The retinal and choroidal vasculature can be the site of pathology in many ocular diseases, and dye-based angiography has been the gold standard diagnostic test for assessing vascular disorders such as choroidal neovascularization, retinal vascular occlusion, diabetic retinopathy, macular telangiectasia and central serous chorioretinopathy.1,2 Though dye-based approaches such as fluorescein angiography and indocyanine green angiography allow for direct visualization of the dynamic properties of vascular flow such as leakage, pooling or staining, they’re not without limitations: Visualization of small vascular details can be difficult, since they may become obscured due to late-phase dye leakage. Furthermore, dye-based tests are time-consuming, require intravenous access and have the potential for systemic side effects, including rare reports of anaphylaxis.3 Optical coherence tomography angiography is a novel imaging technique that may be able to overcome some of the limitations of dye-based approaches­—though it has some limitations as well. In this article, we’ll discuss the clinical utility of OCTA.
Figure 1. Multimodal imaging of a 65-year-old patient with moderate non-proliferative diabetic retinopathy. (A) Color photograph shows intraretinal blot-dot hemorrhages and microaneurysms. (B) Yellow-dashed frame identifies the corresponding 3x3-mm area imaged on OCTA. (C) OCTA segmented at the superficial retinal plexus shows an enlarged foveal avascular zone (FAZ). Microaneurysms can also be easily identified (yellow arrow). (D) OCTA segmented at the deep retinal plexus shows further enlargement of the FAZ. (E) and (F) represent corresponding OCT B-scansegmentation of the superficial and deep plexuses, respectively, with decorrelation signal overlay.

OCTA Explained
OCTA is a noninvasive imaging modality that allows for detection of blood flow and three-dimensional reconstruction of blood vessels using signal decorrelation between consecutive transverse cross-sectional OCT scans. An OCTA image is computed by comparing, on a pixel-by-pixel basis, repeated B-scans acquired at the same retinal location in rapid succession. The rationale behind OCTA imaging is that in non-mobile tissue the reflected signal will be stationary, and thus the repeated B-scans will be identical. Inside vasculature, however, moving erythrocytes cause a time-dependent backscattering of the OCT signal, which manifests as differences among the repeated B-scans.4-6

Basically, OCT angiograms of the posterior pole can be obtained by using one or a combination of two methodologies: amplitude decorrelation and phase-variance. Amplitude decorrelation analyzes amplitude changes in the OCT signal. Split-spectrum amplitude decorrelation partitions the spectrum into smaller spectra and performs the repeated B-scan decorrelation separately for each sub-spectrum, which improves the signal-to-noise ratio.7 Doppler OCT is a phase-based technology from which OCTA has its origins.8,9 It can quantify axial blood flow that’s parallel to the direction of the imaging acquisition device.7,10,11

 Figure 2. Multimodal imaging of a 60-year-old patient with superotemporal branch retinal vein occlusion. (A) Color photograph shows neovascularization of the disc. (B) Late-phase FA shows hyperfluorescence of the optic nerve due to neovascularization leakage. Optical coherence tomography angiography of the vitreous (C) and optic nerve head (D) demonstrates some well-delineated, fine, abnormal vessels. (E) and (F) represent corresponding OCT B-scan segmentation of the optic nerve head and vitreous. The yellow arrow points to the presence of the decorrelation signal on the vitreous interface, indicative of neovascularization flow.
In addition, it’s possible to view OCTA images in tandem with the corresponding structural en face and cross-sectional OCT B-scans. This allows the correlation of clinical and structural features of retinal and choroidal diseases with microvascular features seen on OCTA.

OCTA for Vascular Disease
The retinal capillary network is arranged into 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, 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.12 With the ability to analyze each vascular plexus separately, OCTA has become an important tool for studying retinal vascular diseases such as MacTel, RVO, DR and others. For example, OCTA was used to demonstrate that the superficial and deep retinal capillary plexuses may be affected differently by retinal vascular diseases such as retinal artery and vein occlusion.13-15

Another advantage of OCTA is its superior ability to precisely delineate the vessels surrounding the foveal avascular zone (See Figure 1). In contrast, perifoveal leakage of fluorescein dye may blur the FAZ margins, and FA is limited to primarily delineating the superficial vascular plexus. Increased FAZ size has been correlated to reduced visual acuity prognosis in eyes with retinal vascular disease.16 A recent study demonstrated that the perifoveal intercapillary area on OCTA appears to increase in size as the level of diabetic retinopathy progresses.17 Also, neovascularization of the optic nerve, which can occur in proliferative DR and ischemic retinopathy, can be easily detected using OCTA by viewing the inner retina/optic nerve surface at the most superficial level (See Figure 2).18

It’s been hypothesized that OCTA may show retinal microcirculation impairment in the macula prior to the development of retinopathy.19 One study demonstrated that diabetic individuals without clinical evidence of diabetic retinopathy have larger FAZ sizes as well as FAZ remodeling and subtle capillary non-perfusion compared to normal, non-diabetic control eyes.20 Microaneurysms imaged with FA may not always be apparent on OCTA. This may result from stagnant erythrocytes blocking flow, or the flow in the microaneurysms may be below the threshold of detection of OCTA. Microaneurysms on FA may also correspond to capillary loops or preretinal neovascular tufts on OCTA.21

OCTA for Chorioretinal Disease
Evaluation of CNV using OCTA is one of the most important applications of this modality.4,22,23 OCTA can be used to determine the location of the CNV, its morphology and its response to anti-VEGF therapy. As a baseline, in a normal eye the “outer retina” OCTA scan segmenting between the outer plexiform layer and Bruch’s membrane will be devoid of signal, as there’s no vascular flow in this layer. However, this may not be the case in eyes with CNV.

There are different CNV morphologies on OCTA, but the clinical relevance of this is yet to be determined. CNV can be identified as several small filamentous vessels that form anastomoses (known as “seafan” or “lacy-wheel”), or as vessels associated with a central trunk of vessels (“Medusa”) (Figure 3). Recently, researchers analyzed OCTA patterns of CNV and their potential correspondence to quiescent and progressive CNV characteristics seen on multimodal imaging (FA, IGCA and spectral-domain OCT). In this study, the investigators imaged CNV using OCTA and graded it according to the presence or absence of the following features: well-defined CNV; presence of tiny capillaries; presence of anastomoses and loops; morphology of the vessels termini as opposed to a “dead tree” aspect; and presence of a hypo-intense halo surrounding the CNV. They found a 95-percent agreement between OCTA and the traditional multimodal imaging protocol for a “treatment required” decision in eyes with at least three out of the five features. There was a 91-percent agreement for “treatment not required” when patients presented with fewer than three features.24
Figure 3. Multimodal imaging of a 63-year-old patient with choroidal neovascularization secondary to central serous chorioretinopathy. (A) Color photograph shows a subretinal hemorrhage at the center of the macula surrounded by retinal pigment epithelium clumps. Early (B) and late-phase (C) fluorescein angiography show leakage from CNV. (D) and (E) represent corresponding OCT B-scan segmentation of the outer retinal and choriocapillaris, respectively. Yellow arrowheads point to the decorrelation signal below the RPE detachment suggestive of CNV. (F) OCT angiogram segmented at the level of the outer retina reveals CNV. (G) OCT angiogram segmented at the level of the choriocapillaris. The yellow arrow highlights the hypo-intense halo surrounding the CNV.

Depending on the clinical presentation, OCTA’s sensitivity to visualize abnormal vascular networks may vary. When massive hemorrhage, exudate or fibrotic tissue is present, OCTA signals can be blocked, limiting visualization of CNV. Because CNV secondary to chronic CSCR and myopic CNV are rarely associated with large subretinal hemorrhages that limit penetration of the OCT signal, the abnormal vascular network may be identified with a screening OCTA in such cases.

Choroidal neovascularization can be classified according to the abnormal vascular plexus location in various retinal and choroidal layers: below the retinal pigment epithelium (type 1 CNV); above the RPE (type 2 CNV); and intraretinal (type 3 CNV). On OCTA, CNV classification depends on where the evidence of a vascular decorrelation signal is located. It can be located immediately above the RPE (type 2 CNV), and between Bruch’s membrane and the RPE (type 1 CNV).24 Since there can be OCT signal attenuation from the RPE-Bruch’s membrane complex,25,26 it’s possible that visualization beneath the RPE may influence the type 1 CNV identification. Thus, differences in signal penetration may play an important role in this imaging modality.

SD vs. SS OCTA for CNV
There are currently three FDA-approved OCTA systems. Two of them use a spectral-domain platform operating at ~840-nm wavelength. The third uses swept-source OCTA technology with a longer ~1050-nm wavelength and is in limited commercial release in the United States. It’s possible that SS-OCTA may be less affected by ocular opacity and allow a deeper penetration into the choroid.25-28

SS-OCTA also has less variation in sensitivity with depth (sensitivity roll-off) compared to SD-OCTA. In SD-OCTA, the imaging system is most sensitive to signals coming from reflectors close to what is known as the zero-delay line; as a reflector is moved away from the zero-delay, the system becomes less sensitive to the back-reflected signals.29 This sensitivity roll-off is due to the limited spectral resolution of the spectrometers that are used in SD-OCTA systems. In contrast, SS-OCTA systems don’t use spectrometer-based detection. Instead, in SS systems, it’s the instantaneous linewidth of the swept light source, along with the analog-to-digital acquisition rate, that determine the sensitivity roll-off of the system. This difference enables SS-OCTA systems to have improved sensitivity roll-off compared to SD-OCTA systems,30 which improves visualization of the choroid both on cross-sectional as well as en face OCTA imaging, and may also improve visualization of CNV, especially the sub-RPE component of the membrane.31

Limitations of OCTA
There are some limitations to OCTA imaging in its current configuration. One drawback is its restricted field of view (See Figure 4). The automated scan protocols that are currently available are 2x2 mm, 3x3 mm, 6x6 mm and 8x8 mm. In order to generate an OCT angiogram, OCT scans need to be repeated at least twice at each position in a volumetric raster scan. However, since the number of cross-sectional OCT scans is limited by the scanning speed of the instrument, a larger field of view will have reduced density and resolution.

Figure 4. Multimodal imaging of a 54-year-old patient with branch retinal vein occlusion of the inferior temporal arcade. (A) Color fundus photography shows non-perfused vessels and hyperpigmented laser scars on the inferior temporal retina. (B) Fluorescein angiography. Yellow-dashed frame identifies the corresponding 6x6-mm area imaged on optical coherence tomography angiography. White asterisks denote an ischemic retina not captured due to the small-field coverage. (C) En face OCTA segmented at the superficial retinal plexus shows a non-perfused area of the retina temporal-inferior to the fovea.
OCTA is prone to several artifacts during acquisition or post-acquisition image processing. In order to interpret OCTA images, it’s necessary to be aware of the potential image artifacts that can occur so as not to interpret these as part of the actual anatomy. OCTA works by detection of erythrocyte motion, so any extraneous movement during the image-capturing process may result in motion artifacts, which appear as white or black lines in the flow angiograms, and/or misalignment of the retinal vasculature.

Additionally, superficial vessels may erroneously appear in segmented views of deeper layers, such as the outer retina and choriocapillaris.32 These are termed “projection artifacts,” and may lead to incorrect diagnosis if not promptly identified (i.e., the retinal vessels’ projection may be misinterpreted as CNV).

Another issue is that commercially available OCTA devices are currently expensive, although this may change as the technology becomes more common. Also, there is currently no code beyond the standard OCT imaging code with regards to reimbursement. Finally, in terms of utility, while OCTA provides additional clinical information for the practitioner, such as noninvasive identification of CNV and retinal vascular abnormalities, its usefulness with regards to therapeutic monitoring is unclear.

FA and ICGA demonstrate the dynamic properties of dye within vascular networks, such as leakage in disorders that produce vascular incompetence and exudation, and dye-based angiography is still an important tool for diagnosis and management of chorioretinal diseases, especially when assessing the periphery of the fundus. OCTA is a promising technology, however, as it allows simultaneous assessment of both structural and vascular flow. OCTA is also safer, faster, more easily repeated  and more comfortable for the patient than dye-based angiography, and it may provide more detailed information about blood flow in retinal and choroidal vasculature. 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 for chorioretinal disorders.  

Dr. Novais is a retinal specialist in the department of ophthalmology at the Federal University of São Paulo in Brazil and was, until recently, a postdoctoral research fellow at the New England Eye Center at Tufts Medical Center. Dr. Baumal is an associate professor of ophthalmology at Tufts University School of Medicine in Boston. She may be reached at the New England Eye Center at Tufts Medical Center, 800 Washington St, Box 450, Boston, MA 02116. Email:, phone: 617-636-7950 or fax: 617-636-4866.

The authors have no financial interest in any of the products mentioned.

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