Abstract
Background: Retinal vasculitis has heterogeneous etiologies encompassing infections, autoimmune diseases, masquerades, and idiopathic causes. The heterogeneity in the underlying clinical features and etiologies of retinal vasculitis makes its diagnosis challenging for clinicians, the workup thus becomes quite extensive, and many a times several unwarranted investigations are done to look for a possible etiology. Summary: Timely and accurate diagnosis is crucial for effective management and vision preservation. The algorithmic approach needs understanding of the phenotype, clinical features, as well as imaging biomarkers so that only customized investigations are done in order to make the timely diagnosis and initiate specific therapy wherever required. Key Message: In this review article, we shall present an algorithmic approach that combines clinical assessment, ophthalmic imaging, laboratory investigations, and targeted ancillary tests.
Plain Language Summary
Retinal vasculitis presents a diagnostic challenge due to its diverse etiologies and clinical manifestations. Diagnosis relies on a combination of clinical assessment, ophthalmic imaging, and tailored laboratory investigations. Clinical examination involves identifying specific vascular involvement patterns and associated findings. Ophthalmic imaging techniques such as fundus fluorescein angiography, ultra-widefield fundus photography and angiography, optical coherence tomography, and optical coherence tomography angiography imaging aid in visualizing retinal vascular changes, macular edema, neovascularization, and structural alterations. These modalities provide valuable insights into disease activity, severity, and treatment response. Laboratory diagnostics, guided by clinical and imaging findings, aim to differentiate infectious from noninfectious causes and may include serological assays, inflammatory markers, proteomic analysis, and genetic testing to uncover underlying pathophysiological mechanisms. A tailored approach to diagnosis ensures optimal management and preservation of vision in patients with retinal vasculitis.
Introduction
Retinal vasculitis is a complex and multifactorial inflammatory disorder characterized by inflammation of the retinal blood vessels. The Standardization of Uveitis Nomenclature (SUN) working group recommends that the term “retinal vasculitis” should be used in cases with evidence of ocular inflammation and retinal vascular changes [1]. Currently, a universally accepted classification system for retinal vasculitis is lacking, which can result in diagnostic discrepancies and adversely affect treatment decisions. Nevertheless, the condition has been classified based on etiology (infectious vs. noninfectious), vascular caliber (large, medium, or small vessel disease), and clinical presentation (occlusive or nonocclusive) [2‒4]. While these categories offer some framework for understanding retinal vasculitis, they are not exhaustive and may overlap, possibly complicating diagnosis and treatment. Moreover, the rheumatologists and ophthalmologists may not be always on the same page while using the term “vasculitis.” Rheumatologists typically classify vasculitis based on parameters such as the size of the affected vessel, its anatomical location, and accompanying histological alterations. This classification process typically involves a biopsy for confirmation. The diagnosis of vasculitis implies documented or presumed damage to the vessel wall. Conversely, ophthalmologists diagnose retinal vasculitis by observing perivascular infiltrates during a thorough examination of the dilated eye and through imaging techniques, commonly employing fluorescein angiography (FA). Indicators of vasculitis may include intraretinal hemorrhage, suggesting abnormalities in retinal vessels, or cotton wool spots, which signify local retinal ischemia. Due to the potential harm associated with retinal biopsies, such procedures are infrequent. Angiography findings consistent with retinal vasculitis include fluorescein staining of vessel walls or leakage beyond them. This leakage indicates heightened vascular permeability, representing a distinct diagnostic threshold for vasculitis compared to the histopathological evidence of vessel wall destruction.
Retinal vasculitis is termed as primary when no associated cause can be found after an extensive systemic workup, while secondary retinal vasculitis may have an underlying etiology such as infectious (tuberculosis, toxoplasmosis, syphilis, and herpetic uveitis), noninfectious (systemic immune-mediated conditions like Behcet’s disease, sarcoidosis, systemic vasculitides), neoplastic (e.g., acute leukemia, ocular lymphoma, and paraneoplastic conditions), and other ocular conditions like idiopathic retinal vasculitis, aneurysm, neuroretinitis, birdshot chorioretinopathy, etc. [2] (Table 1). Despite long list of etiological causes, diagnosis of primary retinal vasculitis is not uncommon. Moreover, even upon long-term follow-up of patients with primary retinal vasculitis, the emergence of systemic diseases is rare [5]. On the other hand, many a times rheumatological diseases such as Behcet’s disease or sarcoidosis present with isolated ocular involvement without systemic manifestation. In few patients, the systemic involvement may be restricted to subclinical signs, e.g., lymphadenopathy in sarcoidosis. Therefore, it becomes important to workup the patient thoroughly before making the diagnosis of primary vasculitis.
Infectious retinal vasculitis | |
| |
Noninfectious diseases associated with retinal vasculitis | |
Systemic causes | specific ocular entities |
Behcet’s disease Sarcoidosis | IRVAN syndrome |
Systemic lupus erythematosus Granulomatosis and polyangiitis, Polyarteritis nodosa | Idiopathic frosted branch angiitis Birdshot retinochoroidopathy Pars planitis |
Churg-Strauss syndrome HLA-B27-associated uveitis Sjögren’s syndrome | Intracameral vancomycin prophylaxis |
Relapsing polychondritis Dermatomyositis polymyositis | |
Neurologic disorders: multiple sclerosis, Susac syndrome (microangiopathy of the brain, retina, and cochlea) | |
Masquerade syndromes: conditions masquerading as retinal vasculitis | |
| |
Idiopathic RV | |
No evidence of infectious cause, associated systemic inflammatory disease, or specific ocular entity |
Infectious retinal vasculitis | |
| |
Noninfectious diseases associated with retinal vasculitis | |
Systemic causes | specific ocular entities |
Behcet’s disease Sarcoidosis | IRVAN syndrome |
Systemic lupus erythematosus Granulomatosis and polyangiitis, Polyarteritis nodosa | Idiopathic frosted branch angiitis Birdshot retinochoroidopathy Pars planitis |
Churg-Strauss syndrome HLA-B27-associated uveitis Sjögren’s syndrome | Intracameral vancomycin prophylaxis |
Relapsing polychondritis Dermatomyositis polymyositis | |
Neurologic disorders: multiple sclerosis, Susac syndrome (microangiopathy of the brain, retina, and cochlea) | |
Masquerade syndromes: conditions masquerading as retinal vasculitis | |
| |
Idiopathic RV | |
No evidence of infectious cause, associated systemic inflammatory disease, or specific ocular entity |
Retinal vasculitis may present with a myriad of clinical features like vascular sheathing or perivascular exudation, intraretinal hemorrhages, vascular occlusion, neovascularization, or vascular leakage on angiography [2]. Vaso-occlusion and retinal ischemia are potentially devastating complications of retinal vasculitis that can lead to visual loss. Retinal tissue has an extraordinarily high metabolic requirement, which is usually provided by a highly efficient vascular supply. Insufficient retinal blood flow causes neuroretinal dysfunction and degeneration. Retinal ischemia may result in neovascularization at the optic nerve head or elsewhere in the retina leading to vitreous hemorrhage (VH), fibrovascular proliferation, and eventually tractional retinal detachment (TRD) [6].
The diagnosis of retinal vasculitis is mostly clinical. However imaging modalities like fundus fluorescein angiography (FFA) may help confirm the diagnosis, show the areas of involvement and capillary non-perfusion. Once retinal vasculitis is diagnosed, tailored laboratory workup is indicated to identify any underlying cause. An algorithmic approach to diagnosis of retinal vasculitis should have three major components (Fig. 1):
Detailed history and clinical examination
Ancillary multimodal imaging and imaging biomarkers
Tailored laboratory diagnostics
Detailed History and Clinical Examination
A detailed clinical history and a comprehensive ophthalmic examination should be performed for every case. A thorough understanding of systemic medical history may provide important clues to etiological diagnosis. Immunocompromised patients (e.g., those with acquired immunodeficiency syndrome) raise the possibility of infectious origins. Similarly, history of recurrent oral and genital ulcers may indicate Behcet’s disease as possible etiology, while persistent cough may suggest that the patient is suffering from pulmonary tuberculosis or sarcoidosis. A complete drug history may shed light on the rare cases of drug-induced vasculitis. Numerous drugs have been associated with retinal toxicity and vasculitis. Among them is vancomycin, which has been found to cause hemorrhagic occlusive retinal vasculitis. Likewise, the intravitreal injection of anti-vascular endothelial growth factor, particularly brolucizumab, has been associated with the development of intraocular inflammation and occlusive vasculitis.
A careful insight into patient’s surgical history may aid in the diagnosis of the uncommon toxic posterior segment syndrome, which manifests as occlusive retinal vasculitis following pars plana vitrectomy and silicon oil injection [7]. Various potential mechanisms are postulated for “Silicon oil-induced vasculitis.” These include the occasional presence of impurities, such as low-molecular-weight components, ionic compounds, and compounds with cleavable fluoride in the silicone oil. Direct immunogenic and toxic effects of silicon oil may also have a role to play. Alternatively, the inflammation could be related to silicon oil emulsification and foreign body-type reaction [8].
In the setting of the clinical examination, it is important to look for signs of anterior segment involvement. A non-granulomatous and granulomatous anterior uveitis may be associated with retinitis pigmentosa (RV). Careful slit lamp examination to observe presence/absence of keratic precipitates, and cells in the anterior chamber, sectoral/diffuse iris atrophy are necessary. Other signs such as high intraocular pressure and iris neovascularization may also be observed. Presence of keratic precipitates, broad based posterior synechiae, and iris nodules may point toward granulomatous etiologies like tuberculosis or sarcoidosis. A high intraocular pressure in absence of any topical steroid use and presence of sectoral/diffuse iris atrophy suggests viral etiology.
Regarding the posterior segment examination, it is significant to ascertain the type of vessels (arteries, veins, capillaries) involved. The typical involvement of a certain vessel will point toward a specific diagnosis. It is important to look for concomitant findings in the fundus, like snowballs, snowbanking, retinitis patches, active choroiditis lesions, and chorioretinal scars. Different clinical signs may suggest specific causes (Fig. 1). The presence of perivascular cuffing, characterized by inflammatory infiltrates encircling retinal vessels, may indicate sarcoidosis, multiple sclerosis, or Eales disease. Kyrieleis arteritis is hallmark of toxoplasma infection. On the other hand, the presence of cotton wool spots, indicative of retinal nerve fiber layer infarctions, may suggest systemic associations including systemic lupus erythematosus (SLE), polyarteritis nodosa, and Churg-Strauss disease. Additionally, aneurysmal dilatation of arterioles implicates idiopathic retinal vasculitis, aneurysms, and neuroretinitis as possible etiology. Moreover, identification of patches of retinitis prompts consideration of Behcet’s disease, cytomegalovirus retinitis, acute retinal necrosis (ARN) (caused by herpes simplex virus type, varicella-zoster virus, or HTLV), and toxoplasmosis. Rarely, varicella-zoster retinal vasculitis may present without retinitis. Furthermore, the observation of perivascular choroiditis underscores the need to evaluate for tuberculosis as a potential etiological factor.
Ancillary Multimodal Imaging and Imaging Biomarkers
Imaging plays an important role in the diagnosis and management of patients with retinal vasculitis. FFA is the gold-standard imaging modality in patients with retinal vasculitis to demonstrate vascular leakage, monitor disease activity and response to treatment. In addition to the standard FFA, imaging techniques like ultra-widefield (UWF) fundus photography and angiography, optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and adaptive optics (AO) imaging provide detailed analysis of the nature and severity of retinal vascular inflammation. Multimodal imaging can help identify and delineate capillary non-perfusion, neovascularization, and abnormal anastomosis, thus facilitating the care providers to initiate specific treatment protocols.
Fluorescein Angiography
FA remains the imaging modality of choice, aiding in the diagnosis and follow-up of patients with retinal vasculitis. It also plays important role in monitoring response to therapy and management of complications such as macular edema, peripheral capillary non-perfusion, and retinal neovascularization. The pattern of vascular involvement, highlighted by FA, may help in making a specific diagnosis. The major patterns include specific inflammation of retinal veins known as phlebitis, retinal arteriolar involvement known as arteriolitis and capillary involvement termed as capillaritis. The presence of vessel wall staining and leakage is the most common finding of retinal vasculitis detectable on FA. The leakage can be focal or diffuse highlighting disease activity. Using FA, staging of retinal vasculitis may be performed: (1) stage of active inflammation (with perivascular diffuse or focal whitish infiltrates with fuzzy borders, hemorrhages, retinal edema, cystoid macular edema, and inflammatory vascular occlusions); (2) stage of ischemia (characterized by sclerosed vessels and tortuous collaterals); (3) stage of neovascularization (may present with VH); and (4) stage of sequelae/complications (such as TRD, and neovascular glaucoma, among others) [6, 9]. The various findings on FA in a case of retinal vasculitis are vascular leakage, macular edema, optic disc hyperfluorescence, retinal ischemia and capillary non-perfusion, retinal and optic disc neovascularization and vascular remodeling.
Vascular Leakage
FA typically reveals leakage of dye and staining of the blood vessel wall in eyes with active RV. Leakage arises secondary to inflammation caused by damage to the blood-retinal barrier. It may be diffuse, as seen in Behçet’s uveitis, or segmental (skip lesions) as evident in sarcoidosis (Fig. 2) and multiple sclerosis. Retinal veins are the primary site of active vascular leakage in conditions like Behcet’s disease, sarcoidosis, and tuberculosis, whereas arteriolar leakage is commonly seen in patients with systemic vasculitis, viral infections, and certain bacterial diseases (rickettsial disease, cat scratch disease, and syphilis). Behcet’s disease, pars planitis, and other conditions are often accompanied by diffuse fern-like capillary leakage (Fig. 3) on FFA [3]. RV on FFA may be more extensive than that appreciated by clinical examination. Persistent peripheral vascular leakage is considered as biomarker of poor control of inflammation [9].
Macular Edema
FFA is a useful tool for identifying and assessing macular edema. Progressive localized or diffuse leakage of dye in the macula can be appreciated in later phases of the angiogram. However, in the current era, OCT acts as the gold-standard for qualitative and quantitative assessment of macular edema.
Optic Disc Hyperfluorescence
FA may show late hyperfluorescence and dye leakage from the vessels on the optic nerve head. Optic disc leakage is a commonly observed nonspecific finding attributed to intraocular inflammation. In other cases, it may be observed in infiltrative diseases of the nerve, like sarcoidosis. Fluorescein leakage from new vessels on optic disc is an important finding and should not be missed due to its diagnostic, therapeutic, and prognostic implications.
Retinal Ischemia and Capillary Non-Perfusion
FA may show areas of retinal ischemia. Capillary non-perfusion areas present as hypofluorescent areas with capillary dropout in the periphery and/or posterior pole. Inflammatory branch retinal vein occlusion or branch retinal artery occlusion can also be evaluated effectively with FA. FA can help the clinician to classify RV as occlusive or nonocclusive, thus helping in the diagnosis and management. Severe occlusive RV is a hallmark of tuberculosis (Fig. 4), Behçet disease, Eales disease, viral vasculitis, SLE, and other entities such as Susac’s syndrome [6, 9]. Patients with occlusive vasculitis may be at increased risk for complications like retinal/VH, epiretinal membrane, and severe vision loss. FA can be used to assess the extent of the non-perfused area, the presence of neovascularization, and thus the need and extent for laser photocoagulation. Ischemic maculopathy may be caused by RV involving the posterior pole, which can lead to persistent severe vision loss. FA also acts as a useful investigation to detect ischemic maculopathy.
Retinal and Optic Disc Neovascularization
Proliferation of new vessels on the optic disc or elsewhere in the retina can be triggered by inflammation and retinal ischemia secondary to the release of vascular endothelial growth factor. Posterior segment neovascularization may lead to recurrent VH and TRD with a potentially poor visual outcome. When FA demonstrates extensive capillary non-perfusion areas in the retina or optic disc neovascularization is present, immediate laser photocoagulation to peripheral retinal ischemic areas is necessary. FA is also useful for identifying optic disc neovascularization without associated peripheral retinal ischemia that resolves with anti-inflammatory treatment alone and does not require laser photocoagulation [10].
Vascular Remodeling
Remodeling of retinal capillary vasculature occurs secondary to ischemia. FA can also demonstrate the development of telangiectatic vessels, collateral vessels, and microaneurysms [3].
UWF Fundus Photography and FA
UWF angiography is now being used routinely in patients with RV. The advantages of this modality include shorter scan acquisition time, non-mydriatic imaging and exposure to less bright light. UWF imaging can pick up retinal capillary non-perfusion and neovascularization in the retinal periphery. This helps in detecting disease activity in the retinal periphery that could have been missed on conventional FA. Studies comparing UWF imaging with conventional FA have revealed a higher area of leakage on UWF images when compared with the conventional 9-field montage FA [11].
UWF imaging led to change in the treatment plan for 80% of 20 patients (38 eyes) with RV associated with Behçet’s disease and enabled better monitoring of the disease in 55% of the eyes [12]. UWF imaging has also shown to be useful in the diagnosis and management of intraocular tuberculosis by showing additional areas of capillary non-perfusion, neovascularization, and active RV in 90.9% of eyes, secondary to which treatment plan was changed in 45.5% of the eyes [13]. In a study comparing conventional and UWF-FA in retinal vasculitis, Leder et al. [14] reported that UWF-FA picked up disease activity in more eyes as compared to standard FA (68% vs. 45%). Ultra-widefield fluorescein angiography (UWF-FA) revealed increased leakage compared with simulated 50-degree FA images, as shown by Pecen and colleagues in a retrospective study. The peripheral vascular leakage was missed in 27% of eyes when UWF-FA was not available [15]. In a prospective study, Campbell et al. found a 32% change in management with UWF-FA compared to clinical examination and simulated conventional FA alone. This study also found disease activity in 63% of UWF-FA patients, compared to 51% based on examination and simulated conventional FA [16]. Nicholson et al. compared 9-field montage FA and UWF-FA images in 52 patients with RV. UWF images could detect leakage in more eyes as compared to conventional montage images [17].
Mesquida et al. [12] studied 20 patients (38 eyes) with retinal vasculitis secondary to Behçet’s disease. Imaging revealed active peripheral vascular leakage in 28 out of 33 eyes (84.8%) which was not evident on clinical examination alone. It has also been demonstrated that UWF-FA can be helpful in the diagnosis and treatment of patients with intraocular tuberculosis including patients with tubercular retinal vasculitis, multifocal serpiginous choroiditis, and choroidal granulomas. UWF-FA revealed additional areas of capillary non-perfusion, neovascularization, and active retinal vasculitis in 90.9% of eyes, leading to a change in the treatment plan in 45.5% of eyes. UWF-FA can aid in adjusting immunosuppressive therapy and initiate laser photocoagulation in eyes with activity [18]. UWF-FA can assess vascular perfusion at the posterior pole and far periphery in a single frame, thus acting as a guide in treatment and follow-up.
Limitations of UWF imaging include peripheral artifacts such as eyelashes. Appropriate patient positioning and adequate eye opening may reduce such artifacts. In addition, UWF images are pseudo-colored, unlike conventional imaging, leading to challenges in the interpretation of inflammatory lesions and choroidal neovascularization [13].
Fundus Autofluorescence
Fundus autofluorescence (FAF) is a noninvasive, imaging technique that employs blue, green, or infrared light. Lipofuscin within the retinal pigment epithelium (RPE) is the primary source of the FAF signal, which may be indicative of the altered structure or function of the RPE. Inflammatory retinal and choroidal disorders, such as serpiginous choroidopathy, MEWDS, birdshot chorioretinopathy (BSCR), infectious and noninfectious posterior uveitis, and Behcet’s RV, have been evaluated using FAF 3. Changes in lipofuscin distribution induced by inflammation can manifest as either elevated FAF in areas of stressed RPE or decreased FAF in areas of blocked FAF or dead RPE. Widefield FAF is an effective method for detecting and assessing retinal and chorioretinal involvement in patients with posterior uveitis and RV in several studies [13]. Multiple hyper autofluorescent spots, easily detected with UWF-FAF, may represent RPE changes induced by active RV in the periphery of the retina. In a study by Mesquida et al. [12], 82% of the eyes showed peripheral AF changes outside the posterior pole. The findings included multifocal hypofluorescent spots, and hypofluorescent lesions along retinal vessels. The authors suggested that active RV induces retinal epithelium alterations in the retinal periphery, resulting in AF abnormalities could be frequent in Behçet’s uveitis and are readily. FAF may be useful in monitoring the progress of treatment for patients with RV and detecting inflammation at an early stage [19].
Indocyanine Green Angiography
ICGA is the preferred imaging modality for determining the changes in choroidal circulation. Properties of the ICGA dye like a high molecular weight, and completely protein-bound nature allow, the dye to be poorly leaked through the choriocapillaris fenestrations, allowing for a better view of the choroidal circulation. Patients suffering from retinal vasculitis often have involvement of underlying choroid. Combined FFA and ICGA can help identify the vasculature which is primarily involved in the pathophysiology of the disease (retinal or choroidal). For example, Behcet’s disease primarily affects the retinal vasculature, whereas VKH disease primarily affects the choroidal vasculature. Birdshot chorioretinopathy can impact both the retinal and choroidal vasculature.
Bouchenaki et al. [20] have used ICGA to categorize choroidal vasculitis in posterior uveitis into two groups: (1) primary inflammatory choriocapillaropathy (which presents with choriocapillaris hypoperfusion in entities like multifocal choroiditis, multiple evanescent white dot syndrome, and others) and (2) stromal inflammatory vasculopathy. In the late phase, stromal vasculopathy is characterized by fuzzy appearance of choroidal vasculature and hyper-canescence. Such findings may be associated with retinal vasculitis in ocular sarcoidosis, tuberculosis, and birdshot chorioretinopathy [21]. Significant choroidal vasculature involvement is a potential feature of entities like ARN, which is characterized by peripheral necrotizing retinitis and severe occlusive retinal vasculitis. In 4 ARN patients, ICGA showed hypoperfusion, fuzzy choroidal vasculature, and hyper-canescence [22]. In conjunction with FA, ICGA may be useful for detecting choroidal vasculitis in entities such as granulomatosis with polyangiitis (Wegener’s granulomatosis) [23].
Optical Coherence Tomography
Spectral-domain (SD) and swept-source (SS)-OCT are an essential imaging modality for patients with RV. It assesses RV-related retinal structural secondary changes like macular edema, inner and outer retinal structural changes, serous retinal detachment and other macular complications like epiretinal membrane, and macular atrophy. OCT can distinguish diffuse sponge-like, cystoid, and serous retinal detachment in eyes with uveitic macular edema. Visual acuity correlates with the morphological characteristics of uveitic macular edema and macular thickness in these patients. Comparing the perivascular retinal thickness in retinal vasculitis associated with birdshot chorioretinopathy before and after treatment, Knickelbein et al. [24] found that the mean perivascular retinal thickness decreased as compared to the baseline after 1 month of corticosteroids treatment.
In another study, Zarei et al. [25] analyzed the utility of OCT as compared to FA in monitoring disease activity in patients with Behcet’s disease. They found that the FA inflammatory score positively correlated with the central subfield macular thickness, peripapillary retinal thickness, and peripapillary retinal nerve fiber layer thickness.
Newer OCT modalities like enhanced-depth imaging-OCT and SS technology (SS-OCT) offer substantial benefits compared to SD-OCT. They enable high-quality, simultaneous visualization of the vitreous, retina, and choroid, as well as in-depth analysis of chorioretinal layers like the external limiting membrane, photoreceptor layer, and ellipsoid zone. These advancements are particularly relevant in the context of RV. This allows better analysis of outer retinal layers and choroid which may be involved in RV. Several studies have compared the FA leakage score and subfoveal choroidal thickness, as measured using enhanced-depth imaging-OCT, in patients with retinal vasculitis associated with Behcet’s disease, BSCR, and idiopathic retinal vasculitis. A significant positive correlation has been found between the subfoveal choroidal thickness and leakage score in the total retina [26‒28].
These imaging techniques serve as valuable tools for the documentation and monitoring of secondary structural changes associated with retinal and choroidal lesions in patients with RV. OCT scans passing through involved vessels may reveal focal retinal thickening, loss of normal retinal layers, and vessel wall hyperreflectivity. The vitreous, vitreoretinal interface, retina, and choroid can all be rendered with higher resolution in volumetric images using virtual three-dimensional OCT. Such images may allow spatial visualization and documentation of intraretinal changes and objectively grade anterior chamber and vitreous inflammation.
Optical Coherence Tomography Angiography
In recent years, SD- and SS-OCTA have emerged as a major constituent of the multimodal imaging approach for the diagnosis and management of patients with RV [29, 30]. It helps assess for capillary non-perfusion, telangiectasias, shunts, and enlarged foveal avascular zone [31]. Furthermore, OCTA permits differentiation between superficial and deep retinal vascular plexuses, a distinction that was previously impossible to demonstrate using standard FA alone. Several studies have documented alterations in retinal capillary vessel density associated with RV. Specifically, non-perfusion and hypoperfusion in the superficial and deep capillary plexus have been observed more frequently in patients with RV [29, 32, 33].
Inflammatory choroidal neovascularization is a potential complication of several inflammatory conditions, including sarcoidosis, and OCTA may be helpful in the diagnosis and monitoring of this condition. OCTA has a limited field of view, so the disadvantage remains the inability to detect peripheral RV and cannot highlight active inflammation around affected vessels like FA can.
AO Imaging
One novel method of imaging being used in RV is AO. This technology reduces wavefront aberrations for high-resolution retinal imaging and can assess retinal structural damage in posterior uveitis and RV. [34] In a series by Errera et al. [35], 3 patients with retinal vasculitis underwent fundus imaging by AO. Perivascular opacification with well-defined boundaries was seen on AO images close to active vasculitis foci and resolved after treatment. AO imaging could highlight the extent of vascular involvement more than as compared to conventional imaging. Thus, AO imaging may aid in the diagnosis of RV, its follow-up, and management [34]. In another prospective observational case series of 6 patients with vasculitis secondary to different etiologies, Mahendradas et al. [36] found that AO imaging can detect different sheathing patterns based on etiology and improvement could be documented on subsequent follow-up visits.
Visual Field Testing and Electrophysiology
Despite having normal visual acuity, patients with uveitic diseases may have impaired color vision, contrast sensitivity, visual fields, and electrophysiology. Electroretinography has been utilized in BSCR for disease monitoring and treatment [37]. Poor visual outcome in patients with BSCR was found to be associated with worse SITA SWAP mean deviation at the initial visit. Visual field testing can also assess visual field defects in inflammatory BRAO [38].
Thus, specific ocular imaging, including FFA, optical coherence tomography, and specialized imaging like indocyanine green angiography (ICGA), may be performed following the clinical examination. It is pertinent for the eye physician to identify specific patterns of vascular involvement in these imaging modalities.
This may be followed by revisiting the history and inquiring about specific disease symptomatology based on the information collected from clinical examination and imaging modalities. Also, a relevant review of systems can be performed at this stage. Based on the history, clinical examination, and imaging findings, a tailored approach to relevant systemic can be adopted.
Tailored Laboratory Diagnostics
Establishing an underlying cause responsible for retinal vasculitis is challenging due to the varied nature of pathologies associated with the condition [2, 3]. A tailored approach is preferred to avoid unnecessary investigations. Laboratory tests should be based on medical history, systemic and ocular examination, and imaging biomarkers (Fig. 1). The goal of laboratory testing is to distinguish between infectious and noninfectious causes, as the treatment may change accordingly. For instance, in cases suspected of infectious origins, serological assays targeting specific pathogens such as syphilis, toxoplasmosis, or tuberculin skin testing may prove instrumental. Given the limitations of available serological tests and the challenge of culturing certain pathogens from the ocular tissue, polymerase chain reaction (PCR) has become essential in diagnosing various pathogens involved in infectious uveitis. For example, in viral necrotizing retinitis, PCR analysis of ocular fluids may detect herpes simplex virus type-1 and herpes simplex virus type-2, cytomegalovirus, and varicella-zoster virus. Differentiating these pathogens is crucial since they share numerous clinical characteristics. Additionally, PCR analysis can aid in the management and monitoring of treatment response in such cases. Furthermore, PCR has facilitated the diagnosis of ocular toxoplasmosis and contributed to the identification of ocular tuberculosis through the use of conserved sequences such as IS6110 or the predominant mpb64 gene in the mycobacterial genome.
For noninfectious etiologies such as autoimmune or inflammatory conditions, testing for markers like antinuclear antibodies, erythrocyte sedimentation rate, or C-reactive protein levels can provide valuable diagnostic insights. By tailoring laboratory investigations to the suspected etiology, clinicians can optimize diagnostic accuracy and subsequently tailor treatment strategies accordingly. Furthermore, the judicious use of proteomics or genetic testing may offer additional depth in uncovering the underlying pathophysiological mechanisms driving the vasculitic process.
Protein Markers (Proteomics)
The proteomic studies of ocular biofluids obtained from uveitis patients have greatly improved our understanding of the pathogenesis of uveitis [38]. Different uveitic entities can produce varying concentrations of proteins inside the eye, which can be used as biomarkers [39]. It is now possible to perform proteomic analysis on even small quantities of biological samples, making the use of aqueous humor and vitreous humor more feasible. This provides a new insight into the pathophysiology and therapeutics of various ocular inflammatory diseases. Proteomics also plays an important role in the development of diagnostic, prognostic, and therapeutic monitoring of biomarkers and the development of new therapies for various sight-threatening ocular diseases. Proteomic analysis of vitreous samples by Schrijver et al. [38] showed sarcoid uveitis patients to have higher levels of CCL17 protein compared to those with TB-associated uveitis. Thus, the presence of vitreous CCL17 could potentially serve as a new biomarker for distinguishing between the two conditions. In another study, Velez et al. [40] used vitreous protein profiling to determine cytokine expression in a case of idiopathic autoimmune uveitis. Through the administration of targeted therapy, visual loss was successfully reversed, highlighting the therapeutic potential of protein biomarkers alongside.
Predictive models are being developed using artificial intelligence to predict etiological diagnosis using cytokine profile from ocular fluids. Nezu et al. [41] applied machine learning algorithms to the data of immune mediator levels in aqueous humor to predict the actual diagnoses of particular intraocular diseases. Random forest algorithms based on immune mediators in aqueous humor could successfully predict the diagnosis of vitreoretinal lymphoma, ARN, and endophthalmitis.
Genetic Testing
Genetic testing in RV is indicated for detecting specific genetic mutations like CAPN5, TREX1, and TNFAIP3. These mutations can lead to rare forms of RV. Calpain 5 gene encodes for a calcium-dependent cysteine protease. Mutation in CAPN5 leads to autosomal dominant neovascular inflammatory vitreoretinopathy. In addition to the RV, anterior and posterior chamber inflammation and iris neovascularization are common in this disorder [42]. Mutations in TREX1, an exonuclease, can lead to another form of inherited RV, and it also predisposes the patients to develop SLE. Mutations in TREX1 have been associated with abnormal cerebral and retinal vasculature. These findings associated with retinal ischemia have been labeled as a syndrome known as retinal vasculopathy with cerebral leukodystrophy [43]. A novel auto-inflammatory disease causing RV secondary to the mutations in tumor necrosis factor alpha-induced protein 3 (TNFAIP3) have been reported in the literature. The mutation leads to an increased expression of NF-kB-mediated inflammatory cytokines. The disease presents with oral ulcers, pathergy, skin involvement, macular fibrosis and chorioretinal scarring [44]. These mutations and testing for them should be kept in mind while the ophthalmologist manages the recalcitrant forms of RV with varied clinical features.
Conclusion
Retinal vasculitis presents a diagnostic challenge due to its diverse etiologies and clinical manifestations. Diagnosis relies on a combination of clinical assessment, ophthalmic imaging, and tailored laboratory investigations. Clinical examination involves identifying specific vascular involvement patterns and associated findings. Ophthalmic imaging techniques such as FFA, UWF fundus photography and angiography, OCT, and OCTA imaging aid in visualizing retinal vascular changes, macular edema, neovascularization, and structural alterations. These modalities provide valuable insights into disease activity, severity, and treatment response. Laboratory diagnostics, guided by clinical and imaging findings, aim to differentiate infectious from noninfectious causes and may include serological assays, inflammatory markers, proteomic analysis, and genetic testing to uncover underlying pathophysiological mechanisms. A tailored approach to diagnosis ensures optimal management and preservation of vision in patients with retinal vasculitis.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Atul Arora: research review, primary draft, and writing of the manuscript. Manisha Agarwal, Nicholas Chieh LOH, Hind Amin, and Nitin K Menia: primary draft and writing of the manuscript. Rupesh Agrawal and Vishali Gupta: edition and review of the manuscript.