Unilateral proptosis in a 74-year-old woman

Multisystem disorders can present with protean manifestations. We report a particularly unusual case of a systemic vasculitis in which the principal clinical manifestation was unilateral proptosis caused by an orbital pseudotumour. A 74-year-old woman initially developed nocturnal cough, wheeze, nasal congestion and conjunctival irritation. She was treated with bronchodilators and intranasal steroids without relief. The patient presented four months later with diplopia and left-sided proptosis. An MRI of the orbits revealed increased retro-orbital tissue. Lacrimal gland biopsy showed a polyclonal lymphocytic infiltrate. A presumptive diagnosis of orbital pseudotumour was made and the patient was treated with orbital radiotherapy. This failed to control her worsening proptosis. Increasing headache, malaise, exertional dyspnoea and a 20lb weight loss soon followed. Eye examination revealed persistent left proptosis and diplopia on left lateral gaze. The remainder of her physical examination was normal. Haemoglobin was 9.9g/dL, WBC 5.6 (with a normal differential), platelets 461 and ESR 126. Chest X-Ray demonstrated bilateral reticulonodular infiltrates. Serologic studies included a negative ANA and c-ANCA with a weakly positive p-ANCA and positive antimyeloperoxidase antibodies in a titre of 1:80. A diagnostic video-assisted thoracoscopic lung biopsy was subsequently performed. Histology revealed patchy organizing pneumonia with necrotizing granulomas and vasculitis forming multiple nodules, consistent with Wegener's granulomatosis. The patient was started on 60mg of prednisone daily as well as cyclophosphamide 750mg monthly (for a total of nine doses) and co-trimoxazole bid. The proptosis resolved within days, as did the patient's symptoms. A chest X-ray two months later was completely normal. This case illustrates an unusual manifestation of Wegener's granulomatosis, the heterogeneity of ANCA status and the gratifying response of this disease to appropriate therapy. A 74-year old woman first presented with a three month history of nasal congestion, nocturnal wheezing, dry cough and malaise. She had not previously sought medical attention for her symptoms. She was a non-smoker and had a history of hyperlipidemia and degenerative joint disease. Physical examination, including an otolaryngologic examination, was unremarkable. A CBC and an electrolyte panel were within normal limits. Pulmonary function tests were obtained. She exhibited a positive metacholine challenge. A diagnosis of asthma with allergic rhinitis was made and treatment was initiated with bronchodilators and inhaled corticosteroids without relief. Over the next three months, she developed additional symptoms including fatigue, 4 kilogram weight loss and episodic fevers with night sweats. She also complained of unilateral facial congestion and discomfort as well as transient episodes of diplopia and left retro-orbital pain. Within weeks of the initial symptoms of diplopia, the patient developed left proptosis with increasing orbital discomfort. The systemic symptoms and malaise continued to worsen and she presented for reassessment. A magnetic resonance image (MRI) of the orbit demonstrated an infiltrating mass with enlargement of the superior rectus and levator palpebre muscles. Her thyroid stimulating hormone level was normal. A biopsy of the lacrimal gland (which appeared to be involved on MRI) showed chronic inflammatory changes with reactive plasma cells, histiocytes and lymphocytes. The lymphocyte population in the biopsy was shown to be polyclonal by immunophenotyping. A presumptive diagnosis of orbital inflammatory pseudotumor was made and treatment with oral corticosteroid was initiated. (prednisone 60milligrams/d tapered over 2 weeks to 20 milligrams/d which the patient received for a further 3 weeks). Although initial response was encouraging, orbital inflammation flared when the steroid therapy was discontinued. A 4 week course of radiotherapy (2550 cGy in 17 fractions) was administered to the orbit. This failed to control the proptosis and diplopia. The patient, however, continued to deteriorate with increasing malaise and weakness which confined her to bed for most of the day. A dry, non-productive cough developed and her facial discomfort was increasingly severe. She was admitted to hospital for further evaluation. By this time, she had lost a total of 8.5kg. Physical examination revealed marked left proptosis with diplopia from mechanical restriction related to the inflammatory orbital mass. Repeat otolaryngologic examination was unremarkable. The patient had a Hb of 8.5g/dL, an MCV of 86.7fL. WBC was of 4.4 x 10⁹/L with a normal differential. Platelet count was 380 x 10⁹/L. Serum electrolytes, creatinine and urinalysis were within normal limits. The ESR was 126mmHr^-1 and a serum protein electrophoresis showed polyclonal hypergammaglobulinemia. A chest X-ray (CXR) showed bilateral pulmonary, nodules and a small right pleural effusion. Chest CT confirmed these findings. The patient had a positive p-ANCA with an anti-myeloperoxidase titre of 1:80. Negative studies included c-ANCA, anti-nuclear antibodies (ANA) and rheumatoid factor (RF). Since the initial orbital biopsy was nonspecific and the orbit had recently been radiated, a repeat biopsy was not considered. There were no visible mucosal abnormalities on repeat ENT examination. Cytological examination of the pleural fluid did not reveal malignant cells. Therefore, a previously identified sub-pleural nodule was removed by video-assisted thoracoscopy and submitted for histologic analysis. The identification of necrotizing granulomas with associated vasculitis was compatible with a diagnosis of Wegener's granulomatosis. After the diagnosis was made, the patient was started on high-dose prednisone (80mg daily) and began receiving 750mg of intravenous cyclophosphamide on a monthly basis for a total of nine doses. In addition, trimethoprim-sulfamethoxazole (TMP-SMX) therapy (800/160 -twice daily) was commenced. She had a rapid response to therapy with resolution of proptosis within weeks. CXR was repeated three months after the commencement of therapy and was normal as was a repeat MRI of the orbits. This case illustrates an unusual presentation of Wegener's granulomatosis, with an inflammatory orbital pseudotumor and negative ANCAs. It also demonstrates a gratifying response to appropriate therapy. DISCUSSION: During the diagnostic evaluation of unilateral proptosis, the presence of an orbital inflammatory pseudotumour should always require the exclusion of a systemic vasculitis as the underlying cause. Classically, histologic findings in Wegener's granulomatosis comprise vasculitis, granulomatous inflammation (with or without giant cells) and tissue necrosis. It is interesting to note, however, that this triad is seen in little over half of all orbital biopsies [1,4]. The remainder of orbital biopsies seem to exhibit a range of histopathologic findings - ranging from microscopic vasculitis to a polyclonal lymphocytic infiltrate - as was the case in our patient. A high percentage of patients with Wegener's granulomatosis develop Anti-Neutrophil Cytoplasmic Antibodies (ANCAs). These antibodies are detected by the use of immunofluorescence microscopy and can be divided according to their staining patterns. Cytoplasmic or c-ANCA produce a coarse granular, centrally accentuated cytoplasmic pattern of staining. This is caused by antibodies against proteinase 3, a neutral serine proteinase present in neutrophil azurophilic granules. The sensitivity of c-ANCA depends on the extent and phase of the disease process.