Retinal vasculitis associated with systemic disorders and infections

INTRODUCTION — Retinal vasculitis is characterized by inflammation of the vessels of the retina [1]. Retinal vasculitis can occur in association with an underlying infectious or systemic disease, as part of an ocular disease, or it can be idiopathic. The detection and characterization of retinal vasculitis may help in the diagnosis and management of certain disorders associated with ocular inflammation.

This topic will review the clinical features of retinal vasculitis associated with systemic disorders and infections. Vasculitis of the retinal vessels due to local ocular inflammatory disorders is discussed separately. (See "Retinal vasculitis associated with primary ocular disorders".)

ETIOLOGY — Retinal vasculitis is an inflammatory response isolated to the venous, arterial, or capillary retinal vasculature with inflammation extending towards nonvascular retinal structures with a pattern of extension that demonstrates a retinal blood vessel being the source of the inflammation. This pattern of vasculature-sourced inflammation can be associated with systemic immunologic disorders, systemic infections, or no known systemic association (table 1).

Infectious causes — A variety of different infections are associated with retinal vasculitis. The most common cause of infectious retinal vasculitis is toxoplasmosis, followed by tuberculosis (TB), syphilis, and herpes viral infections. These and several other types of infections that can cause retinal vasculitis are presented below:

●Toxoplasmosis – Toxoplasmosis accounts for as much as 25 percent of cases of posterior uveitis in the United States [2]. The retina is the primary site of eye infection. Whereas in immunocompromised patients, toxoplasmic involvement of the brain is more common than retinal toxoplasmosis, the reverse is true in immunocompetent individuals. Active lesions usually appear as white focal lesions with a severe vitreous inflammatory reaction (picture 1). Vitreo-retinitis is a sine qua non of active ocular toxoplasmosis (picture 2).

The retinal vasculitis usually occurs near active lesions and can affect both venules and arterioles. The arteriolar involvement is often characterized by "skip lesions," in which focal areas of vasculitis are flanked by apparently normal vessels (image 1). Toxoplasmosis is a clinical diagnosis, but serologic studies are helpful in the diagnosis. The diagnosis and treatment of ocular toxoplasmosis are discussed in detail separately. (See "Toxoplasmosis: Ocular disease", section on 'Diagnosis' and "Toxoplasmosis: Ocular disease", section on 'Treatment'.)

●Tuberculosis – Although TB can affect any tissue in the eye and was once a frequent cause of retinal vasculitis, involvement of the eye is now an uncommon manifestation of extrapulmonary TB, being seen in approximately 1 percent of patients [3,4]. Infection with this organism also represented less than 1 percent of all cases of uveitis in a United States cohort.

Retinal involvement is commonly an extension of choroidal disease, which usually results from miliary TB [5,6]. Retinal vasculitis is the most common manifestation of retinal TB [7]. In one series of 12 patients with intraocular TB, 9 had florid ischemic retinal vasculitis [7]. Retinal vasculitis may result in retinal vein occlusion and in subsequent neovascularization [8,9]. (See "Tuberculosis and the eye".)

●Whipple's disease – Whipple's disease is a multisystem infectious disorder characterized by weight loss, diarrhea, abdominal pain, and arthralgias. Ocular involvement of Whipple's disease is uncommon, but includes retinal vasculitis, uveitis, keratitis, vitritis, optic neuritis, and papilledema [10,11]. (See "Whipple's disease".)

●Syphilis – Syphilis can involve almost any structure in the eye [12]. Most patients with ocular syphilis develop diminished visual acuity secondary to posterior uveitis. Retinal vasculitis and other ocular manifestations such as blepharitis, conjunctivitis, iritis, episcleritis, scleritis, chorioretinitis, vitritis, neuroretinitis, disc edema, and retinal detachment can also occur. (See "Neurosyphilis".)

●Lyme disease – A variety of ocular manifestations have been associated with Lyme disease during early disseminated disease. Retinal vasculitis is rare and has only been described in case reports [13,14]. Because of the variability in Lyme disease presentation, this association of retinal vasculitis is unlikely to be detected since many Lyme disease patients would rarely see an ophthalmologist. (See "Clinical manifestations of Lyme disease in adults", section on 'Ocular manifestations'.)

●Cat scratch disease – Retinal vasculitis is a rare manifestation of cat scratch disease (CSD) [15,16]. Other ocular manifestations of this infection include Parinaud oculoglandular syndrome, neuroretinitis, papillitis, optic neuritis, focal retinochorioretinitis, and retinal vascular occlusions. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease".)

●Viral infections – Both herpes simplex and varicella-zoster can cause retinal vasculitis. Herpes simplex retinitis occurs in patients who are congenitally infected or immunosuppressed because of chemotherapy. White retinal infiltrates accompanied by a retinal vasculitis are a hallmark finding in this setting.

Herpes simplex and varicella-zoster virus are also associated with acute retinal necrosis (ARN), a necrotizing retinitis that may occur in healthy immunocompetent individuals [17,18]. The retinal findings associated with ARN start as patchy white-yellow areas that become confluent over time (picture 3). Retinal vasculitis with this disorder typically affects the arterioles more than the veins [19,20]. In rare cases, ARN can present as acute angle-closure glaucoma [18].

Cytomegalovirus retinitis commonly observed in association with HIV infection may also manifest with retinal vasculitis. This disorder is characterized by a slowly progressive necrotizing retinitis of the posterior pole. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)

Systemic immune-mediated causes — Vasculitis of the retinal vessels may occur in association with a number of systemic diseases (table 1). One classification system for the retinal vasculitides associated with systemic disease is by the type and size of the involved retinal vessels (table 2) [1]. Knowledge of the systemic and ocular features in these disorders can help differentiate between the various causes.

Several systemic immune-mediated causes of retinal vasculitis are discussed below. The true prevalence of retinal vasculitis for each of these diseases is difficult to ascertain, and in some cases, is not known. One challenge is that retinal vasculitis can be difficult to differentiate from other causes (eg, thrombotic diseases of the retina can be indistinguishable from retinal vasculitis on angiography). Another issue is that many patients with systemic rheumatic diseases are not evaluated by ophthalmologists who would assess for retinal involvement. Finally, some ophthalmologists do not have expertise in retinal vasculitis or experience with the interpretation of fluorescein angiography. In many cases, wide-field fluorescein angiography is necessary to detect peripheral retinal vasculitis. In the authors' own experience, the use of wide-field angiography is critical for making the diagnosis of retinal vasculitis. Without angiographic imaging, in particular wide-field or peripheral angiography, cases of retinal vasculitis may be diagnosed as other retinal conditions since clinical findings without angiographic testing will result in alternative diagnoses.

●Behçet syndrome – Behçet syndrome is the systemic rheumatic disease most commonly associated with retinal vasculitis. The retinal veins are more commonly affected than the retinal arteries, manifesting clinically as recurrent retinal vaso-occlusive disease in association with the permanent loss of vision (picture 4). Upon examination, patients with acute attacks of retinal vasculitis often have retinal hemorrhages and edema in association with vitreous cells, findings that have to be differentiated from those resulting from viral retinitis. Retinal infiltrates, branch retinal vein occlusion, neovascularization, and vitritis are common posterior pole findings. (See "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Ocular disease'.)

●Systemic lupus erythematosus – Retinal vasculitis is an under-recognized manifestation of systemic lupus erythematosus (SLE). Mild and visually nonthreatening manifestations are common, consisting of cotton-wool spots with or without hemorrhages; they are observed in 3 to 30 percent of ambulatory and hospitalized patients with SLE, respectively [21,22]. The wide range of estimates is largely reflected by the limited quality of the data, with lower rates coming from retrospective studies and higher rates from prospective studies. In the experience of the authors, a fundus abnormality is frequently detected in patients with SLE who are actively flaring. In clinical practice, however, many patients with an active flare of SLE are not examined by a retina specialist, and visual symptoms are often not documented during the clinical evaluation.

A case of retinal vasculitis has been reported as the presenting condition for the diagnosis of SLE [23]. Cotton-wool spots represent edematous and ischemic neuronal tissue. While many of these small retinal lesions may be appreciated on funduscopic examination, fluorescein angiography may be helpful in diagnosing subtle lesions, so the prevalence of angiographic retinopathy is likely even higher than that cited above [24]. Severe lupus retinopathy is characterized by severe ischemia because of vasculitic or thrombotic occlusion; it is observed more commonly in patients with active systemic disease and multiorgan involvement and, hence, correlates with decreased survival [21,24-26]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Ophthalmologic involvement'.)

Retinal vasculitis in SLE typically affects the small arterioles and arteries and correlates with avascular areas on fluorescein angiography. More severe ischemia can result in neovascularization and hemorrhaging (image 2). However, other nonspecific findings including capillary or venous dilatation, arteriolar constriction, and venous engorgement can also be seen in SLE. Very severe and sight-threatening retinal disease in SLE is typically associated with thrombotic occlusion of larger retinal vessels, findings that are often associated with antiphospholipid antibodies observed in antiphospholipid syndrome [27]. The larger retinal vessels affected in SLE can lead to branch or central retinal vein or artery occlusion, leading to profound and irreversible vision loss (picture 5) [24,28,29].

●Giant cell arteritis – Retinal vasculitis is a rare manifestation of ocular involvement related to giant cell arteritis (GCA, also known as Horton disease, cranial arteritis, and temporal arteritis) [30]. The more common ocular manifestation that can result in visual loss in GCA is arteritic anterior ischemic optic neuropathy, due to inflammatory occlusion of the posterior ciliary arteries; this accounts for 80 to 99 percent of visual loss attributable to GCA [31]. Retinal involvement due to GCA is manifested as peripapillary cotton-wool spots, which represent nerve fiber layer infarcts. Central retinal artery occlusion (CRAO) is the second most common cause of visual loss in GCA, affecting up to 20 percent of patients with ocular involvement [31]. (See "Clinical manifestations of giant cell arteritis", section on 'Ocular involvement'.)

●Polyarteritis nodosa – Ocular findings occur frequently in patients with polyarteritis nodosa [32]. However, retinal vasculitis is relatively rare among the ocular manifestations [33]. Anterior segment findings may include episcleritis, scleritis, corneal or scleral ulcers, and uncommonly iritis. Pseudotumor of the orbit or extraocular muscle dysfunction may also be observed. Although the choroidal arteries are most commonly affected, retinal vessel involvement may result in cotton-wool spots, retinal edema, vitritis, and hypertensive changes. Retinal venules may also be affected [32]. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

●HLA-B27-associated conditions – The presence of the human leukocyte antigen B27 (HLA-B27) haplotype is strongly associated with the seronegative spondyloarthropathies, such as ankylosing spondylitis [34,35] (see "Pathogenesis of spondyloarthritis"). Although the main ocular complication in these conditions is recurrent anterior uveitis, posterior segment involvement including vitritis may be observed. The prevalence of posterior segment disease has varied from 4 to 17 percent in different studies [36-38]. Specific disorders included severe vitritis (93 percent), papillitis (84 percent), macular edema (38 percent), retinal vasculitis (24 percent), and vitreous and pars plana exudates (7 percent). The retinal vasculitis may affect both arteries and veins. Occasional patients develop central retinal vein occlusion with disc neovascularization or occult peripheral venular vasculitis [36].

●Relapsing polychondritis – Inflammation of the eye is a common finding in patients with relapsing polychondritis. In a retrospective study of 112 patients, for example, ocular manifestations were present in 21 percent at presentation and eventually developed in 57 percent [39]. The most common findings were scleritis and episcleritis (14 and 39 percent, respectively). In this same study, retinal findings were observed in 9 percent of patients; vasculitis of the retinal vessels was manifested as hemorrhages, vascular occlusions, and cotton-wool spots. These findings were not found at presentation but developed over time. (See "Clinical manifestations of relapsing polychondritis", section on 'Eye involvement'.)

●Inflammatory bowel disease – Retinal vasculitis has been observed in patients with inflammatory bowel disease [40]. In one report of patients with Crohn disease, retinal vasculitis resulted in central retinal vein occlusion in one patient and in branch retinal artery occlusion in another [41]. In one of these patients, the retinal vasculitis preceded the diagnosis of Crohn disease. In the other, arteritis and phlebitis resulted in marked loss of vision [42]. (See "Dermatologic and ocular manifestations of inflammatory bowel disease", section on 'Ocular disease'.)

●Sarcoidosis – Ocular manifestations occur in 20 to 25 percent of patients with sarcoidosis [43,44]. The most common ocular manifestation is uveitis, which is frequently associated with retinal vasculitis [44,45]. (See "Overview of extrapulmonary manifestations of sarcoidosis", section on 'Ocular'.)

●Multiple sclerosis – Optic neuritis is a common presenting manifestation of multiple sclerosis (MS), while retinal vasculitis is rare. The presence of retinal vasculitis in patients presenting with optic neuritis enhances the likelihood of the eventual development of MS. In one study of 50 patients with optic neuritis, for example, 25 percent had retinal abnormalities including retinal venous sheathing and fluorescein leakage without sheathing [46]. Retinal vasculitis was predictive for the development of MS in this cohort. Although most reports have found that retinal vasculitis in MS is limited to perivascular sheathing and vitreous cells, vascular occlusions, capillary closure, vitreous hemorrhage, and neovascularization can occur [47]. (See "Evaluation and diagnosis of multiple sclerosis in adults" and "Clinical presentation, course, and prognosis of multiple sclerosis in adults".)

●Granulomatosis with polyangiitis – The retinopathy associated with granulomatosis with polyangiitis (GPA) is characterized by involvement of the medium- to small-size arterioles; it occurs in less than 3 percent of cases, often resulting in cotton-wool spots and arteriolar occlusion, which are thought to occur due to external wall compression of tissue granulomas [48-50]. The retinopathy associated with GPA is not the classic retinal vasculitis picture. This occlusive retinal vasculitis is less common than optic neuropathy or optic disc vasculitis [51]. Because of the multifactorial pathophysiology of GPA, while mentioned here, it should not be placed in the same category as other diseases associated with typical retinal vasculitis [49,50].

●Susac syndrome – The angiopathy associated with Susac syndrome usually involves arterioles. The arterioles that are affected include cochlea, retinal, and brain. The severity of the arteriolar retinal vasculitis often results in branch retinal artery occlusions and is one of the hallmarks of the syndrome [52].

●Vogt-Koyanagi-Harada disease – Vogt-Koyanagi-Harada (VKH) disease usually presents with a classic uveitis and, if fluorescein angiograms are performed, retinal vasculitis is found in some patients with VKH disease. Other retinal patterns associated with VKH disease are more prevalent. It is unusual for VKH disease to present as a retinal vasculitis without the other more common retinal findings of VKH disease.

Malignancies — Retinal vasculitides have been seen in association with certain malignancies, as well as side effects of systemically administered immune checkpoint inhibitor and chemotherapy drugs. Some cancers documented to produce retinal vasculitis are lymphomas, multiple myelomas, leukemias, and melanomas.

Cancer drugs, especially checkpoint inhibitors such as pembrolizumab, ipilimumab, durvalumab, atezolizumab, and cemiplimab have also been associated with retinal vasculitis. In patients receiving atezolizumab, the retinal vasculitis can accompany acute macular neuroretinopathy (AMN), which affects central vision in addition to the diffuse retinal vasculitis [53].

Primary ocular syndromes — Although many forms of retinal vasculitis are associated with systemic inflammatory or infectious disease, a few forms of retinal vasculitis occur without extraocular or infectious involvement:

●Idiopathic retinal vasculitis

●Pars planitis syndrome

●Birdshot retinochoroidopathy

●Eales' disease

●Hemorrhagic occlusive retinal vasculitis

●Brolucizumab-associated occlusive retinal vasculitis

Retinal vasculitis associated with primary ocular disorders is discussed in detail separately. (See "Retinal vasculitis associated with primary ocular disorders".)

DIAGNOSTIC APPROACH

When to suspect the diagnosis — The diagnosis of retinal vasculitis may be suspected in a patient with an immune-mediated disorder or infectious disease that is known to be associated with retinal vasculitis (see 'Etiology' above) and who presents with any of the following ocular symptoms:

●Decreased or blurry vision with or without pain

●Dry eye symptoms (tearing, burning sensation, redness, irritation)

●Lid inflammation or redness

●Eye mucous discharge

●Ocular or periocular pain

●Scalp and/or periocular tenderness

The initial diagnostic evaluation in a patient with suspected retinal vasculitis should focus on obtaining an expedited eye examination. Once the diagnosis is made, additional testing for the underlying disease is appropriate. (See 'Evaluation for underlying disease' below.)

Clinical features

Ocular symptoms — The classic symptom of retinal vasculitis is a painless decrease in vision. Other symptoms may include a blind spot from ischemia-induced scotomas or floaters from vitritis. With macular involvement, patients may present with metamorphopsia (change in shape of an object) or abnormalities in color vision. Retinal vasculitis can also be asymptomatic.

It is uncertain whether patients develop retinal vasculitis during a flare of a systemic rheumatic disease or in isolation, largely because the underlying disease is often managed by non-ophthalmologists. There have been reported cases of retinal vasculitis as the first presenting sign of systemic lupus erythematosus (SLE), which may suggest that retinal vasculitis may occur in isolation from other signs of SLE [23,54]. Furthermore, an observational study of 69 patients with SLE found clinical evidence of retinopathy in 10 percent of patients [55]. Retinopathy was associated with SLE patients who had central nervous system involvement and the presence of anticardiolipin antibody, as well as a higher disease activity scores.

Ocular examination — Abnormalities in the retinal vessels may be observed upon physical examination. Funduscopic findings include vascular sheathing (visible accumulation of inflammatory cells along vessel walls) (picture 6) and vitreous hemorrhage and cotton-wool spots. The peripheral vessels are often more involved than central arteries and veins, and there are frequently skip areas. With certain disorders such as sarcoidosis, lesions resembling candle-wax drippings or extensive perivascular inflammation may also be observed with indirect ophthalmoscopy.

The retinal vascular abnormalities are better demonstrated by fluorescein angiography (image 3). One of the main changes on fluorescein angiography is perivascular staining, which reflects the increase in vascular permeability (picture 7). Cystoid macular edema, optic nerve edema, and capillary nonperfusion also may be seen.

Diagnosis — The diagnosis of retinal vasculitis is purely clinical and can usually be made on funduscopic examination by an ophthalmologist experienced with uveitis. The gold standard for detecting retinal vasculitis is fluorescein angiography. Findings on fluorescein examination consistent with retinal vasculitis include vascular leakage (perivascular staining) and capillary nonperfusion [56]. It should be emphasized that mere vascular leakage is sufficient to diagnose retinal vasculitis but insufficient to diagnose a systemic vasculitis. This distinction is among the most important reasons why retinal vasculitis correlates poorly with systemic vasculitis.

Differential diagnosis — While retinal vasculitis is a distinct clinical sign, it can often be confused with other retinal vascular pathologies as some of the symptoms or findings in retinal vasculitis may also occur in other conditions.

The differential diagnosis includes:

●Diabetic retinopathy (see "Diabetic retinopathy: Classification and clinical features")

●Hypertensive retinopathy (see "Ocular effects of hypertension")

●Sickle cell retinopathy (see "Overview of the clinical manifestations of sickle cell disease", section on 'Retinopathy')

●Radiation retinopathy (see "Delayed complications of cranial irradiation", section on 'Retinopathy')

●Endophthalmitis (see "Bacterial endophthalmitis" and "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis")

●Retinal angiomatous proliferation (see "Age-related macular degeneration")

●Primary intraocular central nervous system (CNS) lymphoma has presented as retinal vasculitis [57] (see "Primary central nervous system lymphoma: Clinical features, diagnosis, and extent of disease evaluation", section on 'Eyes')

●Retinal detachment (see "Retinal detachment")

●Infectious choroiditis (see "Uveitis: Etiology, clinical manifestations, and diagnosis")

●Multifocal or focal choroiditis (see "Uveitis: Etiology, clinical manifestations, and diagnosis")

EVALUATION FOR UNDERLYING DISEASE — Once a diagnosis of retinal vasculitis is made, the next step should be to determine if one of the systemic conditions described above is present (see 'Etiology' above). Establishing the correct diagnosis is essential if therapy and prognosis are to be optimized. In patients for whom the etiology remains uncertain based on the history and physical examination alone, selected laboratory testing may help elucidate the underlying etiology.

In almost all cases of retinal vasculitis that have systemic findings, these patients should be referred to a rheumatologist or other appropriate specialist if they are not already being followed by one. If retinal vasculitis is the only presenting manifestation, the eye physician should consider referring or co-managing with a rheumatologist if the eye clinician is not comfortable caring for patients with rheumatologic diseases.

The predominance or pattern of retinal vessel involvement can also help narrow the potential etiologies (table 2).

History and examination — Once retinal vasculitis is definitely diagnosed, the subsequent workup should include a thorough history, review of systems, and physical examination to help identify the underlying cause (table 1).

The clinician should also question the patient regarding any history of a known systemic rheumatic disease, and whether they are experiencing other symptoms typically associated with their disease. However, in many cases, retinal vasculitis is the presenting condition for a systemic disease. In a retrospective study, 42.5 percent of patients with retinal vasculitis diagnosed in a single academic center, without known infectious or systemic disease, presented with their undiagnosed condition with retinal vasculitis [58].

Three clinical appearances of retinal vasculitis can present: diffuse, focal, and vaso-occlusive. While there is no histopathologic correlation to be made with these presentations, ophthalmoscopically, these different presentations can often be associated to a particular systemic etiology and can help a retina specialist determine potential systemic associations. For example, systemic conditions such as systemic lupus erythematosus (SLE) often present as diffuse retinal vasculitis. Infectious causes of retinal vasculitis such as toxoplasmosis usually present with focal patterns [59]. Vaso-oclusive disease has been seen with intravitreal injections of brolucizumab and novel anti-vascular endothelial growth factor (VEGF) injection [60].

Examples of some pertinent findings on history and physical examination are as follows:

●Patients with Behçet syndrome who have acute attacks of retinal vasculitis often have retinal hemorrhages and edema in association with vitreous cells, findings that have to be differentiated from those resulting from viral retinitis. Retinal infiltrates, branch retinal vein occlusion, neovascularization, and vitritis are common posterior pole findings.

●Findings with fluorescein angiography in patients with sarcoidosis and ocular disease may include focal periphlebitis, diffuse capillary leakage, new vessel formation, and acute retinopathy [61]. The periphlebitis is described as resembling candle-wax drippings, a finding considered by some to be pathognomonic of sarcoidosis (picture 8) [62]. Focal periphlebitis primarily occurs around the vein and rarely occurs around arteries. Infiltration and vein occlusions of the retina are not usually observed in sarcoidosis but are seen in Behçet syndrome, a characteristic that can differentiate these two disorders [61]. Although vessel occlusions are not typical in sarcoidosis, involvement of the posterior segment is associated with a poor visual outcome [44].

●Concurrent retinal vasculitis and posterior segment involvement must be entertained when evaluating a patient with seronegative spondyloarthropathy and human leukocyte antigen B27 (HLA-B27).

●The ophthalmic manifestations of cat scratch disease (CSD) are classically a neuroretinitis with a macular star.

Additional testing — Only limited diagnostic testing is useful when an associated condition is not apparent despite a thorough medical history and physical examination. In patients in whom the history and examination does suggest a possible cause, diagnostic testing, which is focused upon confirming or excluding the suspected etiology, is warranted for confirmation of the specific diagnosis. In either situation, the use of multiple screening tests (a "shotgun approach") should be avoided.

The following routine tests and specialized serologic assays are appropriate to help identify or exclude systemic disease:

●Routine tests:

•Complete blood count – Patients with systemic inflammatory conditions frequently have abnormalities of the white blood cell count, platelet count, or hematocrit.

•Serum chemistry profile – This should include creatinine, blood urea nitrogen, electrolytes, albumin, total protein, and aminotransferases.

•Urinalysis with microscopy – Urinalysis with microscopic examination of the urine sediment is essential to excluding glomerulonephritis, a common occurrence in some of the systemic diseases associated with scleritis, particularly granulomatosis with polyangiitis (GPA) and systemic lupus erythematosus (SLE).

•Acute phase reactants – Patients with a systemic illness are more likely to have high acute phase reactants. Both the erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) could be checked. While these laboratory tests are of low yield diagnostically for most systemic rheumatic diseases, they are sometimes useful in following responses to therapy and in detecting disease flares.

●Specialized serologic assays:

•Antinuclear antibody testing – Antinuclear antibody (ANA) testing is useful for the exclusion of SLE and several other systemic autoimmune diseases. A strongly positive ANA assay should be followed by additional serologic testing to determine, if possible, the specific antigen responsible for the ANA positivity. This additional testing may include serum antibodies to double-stranded DNA, and antibodies to the Ro, La, Sm, or ribonucleoprotein (RNP) antigens. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

•ANCA testing – Antineutrophil cytoplasmic antibodies (ANCA) assays are likely to be positive in patients with GPA, microscopic polyangiitis (MPA), or eosinophilic granulomatosis with polyangiitis (EGPA). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Testing for ANCA'.)

If an immunofluorescence assay is positive in either a cytoplasmic or perinuclear pattern (ie, C-ANCA or P-ANCA), then confirmation of the presence of the type of ANCA associated with systemic vasculitis, through enzyme immunoassays for antibodies to proteinase-3 or myeloperoxidase, is important.

•Microbial serologies – In patients suspected of an infectious cause, serologic studies for syphilis and HIV should be performed. Other infectious serologic studies should be tailored to degree of suspicion for the specific infection.

●Imaging studies:

•Chest radiography (plain films) – Chest radiography should be performed in all patients to exclude infiltrates and nodules that might be associated with vasculitis, sarcoidosis, or infections such as tuberculosis (TB). Abnormal findings on chest radiographs should be defined further with computed tomography (CT) examination of the lungs and other imaging as required.

Additional testing depends upon the clinical assessment and upon the suspected underlying condition. It is also important to recognize that retinal vasculitis is an extremely uncommon manifestation of the classic systemic vasculitides, with the exception of Behçet syndrome [63]. (See "Overview of and approach to the vasculitides in adults".)

MANAGEMENT AND PROGNOSIS — The management of retinal vasculitis in the setting of a systemic rheumatic disease or infection is largely related to the treatment of the underlying disease. The management of retinal vasculitis associated with primary ocular syndromes is discussed in detail separately. (See "Retinal vasculitis associated with primary ocular disorders".)

In some cases, when patients present with retinal vasculitis, the associated underlying disease is unknown. If the patient is experiencing a decline in vision or if the vasculitis is encroaching on the macula, they have vision-threatening disease, and empiric therapy is initiated while the patient is also evaluated for associated conditions. For such patients, we recommend initial treatment with high doses of systemic glucocorticoids. We typically use an initial dose of the equivalent of prednisone 1 mg/kg (maximum 60 mg) daily.

The rationale for this approach is based on clinical experience and limited observational data, as well as extrapolation from the management of other vasculitides. A retrospective study of 29 patients with vision-threatening disease found that the administration of prednisone (initial dose 1 mg/kg per day) was associated with visual improvement in 60 percent of patients [64]. In a retrospective cohort that included 236 patients with retinal vasculitis, the use of systemic glucocorticoids was associated with a reduced risk of vision loss (hazard ratio [HR] 0.36, 95% CI 0.15-0.82) [65]. When systemic glucocorticoids are used, they must gradually be tapered, typically over a period of months. The approach to the glucocorticoid dose reduction will vary, depending on whether the associated underlying disease is diagnosed. An example of glucocorticoid dosing that might be used is similar to the regimen for the treatment of giant cell arteritis. (See "Treatment of giant cell arteritis", section on 'Glucocorticoids' and "Treatment of giant cell arteritis", section on 'Glucocorticoid tapering'.)

In addition to systemic glucocorticoids, periocular or intraocular glucocorticoids such as triamcinolone acetonide are also typically administered as adjunctive therapy when an infectious etiology for retinal vasculitis has been thoroughly ruled out.

If left untreated, retinal vasculitis may lead to progressive and extensive visual loss. There are limited data on the prognosis of patients with retinal vasculitis secondary to systemic disorders and infections. In retrospective cohort study, factors that were associated with an increased risk of vision loss included the presence of macular ischemia and edema [65]. In addition, retinal ischemia involving two or more quadrants of the retina was correlated with development of new blood vessel formation and ensuing complications. If neovascularization occurs, panretinal photocoagulation can be used to treat retinal neovascularization.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis" and "Society guideline links: Uveitis".)

SUMMARY AND RECOMMENDATIONS

●Causes – Retinal vasculitis is characterized by inflammation of the vessels of the retina. Retinal vasculitis can occur in association with an underlying infectious or systemic disease, as part of an ocular disease, or it can be idiopathic (table 1). (See 'Introduction' above.)

The most common cause of infectious retinal vasculitis is toxoplasmosis, followed by tuberculosis (TB), syphilis, and herpes viral infections. Other infectious causes include Whipple's disease, syphilis, Lyme disease, and cat scratch disease (CSD). (See 'Infectious causes' above.)

Systemic disorders associated with retinal vasculitis include Behçet syndrome, systemic lupus erythematosus (SLE), various forms of systemic vasculitis, and others (table 1). One classification system for the retinal vasculitides associated with systemic disease is by the type and size of the involved retinal vessels (table 2).

A variety of uveitis syndromes occur without extraocular or infectious involvement including idiopathic retinal vasculitis, pars planitis syndrome, birdshot retinochoroidopathy, Eales' disease, and hemorrhagic occlusive retinal vasculitis. (See 'Primary ocular syndromes' above and "Retinal vasculitis associated with primary ocular disorders".)

●Clinical features – The classic symptom of retinal vasculitis is a painless decrease in vision. Other symptoms may include a blind spot from ischemia-induced scotomas or floaters from vitritis. With macular involvement, patients may present with metamorphopsia (change in shape of an object) or abnormalities in color vision. Retinal vasculitis can also be asymptomatic. (See 'Ocular symptoms' above.)

The diagnosis of retinal vasculitis may be suspected in a patient with an immune-mediated disorder or infectious disease that is known to be associated with retinal vasculitis and who presents with any of the following ocular symptoms (see 'When to suspect the diagnosis' above):

•Decreased or blurry vision

•Dry eye symptoms (tearing, burning sensation, redness, irritation)

•Lid inflammation or redness

•Eye mucous discharge

•Ocular or periocular pain

•Scalp and/or periocular tenderness

●Evaluation and diagnosis – The initial diagnostic evaluation in a patient with suspected retinal vasculitis should focus on obtaining an expedited eye examination. The diagnosis of retinal vasculitis is clinical and can usually be made on funduscopic examination by an ophthalmologist experienced with uveitis.

The gold standard for detecting retinal vasculitis is fluorescein angiography. Findings on fluorescein examination consistent with retinal vasculitis include vascular leakage (perivascular staining) and capillary nonperfusion. (See 'Diagnosis' above and 'Ocular examination' above.)

●Subsequent evaluation – Once a diagnosis of retinal vasculitis is made, the subsequent workup should include a thorough history, review of systems, and physical examination to help identify the underlying cause (table 1). Only limited diagnostic testing is useful when an associated condition is not apparent despite a thorough medical history and physical examination. (See 'Evaluation for underlying disease' above.)

●Management – The management of retinal vasculitis in the setting of a systemic rheumatic disease or infection is largely related to the treatment of the underlying disease.

Some patients present with retinal vasculitis without a known associated underlying disease. If such a patient is experiencing a decline in vision or if the vasculitis is encroaching on the macula, empiric therapy is initiated while the patient is evaluated for associated conditions. Left untreated, retinal vasculitis may lead to progressive and extensive visual loss. Thus, for such patients, we recommend initial treatment with high doses of systemic glucocorticoids (Grade 1C). We typically use an initial dose of the equivalent of prednisone 1 mg/kg (maximum 60 mg) daily. (See 'Management and prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Tolentino, MD, who contributed to earlier versions of this topic review.