Part 5 • Uveitic Conditions not Caused by Active Infection Chapter 27 Retinal Vasculitis

Box 27-1  Disorders with retinal vasculitis as a

common finding

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 C2

Chickenpox3

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

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.

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 coworkers4 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).

Eales’ disease

Although Eales’ disease had been discussed by others, the disorder carries the name of Henry Eales who, in 1880,5 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,6 and Moura and colleagues7 reported that strongly positive Mantoux test results were found in 87% of 141 patients. Biswas and colleagues8 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 study9 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,

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Part 5 • Uveitic Conditions not Caused by Active Infection Chapter 27 Retinal Vasculitis

Therese and coworkers,10 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.11 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.12 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 associates13 reported three patients with seizures and/or migraine. An MRI scan in two patients showed a putaminal infarct with white matter edema.

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. Elliot14 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.15 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 associates16 found circulating immune complexes in these patients. Rennie and associates17 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.18 observed

A

B

Figure 27-2.  A and B, Peripheral retinal vasoocclusive disease with neovascularization due to Eales’ disease. (Courtesy of R. Murphy, MD.)

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,19 observing an improvement in visual acuity. Others have used intravitreal injections of steroid. Ishaq et al.20 saw reduction of leakage, but their follow-up was short, whereas Agrawal et al.21 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.22 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 Sinha23 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.

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.24,25 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.26,27 It is not clear whether immunosuppressive agents are beneficial for this condition. Some suggest it may be a matter of dose, as Ishikawa and colleagues28 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 colleagues29 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