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74-Year-Old-Woman With Cough and Proptosis

      A 74-year-old woman first came to Mayo Clinic Rochester with a 3-month history of nasal congestion, dyspnea on exertion associated with occasional wheezing, dry cough, and malaise. She had not previously sought medical attention for her symptoms. She was a nonsmoker and had a personal history of hyperlipidemia and degenerative joint disease and a family history of leukemia. Findings on physical examination, including an otorhinolaryngologic examination, were unremarkable. Pulmonary function tests documented a positive methacholine challenge, but results were otherwise within normal limits. Asthma and allergic rhinitis were diagnosed, and treatment was initiated with inhaled corticosteroid and bronchodilators without relief. During the next 3 months, additional symptoms developed, including fatigue, a 4-kg weight loss, and episodic fevers in conjunction with night sweats. She also complained of left-sided facial congestion and discomfort as well as transient episodes of diplopia and left retro-orbital discomfort.
      • 1.
        Which one of the following diseases is least likely to accountfor the patient's clinical manifestations?
        • a.
          Atopic asthma
        • b.
          Churg-Strauss syndrome
        • c.
          Thyrotoxicosis
        • d.
          Giant cell arteritis
        • e.
          Occult malignant lesion
      In a healthy 74-year-old person with no previous personal or family history of atopy, a diagnosis of atopic asthma is questionable. Asthma does not cause night sweats, weight loss, and malaise. Our patient's systemic symptoms overshadowed the mild reversible bronchospasm documented on pulmonary function testing. Churg-Strauss syndrome should be considered in patients who have asthma and systemic symptoms and who fail to respond to standard therapy for asthma. Patients with Churg-Strauss syndrome initially require high-dose prednisone therapy. Thyrotoxicosis may occasionally manifest as a thyrotoxic crisis with fever, hypennetabolic state, weight loss, and confusion. Vague eye symptoms commonly precede the development of overt dysthyroid eye disease. Giant cell arteritis can cause systemic manifestations of the severity experienced by our patient in association with relatively minor local symptoms. Shoulder girdle tenderness and proximal muscle weakness are often present. Because of involvement of the ophthalmic artery, blindness can develop rapidly-hence the need for early diagnosis and treatment. Finally, in a previously healthy elderly patient with prominent symptoms of malaise, weakness, fever, and night sweats, a malignant lesion should be a consideration. Systemic symptoms are especially prominent in lymphoreticular malignant disease but may also occur in other malignant conditions such as renal cell carcinoma.
      Within weeks after the initial symptoms of diplopia, left proptosis and increasing orbital discomfort developed. The systemic symptoms and malaise continued to worsen, and the patient requested reassessment. A magnetic resonance image (MRI) of the orbit demonstrated an infiltrating mass and enlargement of the superior rectus and levator palpebral muscles (Fig. 1). A sensitive thyrotropin assay showed normal findings.
      Figure thumbnail gr1
      Fig. 1Axial T1 magnetic resonance image, demonstrating abnormal infiltrative tissue (arrow) within intraconal and extraconal segments of left orbit and proptosis of globe.
      • 2.
        Which one of the following clinical conditions is least likely to have caused our patient's unilateral proptosis?
        • a.
          Dysthyroid eye disease
        • b.
          Metastatic disease involving the orbit
        • c.
          Cavernous sinus thrombosis
        • d.
          Sarcoidosis
        • e.
          Orbital pseudotumor
      Despite normal results of thyroid function tests, dysthyroid eye disease could still be responsible for the unilateral proptosis in this patient. Although ocular involvement is usually symmetric, asymmetric involvement is not uncommon. Dysthyroid eye disease can occur out of phase with thyroid involvement and frequently progresses despite adequate control of accompanying thyrotoxicosis. Extraocular muscle enlargement is a common radiographic finding, but the presence of an infiltrating mass should make one seriously question dysthyroid disease. Adenocarcinomas (especially of the breast or lung) occasionally metastasize to the orbit. A tumor can compress the eyeball or optic nerve and cause abnormalities of eye movement as well as vision. Imaging of the involved orbit usually demonstrates an infiltrating mass and underlying bone erosion. Generally, cavernous sinus thrombosis is associated with infections of the orbital or nasal cavities. Unlike in this patient, the initial clinical manifestations of cavernous sinus thrombosis are acute, painful unilateral proptosis and ophthalmoplegia; high fever, headache, nausea, and vomiting often occur. This diagnosis is the least likely possibility in our patient. In sarcoidosis, orbital inflammation may be localized or may be a manifestation of a systemic process. A biopsy may demonstrate sarcoid granulomas or vasculitis.
      • Satorre J
      • Antle CM
      • O'SulIivan R
      • White VA
      • Nugent RA
      • Rootman J
      Orbital lesions with granulomatous inflammation.
      Inflammatory orbital pseudotumor is a vague, nonspecific term. A focus of inflammation in the orbit can produce a mass effect that causes proptosis. Because biopsy of such “masses” shows only inflammation, they have been labeled as “inflammatory orbital pseudotumor.”
      • Snebold NG
      Noninfectious orbital inflammations and vasculitis.
      Inflammatory orbital pseudotumor may exist in isolation or as a manifestation of systemic disease. Various causes should be kept in mind, such as infection, sarcoidosis, or any vasculitis. Therefore, diagnosis of orbital pseudotumor is appropriate in this patient after other diagnoses have been reasonably excluded.
      A biopsy of the lacrimal gland (which appeared to be involved on MRI) showed dense chronic inflammation with reactive plasma cells, histiocytes, and lymphocytes. The lymphocytes in the biopsy specimen were reactive and not monoclonal; thus, the diagnosis of lymphoma was excluded. Inflammatory orbital pseudotumor was diagnosed, and treatment with prednisone was initiated (60 mg/day orally, tapered during a 2-week period to 20 mg/day). Although the initial response was encouraging, orbital inflammation flared whenever the dose was tapered. After 5 weeks of prednisone therapy, a course of irradiation (2,550 cGy in 17 fractions over 4 weeks) was administered to the orbit.
      The patient's condition, however, continued to deteriorate; increasing malaise and weakness confined her to bed for most of the day. Radiotherapy had failed to control the proptosis, and diplopia became constant. A dry, nonproductive cough had developed, and her facial discomfort was increasingly severe. As a result, she was hospitalized for further evaluations.
      By this time, the patient had lost 8.5 kg. Physical examination now revealed severe left proptosis and diplopia from mechanical restriction related to the inflammatory orbital mass. The hemoglobin was 8.5 g/dL, and the mean corpuscular volume was 86.7 fl.. The leukocyte count was 4.4 × 109/L with a normal differential; the platelet count was 380 × 109/L. Serum electrolytes, creatinine, and urinalysis were within normal limits. The erythrocyte sedimentation rate was 126 mm in 1 hour, and serum protein electrophoresis showed a polyclonal hypergammaglobulinemia. A chest roentgenogram disclosed bilateral pulmonary nodules and a small right pleural effusion. The patient had perinuclear staining antineutrophilic cytoplasmic antibodies (pANCAs) with an antimyeloperoxidase titer of 1:80. Negative studies included cANCA (cytoplasmic ANCA), antinuclear antibodies, and rheumatoid factor.
      • 3.
        On the basis of radiographic findings in this clinical setting, which one ofthe following diagnostic possibilities is least likely in our patient?
        • a.
          Metastatic malignant tumor
        • b.
          Classic polyarteritis nodosa
        • c.
          Churg-Strauss syndrome
        • d.
          Tuberculosis
        • e.
          Wegener's granulomatosis
      Neoplastic, infectious, or inflammatory and autoimmune diseases could produce radiologic abnormalities similar to those in our patient. The most common cause of multiple nodular opacities on chest roentgenograms in an elderly patient is metastatic malignant tumor. Classic polyarteritis nodosa is one of the few vasculitides that rarely affect the lung. Microscopic poly angiitis is distinct from classic polyarteritis nodosa, which typically affects medium-size arteries. Pulmonary capillaritis is the most common lesion in microscopic polyangiitis but is absent in classic polyarteritis nodosa.
      • Jennette JC
      • Falk RJ
      • Andrassy K
      • Bacon PA
      • Churg J
      • Gross WL
      • et al.
      Nomenclature of systemic vasculitides: proposal of an international consensus conference.
      This diagnosis is least likely in our patient. Churg-Strauss syndrome is characterized by peripheral eosinophilia, lung infiltrates, asthma, and a small-vessel vasculitis often associated with a neuropathy. Chest roentgenographic changes are usually ill-defined, evanescent infiltrates. This disease may be associated with a positive pANCA and negative cANCA pattern
      • Specks U
      • Homburger HA
      Anti-neutrophil cytoplasmic antibodies.
      and an increased erythrocyte sedimentation rate. We considered this condition a remote possibil- ity because of the absence of eosinophilia. Tuberculosis should always be considered in this setting, although the chest roentgenographic appearance would be atypical. The presence of cutaneous anergy to purified protein derivative in a debilitated patient would not exclude tuberculosis. Wegener's granulomatosis, a disease of unknown cause, is classically characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract. The clinical manifestations are usually confined to the ear, nose, and throat regions. Granulomatous involvement of the lung could produce a radiographic appearance similar to that of our patient. The kidneys are commonly involved, and patients can have a rapidly progressive glomerulonephritis at the time of initial assessment. Pathologically, necrotizing granulomas and associated vasculitis are the hallmarks of this disease.
      • Kalina PH
      • Lie JT
      • Campbell RJ
      • Garrity JA
      Diagnostic value and limitations of orbital biopsy in Wegener's granulomatosis.
      • Goulart RA
      • Mark EJ
      • Rosen S
      Tumefactions as an extravascular manifestation of Wegener's granulomatosis.
      Serologically, this disease is characterized by the presence of ANCAs. These antibodies are detected by the use of immunofluorescence microscopy and are subdivided on the basis of their staining patterns. A cytoplasmic pattern of staining (cANCAs) is typically associated with Wegener's granulomatosis. Despite the atypical serologic picture in this case, our clinical suspicion of Wegener's granulomatosis was high.
      • 4.
        Which one ofthe following procedures is most likely to help confirm the diagnosis in this patient?
        • a.
          Rebiopsy ofleft retro-orbital tissue
        • b.
          Biopsy ofthe nasal passages
        • c.
          Bronchoscopic lung biopsy
        • d.
          Ultrasound-guided thoracentesis
        • e.
          Video-assisted thoracoscopic lung biopsy
      Because the initial orbital biopsy specimen was nonspecific and irradiation of the orbit had recently been done, another retro-orbital biopsy was not considered. In the absence of nasal symptoms, biopsy of the nasal passages is unlikely to be helpful unless a mucosal abnormality is evident. The yield of a bronchoscopic lung biopsy depends on an adequate sample of diseased tissue for diagnosis, which often is difficult to obtain. Moreover, the operator may be unable to reach a previously identified nodule. Although thoracentesis is inexpensive and safe, in an inflammatory condition such as Wegener's granulomatosis, results of pleural fluid analysis are nonspecific. Video-assisted thoracoscopy has replaced open-lung biopsy in many cases; it is less invasive, provides visualization of the pleural surfaces, and can obtain relatively large tissue samples for biopsy.
      In our patient, cytologic examination of the pleural fluid did not reveal malignant cells. Therefore, a previously identified subpleural nodule was removed by video-assisted thoracoscopy. Histologic analysis showed necrotizing granulomas and associated vasculitis, compatible with a diagnosis of Wegener's granulomatosis.
      • 5.
        In light of the histopathologic diagnosis based on lung biopsy, which one of the following options is the most appropriate therapy for this patient?
        • a.
          Corticosteroid, cyclophosphamide, and trimethoprim/sulJamethoxazole (TMP/SMX)
        • b.
          High-dose corticosteroid only
        • c.
          Plasmapheresis
        • d.
          High-dose intravenous immune globulin therapy
        • e.
          MercaptoethanesulJonate sodium (MESNA)
      The treatment of acute Wegener's granulomatosis is based on a corticosteroid and the alkylating agent cyclophosphamide. In the 1970s and 1980s, National Institutes of Health studies proved the effectiveness of this regimen prospectively. The protocol may be summarized as follows: cyclophosphamide, 2 mg/kg per day orally for 1 year; taper 25 mg every 2 to 3 months; prednisone, 1 mg/kg per day orally for 1 month; taper to 60 mg every other day for 1 to 3 months, and then taper for 3 to 9 months until discontinuation. Severely ill patients may receive initial cyclophosphamide dosages up to 5 mg/kg per day and prednisone dosages up to 15 mg/kg per day.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • Hallahan CW
      • Lebovics RS
      • Travis WD
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      Because of the variability of clinical course and aggressiveness of this disease as well as the appreciable systemic toxicity from these medications, alternative regimens have been proposed. Use of pulsed, rather than daily, cyclophosphamide has proved effective in moderately active disease, usually limited to the respiratory tract. 8 Recently, attention has focused on the role of TMP/ SMX in preventing relapse. One study showed a 50% reduction in relapse rate at 2 years with TMP/SMX therapy (160/ 800 mg twice a day) in comparison with placebo,
      • Stegeman CA
      • Tervaert JWC
      • de Jong PE
      • Kallenberg CGM
      • Dutch Co-trimoxazole Wegener Study Group
      Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.
      TMP/ SMX as monotherapy has been suggested in the early stages of disease limited to the respiratory tract.
      • DeRemee RA
      Empiricism and Wegener's granulomatosis [editorial].
      Plasmapheresis is not considered a standard therapy in classic Wegener's granulomatosis. This disease does not involve circulating antibodies such as in myasthenia gravis or other disorders in which such treatment modalities have been useful. High-dose intravenous immune globulin therapy has been used in systemic vasculitides such as Kawasaki's disease and rheumatoid vasculitis, but any benefit in Wegener's granulomatosis has been transient.
      • DeRemee RA
      Empiricism and Wegener's granulomatosis [editorial].
      MESN A is used to protect the urinary tract against the hemorrhagic cystitis resulting from the irritant effects of the metabolites of cyclophosphamide and ifosfamide-in particular, acrolein. It combines with these metabolites to form compounds that are nontoxic to the urinary tract. As such, MESNA has no direct role in the treatment of Wegener's granulomatosis and is not essential when low-dose cyclophosphamide is used.
      After the diagnosis was made, therapy was initiated with high-dose prednisone (80 mg daily) and cyclophosphamide (750 mg intravenously each month for 9 months). The patient responded rapidly, and the proptosis resolved within weeks. At 3 months after initiation of therapy, a chest roentgenogram and orbital MRI showed normal findings. Currently, the patient is free of symptoms with use of maintenance doses of prednisone (10 mg daily) and TMP/SMX (160/800 mg twice daily) for prophylaxis against recurrence of disease.

      DISCUSSION

      This case illustrates an unusual initial manifestation of Wegener's granulomatosis, the less commonly seen pANCA pattern of staining, and a gratifying response to appropriate therapy. Classically, histologic findings in Wegener's granulomatosis include vasculitis, granulomatous inflammation (with or without giant cells), and tissue necrosis. This triad, however, is seen in only about half of all orbital biopsy specimens.
      • Satorre J
      • Antle CM
      • O'SulIivan R
      • White VA
      • Nugent RA
      • Rootman J
      Orbital lesions with granulomatous inflammation.
      • Kalina PH
      • Lie JT
      • Campbell RJ
      • Garrity JA
      Diagnostic value and limitations of orbital biopsy in Wegener's granulomatosis.
      The other biopsy specimens exhibit a range of histopathologic findings—from microscopic vasculitis to nonspecific orbital inflammation (as in our patient). Thus, the presence of even mild inflammation in an orbital biopsy specimen cannot exclude the diagnosis of Wegener's granulomatosis, and the diagnosis of inflammatory orbital pseudotumor should always require exclusion of one of the systemic vasculitides. Accordingly, diagnosis of Wegener's granulomatosis will continue to depend on the appropriate clinical context as well as the patient's ANCA status—cANCAs or pANCAs.
      cANCAs produce a coarse, granular, centrally accentuated cytoplasmic pattern of staining, attributable to antibodies against proteinase 3. The sensitivity of cANCAs depends on the extent and phase of the disease. Although present in more than 90% of patients during the systemic vasculitic phase of Wegener's granulomatosis, cANCAs are present in 65% of those with predominantly granulomatous disease of the respiratory tract and in only 30% of those in remission.
      • Specks U
      • Homburger HA
      Anti-neutrophil cytoplasmic antibodies.
      cANCAs are also found in about 40% of patients with microscopic polyangiitis and in a few patients with Churg-Strauss syndrome. Therefore, the presence of cANCAs must be interpreted in light of the patient's clinical manifestations.
      A perinuclear pattern of staining is produced by pANCAs. These antibodies are directed against myeloperoxidase, elastase, lactoferrin, and lysozyme. pANCAs are seen in most patients with Churg-Strauss syndrome, in a substantial proportion of patients with microscopic polyangiitis, and in other nonvasculitic systemic conditions such as inflammatory bowel disease. Because the presence of pANCAs has been noted in only 5% of patients with Wegener's granulomatosis, they are not useful diagnostically in this disease.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • Hallahan CW
      • Lebovics RS
      • Travis WD
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      Direct proof of pathogenicity of ANCA is still lacking because no good animal model for Wegener's granulomatosis exists. Consequently, the passive transfer experiment, which would prove ANCA pathogenicity, has not been done. cANCAs, however, can be used to monitor the course of disease, inasmuch as titer changes parallel the disease activity. The prognostic significance of increasing titers in predicting relapse remains controversial.
      • Specks U
      • Homburger HA
      Anti-neutrophil cytoplasmic antibodies.
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • Hallahan CW
      • Lebovics RS
      • Travis WD
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      Treatment of this disease with cyclophosphamide and prednisone has dramatically improved survival (the 1-year mortality for untreated patients is 82%), and cures are not unusual. Nevertheless, relapse rates remain high (50% experience a relapse within 5 years).
      • Hoffman GS
      • Kerr GS
      • Leavitt RY
      • Hallahan CW
      • Lebovics RS
      • Travis WD
      • et al.
      Wegener granulomatosis: an analysis of 158 patients.
      • Gross WL
      Treatment of Wegener's granulomatosis in 1994.
      TMP/SMX decreases the relapse rate in some patients. The early observation by DeRemee that TMP/SMX had a beneficial effect on Wegener's granulomatosis in a woman treated for a urinary tract infection led to its use in selected patients with the disease.
      • DeRemee RA
      • McDonald TJ
      • Weiland LH
      Wegener's granulomatosis: observations on treatment with antimicrobial agents.
      Other antibiotics have not been shown to be useful.
      • DeRemee RA
      Empiricism and Wegener's granulomatosis [editorial].
      A recent double-blind, placebo-controlled, Dutch multicenter trial assessed the efficacy of TMP/SMX (160/800 mg twice daily for 24 months) in preventing relapses in patients with Wegener's granulomatosis in remission. At the end of the study, 82% of the treated patients remained in remission, as opposed to 60% in the placebo group. The original observation that TMP/SMX reduces the incidence of relapse in patients in remission was thus proved.
      • Stegeman CA
      • Tervaert JWC
      • de Jong PE
      • Kallenberg CGM
      • Dutch Co-trimoxazole Wegener Study Group
      Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis.
      • DeRemee RA
      Empiricism and Wegener's granulomatosis [editorial].
      The apparent beneficial effect of TMP/SMX on Wegener's granulomatosis raises important questions about the pathogenesis of this disease. A better understanding of its pathogenesis may lead to more effective and better tolerated therapy than is currently available.

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        Noninfectious orbital inflammations and vasculitis.
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        Diagnostic value and limitations of orbital biopsy in Wegener's granulomatosis.
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        Tumefactions as an extravascular manifestation of Wegener's granulomatosis.
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        • Kerr GS
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