The patient was a 58-year-old woman with left eye ptosis and vision loss.
History of the present illness
The patient had a history of Wegener's granulomatosis (WG) first diagnosed in 1995, 13 years before her presentation with the current illness. Her WG had been characterized by a migratory, pauciarticular arthritis; leukocytoclastic vasculitis of the skin; elbow nodules caused by cutaneous extravascular necrotizing granulomata (Churg-Strauss granulomas) (Figure 1); biopsy-proven pauci-immune glomerulonephritis; and necrotizing pulmonary vasculitis. The patient had been treated virtually continuously between 1995 and 2008 with a variety of agents, including several courses of high-dose glucocorticoids, oral cyclophosphamide, and azathioprine.
The patient presented to the Rheumatology Clinic with symptoms for 2 weeks of impaired vision in her left eye and drooping of the left eyelid. In addition, the patient noted that she had had frequent low-grade migraine headaches for at least 6 months. The headaches had worsened over the 2 weeks that preceded her clinic visit and were accompanied by nausea, vomiting, and pain in the region of her left cheek. The headaches were cyclical in nature, worsening one day but subsiding the next. The patient believed that each headache cycle was accompanied by worsening of vision in the left eye and more severe drooping of her left upper eyelid. The patient denied any history of migraine headaches.
The patient had had 2 similar episodes of vision loss in the left eye within 6 months of her presentation. On both occasions, she had presented with amaurosis fugax and vision loss in the left eye. She had been admitted to an outside hospital, undergone magnetic resonance imaging (MRI) studies that had been read as negative, and received the diagnosis of optic neuropathy secondary to WG. During both hospital admissions, the patient had been treated with methylprednisolone 1 gm/day for 3 days, with resolution of her headaches and subjective improvement in her vision.
One month after her second admission for ocular dysfunction, the patient was evaluated as an outpatient by the Neuro-ophthalmology Service at our hospital. At that time, the patient was found to have normal afferent visual fields in both eyes except for a residual inferior arcuate scotoma in the left eye.
Past medical history
WG had been diagnosed when the patient was age 45 years. Her most recent disease flare before the presumed optic neuropathy had occurred 2 years before presentation, at which time she had developed pulmonary infiltrates and undergone a lung biopsy that showed necrotizing, granulomatous inflammation. Over the previous 13 years, she had been treated with combinations of prednisone, azathioprine, and cyclophosphamide. She had no history of glucose intolerance.
At the time of her hospitalization, she was receiving prednisone 10 mg/day. In addition, 3 months before admission she had undergone a course of treatment with rituximab (2 1-gm infusions separated by 2 weeks). This treatment had led to the depletion of circulating B cells. The patient was receiving trimethoprim/sulfamethoxazole as prophylaxis against Pneumocystis jiroveci pneumonia.
Family and social history
The patient's family history was negative for rheumatic diseases, cancer, and ophthalmologic problems. She was receiving disability at the time of admission but had previously worked in social services, delivering meals to the elderly. She lived with her husband and had no children. She had an 18 pack-year smoking history and smoked approximately 10 cigarettes per day. She rarely drank alcohol. Her travel history was remarkable for a trip to Florida 10 months earlier, but otherwise she had traveled little outside of New England.
Review of systems
The patient reported sinus congestion on the left side that was worse at night. She denied any bloody noses or nasal crusting, ocular erythema, oral ulcers, fevers, chills, neck stiffness, photophobia, hearing changes, cough, rhinorrhea, sore throat, or weakness.
Upon admission to the floor, the patient had a temperature of 97.0°F. Her pulse was 108/minute and her blood pressure was 135/79 mm Hg. She was breathing at a rate of 20/minute and her oxygen saturation was 92% on room air. She was a thin woman who appeared older than her stated age. She had an obvious left ptosis. There was no tenderness over her frontal or maxillary sinuses and no neck stiffness. Her dentition was normal. The tympanic membranes and hearing were normal. No cervical or supraclavicular adenopathy was present. Examination of her heart revealed a normal S1 and S2 with no murmurs, rubs, or gallops. Her lungs were clear and her abdomen soft, without hepatosplenomegaly or masses. The radial and pedal artery pulses were normal. She had thin, fragile skin but no rash. The previous Churg-Strauss granulomas over the elbows and knees were not evident.
Upon neurologic examination, the patient's pupils were both 4.5 mm in dim light, but the left pupil was poorly reactive and demonstrated an afferent pupillary defect. In addition to her left ptosis, the patient had severely impaired elevation, depression, abduction, and adduction of the ipsilateral eye, consistent with paresis of the left oculomotor (III), trochlear (IV), and abducens (VI) cranial nerves. Facial sensation was intact, with the exception of slightly impaired sensation in the distribution of the ophthalmic division of the left trigeminal nerve (V1). The patient was only able to detect the movement of large objects in the peripheral visual field of the left eye. The visual acuity and ocular movements of the right eye were normal, as was the remainder of the neurologic examination.
Initial laboratory evaluation
The patient's erythrocyte sedimentation rate was 86 mm/hour (normal value <20) and her serum C-reactive protein level was 37.6 mg/liter (normal value <8.0). The serum creatinine and hematocrit levels were 1.1 mg/dl and 34.5%, respectively. The peripheral white blood cell count was 9,500/mm3. Other laboratory results are shown in Table 1. Flow cytometry was performed to assess the status of her B cells.
Table 1. Serum laboratory results at presentation*
NA = not applicable; ANCA = antineutrophil cytoplasmic antibody; PR3 = proteinase 3.
White blood cell count, per mm3
Differential cell count, %
Platelets, per mm3
Mean corpuscular volume, femtoliters
Urea nitrogen, mg/dl
Total bilirubin, mg/dl
Alkaline phosphatase, units/liter
Aspartate aminotransferase, units/liter
Alanine aminotransferase, units/liter
Prothrombin time, seconds
International normalized ratio
Partial thromboplastin time, seconds
Positive (1:80, speckled)
PR3 ANCA positive (326)
Erythrocyte sedimentation rate, mm/hour
C-reactive protein level, mg/liter
Rapid plasma reagin
Initial hospital course
Computed tomography (CT) scans of the brain, sinuses, and chest were performed. The brain and sinus CT scans demonstrated complete opacification of the left maxillary sinus with signs of chronic inflammatory changes (Figure 2A). The Otolaryngology Service performed a rigid fiberoptic examination that revealed no evidence of a bacterial or fungal infection in the nose. The left middle meatus was swabbed for cultures, which were negative for bacteria and fungi. A chest CT scan revealed multiple cavitary and non-cavitary lesions in all lung lobes, some with surrounding “ground glass” opacity (Figure 2B).
MRI and MR venogram studies showed patent cavernous sinuses, but the tentorial and falcine dura had increased fluid-attenuated inversion recovery signal and enhanced abnormally following gadolinium administration (Figure 3). There was also a subtle signal abnormality in the left orbital apex (Figure 4). A lumbar puncture was performed. The cerebrospinal fluid (CSF) protein level was 61 mg/dl (normal range 15–45). Tubes 1 and 2 had 12 and 9 white blood cells, respectively, with a lymphocytic predominance. There were no red blood cells in the CSF.
A serum assay for antineutrophil cytoplasmic antibodies (ANCAs) was positive by indirect immunofluorescence. An enzyme immunoassay for antibodies directed against proteinase 3 was positive at 326 units (normal value <20). This had increased from 102 units only 1 month before her admission. Antibodies to myeloperoxidase were negative, as was an assay for antibodies to Borrelia burgdorferi, a rapid plasma reagin assay, and blood cultures.
A 58-year-old woman with a history of WG and 2 prior episodes of glucocorticoid-responsive left optic neuropathy presented with headaches, a central scotoma of the left eye, and cranial nerve dysfunction involving the left third, fourth, fifth, and sixth nerves. She had a lymphocytic pleocytosis in her CSF and multiple abnormalities on imaging studies of her sinuses, lungs, and meninges.
The patient's left eye vision loss and cranial nerve abnormalities were consistent with localization of the lesion to the orbital apex (Figure 5). She was diagnosed as having an orbital apex syndrome. Orbital apex syndromes are constellations of neurologic findings that result from dysfunction of the optic, oculomotor, and abducens nerves, as well as involvement of the ophthalmic division of the trigeminal nerve. Some patients also have involvement of the vascular supply and drainage of the posterior orbital regions, the sympathetic innervation of the orbit, and the sensory nerves that supply the forehead. Orbital apex syndromes result from a variety of pathologic processes that lead to crowding or infiltration of the structures within the orbital apex.
The major diagnostic considerations for an orbital apex syndrome in an immunosuppressed patient are an opportunistic infection, a neoplasm, thrombosis of the cavernous sinus, or a space-occupying lesion of some other type (Table 2). We consider each of these major diagnostic possibilities in turn.
Table 2. Differential diagnosis of orbital apex syndromes (ref.2)
Giant cell arteritis
Cavernous sinus thrombosis
Infections are common and potentially life-threatening complications of the treatment of WG. Indeed, infectious complications of therapy are now more likely to lead to death in this disorder than WG is itself (1). It is therefore essential to consider a broad differential of infectious etiologies and to approach the patient with a thoughtful diagnostic evaluation before initiating any immunosuppressive treatment.
This patient's chronic course of WG and the consequent need for years of immunosuppression placed her at particular risk for an opportunistic infection. Moreover, damage to her sinuses and lungs from previous periods of active WG had created potential sites at which opportunistic microbes might thrive. The proximity of the maxillary sinus to the orbital apex was consistent with the spread of infection into the cavernous sinus from a focus within the sinuses. Cavitary pulmonary lesions are among the classic lung findings in WG but are also highly typical of a number of mycobacterial and fungal infections.
Organisms commonly involved in cavernous sinus infections include Mucormycosis, Aspergillus, Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus pneumoniae, Actinomyces, Treponema pallidum, herpes zoster, gram-negative bacilli, and anaerobes (2). Many patients with fungal rhinosinusitis are immunocompromised or have diabetes mellitus as an underlying risk factor. As an example, diabetes mellitus is a notorious predisposing condition for Mucormycosis infections. However, patients do not have to be overtly immunocompromised in order to develop a serious rhinosinusitis infection. The condition known as allergic fungal rhinosinusitis is a chronic disorder that can develop in immunocompetent individuals (3, 4).
The lymphocytic pleocytosis and the meningeal enhancement on the MRI findings were concerning for the possibility of an infection in the orbital apex that had extended into the CSF. Our patient had negative sinus cultures and a negative rapid plasma reagin test result. In addition, her sinuses had been visualized by the Otolaryngology Service, which deemed the likelihood of infection low. Moreover, the patient's sinus imaging was also not consistent with an acute, invasive sinusitis.
Nasopharyngeal cancer, lymphoma, pituitary adenoma, meningioma, and metastatic disease can all cause an orbital apex syndrome (2). Our patient had been treated intensively with cyclophosphamide and azathioprine, both of which are associated with secondary malignancies (5). Her previous hospital admissions for optic neuropathy might have been caused by a secondary malignancy that had regressed following high-dose glucocorticoid treatment. A lymphoma would be particularly likely to partially respond to such therapy. However, her brain CT scan did not demonstrate any mass lesions, and flow cytometry of her CSF was negative.
Cavernous sinus thrombosis
A septic cavernous sinus thrombosis can occur in the setting of periorbital infections, leading to an orbital apex syndrome. An aseptic cavernous sinus thrombosis can also occur in the setting of idiopathic inflammation. Patients with WG are known to be at risk for venous thrombotic events, but these events are typically deep venous thromboses of the legs, frequently complicated by pulmonary emboli (6). Cavernous sinus thrombosis, in contrast, is not a complication that is common to WG. The patient's negative MR venogram result significantly decreased the possibility of this complication (7).
WG can be associated with a host of ocular and orbital complications. These include inflammatory masses within the orbit, episcleritis, conjunctivitis, granulomatous inflammation of the tarsal conjunctivae, scleritis, peripheral ulcerative keratitis, uveitis, retinitis, retinal vascular disease, optic neuropathy, and oculomotor cranial neuropathy (8–13).
Optic neuropathy, which had been diagnosed in our patient within 6 months of her admission, has been reported to occur in patients with WG in multiple case reports and pathology reviews (8, 14, 15–18). The optic neuropathy in patients with WG generally occurs either in isolation or with cranial nerve palsies, meningeal involvement, or ocular manifestations that extended to other portions of the eye. Three mechanisms leading to optic neuropathy in WG have been described: compression of the optic nerve from an inflammatory mass within the orbit, granulomatous inflammation of the optic nerve itself, and anterior ischemic optic neuropathy from vascular compromise of the posterior ciliary artery. The last mechanism is analogous to the most common pathway through which patients with giant cell arteritis lose vision.
It was conceivable that our patient's orbital apex syndrome had been caused by WG-associated inflammation within her orbital apex, manifested by the very subtle signal observed on her MRI finding (Figure 4). This lesion, too small to be detected as a mass lesion on her brain CT scan, was situated as such that it could have accounted for all of the patient's cranial nerve lesions. WG can also cause chronic meningitis that is identical to that with which our patient presented: headache, low-grade lymphocytic pleocytosis, and meningeal enhancement upon MRI (19). In addition, cavitary pulmonary lesions and sinus disease are consistent with (although not diagnostic of) WG. Therefore, WG was a viable explanation for the patient's lymphocytic pleocytosis, dural enhancement, pulmonary cavitary lesions, and maxillary sinusitis, as well as her orbital apex syndrome (20, 21).
One point arguing against WG as a cause of our patient's illness was the fact that she had been treated aggressively for this condition and had been treated with rituximab, an agent designed to deplete B cells, only 3 months earlier. Preliminary investigations of rituximab for the treatment of WG have been encouraging (22, 23), and the results of a randomized trial are awaited (Specks U: unpublished observations). Flow cytometry on the patient's peripheral blood indicated that she was still B cell depleted. Despite this, her serum ANCA titer had increased over the 1 month before admission.
Diagnosis and subsequent course
Infections, malignancies, cavernous sinus thrombosis, and WG were all carefully considered in this patient's differential diagnosis. The patient had had no fevers during either the 2 weeks since the recurrence of her ocular symptoms or over the 6 months that had preceded her presentation. This fact argued against infection, even though her glucocorticoids and other immunosuppressive therapies might have masked systemic signs of an infection. The 2 previous episodes of vision loss also argued against infection, as did the benign findings by the Otolaryngology Service upon examination of the patient's nose and sinuses. However, complete reassurance about an infection in this setting was not possible without surgical exploration of the cavernous sinus. Similar considerations held for malignancies that could have caused this problem. Cavernous sinus thrombosis appeared to be excluded with a reasonable degree of certainty by the negative MR venogram result (7).
On the other hand, several features compellingly argued for WG as the cause of the patient's presentation. First, the 2 previous responses of her vision loss to high doses of glucocorticoids had not led to dissemination of the process, as one might anticipate in the setting of an infection. Furthermore, the patient had findings on her chest CT scan that were consistent with newly active disease in her lungs. Finally, her ANCA titer had risen significantly (despite the absence of peripheral B cells). In view of these considerations and the significant potential morbidity associated with performing a biopsy of the orbital apex region, the decision was made to treat the patient empirically for WG.
THE PATIENT'S COURSE
The patient received 1 gm of methylprednisolone intravenously each day for 3 consecutive days, and was then discharged receiving prednisone 60 mg daily. Her headaches resolved completely and she recovered full extraocular muscle function, including resolution of her ptosis. However, the central scotoma remained unchanged. Followup visual fields testing 4 months after discharge showed a persistent central visual field defect of the affected eye.
WG is an ANCA-associated necrotizing granulomatous disease that classically involves medium and small vessels. In the classic, disseminated form of the disease, both the renal and pulmonary vascular beds are involved. However, WG is a remarkably protean disorder that can present with neurologic, musculoskeletal, dermatologic, gastrointestinal, urologic, cardiac, or ophthalmologic symptoms. Among the multiple ocular complications of WG, orbital apex syndrome has been described (8, 12, 13).
The rheumatologist should consider an orbital apex syndrome when a patient presents with deep, aching orbital pain, diplopia, conjunctival injection, proptosis, loss of vision, ocular motor dysfunction, or combinations of these features. In severe orbital apex syndromes, the patient presents with full ptosis, a dilated pupil, and a numb eye that does not move in any direction. Such a presentation localizes the lesion to the apex of the orbit adjacent to the carotid artery and cavernous sinus, the region through which cranial nerves II, III, IV, VI, and V1 course (Figure 5).
More subtle presentations are challenging and are often missed. For instance, mild ptosis and diplopia in a patient with some orbital pain or the occurrence of a Horner's syndrome in a patient with an abducens neuropathy also suggests an orbital apical localization. In WG, orbital apex syndromes probably stem from a primary granulomatous process that is akin to the process leading to orbital pseudotumors. Alternatively, an orbital apex syndrome could result from the extension of inflammation that originates within a paranasal sinus.
The timing of the patient's presentation with regard to her rituximab therapy is worthy of comment. She developed her full-blown orbital apex syndrome only 3 months after undergoing B cell depletion therapy with rituximab, and she remained B cell depleted at the time of her presentation. Perhaps paradoxically, however, her serum proteinase 3 ANCA assay actually indicated an increase in her ANCA titer at presentation compared with her titer at the time of the first rituximab infusion. These facts underscore some important points about the emerging potential role of rituximab therapy in WG. Although peripheral B cells are depleted by therapies directed against CD20, long-lived plasma cells (which do not bear CD20 on their surfaces) can continue to produce ANCA through stimuli that remain poorly understood. If rituximab proves to be effective in WG, the mechanism of its efficacy will require further elucidation (24). In addition, as our case illustrates, if rituximab is effective for some patients with WG, it is not likely to be effective in all patients. Additional studies will be required to understand the most appropriate clinical settings in which to employ B cell depletion as a treatment strategy.
Orbital apex syndrome caused by Wegener's granulomatosis.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Stone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Cooley, Pless, Stone.
Acquisition of data. Cooley, Pless, Stone.
Analysis and interpretation of data. Cooley, Pless, Stone.