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 factornegative arthritis. In a review of 112 patients, Isaak and colleagues92 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,93 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,92 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 coworkers94 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.95,96 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.97 Retinal vasculitis has been noted in a patient with chronic hepatitis C infection.98

Other viral entities that can present with a retinal vasculitis include Rift Valley fever, dengue,West Nile disease and HTVL-12 (Fig. 27-11). Dengue has been reported by observers in Southeast Asia. In a report by Chan et al.99 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.100 In addition, West Nile virus can present with an ischemic and hemorrhagic retinal vasculitis.101,102 In a review of the disease in North America, Chan103 described that of 14 eyes, 86% had multifocal chorioretinal changes, 43% a vitritis, and 29% sheathing and vasculitis.

Multiple sclerosis

It has been suggested that 9–23% of multiple sclerosis patients will have a perpheral uveitis and retinitis.104 Although these numbers seem high it is clear that it does happen. Friedman105 reported a case where the retinal vasculitis was the initial finding in a case of multiple scleritis.

Tuberculosis

Central retinal artery vasculitis leading to occlusion106 (see Chapter 9) has been noted. A recent study from India of 360 uveitis patients with a positive PPD were found to have fewer recurrences (16% vs 47%) when their steroid treatment was combined with four-drug antitubercular therapy.107

Rheumatoid arthritis

In a report by Giordano and colleagues,108 11 of 60 patients (18.3%) with rheumatoid arthritis had fluorescein angiographic evidence of retinal vasculitis. Matsuo and coworkers109 reported the case of a 37-year-old woman who developed choroiditis and retinal vasculitis while receiving low-dose steroid therapy for her rheumatoid arthritis.

Kikuchi–Fujimoto disease

This necrotizing lymphadenitis is usually self-limiting. Zou and colleagues110 reported a case with bilateral occlusive

retinal vasculitis which developed neovascularization. The patient was treated with methotrexate and prednisone.

Susac syndrome

This syndrome is characterized by a microangiopathy of the brain, retina and cochlea. It affects mostly young women. In one recently reported case111 there were focal nonperfused retinal arterioles with staining of the vessel walls, but no intraocular inflammation was reported. The patient was treated with cyclosphosphamide and improved retinal perfusion was seen.

Sweet syndrome

Acute febrile neutrophilic dermatosis, or Sweet syndrome, is a skin disorder characterized by reddish papules and nodules along with fever, circulating neutrophilia, and neutrophils infiltrating into the dermis.112 Systemic corticosteroids are used to treat the disorder. Anterior segment problems, such as scleritis, glaucoma, and keratitis, have been reported, as has been choroiditis. It has been associated with Crohn’s disease and malignancies. It has been estimated that about a quarter of these patients will have ocular complications.113 In addition, a bilateral retinal vasculitis has been described with this syndrome which was treated with prednisone, colchicine, and diaphenylsulfone.114

Tattooand drug-induced vasculitis

Moschos et al.115 reported the case of a 21-year-old man who, after having mulitple tattoos placed, developed retinal vasculitis and macular edema. He was aggressively treated with immunosuppressive therapy. Another patient was reported to develop retinal vasculitis after trimethoprin sulfamethoxazole-induced urticaria.116 The disease, however, manifested 2 years after the cutaneous problem began. It is possible to theorize that both tattooing and a severe enough cutaneous inflammatory reacton released skin antigens (perhaps melanin like) that are shared with the eye.

In summary, this group of disorders that primarily affect the retinal vasculature frequently presents great challenges to treating physicians. It is remarkable how many disorders can manifest as a retinal vasculitis.117,118 We are learning more about the underlying immune mechanisms of this group of diseases. Whereas immune complexes have tranditionally been hailed as the underlying cause, we are now

seeing alternative hypotheses. One example is the possible role of effector T cells and their ability to activate endothelial cells leading to effector cell homing, whereas Müller cells may be attempting to modulate this response.119 Wallace and coworkers120 have reported a CX3CR1 genotype association (particularly the I249/M280 haplotype) in retinal vasculitis patients in the United Kingdom. These variants may be implicated in leukocyte migration and neuronal protection. We are beginning to learn more of the kinds of inflammatory cell product that are elevated in retinal vasculitis.

Ocular vasculitic disorders with systemic disease

Wallace et al. reported that macrophage inflammatory protein (MIP) 1α and 1β were elevated in the sera of retinal vasculitis patients. Lee et al.121 reported that IFN-β was elevated in the sera of 47% of retinal vasculitis patients tested and stayed elevated for 6–12 months; E-Selectin (an adhesion molecule) was also elevated.

The potential workup for these patients can be very long122,123 (Boxs 27-3–27-5). For well-defined disorders such as Behçet’s disease aggressive therapy is imperative, with various options for immunosuppression available. There

•Complete blood count with differential

•Erythrocyte sedimentation rate

•C-reactive protein

•Serum chemistry panel with tests for renal and liver functions

•Blood sugar

•Urinalysis

•Venereal Disease Research Laboratory (VDRL) test, fluorescent treponemal antibody absorption (FTA-ABS) test

•Tuberculin skin testing

•Toxoplasmosis serology

•Lyme disease serology

•Cat-scratch disease serology

•Human immunodeficiency virus, human T-cell lymphoma virus type 1, cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis virus, and West Nile virus serology

•Polymerase chain reaction to identify pathogens in ocular specimens

•Serum angiotensin-converting enzyme

•Rheumatoid factor

•Antinuclear antibody

•Anti-DNA

•Antineutrophil cytoplasmic antibody

•Antiphospholipid antibodies (lupus anticoagulants and anticardiolipin antibodies)

•Serum complement, CH50, AH50

•Extractable nuclear antigen

•Serum protein electrophoresis

•Serum cryoglobulins

•Human leukocyte antigen testing

•Vitreous biopsy

•Cerebrospinal fluid cytology and cell count Imaging

•Fluorescein angiography

•Optical coherence tomography

•Ultrasonography

•Chest X-ray

•CT scanning

•Magnetic resonance imaging

•Gallium scan

•Sacroiliac X-ray

Box 27-4  Disorders associated with retinal vasculitis

Infectious disorders

•Bacterial disorders (tuberculosis, syphilis, Lyme disease, Whipple’s disease, brucellosis, cat-scratch disease, endophthalmitis)

•Viral disorders (human T-cell lymphoma virus type 1, cytomegalovirus, herpes simplex virus, varicella zoster virus, Rift Valley fever virus, hepatitis, acquired immunodeficiency syndrome, West Nile virus infection)

Parasitic disorders (toxoplasmosis)

•Rickettsial disorders (Mediterranean spotted fever)

Neurologic disorders

•Multiple sclerosis

•Microangiopathy of the brain, retina, and cochlea (Susac syndrome)

Malignancy

•Paraneoplastic syndromes

•Ocular lymphoma

•Acute leukemia

Systemic inflammatory disease

•Behçet’s disease

•Sarcoidosis

•Systemic lupus erythematosus

•Wegener’s granulomatosis

•Polyarteritis nodosa

•Churg–Strauss syndrome

•Relapsing polychondritis

•Sjögren’s A antigen

•Rheumatoid arthritis

•HLA-B27-associated uveitis

•Crohn’s disease

•Post vaccination

•Dermatomyositis

•Takayasu’s disease

•Buerger’s disease

•Polymyositis

Ocular disorders

•Frosted branch angiitis

•Idiopathic retinal vasculitis, aneurysms, and neuroretinitis

•Acute multifocal hemorrhagic retinal vasculitis

•Idiopathic recurrent branch retinal arterial occlusion

•Pars planitis

•Birdshot retinochoroidopathy

Laboratory tests

•Complete blood count with differential

•Erythrocyte sedimentation rate

•C-reactive protein

•Serum chemistry panel with tests for renal and liver functions

•Blood sugar

•Urinalysis

•Venereal Disease Research Laboratory (VDRL) test, fluorescent treponemal antibody absorption (FTA-ABS) test

•Tuberculin skin testing

•Toxoplasmosis serology

•Lyme disease serology

•Cat-scratch disease serology

•Human immunodeficiency virus, human T- cell lymphoma virus type 1, cytomegalovirus, herpes simplex virus, varicella zoster virus, hepatitis virus, and West Nile virus serology

•Polymerase chain reaction to identify pathogens in ocular specimens

•Serum angiotensin-converting enzyme

•Rheumatoid factor

•Antinuclear antibody

•Anti-DNA

•Antineutrophil cytoplasmic antibody

•Antiphospholipid antibodies (lupus anticoagulants and anticardiolipin antibodies)

•Serum complement, CH50, AH50

•Extractable nuclear antigen

•Serum protein electrophoresis

•Serum cryoglobulins

•Human leukocyte antigen testing

•Vitreous biopsy

•Cerebrospinal fluid cytology and cell count

Imaging

•Fluorescein angiography

•Optical coherence tomography

•Ultrasonography

•Chest X-ray

•CT scanning

•Magnetic resonance imaging

•Gallium scan

•Sacroiliac X-ray

The diagnostic workup should be tailored according to the patient’s medical history, review of systems, and physical examination.

have been several references to the use of steroids in this chapter. Howe and colleagues124 reported on the effectiveness of steroid therapy for retinal vasculitis. Of their patients, 29 were given ≥1 mg/kg of prednisolone, and therapy was maintained at a dose of ≥40 mg for at least 5 weeks. Of these 29 patients, 60% had an increase in visual acuity with therapy, and this number increased to 77% when other agents were added to the regimen in eight additional patients. Stanford and Verity125 also spoke of patients with ischemic retinal vasculitis who did not do well with steroid therapy.

However, some cases of retinal vascular disease may be quite severe but are neither associated with a systemic disorder nor well-characterized in the literature. Such an example is seen in Figure 27-12, a patient with intermediate uveitis and severe retinal vascular disease. Not only is the

natural history of severe retinal vascular disease unknown, but frequently it is also not associated with impressive inflammatory disease (Figs 27-13 and 27-14). The therapeutic approach to these patients is problematic and often compounded by the presence of neovascularization. Panretinal photocoagulation (PRP) may have a beneficial effect on the course of retinal vascular disease such as IRVAN. Indeed, this therapy has seemed to be the only modality that has stabilized some severe occurrences of retinal vasculitis. The use of anti-VEGF therapies opens up a new avenue for treatment of these patients. It should be added that we have seen severe inflammatory episodes apparently provoked by PRP. However, even with that risk, it may still be the indicated approach – clearly if there is evidence of capillary dropout on the angiogram, but perhaps even if there is not.