, primarily in the parafovea, where visually signi cant pathology is often present (e.g., macular edema). In addition, SD-OCTA provides high-resolution macular capillary structural details along with a quantitative assessment of disease severity. Thus SD-OCTA provides near-histology-level resolution to assess capillary density and, in addition, is a non-invasive method that can be repeated frequently. [12] Subject And Method Patients A cross-sectional observational study was conducted using recorded data of patients examined at the Nikoukari Eye Hospital (Tabriz, Iran). A total of 55 cases, including 30 patients with refractory uveitic macular edema and 25 patients with intermediate uveitis without macular edema were enrolled between March 2017 and February 2018. Refractory macular edema was de ned as any macular edema that persisted after six months of treatment.
The study followed the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the Tabriz University of Medical Sciences. Written informed consent was obtained and patient con dentiality was safeguarded through study.
Speci c cases such as patients with other ocular diseases, history of eye surgery, pregnant women, inability to keeping the head and eye xed for imaging such as nystagmus, and low image quality were excluded.
All patients underwent OCT-angiography (AngioVue Imaging System (Optovue, Inc., Freemont, CA), using split-spectrum amplitude-decorrelation angiography (SSADA) algorithm. This instrument (Optovue) has an A-scan rate of 70,000 scans per second using a light source centered on 840 nm and a bandwidth of 50 nm. Each OCT-A volume consist of 304 × 304 A-scans with two consecutive B-scans took at each xed position. Each OCT-A volume is acquired in 3 seconds, and two orthogonal OCT-A volumes are acquired for orthogonal registration using motion correction technology. (1,2) This technique minimizes motion artifacts.

Statistical Analysis
Statistical analyses were performed using SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA). Normality was assessed using the Kolmogorov-Smirnov test. An independent-samples t-test was used to compare quantitative data and chi-square analysis was used for qualitative data. Descriptive statistics are expressed as frequency and percentage for categorical variables, mean ± standard error of mean for normally distributed variables. P<0.05 was considered statistically signi cant.

Results
This study enrolled fty-ve eyes with intermediate uveitis: 30 eyes from 20 patients with refractory macular edema due to intermediate uveitis (RME group), and 25 eyes from 17 patients with intermediate uveitis without macular edema (control group). Eight patients in RME group and 7 patients in control group were male (P=0.124). Averaged age of patients was 38.2 ± 7.9 (range 16-58years) in RME group versus 40.3 ± 9.4 (range 21-59 years) in control group. (P=0.753) In refractory macular edema (RME) group underlying cause of intermediate uveitis (IU) was idiopathic in 27 eyes, Multiple Sclerosis related IU in 2 eyes and Tuberculosis related IU in one eye. In the control group, 22 eyes had idiopathic IU, 1 eye rheumatoid arthritis related IU, 1 eye sarcoidosis IU and 1 eye Tuberculosis related IU.
In the examination period, there was neither active in ammation in RME patients nor reported history of macular edema in the control group. All patients in both groups were phakic and negative for previous ocular surgery.
Vascular structure of whole image in the size of 6 × 6 mm, fovea (1.5 ×1.5 mm) and parafovea (0.5 mm circle around fovea) were analyzed in the two groups using super cial and deep layer vascular information.
Super cial layer density in RME and control group were 41.91± 5.36 vs 45.77 ± 5.55 in whole image, 17.09 ± 8.27 vs 17.93 ± 6.72 in fovea and 39.02 ± 9.75 vs 47.47 ± 6.75 in parafovea respectively. There were signi cant differences in super cial density of whole image and parafovea between the two groups (P=0.027, p= 0.001 respectively) however there was no signi cant difference between the two groups in fovea super cial density (P=0.711).
There was no signi cant difference in deep layer density between the two groups (P>0.05).
Cystoid space was seen in the super cial capillary plexus in all 30 eyes in the RME group and in the deep capillary plexus in 20 eyes (66%). (Figures 1 and 2) Compared to the control group, whole image thicknesses of macula, central foveal thicknesses and parafoveal thicknesses were signi cantly higher in the RME group. (Table 1) There were no signi cant differences between the two groups in FAZ, FAZ perimeter, acircularity index, or the foveal vessel density in 300µm-wide region around the FAZ (P>0 . 05) (Table 1 , Figure 3).
There was no signi cant qualitative differences in overview images of OCT angiography print-out and vascular changes in the two groups such as capillary tuft, telangiectatic vessels or micro-aneurism.

Discussion
Leakage and trilaminar or triplanar patterns of the capillary plexus, particularly the deep capillary plexus limit evaluation of the foveal microvascular structure using fluorescein angiography (FA). [14][15][16] Other factors also limit FA visualization, including cataracts and blockage from macular edema. On the other hand, OCT angiography makes depth-resolved high-resolution images of both super cial and deep retinal capillary networks, making it possible to recognize microvascular abnormalities may not be identi ed using FA.
Our study found that vessel density in super cial capillary plexus was low in eyes with intermediate uveitis-related refractory macular edema compared to intermediate uveitis without macular edema.
In our study there was no signi cant difference in deep vessels density in fovea and parafovea and whole image between the two groups.
No signi cant differences were observed in FAZ, FAZ perimeter, Acircularity index and foveal vessel density in a 300-µm-wide region around FAZ between the two groups.
Study of Alice Y.Kim et al [17] , revealed that Uveitic Macular edema was related with deep retinal layer vascular alteration. This study indicates that it is very unlikely to attribute causality of these vascular changes to either macular edema or uveitis alone. This study did not exclude patients with other ocular disease such as diabetic retinopathy. In their analysis, signi cant alterations in the deep capillary network were co-localized with intra retinal cystoid spaces (generally, the inner nuclear and plexiform layers). [17] likewise, in another study conducted by Khotchali et al, cystoid space in DCP was more than SCP, so DCP density was altered more than SCP density in uveitic CME. [18] According to our ndings, intermediate uveitis related refractory macular edema was associated with microvascular changes compared to intermediate uveitis without macular edema. But changes were not in deep layers.
Spaida et al. noted that an important mechanism in the development of CME in retinal vascular disease such as diabetic retinopathy may be DCP ischemia. [19] All of our patients had intermediate uveitis, thus in ammation of vitreous in these patients may cause ischemia of inner retina and alteration of super cial layer density versus deep layer density.
Although mechanical dislocation of vessels from super cial layers into deep layers may lead to their microvascular changes and refractory macular edema.
Super cial vessels density in parafovea and whole image of macula was signi cantly lower than in refractory macular edema. These results are consistent with the reports of Tian et al study. They concluded that super cial vessels density in intermediate uveitis with CME was varied more than deep capillary density and the presence of CME rather than disease entity impacted vessels density of SCP. [20] Conclusion In our study, intermediate uveitis related refractory macular edema was associated with microvascular changes compared to intermediate uveitis without macular edema.
Super cial vessels density in parafovea and whole image of macula was signi cantly lower in refractory macular edema.
Micro-cystic change in inner retina and ischemia may be the cause of alteration in super cial layer density in refractory macular edema.
Low number of patients, lack of choroidal vessels microvascular data, limitation of patients in one type of uveitis (IU) and lack of access to history of onset of disease and treatment were some limitations of our study. We suggest other studies to be planned with all types of uveitis and in the durations of active and inactive in ammation to con rm or decline our ndings.

Declarations
Funding: This research received no speci c grant from any funding agency in the public, commercial, or not-forpro t sectors.

Con icts of interest:
The Authors declare that there is no con ict of interest. This study was approved by the Ethics Committee of the Tabriz University of Medical Sciences. Written informed consent was obtained and patient con dentiality was safeguarded through study Consent for publication: The signed Consent ensures that the Publisher has the Author's permission to publish the relevant Contribution.
Availability of data and material: The authors con rm that the data supporting the ndings of this study are available from the corresponding author on request.  Vascular structure of super cial layer of retina in the same patient with refractory uveitic macular edema. Note the quantitative data in the table.