Retinal Vasculitis






Key concepts





  • Retinal vascular changes can be seen in many ocular inflammatory entities, some associated with systemic disease and others not.



  • Fluorescein angiography is very important to evaluate the full extent of the vascular disease.



  • Therapy for the ocular disease needs to be coordinated with those treating the systemic illness.



Retinal vascular involvement is a common occurrence in many cases of posterior and intermediate uveitis. The use of the term vasculitis is somewhat of a misnomer, because it suggests that the underlying mechanism leading to these alterations is a type III hypersensitivity reaction – that is, one of immune complexes. We simply do not know whether this is true. Indeed, the evidence available in experimental models, as well as from eyes that have been evaluated, suggests that this is not the case. The meager pathologic data available indicate that the most accurate term for these entities probably is perivasculitis and, in most cases, phlebitis. Although there are conditions in which the retinal vascular component is the predominant feature of the ocular disease, the ubiquitous nature of these retinal vascular alterations indicates that ‘retinal vasculitis’ can also be a clinical sign. Behçet’s disease is perhaps the sine qua non of retinal vasculitis (see Chapter 26 ); however, myriad disorders can have a similar presentation. It has been suggested that the retinal veins are involved in Behçet’s disease, tuberculosis, sarcoidosis, multiple sclerosis, pars planitis, Eales’ disease, and the ocular manifestations of human immunodeficiency virus (HIV). Arteriolar involvement is more common in systemic disorders with predominantly arterial involvement, such as polyarteritis nodosa and systemic lupus erythematosus (SLE). Lymphoma, albeit rare, should always be considered as a possible underlying cause of retinal vasculitis.




Clinical characteristics


Although this chapter deals with multiple mechanisms, patients with retinal vasculitis most often report a painless decrease in or marked loss of vision, which may at times be accompanied by floaters. There can also be large areas of scotomata relating to the areas of ischemia. If the retinal vascular changes are in the periphery of the fundus, then patients may report minimal symptoms or none at all, even in light of marked changes noted on ocular examination.


An examination of the retina shows striking vascular alterations, sometimes best seen with fluorescein angiography. Active vascular disease is characterized by sheathing of the vessels or, in some conditions, such as sarcoidosis, an immense inflammatory response around the vessels that has been described as ‘candle-wax drippings.’ Sheathing can skip along the length of a vessel. Although we can only presume what is occurring histologically, it is thought that a perivasculitis is underlying what we describe clinically as sheathing: large numbers of cells either leaving or entering the vessels. What is drawing them there? We do not know, and speculation abounds. It could be due to the expression of vascular endothelial antigens, to the presence of adhesion molecules, to simple passage of immune cells through the vessel wall to reach the retina and its uveitogenic antigens, or to a mixture of all of these.


Another characteristic of retinal vasculitis is the occlusive retinopathy that can be prominent in some patients. Large areas of capillary dropout are commonly seen. In many inflammatory conditions of the retina the capillary-free zone takes on a markedly jagged and enlarged appearance. Often, in addition to capillary dropout one sees vascular architectural alterations just temporal to the macula, sometimes manifesting as arteriolar/venular anastomoses and crossing of vessels over the horizontal raphe.


The involvement of primarily the retinal vasculature in an inflammatory disorder is rather commonly seen, the best example being Behçet’s disease, discussed in Chapter 26 . However, other well-recognized entities, such as birdshot retinochoroidopathy (see Chapter 25 ) and sarcoidosis (see Chapter 22 ), as well as infectious processes, have or can have marked involvement of the retinal vasculature, although we frequently do not think of these diseases in that sense. Indeed, the entities with a significant retinal vasculature component are listed in Box 27-1 . It is important to note that noninflammatory conditions can also lead to what appears to be a retinal vasculitis. Venous obstruction, Coats’ disease, and diabetes mellitus can mimic the changes seen in an inflammation-driven process.



Box 27-1

Disorders with retinal vasculitis as a common finding

Reproduced with permission from Samuel, M.A., et al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology 2007;114(8): pp. 1526–1529.





  • SYSTEMIC DISORDERS



  • Behçet’s disease



  • Sarcoidosis



  • Systemic lupus erythematosus



  • Postvaccination



  • Multiple sclerosis



  • Wegener’s granulomatosis



  • Takayasu’s disease



  • Buerger’s disease



  • Polyarteritis nodosa



  • Polymyositis



  • Dermatomyositis



  • Whipple’s disease



  • Crohn’s disease



  • Sjögren’s A antigen



  • Kikuchi–Fujimoto disease



  • Susac’s syndrome



  • INFECTIOUS DISORDERS



  • Syphilis



  • Cat scratch fever



  • Hepatitis C



  • Chickenpox



  • Toxoplasmosis



  • Toxocariasis



  • Coccidiomycosis



  • Tuberculosis



  • Cytomegalovirus infection



  • Herpes simplex



  • Herpes zoster



  • Rift Valley fever virus



  • West Nile virus



  • Acute retinal necrosis



  • Candidiasis



  • Leptospirosis



  • Rickettsia



  • Mediterranean spotted fever



  • Brucellosis



  • Amebiasis



  • Mononucleosis



  • Lyme disease



  • Hepatitis B



  • OCULAR DISORDERS



  • Birdshot retinochoroidopathy



  • Pars planitis



  • Eales’ disease



  • Choroiditis



  • Retinal arteritis and aneurysms



  • Behçet’s retina sine systemic disease



  • Vein occlusion



  • NEOPLASMS



  • Paraneoplastic syndromes



  • Ocular and systemic lymphoma



  • Acute leukemia




Although a systemic evaluation for the patient with ocular vasculitis being seen for the first time makes sense, the reader should be aware of our experience. We reviewed our evaluation of 25 patients with ‘primary’ ocular vasculitis. Only one had a history suggestive of systemic disease (lupus erythematosus). False-positive diagnostic test results were obtained in five of 24 (20.8%) of these patients. No underlying disease was found in any of these patients at review some 4 years later.




Ocular vasculitic disorders without systemic disease


We have seen patients with ocular findings that are indistinguishable from those in patients with Behçet’s disease. These patients have none of the typical systemic findings but yet will have recurrent episodes of retinal vasculitis. In addition, some of these persons show HLA-B51 positivity. The possibility that they may develop Behçet’s disease certainly exists. However, on a statistical basis one would expect other features of the disorder to develop within 3 years of the appearance of the first criteria, and this has not been the case. The recurrent episodes of retinal vasculitis (and retinitis) are frequently difficult to control and may require the use of other immunosuppressive agents in addition to prednisone. Lueck and coworkers reported the case of a patient with recurrent steroid-sensitive uveitis and central nervous system (CNS) disease thought to be due to sarcoidosis. Postmortem examination revealed a histologic picture compatible with that for Behçet’s disease, despite the patient’s lack of any of the systemic stigmata associated with this diagnosis. The authors have called this entity the Behçet’s MINUS syndrome (multifocal intermittent neurologic and uveitic syndrome).


We have seen other patients with severe retinal vasculitis that appears to be unassociated with systemic disease; often attempts to identify an underlying abnormality (e.g., immune complexes or sedimentation rate) prove fruitless. The disorder frequently may continue despite aggressive immunotherapy ( Fig. 27-1 ).




Figure 27-1.


This 17-year-old Hispanic woman complained of decreased vision. She was found to have a retinal vasculitis in both eyes. A, Montage and fundus findings. Note the peripheral retinal capillary loss. Laser photocoagulation had been started in the periphery of the OS before referral to the NEI. B, OCT of both eyes showing macular edema and subretinal fluid. An extensive evaluation revealed no systemic abnormality. She was stabilized on prednisone and ciclosporin in the short term.


Eales’ disease


Although Eales’ disease had been discussed by others, the disorder carries the name of Henry Eales who, in 1880, described five young men with recurring vitreal and retinal hemorrhages associated with constipation and epistaxis. The definition of the condition has varied considerably over the years. Our group defines Eales’ disease as an idiopathic condition that manifests as an obliterative perivasculitis (particularly involving the venule side) affecting the retina in multiple quadrants, starting at or anterior to the equator and progressing posteriorly. The disease sometimes is accompanied by neovascularization, without vitritis, obvious uveal inflammation, or obvious systemic disease. It is in essence a diagnosis of exclusion and probably includes a heterogeneous patient population. There is a strong association with purified protein derivative skin test positivity, and Moura and colleagues reported that strongly positive Mantoux test results were found in 87% of 141 patients. Biswas and colleagues published two papers further evaluating the relationship between tuberculosis and Eales’ disease in India. In one study, polymerase chain reaction (PCR) was performed on 12 vitrectomy specimens from patients with Eales’ disease and on 45 specimens from patients without Eales’ disease. This methodology had the sensitivity to detect 2.5 pg of Mycobacterium tuberculosis . Five of the 12 specimens (41.6%) from the patients with Eales’ disease versus one of 45 specimens (2.2%) from the patients without Eales disease were positive for M. tuberculosis . In their second study 11 of 23 epiretinal membranes (47.8%) versus three of 27 control epiretinal membranes (11.1%) (p = 0.001) were positive for the M. tuberculosis genome. In another study from India, Therese and coworkers, using PCR, reported finding M. fortuitum and M. chelonae in vitrectomy specimens, thereby suggesting that other mycobacteria could initiate similar immune responses. The disease has been estimated to affect 1% of adult males in India and usually occurs in patients under 40 years of age. The process has minimal inflammation associated with it.


The disorder may start with retinal edema, followed by a progressive cuffing of the venules (periphlebitis), and then by peripheral retinal vascular nonperfusion and retinal neovascularization. The condition affects the retinal periphery, but on occasion it can begin at the optic nerve head, mimicking a vein occlusion. Only with the more characteristic peripheral retinal signs will the diagnosis become clear. The arteries are not involved. Unlike occlusions that result from arteriosclerotic plaques, this occlusion does not usually occur at an arteriovenous crossing. The periphlebitis may occlude substantial portions of a vein, but in an irregular fashion. Unlike vein occlusions in the posterior pole, those in the periphery will not cause cottonwool spots. The development of neovascularization may be rapid. Fluorescein angiographic examination of the retinal vasculature may show nonperfusion, arteriovenous shunting, and neovascularization ( Fig. 27-2 ). Recurrent vitreous hemorrhage, with ensuing vitreous contraction and retinal detachment, is a serious risk in this disorder. Although the disease is thought to be an ocular disorder, Biswas and associates reported three patients with seizures and/or migraine. An MRI scan in two patients showed a putaminal infarct with white matter edema.




Figure 27-2.


A and B, Peripheral retinal vasoocclusive disease with neovascularization due to Eales’ disease.

(Courtesy of R. Murphy, MD.)


Although the disease may proceed with its full-blown clinical picture as described, in some patients the process may spontaneously reverse itself. The visual prognosis in these patients is not totally hopeless. Elliot reported that 25 of 46 eyes he followed for an average of 6 years had a visual acuity of 20/50 or better, whereas 26% had a vision of 20/200 or worse. The exact role of the immune system remains unclear. However, Murugeswari et al. have shown a correlation between VEGF and IL-6 levels in the vitreous specimens of Eales’ disease patients, with IL-8 and MCP-1 also being elevated compared to controls. This would suggest that at least locally active inflammatory factors are being produced. Part of the definition calls for minimal or no evidence of inflammatory disease. Muthukkaruppan and associates found circulating immune complexes in these patients. Rennie and associates have also noted vestibuloauditory problems associated with the ocular condition, suggesting that this is indeed a systemic ailment. The notion that the disease is due to tuberculosis hypersensitivity is difficult to support because it does not seem to be found in greater numbers of patients in countries in which the population is actively immunized with bacille Calmette–Guérin vaccine. It may be that mycobacterial antigens are particularly good initiators of a still-undefined disease mechanism, but that other antigens are probably capable of producing the same effect. Alternatively a specific genetically determined immune background may put some patients at higher risk for development of the disease.


For patients with capillary dropout and neovascularization, laser ablation could be contemplated. Vitrectomy certainly plays a role in the management of patients who have recurrent vitreous hemorrhages. Dehghan et al. observed that in their study of 67 eyes, vitrectomy and laser photocoagulation resulted in improved visual acuity and regression of neovascularization. Most other observers will consider other therapy. Some have resorted to systemic immunosuppression, including methotrexate, observing an improvement in visual acuity. Others have used intravitreal injections of steroid. Ishaq et al. saw reduction of leakage, but their follow-up was short, whereas Agrawal et al. saw a reduction in inflammatory activity in the eye in two cases, one of which recurred ( Fig. 27-3 ). Others have reported the use of anti-VEGF thearpies. Akova et al. reported regression and no recurrence of disease after 12 months in a patient whose disorder was not responsive to panretinal photocoagulation and who received 1.25 mg of bevacizumab intravitreally. Kumar and Sinha reported a similarly positive result in a patient they treated. The evaluation of these therapies is made very difficult by the natural history of the disease, which suggests that it may regress by itself. Moreover, it appears that many approaches may be valuable, but the difficulty is choosing the best one for your patient.




Figure 27-3.


Fundus photographs of eye with Eales’ disease. A, Before intravitreal steroid therapy and B, 8 weeks after the injection.

(Reproduced with permission from Ishaq, M, et al. Intravitreal steroids may facilitate treatment of Eales’ disease (idiopathic retinal vasculitis): an interventional case series. Eye. 2007;21(11): 1403–1405.)


Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN syndrome)


A rare condition with multiple saccular and fusiform aneurysms involving the larger arterioles, combined with peripheral vascular nonperfusion and uveitis, has been reported. , The degree of nonperfusion can be quite profound ( Fig. 27-4 ). A neuroretinitis, as well as retinal neovascularization, optic nerve head swelling, and anterior uveitis, can be associated with this disorder, which occurs in younger persons. The underlying nature of the disorder remains in doubt. It is interesting that the disease appears quite dynamic, with the aneurysms reported to regress and appear elsewhere sometimes quite rapidly. , It is not clear whether immunosuppressive agents are beneficial for this condition. Some suggest it may be a matter of dose, as Ishikawa and colleagues reported the case of a 15-year-old whose ocular disease did not respond to oral steroid, but did respond with 500 mg of intravenously administered prednisolone. This may reflect that the disease is at the level of the retinal vasculature rather than the immune system. Jampol and colleagues reported a patient with occlusive retinal arteriolitis with neovascularization. Although the disease course in the 34-year-old white woman had some similarities to the entity just described, no aneurysms were noted. The disease has been seen in a pregant woman in a hypercoaguable state, and peripheral venule and arteriolar occlusions have been noted, again suggesting the local, vascular element to the disorder. Laser photocoagulation has been shown to have a benefit in only a relatively small number of patients. Abu El-Asrar and colleagues reported regression of IRVAN aneurysms in a patient with allergic fundal sinusitis, and Tomita and coworkers reported that the regression remained long after photocoagulation of the nonperfused areas of retina. Samuel et al. reviewed 44 eyes with this condition and offer a scoring system for the disease ( Box 27-2 ). They conclude that retinal laser photocoagulation should be performed as early as possible if there are areas of widespread retinal nonperfusion.




Figure 27-4.


A to C, A patient with retinal aneurysms and arteritis. Note extensive exudate and hemorrhage, sheathing of vessels, and macroaneurysms. Extensive capillary dropout was seen just beyond these areas of exudate.


Box 27-2

Ocular findings in IRVAN

From: Samuel MA, et al. Idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (IRVAN): new observations and a proposed staging system. Ophthalmology 2007; 114(8): 1526–1529.


Stage findings



  • 1

    Macroaneurysms, exudation, neuroretinitis, retinal vasculitis


  • 2

    Capillary nonperfusion (angiographic evidence)


  • 3

    Posterior segment neovascularization of disc or elsewhere and/or vitreous hemorrhage


  • 4

    Anterior segment neovascularization (rubeosis iridis)


  • 5

    Neovascular glaucoma




Frosted branch angiitis


Frosted branch angiitis has been described by Walker et al. as ‘florid translucent retinal perivascular sheathing.’ It was first reported in a 6-year-old boy with vessels resembling frosted branches, and is generally found in younger individuals. The disorder usually results in a severe drop in visual acuity, at least during the acute period. Although both arteries and veins may be involved, the venules tend to be more commonly affected ( Fig. 27-5 ). About three-quarters of reported cases have been bilateral; it has no gender preference, and more than 65–70% of patients have been reported to have retinal edema and an intermediate uveitis. One case reported macular choroidal neovascularization associated with the disorder. This is an ocular sign and can have many causes, some of which are infectious. It has been reported to occur before and after the appearance of ocular toxoplasmosis, , and after influenza A exposure, but it can be idiopathic with no obvious systemic cause. One can speculate that it is an extreme example of a diffuse perivasculitis. The ‘frosting’ around the vessels could be in fact thousands (millions?) of cells that are moving through the vascular wall into the retina.




Figure 27-5.


Fundus of a young boy with idiopathic frosted branch angiitis. Yannuzzi has suggested that angiitis is seen in children, whereas periphlebitis generally is noted in young adults.

(Courtesy of L. A. Yannuzzi, MD.)


The condition will disappear with proper and aggressive therapy, but of course the key is choosing the ‘proper’ therapy. Frosted branch angiitis has been associated with ocular cytomegalovirus in patients with AIDS. Resolution of the findings in adults is seen with aggressive anticytomegalovirus (CMV) therapy. In an HIV-positive child we saw, the angiitis persisted even after therapy with intravenous ganciclovir and foscarnet and resolution of the antigenemia. This suggested that even in the context of HIV infection, CMV is not the sole cause of this ocular finding. Other infectious conditions in which this sign has developed include tuberculosis, syphilis, and herpes simplex type 2 virus infection. Others have found it to be associated with aseptic meningitis, lymphoma, leukemia, sarcoidosis, multiple sclerosis, pars planitis, and SLE. Masuda and coworkers reported a patient with frosted branch angiitis with yellow-white placoid lesions, with an evaluation suggesting an occlusion of the choriocapillaris. Borkowski and Jampol reported retinal and disk neovascularization in a patient with bilateral frosted branch angiitis who also had peripheral retinal ischemia. Retinal neovascularization was noted by Kleiner and colleagues after multiple branch vein occlusions. Borkowski and Jampol’s patient was treated with steroids and photocoagulation, with a good outcome. Responsiveness of this disorder to steroid therapy was also reported by Sykes and Horton in a patient who also had Crohn’s disease.


Scleritis


Although scleritis certainly is not a disease of the retinal vasculature, it seems important to discuss it and how it may relate to intraocular inflammatory disease. The vasculature near the scleritis appears to be integrally involved in the inflammatory/pathologic process, with medial necrosis, perivasculitis, or thrombosis often seen. , The inflammatory reaction associated with anterior scleritis can spill over into the eye, leading to anterior or even intermediate uveitis. Posterior scleritis is an entity that is frequently not included in the differential diagnosis of posterior pole lesions ( Fig. 27-6 ). This disorder may not be associated with anterior segment changes. Patients frequently report ocular pain, although the eye does not appear inflamed. At times the conjunctiva may be slightly boggy. There may be a mild vitreous inflammatory response associated with a drop in visual acuity. Careful examination of the posterior segment may reveal choroidal folds or even a thickening of the retina, although these processes are often subtle and difficult to determine. Ultrasound examination of the globe is a very useful tool to help in the diagnosis. In many patients the disease responds to corticosteroid therapy, although relapse may occur once the dosage is reduced.




Figure 27-6.


Although not retinal vasculitis, posterior scleritis should be considered in patients with poor vision, pain, uveitis, and striae of choroid.

(Courtesy of David Cogan, MD.)


A note of caution is warranted. Although most cases of posterior scleritis are not associated with a systemic disorder, it is fitting to consider this caveat. The ophthalmologist always needs to be aware of the fact that this entity can manifest as a systemic disorder, and a careful rheumatologic evaluation seems warranted for most patients (see Chapter 20 ).




Ocular vasculitic disorders with systemic disease


Perhaps the most common systemic entities that we see with a marked vascular component are sarcoidosis ( Fig. 27-7 ), Behçet’s disease, and multiple sclerosis. Although sarcoidosis is usually not thought of as the basis for a retinal vasculitis, it can cause myriad ocular manifestations, including severe involvement of the retinal vasculature (see Chapter 22 ). Multiple sclerosis was first associated with ocular inflammatory disease at the turn of the 20th century. In an early article, Rucker suggested that perhaps 20% of patients with multiple sclerosis may have retinal sheathing (i.e., vasculitis); others, such as Breger and Leopold, have reported this finding in an even higher percentage of patients (14 of 52, 27%). In our experience, it would seem that generally less than 5–8% of these patients have this complication.




Figure 27-7.


A 50-year-old African-American woman with sarcoidosis and marked pulmonary involvement who presented with a bilateral retinal vasculitis. The fundus picture of the left eye shows multiple retinal hemorrhages.


Apart from the more common ocular entities, retinal vasculitis can be associated with several systemic entities, many of which are among the collagen-vascular group of disorders. A key point to consider in making these diagnoses is that usually the patient’s complaints are associated with a subacute chronic disorder. The findings include malaise, weight loss, arthritis, fever, and rash. An important finding is mononeuritis multiplex. This is an acute neuropathy that begins at one named nerve root and then progresses to one or more other nerve roots, one at a time. It more commonly affects the nerve roots of the lower extremities and can have an abrupt painful onset, with the patient reporting deep muscle pain. It is a common presenting sign in polyarteritis nodosa and occurs in a significant number of patients with SLE and rheumatoid arthritis later in the course of their disease. The ophthalmologist should be aware that other disorders can cause mononeuritis multiplex, including diabetes, paraneoplastic syndromes, and even jellyfish stings. ,


Some of the diseases that need to be considered in the search for a systemic cause for retinal vasculitis include those discussed in the following sections.


Systemic lupus erythematosus


SLE is a common systemic disorder that is diagnosed by use of a combination of clinical and laboratory criteria. A more mild form of the ocular disease may have a microangiopathy in which vasoocclusion and vasculitis are less common. Retinal vasculitis can rarely be the presenting finding. Histology of such eyes has shown capillary lumen obliteration and the deposition of IgG. Thought to be the classic immune complex disorder, it affects the eye with severe intraocular complications in a relatively small number of patients. However, when it does, it can be extremely problematic because it is sometimes difficult to provide adequate therapy. Jabs and coworkers reported on 11 patients with severe retinal vasoocclusive disease and poor visual outcome often associated with CNS involvement in SLE ( Figs 27-8 , 27-9 , 27-10 ). Antiphospholipid antibodies are associated with the vasoocculusive ocular disease, leading, it is thought, to microthrombi. Therefore, anticoagulation must be considered in preventing further thrombosis. Proliferative retinopathy can be a serious problem as well. It should be mentioned that antiphospholipid antibodies may cross-react with cardiolipin, which is used in some syphilis testing. This condition raises the intellectually interesting but also practically important question as to whether therapy should consist of laser photocoagulation or systemic immunotherapy to stop the underlying inflammatory process that presumably induces the retinal vascular alterations. Although aggressive systemic immunosuppression therapy is often needed, plasmapharesis has been used acutely in conjunction with immunosuppression to reverse the ocular pathology.




Figure 27-8.


Systemic lupus erythematosus. A, Fundus shows multiple cottonwool spots, arterial occlusion, vascular sheathing, and intraretinal hemorrhage. B, Extensive nonperfusion, with staining of retinal vessels walls.

(Courtesy of DA Jabs, MD; from Jabs DA, Fine SL, Hochberg MC et al. Severe retinal vaso-occlusive disease in systemic lupus erythematosus. Arch Ophthalmol 1986; 104: 558–563.



Figure 27-9.


Fundus of a young woman with difficult-to-control systemic lupus erythematosus. Extensive nerve fiber infarcts and hemorrhage create a dramatic picture, with maintenance of good visual acuity. Retinopathy resolved after disease was controlled.



Figure 27-10.


This 15-year-old African-American girl presented with a decrease in vision and systemic symptoms compatible with SLE. A, The fundus as it appeared at the initial examination at the NEI. Note the retinal hemorrhages and remarkable degree of loss of vasculature seen on the angiogram. B, One year later, after systemic immunosuppressive therapy and laser. The patient has retained good central vision but the optic nerve changes remain disquieting.




Polyarteritis nodosa


Polyarteritis nodosa was first described by Kussmaul and Maier in 1866. It is a necrotizing vasculitis that involves the medium-sized muscular arteries and smaller arterioles. It can present as a bilateral iritis, vitreitis, and retinal vasculitis involving both the veins and arteries, which can very aggressive in nature, , with one case reported manifesting a central retinal artery occlusion as well. It has been estimated that up to 20% of these patients may have ocular involvement. Mononeuritis multiplex, an acute neuropathy described earlier, has been estimated to develop in two-thirds of patients with polyarteritis nodosa. The most common sites are in the lower extremities. This is a potentially fatal disorder: 5-year survival is 13% if the patient is untreated, versus 80% in those who are treated. Current therapy usually consists of corticosteroids and cyclophosphamide.


Wegener’s granulomatosis


Wegener’s granulomatosis is characterized by a necrotizing granulomatous vasculitis of the upper and lower respiratory tract, systemic small vessel vasculitis that can involve multiple organs, and a focal necrotizing glomerulonephritis. Ocular complications, including uveitis, scleritis, and retinal vasculitis, can occur in 16% of patients. , One must remember that, except for mild anterior segment disease, the eye disease does not respond to topical medications, and that the systemic therapy usually indicated for the disease needs to be employed. It is also important to remember that the cytoplasmic antineutrophil antibody (ANCA) test is highly specific for this disease. Soukasian and coworkers reported that the ANCA test result was positive in seven patients with scleritis due to Wegener’s granulomatosis but negative in 54 patients with ocular inflammatory disease due to other causes. Others have reported the usefulness of this test, not only for diagnosis but also for following the course of the disease. , Antinuclear cytoplasmic antibodies are a marker not only for Wegener’s granulomatosis, but also for necrotizing vasculitis, Churg–Strauss syndrome, microscopic polyangiitis, and idiopathic crescentic glomerulonephritis. Indeed, Gallagher found ANCA-positive patients with retinal vasculitis having microscopic polyangiitis.


Two caveats should be kept in mind by the eyecare physician. Two patterns of ANCA are reported – a cytoplasmic pattern (cANCA), which is believed to be more specific for Wegener’s granulomatosis, and a peripheral pattern (pANCA), which is less useful in making the diagnosis. Young, in testing patients with uveitis, used the ANCA test and found positive results in those with chronic uveitis of various underlying causes. Because this test is interpreted manually, so that there can be great variation in results, an enzyme-linked immunosorbent assay, directed towards proteinase 3, is now being used. The second caveat is that if a high suspicion remains in the physician’s mind it is useful to repeat the cANCA test, because results may initially be negative in patients with Wegener’s granulomatosis localized to the orbit or eye, but will become positive with time.


Whipple’s disease


Whipple’s disease is a multisystem disorder, usually manifested by malabsorption, diarrhea, and polyarthritis, that was described by George Hoyt Whipple at the beginning of the last century. The first case report with eye findings was ascribed to Jones and Paulley in 1949; it has been estimated that <5% of patients will have uveitis. The disease is believed to be caused by the Whipple’s disease bacillus Tropheryma whippleii , which can be found in vitreous specimens using electron microscopy and PCR, along with foamy macrophages. In some patients, fluorescein angiographic results show diffuse vasculitis with hemorrhages, exudates, retinal capillary occlusion, and choroidal folds. Although the gastrointestinal complaints are typically present, others have reported patients with minimal symptoms related to that organ system, and Bodaghi and colleagues reported a similar constellation of problems due to Arthrobacter infection. Lo Monaco and colleagues have stressed the neurologic signs found in one patient who had a retinal vasculitis, and who was treated with high-dose steroid and cyclosphosphamide. Chan and associates emphasized the need for early diagnosis, because early antibiotic therapy leads to a greater chance of resolution.


Inflammatory bowel disease


Crohn’s disease commonly affects the eye in several ways, including uveitis (pars planitis), retinitis, scleritis, and keratitis. However, Duker and colleagues reported the case of a patient with a severe bilateral, obliterative, retinal arteritis, and phlebitis. There are case reports of both bilateral and unilateral retinal vasculitis with Crohn’s disease. , The disorder appeared to respond to systemic corticosteroid and cyclophosphamide therapy. Ruby and Jampol reported two patients with retinal vascular disease, one of whom had disease involving both the retinal arteries and veins, with an apparent branch retinal artery occlusion. In one report, Felekis and coworkers evaluated 60 patients with inflammatory bowel disease of whom 23 had Crohn’s disease. Only one case of retinal vasculitis was noted, and this was in a patient with ulcerative colitis.


Autoantibodies to Sjögren’s syndrome A antigen


This systemic lupus-like illness may be systemically mild, but retinal arteriolitis that leads to retinal ischemia, optic disk, and retinal neovascularization may occur.


Retinal vein occlusion


It is important to note that putative nonimmune mechanisms may lead to ophthalmoscopic findings that mimic an immune-driven pathologic condition such as retinal vein occlusion. After thrombosis, the vein occlusion can develop a secondary perivasculitis.


Relapsing polychondritis


Relapsing polychondritis is a systemic inflammatory disease of connective tissue that may have associated ocular manifestations. The diagnosis is characteristically made by observation of inflammation of the cartilage of the nose, earlobes, or trachea. Inflammation at two of these sites suffices for the diagnosis. Alternately, inflammation of one such site combined with two of the following associated signs is consistent with a diagnosis: hearing loss, vestibular imbalance, ocular inflammation, or rheumatoid factor-negative arthritis. In a review of 112 patients, Isaak and colleagues found ocular signs or symptoms in 21 at the time of diagnosis. Ocular involvement occurred in 57 of these patients at some time during the course of their disease. The most common ocular findings were episcleritis (39%) and scleritis (14%). Iridocyclitis has been observed in as many as 30% of patients with this disease, but was found in only 9% of patients in the series of Isaak and coworkers. Retinopathy, primarily exudates, and hemorrhages were seen in 9% as well. Occasionally retinal vascular occlusions, serous retinal detachments, and optic neuropathy develop. A systemic vasculitis was reported in 9% of patients, demonstrating the systemic inflammatory nature of this syndrome. Vessels of any caliber may be involved. It is possible that although the episcleral and scleral involvement in this disease is immunologically similar to the mechanisms that lead to inflammation of the cartilage, the other ocular manifestations that are seen are not tissue specific but part of the varied accompanying systemic vascular involvement.


Viral diseases


The exact role of viruses in the development of a vasculitis of the retinal vasculature with no overt destruction of the retina itself remains to be defined. It is clear that viruses can cause vascular endothelial cells to express receptors that might make them more susceptible to involvement in an immune event. Iwase and coworkers reported on a 6-year-old child who first developed a dendritic corneal ulcer and iritis due to herpes simplex virus type 1, followed by a drop in vision due to a retinal periphlebitis and vitreal inflammatory reaction that responded to aciclovir therapy. Herpes zoster has been implicated in several cases. Retinal vasculitis has been reported in association with chickenpox. , Yet another patient had a unilateral retinal varicella zoster retinitis with no systemic symptomology, proven by PCR performed on the aqueous. The patient was treated with antiviral therapy. Retinal vasculitis has been noted in a patient with chronic hepatitis C infection.


Other viral entities that can present with a retinal vasculitis include Rift Valley fever, dengue,West Nile disease and HTVL-1 ( Fig. 27-11 ). Dengue has been reported by observers in Southeast Asia. In a report by Chan et al. from Singapore, 12 of 13 patients with dengue had central visual impairment, which seemed to coincide with the nadir of the patients’ thrombocytopenia. All recovered vision to 20/30 or better. In a case report, a patient who suffered from a C4 deficiency that predisposes to autoimmune disorders presented with a retinal vasculitis and a macular detachment. In addition, West Nile virus can present with an ischemic and hemorrhagic retinal vasculitis. , In a review of the disease in North America, Chan described that of 14 eyes, 86% had multifocal chorioretinal changes, 43% a vitritis, and 29% sheathing and vasculitis.


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