Tranos et al. Journal of Ophthalmic Inflammation and Infection
https://doi.org/10.1186/s12348-019-0190-y
(2019) 9:21
Journal of Ophthalmic
Inflammation and Infection
REVIEW
Open Access
Optical coherence tomography
angiography in uveitis
Paris Tranos1, Evdoxia-Maria Karasavvidou1,2*, Olga Gkorou1 and Carlos Pavesio3
Abstract
Before the introduction of optical coherence tomography angiography (OCTA) in the early 2000s, dye-based
angiography was considered the “gold standard” for the diagnosis and monitoring of ocular inflammation. OCTA is
a novel technique, which demonstrates capillary networks based on the amount of light returned from moving
blood cells, providing further information on pathophysiological changes in uveitis.
The aim of this review is to describe the basic principles of OCTA and its application to ocular inflammatory
disorders. It particularly emphasizes on its contribution not only in the diagnosis and management of the disease
but also in the identification of possible complications, comparing it with fundus fluorescein angiography (FFA) and
indocyanine green angiography (ICGA). Although the advent of OCTA has remarkably enhanced the assessment of
uveitic entities, we highlight the need for further investigation in order to better understand its application to these
conditions.
Keywords: Optical coherence tomography angiography, Uveitis, Chorioretinal inflammation, Dye-based
angiography, Blood flow
Introduction
In recent years various imaging modalities have emerged
facilitating effective investigation, diagnosis and monitoring
of ocular disorders [1]. In 2006, Makita et al. first described
optical coherence tomography angiography (OCTA), a
novel imaging modality which utilizes the advances in
OCT technology to provide new insight in retinal microvascular changes, without the requirement of intravenous
dye injection. This innovative technique provides highresolution angiographic information that can be objectively
correlated to OCT anatomic findings [2–4].
Uveitis is associated with a spectrum of pathologic
processes including inflammation, vascular occlusion or
leakage, local ischemia, and alteration of cellular mediators. Visually debilitating complications such as macular
edema and neovascularization among others may potentially occur. Also, some inflammatory lesions may be
difficult to differentiate from a vascular lesion. Early
identification and monitoring of these changes may be
* Correspondence: evikarassavidou@gmail.com
1
Vitreoretinal & Uveitis Department, Ophthalmica Clinic, Vas.Olgas 196 and
Ploutonos, 546 55 Thessaloniki, Greece
2
Department of Ophthalmology, Hippokrateio General Hospital of
Thessaloniki, 49 Konstantinoupoleos Street, 546 42 Thessaloniki, Greece
Full list of author information is available at the end of the article
critical in the optimal management of patients with
uveitis. Recent studies suggest that the use of OCTA, in
conjunction with the other imaging modalities, can be
advantageous in patients with ocular inflammation,
revealing features which may improve our knowledge on
pathophysiology and natural course of the disease and
guide decision making for the uveitis specialist [3].
In this review, a comprehensive overview of the principles of OCTA and its application to ocular inflammatory
disorders has been performed.
Dye-based angiography
Fundus fluorescein angiography
Fundus fluorescein angiography (FFA) is an imaging
modality based on the intravenous administration of
fluorescein dye [5]. This technique is widely used predominantly for the demonstration of retinal vascular
abnormalities, especially leakage, macular or optic disc
edema and non-perfusion [6]. However, vascular features
of the retina may be underestimated due to the limited
resolution of FFA and, as an example, choroidal neovascularization (CNV) may not be detected due to masking
from coexisting subretinal hemorrhage [7]. Fluorescein
molecular size is also an important issue, as small
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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Tranos et al. Journal of Ophthalmic Inflammation and Infection
(2019) 9:21
molecules leak more quickly and prevent detailed view
of the vascular structures [8]. Fundus fluorescein angiography can be associated with mild (nausea, vomiting,
sneezing, pruritus) or more severe adverse reactions
(syncope, local tissue necrosis, thrombophlebitis, local
skin eruptions at the site of injection) [9]. Cardiovascular
shock, myocardial infarction, laryngeal edema and
bronchospasm have also been reported and are important contributors to the mortality rate [10].
Indocyanine green angiography
Yannuzzi et al. [11] first described indocyanine green
angiography (ICGA), which is usually performed to reveal choroidal involvement in uveitis and identify occult
choroidal neovascularization (CNV) [12, 13], polypoidal
choroidopathy, and CNV complicated with subretinal
hemorrhage [14]. In comparison with FFA, the emission
wavelength of indocyanine green (ICG) is longer; thus,
deeper retinal structures can be better visualized. Additionally, a higher proportion of ICG is albumin bound
(~ 98%) [15], so the leakage of dye decreases and the
signal to noise ratio improves. Consequently, ICGA is
more reliable in imaging the choroidal vasculature and
choroidal pathology allowing better visualization of the
choriocapillaris and choroidal stroma, which are affected
in many visually threatening inflammatory conditions.
Nevertheless, this method has limitations similar to FFA
since presence of subretinal fluid, subretinal hemorrhage
or retinal pigment epithelium (RPE) detachment may
also obscure CNV or other retinal features [16]. Severe
adverse reactions have also been reported during ICGA,
especially in subjects with iodine allergies [15, 17].
Optical coherence tomography angiography
Basic principles
Optical coherence tomography angiography is an expansion of spectral-domain optical coherence tomography
(SD-OCT) [1], providing detailed visualization of functional vasculature of ocular tissue [18].
The basic principle of OCTA relies on the variation in
OCT signal produced by the reflectance of light off the
surface of moving red blood cells [1, 18]. Structural
tissues generate steady signal, while flowing blood cells
produce signal that changes over time because of the
continuous motion. OCTA scans are repeated over the
same area in order to discriminate the moving particles
from static tissue [18]. OCT device emits light which
can be reflected, refracted, or absorbed [1] and uses two
main methods to develop the angiographic contrast: (1)
the amplitude decorrelation (or intensity) and (2) the
phase variance. These two methods compare the differences between the light reflected in various vessels and
the background, aiming to detect significant motion and
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allowing detailed depiction of retinal and choroidal microvasculature [1].
Limitations and artifacts
Despite its many advantages over dye-based angiography
techniques, OCTA has some technical limitations. The
limited view of field (8 mm x 8 mm) of the currently
available devices prevents the wide visualization of the
posterior pole and restricts the evaluation of pathology
predominantly affecting the peripheral retina. OCTA
provides more concise depiction of ocular microcirculation. Nevertheless, it requires accurate segmentation for
the identification and quantification of vascular abnormalities of the eye [4].
In line with any other imaging methods, OCTA can be influenced by artifacts which may lead to data misinterpretation.
Media opacities such as cataract, small pupil or
defocusing of the light beam have the potential of producing weakened OCT signal and inaccurate flow information. All these shortcomings may be moderated by
focusing and centering the OCT beam and by dilating
the patients’ pupils [4]. In addition, small eye movements, such as changes of fixation, saccadic or movements associated with tremor and breathing, are sources
of artifacts that could lead to overestimation of flow signal [1, 4]. However, eye tracking software and motion
correction techniques have become available on commercial OCTA devices, decreasing the defects of OCTA
scans [19–21]. Moreover, flowing red blood cells into
the vessels of superficial choroidal plexus can cast
shadows over the deeper vascular layers [4]. These artifacts result in projection of the same vascular pattern of
superficial layers on deeper retinal circulation including
the normally avascular layer of photoreceptors. Consequently, detection and quantification of vascular abnormalities in the outer retina may become difficult due to
blockage from projection artifacts, which can be misinterpreted [22]. OCTA devices have a threshold for slow
flow signal detection; hence, areas with blood flow under
this threshold may not be detected and incorrectly
maybe characterized as non-perfused [1].
Optical coherence tomography angiography in
uveitis
Optical coherence tomography angiography vs dye-based
angiography
Due to its micromolecular properties, fluorescein may
easily leak from retinal vessels with the slightest disruption of the blood-retinal barrier. FFA is a very sensitive
imaging modality for the detection of retinal vessel inflammation, because even minor inflammation of the
retinal vessel wall may result in vascular leakage. This
leakage on FFA is extremely useful feature in order to
assess the activity of underlying uveitis, both in terms of
Tranos et al. Journal of Ophthalmic Inflammation and Infection
(2019) 9:21
intensity and extent. On the other hand, OCTA is not
able to detect leakage, but can depict changes in the
vessel density of superficial or deep capillary plexus in
vasculitis. Kim et al. [2] identified that the parafoveal
capillary density in the superficial retinal plexus was significantly lower in eyes with retinal vasculitis compared
with healthy ones. These results suggest that OCTA can
potentially be used to quantitatively measure the effects
of intraocular inflammation.
Dye-based angiography poorly visualizes the deep capillary plexus (DCP) in contrast to OCTA. Evaluation of
deeper vascular components can be useful in some uveitis entities including birdshot retinochoroiditis, which
has been shown to be associated with decreased flow
density in the DCP [23]. Lower flow density is not necessarily associated with non-perfusion. Leakage of plasma
outside the vessel wall in retinal vasculitis results in
decrease of flow velocity inside the vessel. However, in
active inflammation accompanied by leakage on FFA,
retinal circulation can be identified on OCTA scans despite the lower flow velocity.
Dye leakage in posterior uveitis may be helpful for the
assessment of the inflammatory activity, but it can be restrictive in the evaluation of adjacent capillary perfusion.
In this respect, the use of OCTA has proven advantageous, providing details on microvascular morphology
and information about capillary perfusion in both superficial and deep capillary plexus.
FFA is considered the “gold standard” for the detection of any type of CNV [24]. However, even with
multimodal imaging, it is very difficult to differentiate
active inflammatory lesions from inflammatory CNV,
as both have the potential to cause a breakdown in the
blood-retina barrier. Usually, inflammatory CNV is
characterized by early hyperfluorescence with late leakage, while inflammation shows early hypofluorescence
with late hyperfluorescence on FFA [25]. Not infrequently, this early hyperfluorescence of CNV may not
be obvious due to blockage from inflammatory component or hemorrhage. Moreover, inflammatory lesions
may show early hyperfluorescence because of the window defect caused by RPE damage, which may be
present adjacent to new active lesions.
ICGA provides better imaging of the choroidal vasculature through the RPE [26] since in contrast to
FFA, the lesions are not obstructed by significant choriocapillaris leakage [27]. ICGA leakage results from
significant damage to retinal and choroidal stroma vessels, but dye leakage from fenestrated choriocapillaris
may be very slow in case of inflammation. Herbort
et al. demonstrated the involvement of choriocapillaris
and choroidal stroma in the pathophysiology of several
inflammatory diseases of the fundus which can cause
characteristic findings on ICGA [28].
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Microvascular changes in uveitis
OCTA is the only imaging method that can depict
microvascular changes of the superficial and deep capillary plexus in detail, since there is no masking by leakage, pooling or window defects [29, 30] (Table 1).
The stability of ocular function at the level of neurosensory retina is largely dependent on the integrity of
the inner and outer blood-retinal barrier [31, 32]. The
human immune system produces inflammation by
releasing various inflammatory mediators including
prostaglandins, interleukins (e.g., IL-1, IL-2, and IL-6),
interferon gamma and tumor necrosis factor alpha
(TNF-a). All these mediators contribute to the disruption of the inner blood-retinal barrier, resulting in an influx of fluid from vessels to the intraretinal or subretinal
space and formation of extracellular edema.
Recent studies using OCTA showed that uveitic macular edema is associated with changes in the density or
morphology of deep capillary plexus (DCP). Their
analysis revealed a significantly lower vessel density in
DCP in uveitic eyes complicated by macular edema. In
addition, ocular inflammation was associated with parafoveal capillary loss in the superficial capillary plexus regardless of the presence of macular edema [2]. Besette
et al. [1] identified similar findings including the remodeling of capillaries and the irregularity and/or enlargement of foveal avascular zone (FAZ) in uveitis patients.
Blood flow changes associated with active inflammation are characterized by capillary dropout or loss in the
SCP that can be identified as hypo-perfused areas in
OCTA. However, apparent areas of non-perfusion may
only represent slow flow, considering the inadequacy of
the device in detecting slow flow signal [1].
OCTA in anterior uveitis
Pichi et al. was the first to demonstrate quantitatively
the iris vasculature of subjects with anterior uveitis using
OCTA. By applying the appropriate settings for iris
scanning, they found that inflamed irises had better
highlighted microvasculature than the healthy ones, with
radial small vessels packed more densely towards the
pupillary margin and irregular vessels arranged less
densely towards the iris root [1].
In order to quantify the increase in flow and the dilation of vessels which occur in anterior uveitis, Pichi
et al. compared the brightness of grayscale OCTA scans
before and after uveitis treatment. Their measurements
showed that the brightness was significantly increased in
severe inflammation than in mild cases. In addition to
measuring brightness, they attempted to calculate the
vascular volume of inflamed irises. Study data revealed
much higher vascular volume in eyes with 4+ anterior
chamber cells, decreasing with improvement of inflammation. Those results based on OCTA measurements
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Table 1 Pathological features detected on different layers of OCTA in various uveitis entities
Superficial capillary
plexus
Deep capillary plexus
Retinal vasculitis
-Decreased flow density
-Enlargement/ Irregularity of FAZ
-Capillary remodeling
-Grayish hypo/non perfused areas
-Elevated, dilated or shunting
perifoveal vessels
-Well delineated flow void areas
Birdshot
retinochoroiditis
-Telangiectatic vessels
-Increased intercapillary space in
the perifoveal region
Ocular
toxoplasmosis
Outer retina
Choriocapillaris
Choroid
Neovascular network arising from
retinal vasculature with no
contribution of the choroid
MEWDS
Normal flow
APMPPE
Flow reduction
and ischemia
PIC/MCP
Tangled vessels
arising from
choriocapillaris
Serpiginous
choroiditis
Flow reduction and
ischemia
-Focal flow
reduction (MCP)
-Tangled vessels
extending into
outer retina
Flow reduction in
areas of active
lesions
Better delineated
vessels in areas of
inactive lesions
Sarcoidosis
Flow void areas
Tuberculosis
-Flow void areas
-Tangled vessels
arising from
choriocapillaris
VKH
Uveitic macular
edema
Focal flow void
Decreased capillary density
Inflammatory
CNV
established a new perspective in the qualitative and
quantitative assessment of iris vasculature using OCTA.
However, this approach is limited due to some anatomical and technical parameters:
(1) Pupil size needs to be constant as it may affect the
morphology of iris vasculature and OCTA results.
(2) OCTA measurements may not be reproducible
because of differences in iris pigmentation.
(3) Ocular tissue refraction of OCTA beam can give a
false impression of anterior segment physical
characteristics.
OCTA in retinal vasculitis
Retinal vasculitis may be a consequence of various ocular and systemic diseases including systemic lupus erythematosus (SLE), Adamantiades-Behçet disease (ABD),
multiple sclerosis (MS), ocular tuberculosis (TB), and
sarcoidosis among others. Inflammation of retinal vessels
may be a component of almost all types of intermediate
and posterior uveitis.
Neovascular
network
In active vasculitis, fundoscopy reveals focal, multifocal, or diffuse white sheathing of retinal vessels. Perivascular infiltration by inflammatory cells accounts for
the pathological vessel sheathing, which is postulated
to generate the blurred margins of vessels. Retinal vasculitis may be accompanied by other vascular changes
including telangectasias, vascular anastomosis, microaneurysms, macroaneurysms and optic disc or preretinal neovascularization [1].
FFA remains a remarkably useful imaging modality for
the diagnosis and monitoring of retinal vasculitis. Fluorescein is able to escape through breaks in blood-retinal
barrier, allowing the detection of vascular occlusion or
leakage [3]. On the other hand, recent studies have
shown that OCTA can demonstrate enlargement and/or
irregularity of the foveal avascular zone (FAZ) and capillary remodeling [1], specifically in patients with involvement of the macula.
Khairallah et al. [33] with the aid of OCTA highlighted
the presence of grayish nonperfused/hypoperfused areas
mostly involving the deep capillary plexus (DCP) in patients with ABD vasculitis. Similar findings have been
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observed in retinal vascular occlusion, diabetic retinopathy and sickle cell retinopathy [34–38]. Deep capillaries
are more susceptible to ischemia as they are not directly
connected to arterioles. Additional findings included elevated, dilated, or shunting perifoveal capillary vessels
and well-delineated black, roundish, or elongated areas
devoid of flow. The formation of cystoid spaces displacing the peripheral capillaries might explain the total
absence of flow in these areas. However, caution should
be taken as retinal atrophic alterations, involving the
macula and the retinal nerve fibers, may produce projection artifacts on OCTA, indicating nonperfusion/hypoperfusion of both the superficial and deep capillary
plexus, where none exists.
OCTA in retinitis and choroiditis
Birdshot retinochoroiditis
Birdshot retinochoroiditis (BRC) is a rare bilateral
chronic posterior uveitis, strongly associated with human
leukocyte antigen (HLA) A29 [39]. Clinical picture is
characteristic, with multiple scatter, oval, creamy white
hypopigmented choroidal lesions, vitritis, retinal vasculitis, and macular edema.
De Carlo et al. [40] performed OCTA on eight eyes
with BRC to evaluate the microvascular alterations occurring in the superficial retinal capillary plexus of the
posterior pole. Their study data revealed the presence of
abnormal telangiectatic vessels and an increase of intercapillary spaces in all affected eyes. They also observed
capillary dilatations and loops in seven of the total eight
eyes examined.
Twenty-two patients (forty-four eyes) with BRC,
which were considered inactive based on clinical
examination and imaging with OCT and FFA, were
evaluated by Pichi et al. [1]. In their series, foveal avascular zone (FAZ) and the area of capillary nonperfusion were delineated and measured with the use
of OCTA at the level of superficial capillary plexus
(SCP). Their results showed that subjects with BRC
had a larger FAZ area compared with the healthy ones.
Another important microvascular change being noticed was the enlargement of perifoveal intercapillary
spaces in all eyes with BRC, representing areas of perifoveal ischemia. All these findings could lead to the assumption that chronic BRC induces hypoperfusion of
the SCP, resulting in tissue hypoxia and cellular death.
In another study held by Pohlmann et al. 64 eyes of 32
subjects with BRC were classified according to disease
activity and duration of the disease. They were evaluated
with multimodal imaging which revealed that active
BRC was associated with retinal vasculitis and hyperfluorescence of the optic disc on FFA as well as hypofluorescent areas on ICGA. In all eyes, OCTA
demonstrated capillary loops and telangiectatic vessels,
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altered retinal vascular architecture and rarefication of
C-scans in retinal layers. However, increased rarefication
of C-scans and altered retinal vascular architecture in
SCP and DCP were significantly correlated with disease
activity [41].
Ocular toxoplasmosis
Ocular toxoplasmosis is frequently associated with retinal vasculitis, and may also result in serous retinal detachment, occlusive vascular disease, macular edema and
CNV. Dye-based angiography is usually performed for
the diagnosis of atypical cases and the identification of
complications. On FFA, the lesion appears hypofluorescent in the early images followed by gradual leakage
from surrounding vessels. In the presence of CNV, a
typical progressive leakage over the area of new vessels
is demonstrated on FFA. On ICGA, the main lesion of
ocular toxoplasmosis is depicted as a hypofluorescent
area with multiple satellite hypofluorescent foci, whereas
CNV appears hyperfluorescent [3]. ICGA also shows involvement of the choriocapillary and choroid in acute
toxoplasmic retinitis.
Spaide [42] recently described the use of OCTA in
order to evaluate an area of CNV in a patient with ocular toxoplasmosis. Leakage on FFA indicated the presence of CNV but its precise anatomy could not be
identified. OCTA scans showed significant contribution
to the neovascular tissue from the retinal vasculature
without any participation from the choroid. Hence, it is
obvious that we can perform OCTA to assess the origin
of abnormal vessels developed not only in toxoplasmosis
but also in other inflammatory diseases.
OCT-A in choroiditis (choriocapillaropathies and stromal
choroiditis)
Multiple evanescent white dot syndrome
Multimodal imaging can be extremely useful in patients
with multiple evanescent white dot syndrome (MEWDS)
and subtle clinical findings. Electroretinography (ERG)
demonstrates photoreceptor dysfunction [43], while in
fundus autofluorescence (FAF) hyperfluorescent spots
are highlighted in the early stages, as the RPE autofluorescence is unmasked due to misalignment of the photoreceptors or metabolic changes affecting RPE [44]. FFA
shows early hyperfluorescence of the dots with late
staining, while on ICGA more numerous hypofluorescent spots are illustrated than the corresponding seen
clinically or on FFA [45, 46]. On structural en face OCT
hyporeflectivity is seen at the level of the RPEphotoreceptor complex that co-localizes with the hypofluorescent spots on ICGA, supporting the hypothesis
that the dark areas on ICGA are attributable to focal
non-functional RPE cells not absorbing the ICG molecule. OCTA is of great importance in revealing that
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within the corresponding hypofluorescent spots of
ICGA, the choriocapillaris and retinal capillary blood
flow are completely normal. This reinforces the concept
that choriocapillaris may not be involved in this disease
and the primary cause of it stands at the level of RPEphotoreceptor complex [1, 23, 47–49]
Acute posterior multifocal placoid pigment epitheliopathy
FFA demonstrates early hypofluorescence of the acute
posterior multifocal placoid pigment epitheliopathy
(APMPPE) lesions and late hyperfluorescence due to
staining [50–52]. APMPPE has been proposed to be a
result of ischemia and acute inflammation of the
choriocapillaris, but not of the medium and large sized
choroidal vessels, leading to RPE abnormalities [53–55].
This inner choroidal involvement as prominent feature
is supported by the ICGA findings of hypofluorescent
areas corresponding to the lesions observed on FFA
[51, 52, 56, 57]. OCT imaging manifests increased
inner choroidal hyporeflectivity or lucency [52, 58], ellipsoid zone disruption and sub-RPE drusenoid abnormalities with RPE atrophy ensuing in the course of the
disease, all of which co-localize with the primary zone
of choroidal hypoperfusion [1, 59]. OCTA imaging
confirmed that hypothesis of inner choroidal or choriocapillaris flow reduction, as it illustrates true choriocapillaris flow-void areas that correspond to the ICGA
hypofluorescent spots and are of the same or larger
size. These findings are not artifacts, since they are not
associated with signal attenuation or blockage due to
overlying RPE alterations [1, 23, 58–63]. Other studies
have also showed progressive recovery of blood flow
with reduction of the ill perfused area and evidence of
vascular reperfusion [1, 59, 60, 62].
Multifocal choroiditis and panuveitis
Along with direct damage of the retina and RPE due to
inflammation, common vision-threatening complications of multifocal choroiditis and panuveitis (MCP)
include inflammatory CNV, cystoid macular edema
and subretinal fibrosis [64–67]. In active disease, FFA
shows early hypofluorescence due to blockage from
the lesions and late hyperfluorescence due to staining,
while atrophic scars look hyperfluorescent due to window defect [3, 68, 69]. ICGA illustrates hypofluorescent acute lesions, some of which may not be clinically
apparent [26]. On OCT inflammatory lesions are typically presented as homogenous elevations of the RPE
that may penetrate into the subretinal space and outer
retina [1, 23, 66, 70, 71]. More heterogeneous subretinal material, occasionally with a sub-RPE component,
may indicate the presence of CNV [23, 66, 71, 72].
However, differentiating purely inflammatory lesions
from inflammatory CNVs can be potentially difficult,
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as both lesions may leak on FFA [23, 66]. OCTA has
been used to assess vascular alterations and is able to
precisely identify CNV as a lacy vascular network at
the level of a normally avascular area of outer retina.
Although OCTA cannot accurately define the level of
CNV activity in cases of inflammatory CNV, it is the
diagnostic modality of choice since findings of other
imaging modalities can be largely equivocal and difficult to interpret [1, 3, 23, 64, 66, 73, 74]. Therefore,
OCTA findings are crucial and may entirely determine
the therapeutic approach, because a combination of
immunosuppressive agents with intravitreal anti-VEGF
therapy in cases of inflammatory CNV is mandatory, as
opposed to monotherapy with immunosuppression in
purely inflammatory lesions without CNV. OCTA at
the level of choriocapillaris has also shown flow-void
areas that correspond to the hypofluorescent areas on
ICGA. However, caution should be taken in cases
where RPE atrophy is present, which may result in a
hyper intense vascular network on OCTA, attributable
to the visible Sattler layer’s vessels under the atrophic
RPE and the undetected signal of the choriocapillaris
blood flow [73].
Punctate inner choroidopathy
The clinical course of punctate inner choroidopathy
(PIC) is considered to be benign unless complicated with
vision-threatening consequences, which include subretinal fibrosis and CNV [3, 66, 75, 76].
In the acute phase, FFA depicts early hypofluorescent
spots with late staining, while CNV is typically illustrated
with a lacy hyperfluorescent pattern followed by late leakage [3, 77, 78]. On ICGA hypofluorescent spots are evident
at the level of choriocapillaris [3]. On OCT active lesions
are typically presented as elevations of the RPE, which may
extend into inner retina, which decrease converting to
areas of sub-RPE accumulations or outer retinal disruption
when inactive. Hyperreflective heterogeneous subretinal
material, accompanied or not with intraretinal fluid, may
be indicative of a neovascular membrane [3, 23, 66]. OCTA
has been shown to effectively reveal and confirm the
presence of a neovascular network of choroidal origin in
patients with PIC, even in apparently inactive cases,
suggesting an increased risk of recurrence [79] (Fig. 1).
Similar to MCP, OCTA findings can be advantageous
in differentiating purely inflammatory lesions from inflammatory CNV, in cases where findings from other
imaging modalities are inconclusive. Moreover, it can
be useful in monitoring patients with CNV and its response to therapy [3, 66].
Serpiginous choroiditis
Fundus autofluorescence (FAF) is remarkably useful in
evaluating the inflammatory activity of serpiginous
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Fig. 1 FFA and structural OCT of a 36-year-old myopic woman with punctate inner choroidopathy complicated by choroidal neovascular
membrane (CNV) (a). OCTA illustrates the lacy pattern of the CNV (b) associated with blood flow (yellow color) within the fibrovascular pigment
epithelial detachment in the combined structural OCT/OCT-A (c)
choroiditis and the risk of its progression [80]. On FAF
inactive lesions are shown hypofluorescent with sharp
borders, while active lesions appear as areas of hyperfluorescence at the margin of the hypofluorescent
lesions [81]. On FFA active lesions show early hypofluorescence with late hyperfluorescence and inactive
ones show window defects. ICGA of inactive lesions
reveals marked hypofluorescence throughout all phases
of the angiogram (Fig. 2a, b). On both FFA/ICGA perfusion defects of the choriocapillaris seem to be more
extensive than the RPE damage shown on FAF, which
suggests that choroidal damage precedes RPE damage
[80, 82]. OCTA of choriocapillaris on active lesions
shows clearly demarcated flow-deficit areas that
correspond precisely to the hypofluorescent lesions on
ICGA [82, 83]. Conversely, inactive lesions demonstrate some detectable flow within the areas of flow
void, indicating deeper medium-to-large choroidal vessels existence and choriocapillaris loss, better detected
on OCTA than on ICGA [23, 84, 85].
Sarcoidosis
In sarcoidosis, FFA is useful in revealing retinal vasculitis, while ICGA illustrates punctuate hypofluorescence
[26]. OCTA may miss small granulomas with diameter
smaller than the size of choriocapillaris lobules. In contrast, larger granulomas which occupy the full thickness
of the choroid [86, 87], block the choriocapillaris,
leading to the appearance of flow void areas on OCTA
[1]. These areas co-localize with the hypofluorescent
spots on ICGA, as well as with the hyporeflective choroidal lesions on enhanced depth imaging OCT (EDIOCT) [1, 23].
Tuberculosis
Since tuberculosis (TB) is predominantly a choroidal
disease, ICGA provides useful imaging information in
patients with TB posterior uveitis effectively detecting
even very subtle lesions, not visible on FFA and FAF
[88–90]. Partial thickness tubercular choroidal granulomas are shown as hypofluorescent lesions that become isofluorescent during the late phases, whereas
full thickness ones remain hypofluorescent throughout
the study [88, 91, 92]. These granulomas appear as
hyporeflective lesions on EDI-OCT [89, 91]. FFA of
choroidal tubercles and granulomas shows early hypofluorescence with late hyperfluorescence or isofluorescence as
the deep choroidal lesions, may disappear after the early
phase of the FFA due to the choriocapillary flush.
Inactive healed tubercles show transmission hyperfluorescence, while large solitary granulomas show early
and progressively increasing hyperfluorescence and late
pooling of dye in subretinal space of overlying exudative
retinal detachment [93–95].
OCTA is able to depict these lesions as welldelineated flow void areas due to hypoperfusion of the
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Fig. 2 Multimodal imaging of a 56-year-old Caucasian man with serpiginous chorioretinopathy. Late frame of combined FFA and ICG illustrating
staining and hypofluorescence of the placoid lesion respectively (a, b), OCT demonstrates the presence of a hyper-reflective subfoveal lesion
accompanied by accumulation of intraretinal fluid and disorganization of the outer retina nasal to the lesion (c). OCTA reveals the presence of a
type II choroidal neovascular membrane associated with blood flow in the combined structural OCT/OCT-A (d, e). Note the blood flow at the
nasal aspect of the same slab corresponding to projection artifact of the normal overlying retinal vessels
choriocapillaris, correlated well with the findings on
ICGA and EDI-OCT. Few preserved islands of choriocapillaris may appear in the center of these areas. During
the healing process, as a result of the choriocapillaris
atrophy in some patients, medium-to-large choroidal
vessels may be visualized in choriocapillaris zone on en
face OCTA [89]. Vascular abnormalities, including nonneovascular tufts, tangled vessels and neovascular membranes may also be assessed with OCTA, which clearly
demarcates the involvement of various retinochoroidal
layers [85, 89].
become isofluorescent during the late phase, depending
on the depth of choroidal involvement. On OCTA, multiple dark foci are illustrated in the choriocapillaris layer,
with the slab located below the RPE-Bruch’s membrane
complex [1, 96] indicating loss or severe hypoperfusion
of the choriocapillaris. These foci appear as areas of flow
void with discrete and sharply demarcated edges that
consistently overlap with the hypofluorescent spots of
the ICGA [23, 97]. This, in conjunction with no signal
loss on the structural en face OCT, supports the hypothesis of true focal choriocapillaris ischemia [98, 99].
Vogt-Koyanagi-Harada
Complications of uveitis
Multimodal imaging is mandatory in order to differentiate Vogt-Koyanagi-Harada (VKH) from other clinical
entities with overlapping features. OCT typically demonstrates multilobular serous macular detachments, with
occasional subretinal hyper-reflective material within
subretinal fluid that probably represents fibrin. In
addition, using EDI-OCT Maruko et al. found increased
choroidal thickness during the acute phase. FFA shows
multifocal hyperfluorescent dots at the level of the RPE
due to leakage or staining and late central pooling of dye
in subretinal space. ICGA shows evenly distributed
hypofluorescent spots (indicating active inflammation of
the choroid) which may remain hypofluorescent or
Macular edema
Spectral-domain OCT (SD-OCT) is the imaging modality of choice for the identification and monitoring of
uveitic CME as well as the evaluation of its response to
treatment [100, 101].
Carrying out a quantitative OCTA analysis, Kim et al.
[2] highlighted the presence of distinct areas with impaired retinal perfusion in patients with uveitic macular
edema. More specifically, their data revealed remarkably
decreased vascular density parameters, including skeleton and vessel density in deep retinal layer (DRL) of
uveitic eyes with active CME compared with normal
eyes. These alterations in deep capillary plexus (DCP)
Tranos et al. Journal of Ophthalmic Inflammation and Infection
(2019) 9:21
corresponded to the site of intraretinal cystoid spaces in
inner retina, suggesting that CME may lead to displacement of retinal capillaries or even attenuation of the
DRL signal (Fig. 3).
Retinal ischemia
Uveitis is frequently associated with vascular inflammation, which may lead to occlusive vasculitis characterized
by retinal ischemia. Fundoscopy reveals cotton-wool
spots and hemorrhages, followed by the development of
telangiectatic vessels and neovascularization in more severe cases [102].
Retinal vascular occlusion is demonstrated on FFA as
areas of capillary shutdown. OCTA may facilitate the
evaluation of such patients by providing detailed information on ischemic areas, which present with increased
intercapillary spaces on OCTA scans. The limitation, as
previously mentioned, is the inability to obtain OCTA
images of the peripheral retina.
Page 9 of 13
Although FFA is capable of demonstrating retinal NV,
it cannot separately illustrate the major retinal capillary
networks (superficial and deep) and may fail to reveal
retinal ischemia in some of the aforementioned diseases
[105]. OCTA is the imaging modality that provides
detailed delineation of the microvascular structures and
their potential abnormalities [105–107]. Furthermore,
OCTA facilitates assessment of the precise spatial extent
(depth and size) and morphological features of these
intraretinal abnormalities that cannot be clearly visualized on FFA [106, 108]. Neovascular complex usually
appears on OCTA as a small tuft of high-flow tiny vessels with curvilinear morphology, while abnormal retinal
circulation’s communications or pathological retinalretinal anastomosis can also be detected [106, 109–111].
OCTA may also be sensitive enough to reveal the extent
of macular ischemia and record vascular flow changes
during the course of the disease [106, 112]. However,
vascular alterations in far or mid-periphery have to be
determined by FFA [106].
Retinal neovascularization
Retinal NV may develop in uveitic patients through inflammatory and ischemic mechanisms. It is frequently
seen in Behçet’s disease (ABD), sarcoidosis, pars planitis,
Eales disease, tuberculosis, systemic lupus erythematosus
(SLE), and idiopathic retinal vasculitis [103, 104].
Choroidal neovascularization
Choroidal neovascularization (CNV) is one of the main
sight-threatening complications in uveitis with an incidence of 2% within uveitic population [113]. It predominantly occurs in eyes with posterior uveitis, being
Fig. 3 Multimodal imaging of a 36-year-old Caucasian woman with intermediate uveitis. Color photo showing cystoid spaces with abnormal
foveal reflex (a), FFA demonstrating petaloid pattern of fluorescein leakage along with hyperfluorescence of the optic disc (b), C-scan taken at the
level of superficial vascular plexus with the corresponding en-face image exhibiting clearly visible cystoid lesions (c), the OCT-A illustrates flow
void cystoid areas at the macula coupled with an enlargement of the foveal avascular zone (d), the B-scan OCT angiogram passing through the
foveal depression (e)
Tranos et al. Journal of Ophthalmic Inflammation and Infection
(2019) 9:21
particularly common in MCP, PIC, ocular histoplasmosis
syndrome, and serpiginous choroiditis [3, 64–66, 75, 78,
79, 114, 115] (Fig. 2c).
It has been suggested that a combination of inflammatory and associated ischemic events decompensate the
previously established balance between normal angiogenetic factors and various inflammatory mediators. The
choroid-produced vascular endothelial factor (VEGF)
and inflammatory mediators, including interleukin-1 (IL1) and tumor necrosis factor a (TNF-a), play a role in
the development of inflammatory CNV through the disruption of the choriocapillaris, Bruch’s membrane and
retinal pigment epithelium (RPE) [1, 3, 116–119].
Early diagnosis of CNV is crucial in order to accomplish more effective management and favorable prognosis of the disease. However, differentiating purely
inflammatory lesions from inflammatory CNV can be
challenging in uveitic patients [1, 64, 120, 121].
OCTA may facilitate early detection of CNV, when
findings of other imaging modalities are inconclusive. It
has the utility of delineating a well-circumscribed neovascular network inside the area of a lesion without being obscured by dye leakage [64, 66] (Fig. 2d, e). OCTA
is effective in revealing CNV despite existing subretinal
fluid or hemorrhage, prevailing in such cases over FFA
[64]. In addition, it is very efficient in monitoring the
progress of CNV lesions that were under treatment and
their response to it. Lesions that show no blood flow signal on OCTA can be distinguished from potential CNV
lesions and therefore are classified as purely inflammatory one s[59]. Although it has demonstrated higher sensitivity in identifying CNV than conventional dye-based
angiography, it still lacks the ability to determine which
neovascular membranes are clinically active [66, 122]. It
can be speculated that CNV which are identified on
OCTA without active leakage on FFA may represent
“quiescent CNV” which requires a different follow-up
schedule [64]. S-OCT of the OCTA has lately been
proved really helpful in this direction. It allows active
flow detection (which is usually colored) and, therefore,
valuable information about perfusion of vessels in order
to distinguish active CNV lesions [123]. Overall, OCTA
alone cannot distinguish between active and inactive
CNVs and should be integrated into a multimodal imaging approach [124]. However, it is a critical adjunct in
identifying the presence of CNV and, therefore, a coguide in the therapeutic management and monitoring of
those patients [1, 66].
Conclusions
Undoubtedly OCTA is gaining increasing popularity
among retina specialists turning into an invaluable asset
in the assessment of various retinal diseases, including
uveitis. It has the potential to significantly alter the
Page 10 of 13
approach in diagnosis and management of uveitic entities by shedding new light into the pathophysiology of
abnormal vascular changes in inflammatory conditions.
Therefore, a future of a more optimal, non-invasive and
valid monitoring of the uveitic patients is becoming apparent with the contribution of this imaging modality.
OCTA is able to detect and investigate a lesion and its
precise spatial extent and to calculate the area and density of microvascular flow, as well as flow void areas, in a
three-dimensional manner. Furthermore, it overcomes
the burden of the masking effect by other elements
noticed in conventional angiography. This along with
the potentially future established measurements of other
flow indices on OCTA, through the chorioretinal vascular plexus and through the avascular compartments,
make OCTA unique in quantifying vascular perfusion
and ischemia in uveitic disease. Additionally, earlier
detection of a uveitic entity or its recurrence may be
possible, even before the manifestation of obvious morphological changes and clinical signs.
OCTA is useful for detecting CNV with some limitations. This imaging modality lacks the ability to delineate
activity of neovascular membranes. Certain areas including prevention and identification of image artifacts and
projection errors require improvement.
More precise information about deeper structures may
also be obtained by future use of longer wavelength monochromatic light, while the requirement of larger fields of
view with higher resolution and decreased motion artifacts
may be fulfilled by larger scan-patterns or faster scanning
speeds. OCTA has the following limitations: inability to illustrate leakage and detect blood flow below the slowest
detectable flow. Nevertheless, its non-invasive and reproducible nature can assist in a better patient compliance.
Overall, OCTA is a promising tool that continues to
evolve and may diminish the need of dye-based angiograms in the future. It has been shown to have high potential to impact clinical care in uveitis however, despite
its promising future, it is of note that there is limited
experience in this technology, and further large scale
studies are required in order to establish it as an irreplaceable clinical utility.
Abbreviations
ABD: Adamantiades-Behçet disease; APMPPE: Acute posterior multifocal
placoid pigment epitheliopathy; BRC: Birdshot retinochoroiditis; CME: Cystoid
macular edema; CNV: Choroidal neovascularization; DCP: Deep capillary
plexus; DRL: Deep retinal layer; EDI: Enhanced depth imaging; FAF: Fundus
autofluorescence; FAZ: Foveal avascular zone; FFA: Fundus fluorescein
angiography; HLA: Human leukocyte antigen; ICGA: Indocyanine green
angiography; IL: Interleukin; MCP: Multifocal choroiditis and panuveitis;
MEWDS: Multiple evanescent white dot syndrome; MS: Multiple sclerosis;
OCT: Optical coherence tomography; OCTA: Optical coherence tomography
angiography; PIC: Punctate inner choroidopathy; RPE: Retinal pigment
epithelium; SCP: Superficial capillary plexus; SD: Spectral domain;
SLE: Systemic lupus erythematosus; TB: Tuberculosis; TB: Tuberculosis;
TNF: Tumor necrosis factor; VKH: Vogt-Koyanagi-Harada
Tranos et al. Journal of Ophthalmic Inflammation and Infection
(2019) 9:21
Acknowledgements
Not applicable.
Authors’ contributions
Authors PT, EMK, OG, and CP contributed to various sections of the
manuscript. The idea was conceived by PT. The data and literature review as
well as drafting of the manuscript was performed by all the authors. PT
compiled all the sections from various authors. The final manuscript was
read, critically reviewed, and submitted for publication by all the authors.
Funding
The research was supported by the National Institute for Health Research
(NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS
Foundation Trust and UCL Institute of Ophthalmology. The views expressed
are those of the author(s) and not necessarily those of the NHS, the NIHR or
the Department of Health.
Availability of data and materials
Since this is a review article, there are no data repositories for this
manuscript.
Ethics approval and consent to participate
Since this is a review article, there are no data repositories for this
manuscript.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Vitreoretinal & Uveitis Department, Ophthalmica Clinic, Vas.Olgas 196 and
Ploutonos, 546 55 Thessaloniki, Greece. 2Department of Ophthalmology,
Hippokrateio General Hospital of Thessaloniki, 49 Konstantinoupoleos Street,
546 42 Thessaloniki, Greece. 3Uveitis Department, Moorfields Eye Hospital,
162 City Rd, London EC1V 2PD, UK.
Received: 13 December 2018 Accepted: 18 November 2019
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