IMMUNE COMPLEXES

Immune complexes are formed by the association of an antibody with an antigen. Low levels of circulating immune complexes are found in most people and may promote the efficient removal of tissue debris or excess antigen. Immune complexes can activate the complement cascade, attracting polymorphonuclear leukocytes that release proteolytic enzymes, and cause tissue or vascular injury.

Circulating immune complexes and complement abnormalities have been reported in connective tissue diseases such as systemic lupus erythematosus (SLE) and polyarteritis nodosa, in Behçet's disease, in HLA-B27+ uveitis, and in idiopathic retinal vasculitis.^1–3 The Arthus reaction is a model for immune complex vasculitis and produces histopathologic changes resembling those seen in Behçet's disease.⁴ Because of these findings, retinal vasculitis was postulated to be due to immune complex deposition.⁵ However, the role of immune complex-mediated tissue damage in the eye remains unclear. Studies on idiopathic retinal vasculitis suggest that immune complexes may actually have a protective function, neutralizing anti-retinal autoantibodies.^6,7

AUTOANTIBODIES

Antibodies may bind directly to surface antigens of cells and tissues, leading to activation of the complement system and effector cells, resulting in cell lysis or cytotoxic damage.⁸ An example of antibody-mediated ocular disease is cancer-related retinopathy (CAR), in which antibodies that are produced against a tumor cross-react with retinal tissue, causing retinal damage.⁹

Antibodies to human vascular endothelial cells have been detected in the sera of patients with a variety of vasculitic disorders, including Wegener's granulomatosis and polyarteritis nodosa.^10–13 Autoantibodies to endothelial cells were found in 47% of patients with retinal vasculitis associated with systemic disease and in 35% of patients with idiopathic retinal vasculitis.¹⁴ In the same study, only 1% of normal controls had anti-endothelial cell antibodies. Possible mechanisms by which they induce vascular damage include complement fixation, neutrophil recruitment, and antibody-dependent cellular cytotoxicity.¹⁵ In Behçet's disease, anti-endothelial cell antibodies have been associated with systemic thrombotic complications.¹⁴

Anti-neutrophilic cytoplasmic autoantibodies have been detected in patients with Wegener's granulomatosis. It is postulated that these antibodies interact with stimulated neutrophils, resulting in their activation.¹⁶ The activated neutrophils then adhere to vascular endothelia and undergo degranulation, generating oxygen radicals that result in endothelial cell injury and inflammation.¹⁷ In vitro observations also indicate that anti-neutrophilic cytoplasmic autoantibodies may interact directly with endothelial cells.¹⁶

OTHER MECHANISMS

Delayed hypersensitivity plays a role in Wegener's granulomatosis, sarcoidosis, and sympathetic ophthalmia.⁸ In sarcoidosis, the macrophage is thought to initiate the inflammatory response.¹⁸ Abnormal cell-mediated immune responses to photoreceptor antigens have been found in idiopathic retinal vasculitis,¹⁹ and patients with retinal vasculitis have also been shown to have higher levels of natural killer cell activity.²⁰

PERIPHLEBITIS AND PHLEBITIS

Venous inflammation is much more common than arteritis. Early venous changes include patchy dilatation, venous irregularity, and perivenous cuffing. These cuffs are made up of white blood cells and vary greatly in density, from minimal obscuration of a vein to complete concealment of the blood column without occlusion. Vitreous cells may be present over the vessels. Vascular sheathing appears as white lines along the vein walls and may result in venous flow impedance and vein occlusion (Figs. 1 and 2).²⁵ It may be clinically difficult to distinguish perivenous inflammation from true phlebitis. Any vein from the optic nerve head to the peripheral retina is susceptible.

If inflammation is prolonged, secondary changes such as thickening of the vein wall and endothelial cell proliferation may occur. These can lead to narrowing and obstruction of the lumen, thrombosis, and necrosis. Other late changes secondary to vascular occlusion include telangiectasia, microaneurysms, and neovascularization.²¹ Histopathologically, polymorphonuclear leukocytes are the predominant cell type early in the disease, but lymphocytes accompanied by an occasional plasma cell, giant cell, or epithelioid cell become the predominant cell types later in the disease.²⁵

Fluorescein angiography often reveals focal areas of staining or dye leakage even before ophthalmoscopically visible signs are present (Fig. 3). In advanced cases of periphlebitis, angiography may show diffuse leakage of dye from retinal veins and capillaries.²⁶

ARTERITIS AND PERIARTERITIS

The arterial changes in retinal vasculitis are varied. Immune complex deposition in precapillary arterioles may result in cotton-wool spots, as seen in SLE and certain infectious conditions.^27,28 Aneurysmal dilatation of arteries has been observed in various infections, connective tissue diseases, and hypersensitivity vasculitides (Fig. 4).²⁹

Arterioles may show segmental, periarteriolar, hard, yellowish nodular plaques (kyrieleis arteriolitis) that do not extend beyond the thickness of the vessel wall. The plaques are not visible angiographically and do not alter dye transit or cause permeability changes. Primarily associated with toxoplasmosis, they have also been seen in lues, tuberculosis, cytomegalovirus, and herpes zoster retinopathy.^30–32

Severe inflammation can result in dense irregular sheathing of large arterial segments. This sheathing can conceal the blood column and extend beyond the width of the vessel wall. As the inflammation subsides, the arteries become white ghost vessels. Fluorescein angiography shows arteriolar occlusion with surrounding capillary nonperfusion. After arteriolar occlusions, neovascularization may occur in the areas of nonperfused retina (Fig. 5). This picture has been seen in connective tissue diseases, necrotizing viral retinitis, and Eales' disease.³³ Pigment proliferation in a bone spicule pattern may also occur around and beyond the occluded arterioles.

EALES' DISEASE

Eales' disease was initially described as recurrent retinal and vitreal hemorrhages, epistaxis, constipation, and headaches in young men.³⁴ It has since been redefined as an idiopathic obliterative peripheral retinovasculopathy with variable degrees of nonperfusion, vascular sheathing, retinal vascular abnormalities, peripheral retinal neovascularization, and hemorrhage (Fig. 6).³⁵ It usually affects men in the third decade of life and is bilateral in up to 90% of cases.³⁶ Many patients are symptomatic in only one eye, but fundus examination of the fellow eye may reveal early changes such as periphlebitis, vascular sheathing, and peripheral retinal nonperfusion.³⁷ The presenting symptom in 90% of patients is a painless blurring of vision, often due to vitreous hemorrhage.³⁶

The clinical manifestations of Eales' disease result from three basic pathologic changes: inflammation, ischemia, and neovascularization.³⁸ Vitreous cells are present and anterior segment inflammation is variable. In early stages, venous dilatation and tortuosity are seen in the periphery.³⁷ Accumulation of exudate around peripheral retinal venules appears as thin white lines parallel to the blood column and can obscure the vessel. Areas of vascular sheathing frequently leak fluorescein dye; however, the sheathing does not always correspond to the staining, nor is the amount of leakage proportional to the activity of the inflammation.³⁷

Progression of Eales' disease results in widespread venous occlusion, perivenular or arteriolar exudation, extensive sheathing, and retinal hemorrhage. Involved vessels become obliterated and avascular areas develop in the periphery. The junction between nonperfused and perfused retina is usually sharply demarcated.³⁷ Vascular abnormalities seen at this junction include microaneurysms, venovenous shunts, venous beading, hard exudates, and cotton-wool spots.^39,40 Obliteration of peripheral venules and arterioles and branch retinal vein occlusions can be confirmed angiographically.⁴¹

Capillary nonperfusion leads to peripheral and disc neovascularization; this is observed in up to 80% of patients with Eales' disease³⁷ and contributes to the development of fibrous proliferation and the risk of retinal detachment. Peripheral neovascularization is more common and is frequently located at the junction between perfused and nonperfused retina. Bleeding from damaged or abnormal vessels may result in vitreous hemorrhage. Extension of nonperfusion into the posterior pole may result in decreased visual acuity due to macular edema or epiretinal membrane or macular hole formation. Some patients develop anterior uveitis, cataracts, rubeosis iridis, secondary neovascular glaucoma, and optic atrophy in the late stages of the disease.³⁷

There is histopathologic evidence of lymphocytic and granulomatous infiltration of vessel walls and lumina, and perivascular spaces.⁴² The cause of Eales' disease, however, is unknown. It may represent a hypersensitivity reaction to tuberculoprotein. This hypothesis stems from isolated reports of vasculitis after skin testing or BCG vaccine and the prevalence of positive purified protein derivative testing in patients with the disease.⁴³ Tubercles in the venous walls were also reported in the older literature.⁴⁴ One study found elevated IgA and IgG levels in patients with Eales' disease,⁴⁵ whereas other studies showed no immunoglobulin abnormality.^46,47 Abnormal levels of circulating immune complexes have also been reported.⁴⁸ Eales' disease probably has more than one cause.

IDIOPATHIC RETINAL VASCULITIS

Retinal vasculitis occurring in isolation, with no systemic association, has been referred to as idiopathic retinal vasculitis.⁴⁹ Typical findings include inflammatory cells in the vitreous and sheathing of retinal veins and postcapillary venules. Fluorescein angiography may show diffuse capillary leakage.⁵⁰ Idiopathic retinal vasculitis can be classified into ischemic and nonischemic forms. Patients with ischemic retinal vasculitis have a worse visual outcome despite aggressive systemic treatment than those with nonischemic retinal vasculitis.⁴⁹ A few patients with idiopathic retinal vasculitis have disseminated central nervous system lesions characteristic of multiple sclerosis.⁵⁰ Lyme disease and cat scratch disease (Bartonella henselae) have been anecdotally associated with retinal vasculitis.^51–53

OPTIC DISC VASCULITIS

Optic disc vasculitis (papillophlebitis) is a unilateral, idiopathic, usually benign condition that primarily affects healthy adults younger than 40.⁵⁴ The only symptom is blurred vision. Retinal findings include edema of the optic disc and adjacent retina, markedly dilated and tortuous retinal veins with minimal arterial involvement, and a variable amount of retinal hemorrhage (Fig. 7). Other findings include venous sheathing, retinociliary shunt vessels, and depigmentation of the macular area.⁵⁵ Vitreous cells are absent or scant. Fluorescein angiography findings may include delayed venous filling, marked retinal venous dilatation, and massive dye leakage from the optic nerve head and large retinal veins.⁵⁴

Hayreh divided the disease into two types: type 1, with optic disc edema and good visual outcome as the dominant features, and type 2, with a clinical picture similar to central retinal vein occlusion.⁵⁴ In the second type, the visual outcome depends on the site and extent of the lesion. Hayreh suggested that type 1 is due to a mild nonspecific vasculitis of the ciliary vessels, whereas type 2 is probably due to phlebitis of the central retinal vein within the optic nerve head or retrolaminar region.⁵⁴

Papillophlebitis is self-limited, lasting 6 to 18 months, and the visual acuity is seldom severely decreased. Unlike peripheral retinal vasculitis (Eales' disease), optic disc vasculitis is rarely recurrent or associated with vitreous hemorrhage. No therapy is necessary, although corticosteroids have been reported to shorten the course. There is controversy over the existence of papillophlebitis, and some believe it represents a mild central retinal vein occlusion in a young person.⁵⁶

INTERMEDIATE UVEITIS

Intermediate uveitis is a syndrome with a noninflamed external eye, low-grade anterior segment reaction without synechia formation, and vitreous inflammation. Mild periphlebitis and optic disc and macular edema may also occur. Intermediate uveitis includes “pars planitis” and conditions that have been previously called chronic cyclitis, vitritis, and peripheral uveitis. This syndrome has been associated with several systemic diseases, including multiple sclerosis, Whipple's disease, and reticulum cell sarcoma.⁵⁷ Pars planitis is associated with the HLA-DR2 antigen and the temporal development of multiple sclerosis.²³

Pars planitis, the classic intermediate uveitis that usually occurs in young people, is distinguished by the presence of whitish gray cellular exudate (snowbanking) over the inferior pars plana. Retinal vascular involvement has been reported in 13% to 77% of cases of pars planitis.^58,59 Peripheral retinal veins appear dilated, segmented, and tortuous, some with vascular sheathing. Retinal vascular leakage is common and was found in 79% of fluorescein angiograms in one study.⁶⁰ Patchy perivenous staining in the posterior pole may accompany the closely spaced spots of fluorescein stain along peripheral venules. Arterial involvement has been reported infrequently.⁶¹ Although the natural course is usually one of chronic smoldering inflammation, vein occlusions, peripheral and disc neovascularization, vitreous hemorrhage, and retinal detachment have been observed.^61,62 Histopathologic examination reveals thickening of the vessel wall and perivascular round cell cuffing.⁶³ These changes can be observed as far posteriorly as the optic nerve.

ACUTE RETINAL NECROSIS

Acute retinal necrosis is predominantly a fulminant retinitis with an associated obliterative vasculitis of the retina, uvea, and optic nerve.⁶⁴ Acute retinal necrosis is characterized by panuveitis, vitritis, vaso-occlusive retinal arteritis, and necrotizing retinitis.⁶⁵

Vitreous haze often makes fundus examination difficult, but frequently arteriolar occlusions can be seen associated with these areas of white retina. There is an abrupt border between normal and abnormal retina, suggestive of an ischemic process. Progression results in retinal artery narrowing and sheathing. Perivenous sheathing and intraretinal hemorrhage may also be present. Angiographically, there is arteriolar obliteration and absence of capillary perfusion in affected areas, as well as dye leakage and vessel wall staining in the late phase.

Electron microscopy, immunohistochemical techniques, and viral culture studies implicate members of the herpesvirus family in the genesis of acute retinal necrosis.^66–70

FROSTED BRANCH ANGIITIS

Frosted branch angiitis, an inflammatory condition of unknown origin, is characterized by widespread periphlebitis with intraretinal hemorrhage in otherwise healthy patients. It is an acute condition and may be unilateral or bilateral. Fundus examinations reveal severe white sheathing of retinal vessels, resembling frosted tree branches. Although both arteries and veins may be involved, the venules tend to be more commonly affected. The inflammatory exudates around retinal vessels may be related to deposition of antigen-antibody complexes.^71,72 Anterior chamber and vitreous inflammation may be seen. On fluorescein angiography, there is late staining and dye leakage with no evidence of stasis or occlusions.²¹ Frosted branch angiitis has also been reported in patents with cytomegalovirus retinitis (Fig. 8).⁷³

IDIOPATHIC RETINAL VASCULITIS, ANEURYSMS, AND NEURORETINITIS

Idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome usually affects young, healthy persons and has a slight female predominance.⁷⁴ There are no systemic abnormalities. Retinal findings include dilatation of the retinal and optic nerve head arterioles, vasculitis, neuroretinitis, and extensive peripheral capillary nonperfusion. Retinal neovascularization, optic nerve head swelling, and anterior uveitis can occur. Systemic corticosteroids have little effect on the progression of the disease.⁷⁴

Birdshot retinochoroidopathy is a bilateral intraocular inflammation affecting patients in the fifth to eight decades of life, with a slight female predilection. The most common complaints include floaters, progressive loss of vision, photopsias, and nyctalopia. The characteristic fundus findings are multiple depigmented or cream-colored lesions at the level of the retinal pigment epithelium and choroid.

Retinal vascular abnormalities commonly seen in birdshot retinochoroidopathy include narrowing of retinal arterioles, sheathing of retinal vessels, vascular tortuosity, focal dilatation, and retinal neovascularization.⁷⁵ Veins are more frequently involved than arteries. Retinal vascular leakage, papillitis, and cystoid macular edema may be seen on fluorescein angiography.⁷⁶

RADIATION RETINOPATHY

Radiation damage to small retinal blood vessels may result in cotton-wool spots, retinal hemorrhages, microaneurysms, hard exudates, telangiectases, perivascular sheathing, and capillary nonperfusion. Vitreous cells are rare. Radiation retinopathy usually occurs several years after radiation is administered. Although direct effect on the vascular endothelium is thought to be the primary pathogenic mechanism, there is evidence for immune complex-mediated interactions.⁷⁷

Systemic lupus erythematosus is characterized by autoantibody formation and small vessel occlusions. Ocular manifestations occur in approximately 15% of SLE patients, with retinal vasculitis reported in 5% of these patients.⁷⁸ The retinopathy of SLE is primarily a diffuse arteriolar occlusive vasculitis,^79,80 and there may be microangiopathy with cotton-wool spots and intraretinal hemorrhage (Fig. 9).⁸¹ Patients with only cotton-wool spots have a favorable prognosis.⁸² However, vaso-occlusive retinopathy carries a more severe prognosis, with about 50% of patients eventually becoming legally blind.⁸³

Retinal manifestations of SLE may also include capillary nonperfusion, venous stasis, papilledema, and retinal edema. Occasionally, periphlebitis, perivenous sheathing, and branch or central vein occlusion are also found. Fluorescein angiography may show focal leakage from capillaries and arterioles, optic disc leakage, large vessel obstruction, delayed venous filling, microaneurysms, capillary nonperfusion, and neovascularization.

Involvement of the central nervous system was reported in 73% of patients with severe lupus retinopathy.⁸³ A lupus-like syndrome of multiple branch retinal artery occlusions and neurologic disturbances affecting young women has been described.⁸⁴ Although these patients do not fulfill the criteria for SLE, their disease suggests immune complex-mediated vasculitis similar to SLE. Patients with idiopathic retinal vasculitis may have positive blood tests for anti-phospholipid antibodies, lupus anticoagulant, and anti-nuclear antibodies without having definitive SLE.

Autoimmune mechanisms are believed to be the cause of SLE retinopathy.⁸¹ SLE patients with elevated anti-phospholipid antibodies have a higher risk of developing occlusive retinal vascular disease,⁸⁵ and immune complexes have been found in the walls of retinal and choroidal vessels.^27,86

RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a chronic systemic disease with symmetric inflammation of small joints, rheumatoid nodules, and a positive test for serum rheumatoid factor. Systemic vasculitis involving small to medium-sized vessels can occur.⁸⁷ Retinal vasculitis was found on fluorescein angiography in 18% of patients with definite or classic rheumatoid arthritis, even if there was no clinical or ophthalmoscopic evidence of retinal vessel inflammation.⁸⁸ Retinal vasculitis tends to occur during active phases of rheumatoid arthritis, as shown by a positive C-reactive protein test and an elevated erythrocyte sedimentation rate (Fig. 10).^87,88

OTHER CONNECTIVE TISSUE DISEASES

Dermatomyositis and relapsing polychondritis have been associated with an ischemic retinopathy that resembles lupus.^89,90 Retinopathy associated with dermatomyositis is rare and usually resolves without residual complications. Retinal findings may include cotton-wool spots, intraretinal hemorrhages, and macular edema, suggestive of an occlusive vasculitis process.⁹¹ Profound visual loss is caused by macular hemorrhage or edema, which produces central scotomas. Relapsing polychondritis is a rare connective tissue disease with inflammation of the auricular, nasal, and laryngotracheal cartilage.⁹² Ocular findings include episcleritis, scleritis, proptosis, corneal infiltrates, iridocyclitis, optic neuritis, ischemic optic neuropathy, exudative retinal detachment, chorioretinitis, cotton-wool spots, vascular occlusions, and retinal vasculitis.⁹⁰

SUSAC SYNDROME

Susac syndrome is an occlusive arteriolar disease characterized by infarcts in the retina, cochlea, and brain. Findings include recurrent multifocal branch retinal artery occlusions, sensorineural hearing loss, and neuropsychiatric abnormalities. A patient with scleroderma who developed all the features of Susac syndrome was recently reported (Fig. 11).⁹³

INFLAMMATORY BOWEL DISEASE

Systemic vasculitis is a part of the extraintestinal complications of Crohn's disease and ulcerative colitis. The vasculitis can affect the brain, skin, and lungs. The eye may be involved, although retinal vasculitis is rare. Previously reported retinal findings include venous sheathing with retinal edema, venous dilatation and tortuosity, and vessel attenuation with sheathing of the retinal arteries.^94–96 Fluorescein angiography shows diffuse venous leakage with areas of retinal ischemia. A possible pathogenic mechanism is inflammatory microvascular occlusion associated with the vasculitis.⁹⁴

SYSTEMIC NECROTIZING VASCULITIS

The systemic necrotizing vasculitides are distinguished by their clinical presentation, the size of vessels involved, and the type of cellular infiltrate (Table 1).

TABLE 1. Characteristics of Systemic Necrotizing Vasculitis

Wegener's Granulomatosis

Wegener's granulomatosis is a disease of unknown cause characterized by granulomatous inflammation and necrotizing vasculitis of the respiratory tract and kidneys.⁹⁷ Ocular manifestations occur in 30% to 60% of patients, with retinal vasculature involvement in 7% to 18% of patients.⁹⁸ The disease affects men more frequently than women, with a high percentage of patients being positive for the anti-neutrophilic cytoplasmic antibody.⁹⁹ This antibody has a high sensitivity and specificity, making it useful as a marker for disease activity.¹⁰⁰ Focal retinal infarctions, major vascular occlusions, disseminated retinitis, and severe posterior uveitis mimicking Eales' and Behçet's disease have been reported.⁹⁸ Bilateral cotton-wool spots have also been reported as an initial ocular manifestation; this finding has been interpreted as focal retinal inflammatory vasculitis.¹⁰¹ Histopathologic features include inflammation of small and medium-sized vessels, necrosis, and granuloma formation.²¹

Polyarteritis Nodosa

Polyarteritis nodosa is more common in males (3:1) and usually occurs in the second to fifth decade of life. It can affect any organ system except the lung. Ocular involvement is relatively uncommon, occurring in 10% to 20% of patients, and can present as a bilateral iritis, vitritis, and retinal vasculitis.¹⁰² Usually only the arteries are affected, with the adjacent veins occasionally involved by extension of the inflammation from the contiguously affected artery. Choroidal vasculitis is a more common manifestation of polyarteritis nodosa.^102,103 Papilledema or papillitis may occur due to optic nerve vascular involvement.²¹ Fluorescein angiography may show delayed choroidal filling, staining of the involved arterial segments, or thrombosis of the retinal veins.¹⁰²

Churg-Strauss Syndrome

Churg-Strauss syndrome (allergic granulomatous angiitis) is a progressive multisystemic necrotizing vasculitis that primarily affects the lungs. Its salient features include a history of bronchial asthma, hypereosinophilia, and cardiac and peripheral nervous system involvement.^104,105 Ocular manifestations, although uncommon, include conjunctival granulomas, marginal corneal ulceration, cranial nerve palsies, retinal emboli, and optic disc vasculitis.¹⁰⁶ The necrotizing vasculitis affects small arteries and veins, and eosinophils are the predominant inflammatory cell.¹⁰⁷ The vascular lesions may involve the central or branch retinal arteries, the choroidal plexus, or the posterior ciliary arteries, causing anterior ischemic optic neuropathy and scattered areas of retinal infarction.^108,109

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is a lymphoproliferative disorder predominantly affecting the lungs. It is distinguished histopathologically from Wegener's granulomatosis by its angiodestructive infiltration by lymphocytes, plasmacytoid cells, histiocytes, and atypical reticuloendothelial cells. Peripheral retinal vasculitis of arterioles and venules, vascular occlusions, diffuse vascular sheathing in the posterior pole, and pallid disc edema have been reported.^98,110,111 One study suggested that Epstein-Barr virus may play a role in the evolution of angiocentric immunoproliferative disorders such as lymphomatoid granulomatosis into malignant lymphoma.¹¹²

Giant Cell Arteritis

Giant cell arteritis is a segmental vasculitis usually affecting elderly patients. It is a granulomatous panarteritis that may involve large and medium-sized arteries in almost any organ system in the body.¹¹³ The most commonly affected vessels are the superficial temporal, vertebral, ophthalmic, and posterior ciliary arteries. Ischemic retinal changes result primarily from damage to large extraocular vessels and not from direct retinal vascular involvement. Anterior ischemic optic neuropathy is the most common cause of visual loss in patients with giant cell arteritis.¹¹⁴ Inflammation or thrombosis of the ophthalmic artery or central retinal artery may reduce the blood flow in retinal arterioles and may lead to the development of branch retinal artery occlusion.¹¹⁴ Cotton-wool spots have also been reported as an early ophthalmoscopic finding.¹¹⁵

Takayasu's Disease

Takayasu's disease is a life-threatening, idiopathic, large vessel vasculitis involving the aorta and its major branches.¹¹³ It usually occurs in young women. Ocular changes have been reported in 60% to 67% of patients.^116,117 Retinal findings, depending on the stage of the disease, can include dilated and tortuous vessels, microaneurysms, arteriovenous anastomosis, and vitreous hemorrhage with proliferative retinopathy that can mimic severe diabetic retinopathy.¹¹⁸

Drug-Induced Vasculitis

Drug-induced vasculitis represents a diverse group of systemic conditions that predominantly involve small vessels (usually venules) and have a recognizable precipitating event. It usually occurs 7 to 10 days after exposure, but it can also occur months after initial drug use, or even after the drug has been withdrawn.¹¹⁹ There is evidence to suggest that it is mediated by immune complex deposition. Fundus findings can include retinal and macular edema, disc hyperemia, venous congestion, vascular sheathing, and retinal hemorrhages. Fluorescein angiography may show delayed filling of the veins in the affected retina, with late staining.¹¹⁹ Drugs reported to cause retinal vasculitis include methamphetamines,^120,121 hormones for infertility and contraception,¹¹⁹ and procainamide, which induces a lupus-like syndrome.¹²²

Leukocytoclastic Vasculitis

Leukocytoclastic vasculitis is an entity most commonly associated with connective tissue diseases and usually affects postcapillary venules less than 0.1 mm in diameter.¹²³ Typical histopathologic features include vessel wall inflammation, swelling of the endothelial cells, necrosis and fibrin in the wall, and nuclear dusting or fragmentation of neutrophils (leukocytoclasis) within the vessel wall. Frequently, purpura and urticaria occur. Ocular involvement is rare, and reported ocular manifestations include anterior uveitis, corneal ulceration, chemosis, and subconjunctival hemorrhage.^124–126 A case of bilateral panuveitis associated with multifocal retinitis and vasculitis has been reported.¹²³ Fluorescein angiography in this patient demonstrated staining of the vessel walls in the posterior pole (Fig. 12).

SARCOIDOSIS

Ocular involvement in systemic sarcoidosis has been reported in 25% to 54% of patients and is bilateral in more than 70% of cases.^127–130 Anterior uveitis is the most common ocular manifestation, occurring in about two thirds of patients.¹³¹ Inflammation of the posterior segment is less common and occurs in 6% to 33% of patients with sarcoidosis.^127,132,133 Posterior segment changes include chorioretinal granulomas, chorioretinitis, retinal periphlebitis, macular edema, optic nerve edema, optic nerve granulomas, vitreous cellular infiltration (string of pearls and snowballs), and new vessel formation, either on the optic disc or elsewhere in the retina, as well as in the subretinal space.¹³⁴

Periphlebitis is the most common retinal finding in sarcoidosis, with an incidence of 45% to 73%.^135,136 Segmental sheathing or cuffing of venules is common, and periarterial sheathing is rarely observed.¹³⁰ Although less common, the central retinal vein or one of its main tributaries may also become inflamed and subsequently occluded.^137,138 Branch retinal vein occlusion is usually caused by thrombosis of the vein at the site of arteriovenous crossing or obstruction of the lumen by a choroidal granuloma.^138–141 Obstruction of smaller peripheral venules may be associated with ischemia and neovascular membranes of the disc and peripheral retina.^134,142 Fluorescein angiography may reveal focal perivenous leakage, often with optic disc leakage.

“Candle wax drippings” is a term used to describe the yellow-white, waxy retinal exudates that appear along retinal veins in the inferior equatorial retina and occasionally in the posterior pole. These exudates have been reported in 20% to 36% of cases of sarcoid retinopathy.^135,136 Histopathologically, candle wax drippings and periphlebitis represent chorioretinal granulomas and perivascular accumulations of epithelioid cells and lymphocytes, respectively.¹⁴³ Thus, candle wax drippings may be correctly termed granulomatous periphlebitis (Fig. 13).

BEHÇET'S DISEASE

Behçet's disease is a multisystemic, episodic, inflammatory, occlusive arteriolar disease of unknown cause. The classic major criteria are aphthous stomatitis, aphthous genital ulcers, and hypopyon uveitis. Minor criteria include arthralgias, gastroenteritis, epididymitis, vascular occlusions, thrombophlebitis, and neuropsychiatric involvement. Ocular involvement is found in 70% to 85% and retinal lesions in up to 50% of patients.^144,145 In 20% of patients, ocular disease is one of the initial manifestations.¹⁴⁵ Retinal vasculitis is one of the criteria that can be used to make a diagnosis of complete Behçet's disease.

Commonly observed fundus lesions include hyperemia of the optic disc with blurring of the margins, macular edema, retinal edema, vascular sheathing (venous sheathing preceding arterial sheathing), retinal exudates, and retinal hemorrhage.¹⁴⁶ Massive whitish-yellow exudate may accumulate in the deeper retinal layers during acute episodes, while the overlying retina shows turbidity and edema.¹⁴⁶ Retinal atrophy commonly follows retinal exudate and hemorrhage. Optic atrophy is the second most common fundus finding after optic disc hyperemia.¹⁴⁶ After repeated attacks, vascular sheathing, central retinal artery or vein occlusion, retinal neovascularization, vitreous hemorrhage, and papilledema may develop. Silver-wired occluded vessels may be seen. In end-stage disease, retinal vessels may not be visible beyond the arcades, and a diffuse stippled retinal pigment epithelium pattern is present (Fig. 14).

Fluorescein angiography during an acute attack shows marked capillary dilatation and hyperpermeability, diffuse dye leakage from small venules with resultant tissue staining, and secondary localized occlusions in the form of acute thromboangiitis obliterans.¹⁴⁶ Leakage from larger vessels and the optic nerve head may be seen in the late stages of the disease.

The basic pathologic features are perivascular leukocytic infiltrates, endothelial cell proliferation with obliteration of the vascular lumen, thrombosis, and fibrinoid degeneration. It has been suggested that Behçet's disease is an immune-mediated occlusive vasculitis.¹⁴⁷ Functional endothelial alteration has also been considered as a pathogenic mechanism.²² Recently, a possible association between Behçet's disease and viral infection, notably chronic hepatitis C infection, has been reported.¹⁴⁸

MULTIPLE SCLEROSIS

Retinal periphlebitis has been observed in 8.5% to 44% of patients with multiple sclerosis.^149–151 Severe occlusive peripheral vasculitis resulting in peripheral retinal neovascularization has been reported.¹⁵²

Angiographically, dye leakage in the area of sheathing and late staining of the venous wall may be seen.¹⁵³ Focal leakage on fluorescein angiography correlating with venous cuffing usually resolves in 4 to 6 months; diffuse leakage with late staining has a slower course of resolution and is considered a clinical marker of previous acute venous changes.¹⁵³ Arteriolar involvement is uncommon.

An association between the breakdown of the blood-retinal barrier on fluorescein angiography and the breakdown of the blood-brain barrier on Gd-DTPA-enhanced magnetic resonance imaging of brain has been shown in several studies of patients with multiple sclerosis.¹⁵⁴ Retinal periphlebitis has been considered a basic initial lesion for plaque formation in the central nervous system.¹⁵⁴ Recently, human herpes virus-6 (HHV-6), a newly described beta-herpes virus that shares homology with cytomegalovirus, has been reported to be present in active plaques in the brain of patients with multiple sclerosis.^155,156

TABLE 2. Retinal Vascular Findings Associated With Infections

BACTERIAL ENDOPHTHALMITIS

Retinal periphlebitis has been described in early staphylococcal endophthalmitis and has been reproduced experimentally by intravitreal staphylococcal injections in monkeys.¹⁵⁷ Retinal periphlebitis was found in 26 of 28 human autopsy eyes with bacterial endophthalmitis.¹⁵⁸ Cotton-wool spots, retinal hemorrhages, and Roth spots (white-centered hemorrhages) were observed in septic patients without intraocular inflammation and may represent infectious embolization to the retinal circulation.^159,160

TUBERCULOUS PERIPHLEBITIS

Periphlebitis is considered the most common retinal manifestation of tuberculosis.¹⁶¹ It is usually associated with peripheral capillary closure that may lead to ischemia and new vessel formation.¹⁶² The diagnosis of tuberculosis-related retinal vasculitis is presumptive and can be controversial. It is usually based on the clinical picture with a positive tuberculin skin test.¹⁶³ The exclusion of other possible causes and a favorable response to antituberculosis medications support the diagnosis.¹⁶³

The pathogenesis of tuberculosis-related retinal vasculitis is still unclear, but two mechanisms have been suggested.^162,164 One mechanism involves an infectious process, wherein the tuberculous bacilli are directly responsible for the observed lesions. This mechanism seems probable when tubercles are present in the choroid. The alternative hypothesis suggests that hypersensitivity mechanisms are responsible for retinal vasculitis.^162,164 The relation of tuberculous periphlebitis and Eales' disease must be considered.

SYPHILITIC UVEITIS

Periphlebitis is mostly found in congenital syphilis and was the only vascular lesion in a case of acquired lues, mimicking a branch vein occlusion.165 Secondary syphilis can be accompanied by severe posterior uveitis. Retinal vasculitis usually accompanies syphilitic chorioretinitis.^166,167 The vitreous may show a dense haze, and gray exudates may be seen in the posterior pole, along retinal vessels, and around the optic nerve head. Syphilis can also present as a necrotizing retinitis with marked sheathing of arteries and veins.¹⁶⁸ Although uncommon, primary syphilitic vasculitis can occur, affecting both arteries and veins.¹⁶⁹ It is associated with retinal and preretinal hemorrhages and neovascularization.

RARE VIRAL INFECTIONS

Rare viral infections associated with retinal vasculitis include influenza, infectious mononucleosis, and Rift Valley fever, which is an arthropod-borne viral infection of sheep and cattle that is spread by an insect bite. Macular retinitis and vascular occlusions secondary to proliferation of viral particles in vascular endothelial cells have been reported.¹⁷⁰

TOXOPLASMOSIS

Ocular toxoplasmosis typically causes a necrotizing retinitis with a reactive choroiditis. There may also be periphlebitis with or without venous obstruction, arteritis and arteriolar occlusions, retinal hemorrhages, and Roth spots.^171–173 Yellow refractile deposits (segmental periarteritis) along the arteries in the posterior pole have been described.^30,31,174 These plaques are numerous during the active stage of chorioretinitis and resolve as the inflammation subsides. The plaques do not obstruct blood flow and are on the outside of vessels. Diffuse perivenous sheathing has been observed in the vicinity of, as well as distant from, the chorioretinitis.

UNCOMMON PARASITIC INFECTIONS

Rickettsia, the causative agent of Rocky Mountain spotted fever, are obligate intracellular parasites with a preference for vascular endothelium.¹⁷⁵ They primarily affect small arterioles, causing vessel wall necrosis, thrombosis, and hemorrhage. Ophthalmoscopic features of rickettsial infection include artery and vein occlusions with a clinical picture similar to Eales' disease.

Babesiosis is a rare tickborne intraerythrocytic parasitic disease similar to malaria. It is characterized by fever, lymphadenopathy, arthralgias, and hemolytic anemia. Splenectomized patients, elderly persons, and immunocompromised and HIV-infected patients are especially predisposed to infection with babesiosis.¹⁷⁶ A case of babesiosis mimicking lupus retinopathy has been reported.¹⁷⁷ It is believed that the cotton-wool spots observed were caused by immune complex-mediated retinal arteriolitis.

Hemorrhagic vasculitis with perivascular eosinophilic and plasma cell infiltrates has been observed in experimental onchocerciasis.¹⁷⁸ Onchocerciasis-related eye disease is an important cause of blindness, especially in the forest-savanna mosaic areas of Nigeria.¹⁷⁹ The onchocercarial-induced lesions that are responsible for visual impairment and blindness are chorioretinitis and optic nerve disease.¹⁷⁹

Giardia lamblia, an intestinal parasite, has also been associated with iridocyclitis, vitritis, and patchy retinal arteritis.¹⁸⁰

ACQUIRED IMMUNE DEFICIENCY SYNDROME

Retinal microvasculopathy, the most common ocular manifestation of HIV infection, occurs in up to 70% of patients.¹⁸¹ The most common clinical presentation of retinal microvasculopathy is cotton-wool spots, reported in 26% to 53% of cases.¹⁸² Cotton-wool spots may be associated with other microvascular abnormalities, such as superficial or deep retinal hemorrhages, white-centered retinal hemorrhages (Roth spots), microaneurysms, and intraretinal microvascular abnormalities.

Retinal microvasculopathy occurs with increasing frequency as the CD4 T-cell count decreases. The cause and pathogenesis of the microvasculopathy are uncertain, but it is likely that either direct infection of vascular endothelial cells by HIV, immune complex deposition in retinal arterioles, or both, are involved.¹⁸² Endothelin-1, a cytokine with a potent vasoconstriction activity, has also been considered to play a role in its pathogenesis.¹⁸³ Coinfection with hepatitis C virus has also been proposed as a precipitating factor for the development of HIV microangiopathy.¹⁸⁴ Periphlebitis has been reported in a few patients with HIV infection.^185–187

TABLE 3. Diagnostic Evaluation of Retinal Vasculitis

  History
  Past illnesses
  Racial background; sarcoidosis, Beh<acc>et's disease
  Travel history: parasitic infestation
  Presence of pets: toxoplasmosis
  Conditions leading to immunosuppression: AIDS, viral retinitis
  Ocular Examination
  Anterior segment: cornea, anterior chamber
  Posterior segment
  Vitreous cells
  Retinal vascular sheathing
  Macular edema
  Chorioretinal inflammation
  Retinal hemorrhage, neovascularization, cotton-wool spots
  Laboratory Investigations
  Immunologic studies
  Autoantibodies (ANA, ANCA, anti-phospholipin, anti-monocyte cytoplasmic and anti-cardiolipin): SLE, Beh<acc>et's dermatomyositis, Wegener's granulomatosis, sarcoidosis
  VDRL or RPR, FTA-ABS or MHA-TP: syphilis
  ELISA test: toxocariasis
  Serologic tests: toxoplasmosis, Lyme disease
  HLA typing: Beh<acc>et's disease, birdshot retinochoroidopathy
  Skin testing
  PPD: tuberculosis
  Radiologic studies
  Chest film: tuberculosis, sarcoidosis
  Gallium scan: sarcoidosis
  Computed tomography (brain): multiple sclerosis, CNS lupus, CNS sarcoidosis
  Computed tomography (chest): sarcoidosis
  Magnetic resonance imaging (brain): multiple sclerosis, CNS lupus, CNS sarcoidosis
  Miscellaneous tests
  Cultures: viral, bacterial, fungal
  Stool examination for ova and parasites
  Agglutinins: Rickettsiae infection
  Angiotensin converting enzyme: sarcoidosis
  Serum lysozyme: sarcoidosis
  Vitreous fluorophotometry: intermediate uveitis
  Surgical investigations
  Aqueous analysis
  Vitreous analysis: intermediate uveitis, viral retinitis, tumor
  Polymerase chain reaction-based assays of aqueous and vitreous for infectious retinitis
  Cytopathologic and flow cytometric analysis of vitreous for intraocular lymphoma
  Interleukin-10 level in the vitreous for intraocular lymphoma
  Conjunctival biopsy: sarcoidosis
  Choroidal biopsy: intermediate uveitis, viral retinitis, tumor

Physical examination is important in diagnosing systemic conditions such as Behçet's disease and connective tissue disease. The location of retinal vasculitis (central vs peripheral), the predominant vessel involved (artery vs vein), and the specific ocular features (e.g., necrotizing retinitis, granulomatous uveitis, vitreal snowballs) may suggest a specific diagnostic category.

Viral, fungal, and blood cultures can be useful in the evaluation of immunosuppressed patients with retinal vasculitis. Immunologic studies such as autoantibody tests (anti-nuclear, anti-neutrophilic cytoplasmic, anti-monocyte cytoplasmic, and anti-cardiolipin antibodies), enzyme-linked immunosorbent assays (ELISA), VDRL and fluorescent treponemal antibody absorption tests, and HLA typing are important in diagnosing collagen vascular disease, Wegener's granulomatosis, ulcerative colitis, sarcoidosis, Crohn's disease, toxocariasis, syphilis, and Behçet's disease.^196,197

Polymerase chain reaction (PCR) of vitreous samples may be used to diagnose viral, bacterial, and fungal infection. PCR-based assays of aqueous and vitreous samples are specific and sensitive in the diagnostic evaluation of patients with infectious retinitis.^198,199 Vitreoretinal and sclerochorioretinal biopsies provide tissue for light and electron microscopic studies, immunohistochemical techniques, and tissue cultures in cases of viral retinitis, acute retinal necrosis, and disorders of unknown cause (e.g., birdshot retinochoroidopathy).¹⁸⁵ Agglutination tests have been used in rickettsial infections.

Radiologic studies such as chest films aid in the diagnosis of sarcoidosis and tuberculosis. Computed tomographic scanning and magnetic resonance imaging of the brain may detect cerebrovascular lesions in multiple sclerosis, neurosarcoid, and central nervous system lupus.

Interleukin-10 (IL-10) levels in the vitreous may also be obtained in patients suspected of having intraocular lymphoma, because they may correlate with clinical activity and the number of malignant cells.²⁰⁰ An IL-10 to interleukin-6 (IL-6) ratio greater than 1.0 in the vitreous or cerebrospinal fluid is a useful predictor of the presence of lymphoma cells, but an elevated ratio is not always associated with intraocular/central nervous system lymphoma.^201,202 Cytopathologic and flow cytometric analysis of vitreous cellular specimens is used in the diagnosis of intraocular lymphoma.²⁰³

Although corticosteroids reduce inflammation, the risks may outweigh the benefits if central vision is not threatened. In optic disc vasculitis (papillophlebitis), the disease tends to follow a benign course even if untreated.

There are several diseases in which steroids are either contraindicated (viral and fungal retinitis) or ineffective alone ( Behçet's disease, Wegener's granulomatosis, polyarteritis nodosa). Cytotoxic agents such as cyclophosphamide, chlorambucil, and azathioprine have been used with great success in the latter group. The use of cyclophosphamide combined with prednisone has been highly effective in up to 90% of patients with Wegener's granulomatosis.²⁰⁵ High-dose short-term chlorambucil treatment has been successful for intractable, sightthreatening uveitis, without the development of systemic malignancy.²⁰⁶ In one study, cyclosporin administration resulted in improvement in 15 of 16 patients with uveitis ( Behçet's disease, pars planitis, sarcoidosis, Vogt-Koyanagi-Harada syndrome, and birdshot retinochoroidopathy) resistant to both corticosteroids and cytotoxic agents.²⁰⁷ Renal toxicity is the major drawback to broader acceptance of this drug. FK 506 (tacrolimus) has also been used in refractory uveitis associated with Behçet's disease.²⁰⁸ Recently, interferon alpha has been used in patients with Behçet's disease, with lack of significant systemic and ocular side effects.^209–211

Infectious retinitis must be treated with the appropriate antibiotics. The addition of corticosteroids to temper inflammatory damage must be done cautiously.

Nonmedical therapy may be necessary in certain cases of retinal vasculitis. Laser photocoagulation is effective in the treatment of retinal neovascularization in many conditions, including Eales' disease, sarcoidosis, and SLE. Vitrectomy and scleral buckling may be done for persistent vitreous hemorrhage and retinal detachment caused by the retinal vascular inflammation.

Neovascularization can occur at the disc or in the periphery as a complication of retinal vasculitis. Because neovascularization can lead to devastating hemorrhages and tractional retinal detachments, neovascularization should not be neglected.⁴⁹ Inflammatory-induced neovascularization often responds to anti-inflammatory therapy such as high-dose oral corticosteroids, which should be the first-line therapy. If there is no regression of the neovascularization after 3 to 4 weeks of anti-inflammatory therapy, then laser therapy to the ischemic areas should be considered.

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