Optical coherence tomography angiography in uveitis

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 non-perfusion 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, 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 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.

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 RPE-photoreceptor 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 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 RPE-photoreceptor complex [1, 23, 47‐49]

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].

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, 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].

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].

Fundus autofluorescence (FAF) is remarkably useful in evaluating the inflammatory activity of serpiginous 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].

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 (EDI-OCT) [1, 23].

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 well-delineated flow void areas due to hypoperfusion of the 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 non-neovascular tufts, tangled vessels and neovascular membranes may also be assessed with OCTA, which clearly demarcates the involvement of various retinochoroidal layers [85, 89].

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 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].