Paula Durkin* was referred to us for evaluation of decreased vision and restricted movements of the right eye. The 37-year-old woman said that her problems had begun nine months earlier, with sinusitis. This had improved following antibiotics, steroids and sinus surgery.

Two months later, however, she developed recurrence of right periorbital pain and a right sixth nerve palsy. An orbital CT scan revealed an abnormality in the right sphenoid sinus with extension into the right orbital apex (Fig. 1). Again, there was clinical improvement with steroids (40 milligrams per day) and antibiotics, but repeat neuroimaging showed no improvement. Sphenoidectomy and biopsy of the sinus were performed and the tissue revealed inflammation and necrosis. No infectious process was identified.

During this nine-month period, vision on the right had declined from an initial acuity of 20/25 to counting fingers. Her symptoms and visual acuity were noted to wax and wane in direct correlation with her steroid dosage.

We Get a Look
By the time she was referred to us, the visual acuity of the right eye was counting fingers at six feet with a relative afferent pupillary defect, reduced color perception, proptosis, conjunctival redness and diminution of eye movements in all directions. Optic disc edema was present on funduscopy. Ms. Durkin’s left eye was normal and her general medical exam was unremarkable. 

CBC (complete blood count), BMP (basic metabolic panel), ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), RPR (rapid plasma reagin), ACE (angiotensin-converting enzyme) and thyroid panel were all within normal limits. ANA (antinuclear antibodies test) was positive at 1:320, cANCA (cytoplasmic pattern of antineutrophil cytoplasmic antibodies) was 1:256 (normal < 1:16) and PR3 (proteinase 3) > 100 (normal 3.5). A review of the biopsy material from the paranasal sinuses showed collagen necrosis and infiltration with polymorphonuclear leukocytes and eosinophils (Figs. 2a, 2b).

What’s Your Diagnosis?
(1) After recurrence of right periorbital pain and a right sixth nerve palsy, Ms. Durkin underwent a CT scan. This demonstrated soft tissue mass in the right orbital apex with displacement of the optic nerve. (2A) The biopsy material from her paranasal sinuses revealed granulomatous changes and infiltration with polymorphonuclear leukocytes and eosinophils. (2B) A higher power view of material illustrates extensive collagen necrosis (Hematoxylin and Eosin).

Diagnosis and Treatment
On the basis of clinical presentation, high cANCA and PR3 levels, and histopathology, we made the diagnosis of Wegener’s granulomatosis with orbital involvement. The patient was begun on cyclophosphamide (Cytoxan) 175 mg per day, and prednisone was reduced to 20 mg per day.

Within two months of beginning cyclophosphamide, visual acuity in the right eye improved to 20/80 with a decrease in right optic disc edema. Because of leukopenia, cyclophosphamide was reduced to 50 mg per day, and two months later there was no further clinical improvement. Therefore, cyclophosphamide was increased to 75 mg per day and prednisone reduced to 15 mg per day. One month later vision on the right was 20/25 and optic disc edema had resolved with temporal disc pallor.

Despite clinical improvement, over this five-month period there was slight growth of the right orbital inflammatory mass on follow-up CT scanning (Fig. 3). The patient was begun on infliximab (Remicade), which is a tumor necrosis factor-alpha (TNF-alpha) blocker. Follow-up imaging three months later demonstrated near complete resolution of the inflammatory process (Fig. 4).

CT Scans Show Clinical Course
(3) Five months after initiation of cyclophosphamide and prednisone with enlargement of orbital mass. (4) Three months after adjunctive therapy with infliximab. This scan shows near complete resolution of orbital inflammation.

Comment
Wegener’s granulomatosis is a systemic disorder of unknown cause. Clinically there are two forms—generalized and limited. Our patient had the latter. Wegener’s granulomatosis typically affects Caucasians in the fourth and fifth decades of life with a slight male predilection (1.5:1), though females are more commonly affected in cases with limited disease. It is rare, with a prevalence of 8.5 cases per million people.¹

Diagnosis. The diagnosis includes the triad of 1) necrotizing granuloma of the upper and lower respiratory tracts, 2) necrotizing vasculitis and 3) nephritis. Establishing the correct diagnosis relies upon a combination of histopathologic findings of granulomatous foci, collagen necrosis, infiltration of polymorphonuclear leukocytes and eosinophils combined with a positive cANCA titer (60 to 90 percent of patients).²

Pathogenesis. The pathogenesis is largely unknown but is felt to represent a hypersensitivity disorder. ANCA plays an important role through activation of phagocytic cells and is directed against PR3, a myeloblastin found on the plasma membrane of neutrophils from patients with Wegener’s. Moreover, TNF-alpha and interleukin-8, both of which are elevated in Wegener’s, induce the translocation of PR3 from intragranular loci to the surface of neutrophils.¹ This is why TNF-alpha blockers such as infliximab may be effective in this disease.³ In the systemic form, Wegener’s granulomatosis can affect virtually any organ system but generally involves the paranasal sinuses, lungs and kidneys. Cardiac, joint, skin and central nervous system involvement may also be encountered. Wegener’s may also involve both ocular and orbital tissues.

Ophthalmic disease. There are ocular findings in 16 percent of patients at presentation. These include uveitis, conjunctivitis, scleritis, peripheral ulcerative keratitis, retinal vasculitis and optic neuritis. Orbital involvement is most often due to contiguous spread of the inflammatory process from the paranasal sinuses.¹

Therapy. Therapeutic modalities in the past primarily depended upon the use of corticosteroids. In systemic cases treated with steroids alone, the two-year mortality rate was as high as 90 percent. More recently the addition of cyclophosphamide has improved the prognosis substantially with induced remission in systemic cases up to 93 percent. Current treatment recommendations are cyclophosphamide 2 mg per kg per day and prednisone 1 mg per kg per day.¹ Additional therapy includes prophylaxis against Pneumocystis carinii pneumonia (usually Bactrim, which is a combination preparation of trimethoprim and sulfamethoxazole). As in this case, TNF-alpha antagonists may be useful in patients refractory to conventional therapy.³ With improved treatment methods available, the prognosis for both forms of Wegener’s granulomatosis will continue to improve.

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1 Albert, D. M. et al. Principles and Practice of Ophthalmology, 2nd edition (Philadelphia: W. B. Saunders Company, 2000).
2 Perry, S. R. et al. Ophthalmology 1997;104: 683–694.
3 Stone, J. H. et al. Arthritis Rheum 2001;44: 1149–1154.

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Dr. Aldridge is in private practice in Bainbridge, Ga. Dr. Kline is chairman of ophthalmology at the University of Alabama in Birmingham, and he specializes in neuro-ophthalmology.

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* Patient name is fictitious.