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Male presents with left-sided, painful proptosis, decreased vision: What is diagnosis?
By Courtney Y. Kauh, MD, MS; Cesar A. Briceno, MD; Victor M. Elner, MD, PhD; Christine C. Nelson, MD, FACS
A 69-year-old African American man was transferred from an outside hospital, having been brought in from his nursing home for worsening left orbital proptosis of unknown duration.
The patient had developed dementia over the course of 1 year and was largely uncommunicative and hard of hearing. However, he was able to report painful swelling of his left eye for about 3 months.
His past medical history, obtained from nursing home records, confirmed his 3-month history of left ocular proptosis and was significant for microscopic hematuria and end-stage renal disease of unknown etiology. Other diseases listed were cerebrovascular accident, lymphoma, hypertension, diabetes, thyroid disease, arthritis, and vocal cord granuloma.
His ocular history was significant for cataracts, bilateral uveitis, and elevated left IOP. Medications included warfarin and several drugs for kidney disease and hypertension, as well as brimonidine in the left eye.
His visual acuity was 20/100, right and no light perception, left. He had a left afferent pupillary defect. IOPs were 17 mm Hg, right and averaged 34 mm Hg, left.
There was 6 mm of relative left ocular proptosis with increased resistance to retropulsion. Sensation was intact and symmetric over the cranial nerve V1-V3 distributions, bilaterally. The soft, boggy left upper eyelid was easily elevated manually.
Right ocular ductions were normal, but ductions of the left hypotropic and exotropic eye were absent (Figures 1 and 2).
The patient was afebrile and hypertensive; laboratory studies showed hypokalemia, hypercalcemia, azotemia, and elevated creatinine, and he had a normal white blood cell count.
The computed tomography (CT) scan from the referring hospital revealed a mass occupying most of the left orbit, extending into the orbital apex. The mass caused displacement and distortion of the globe and optic nerve.
His paranasal sinuses appeared well pneumatized, but there was complete bilateral opacification of the mastoid sinuses and middle ear cavities (Figures 3 and 4).
The differential diagnosis for his unilateral proptosis included: acute etiologies such as infectious (cellulitis), hemorrhagic (retrobulbar hemorrhage), and vascular (cavernous sinus thrombophlebitis) causes, as well as chronic etiologies such as inflammatory (Graves’ disease, sarcoidosis, ANCA-associated vasculitides, idiopathic orbital inflammatory pseudotumor), and malignant (lymphoma, lacrimal gland tumor) causes.
Given the patient’s history and clinical presentation, a chronic process was suspected. Because of his history of lymphoma and concern that the orbital mass represented a recurrence, orbital biopsy was performed through a lid crease approach to obtain a tissue diagnosis.
Histopathologic findings were diagnostic of Wegener’s granulomatosis.
Further evaluation of the patient revealed elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), as well as positive C-ANCA levels all of which confirmed the diagnosis. A CT scan of the chest was negative for pulmonary involvement.
One month after promptly beginning cyclophosphamide and prednisone treatment, his orbital proptosis was found to be improved.
However, 4 months later, the proptosis worsened and the patient was switched from cyclophosphamide to rituximab, which he is currently continuing.
Wegener's granulomatosis is an idiopathic, systemic inflammatory autoimmune disease that is characterized by a classical clinical triad of: granulomatous inflammation of the respiratory tract, necrotizing vasculitis, and glomerulonephritis.
Peak incidence is in the fourth to fifth decade of life, affecting the sexes equally. It is more common among Caucasians and rare in African Americans.1
Immunofluorescence staining for this disease is positive for cytoplasmic antinuclear cytoplasmic antibodies (c-ANCA) in 80-90% of patients.2
These antibodies are directed against enzymes in granules of neutrophils and monocytes, namely serine proteinase 3 (PR3) or myeloperoxidase (MPO).
Eye symptoms and signs are the first manifestation of Wegener’s granulomatosis in 15% of patients, while an additional 35% to 45% develop eye involvement during the course of their disease.1,3
Inflammation can occur in different parts of the eyes and may result in conjunctivitis, episcleritis, keratitis, scleritis, uveitis as well as vasculitis of the retina.2
Orbital involvement has been reported in 15% of patients.4
These patients may present with proptosis, diplopia, and lacrimal drainage system obstruction, as well as lid erythema, orbital pain, bony erosion, or compressive optic neuropathy.
Disease involving the orbit most commonly presents as subacute painful proptosis. Typically, it starts with gradually but progressively increasing pain and proptosis over 1 to 2 months, followed by rapid deterioration with exacerbated pain, inflammation, optic nerve compression, and visual loss.5
The classic features of Wegener’s granulomatosis are vasculitis, glomerulonephritis and granulomas of the upper and lower respiratory tract.
However, it can affect almost any organ system and often presents with nonspecific symptoms and signs, resulting in misdiagnosis or delay in diagnosis.
In 90% of patients, upper respiratory disease is often the initial presentation,1but it may be unrecognized for several months until other manifestations of Wegener’s granulomatosis arise. When the respiratory system is affected, nasal obstruction, nasal crusting, frequent nosebleeds, chronic sinusitis, and subglottic stenosis can occur.
Also pulmonary nodular disease and necrotizing granulomatous inflammation can occur and cause non-specific symptoms, such as cough, dyspnea, hemoptysis, and post-obstructive infection.
Renal involvement is common with about 80% of patients affected.2Inflammation occurring in the kidneys can lead to proteinuria and hematuria and if it is not treated aggressively, kidney failure may occur.
When the musculoskeletal system is involved, ill-defined myalgia and arthralgia or arthritis may be present.
Many kinds of skin rashes may occur, the most common form appearing as small purple or red dots on the lower extremities, known as palpable purpura.
About 21% to 45% of patients with generalized disease can have some degree of neurological involvement that can manifest as stroke, seizures, multiple cranial neuropathies, polyneuritis, and peripheral neuropathy.6Inflammation can also lead to blockage of eustachian tubes and cause chronic middle ear infections or directly result in hearing loss.
A limited form of the disease affecting fewer and less vital tissues with non-life threatening inflammation also exists.7
Laboratory studies usually reveal elevated ESR and CRP. In patients with renal involvement, urinalysis may show microscopic hematuria and proteinuria that are manifestations of underlying glomerulonephritis.
Results of serological testing for c-ANCA are positive in the majority of patients with systemic involvement and are positively correlated with disease activity. In limited disease, a negative c-ANCA result is more common. A negative result does not exclude the diagnosis of either form of the disease.
The gold standard for diagnosis of Wegener’s granulomatosis is a tissue biopsy, which demonstrates a constellation of microabscesses, granulomatous inflammation, and necrotizing vasculitis and often causing parenchymal necrosis. The inflammatory infiltrate may also include scattered neutrophils, giant cells, lymphocytes, plasma cells, and eosinophils. Focal areas of necrosis are often associated with obliteration of normal fat8(Figures 5 and 6).
The aim of therapy is to induce and maintain disease remission. Early effective treatment is important because it can significantly reduce morbidity and mortality.
Current treatment recommendations depend on the severity and activity of disease, with most cases treated using a combination of corticosteroids and a cytotoxic or biologic agent. Typical agents are cyclophosphamide and rituximab for initial treatment of active, severe disease followed by better-tolerated agents, including methotrexate or azathioprine for maintenance therapy. 9,10
If left untreated, the disease is often fatal. Historically about 90% of patients died within 2 years. Improved treatment regimens have resulted in improved survival and reduced morbidity with most studies now reporting a 5-year survival of 70% to 80%.11About one-third of patients relapse usually within 18 months of stopping treatment, but recurrence can occur at any time.12
Our patient presented with unilateral ocular involvement that led to a delayed diagnosis of Wegener’s granulomatosis. His medical history revealed end-stage renal disease, stroke, hearing loss, arthritis, and vocal cord granuloma, most or all of which were probably manifestations of the disease.
Wegener’s granulomatosis is a multisystem vasculitis that often presents with non-specific generalized symptoms and signs affecting various tissues. Because of this, delay in diagnosis is common.
However, early effective treatment significantly improves morbidity and mortality.
Ophthalmologic involvement is common and other systemic manifestations should be sought. It is important for ophthalmologists to keep this disease in their differential diagnosis when evaluating eye disease, because early recognition may significantly improve outcomes of this highly morbid disease.
1. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488–498.
2. Tarabishy AB, Schulte M, Papaliodis GN, Hoffman GS. Wegener's granulomatosis: clinical manifestations, differential diagnosis, and management of ocular and systemic disease. Surv Ophthalmol. 2010;55:429–444. doi:10.1016/j.survophthal.2009.12.003.
3. Pakrou N, Selva D, Leibovitch I. Wegener's granulomatosis: ophthalmic manifestations and management. Semin Arthritis Rheum. 2006;35:284–292. doi:10.1016/j.semarthrit.2005.12.003.
4. Sadiq SA, Jennings CR, Jones NS, Downes RN. Wegener's granulomatosis: The ocular manifestations revisited. Orbit. 2000;19:253–261.
5. Santiago YM, Fay A. Wegener's granulomatosis of the orbit: a review of clinical features and updates in diagnosis and treatment. Semin Ophthalmol. 2011;26:349–355. doi:10.3109/08820538.2011.588662.
6. Almouhawis HA, Leao JC, Fedele S, Porter SR. Wegener's granulomatosis: a review of clinical features and an update in diagnosis and treatment. J Oral Pathol Med. 2013;42:507–516. doi:10.1111/jop.12030.
7. Carrington CB, Liebow A. Limited forms of angiitis and granulomatosis of Wegener's type. Am J Med. 1966;41:497–527.
8. Fechner FP, Faquin WC, Pilch BZ. Wegener's granulomatosis of the orbit: a clinicopathological study of 15 patients. Laryngoscope. 2002;112:1945–1950. doi:10.1097/00005537-200211000-00007.
9. Langford CA. Update on the treatment of granulomatosis with polyangiitis (Wegener's). Curr Treat Options Cardiovasc Med. 2012;14:164–176. doi:10.1007/s11936-012-0165-x.
10. Geetha D, Seo P. Advances in therapy for ANCA-associated vasculitis. Curr Rheumatol Rep. 2012;14:509–515. doi:10.1007/s11926-012-0284-0.
11. Semple D, Keogh J, Forni L, Venn R. Clinical review: Vasculitis on the intensive care unit – part 2: treatment and prognosis. Crit Care. 2005;9:193–197. doi:10.1186/cc2937.
12. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response and relapse in antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. 1996;7:33–39.
Courtney Y. Kauh, MD, MS, is resident, ophthalmology and visual sciences, University of Michigan Kellogg Eye Center, Ann Arbor.
Cesar A. Briceno, MD, is assistant professor, ophthalmology and visual sciences, University of Michigan Kellogg Eye Center, Ann Arbor.
Victor M. Elner, MD, Ph.D, is Ravitz Foundation Professor, ophthalmology and visual sciences; professor, Department of Pathology, University of Michigan Kellogg Eye Center, Ann Arbor.
Christine C. Nelson, MD, FACS, is professor, ophthalmology and visual sciences; Bartley R. Frueh, MD and Frueh Family Collegiate Professor in Eye Plastics and Orbital Surgery; and professor, Department of Surgery, Plastic Surgery Section, University of Michigan, Ann Arbor.
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