survey of ophthalmology 66 (2021) 54e67

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Major review Retinal : A framework and proposal for a classification system

Ghazala A. Datoo O’Keefe, MDa,*, Narsing Rao, MDb a Assistant Professor of Ophthalmology, Section of Vitreoretinal Surgery and Diseases, Section of Uveitis and Vasculitis, Emory University School of Medicine, Atlanta, Georgia, USA b Grace and Emery Beardsley Professor and Chair, USC Department of Ophthalmology; USC Roski Eye Institute; Director of the Uveitis Service and Ophthalmic Pathology Laboratory, The Keck School of Medicine, University of Southern Califonia, Los Angeles, California, USA article info abstract

Article history: Retinal vasculitis, a poorly understood process involving inflammation or ischemia of the Received 24 July 2019 retinal vessel wall, may occur in association with a systemic process, although it can also Received in revised form 12 May be isolated to the retina. Because of the limited ability to perform histopathological studies 2020 on retinal vessels, there is no gold standard for diagnosis. Thus, there is utility in creating a Available online 22 May 2020 classification system for retinal vasculitis and improving diagnostic strategies for this disease. We provide a framework for understanding retinal vasculitis based on size, Keywords: location, and etiology. We hope that this information can be implemented in the clinical retinal vasculitis setting to provide some diagnostic strategies for this often confusing entity. vasculitis ª 2020 Elsevier Inc. All rights reserved. uveitis inflammation birdshot infectious uveitis noninfectious uveitis systemic vasculitis

1. Introduction associated with systemic vasculitis as there is not easy access to tissue specimens. While retinal vasculitis may occur in Retinal vasculitis, or inflammation of the blood vessel wall, is association with systemic vasculitis, it can also be isolated to a poorly understood entity. This is in part due to the lack of the retina. It may also occur secondary to infectious or histopathological evidence, a gold standard for diagnosing noninfectious intraocular inflammation. Usually when it is any form of vasculitis, consisting of inflammatory cell infil- associated with an infectious etiology, there are associated tration of the vessel wall. It is a clinical diagnosis associated changes to the retina including, but not limited to, retinal with inflammation or ischemia of the retina; however, histo- whitening or a chorioretinitis.56 Fluorescein angiography is pathological analysis cannot be fulfilled unless it is also used to evaluate the presence and extent of retinal vasculitis,

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. * Corresponding author: Ghazala A. Datoo O’Keefe, MD, Emory Eye Center, 1365 Clifton Road B, Suite B2400C, Atlanta, GA, 30322. E-mail address: [email protected] (G.A. Datoo O’Keefe). 0039-6257/$ e see front matter ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.survophthal.2020.05.004 survey of ophthalmology 66 (2021) 54e67 55

but cannot reliably differentiate between vascular damage manifestations associated with and from other causes such as diabetic retinopathy or vascular Takayasu arteritis in the literature correspond to sequelae of occlusions, and true vasculitis.96 Ultrawidefield (UWF) imag- poor perfusion of the retina and other ocular structures from ing demonstrates areas of varying peripheral retinal leakage, large-vessel disease affecting the internal carotid artery or the the implication of which, to the management of disease, is ophthalmic artery branching from it. Examples of these currently uncertain. In 2005, the working group for the Stan- include ocular ischemic syndrome, iris neovascularization, dardization of Uveitis Nomenclature reported that “there was anterior ischemic optic neuropathy, neovascular glaucoma, consensus that the definition of retinal vasculitis required and hypertensive retinopathy.92 They do not manifest as more work”.59 Despite its relatively frequent occurrence in retinal vasculitis.The ocular ischemic syndrome from large- uveitis and related intraocular inflammations, our under- vessel disease84 can present with clinical findings of non- standing of the diagnosis and treatment of this entity is poor. perfusion and peripheral retinal ischemia and not as a retinal Vasculitis, as a diagnosis, was first described by Kussmaul vasculitis. in 1866 in the setting of a patient who died of a disease marked Posterior and anterior ciliary vessels represent medium by fever and progressive weakness, which was later called size vessels. Sequelae of medium-vessel vasculitis manifest .61 Despite being recognized for 150 years, primarily as a scleritis and peripheral ulcerating keratitis, our understanding of the mechanism behind the inflamma- as well as uveitis associated with polyarteritis nodosa and tion is incomplete. In an attempt to understand various sys- Kawasaki disease.29 The medium-vessel vasculitides are temic inflammatory vascular diseases, a nomenclature was more likely to be acute, necrotizing in nature61 and have a proposed for systemic vasculitis by Zeek in 1952123 by classi- high mortality rate.41,44 Similar to large-vessel disease, fying the necrotizing angiitides which was then elaborated medium-vessel disease does not appear to cause retinal upon by Fauci in 1978 using information regarding histopa- vasculitis; however, it can cause infarction of the choroid or thology and etiology of disease.41 Vessel size was first used in retina from either perfusion abnormalities or inflammation addition to this existing classification in 1994 at the Chapel involving the choroidal vasculature of Haller and Sattler Hill Consensus Conference60 as well as in a subsequent revi- layers.38,55 sion.61 More recently, an attempt has been made to create a Retinal vasculitis then is mostly a disease of small vessels, more clinically relevant integrated nomenclature for the sys- seen clinically as fluffy white sheathing along the vessels and temic vasculitides.95 usually associated with vitritis.50 It is suggested that circu- There has been a lack of similar framework in the lating immune complexes are involved in the pathogenesis of ophthalmology literature, likely due to the segregation of the this disease, but data are limited.11,120 It has also been induced disease in the eye and the limited ability to perform histo- experimentally by provoking an immune response against pathological studies on retinal vessels. The diagnosis is made rhodopsin kinase, or S antigen.99 Although, as stated previ- based on a clinical examination of the retinal vasculature, ously, vessel leakage on fluorescein angiography cannot reli- which may demonstrate sheathing of the retinal vessels, focal ably distinguish between vasculitis and vasculopathies; fluffy white cuffs around the vasculature, nodular periarter- clinically, the diagnosis of retinal vasculitis is supported by iolar plaques, and the presence of cells in the vitreous cavity.50 fluorescein angiography that shows vascular leakage with or In the absence of histopathological confirmation and based on without macular edema.120 Retinal vasculitis can be confusing clinical features and retinal vascular imaging, we believe there because the complications seen can be mimicked by nonin- is utility in thinking about retinal vasculitis based on the flammatory disorders; for example, noninflammatory vessel size and type and agree in principal with the 2016 in- vascular sclerosis can be confused with inflammatory tegrated nomenclature by Prete and colleagues.95 We propose sheathing.56 There are no clear-cut features that distinguish a framework for understanding retinal vasculitis based on the vasculitis from vasculopathy, although certain findings may framework set forth by prior nomenclatures for systemic assist in the differentiation. The presence of vitreous cells vasculitides, realizing that retinal vasculitis frequently occurs may point toward a vasculitis. Concurrent diagnoses of dia- in the absence of systemic vasculitis.98 We believe that this betes mellitus and hypertension in a patient with sudden framework will be useful for the understanding of retinal onset of vision loss and a clinical findings of four quadrants of vasculitis, whether idiopathic or in the setting of systemic dot-blot hemorrhages is more likely to be a retinal vein oc- disease. In addition, we will recommend some diagnostic clusion. UWF imaging is being used increasingly frequently to strategies for this often confusing entity. evaluate peripheral retinal findings in patients. Leakage of peripheral retinal vessels has been documented in up to 42% of patients with anterior uveitis, 44% of whom did not have 2. Background clinically active disease.28 Cystoid macular edema associated with anterior uveitis was more common in those with pe- Before the creation of a framework, it is vital to understand ripheral retinal leakage, and 44% of those with peripheral that we encounter mostly small-vessel vasculitis in the retina retinal leakage had a specific etiology of their anterior uveitis as a result of the histological makeup of the retinal vascula- including ankylosing spondylitis, juvenile idiopathic arthritis, ture. Large-vessel vasculitis such as aortitis, giant cell arter- and tubulointerstitial nephritis and uveitis.28 More work itis, and Takayasu arteritis primarily affect large ophthalmic needs to be done to evaluate the prognostic importance of vessels. Ocular involvement is well known in both giant cell peripheral retinal leakage in uveitis. arteritis and Takayasu arteritis; however, these do not Adaptive optics ophthalmoscopy (AOO) is an optoelectronic generally manifest as retinal vasculitis. The ocular technology that allows quantitative analysis of microvascular 56 survey of ophthalmology 66 (2021) 54e67

structures and can demonstrate fusiform or linear opacities on involved and whether involvement is limited to the eye or in- both sides of the vessels in vascular sheathing.38 Errera and volves multiple organs, for a more comprehensive evaluation coworkers utilized flood illumination AOO in 12 eyes of 12 pa- (Table 1). This can be used in conjunction with the phlebitis tients with retinal vasculitisofvaryingetiologiesto demonstrate versus arteritis classification if needed. There may be some areas of vascular sheathing on AOO that were not evident on overlap among these entities when classifying the vasculitis by fundus photography or on fluorescein angiography. They did, vessel size versus disease pathogenesis, for example SLE affects however, note that all areas with leakage on fluorescein angio- vessels of variable size, and the pathogenesis involves the gram had abnormal perivascular sheathing when evaluated deposition of immune complexes in tissues, but in these cases, using AOO.38 Mahendradas and coworkers evaluated six pa- the entities are categorized primarily on the size of vessels tients with retinal vasculitis prospectively using AAO. They involved in the disease as the pathogenesis of some of these were able to demonstrate subclinical inflammation in a patient conditions are multifold and still evolving. with Takayasu arteritis and noted that improvement in vascu- litis noted on AAO was seen with treatment.75 AOO, however, is 1. Retinal vasculitis associated with primary systemic still in its infancy, with limited data available and an inability to vasculitides image the peripheral retina through hazy media.38,75 a. Retinal vasculitis associated with variable size vessel Retinal vasculitis is rarely associated with a systemic vasculitides (Behc¸et disease, SLE) vasculitis,98 but when they occur concurrently, the underlying b. Retinal vasculitis associated with small-vessel vasculit- systemic vasculitis may be associated with significant ides (antineutrophil cytoplasmic antibodies [ANCA]- morbidity or mortality. Furthermore, while retinal vasculitis is associated vasculitis and immune complex-associated not frequently associated with systemic vasculitis, it can be vasculitis) associated with underlying systemic disease. Thus, we 2. Retinal vasculitis associated with systemic infectious and recommend that the presence of retinal vasculitis requires an noninfectious diseases (tuberculosis, syphilis, rickettsial investigation directed by the clinical findings and a review of disease, cat-scratch disease, ) systems, as well as a systemic evaluation in the affected pa- 3. Organ-limited retinal vasculitis (birdshot chorioretinitis, tient to rule out underlying systemic disease. , idiopathic retinal vasculitis, aneurysms, and Historically, vasculitis has been organized based on neuroretinitis syndrome) involvement of either arteries, veins, or both.100 Thisisa 4. Retinal vasculitis from a putative identifiable trigger (drug- useful approach to evaluating the potential etiology of induced vasculitis, vaccination-associated vasculitis, and disease; for example, primarily retinal arterial involvement tattoo-related vasculitis) is associated with systemic lupus erythematosus (SLE), idiopathic retinal vasculitis, or viral etiologies including herpes simplex virus or varicella zoster virus, among 2.1. Retinal vasculitis associated with primary systemic others; whereas a primary retinal phlebitis is associated vasculitis with sarcoidosis, pars planitis, birdshot chorioretinopathy and so forth. This approach, however, is not comprehen- This first group includes retinal vasculitis associated with sive, and important etiologies of retinal vasculitis may be systemic vasculitides that affect either vessels of variable size left out if following this guideline in isolation. such as Behc¸et disease or SLE, or small-vessel vasculitis We propose using the following framework to categorize (ANCA-associated vasculitis or immune complex-associated retinal vasculitis, based on clinical findings of the size of vessel vasculitis).

Table 1 e Laboratory and clinical investigations of retinal vasculitis Systemic vasculitis Systemic disease Organ-limited vasculitis Putative identifiable trigger

Complete blood count with QuantiFERON-TB Gold or Toxoplasmosis IgG/IgM Elicited by the history and differential tuberculin skin test review of systems. Creatinine Bartonella IgG/IgM Erythrocyte sedimentation rate VDRL Lyme IgG/IgM Urinalysis FTA-ABS HTLV-1 IgG/IgM Proteinase 3 antibody Angiotensin-converting enzyme CMV IgG/IgM Myeloperoxidase antibody CT chest HSV IgG/IgM Complement C1q CNS imaging VZV IgG/IgM Complement C3, C4, CH50 Chorioretinal biopsy West nile virus IgG/IgM Antinuclear antibody Aqueous fluid PCR (HSV, VZV, CMV, Anti-phospholipid antibody toxoplasma) HLA B51 Angiotensin-converting enzyme Angiotensin-converting enzyme CT chest CT chest HLA A29

VDRL, venereal disease research laboratory; FTA-ABS, fluorescent treponemal antibody absorption; HTLV-1, ▪; CMV, cytomegalovirus; CT, computed tomography; HSV, herpes simplex virus; CNS, central nervous system; VZV, varicella zoster virus; PCR, polymerase chain reaction. survey of ophthalmology 66 (2021) 54e67 57

2.2. Retinal vasculitis associated with variable size ischemia and vitreous hemorrhage, more consistent with a vessel vasculitides thrombotic microangiopathy.68 Treatment for SLE associated with APL antibodies combines the use of immunosuppression Behc¸et disease, which predominantly affects those of Middle with anticoagulation, but it is unclear whether there can be Eastern, Mediterranean, and Asian descent, is notable because demonstrable improvement with anticoagulation after the it can cause inflammation of vessels of variable sizes.42 It re- initial insult to the retina.12,79 In refractory cases, treatment sults in an occlusive vasculopathy with a variable amount of may also include plasmapheresis.9 Figure 1 shows images of a inflammation in the eye. Systemic manifestations of Behc¸et young male patient who presented with acute vision loss and disease are broad due to the involvement of multiple sizes of was diagnosed with SLE and the presence of APL antibodies. In blood vessels. These manifestations include ulcerations of case reports of retinal ischemia, laser photocoagulation and mucosal tissue, erythema nodosum, arthritis, respiratory injections of antivascular endothelial growth factor (bev- tract involvement, pericarditis, meningoencephalitis, and acizumab) have been shown to modestly improve outcomes.21 dural sinus thromboses, along with ophthalmic complica- tions. Ocular involvement includes anterior uveitis with a 2.3. Retinal vasculitis associated with systemic small- shifting hypopyon, optic atrophy, papilledema, and occlusive vessel vasculitis retinal vasculitis. Historically, treatment for Behc¸et disease involved systemic corticosteroids in addition to immuno- This is a rare cause of retinal vasculitis but carries potentially modulatory and cytotoxic agents (azathioprine, cyclosporine, devastating morbidity and mortality. It can be further broken cyclophosphamide, chlorambucil); however, anti-tumor down into systemic ANCA-associated vasculitis vs immune necrosis factor agents such as adalimumab and infliximab complex-associated vasculitis. ANCA-associated vasculitis is have recently shown to be effective in the treatment of a group of diseases that are associated with either ANCA Behc¸et’s disease.14 They are recommended in patients who specific for myeloperoxidase or for proteinase 3 (PR3-ANCA) have failed standard immunomodulatory treatment.71 but, more importantly, are associated with little to no immune SLE is considered a secondary vasculitis that affects vessels complex deposition.61 Atypical p-ANCA positivity is not of variable sizes and can result in devastating vision loss, associated with retinal vasculitis but can be associated with which can be a presenting symptom.16,48,88 Systemic mani- either anterior uveitis or scleritis.37 festations of SLE include the classic malar rash and discoid This group of conditions affects predominantly small ves- skin changes, arthritis, fevers, myalgias, pericarditis, sels such as capillaries, venules, or arterioles and is necro- myocarditis, nephritis, and Raynaud phenomenon. Optic tizing in nature. Microscopic polyangiitis; granulomatosis neuritis can be a devastating complication of SLE.72 Fundus with polyangiitis (GPA), formerly known as Wegener gran- changes frequently involve the posterior pole and can include ulomatosis; and eosinophilic granulomatosis with poly- cotton wool spots, retinal hemorrhages, and sheathing of angiitis, formerly known as Churg-Strauss syndrome; make vessels. Capillary nonperfusion and occlusive changes may up the ANCA-associated vasculitides. Systemic manifesta- also occur, which are vision threatening. Notably, patients do tions of these vasculitides include involvement of the respi- not usually have an associated anterior uveitis or vitritis. Pa- ratory tract as a pulmonary capillaritis with or without tients with SLE who have positive antiphospholipid (APL) an- hemorrhage, necrotizing glomerulonephritis, and, in eosino- tibodies are at the highest risk of developing retinal vascular philic granulomatosis with polyangiitis specifically, eosino- occlusions and retinal ischemia, specifically frosted branch philia with asthma and nasal polyps. Ophthalmic angiitis.12,80 Contrast it to the more common features of lupus manifestations in ANCA-associated vasculitis vary from 34% retinopathy outlined previously; however, those with APL in GPA and 11.1% in eosinophilic granulomatosis with poly- antibodies present as an occlusive retinopathy, with severe angiitis to 8.9% in microscopic polyangiitis in one study. The

Fig. 1 e Optos ultrawidefield image and fluorescein angiogram of a patient with ischemic vasculitis secondary to systemic lupus erythematosus (SLE). The left eye was less affected than the right eye, and images were taken after the initiation of treatment, showing improvement in vasculitis, but still with significant ischemic changes. 58 survey of ophthalmology 66 (2021) 54e67

most common manifestations included conjunctivitis (52.1% multicenter study but found that of the 962 patients in the in GPA), episcleritis (39.3% in GPA), and blurred vision (30% in study, only 59 patients (6.1%) underwent polymerase chain eosinophilic granulomatosis with polyangiitis).102 Patients reaction testing. Of those patients who tested negative for TB can present with sheathing of peripheral retinal vessels, polymerase chain reaction (26/59 patients), 30.77% were sequelae of ischemia including neovascularization and vitre- diagnosed with systemic TB, including military TB and TB ous hemorrhage,45 or scleritis.34 meningitis, demonstrating the limited factor of the sensitivity On the other hand, immune complex-associated vasculitis of the polymerase chain reaction test.3 The authors state this is associated with marked deposits in the vessel walls of limitation is due to the lack of standardization of the test. At either complement or immunoglobulin. Arterioles are less this time, the diagnosis of tubercular uveitis is primarily made involved than in ANCA-associated vasculitis; however, the by the clinician based on the constellation of clinical findings kidneys are more frequently involved.61 Cryoglobulinemic and systemic symptoms. vasculitis is an example of immune complex-associated Viral etiologies such as cytomegalovirus, herpes simplex, vasculitis that can be seen in patients with hepatitis C viral or varicella zoster result in inflammation preferentially sur- infection or multiple myeloma. It can result in a purpura, rounding arterioles that can result in occlusion107,121 and neuropathies, and acute kidney injury. Cryoglobulinemia can usually have associated chorioretinal involvement frequently result in a hyperviscosity syndrome with a dilated or tortuous in the form of retinitis.56 Viral etiologies of retinal inflamma- appearance of retinal blood vessels, either the direct effects of tion can be associated with devastating vision loss and can be hyperviscosity resulting in a Purtscher-like retinop- present in the absence of overt systemic signs of infections athy27,82,104 or from a vasculitis of the central retinal artery.116 except in the immunocompromised patient. Interestingly, Another example is antieglomerular basement membrane HIV, in and of itself, does not cause a retinal vasculitis but a disease, which predominantly affects glomerular capillaries, histological retinal microvasculopathy, which can progress to pulmonary capillaries, or both. Patients present with what is seen clinically as cotton wool spots or HIV retinop- glomerulonephritis from the renal involvement and pulmo- athy. These cotton wool spots are, however, a risk factor for nary hemorrhage due to the basement membrane involve- developing cytomegalovirus retinitis, suggesting that the ment in the capillaries of the lungs.61 Retinal involvement is microvasculopathy may play a role in pathogenesis of viral rare in antiglomerular basement membrane disease and infection allowing cytomegalovirus-infected leukocytes to consists of retinal hemorrhages and exudates, as well as se- travel through the vessel wall.55 Toxoplasmosis can also result rous retinal detachments25; however, it is more likely that the in an inflammatory vasculitis causing vascular occlusion.5,87 findings are secondary to damage from hypertension as a The finding of focal areas of necrotizing retinochoroiditis, or result of progressive kidney failure as opposed to direct older lesions elsewhere in the retina, makes the diagnosis of damage from antibody deposits in the basement membrane toxoplasmosis more likely and a broad workup is rarely of the retinal vasculature. needed. Although retinal arteriolar changes are recognized as Kyrieleis arteritis in toxoplasma retinochoroiditis, one paper 2.4. Retinal vasculitis associated with systemic postulates that the plaques may correlate to vascular endo- infectious and noninfectious disease thelial damage instead of a true periarteritis based on a new evaluation of fluorescein and indocyanine green angiog- This group of retinal vasculitides is further divided into two raphy.93 Treatment of infectious causes is directed toward the subgroups: those associated with infectious causes and those underlying infectious entity. In specific situations, such as in associated with noninfectious causes. Noninfectious retinal toxoplasmosis, syphilis, and acute retinal necrosis from vasculitis comprises conditions in which there is an under- herpetic infection, corticosteroids can be added 24e36 hours lying systemic disease. after antimicrobials. The infectious etiologies can cause retinal vasculitis Noninfectious retinal vasculitides comprise conditions in through direct or indirect mechanisms. Direct invasion of the which there is a systemic disease, such as sarcoidosis, multiple pathogen and proliferation within the vessel wall can occur sclerosis, and so forth. Sarcoidosis, though not considered a with Treponema pallidum,127 Rickettsia conorii,19,23,63 Epstein- true vasculitis, causes an inflammatory response primarily Barr virus,66 tuberculosis,110 and bartonella,94,119 among around veins that can result in occlusion of the small vessels.56 other conditions. Vasculitis associated with infection of the An intermittent cuffing of veins has been described as “candle retina and choroid occurs most commonly in Treponema pal- wax drippings,” although diffuse perivenous sheathing is more lidum,127 tuberculosis,70,83 and herpes family viruses.108 Any commonly seen. The retinal veins in this entity reveal granu- associated systemic manifestations usually correspond to the lomatous inflammatory cell infiltration and periarterial infectious etiology. For example, patients infected with sheathing is rarely noted. Patients frequently have inflamma- syphilis may have a history of a genital sore or a rash over the tion in the vitreous cavity or clumps of vitreous debris inferiorly palms of the hands and soles of their feet. on the retinal surface, described as “snowballs.” In addition, Vasculitis can also be associated with occult systemic in- they can have deep, yellow, small, circular choroidal lesions fections, such as systemic tuberculosis. In this situation, and larger choroidal granulomas that resolve with treatment.85 manifestations of infection occur solely in the eye in the Patients with can be noted to have a pe- absence of other systemic symptoms.7,89 The diagnosis of ripheral peri-phlebitis (56%e75.9%) on fluorescein angiography tubercular uveitis continues to be difficult to make. The usually in the setting of concurrent or pars Collaborative Ocular Tuberculosis Study evaluated 962 pa- planitis which is noted in 81e93% of patients with multiple tients diagnosed with tuberculosis (TB) uveitis in a sclerosis.32,125 survey of ophthalmology 66 (2021) 54e67 59

Susac syndrome is a condition marked by involvement of 29 positivity is strongly associated with this condition, and retinal arterioles along with a microangiopathy affecting the frequently noted complications include diffuse retinal vascular brain and cochlea. Symptoms include headache, confusion, and leakage or cystoid macular edema.85 These retinal vessels show hearing changes. Fundus examination shows sheathing of the infiltration of chronic inflammatory cells. Treatment frequently arterioles with multiple branch retinal artery occlusions targets elimination of macular edema and quiescence of the without significant inflammation. It has been argued that this choroidal disease on indocyanine green angiography.30 Treat- condition is primarily a vasculopathy associated with anti- ment for birdshot chorioretinopathy involves a combination of endothelial cell antibodyemediated microvascular injury73 local and systemic corticosteroids along with immunomodula- involving capillaries and small vessels; however, there are tors such as cyclosporine A, methotrexate, and mycophenolate multiple case reports of patients responding to immunosup- mofetil. Anti-tumor necrosis factor agents are considered pressive agents, including a case series of 19 patients,126 as well effective as well,71 and patients with elevated IL-6 levels may as an autopsy report on neuropathological findings in a young benefit from tacrolimus.24 woman that revealed perivascular inflammation involving Eales disease is an obliterative vasculitis of unclear etiology small vessels associated with vascular narrowing and occlusion affecting otherwise healthy young men usually from the Indian in the eyes and brain.2 The etiology of this condition remains subcontinent, and polymerase chain reaction analysis can unclear, though immunosuppression has a place in treatment, reveal Mycobacterium tuberculosis DNA in the affected tissue.20 and thus, we include it as an inflammatory cause of vasculitis. Fundus findings include sheathing of retinal vasculature, There have been case reports of patients with inflamma- occlusive vasculitis involving venules more than arterioles, tory bowel disease, such as Crohn disease or ulcerative colitis, capillary nonperfusion, neovascularization, vitreous hemor- developing retinal vasculitis or central retinal vein rhage, and tractional retinal detachments.85 The treatment for occlusions.36,46,78,103,115 This is a very sporadically published recurrent vitreous hemorrhage, a hallmark of Eales disease, is finding but a recent review of the association of inflammatory usually vitrectomy; however, intravitreal bevacizumab has also bowel disease with systemic vasculitis found associations been effective as an adjunctive therapy.31,117 Systemic immu- with large vessels vasculitis (predominantly Takayasu arter- nosuppression15 and intravitreal corticosteroid injections6,57 itis), ANCA-associated vasculitis (predominantly GPA), 5 with have also been used with varying success. isolated cutaneous vasculitis and 6 with other forms of Idiopathic retinal vasculitis, aneurysms, and neuroretinitis vasculitis.114 This finding may argue in favor of sporadic cases syndrome is an example of organ-limited primary retinal of retinal vasculitis associated with inflammatory bowel dis- vasculitis with certain specific features, particularly, the ease but needs to be further studied. presence of aneurysms of the arterioles as well peripheral Finally, retinal vasculitis has also been reported as a vascular nonperfusion and exudations. Neuroretinitis and presenting symptom of intraocular or central nervous sys- anterior uveitis may also be present in this condition. Patients tem lymphoma.22,65,74 It has also been reported as the first can develop posterior segment neovascularization due to sign of relapsed Hodgkin lymphoma8 or of metastatic B cell ischemia, anterior segment neovascularization, and neo- lymphoma.106 It should be considered on the differential in vascular glaucoma. Treatment has been limited to laser patients who are at risk of recurrent or metastatic lym- photocoagulation of the nonperfused areas of the retina,85 phoma or in patients unresponsive to treatment for retinal although there have been reports of successful control with vasculitis. systemic immunosuppression10 and local antie vascular endothelial growth factor (VEGF) injections.13 2.5. Organ-limited retinal vasculitis Peregrin and coworkers performed a review of all retinal vasculitis cases and found an incidence of 5.7% of idiopathic Organ-limited vasculitis can be manifestations of systemic retinal vasculitis (11 patients out of 192).91 In their analysis, infections or of a noninfectious etiology with clinical features they found this entity affected more women than men, with limited to the retinal vasculature, retina, and choroid. These an average age of 37 years (range 18e52 years). It commonly vasculitides are managed with systemic intervention supple- presented as a bilateral phlebitis as opposed to an arteritis, mented by local treatment in the form of intravitreal delivery and peripheral ischemia and neovascularization were the of antimicrobials and/or anti-inflammatory agents. Clinical most common findings (37% of eyes). Figure 2 shows a patient manifestation limited to the eye can be seen in infectious with unilateral retinal vasculitis presenting with a branch conditions such as tuberculosis, herpesviridae, syphilis, and retinal vein occlusion. Systemic workup was negative. Treat- ocular toxoplasmosis, amongst others. Noninfectious sys- ment for this disease includes intravitreal corticosteroids and temic conditions, such as sarcoidosis, may also present with bevacizumab, retinal photocoagulation, pars plans vitrec- organ-limited retinal vasculitis. tomy, oral glucocorticoids, and systemic immunosuppres- Unlike the aforementioned entities, birdshot chorioretinop- sion.91 There have been seven different case series on this athy is a typical example of nonsystemic retinal vasculitis iso- entity from 1988 to 2017, with the aforementioned charac- lated to the eye secondary to a noninfectious etiology. This teristics being similar across all series.18,51,64,76,86,91,112 entity is characterized by the clinical appearance of a retinal vasculitis; however, the underlying choroidal inflammation is 2.6. Retinal vasculitis from a putative identifiable the primary driver of disease. Patients have bilateral and trigger possibly asymmetric disease, low-grade anterior segment inflammation, low-grade vitreous inflammation, and deep cir- We have included the following etiologies under “putative cular or oval cream-colored lesions in the posterior pole. HLA A- triggers”: drug-induced vasculitis, vaccination-associated 60 survey of ophthalmology 66 (2021) 54e67

Fig. 2 e Optos ultrawidefield and fluorescein angiogram images of a patient with idiopathic retinal vasculitis presenting with a retinal vein occlusion.

vasculitis,69 and tattoo-related vasculitis.81 In these condi- from a patient with nephrotic syndrome and hypertension tions, there is a precipitating event or exposure that results in secondary to minimal change disease presenting with a inflammation of the retinal vasculature though the etiology combined central retinal artery and vein occlusion and retinal remains unclear for most. For example, methamphetamine phlebitis. can cause retinal vasculitis or a necrotizing angiitis,54,109 as When variable size vessel vasculitis is suspected, a workup can trimethoprim sulfamethoxazole,17 checkpoint inhibitors should also include evaluation of the kidneys, antinuclear for metastatic melanoma,43,77 hepatitis C,1 and interferon antibody, or in some cases, an extended antinuclear antibody treatment,53,97,124 but the mechanisms for the above are likely (ENA) panel. Complement C3, C4, CH50 levels are also indi- to be different in each case. Treatment includes removal of the cated in this subset of vasculitis. In addition, APL antibodies inciting event when possible, intravitreal and systemic corti- (lupus anticoagulant or anticardiolipin antibody) should not costeroids, and in some cases, immunosuppressive therapy.81 be forgotten, especially in cases of extensive or ischemic Of note, this group of conditions is separate from similar vasculitis. Figure 4 demonstrates significant vascular conditions resulting in retinal disease due to alternate path- sheathing, capillary dropout, vitreous condensations, and ogenesis, such as multiple myeloma or hepatitis C-induced peripheral white-centered hemorrhages scattered in the pe- cryoglobulinemic vasculitis, though these should be ruled out ripheral retina in a patient with SLE-related vasculitis. Imag- as possible etiologies, based on the elicited history and review ing of the central nervous system is indicated if the patient of systems. has any neurological symptoms or if they manifest physical changes concerning for Behc¸et’s disease. HLA B51 can be 2.7. Laboratory and clinical investigations helpful but is not necessary to make the diagnosis of Behc¸et’s disease. Laboratory investigations in a patient with retinal vasculitis When concerned about an infectious etiology, the should be guided by the history, the course of disease, and the following serologies may be appropriate depending on the review of systems, with a focus on symptomatology experi- clinical picture: toxoplasmosis, bartonella, Lyme disease, enced by the patient. At a minimum, a complete blood count HTLV-1, cytomegalovirus, herpes simplex virus, varicella with differential, erythrocyte sedimentation rate, urinalysis, zoster virus, and West Nile virus serologies. An analysis of QuantiFERON-TB Gold test or tuberculin skin test, venereal ocular fluid using polymerase chain reaction is especially disease research laboratory and fluorescent treponemal helpful to identify pathogens. New testing, such as meta- antibody absorption should be performed. A complete meta- genomic deep sequencing, is promising to distinguish a broad bolic panel, chest X-ray, and hepatitis panel are useful if a number of pathogens from a limited amount of fluid.35,49 patient needs treatment with systemic immunosuppressive For noninfectious etiologies associated with a systemic agents or biologics. condition such as sarcoidosis, serum angiotensin-converting For concerns of predominant small-vessel vasculitis, the enzyme or lysozyme, and computed tomography chest may workup should include testing for ANCAs by antigen-specific be helpful, although one should also be aware of any con- enzyme-linked immunosorbent assay. In situations, where current ACE inhibitors the patient may be taking. central there is a high concern for ANCA-associated vasculitis, based nervous system imaging should be undertaken if multiple on the history elicited by the patient, there may be utility in sclerosis or Susac’s syndrome is of concern. More invasive ordering proteinase 3 (PR3) and myeloperoxidase antibodies approaches, such as a chorioretinal biopsy, may be necessary as independent tests to improve the positive predictive value to evaluate for lymphoma. of the test over ANCA immunofluorescence.113 Concurrent For infectious, organ-limited vasculitis, analysis of ocular evaluation of the kidneys is also important, and a creatinine fluid is important to rule out herpes viridae family infectious (Cr) and urinalysis (UA) is indicated. Figure 3 shows images or toxoplasmosis. For noninfectious organ-limited disease, survey of ophthalmology 66 (2021) 54e67 61

Fig. 3 e Optos ultrawidefield images of a patient with nephrotic syndrome and hypertension secondary to minimal change disease presenting with a combined central retinal artery and vein occlusion and retinal phlebitis.

such as in birdshot chorioretinopathy, HLA A29 testing can be mycophenolate mofetil) as well as calcineurin inhibitors useful, although imaging with indocyanine green angiography (cyclosporine A and tacrolimus) and alkylating agents and electroretinogram testing may be diagnostic. Figure 5 (cyclophosphamide and chlorambucil) have also been used emphasizes the utility of indocyanine green angiography in order to achieve a durable corticosteroid-free (ICG) and fluorescein angiography in the diagnosis of birdshot remission.47,58,76,86,91 chorioretinopathy. Fabiani and coworkers recently evaluated infliximab Finally, for vasculitis with a putative identifiable trigger, a versus adalimumab for recalcitrant retinal vasculitis.39 Of 82 good history will help determine if the vasculitis followed a eyes, 45% received infliximab and 54% received adalimu- vaccination or recent tattoo, or is due to a mimicking condi- mab. Retinal vasculitis was seen to improve with both tion such as intravitreal lymphoma wherein a vitreoretinal agents. Interestingly, a significant number of non- biopsy will be useful. responders at the 3-month mark showed a favorable treat- As mentioned previously, testing is only useful in the ment response at the 12-month mark. There was no setting of a good history and review of systems elicited from appreciable difference in those who were biologic naı¨ve or the patient. those already exposed to other biologics at the follow-up. The goal then can reasonably be steroid-free remission for 2.8. Treatment options those with retinal vasculitis if the disease is initially severe enough to warrant oral corticosteroids. Rituximab, a Using a similar approach, treatments can be tailored monoclonal antibody to CD20 on B cells used to treat B-cell depending on the subtype of retinal vasculitis present (Table 2). lymphomas and , has similar efficacy to The mainstay of initial systemic therapy for retinal cyclophosphamide for ANCAeassociated vasculitides.62 vasculitis from noninfectious causes continues to be oral Other studies have also shown the efficacy of rituximab in corticosteroids.76,91 Immunosuppressive agents such as the treatment of ANCA-associated vasculitis, including one antimetabolites (azathioprine, methotrexate, and that showed equivalent control in patients treated with a

Fig. 4 e Optos ultrawidefield image and fluorescein angiogram of a patient with retinal vasculitis and systemic Sjogren disease and autoimmune hepatitis. Note the vascular sheathing, capillary dropout, and white-centered hemorrhages diffusely throughout the retina. 62 survey of ophthalmology 66 (2021) 54e67

Fig. 5 e AeD: Optos ultrawidefield image of a patient with birdshot chorioretinitis. (A and B) Bilateral Optos images showing some depigmented lesions more prominent in the left eye with areas of vascular sheathing. (C) Fluorescein angiogram demonstrating vasculitis and disc leakage in the left eye. (D) Late frame of ICG with hypocyanescent dark dots diffusely in the macula and periphery. ICG, indocyanine green angiography.

tailored vs fixed schedule infusion.26 Rituximab or cyclo- Treatment for infectious retinal vasculitis is targeted to- phosphamide in addition to glucocorticoids is recom- ward the underlying causative microorganism. In cases such mended in cases of organ-threatening ANCA-associated as retinal necrosis secondary to varicella-zoster virus or in vasculitis as induction followed by methotrexate, whereas toxoplasma chorioretinitis, treatment is relatively straight- methotrexate and glucocorticoids can be used as induction forward, whereas in presumed tuberculosis-related vasculitis, therapy for nonorgan-threatening ANCA vasculitis.122 The the treatment is more nuanced with the addition of cortico- extent of retinal vasculitis and damage to the retina from steroids as needed to control the hypersensitivity response to concurrent ischemia and necrosis should be taken into the mycobacterium.52 Agrawal and colleagues recently out- consideration when determining whether organ- lined a retrospective cohort of 110 patients with peripheral threatening vasculitis is present in addition to systemic retinal vasculitis in the United Kingdom.7 Of these patients, disease. 63% had tubercular RV, a presumptive diagnosis based on For variable vessel vasculitis, after high-dose corticoste- clinical examination as well as evidence of concurrent TB roids, first-line agents such as antimetabolites can also be infection, such as positive QuantiFERON-TB Gold, tuberculin used, though an expert panel of the American Uveitis Society skin test, or biopsy (in systemic TB). None of the cases in this recommended anti-tumor necrosis factor agents as the first- study cohort had a definitive diagnosis of TB based on poly- line therapy for Behc¸et disease.71 merase chain reaction or ocular biopsy. Patients were treated For patients with retinal vasculitis associated with nonin- with antitubercular therapy if they had high levels of inflam- fectious systemic disease, such as sarcoidosis, Dana and co- mation requiring ongoing use of oral corticosteroids. In their workers demonstrated that oral corticosteroid therapy is cohort, 85% of patients treated with antitubercular therapy associated with a 93% reduction in the odds of visual were able to be tapered to doses below 10 mg/day. Agarwal impairment in patients with sarcoid uveitis.33 but in the and coworkers also demonstrated the efficacy of an intra- absence of improvement, therapy can be stepped-up to vitreal dexamethasone implant in the treatment of tubercu- include adalimumab or alternative biologics.40,76,91 lous uveitis, in addition to antitubercular therapy.4 survey of ophthalmology 66 (2021) 54e67 63

Table 2 e Treatment for retinal vasculitis Systemic vasculitis Systemic disease Organ-limited vasculitis Putative identifiable trigger

Oral corticosteroids Treat underlying infection A. infectious retinitis Withdrawal of offending agent Rituximab Can add corticosteroids Treat underlying infection Oral corticosteroids Anti-TNF Can add corticosteroids Treatment of underlying condition Cyclophosphamide B. noninfectious retinitis Corticosteroids Methotrexate Azathioprine Cellcept Anti-TNF

TNF, tumor necrosis factor.

In those with organ-limited, noninfectious retinal vascu- litis, treatment can be localized to the eye, though systemic 3. Conclusion treatment may be warranted in certain cases. For example, in birdshot chorioretinitis, the mainstay of treatment is In conclusion, retinal vasculitis can be associated with or immunomodulatory therapy with adjunctive oral, peri- caused by a myriad of different conditions, some of which ocular, or intravitreal corticosteroids. Immunomodulatory carry substantial risk of morbidity or mortality. It can be the therapy may consist of methotrexate,101 azathioprine,67 presenting symptom for certain diseases such as sarcoidosis mycophenolate mofetil,67 cyclophosphamide,67 or anti- or SLE. It is important to have a broad differential in mind tumor necrosis factor alpha agents.118 Oral corticosteroids when assessing this disease and targeting the workup to that are not considered sufficient control for this entity as pa- differential. Here, we have proposed a way to approach this tients usually have significant macular edema on doses of disease, realizing that our understanding of retinal vasculitis oral corticosteroids in dosages above the acceptable level for is limited to our clinical evaluation and what has been re- long-term use. Furthermore, use of local corticosteroid ported in the literature. therapy in the form of periocular injections or implants in- creases the risk of cataract surgery, elevated intraocular pressure, and possible glaucoma surgery. 4. Method of literature search Pan-retinal photocoagulation and pars plana vitrectomy have been documented as treatments for retinal vasculitis in A literature search was performed in PubMed using the key- two prior case series.47,91 Both studies saw rates of pars plana words “retinal,” “vasculitis,” “systemic vasculitis,” “arteritis,” vitrectomy for retinal vasculitis of approximately 30%, most “retinitis,” “central nervous system vasculitis.” commonly for vitreous hemorrhage, and reported a range of 40%47 to 60%91 for pan-retinal photocoagulation performed for vasculitis in their case series. Intravitreal anti-VEGF has had 5. Disclosures mixed results for the treatment of retinal vasculitis and vit- reous hemorrhage,9,90,105,111 but it is vital to understand that Ghazala O’Keefe served on an advisory board for EyePoint anti-VEGF agents can only be used as an adjunct to more Pharmaceuticals in 2019. The other author has no conflicts of definitive treatments for retinal neovascularization or vitre- interest to disclose. ous hemorrhage. It is not a sufficient treatment in and of itself for retinal vasculitis, and care must also be taken in situations references where there is a risk of a tractional retinal detachment.90 Finally, for those with vasculitis related to a putative identifiable trigger, the underlying etiology will help to drive the treatment in addition to corticosteroids as needed. 1. Abe T, Nakajima A, Satoh N, et al. Clinical characteristics of hepatitis C virus-associated retinopathy. Jpn J Ophthalmol. In summary, treatment for infectious retinal vasculitis 1995;39(4):411e9 should be directed toward the underlying microorganism with 2. Agamanolis DP, Klonk C, Bigley K, Rennebohm RM. adjunctive therapy including intravitreal or periocular corti- Neuropathological findings in Susac syndrome: An autopsy costeroids, or anti-VEGF injections. Treatment for noninfec- report. J Neuropathol Exp Neurol. 2019;78(6):515e9 tious retinal vasculitis is primarily oral corticosteroids but 3. Agarwal A, Agrawal R, Gunasekaran DV, et al. The with a transition to steroid-sparing agents, including con- Collaborative Ocular Tuberculosis Study (COTS)-1 report 3: ventional disease-modifying antirheumatic drug or biologic Polymerase chain reaction in the diagnosis and management of tubercular uveitis: Global trends. Ocul agents. Panretinal photocoagulation and pars plana vitrec- Immunol Inflamm. 2019;27(3):465e73 tomy should be utilized in the setting of ischemia, neo- 4. Agarwal A, Handa S, Aggarwal K, et al. The role of vascularization, and vitreous hemorrhage with or without dexamethasone implant in the management of tubercular anti-VEGF agents as deemed necessary. uveitis. Ocul Immunol Inflamm. 2018;26(6):884e92 64 survey of ophthalmology 66 (2021) 54e67

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