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Show ORIGINAL CONTRIBUTION Bilateral Optic Neuritis in Wegener Granulomatosis Mario Luiz Ribeiro Monteiro, MD, Wander Inturias Sergillo Borges, MD, Carolina do Val Ferreira Ramos, MD, Leandro Tavares Lucato, MD, and Claudia Costa Leite, MD Abstract: A 32- year- old patient with recurrent sinusitis had severe visual loss from optic neuropathy. Imaging revealed severe bone destruction and soft tissue densities of the paranasal sinuses and enhancement of the dura of the frontal sinuses, optic canals, and superior orbital fissures bilaterally. Endoscopic sinusectomy with biopsy showed granulomatous vasculitis compatible with Wegener granulomatosis ( WG). The patient was treated with intravenous and oral corticosteroids and oral cyclophosphamide that led to rapid and dramatic visual recovery. This case draws attention to the fact that optic neuritis may be an early inflammatory manifestation of WG and that rapid diagnosis and aggressive anti- inflammatory treatment is critical before inflammation of arteries leads to infarction and irreversible visual loss. ( J Neuro- Ophthalmol 2005; 25: 25- 28) egener granulomatosis ( WG) is one of several vas-culitides that primarily affect small- caliber vessels of the arterial system ( 1,2). Its clinicopathologic manifestations are sufficiently characteristic for a diagnosis, although the cause remains unidentified. Microvasculitis produces necrotizing granulomas in the lungs, generalized focal necrotizing vasculitis, and glomerulonephritis. Focal necrotizing vasculitis may involve all organs. Left untreated, the disease is rapidly fatal, usually because of renal involvement ( 3- 5). Visual loss in WG may result from choroidal, retinal, or optic nerve involvement ( 6,7). Very few cases have been reported in which optic nerve involvement is the prominent feature of the disease ( 4,8- 10). This article reports a patient with recurrent sinusitis associated with bilateral optic neuritis as one of the earliest signs of WG and emphasizes the importance of its early recognition. From the Departments of Ophthalmology ( MLRM, WISB, CdVFR) and Radiology ( LTL, CCL), Hospital das Clinicas of the University of Sao Paulo Medical School, Sao Paulo, Brazil. Address correspondence to Mario Monteiro, MD, Av. Angelica 1757 Conj. 61, 01227- 200, Sao Paulo, SP, Brazil; E- mail: mlrmonteiro@ terra. com. br CASE REPORT A 32- year- old man presented with a 4- month history of recurrent sinusitis and a 1 - month history of right- sided hearing loss and marked bilateral visual loss. Four weeks earlier, the patient had rapidly lost vision in the OS over a 2- day period; 1 week earlier, visual loss had occurred in the OD. On our examination, visual acuity was finger counting OD and no light perception OS. Confrontation visual field examination showed diffuse field constriction OD. A relative afferent pupillary defect was present OS. Fundus examination was normal OD and showed optic disc edema OS. He had a partial right facial palsy with incomplete lid closure. Computerized tomography ( CT) scan showed severe bone destruction of the nasal septum and turbinates with a dehiscent medial orbital wall and material with soft- tissue density filling up the anterior and inferior aspects of the frontal sinuses with some thickening of the adjacent bony structures on the right ( Fig. 1). Axial Tl- weighted post-contrast magnetic resonance imaging ( MRI) revealed enhancing tissue involving the ethmoidal cells, the extraconal space of the orbit bilaterally, and the optic canal region. Coronal views showed inflamed masses in the ethmoidal cells and orbits bilaterally and thickening and enhancement of the dura and arachnoid in anterior fossa floor bilaterally. Enhancing tissue could be observed around the optic nerves and in the superior orbital fissures in the orbital apex and in the meninges adjacent to the intracranial optic nerves. A lumbar puncture revealed clear and colorless cerebrospinal fluid under normal pressure. Cerebrospinal fluid analysis revealed 10 cells with lymphocytic predominance ( 92%). A chest CT scan disclosed peribronchial thickening. Laboratory investigations revealed positive cytoplasmic antineutrophilic cytoplasmic antibodies. Endoscopic sinusectomy with biopsy showed granulomatous vasculitis of the mucosa and bone; bronchoscopy with biopsy of the lung revealed an inflammatory process compatible with WG. The patient was treated with cyclophosphamide 150 mg/ d and oral prednisone 60 mg/ d, and 2 weeks later with intravenous methylprednisolone 1 g/ d for 3 consecutive days. Visual acuity improved to 20/ 25 OD and 20/ 30 OS within 3 weeks of treatment initiation. Optic disc pallor J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 25 J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 Monteiro et al FIG. 1. A. Coronal CT with bone windowing demonstrates soft tissue density filling the anterior and inferior aspects of the frontal sinuses, with some thickening of the adjacent bony structures on the right side. The medial walls of the orbits are dehiscent, especially on the right. Both middle and inferior turbinates are partially destroyed. B. Axial T1- weighted, fat-saturated, enhanced MRI demonstrates enhancing tissue in the ethmoid cells, the extraconal space bilaterally, the optic canal areas, and around the optic nerves ( arrows). The hyperintensity in the medial left orbit is an artifact related to heterogeneous fat saturation. C. Coronal T1 - weighted, fat- saturated, enhanced MRI demonstrates tissue extending from the ethmoid cells to the extraconal areas of the orbits bilaterally. There is thickening and enhancement of the dura and arachnoid of the floor of the anterior fossa bilaterally, extending to the falx cerebri. The medial walls of the maxillary sinuses are not visualized because of bone destruction. D. Coronal T1- weighted, fat- saturated, enhanced MRI in the plane of the optic canals demonstrates enhancing tissue around the optic nerves, superior orbital fissures, and meninges above the sphenoid bone. E. Coronal T1 - weighted, fat- saturated, enhanced MRI shows meningeal thickening and enhancement adjacent to the intracranial optic nerves ( arrows) medial to the posterior clinoid processes. developed OS. A Goldmann visual field showed paracentral scotomas temporally OD and marked temporal field depression OS ( Fig. 2). The patient continued treatment with prednisone and cyclophosphamide. Two months later, visual acuity was 20/ 20 OD and 20/ 30 OS. The visual field had returned to normal OD and revealed a temporal depression OS. The partial right facial palsy resulting in some lagophthalmos OD had improved significantly. Oral prednisone was gradually tapered and trimethoprim- sulfamethoxazole was added to the treatment. Because of bone marrow depression, FIG. 2. Goldmann visual fields showing paracentral scotomas OD and temporal depression OS. cyclophosphamide was replaced with methotrexate 9 months later. One year after diagnosis, the patient had stable visual function without disease activity based on clinical and laboratory findings, on prednisone 15 mg/ d, methotrexate 20 mg/ wk, trimethoprim 320 mg/ d, and sulfamethoxazole 1,600 mg/ d. DISCUSSION WG is a rare disease related to a hypersensitivity reaction to an unidentified allergen or to autoimmunity ( 4,11). The mean age at onset is 40 years, with a male- to- female ratio of 3: 2. The classic form of WG is characterized by necrotizing granulomatous vasculitis of the lung and upper respiratory tract accompanied by glomerulonephritis and a variable degree of systemic small- vessel vasculitis. The disease may be rapidly progressive and lead to death. A limited form of the disease, in which glomerulonephritis is absent, may also occur, although kidney involvement eventually develops in most such patients ( 1,3,11). In 73% of patients, the initial symptoms involve the upper airways ( 1,4). Nasal mucosa and paranasal sinuses are initially affected in up to 95% of cases ( 10). The typical manifestation includes persistent nasal obstruction, lingering 26 © 2005 Lippincott Williams & Wilkins Bilateral Optic Neuritis J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 upper respiratory infection, and sinusitis. Hearing loss is a frequent finding in WG, resulting from cochlear nerve involvement or chronic Eustachian tube blockage ( 5,10). Facial palsy occurs in 5% of WG patients ( 10). Our patient presented with cough and recurrent sinusitis, which were treated with antibiotics before the diagnosis of WG had been established. When hearing loss, facial palsy, and severe visual loss occurred, investigations led to the diagnosis. Patients with WG frequently present initially to the ophthalmologist ( 8). The high rate of ophthalmic manifestations is partly caused by the proximity of the orbit to the upper airways, but isolated ophthalmic involvement occurs as part of a focal necrotizing vasculitis ( 10,11). Orbit involvement is the most common ophthalmic manifestation in WG ( 3,7,10,11,13) and can be the first sign of the disease. Orbital pain, rapidly increasing proptosis, and ophthalmoplegia are the most frequent manifestations related to orbital involvement. Other ophthalmic manifestations include keratitis, scleritis, uveitis, retinal vascular and choroidal occlusions, and optic nerve involvement ( 3,10- 13). Neurological manifestations of WG are also common in generalized and even in limited forms of the disease, occurring in 22% to 54% of cases ( 5,14- 18). The most common neurologic manifestation is peripheral neuropathy, particularly mononeuropathy multiplex. Other manifestations include multiple cranial neuropathies, ophthalmoplegia, meningitis, meningeal thickening, strokes, seizures, and cerebritis ( 5,18). Among the cranial nerves, the optic, abducens, and facial nerves are most frequently affected, followed by the trigeminal, acoustic, oculomotor, trochlear, hypoglossal, glossopharyngeal, and vagus nerves ( 18). Drachman ( 14) proposed three mechanisms for central nervous system involvement in WG: ( 1) direct invasion from the adjacent paranasal sinuses; ( 2) remote effect of the granulomatous inflammation; and ( 3) vasculitis of the central nervous system. Cranial neuropathies may also result from extensive meningeal involvement ( 18). Visual loss in patients with an established diagnosis of WG has been well- documented by several authors ( 3,7,13). However, in only a small number of cases has visual loss been the presenting sign of the disease ( 4,8- 10). Belden et al ( 8) reported a 55- year- old woman who presented with bilateral isolated consecutive posterior optic neuropathy in a limited form of WG. Duran et al ( 9) studied a 67- year- old patient with unilateral ischemic optic neuropathy and anti- neutrophil cytoplasmic antibody ( ANCA)- positive small- vessel vasculitis compatible with either WG or microscopic polyangiitis. Niskopoulu and Toit ( 4) reported a 39- year- old man with a history of renal transplant who had a superior and nasal swelling of one orbit and later had contralateral optic neuritis. A biopsy of the orbital lesion was compatible with WG. Foster et al ( 10) reported a 26- year- old man who presented with a 3- week history of progressive visual loss associated with marked ipsilateral ophthalmoplegia. Our patient had an atypical presentation considering that he had no external signs of orbital involvement such as proptosis or gaze restriction. The only ophthalmic sign was visual loss from optic nerve involvement. In WG, the optic nerve may be affected by vasculitic infarction, spread of inflammation from the sinuses ( atypical optic neuritis), or compression from inflammatory orbital pseudotumor ( 1,7,10). Optic nerve compression and ischemia from vasculitic involvement are considered the most common mechanisms ( 3,7,9). In our case, however, the most likely mechanism was bilateral inflammation ( optic neuritis) secondary to an adjacent inflammatory process. This hypothesis is supported by the following facts: ( 1) although CT and MRI showed severe bone destruction and soft tissue densities filling the paranasal sinuses and the medial orbit, there were no orbital masses compressing the optic nerves; presumably sinusal and meningeal inflammation spread to involve both optic nerves in the orbital apex, optic canals, and intracranial segments; and ( 2) a dramatic and rapid response to the corticosteroid therapy, with visual acuity recovering from finger counting OD and no light perception OS to 20/ 20 OD and 20/ 30 OS within 3 weeks of starting treatment. Well- documented cases of optic neuritis in WG have been rarely reported ( 4,10). Niskopoulu and Toit ( 4) reported a patient in whom acute visual loss developed, followed by marked recovery with oral corticosteroid treatment. CT scan excluded a compressive lesion ( no MRI study was reported). Foster et al ( 10) reported a 26- year- old man with a history of 11 years of nasal crusting and nonpurulent blood- tinged nasal discharge in whom monocular decline of visual acuity to 20/ 200 developed over 3 weeks associated with contralateral ophthalmoplegia and who recovered vision and ocular rotations after treatment with cyclophosphamide and prednisone; MRI documented no abnormalities. It is conceivable that other cases reported as ischemic optic nerve involvement in WG also had an optic nerve inflammation initially that was later complicated by vasculitic infarction. For example, the 55- year- old patient reported by Belden et al ( 8) had visual deficits that had initially improved spontaneously but later worsened to hand motions despite treatment with a small dose of oral prednisone ( 10 mg/ day). Two weeks later, finger counting visual loss developed in the fellow eye. Treatment with intravenous methylprednisolone 500 mg/ d for 5 days resulted in only slight visual improvement. MRI scans initially showed enhancement of the optic nerve sheaths and dura overlying the cavernous sinus, similar to the findings in our case. We believe that such imaging findings suggest inflammation that can be rapidly complicated by infarction. Perhaps 27 J Neuro- Ophthalmol, Vol. 25, No. 1, 2005 Monteiro et al aggressive anti- inflammatory treatment at a very early stage would preserve vision. The diagnosis of WG should be suspected on clinical and laboratory grounds and confirmed through histopathologic study. Because of the generalized inflammatory process, an increased erythrocyte sedimentation ratio may be observed, with values often more than 100 mm during the acute phase of the illness ( 3). Moderate anemia is sometimes associated. The presence of cytoplasmic antineutrophilic cytoplasmic antibodies has been observed in more than 90% of the patients in the classic active form and in 67% to 86% in the limited form of WG ( 1), but the absence of this antibody does not exclude the diagnosis. The optimal treatment of WG is a combination of corticosteroids and cyclophosphamide, which is effective in 90% of cases ( 19). Once remission is achieved, cyclophosphamide and corticosteroids are frequently continued for 9 to 12 months ( 10). Relapses are experienced in at least 50% of cases and the usual therapeutic management is prolonged readministration of cyclophosphamide. Severe side effects of cyclophosphamide, such as malignancies and bone marrow toxicity, are frequent in patients with high cumulative doses of the drug ( 19). Alternative or adjunctive therapies, especially for maintenance treatment, include methotrexate, azathioprine, mycophenolate mofetil, and trimethoprim-sulfamethoxazole ( 6,10,19- 21). Such medications usually demonstrate fewer side effects but disease recurrence is more frequent ( 20). Recent studies have shown a promising action of inflimaxib, an antibody directed against tumor necrosis factor- a, which plays an important role in the inflammatory cascade ( 22,23). Kleinert et al ( 22) reported a patient in whom acute renal failure developed despite intense conventional immunosuppression with cyclophosphamide, azathioprine, and corticosteroids. Inflimaxib was administered six times during a 6- month period together with conventional therapy, resulting in substantial renal improvement and clinical remission. Further studies are necessary to better define the effects of inflimaxib and other tumor necrosis factor antagonists in WG. Our case draws attention to the fact that optic neuritis may be an early manifestation of WG and lead to rapidly progressive visual loss, presumably on the basis of inflammation. 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