Spectral-Domain Optical Coherence Tomography Angiography Findings in Multifocal Choroiditis With Active Lesions




Purpose


To describe optical coherence tomography angiography (OCTA) findings in multifocal choroiditis (MFC) with active lesions and to characterize the concordance between the OCTA and other traditional imaging modalities.


Design


Reliability and validity analysis.


Methods


Patients with suspected choroidal neovascularization (CNV) or acute inflammatory lesions associated with MFC were assessed in this study. All participants underwent preliminary traditional multimodal imaging including color fundus photography, fundus autofluorescence, near-infrared reflectance imaging, spectral-domain optical coherence tomography, and fluorescence angiography (FA). The participants were prospectively recruited to perform OCTA. OCTA findings of active lesions were compared with other traditional imaging results. Vascular flow signal representing CNV was identified, and a quantitative analysis of CNV size was performed on OCTA.


Results


Fifty-two eyes of 26 MFC patients (14 were bilaterally affected and 12 were unilaterally affected) were included. Among the 23 active CNV cases, 20 were confirmed on OCTA while the other 3 were invalid owing to severe motion artifacts. OCTA of CNV showed a well-circumscribed vascular network (mean flow area, 0.271 mm 2 [± 0.144 mm 2 ]). Among the 34 inflammatory lesions in 13 eyes, 32 showed no blood flow in the outer retina on OCTA while the other 2 showed blood flow signal.


Conclusions


OCTA has a predominant advantage in differentiating CNV from inflammatory lesions. It also allows the visualization of detailed vascular structure of CNV and the function of flow area measurement realizes the quantitative analysis of CNV. Hence, it could be an alternative option for CNV identification and may better guide treatment.


Multifocal choroiditis (MFC) is a chronic, recurrent, often bilateral, ocular inflammatory disorder of unknown etiopathogenesis that is more common in young or middle-aged myopic women. Patients with MFC may complain of blurred vision, floaters, scotomas, and photopsia. The inflammation results in the formation of multiple grayish or yellow-white, punched-out chorioretinal lesions that may progress to secondary inflammatory choroidal neovascularization (CNV), discrete pigmented fibrotic scars, atrophy, or curvilinear chorioretinal streak. The frequency of CNV is nearly 33.3% in patients with MFC, and the risk of developing CNV is also high, even in patients without clinical evidence of acute inflammation. The presence of CNV may be responsible for severe central visual loss, and hence prompt therapy is very important. In patients with only active inflammation, corticosteroid and immunomodulatory therapy is usually needed. However, in patients with active CNV, an intravitreal injection of an anti–vascular endothelial growth factor (VEGF) agent is required as well. Recognition of pathologic changes is required in treatment decision making. Early detection and monitoring of a new or recurrent active CNV is crucial for preventing progressive and irreversible vision loss in patients with MFC.


Nowadays, multimodal imaging plays an increasingly important role in diagnosing MFC nowadays. However, the distinction between active CNV and other lesions such as inflammation remains unclear in many cases. Color and red-free photography, near-infrared reflectance (NIR) imaging, and fundus autofluorescence (FAF) imaging are of little value in distinguishing active inflammation from CNV. Indocyanine green angiography (ICGA) may fail to identify CNV if the vascular change is insignificant, especially at the beginning of the disease. Spectral-domain optical coherence tomography (SDOCT) has become an important noninvasive method for structural imaging of patients with suspected CNV. However, both the inflammation and CNV may appear as hyperreflective signals on OCT, making it difficult to differentiate one from another. The gold standard for identifying CNV currently is fluorescence angiography (FA), but the possible adverse reactions to the dye, including nausea, allergy, and, rarely, anaphylaxis, limit the use of this invasive method. Therefore, an imaging modality that would help in unequivocal diagnosis of CNV in this population would be invaluable.


Recently a new imaging technology, the optical coherence tomography angiography (OCTA) using an algorithm called “split-spectrum amplitude-decorrelation angiography” (SSADA), has allowed for new insights into the visualization of normal and pathologic vascularization. It detects motion in the blood vessel lumen by measuring the variation in reflected OCT signal amplitude between consecutive cross-sectional scans. The use of the SSADA algorithm improves the signal-to-noise ratio of flow detection and provides a better visualization of the blood flow in selected retinal layers.


The present study evaluated a cohort of patients with MFC using both OCTA and other traditional imaging technologies to describe the concordance in detecting CNV in MFC. Also, the sensitivity and specificity of OCTA were evaluated using FA as the ground truth. This study did not distinguish between punctate inner choroidopathy (PIC) and MFC, which were considered as different entities in the past. According to the multimodal imaging study by Spade and associates, MFC and PIC might be the same disease, since they target the same structures, in the same phenotypic manner, and are treated in the same way.


Methods


This reliability and validity analysis study was approved by the Institutional Review Board and Ethics Committee of Shanghai First People’s Hospital, which allowed recruitment of patients and performing of multimodal imaging examination, including OCTA scans. Informed consents were obtained from all the patients. The research adhered to the tenets of the Declaration of Helsinki.


This study investigated 52 eyes of 26 MFC patients with active lesions seen by 2 physicians (S.Y. and Y.G.) in the ophthalmology department of Shanghai First People’s Hospital from August 1, 2014 to September 30, 2015. The diagnostic criteria of MFC were based on the original descriptions of both MFC and PIC adapted from previous reports by Spaide and associates. Active lesions were thought to be present in the following cases: (1) new symptoms with lesions in the posterior pole of the eyes without any previous diagnosis; (2) new or reactivated old lesions in an eye with a known diagnosis; (3) subretinal fluid (SRF)/intraretinal fluid (IRF) ; or (4) leakage on FA.


Before recruitment, the participants underwent comprehensive examination to identify any underlying systemic inflammatory or infectious etiology. Ophthalmic examination included best-corrected visual acuity (BCVA), anterior segment examination, dilated fundus biomicroscopy, and preliminary multimodal imaging such as color photography (Zeiss Visucam 200 digital fundus camera; Carl Zeiss Meditec AG, Jena, Germany), FAF, NIR, SDOCT, and FA (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). CNV was defined based on (1) the history and clinical signs, (2) the typical FA features, and (3) OCT appearance. Active CNV lesions were differentiated from inactive CNV lesions by progressive pooling of dye leakage on FA, or subretinal/intraretinal hemorrhage and/or fluid accumulation on OCT. Inflammatory lesions were identified by the appearance of multiple yellow-white chorioretinal lesions in the absence of characteristics of CNV on OCT and FA. The lesion identification was conducted by 2 trained readers (S.Y. and G.Y.) independently. The ones that were not agreed upon were sent to a third reader.


After recruitment, all participants underwent OCTA using the instrument from Optovue RTVue XR Avanti (Optovue, Inc, Fremont, California, USA). This instrument captured 2 consecutive B-scans at each fixed position, and SSADA was used to analyze the OCTA information and remove artifacts. The OCTA angiograms were separately projected into en face views in 4 layers (superficial retina, deep retina, outer retina, and choroid capillary) automatically. The outer retina layer was defined from beneath the outer plexiform layer (OPL) to the Bruch membrane (BM). In healthy individuals, the outer retina is normally avascular. Therefore, after accurate segmentation and artifact removal, any flow in this layer can be interpreted as abnormal vessels such as CNV.


The 6 mm × 6 mm OCTA images were used primarily to evaluate each MFC eye to include as many lesions as possible. If any lesion was detected on the 6 mm × 6 mm OCT angiogram, a more detailed evaluation was performed using the 3 mm × 3 mm OCTA. The OCTA images were assessed for the presence of CNV, CNV size, location, structural information, and morphologic appearance through independent evaluation by another 2 trained readers (L.C. and X.C.); again, the ones that were not agreed upon were sent to a third reader. Both of the OCTA readers were masked to the disease-related information and other imaging results. To obtain information about the CNV size, the quantitative analysis tool of the updated AngioVue v2015.100.0.3 system was used to calculate the flow area of each CNV lesion, and the greatest linear dimension was also measured for comparison. In flow area measurement, the outline of CNV was drawn manually and then the flow area was calculated automatically by the system. The appearance of CNV on the OCTA image was classified as well circumscribed or poorly circumscribed. While assessing an OCTA image, manual adjustment was done if the boundaries were misaligned. Besides, the Angio Overlay function of the AngioVue v2015.100.0.3 system, in which the B-scans were overlaid with the blood flow signal, was used to assist in CNV detection on the cross-sectional view.


Concurrently, to estimate the sensitivity and specificity of OCTA in detecting active CNV, the FA images of the same cohort, as the ground truth, were reviewed independently by another 2 trained readers (S.W. and L.M.), who had no idea about the diagnosis and other imaging findings. The sensitivity, specificity, and positive and negative predictive values were calculated for OCTA compared with FA. The statistical analysis was performed using SAS Software Version 9.2 (SAS Institute Inc, Cary, North Carolina, USA).




Results


This study included 52 eyes of 26 MFC patients (22 female and 4 male) with a mean age of 46.3 ± 12.3 years; 12 patients were unilaterally and 14 were bilaterally affected. The median BCVA for the affected eyes at presentation was 20/63 (range, FC [fingers counting]/30 cm to 20/20), while the median BCVA for the unaffected eye was 20/25 (range, 20/32 to 20/20). Of the 40 affected eyes, 20 had CNV lesions, 6 had acute inflammatory lesions, 7 had both CNV and inflammatory lesions, and the remaining 7 eyes had only atrophy lesions. Among the 27 eyes with CNV, 22 had active CNV, 4 had inactive CNV, and 1 had both. The patients’ demographic characteristics and information about lesions are shown in Table 1 .



Table 1

Summary Data of Patients With Multifocal Choroiditis








































































































































































































































































































































































































































































Case No. Sex Age (y) Eye BCVA Affected Eye (Y/N) Lesion Type a , b FA (Y/N) c OCTA (Y/N) d
1 M 35 OD 20/667 Y aCNV/inaCNV Y/N Y/Y
OS 20/32 Y aCNV Y Y
2 F 47 OD 20/25 Y INF N N
OS 20/100 Y aCNV/INF Y/N Y/N
3 F 54 OD 20/63 Y Atrophy N N
OS FC/30 cm Y aCNV Y Y
4 F 55 OD 20/200 Y aCNV Y Y
OS 20/50 Y Atrophy N N
5 F 29 OD 20/20 Y Atrophy N N
OS FC/30 cm Y aCNV/INF ×3 Y/N Y/N
6 F 34 OD 20/20 Y aCNV/INF ×3 Y/N Y/N
OS 20/20 N N N
7 F 33 OD 20/20 N N N
OS 20/80 Y INF×2 N Y
8 F 28 OD 20/25 Y aCNV/INF ×4 Y/N Y/N
OS 20/20 Y INF N N
9 F 57 OD 20/32 N N N
OS 20/667 Y aCNV/INF Y/Y Y/N
10 F 64 OD 20/667 Y Atrophy N N
OS 20/50 Y aCNV Y Y
11 F 64 OD 20/400 Y inaCNV N N
OS 20/32 Y aCNV Y Y
12 F 35 OD 20/20 Y inaCNV N Y
OS 20/200 Y aCNV Y Y
13 F 36 OD 20/80 Y aCNV Y N
OS 20/200 Y aCNV Y Y
14 F 45 OD 20/25 Y INF ×4 N N
OS 20/20 N N N
15 F 45 OD 20/125 Y inaCNV/INF ×4 N/N Y/N
OS 20/200 Y aCNV Y N
16 F 70 OD 20/250 Y Atrophy N N
OS 20/80 Y aCNV Y Y
17 F 61 OD 20/25 N N N
OS 20/200 Y aCNV Y Y
18 F 58 OD 20/20 N N N
OS 20/25 Y aCNV Y N
19 M 60 OD 20/25 N N N
OS 20/20 Y Atrophy N N
20 F 59 OD 20/63 Y Atrophy N N
OS 20/40 Y aCNV Y Y
21 F 41 OD 20/32 Y INF ×2 N N
OS 20/32 N N N
22 M 40 OD 20/63 Y aCNV Y Y
OS 20/25 N N N
23 F 27 OD 20/32 N N N
OS 20/63 Y aCNV Y Y
24 F 29 OD 20/32 N N N
OS 20/125 Y aCNV/INF ×7 Y/N Y/N
25 M 32 OD 20/25 Y inaCNV N N
OS 20/25 Y INF N N
26 F 66 OD 20/25 N N N
OS 20/200 Y aCNV Y Y

BCVA = best-corrected visual acuity; CNV = choroidal neovascularization; FA = fluorescence angiography; FC = fingers counting; OCTA = optical coherence tomography angiography.

a Lesion types are defined as follows: aCNV (active CNV lesions); inaCNV (inactive CNV lesions); INF (inflammatory lesions); Atrophy (atrophy lesions). In the affected eyes in which there are other kinds of lesions, atrophy lesions are not shown.


b There are usually more than 1 active inflammatory lesions in 1 eye; numbers of lesions are noted by “x” (34 active inflammatory lesions in total).


c Y means that there were active CNV lesions according to the FA findings; N means there were no active CNV lesions according to FA.


d Y means that there were blood flow signals representing CNV on OCTA; N means no CNV was detected on OCTA.



Of the 23 active CNV cases, all were demonstrated on FA and 20 (87.0%) were identified on OCTA, while the other 3 (13.0%) could not be identified owing to poor image quality. The sensitivity of OCTA in detecting active CNV abnormalities using FA as the ground truth was 87.0%, and the specificity was 89.7% ( Table 2 ). A total of 34 acute inflammatory lesions from 13 eyes were observed, of which 32 (94.1%) showed no blood flow in the outer retina on OCTA and the other 2 (5.9%) showed blood flow signal (Case 2). Among the 5 inactive CNV lesions, 3 (60.0%) showed blood flow signal on OCTA (Case 5).



Table 2

Sensitivity and Specificity of Optical Coherence Tomography Angiography in Diagnosing Active Choroidal Neovascularization Among Multifocal Choroiditis Patients Using Fluorescence Angiography as the Ground Truth


























OCTA FA Diagnostic Accuracy
Yes No
Yes 20 3 Positive predictive value 87.0%
No 3 a 26 Negative predictive value 89.7%
Diagnostic Accuracy Sensitivity
87.0%
Specificity
89.7%

FA = fluorescence angiography; OCTA = optical coherence tomography angiography.

a No choroidal neovascularization was identified on OCTA in these 3 cases owing to poor image quality.



Characteristics of Active Choroidal Neovascularization Lesions on Optical Coherence Tomography Angiography, Fluorescence Angiography, Spectral-Domain Optical Coherence Tomography, and Fundus Autofluorescence


Characteristics of active CNV lesions on OCTA, FA, SDOCT, and FAF are shown in Tables 3–5 .



Table 3

Characteristics of Active Choroidal Neovascularization Lesions on Optical Coherence Tomography Angiography and Fluorescence Angiography













































































































Item Characteristic Number of Cases Proportion
OCTA
En face view
GLD <1000 μm 12 52.2%
1000∼2000 μm 8 34.8%
>2000 μm 0 0.0%
No blood flow signal 3 13.0%
Total 23 100.0%
Flow area <0.3 12 52.2%
0.3∼0.6 8 34.8%
>0.6 0 0.0%
No blood flow signal 3 13.0%
Total 23 100.0%
CNV shape Well circumscribed 19 82.6%
Poorly circumscribed 1 4.3%
No blood flow signal 3 13.0%
Total 23 100.0%
Angio overlay With blood flow signal 20 87.0%
No blood flow signal 3 13.0%
Total 23 100.0%
FA
Active CNV appearance Early hyperfluorescence with late leakage 23 100.0%
No leakage 0 0%
Total 23 100.0%

CNV = choroidal neovascularization; FA = fluorescence angiography; GLD= greatest linear dimension; OCT = optical coherence tomography angiography.


Table 4

Characteristics of Active Choroidal Neovascularization Lesions on Spectral-Domain Optical Coherence Tomography






























































































Item Characteristic Number of Cases Proportion
CNV Type Type 1 3 13.0%
Type 2 13 56.5%
Mixed 7 30.4%
Total 23 100.0%
Fluid Intraretinal fluid 3 13.0%
Subretinal fluid 3 13.0%
Both 5 21.7%
No fluid 12 52.2%
Total 23 100.0%
Hemorrhage Yes 1 4.3%
No 22 95.7%
Total 23 100.0%
Ellipsoid zone Intact 0 0.0%
Discontinued 6 26.1%
Disappeared 17 73.9%
Total 23 100.0%
Choroid under CNV Increased reflectivity 5 21.7%
Decreased reflectivity 18 78.3%
No change 0 0.0%
Total 23 100.0%

CNV = choroidal neovascularization.


Table 5

Characteristics of Active Choroidal Neovascularization Lesions on Fundus Autofluorescence
















































Characteristic Number of Cases Proportion
Hyper-AF 2 8.7%
Hypo-AF 4 17.4%
Iso-AF 1 4.3%
Mixed
Hyper-AF ringed by hypo-AF 4 17.4%
Hyper-AF with central hypo-AF 1 4.3%
Hyper-AF with central and surrounding hypo-AF 3 13.0%
Hypo-AF ringed by hyper-AF 7 30.4%
Normal -AF ringed by hypo-AF 1 4.3%
Total 23 100.0%

AF = autofluorescence.


Except for the 3 negative cases, the CNV lesions revealed on OCTA shared similar characteristics of well-circumscribed vascular networks in different shapes. The mean greatest linear dimension was 950 μm (± 368 μm; range, 350–1786 μm). A total of 52.2% of the lesions were smaller than 1000 μm and all were within 2000 μm. The CNV areas were also evaluated by the tool of flow area measurement, and the mean area was 0.271 mm 2 (± 0.144 mm 2 ; range, 0.053–0.536 mm 2 ). A total of 52.2% were smaller than 0.3 mm 2 and all were within 0.6 mm 2 . Angio Overlay function could also detect the blood flow signal of CNV on the cross-sectional section and distinguish it from the projection artifact ( Figure 1 ).




Figure 1


Optical coherence tomography angiography (OCTA) images showing case examples of choroidal neovascularization secondary to multifocal choroiditis. (Top left) A 3 × 3-mm OCTA image shows a well-circumscribed round shaped choroidal neovascularization (CNV) with a greatest linear dimension of 550 μm. (Middle left) The flow area of CNV detected by the Angio quantitative analysis tool is 0.193 mm 2 with a yellow mask showing the detected vessels. (Bottom left) The Angio Overlay image reveals the blood flow signal on the corresponding B-scan. (Top center) A 3 × 3-mm OCTA image shows a well-circumscribed tadpole-shaped CNV (greatest linear dimension is 1375 μm), and (Middle center) the flow area is 0.155 mm 2 . (Bottom center) The corresponding Angio Overlay image shows flow signal beneath retinal pigment epithelium (RPE) with discontinued ellipsoid zone band and underlying hyporeflective choroid. (Top right) A 6 × 6-mm OCTA image shows a well-circumscribed “Benz”-shaped CNV (greatest linear dimension is 1756 μm), (Middle right) the flow area of which is 0.510 mm 2 . (Bottom right) Angio Overlay image reveals a hump-like hyperreflective subretinal material with red blood flow signal.


In the present study, all of the 23 active secondary CNV lesions had the classic appearance on FA with early hyperfluorescence and late leakage. The lesions presented as hyperreflective heterogeneous material on SDOCT, mostly (56.5%) beneath the neurosensory retina, some (13.0%) beneath the retinal pigment epithelium (RPE), or both (30.4%). SRF or IRF was detected in 11 (47.8%) of the cases, and only 1 case (4.3%) had hemorrhage. The ellipsoid zone was discontinued or disappeared. The FAF appearance was diverse, from decrease to increase of autofluorescence.


Characteristics of Acute Inflammatory Lesions on Optical Coherence Tomography Angiography, Fluorescence Angiography, Spectral-Domain Optical Coherence Tomography, and Fundus Autofluorescence


Characteristics of acute inflammatory lesions on OCTA, FA, SDOCT, and FAF are shown in Tables 6–8 .



Table 6

Characteristics of Acute Inflammatory Lesions on Optical Coherence Tomography Angiography and Fluorescence Angiography











































































Item Characteristic Number of Cases Proportion
OCTA
En face view of outer retina layer With blood flow signal 2 5.9%
No blood flow signal 32 94.1%
Total 34 100.0%
Angio Overlay With blood flow signal 2 5.9%
No blood flow signal 32 94.1%
Total 34 100.0%
FA
Early frame Hyperfluorescence 8 23.5%
Hypofluorescence 14 41.2%
isofluorescence 12 35.3%
Total 34 100.0%
Late frame With leakage 34 100.0%
No leakage 0 0.0%
Total 34 100.0%

FA = fluorescence angiography; OCTA = optical coherence tomography angiography.


Table 7

Characteristics of Acute Inflammatory Lesions on Spectral-Domain Optical Coherence Tomography






























































































Item Characteristic Number of Cases Proportion
Location Outer retina layer 7 20.6%
Sub-RPE 12 35.3%
Sub-RPE with outer retinal infiltration 15 44.1%
Total 34 100.0%
Fluid Intraretinal fluid 0 0.0%
Subretinal fluid 3 8.8%
Both 0 0.0%
No fluid 31 91.2%
Total 34 100.0%
Hemorrhage Yes 0 0.0%
No 34 100.0%
Total 34 100.0%
Ellipsoid zone Intact 7 20.6%
Discontinued 13 38.2%
Disappeared 14 41.2%
Total 34 100.0%
Choroid under inflammatory lesion Increased reflectivity 27 79.4%
Decreased reflectivity 5 14.7%
No change 2 5.9%
Total 34 100.0%

RPE = retinal pigment epithelium.


Table 8

Characteristics of Acute Inflammatory Lesions on Fundus Autofluorescence
































Characteristic Number of Cases Proportion
Hyper-AF 8 23.5%
Hypo-AF 19 55.9%
Iso-AF 0 0.0%
Mixed
Hyper-AF with central hypo-AF 7 20.6%
Total 34 100.0%

AF = autofluorescence.


When analyzing the multimodal imaging characteristics of inflammation, all multiple lesions detected in 1 eye, concurrently or successively, were included.


No blood flow signal in the outer retinal layer was detected for acute inflammatory lesions on OCTA, except for 2 lesions (5.9%) that will be described later in Case 2. The Angio Overlay function demonstrated similar results. On FA, these lesions appeared differently, from hypofluorescence (41.2%) to isofluorescence (35.3%) to hyperfluorescence (23.5%), in the early phase, and all showed leakage in the late phase. One inflammatory lesion was misidentified as CNV by the FA readers ( Figure 2 ). On SDOCT, these lesions presented as sub-RPE or outer retinal hyperreflective homogeneous material. Fluid accumulation was only seen in 3 cases (8.8%), but SRF was a possibility. Damage of the ellipsoid zone band was found in 27 (79.4%) of the cases. Similar to CNV, inflammatory lesions also lack typical characteristics on FAF.




Figure 2


Images of a multifocal choroiditis patient whose fluorescence angiogram shows false-positive results of an inflammatory lesion. (Top left) Color photograph of the left eye shows a choroidal neovascularization (CNV) in the macula area and yellowish inflammation in the inferior temporal area. (Top right) OCTA en face view of the 2 lesions reveals a vascular network of the CNV (yellow box) without positive findings of the inflammation (green box). (Second row, left) Spectral-domain optical coherence tomography (SDOCT) image through the CNV shows a subretinal hyperreflective lesion. (Second row, right) SDOCT through the inflammation shows a medium reflective lesion in the outer retina layer. (Third row, left) The hyperfluorescence of the 2 lesions (yellow box and green box) appear almost at the same time, early in the angiographic sequence. (Third row, right) Both lesions have leakage (yellow box and green box) on the late-frame fluorescence angiograhy (FA) image, and the inflammation (green box) is considered as CNV by the 2 FA readers who were masked to the disease-related information. (Bottom left) Angio Overlay image of the CNV lesion shows blood flow. (Bottom right) No blood flow signal was found on the Angio Overlay image of the inflammation lesion.

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Jan 5, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Spectral-Domain Optical Coherence Tomography Angiography Findings in Multifocal Choroiditis With Active Lesions
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