Multimodal Imaging in Retinal Vasculitis

Retinal vasculitis (RV) is an inflammatory disease affecting the retinal vessels situated in the inner plexiform layer of the retina, posing a significant threat to vision [1]. It was first mentioned in 1784 by John Hunter in his report “Observations on the inflammation of the internal coats of the veins” [2, 3]. This condition can manifest as either an idiopathic disorder or secondary to infectious or noninfectious diseases, masquerade syndromes, isolated ocular disorders, or drug-induced reactions (Table 1) [4]. Abd El Latif et al. [5] reported infectious etiology in 16% of cases, systemic inflammatory diseases in 38%, and isolated RV in 43%. Traditionally, RV classification has been based on vascular caliber (small, medium, or large vessel) and clinical appearance (occlusive or nonocclusive). However, there is currently no consensus or standardized grading system for RV [6].

Studies have indicated that the annual incidence of RV ranges from 1 to 2 cases per 10,000 individuals [7]. Ethnicity is believed to play a role in the variation of RV occurrence and frequency worldwide. In the USA, the estimated incidence is 1–2 new cases per 100,000 population annually [8]. One study reports that 15% of patients with uveitis may also present with RV [9]. Within the Asian population, 18.5% of cases are associated with RV, a leading disease that includes sarcoidosis and cytomegalovirus retinitis [10]. Research conducted at an eye center in Saudi Arabia involving 132 patients diagnosed with Behçet’s disease (BD) revealed that panuveitis emerged as the predominant presentation simultaneously. The study observed that 26% of the patients exhibited RV at diagnosis [11].

During the fundoscopy examination, this disease presents features such as perivascular sheathing, cuffing, retinal vessel occlusion, vascular leakage, neovascularization secondary to ischemia, cotton-wool spots, and intraretinal hemorrhage. Inflammation affecting retinal veins is termed phlebitis, while the involvement of retinal arterioles is referred to as arteriolitis [12]. Several factors can contribute to visual loss in cases of RV, including retinal nonperfusion, neovascularization, vitreous hemorrhage, macular edema, tractional retinal detachment, formation of epiretinal membrane, and development of neovascular glaucoma [13].

This review aimed to demonstrate the array of tools available for evaluating the retinal vasculature in patients with RV, including fluorescein angiography (FA) and indocyanine green angiography (ICGA), optical coherence tomography angiography (OCTA), and adaptive optical imaging (AO). Both techniques are essential for a comprehensive assessment and to enhance our comprehension of pathoanatomic aspects [14].

A literature search was conducted using the PubMed and Medline databases. Our research focused on keywords such as “RV,” “fluorescein angiography,” “optical coherence tomography,” “optical coherence tomography angiography,” “indocyanine green angiography,” adaptive optical imaging, and “multimodal imaging.” We reviewed papers published from 1997 to 2024, and only references in the English language were considered for inclusion.

FA is the primary imaging modality for diagnosing and monitoring RV, allowing visualization of vascular and perivascular leakage, aiding in identifying the pattern and extent of inflammation, whether it affects veins (phlebitis) or arterioles (arteriolitis). FA also facilitates the staging of RV, distinguishing between active inflammation, ischemia, neovascularization, and associated complications [1, 15].

In angiograms, RV presents as vascular leakage, characterized by progressive hyperfluorescence originating from retinal vessels, segments, or entire lengths of vessels, indicating inflammation and disease activity. This leakage can affect arterioles, venules, or capillaries and may present focal, segmental, or diffuse patterns [16]. Arteriolitis can be associated with systemic diseases such as granulomatosis with polyangiitis, polyarteritis nodosa, Churg-Strauss syndrome, and systemic lupus erythematosus, or with local inflammatory conditions like acute retinal necrosis and syphilis [17].

Periphlebitis often presents as venular leakage observed on FA, as seen in idiopathic RV. In this condition, a diffuse staining pattern affecting both the posterior pole and periphery may be evident, often accompanied by macular ischemia. For example, in pars planitis, FA typically reveals diffuse or segmental staining concentrated in the retinal periphery, along with venular staining and leakage. A characteristic “fern pattern” of small vessel hyperfluorescence may be observed alongside peripheral nonperfusion (Fig. 1a) [18]. Conversely, in birdshot chorioretinitis, a diffuse staining pattern affecting the posterior pole and optic disc is commonly observed on FA, indicating leakage [19].

In certain instances, such as sarcoidosis-associated periphlebitis, a unique FA pattern is characterized by segmental or diffuse vascular staining and leakage (Fig. 2a, b). Occasionally, this pattern is accompanied by yellow perivascular exudates, resembling candle wax drippings. Other features include Kyrieleis arteriolitis, characterized by an accumulation of periarterial nodular exudates or plaques, which can be observed in toxoplasmosis (Fig. 2) [20]. Moreover, uveitic syndromes like BD and granulomatosis with polyangiitis can exhibit both arteriolar and venular leakage on FA [21].

Abraham et al. conducted a study to evaluate the efficacy of FA in 14 pediatric patients diagnosed with quiescent intermediate uveitis (43%), posterior uveitis (43%), and panuveitis (14%). Their investigation revealed that 79% of these patients displayed indications of occult RV during FA examination [22].

Cryoglobulinemia is a rare condition characterized by the presence of serum cryoglobulin proteins and is often associated with hepatitis C, HIV, and lymphoproliferative disorders. In a retrospective case series by Thomas et al. [23], 5 female patients diagnosed with RV attributed to cryoglobulinemia were described. FA revealed leakage in small or large vessels in all patients, with no evidence of retinal vascular occlusions or neovascularization. Additionally, one case presented cystoid macular edema on OCT.

Kawasaki disease is a medium-sized vasculitis affecting primarily children. Most commonly, patients present with nonexudative bulbar conjunctivitis and other manifestations such as papilledema, papillitis, vitreous opacities, vitritis, retinitis, and rarely RV. Suganama et al. [24] documented a case involving a 5-year-old child with complicated Kawasaki disease exhibiting anterior uveitis. Fundus examination revealed vitreous haze, tortuous vascular vessels, sheathing, and exudates around the vessels. After infection etiologies were ruled out, treatment with infliximab led to the resolution of RV within 42 days of treatment.

Giant cell arteritis, the typical primary vasculitis in adults, is a granulomatous inflammation of medium- to large-sized vessels that affects older people. The etiopathogenesis is not dilapidated. This disease produces an arteritic anterior ischemic optic neuropathy and, less commonly, cilioretinal artery occlusion, choroidal infarction, and ischemia of the optic chiasm [25]. Ahmad et al. reported a case involving a 76-year-old African American with a history of arteritic ischemic optic neuropathy attributed to giant cell arteritis, confirmed by biopsy. Fundus examination on the left eye revealed optic nerve head pallor. FA in the early phase showed a slowed arteriolar filling, and in the late phase, it exhibited peripheral arteriolar leakage and choroidal nonperfusion on the left eye [26].

Distinctive features characterize occlusive RV, including retinal capillary dropout, nonperfusion regions, and retinal vascular staining and leakage. These manifestations can affect both retinal arterioles, as seen in conditions like acute retinal necrosis syndrome [17]. In contrast, Susac syndrome presents with Gass plaques, which are yellow retinal arterial plaques along the course of obstructed arteries. On FA, they appear as characteristic focal, nonperfused arterioles (Fig. 3) displaying multiple areas of segmental staining. Additionally, nonocclusive disorders such as multiple sclerosis, syphilis, toxoplasmosis, tuberculosis, and pars planitis may also exhibit similar FA findings [17, 19]. Occlusive periphlebitis has the potential to induce retinal edema, intraretinal hemorrhages, and hemorrhagic infarction of the retina. The occurrence of poor visual outcomes in certain patients with RV, despite receiving adequate therapy, may be attributed to macular ischemia [16, 17, 19].

FA imaging modality can assist in delineating the extent of non-perfusion areas, identifying the presence of neovascularization, and evaluating the necessity and scope of laser photocoagulation [19]. Despite the limitations of conventional fundus cameras in capturing a wide field of view, the introduction of ultrawide field (UWF) imaging has revolutionized retinal imaging. UWF imaging can capture details of the retinal field spanning over 200° in a single image, making it ideally suited for documenting the entire extent of pathology in RV. Its ability to provide comprehensive visualization of the retina allows for early detection of disease progression. It facilitates a better understanding of disease patterns, enabling early diagnosis and timely intervention [27, 28].

Tanaka et al. conducted a comparative study between standard FA and UWF FA to assess sarcoid uveitis activity. They employed the scoring system established by the Angiography Scoring for Uveitis Working Group (ASUWG) to evaluate angiographic signs. The study revealed an intraclass correlation coefficient for standard UWF FA 0.87 and FA 0.77. Moreover, the total scores obtained were 14.6 for UWF FA and 12.0 for standard FA. Notably, UWF FA demonstrated higher scores than standard FA, particularly in posterior retinal vascular staining or leakage, peripheral capillary leakage, and optic disc hyperfluorescence [29].

Multiple studies have highlighted the correlation between angiographic leakage and inflammatory activity, with UWF FA showing enhanced detection of peripheral vascular leakage [30]. In a large cohort of patients with uveitis, it was analyzed with UWF FA for peripheral vascular leakage quantification. Focal vasculitis (r = 0.441, p = 0.001) and peripheral ischemia were found to correlate with neovascularization-related leakage (r = 0.462, p = 0.001) [31]. Additionally, this study utilized a stepwise multiple regression analysis, revealing that poor visual acuity was associated with central macular thickness and foveal avascular zone size (R²-adjusted = 0.45, p = 0.001) [31].

Sheemar et al. [28] thoroughly evaluated 200 patients (400 eyes) diagnosed with RV, categorizing them into three zones and stratifying the extent of capillary non-perfusion based on clock hours. Utilizing UWF FA, they discovered a significant correlation between a larger area of capillary non-perfusion and an increased likelihood of retinal neovascularization occurrence (65% in cases with ≥4 clock hours compared to 45% in those with 1–3 clock hours; p = 0.002). Furthermore, they observed that RV confined to the peripheral zone exhibited a notably low odds ratio for the development of retinal neovascularization.

Brolucizumab is a vascular endothelial growth factor inhibitor. This treatment has been authorized to manage neovascular age-related macular degeneration and diabetic macular edema [32]. Baumal et al. [33] reported a retrospective case series of 15 eyes that presented RV and intraocular inflammation after intravitreal injection of brolucizumab. These cases were characterized by occlusive vasculitis of small or large vessels, perivenular hemorrhages, and phlebitis foci. Singer et al. [34] conducted a post hoc analysis of 70 eyes with intraocular inflammation secondary to brolucizumab. The study revealed that the median time to the first episode of intraocular inflammation following brolucizumab injection was 18 days (interquartile range, 4.0–29.0 days). Among the affected patients, 61 eyes (87.1%) were treated with systemic corticosteroids and topical treatment, and three eyes required intravitreal injections of steroids. Inflammation was resolved in 79.6% (39) of the eyes of the cases, with 10.2% (5 eyes) experiencing resolution but presenting sequelae, while five eyes did not resolve by the end of the study. Another post hoc analysis by Monés et al. [35] reported a 2.1% risk of RV and intraocular inflammation associated with brolucizumab.

Optical coherence tomography (OCT) provides high-resolution cross-sectional imaging of retinal layers, allowing for the detection of subtle structural changes indicative of RV. With OCT, inflamed retinal vessels can be identified, showcasing enlarged vessels, hyperreflective vessel walls (Fig. 4c), hyperreflective lumens, and inflammatory material in the adjacent vitreous. Moreover, OCT assists in evaluating macular edema, vitreomacular traction, and retinal thickening (Fig. 1b), thereby aiding in the guidance of therapeutic interventions and the monitoring of treatment response [36].

Spaide et al. [37] evaluated 5 patients with RV using spectral domain OCT and reported focal thickening of the retina with loss of retinal lamination. Another study by Chen et al. [38] included 72 patients (115 eyes) with intermediate uveitis and panuveitis, assessing macular volume (MV) via OCT as a marker for active vascular leakage. They found that MV in the 6-mm circle showed the strongest correlation with leakage scores, explaining 57% of the variation in leakage (p > 0.001). MV in the 3-mm circle and central subfield thickness explained 45.8% and 39.5% of the variation, respectively. These findings suggest that MV can be a quantitative parameter for monitoring RV in uveitis (Fig. 1b).

Teussink et al. [39] conducted a case series on OCT findings in 21 patients (42 eyes) with birdshot chorioretinopathy (BCR), reporting a disruption of the ellipsoid zone in 33% of patients. Four patients showed reconstitution of the disrupted ellipsoid zones after the resolution of RV, while 3 patients with poorly responsive RV did not exhibit reconstitution. The authors concluded that ellipsoid zone disruption may be associated with the activity of RV.

Goel et al. [40] conducted a cross-sectional study on 79 eyes of 66 patients with Eales disease who underwent spectral domain-OCT. The Authors reported that eyes with active RV affecting large vessels were primarily complicated by macular edema (CMT 315.3 ± 102.3 μm) (24%), followed by epiretinal membrane and macular thinning (11.4%), hard exudates (6.3%), and inner retinal or inner limiting membrane folds (3.8%).

Enhanced-depth imaging optical coherence tomography (EDI-OCT) greatly enhances OCT’s diagnostic capabilities, particularly improving the visualization of structures like the external limiting membrane, photoreceptor layer, and choriocapillaris. EDI-OCT enables better localization and characterization of pathological changes linked to RV. This advanced imaging capability allows clinicians to more accurately assess the extent and severity of the disease, monitor disease progression, and evaluate treatment responses [36].

Shirahama et al. [41] analyzed 30 patients with Behcet’s uveitis (BU) (51 eyes), assessing vasculitis severity with a FA leakage score and correlating it with a subfoveal choroidal thickness measured via EDI-OCT. They reported a positive correlation between subfoveal choroidal thickness and leakage score across the total retina (r² = 0.210, p < 0.05) [42]. In a case-control study, Kumar et al. [43] compared 23 patients with acute idiopathic RV (36 eyes) to 25 control patients (50 eyes) using EDI-OCT. They found a significantly greater subfoveal choroidal thickness in the vasculitis group compared to the control group (338.86 ± 28.72 μm; vs. 296.72 ± 19.45 μm; p < 0.001, Mann-Whitney U test).

OCTA is an advanced noninvasive diagnostic tool for chorioretinal diseases [44‒46]. It creates three-dimensional images of retinal and choroidal capillaries using Doppler OCT, allowing for detecting erythrocyte movement within retinal blood vessels in seconds without the need for contrast agents [47‒49]. In cases of RV, OCTA enhances the assessment of perifoveal microvascular abnormalities, including capillary non-perfusion areas, enlarged foveal avascular zones, telangiectasias, and shunts [18, 50].

Some studies have noted retinal capillary vessel density (VD) changes associated with RV [51, 52]. Noorikolouri et al. [53] examined 31 patients with RV using FA and Swept-source OCT-A (SS-OCTA) with the PLEX Elite 9000 system, featuring 12 × 12 mm OCTA scans centered on the fovea. They found a correlation between visible retinal vascular leakage on FA and increased perivascular retinal thickness on SS-OCTA in 17 patients (Fig. 2c, d). Five patients underwent a second examination following vasculitis treatment, with three showing improved retinal vascular leakage on posttreatment FA and reduced perivascular retinal thickness on SS-OCTA scans. Moreover, 4 eyes of two patients exhibited capillary non-perfusion on both FA and SS-OCTA. Retinal ischemia was a flow loss on en-face scans of the superficial and deep retinal plexus slabs. Notably, regions with decreased retinal thickness on pseudo-color retinal thickness maps and B-scans corresponded with hypoperfusion areas on FA (Fig. 4).

A study conducted on patients with occlusive RV in BD utilized OCTA to assess the retinal vascular plexus and microperimetry to evaluate macular sensitivity. This cross-sectional structural and functional study of the parafoveal retina compared BU patients to age- and sex-matched non-ocular BD and healthy subjects. The foveal avascular zone area and VD in the superficial and intermediate vascular plexuses did not differ significantly between the groups. However, variance analysis revealed a reduction (p < 0.05) in parafoveal VD in DCP in BU patients, particularly in the nasal quadrant (∼20%) [54].

Furthermore, a study comprising 40 eyes from 29 patients with fernlike leakage utilized clinical assessments and multimodal imaging, including UWFA and wide-angle SS-OCTA. The results revealed a deep capillary plexus flow signal in all cases, with impairment in the superficial vascular plexus (SVP) in six eyes. Areas exhibiting altered SVP and DCP flow signals on SS-OCTA corresponded with regions of perivenular fern-like leakage on UWFA (Fig. 1c), particularly at the posterior pole. DCP flow signal attenuation exceeded SVP, indicating a more significant vascular disruption in deep retinal layers. This correlation underscores SS-OCTA’s potential for understanding retinal vascular disorders, particularly in elucidating the spatial relationships between vascular changes and characteristic leakage patterns [18].

Since its introduction for diagnostic purposes in humans in 1950, indocyanine green dye has played a crucial role in medical imaging. ICGA can penetrate pigmented layers, lipid deposits, hemorrhages, and serous exudation much better than FA as it is fluorescence in the near-infrared spectrum (830 nm) [55, 56]. ICGA has been used to diagnose occult choroidal neovascularization in age-related macular degeneration and has contributed to understanding the pathophysiology of chorioretinal inflammatory disorders. Its applications extend from the anterior to the posterior segment [57‒59]. Choroidal abnormalities associated with RV include patchy hypofluorescence, indistinct choroidal vasculature, and late hypercianescence of choroidal vessels. Signs of choroidal inflammation in ICGA include hypofluorescence, dark dots, and fuzzy choroidal vessels. Inflammatory granulomas entities such as tuberculoma and sarcoid choroidal granulomas can appear as mass lesions obstructing standard ICG dye infusion, resulting in areas of hypofluorescence or no fluorescence [60]. In active cases of BCR, ICGA shows hypofluorescence dark dots in the intermediate phase; these lesions may disappear or persist into later stages. In chronic cases, the persistence of hypofluorescent dark dots is attributed to choroidal granulomas or chorioretinal atrophy [61]. The size of the granulomas determines their appearance in later phases, with larger ones causing complete dye blockage and appearing as dark dots. In comparison, smaller ones become isofluorescence in late ICG phases. Vascular leakage from large choroidal vessels in ICGA presents as blurred-bordered vessels, known as “vascular fuzziness,” seen during the intermediate phase and transitioning to diffuse hyperfluorescence later [57, 58].

The combination of FA and ICGA provides valuable insights into retinal and choroidal vasculature, respectively, mainly when inflammation affects both the retina and choroid, as observed in diseases like Vogt-Koyanagi-Harada disease and BCR [27]. In BCR, ICGA plays a crucial role, mainly when lesions are not visible on fundus examination. During early and mid-phase, these lesions are hyperfluorescent, likely due to inflammatory infiltrates; in the late phase, some lesions transition to fluorescent, suggesting incomplete occupation of the choroidal stroma by inflammatory lesions. However, atrophic lesions may remain hyperfluorescent during the late phase and appear hyperfluorescent in FA due to a window defect. Additionally, studies have shown a reduction in lesions between periods of disease activity and inactivity [62]. Multimodal imaging with FA and ICGA has been utilized to study periarteritis (Kyrieleis plaques) in 25 eyes with infectious uveitis, 23 eyes with toxoplasma retinochoroiditis, and 2 with cytomegalovirus retinitis in patients with HIV infection. The lesions exhibited increased fundus autofluorescence and early hypofluorescence, followed by late hyperfluorescence (Fig. 3b) in both angiographies [20].

Bouchenaki et al. [63] thoroughly analyzed the medical records of patients with active posterior uveitis who underwent combined FA and ICGA. They classified choroidal vasculitis into two angiographic patterns: primary inflammatory choriocapillaris and stromal vasculopathy. The first pattern showed hypofluorescent zones across all angiographic phases, indicating choriocapillaris nonperfusion, observed in conditions like multiple evanescent white dot syndrome and multifocal choroiditis. However, some studies reported that hypofluorescent areas can be possible due to hypothetically damaged RPE cells [64]. Chang et al. [65] reported a study with in vitro RPE cells with ICG in which they postulate that differing fluorescence patterns in the late phase are due to increased infrared fluorescence in damaged RPE cells. The second pattern exhibited a fuzzy appearance of choroidal vessels in intermediate phases and diffuse choroidal hyperfluorescence in late stages, suggesting inflammation of larger stromal vessels, seen in diseases like sarcoidosis, tuberculosis, BCR, and BU. Optic disc hyperfluorescence, rare in ICGA, may occur in severe VKH and posterior scleritis. Additionally, patients with posterior scleritis show enlargement of vortex veins in ICGA.

Howe et al. concluded that ICGA was valuable for identifying choroidal pathology in inflammatory uveitis, with lesions corresponding to hypofluorescence or hyperfluorescence in the early and late stages of active choroiditis on FA. FA and ICGA show similarities in the initial phases of posterior inflammatory diseases. However, a notable distinction emerges in the recirculation period, during which ICG seeps from fenestrated choroidal capillaries, gradually saturating the entire choroidal thickness. ICGA aids in distinguishing between various inflammatory conditions that exhibit similar clinical appearances [63, 66, 67].

Adaptive optical imaging (AO) was used for the first time in ophthalmology by Liang [68] to capture high-resolution and high-quality acquired retinal images. This tool provides noninvasive retina imaging, which improves the lateral resolution of the fundus image and enables the evaluation of nerve fibers, ganglion cells, lamina cribs, photoreceptors, and retinal blood vessels [69]. RV in the form of vascular sheathing can be visualized as fusiform or linear opacities on both sides of the vessels, allowing for the follow-up of the disease, monitoring, and tracking its reduction and resolution after treatment [70]. Mahendradas et al. [71] reported a case series of 6 patients with RV due to different autoimmune diseases, in which they measured with AO parameters such as sheathing, length, sheathing width, and wall-to-wall dimensions at the onset of the disease and during follow-up assessments. The authors report distinct patterns of sheathing correlated with the etiologies of RV and observed a reduction throughout follow-up. Another study evaluated 20 cases of RV that underwent AO imaging, and they concluded that perivenous sheathing could be quantitative analyzed and monitored at the same time and suggested in RV that perivascular infiltration may contribute to venous occlusion due to a compressive effect [72].

RV is a serious problem that affects vision and can be challenging to treat. Adapting research and treatments to patients’ needs is essential for improving diagnosis, treatment, and outcomes. Multimodal imaging plays a crucial role in the comprehensive evaluation of RV, providing valuable information about the disease and facilitating personalized treatment strategies. However, a lack of studies on OCT in RV has been observed, indicating that current OCT technologies will unlikely replace FA shortly for identifying active RV and associated non-perfusion.

The authors report no conflicts of interest. They are alone responsible for the content and writing of the paper.

No funding has been received for the present review.

Y.P.: manuscript drafting and literature review. P.N.: manuscript editing. F.P.: final manuscript approval.