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Julian D. Perry, MD
Wegener's granulomatosis is characterized by necrotizing granulomatosis lesions of the respiratory tract, glomerulonephritis, and vasculitis.1 However, Wegener's granulomatosis can affect almost any organ system, as its ocular and orbital manifestations are protean.
The condition was first described by Frederick Wegener in 1936.2 A limited form of the disease without renal involvement exists. Limited Wegener's granulomatosis may also be associated with orbital manifestations. This disease is uncommon and diagnosis may often be difficult. Specific incidence and prevalence data are difficult to calculate, but prevalence is estimated at approximately three cases per 100,000.3 Wegener's granulomatosis may occur more often in men than in women, and the mean age of onset is approximately 45 years.
Ocular involvement in Wegener's granulomatosis is the result of focal vasculitis of small arteries, arterioles, and veins.4 Ocular or orbital involvement is seen in 28% to 87% of patients with Wegener's granulomatosis.5-8
The ophthalmic manifestations of Wegener's granulomatosis are associated with paranasal sinus disease and may be the presenting symptoms in up to 16% of patients. The orbit is most frequently involved with proptosis or orbital cellulitis from contiguous sinusitis; however, the disease can affect almost any ocular structure.7 Other common sites of ophthalmic disease include the sclera and episclera, conjunctiva, and nasolacrimal drainage system.5-9
Orbital inflammation results from extension of paranasal sinus disease; however, it may arise de novo within one or both orbits and may be the first clinical manifestation of the disease. Patients may present with orbital pain, swelling, redness, proptosis, and diplopia (Slide 1).10 Compressive optic neuropathy develops as a consequence of orbital inflammation (Slide 2).
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In some patients with orbital disease, the disease is limited to the orbit; however, sinonasal involvement or systemic disease is common. Computed tomography typically shows a soft tissue orbital mass that may be associated with contiguous sinus disease (Slide 3).
Although some reports have shown that orbital disease typically presents in the localized form and results in a good outcome with aggressive medical treatment, other reports show a worse prognosis for vision or salvaging the eye in the context of orbital disease.10-13
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Nasolacrimal duct obstruction is found in approximately 7% of patients with Wegener's granulomatosis.5 Nasolacrimal duct involvement can result in epiphora, dacryocystitis, and draining fistulas (Slide 4). Older studies suggest that external dacryocystorhinostomy (DCR) may not effectively treat the nasolacrimal duct obstruction of Wegener's granulomatosis; however, a more recent report suggests that external DCR safely and effectively treats lacrimal obstruction in patients with this disease.14 Increasing perioperative immunosuppression may improve the success rate of DCR surgery in the setting of Wegener's granulomatosis.14
The scleritis that occurs in Wegener's granulomatosis can be of any type, but is often diffuse anterior or necrotizing.15,16 Women may be more likely to have non-necrotizing disease, while men may be more likely to have the necrotizing variety. The inflammation of the sclera and episclera may progress to scleral necrosis and perforation. Conjunctivitis, episcleritis, corneoscleral ulceration, and uveitis may accompany the scleritis or they can occur as isolated findings.15-18
Tarsal-conjunctival disease has been described as a common finding in patients with Wegener's granulomatosis, occurring in approximately 16% of patients.17 Tarsal-conjunctival disease can manifest as conjunctival hyperemia and granuloma formation, areas of necrosis, or active fibrovascular changes in the tarsus or conjunctiva.17
Wegener's granulomatosis may also manifest as inactive fibrovascular scarring. The tarsal-conjunctival disease may be associated with subglottic stenosis, which can lead to laryngeal obstruction and respiratory failure.17 Patients with tarsal-conjunctival disease should be referred for laryngeal evaluation.17
Intraocular findings are typically due to vasculitis, which may cause iritis and retinitis. Although vasculitis is common, intraocular granulomas have also been reported.19,20 Intraocular granulomas occurring in the region of the ciliary body may produce vitreous hemorrhage.20 Ultrasound biomicroscopy may be useful in detecting scleral granulomas that progress inside the eye. Intraocular granulomas are less common than vasculitis.
Vasculitis can affect nearly any ocular or orbital structure. Vasculitis within the retina and optic nerve occurs in approximately 10% to 18% of patients.5,7 Asymptomatic cotton-wool spots may occur, and some patients develop retinal artery occlusion, retinal vein occlusion, or both. Severe retinal vasculitis may lead to neovascularization, vitreous hemorrhage, and rubiotic glaucoma.
Anterior and posterior optic neuropathy may occur and the optic neuropathy in Wegener's granulomatosis may result from ischemia or from compression by orbital inflammation.10,11 Horner's syndrome, cranial nerve palsy, and cavernous sinus thrombosis represent other possible neuro-ophthalmological manifestations of Wegener's granulomatosis.
The pathogenesis of Wegener's granulomatosis is poorly understood but likely involves hypersensitivity mechanisms. An alteration of cell-mediated immunity may decrease the chemotactic response of polymorphonuclear leukocytes (PMNs) and cause antibodies to cytoplasmic antigens within the PMNs.20The clinical course, with involvement of the respiratory tract followed by glomeruloephritis, implicates a pathogenic agent, as does the beneficial effect of antimicrobial agents in some patients.21
However, no pathogenic agent has yet been identified. Genetic susceptibility may also play a role, as patients with the disease have an increased frequency of HLA-DR2. Antineutrophil cytoplasmic autoantibodies (ANCA) directed to protein 3 or myeloperoxidase are closely associated with the disease.20 These antibodies may act at the interface of neutrophils and endothelial cells.
ANCAs alone are not sufficient to cause disease - exogenous factors may be involved, as well. Silica and the carriage of Staphylococcus aureus have been proposed as exogenous factors.20 Nasal colonization of S aureus has been reported as an independent risk factor for relapse.21-23 The interplay of autoimmunity with environmental and genetic factors determines clinical expression. Disease activitism may produce a clonal activation of T cells.
Laboratory evaluation of patients with Wegener's granulomatosis may disclose anemia, elevated erythrocyte sedimentation rate, thrombocytosis, hypergammaglobulinemia, elevated C-reactive protein, proteinuria, hematinuria, abnormal densities on chest radiograph, and the presence of ANCAs (antineutrophil cytoplasmic auto-antibodies).24
The c-ANCAs are associated with Wegener's granulomatosis, and p-ANCAs are nonspecific markers for the disease. Although c-ANCAs have a high specificity for Wegener's granulomatosis, patients with the limited form of the disease may be seronegative. Failure of c-ANCA titers to return to normal after treatment may predict patients at risk for recurrent ocular complications.
The histopathologic classic triad of vasculitis, tissue necrosis, and granulomatous inflammation may occur in 50% of orbital biopsies.4 The diagnosis of Wegener's granulomatosis may be established on the basis of clinical features, the presence of c-ANCAs in the serum, and histopathologic demonstration of necrotizing granulomas with vasculitis. However, the diagnosis is often difficult to establish. Because most patients develop upper respiratory tract lesions early in the course of the illness, biopsy of nasal mucosa or infected sinus tissues often offers the best opportunity to secure a histologic diagnosis.
Granulomatous lesions on T2-weighted magnetic resonance imaging studies show increased signal intensity and enhance after intravenous injection with gadolinium.
The clinical course of Wegener's granulomatosis depends upon the extent of disease and treatment. Until the early 1970s, the mean survival was 5 months, with an 82% mortality rate within 1 year.2 Corticosteroids and cytotoxic agents have improved the prognosis of Wegener's granulomatosis, although treatment is associated with significant toxicity and adverse effects.
Corticosteroids significantly improve ocular and orbital inflammation; however, the effect on survival is modest and most patients with generalized disease fail to achieve full remission with corticosteroid therapy. The addition of cyclophosphamide has substantially reduced morbidity and increased survival. Cytotoxic agents have less measurable effect in patients with advanced renal insufficiency.2
The standard therapy for Wegener's granulomatosis is daily oral cyclophosphamide and corticosteroids. Oral cyclophosphamide begins at approximately 2 mg/kg/day and can be increased to doses as high as 3 mg/kg/day to 5 mg/kg/day for life-threatening complications.9
Corticosteroids are started at high doses, greater than 1 mg/kg/day, and can be tapered after clinical improvement is noted.9 Pulse therapy of cyclophosphamide or corticosteroids may play a role for life-threatening or sight-threatening complications. Disease relapse is common, occurring in nearly one-half of patients.9
Management of relapse is individualized and based on the severity of the relapse and the degree of immunosuppression. Several alternative therapies exist including methotrexate, cyclosporin A, and trimethaprim-sulfamethoxazole. Methotrexate is a reversible inhibitor of dihydrofolate reductase and a potent inhibitor of DNA synthesis. Previous trials indicate that methotrexate may be a reasonable alternative to cyclophosphamide with fewer adverse effects. Cyclosporin A has been used in a limited number of patients and may result in temporary improvement of symptoms.
The beneficial effect of trimethaprim-sulfamethoxazole has been confirmed in several uncontrolled clinical studies. Use of this adjuvant therapy may increase the rate of patients who achieve remission. This antibiotic therapy may also decrease the rate of respiratory and non-respiratory infections. The mechanism for the beneficial effect of trimethaprim-sulfamethoxazole in Wegener's granulomatosis remains unclear.22-24 The drug may exert its protective effect by reducing infections or it may have a specific anti-inflammatory effect mediated by its interference with the formation of oxygen-derived radicals.
Disease activity is monitored by following the clinical course, radiographic studies, and serum marker levels. c-ANCAs are a somewhat reliable marker for monitoring disease activity and extent. However, a positive correlation between increased disease activity and increased c-ANCA titer was found in 64% of patients from the National Institutes of Health.25 A rising c-ANCA titer predictive of clinical exacerbation occurred in fewer than one-quarter of patients with milder disease.25
Wegener's granulomatosis remains an enigmatic disease with protean ophthalmological manifestations. Diagnosis and treatment often present challenges and patients with orbital disease suffer severe sequelae. The advent of cyclophosphamide treatment revolutionized the treatment of this condition. Advances will allow for more precise and less toxic therapies.
