Fluorescein angiography (FA) and indocyanine green angiography (ICGA) are considered the gold-standard tests for the assessment of vascular diseases of the retina and choroid, in particular primary or secondary macular neovascularization (MNV), diabetic retinopathy, retinal vascular occlusions, macular telangiectasia, and central serous chorioretinopathy (CSCR).1–4 These imaging modalities evaluate the transit of venous contrast over time, allowing direct visualization from leakage and pooling of dye. However, these methods may be limited in the detailed evaluation of vessels and feeder vessels, which can be obscured by hyperfluorescence, especially in the late phase of dye transit. These tests are also fundamentally invasive, requiring the intravenous infusion of dye that can be associated with systemic side effects and rarely, anaphylaxis.5–7
Optical coherence tomography angiography (OCTA) is a noninvasive imaging modality that allows for the detection of blood flow and three-dimensional reconstruction of blood vessels using signal decorrelation between consecutive transverse cross-sectional OCT scans.8 Basically, OCT angiograms of the retina can be obtained by using one or a combination of two methodologies: phase-variance and amplitude decorrelation. Doppler OCT is a phase-based technology from which OCTA has its origins.9,10 Doppler OCT can quantify axial blood flow that is parallel to the direction of the imaging acquisition device.11–13 Amplitude decorrelation analyzes amplitude changes in OCT signal. Split-spectrum amplitude decorrelation partitions the spectrum into smaller spectrums and performs the repeated B-scan decorrelation separately for each subspectrum, which improves the signal-to-noise ratio.12
Optical microangiography uses a combination of phase and amplitude information to generate an image with a theoretical increased sensitivity for flow in microvasculature.12 It has the potential to measure hemoglobin oxygen saturation in the microvasculature by applying a spectroscopic analysis on the visible light spectral range.14,15 However, a major challenge is that this technology is very susceptible to movement artifacts and changes in reflectivity between tissue types.16,17
The retinal capillary network is arranged in morphologically distinct layers. The superficial retinal capillary plexus is located predominantly within the ganglion cell layer, and the deep retinal capillary plexus is located at the outer boundary of the inner nuclear layer (INL), with a smaller intermediate retinal capillary plexus at the inner margin of the inner nuclear layer. The vascular layers of the retina are connected by perpendicularly positioned vessels.18 Research suggests that the superficial and deep retinal capillary plexuses may be disproportionately affected in retinal vascular disease.19
The purpose of this article is to demonstrate the applicability of the OCTA in some of the most prevalent diseases of the retina and choroid, highlighting its strengths and weaknesses compared to dye-based angiography.
Macular neovascularization (MNV) is the abnormal growth of a neovascular network from the choroid or retina. It can be associated with various pathological conditions of the retina and choroid, including age-related macular degeneration, high myopia, and CSCR. Recently, there has been a terminology shift from “choroidal” to the more general “macular” neovascularization, considering the abnormal vascular plexus of the neovascular membrane can be located in various retinal and choroidal layers: below the retinal pigment epithelium (RPE) (type 1 MNV), above the RPE (type 2 MNV), and intraretinal (type 3 MNV).20,21 The use of the OCTA for diagnosing MNV has been extensively reported due to the high sensitivity and specificity of the technique.22,23 de Carlo et al. reported a sensitivity and specificity of CNV detection by OCTA of 50% and 91%, respectively, compared to FA.24
The neovascular membrane identified on OCTA may present with many morphological variations, whose clinical relevance is still to be determined. The “seafan” pattern (Figure 1) is noted to have several small filamentous vessels that form anastomoses and have a similar appearance to retinal neovascularization seen in patients with sickle cell retinopathy. In the “medusa-shaped” MNV, the vessels are associated with a central trunk of vessels. Interestingly, these patterns can change with treatment.25 Type 1 MNV is often more difficult to identify with an 840-nm SDOCTA, which is prone to signal roll off below the RPE.26,27 Most MNV can be more clearly and extensively visualized with a swept-source OCTA device that uses a longer wavelength of 1,050 nm.28
Optical coherence tomography angiography (OCTA) using the spectral-domain Avanti (Optovue, Fremont, CA) with corresponding OCT B-scan of a patient with active macular neovascularization (MNV). (A) En face OCTA of the outer retina shows the neovascular membrane (yellow arrow). (B) OCT B-scan with outer retina segmentation delineated by the green and red lines and OCTA decorrelation signal overlay. (C) En face OCTA of the choriocapillaris shows a “seafan” shaped type 1 MNV (yellow arrow). (D) OCT B-scan with choriocapillaris segmentation delineated by the two parallel red lines. OCTA decorrelation signal overlay indicates the presence of flow inside the pigment epithelium detachment (yellow arrowhead). (E) Corresponding high-definition OCT B-scan line shows subretinal fluid (yellow asterisk) and hyperreflective image under the retinal pigment epithelium that corresponds to type 1 MNV (yellow arrow).
An advantage of OCTA in imaging MNV, compared with dye-based angiography, is the ability to have repeated serial examinations with no additional risk to the patient.24 Furthermore, patients with asymptomatic, nonexudative MNV without evidence of fluid on structural cross-sectional OCT images can be identified by OCTA.29 Since it is not common practice to submit asymptomatic patients to dye-based angiography, the OCT angiogram may be an important diagnostic tool to allow for the identification of these cases, although their clinical management is still a matter of debate.29 For type 3 MNV, OCTA is able to detect flow within a tuft-shaped abnormal outer retinal neovascular complex that communicates with the deep retinal capillary plexus.30
Diabetic Retinopathy and Diabetic Macular Edema
OCTA in eyes with diabetic retinopathy can identify areas of decreased retinal capillary perfusion, both in the posterior pole and mid-periphery. As with FA, OCTA can visualize alterations in the size and shape of the foveal avascular zone (FAZ), as well as perifoveal areas of microvascular flow impairment, which are caused by small vessel disease.31,32 Takase et al. suggested that OCTA in diabetic eyes may show retinal microcirculation impairment in the macula even before retinopathy develops.33 Moreover, these vascular abnormalities are more pronounced in the deep vascular layer.34 With the progression of ischemia, interruptions in macular capillaries, microvascular loops, and increased small capillary tortuosity may also be identified (Figure 2).8,35
Optical coherence tomography angiography (OCTA) using the spectral-domain Avanti (Optovue, Fremont, CA) with corresponding OCT B-scan of a patient with diabetic macular edema. (A) En face OCTA of the superficial plexus shows foveal avascular zone (FAZ) enlargement (yellow dotted line) and focal vascular dilations that correspond to microaneurysms (yellow arrows). (B) OCT B-scan with superficial retinal plexus segmentation delineated by the red and green lines and OCTA decorrelation signal overlay. (C) Deep plexus segmentation shows further FAZ enlargement (green dotted line) and microaneurysms (yellow arrows). (D) OCT B-scan with deep retinal plexus segmentation delineated by the two parallel green lines. (E) Corresponding high-definition OCT B-scan line shows hyporeflective areas that correspond to intraretinal cysts (yellow asterisks) and a hyperreflective area that corresponds to hard exudates (yellow arrow).
Analysis of the OCTA images indicates that the microaneurysms observed in FA images correspond to focally dilated saccular or fusiform capillaries located mainly in the deep plexus. Since OCTA uses a volumetric image acquisition, it is possible to determine the exact depth-resolved location of the microaneurysms in the superficial and deep vascular plexuses. However, the slow blood flow inside some of these microaneurysms can be below the threshold of detection of the OCTA and may affect visualization of microaneurysms on OCTA.36 Huang et al. recently demonstrated that some focal hyperfluorescent points classified as leaking microaneurysms on FA can be visualized as neovascular tufts of vessels above the inner limiting membrane on OCTA.37
In diabetic macular edema (DME), OCT angiograms can identify cystoid spaces that differentiates them from areas of ischemia based on the reflectivity and the pattern of the vasculature around this location.38 The cystoid spaces have smooth oval shape, whereas the areas of capillary nonperfusion have more ragged edges. In addition, it is possible to view OCTA images alongside the corresponding structural en face and cross-sectional OCT scans. This allows the correlation of clinical features of DME with microvascular features seen on OCTA.
Retinal Vein Occlusion
With high-density scans, OCTA can identify changes in the superficial and deep retinal vascular plexuses, such as vascular looping and telangiectatic vessels, which would normally be obscured in FA due to leakage. OCTA easily identifies vascular changes in retinal vein occlusion (RVO), such as vascular looping, collaterals, telangiectatic vessels, vessel thickening, and focally dilated microaneurysms at the border of the ischemic areas. These changes are often present in both the superficial and deep vascular plexuses. Truncated vessels with abrupt interruptions with terminal dilations at the site of occlusion are shown on OCTA, especially in branch retinal vein occlusion (BRVO).
With the ability to analyze each vascular plexus separately, OCTA can view arteriovenous anastomoses between the superficial and deep plexuses. Areas of capillary nonperfusion on FA can also be identified on OCTA images (Figure 3).39 Using OCTA, Kashani et al. showed that decreased flow is more prominent in the deep vascular plexus.40 Another advantage of OCTA is the ability to precisely delineate the FAZ, which has been already related to low visual acuity prognosis when enlarged in patients with BRVO.41 In addition, neovascularization of the optic nerve, which can occur in ischemic RVOs, can be easily detected using OCTA.
Multimodal imaging analysis of a patient with branch retinal vein occlusion. (A) Fluorescein angiography (FA) shows a nonperfused area (yellow asterisks) and vascular loop (yellow arrow). (B) Optical coherence tomography (OCT) angiography using the spectral-domain Avanti (Optovue, Fremont, CA) of the superficial plexus shows an avascular retina (yellow asterisks) and vascular loop (yellow arrow) seen on FA. Upper right box shows corresponding OCT B-scan with superficial retinal plexus segmentation delineated by the red and green lines. (C) Corresponding OCT B-scan shows a hyporeflective area that corresponds to cystoid macular edema.
Paracentral Acute Middle Maculopathy
Paracentral acute middle maculopathy (PAMM) presents as an acute-onset paracentral scotoma. These paracentral lesions have been recently described to be best detected using OCT and near-infrared reflectance imaging. Features of OCT B-scans include hyperreflective bands at the level of the inner nuclear layer.19 After resolution of these lesions, retinal architecture can be affected by subsequent inner retinal layer atrophy, which is accompanied by a permanent paracentral scotoma. PAAM can be idiopathic, or secondary to local retinal vascular or systemic diseases, such as artery and vein occlusions, sickle cell retinopathy, or Purtscher retinopathy.42–46 It has been hypothesized that these band-like lesions are secondary to deep retinal capillary ischemia since the intermediate and deep retinal capillary plexuses are responsible for nourishing the inner and outer boundaries of the inner nuclear layer, respectively.
The depth-resolved characteristic of OCTA makes this imaging modality an important exam to diagnose and follow patients with PAMM. When only a small area is affected, acute PAMM lesions show little or no changes in the deep retinal capillary plexus perfusion. However, patients with diffuse paracentral acute middle maculopathy can present with pruning of the deep capillary plexus with decreased vascular flow. In eyes with retinal atrophy secondary to old PAMM lesions, there is a significant reduction of the retinal deep capillary plexus density. In a recent study in patients with PAMM, Nemiroff et al. showed that the deep capillary plexus density is significantly attenuated when compared to the unaffected fellow eye.47 The ability of OCTA to identify focal capillary defects that may not be detected on FA is a potential advantage of OCTA. As in this specific disease, OCT angiograms can be especially useful for cases in which FA cannot be used, such as pregnancy or allergy.
Central Serous Chorioretinopathy
Recent studies using OCTA have found that patients with CSCR often have large semiconfluent areas of decreased flow adjacent to areas of increased choroidal flow.48 These findings are consistent with earlier studies that indicate that CSCR was associated with focal filling defects in the choriocapillaris adjacent to dilated, tortuous feeding arterioles and dilated venules.49–52
Leaking extravascular fluid in CSCR patients cannot be visualized by OCTA for several reasons (Figure 4). CSCR is a consequence of leaking fluid, not erythrocytes, and this fluid does not strongly backscatter the incident OCT beam; thus, it cannot be visualized on OCTA. Additionally, the relatively low rate of leakage in CSCR means that even if the fluid did appreciably backscatter the OCT beam, the decorrelation would not be detectable with OCTA, which is typically sensitive to backscatter with speeds in the mm/s range.
Multimodal imaging of a patient with acute central serous chorioretinopathy. (A) Fundus photography shows a neurosensory retinal detachment at the center of the macula (asterisk). (B) Late-stage fluorescein angiography (FA) indicates an “inkblot” leakage (arrow). (C) Late-stage indocyanine green angiography (ICGA) shows a hyperfluorescent hotspot corresponding to the FA leakage site (arrow). (D) Optical coherence tomography (OCT) B-scan illustrates a serous detachment of the neurosensory retina without retinal pigment epithelium detachment. There is a mild thickening of the choroid. (E) OCT B-scan with choriocapillaris segmentation delineated by the two parallel red lines and OCTA decorrelation signal overlay. (F) OCT angiography (OCTA) using the spectral-domain Avanti (Optovue, Fremont, CA) segmented at the choriocapillaris (CC) indicates a loss of central OCT angiogram signals (dashed line) and central areas of irregular CC signal corresponding to sites of late staining on ICGA with surrounding hotspot areas. (G) Corresponding structural en face OCT shows signal loss secondary to the fluid blockage (dashed line) at the same area of the OCTA.
The most important application of OCTA in CSCR is the assessment of secondary MNV in chronic CSCR. Since MNV in CSCR is rarely associated with massive subretinal hemorrhages that would limit penetration of OCT signal, CSCR associated MNV may be more easily identified with a screening OCTA (Figure 5).53
Multimodal imaging of a patient with chronic central serous chorioretinopathy with secondary choroidal neovascularization. (A) Fundus photography shows mottled retinal pigment epithelium (RPE) without the presence of intra- or subretinal hemorrhage. (B) Mid-phase fluorescein angiography shows areas of central hyperfluorescence. (C) High-definition optical coherence tomography (OCT) B-scan line centered on the fovea shows a flat RPE detachment (asterisk) associated with subretinal fluid and a thickened choroid. (D) OCT B-scan with choriocapillaris (CC) segmentation delineated by two parallel red lines. OCT angiography (OCTA) decorrelation signal overlay using the spectral-domain Avanti (Optovue, Fremont, CA) indicates the presence of flow below the pigment epithelium detachment (yellow arrowheads). (E) OCTA segmented at the CC shows the neovascular membrane complex (yellow dashed-line).
Macular Telangiectasia Type 2
The etiology of macular telangiectasia type 2 (MacTel2) is not yet fully elucidated; however, the understanding of its pathophysiology is greatly enhanced with OCTA visualization. Historically, the gold standard for the diagnosis of MacTel2 was FA. FA demonstrated dilation of perifoveal capillaries and the presence of temporal parafoveal leakage. The FA may also demonstrate right angled vessels, as well as subretinal anastomoses with or without MNV formation.54,55 In the past decade, OCT has become a valuable tool for the diagnosis and study of MacTel2 and, unlike other causes of macular edema such as diabetes and vein occlusion, retinal hyporeflective intraretinal spaces (or cavities) and macular leakage in FA are not usually related to macular thickening.56,57
OCTA can accurately identify microvascular abnormalities in the perifoveal region. The absence of the typical leakage associated with FA also facilitates the visualization of the juxtafoveal microvasculature in patients with MacTel2. In early stages of the disease, it is possible to detect dilated vessels in the deep retinal capillary plexus that are more pronounced in the temporal region of the fovea. In the intermediate nonproliferative stage, the telangiectatic vessels can develop the appearance of microaneurysms that extend from the deep plexus to the outer retina, which is partly due to the atrophy of the outer retina. The OCTA can also visualize areas of perifoveal nonperfusion (Figures 6 and 7).58 In late stages of MacTel2, the distortion of the capillary plexus is more dramatic and associated with prominent anastomoses. These may extend into the outer retina, thus affecting the layer of photoreceptors and possibly generating subretinal neovascularization (Figure 8). It is important to differentiate neovascularization from vascular displacement due to outer retina atrophy and OCTA segmentation issues on affected retinas when vessels are found in the outer nuclear layer.59
Optical coherence tomography angiography (OCTA) using a modified spectral-domain Cirrus OCT (Angioplex; Carl Zeiss Meditec, Dublin, CA) and fluorescein angiography (FA) images of the right eye of a 62-year-old woman with intermediate, nonproliferative macular telangiectasia type 2. (A) Early-phase FA image shows hyperfluorescence in the temporal juxtafoveal region. (B) Late-phase FA image with increased hyperfluorescence and leakage. (C) Magnified early stage FA image shows a detailed view of the hyperfluorescent area that represents the telangiectatic microvasculature. (D) Composite en face color-coded flow OCTA image demonstrates abnormalities that correspond well to the microvascular abnormalities seen in the early stage FA image. GCL-ELM = ganglion cell layer + external limiting membrane.
En face flow optical coherence tomography angiography (OCTA) (A–C) using a modified spectral-domain Cirrus OCT (Angioplex; Carl Zeiss Meditec, Dublin, CA) of the superficial, deeper plexus, and avascular retina layers, with respective B-scans (D–F) of the same eye showed on Figure 5. On the B-scans, it is possible to see intraretinal cavities and outer retina loss, characteristic of macular telangiectasia type 2. (A) Superficial en face flow OCTA image showing the presence of microvascular abnormalities in the juxtafoveal region. (B) Deeper plexus en face flow OCTA image showing the telangiectatic and dilated vessels in the middle retinal layers. (C) Avascular retina en face flow OCTA image detecting with details the anastomotic telangiectatic dilated vessels. (D–F) representative B-scans showing the boundaries (red lines) of the slabs that created the en face flow image showed in A–C.
En face flow optical coherence tomography angiography (OCTA) (A–C) of the right eye of a 57-year-old woman with late, proliferative macular telangiectasia type 2 using a modified spectral-domain Cirrus OCT (Angioplex; Carl Zeiss Meditec, Dublin, CA) of the total retina color-coded, superficial, deeper plexus, and outer retina layers, with respective B- scans (D–F). On the B-scans it is possible to see intraretinal cavities and outer retina loss, characteristic of macular telangiectasia type 2. (A) Superficial en face flow OCTA image showing the presence of microvascular abnormalities in the juxtafoveal region. (B) Deeper plexus en face flow OCTA image showing the telangiectatic and dilated vessels in the middle retinal layers. (C) Outer retina en face flow OCTA image detecting a neovascular network that is not apparent on the structure B-scan. (D–F) Representative B-scans showing the boundaries (red lines) of the slabs that created the en face flow image showed on A–C.
Previously, it was thought the MNV arose exclusively from the retinal circulation, but the OCTA images indicate that the neovascular complex communicates both with retinal and choroidal circulations. It is not clear whether choroidal involvement is present in all MacTel2 associated MNV, or whether choroidal involvement is only present when macular edema is detected.60
OCTA has also shown that the size of the vessels and the size of the anastomoses in the retina decrease after antiangiogenic therapy; however, it is still not possible to determine whether treatment causes complete regression of these lesions or if the blood flow decreases to below the level of detection with current OCTA algorithms.60
Although FA and ICGA remain useful imaging modalities to assess chorioretinal vascular disorders, they are limited to a two-dimensional evaluation of the vascular plexuses and require the use of intravenous contrast that can result in systemic side effects and, rarely, anaphylaxis.5–7,61 OCTA is a fast, noninvasive technology that does not require the use of dye and is capable of showing depth-resolved images of the chorioretinal vasculature. Image quality is less affected by the presence of cataracts and can be repeated frequently for monitoring of macula conditions. OCT angiograms derived from a high number of cross-sectional OCT scans may provide a better documentation of the microvasculature in the macular area when compared to FA and ICG.62,63
Since FA images are limited to the superficial retinal plexus, disorders affecting deeper capillary layers are not completely evaluated with this imaging modality. The depth-resolved, three-dimensional, retinal vascular analysis with OCTA will help us to better understand and characterize the pathophysiology of the diseases affecting deeper vascular segments of the retina, such as in MacTel2 and cases of deep capillary plexus ischemia.43,58 There is a growing interest in the selective visualization of the retinal microvasculature plexuses since recent studies have demonstrated the most prominent vascular changes are located in the deep plexus,43,44 and the depth and area affected by the reduced vascular perfusion plays an important role in the visual prognosis. Since dye-based angiography does not have the ability to assess capillary plexuses separately, it may fail to diagnose ischemia of the deep plexuses.64,65 Additionally, patterns of MNV can be distinguished in greater detail and may assist in their diagnosis and in treatment decisions.22,66
However, OCTA has some limitations, and one of its major drawbacks is the restricted field of view. Currently, chorioretinal scan protocols commonly available are 2 mm × 2 mm, 3 mm × 3 mm, 6 mm × 6 mm, and 8 mm × 8 mm. Since the number of cross-sectional OCT scans is limited by the scanning speed of the instrument and B-scans need to be repeated at least twice at each position in a volumetric raster scan, a higher field of view will present a lower resolution either due to fewer A-scans per B-scan length or fewer B-scan positions in a given area. Furthermore, OCTA is prone to several artifacts during acquisition or postacquisition image processing. The method is extremely sensitive to motion, and any movement during the capturing process may result in motion artifacts shown as white lines or black lines in the flow angiograms and/or misalignment of the retinal vasculature. Additionally, superficial vessels may appear in deeper layers, such as the outer retina and choriocapillaris.35 This situation, also called projection artifact, may lead to the wrong diagnosis if not promptly identified (ie, the retinal vessels projection may be misinterpreted as MNV) (Figure 9).
Optical coherence tomography angiography (OCTA) (Avanti; Optovue, Fremont, CA) projection artifacts. (A) Superficial plexus segmentation shows normal vasculature (yellow arrowheads). (B) OCT B-scan with superficial segmentation delineated by the red and green lines. (C) Choriocapillaris (CC) segmentation shows projection artifact from superficial vessels (yellow arrowheads). (D) OCT B-scan with CC segmentation delineated by two parallel red lines.
In summary, FA and ICGA rely on the pattern of dye distribution within vascular networks and can demonstrate leakage of dyes in diseases that result in vascular incompetence and exudation. These dye-based angiographic approaches are still important tools for the diagnosis and management of chorioretinal diseases, especially when assessing the periphery of the fundus. OCTA, however, is a promising technology, allowing both structural and vascular assessment at the same time. Moreover, OCTA is safer, faster, less expensive, more easily repeated, more comfortable for the patient, and less resource-intensive than traditional dye-based angiography, and it provides better visualization of the retinochoroidal microvascular and neovascular networks. The ability to rapidly obtain images of vascular plexuses and assess the integrity of retinal and choroidal perfusion should prove invaluable as a screening and diagnostic strategy that will improve early detection and management of chorioretinal disorders.