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Introduction

Punctuate inner choroidopathy (PIC) is an ocular inflammatory disease mostly affecting young myopic women. Patients with PIC present symptoms of loss of central visual acuity (VA), metamorphic and scotomata. Although PIC is usually a benign disease; complications such as choroidal neovascularization (CNV) and subretinal fibrosis can lead to severe vision loss [1]. Inflammation may play a pathogenic role in PIC; while choroidal neovascularization is a very common complication as the disease progressed [2]. However, hyper-fluorescence and leakage can be found in both active inflammatory lesions and CNV, it is difficult to differentiate them by fundus fluorescein angiography (FFA). The newly developed optical coherence tomography angiography (OCTA) provides the abnormal blood flow signals, which can aid in the differential diagnosis of choroidal neovascularization and inflammation[3]. but it is not widely used than optical coherence tomography (OCT) in grassroots medical institutions[4]. In order to easily distinguish the PIC inflammation lesion and secondary CNV, we utilized spectral domain OCT (SD-OCT) to study the morphological characteristics of these lesions. SD-OCT can detect the morphological changes of different layers of the retina and choroid with high sensitivity, specificity and depth-resolution. Thus, it will be a good tool to study PIC, which usually affects the level of the deep retina and choroid.

Methods

17 patients (18 eyes) with PIC who complained acute blurring of vision within 4 weeks from Xiamen Eye Center between April 2019 and April 2020 were included in the study. The inclusion criteria were: (1) Presence of punctate, yellow-white lesions (most ≤ 500μm) in the posterior pole; (2) SD-OCT imaging revealed lesions at the level of the deep retina and choroid; (3) SD-OCTA showed no evidence of CNV. Exclusion criteria were: (1) Eye diseases such as retinal vascular occlusions, diabetic retinopathy, age-related macular degeneration, optic nerve diseases and glaucoma that affect vision; (2) Any other type of CNV; (3) After any treatment such as anti-vascular endothelial growth factor (VEGF), glucocorticoid; (4) Other white dot syndromes, such as diffuse subretinal fibrosis, acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroiditis. Each patient underwent best corrected visual acuity (BCVA) measurement with logMAR charts, slit lamp examination, dilated fundoscopy, fundus photography (KOWA nonmyd WX3D, Optos 200Tx), SD-OCT (Spectralis SD-OCT, Cirrus HD-OCT5000), and SD-OCTA (Cirrus HD-5000). SD-OCT was performed with enhanced depth imaging (EDI) and eye tracking function using a line scan, star scan, volume scan modes which across macular fovea and cover lesions. All patients were diagnosed as PIC without CNV based on OCT and OCTA at initial visit. The patients were scheduled to visit every 4 weeks and followed up at least 12 weeks. Based on OCTA, the patients were then classified into two groups by the combination with/without CNV during follow-up. The SD-OCT images of each group were recorded to find whether hyper-transmission, hypo-transmission, RPE disruption and EZ damage were present at 4, 8, 12 weeks of following up, respectively. In addition, the rate of these morphological signs showed up in SD-OCT images were calculated and the association between the rate of the morphological signs and the incidence of secondary CNV in PIC were analyzed. Two reviewers (CYR and LMH) separately assessed all the images. Discrepancies in their findings were referred to a fundus specialist for a final determination.

Statistical Analysis

Normality of the variables was examined by Shapiro-Wilk normality test. The age, refractive error, VA were normalized (P=0.278, P=0.243, P=0.401). The measurement data were expressed as mean±standard deviation; the enumeration data were expressed as a constituent count or percentage. The rates of morphological signs on OCT and the incidence of PIC with secondary CN were compared by Fisher’s exact test, respectively. A P value of < 0.05 was considered to be statistically significant.

Result

Patients characteristics: A total of 17 patients (18 eyes) with PIC who complained of acute blurring of vision within 4 weeks were enrolled in the study. The mean age was 31.89±9.19 years old (ranging from 18 to 53 years old). Eleven (61.1%) of them were female. The mean refractive error was -10.47±4.38 diopter (ranging from -2.00 D to -18.00 D). The best corrected visual acuity (Log MAR) at baseline was 0.69±0.33. Choroidal neovascularization was confirmed by SD-OCTA developed in 5 eyes (27.8%) during follow-up (Table1). Thirteen (72.2%) patients without any evidence of CNV throughout the time of observation required no therapeutic intervention, as their inflammatory lesions resolved and their visual acuity improved; at last visit, the average visual acuity was 0.31±0.20. All the patients with CNV received vascular endothelial growth factor inhibitors (anti-VEGF) treatment, and the CNV lesions resolved following with improved vision acuity.

SD-OCT Features

RPE and Bruch’s membrane integrity: At baseline, all 18 eyes had neither RPE disruption nor Bruch’s membrane (BM) disruption, while bulged RPE was observed in 5 eyes (Table 2). At 4 weeks of follow-up, these 5 eyes had RPE disruption and developed secondary CNV that was confirmed by SD-OCTA. During the 12-week follow-up, RPE/BM disruption was observed in all 5 eyes with CNV, but was not in the other 13 eyes. At 4, 8, 12 weeks of follow up, the incidence of RPE disruption was significant higher in PIC-CNV eyes when compared with PIC only eyes (P=0.001, Table 2). All patients showed evidence of homogenous or heterogenous material in macular fovea on SD-OCT images. Five cases which developed secondary CNV have been detected sub-RPE hyper-reflective material, while bulging homogenous hyper- or hypo-reflective material located were detected above intact RPE in the eyes without CNV.

Result

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Choroidal transmission: None of the 18 eyes had hyper-transmission at baseline. At the 4 weeks follow-up, a total of 5 eyes had choroidal hyper-transmission and CNV, of which 2 eyes had a choroidal hypo-transmission component adjoined to hyper-transmission zone, at the 8 and 12 weeks follow-up, hypo-transmission was also observed in the other 3 eyes (Table 2). At 4, 8, 12 weeks, the incidence of choroidal hyper-transmission in PIC-CNV eyes was 100% while in the eyes without CNV was 0. Lesions with hyper-transmission had higher risk in developing CNV compared with the eyes without hyper-transmission (P=1.17×10 -3) (Table 2). At 4 weeks follow-up, the incidence of choroidal hypo-transmission had no significant difference in the eyes with PIC only and PIC with CNV (PIC-CNV) (P=0.065); while at 8,12 weeks follow-up, the incidence of choroidal hypo-transmission was significantly higher in PICCNV eyes than eyes with PIC only (P=0.001,0.001) (Table 2).

Damage of EZ: All the 18 eyes had ellipsoid zone (EZ) elevation or disruption at baseline. EZ recovery began from 4 weeks. The recovery rate increased from (5/18) 27.8% at 4 weeks to (8/18) 44.4% at 8 weeks, and about (9/18) a half of EZ recovered at 12 weeks (Table 2). There was no significant difference in the incidence of EZ damage between PIC-CNV and PIC patients (P=0.150,0.196,0.353) (Table 2).

Result

Case 1

A 28-year-old male complained of vision loss and metamorphism of his right eye with ten days of evolution. He had a history of high myopia and Lasik surgery. The best-corrected visual acuity (BCVA) in the right eye (RE) was 20/80 (6/24 in Snellen visual acuity of 6 meters) and in the left eye (LE) was 20/20 (6/6 in Snellen visual acuity of 6 meters). There were no signs of inflammation in the anterior chamber or vitreous cavity. Fundoscopy evidenced local edema with sporadic, small, round, yellow-white lesions limited to the posterior pole of right eye and revealed no hemorrhage (Figure 1a). SD-OCT showed the presence of focal elevations of the EZ band with underlying hyper-reflective material. RPE and BM were integral and neither choroidal hyper-transmission nor hypo-transmission was observed below the lesion (Figure 1b).No sign of CNV was found using OCTA (Figure 1c and 1f). We diagnosed the patient with punctate inner choroidopathy without CNV, and regular follow-up visits were scheduled. Two weeks later, his visual acuity was 20/50 (6/15 in Snellen visual acuity of 6 meters), and the blurred vision was alleviated. SD-OCT showed hyper-reflective materials under EZ were absorbed and choroid maintained normal transmission (Figure 1e).

Case 2

A 22-year-old breast feeding women was referred to our hospital with the complaint of metamorphopsia for two days in her right eye. She had myopia (-5.5 D) in both eyes. At the initial visit, her best-corrected visual acuity (BCVA) was 20/50 (6/15 in Snellen visual acuity of 6 meters) in the right eye and was 20/20 (6/6 in Snellen visual acuity of 6 meters) in the left eye. No remarkable changes were revealed in either ocular anterior segments by slit-lamp examination. Fundus photography showed a distributed yellow-white lesion in her macular region (Figure 2a). SD-OCT imaging revealed disruption of the EZ zone with minimal sub-retinal fluid and a slight elevation of RPE, no choroidal hyper-or hypo-transmission below the level of RPE was observed (Figure 2b). A follow up without any treatment was advised. Two weeks later, the patient came back with a complaint of decreased visual acuity, which was 20/200 (6/60 in Snellen visual acuity of 6 meters) in the right eye. A small yellow-white lesion appeared in the inferior nasal of fovea (Figure 2c). SD-OCT imaging showed a moderate reflective material under RPE with a disruption of BM (Bruch’s membrane), and hyper-transmission in choroid. The 3×3 mm SD-OCTA en face image showed an abnormal vascular network (Figure 2d). As the disease progressed, SD-OCT images began to show an area of choroidal hypo-transmission adjacent to the areas of a choroidal hyper-transmission (Figure 2e). The patient was diagnosed with CNV secondary to PIC. We advised the patient to receive anti-VEGF treatment, but she refused, which made the deterioration of disease (Figure 2g,2h). Finally, the patient agreed to receive anti-VEGF, and her BCVA improved to 20/125 (6/38 in Snellen visual acuity of 6 meters), accompanied with the shrinkage of the neovascularization (Figure 3).

Discussion

Previous studies suggested the incidences of inflammatory CNV are range from 56.3% to 75% [5-8], and the incidences may increase over time [9] with repeated episodes of PIC. As a common complication of PIC, secondary CNV has similar features to inflammation lesions. They both present symptoms of vision loss, scotomata or metamorphopsia, cause infiltrating lesions and show heterogeneous material in the outer retina and sub retinal space. Since hyper-fluorescent and leakage can be found in both active inflammatory lesions and CNV, it is difficult to distinguish them through FFA. OCTA could significantly improve the detection rate, identify CNV from inflammatory lesions by catching abnormal blood flow signs in different layers of the retina [3, 10-12]. However, OCTA are not widely used than OCT in grassroots medical institutions. In order to find a routine and available instrument to help distinguish the PIC inflammatory lesion from secondary CNV, we characterized SD-OCT features of PIC patients with clinical symptoms and tracked the changes during patients’ follow-up. We reported 17 patients (18 eyes) had recent acute blurring of vision and diagnosed with PIC, during three months of follow-up, five eyes (27.8%) with PIC lesions developed secondary CNV confirmed by OCTA within four weeks in a natural course. We found that the changes of microstructure on SD-OCT images could provide special information for distinguishing inflammatory lesions and PIC-CNV, especially the choroidal transmission and the microstructure of outer retinal layer, RPE and BM.

Channa, et al. [1] and Watzke et al [13] described that clinically active patients would have RPE elevation with sub-RPE abnormal signals. Amer et al [14] found that half of the inflammatory lesions were confined between an intact BM and RPE; while all inflammatory CNV had associated fluid exudation, and signs of RPE and photoreceptor cell disruption. Our results are consistent to these published data [4]. We have comprehensively observed and tracked the morphological characteristics such as RPE breaking point using SD-OCT star scan and volume modes to prevent lesions from neglecting. The focal RPE elevation without breakage could be found in 5 eyes within 4 weeks after first symptom appeared. All of these 5 eyes have the presence of RPE disruption along with hyper-reflective sub-RPE deposits at 4 weeks follow-up, as well as secondary CNV formation confirmed by OCTA. We also observed that bulging homogenous hyper- or hypo-reflective material located above intact RPE in the eyes without CNV. The incidence of PIC-CNV was significantly higher in eyes with RPE disruption compared with eyes without RPE disruption, because inflammatory CNV usually growth from the sub-RPE space, through a breach in RPE, into either the sub retinal space or the outer retinal layers. The sub-RPE hyper-reflective deposits were the result of aggregation of inflammatory cells [15, 16]. Most importantly, we have found that choroidal hyper-transmission is also a characteristic sign of inflammatory CNV using SD-OCT EDI mode. None of the eyes had choroidal hyper-transmission at baseline. At 4 weeks follow-up, 5 eyes had RPE disruption along with choroidal hyper-transmission band below the PRE and were confirmed as secondary CNV by OCTA. As the secondary inflammatory CNV progressed, a choroidal hypo-transmission component could be detected in the middle of hyper-transmission zone, whereas this change could not be found in inflammatory lesions.

This study indicated a significant correlation between high transmission and the incidence of PIC-CNV at 4, 8 and 12 weeks as well as a significant association between hypo-transmission and PIC-CNV after 8 weeks. Therefore, the choroidal hyper-transmission highly suggested the occurrence of inflammatory CNV especially within 4 weeks. We speculated this hyper-transmission characteristic was accompanied with inflammation and RPE defects. Previous researchers considered that the presence of choroidal hyper-transmissions was due to the loss of melanin granules and disruption of the RPE and photoreceptors in acute inflamed lessons [17,18,]. For example,

Pachydaki SI et al. [19] reported a histopathological and electron microscopic analysis of excised PIC-associated CNV demonstrated a focus of inner choroidal inflammatory cells which was composed of mature small lymphocytes. A similar study also showed the occurrence of pigment granules extracellularly from focally damaged choroidal melanocytes [14]. And the choroidal hyper reflectivity appeared to be improved after treatment with anti-inflammatory or anti-VEGF therapy [18]. As we all known, materials that have high light absorptivity and reflectivity such as hemorrhage, pigment or scars will lead to a shadow of the signals below on OCT images [18]. These pathological changes in CNV complex resulted in an area of choroidal hypo-transmission associated with the lesion, which can be found in both myopic CNV (mCNV) and advanced PIC-CNV. However, due tothe different pathogenesis, mCNV had only choroidal hypo-transmission and absence of hyper-transmission through all the course [4]. Therefore, the mixed lesip>In this study, all the ellipsoid zone (EZ) bands had defects at baseline. At the 4 weeks follow-up, we found that the defects of EZ including elevation or disruption started to recovered, and the recovery rate increased with time from 27.8% at 4 weeks to 44.4% at 8 weeks, and about a half of EZ recovered at 12 weeks. The restoration of ellipsoid zone has been previously noted in PIC and in other inflammatory conditions [1]. Spaide RF et al [20] considered that loss of EZ bands improved over time and was corresponding to the improvement of visual function. Our results were consisted with this conclusion. In this study, we have found EZ recovered along with vision improvement, which was observed in the eyes without outer retinal atrophic changes or in the eyes with significantly shrinkage of CNV after prompt treatment; while the eyes which developed new secondary CNV or had progressive CNV with extensive fibrosis showed persistent EZ disruption. Therefore, we think that the restoration of EZ was highly relative to the stage of disease and degree of damage.

In conclusion, RPE disruption and choroidal hyper-transmission in SD-OCT are signs of inflammatory CNV in PIC, and SD-OCT is a useful tool for the differentiation and track of the progression of inflammatory lesions and inflammatory CNV in PIC. The increase of sampler size will greatly strengthen our study since a limited number of eyes was analyzed in this study. Future analysis of SD-OCT in patients with inflammatory diseases other than PIC may also provide more insight into the pathological processes and be helpful to monitor the prognosis of inflammatory CNV, which will enable us to better understand of retinochoroid diagnosis and the effect of treatment.

Ethical Approval

This study was conducted under the tenets of the Declarations of Helsinki and was approved by the ethics board of Xiamen University affiliated Xiamen Eye Center, Xiamen, China. Written informed consent was obtained from all patients. All patients provided informed consent after a thorough description of the nature and consequences of the study.

Acknowledgement

This study was supported by grant from the National Science Foundation for Young Scientists of China (Grant NO. 31807795) and the Science and Technology Program of Xiamen (3502Z20174002).