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June 22, 2023
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Woman presents with periorbital edema, ptosis and ocular redness

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A 54-year-old woman presented to the emergency department at Beth Israel Lahey Hospital with episodes of unmeasured fever, left-sided facial and periorbital swelling, and conjunctival redness for 12 days.

She reported sudden right-sided hearing loss 20 days prior, 2 months after an upper respiratory infection for which she was seen by an outside otolaryngologist and was prescribed a 60 mg oral prednisone taper with minimal improvement. Seven days before the emergency visit, she was started on trimethoprim/sulfamethoxazole and a second oral prednisone taper by the same provider after developing left ear “fullness” and swelling of her feet and ankles despite being on treatment.

1. A) External photograph shows left ptosis with mild left eyelid edema. The left facial edema was not appreciated on this exam. B) Exposure of the supero-temporal bulbar and tarsal conjunctiva shows irregular and hyperemic mass at the location of the lacrimal gland. Source: William Binotti, MD, Susan M. Tucker, MD, and Sarkis H. Soukiasian, MD
Yi Ling Dai
Teresa P. Horan

She denied vision changes, pain with extraocular movement, flashes, floaters, discharge, diplopia, vertigo, nausea, confusion, weakness or facial drooping. She had no ocular history. Her family history was significant for colon cancer in her father, rheumatoid arthritis in her mother, celiac disease in her sister and aunt, and autoimmune hepatitis in her sister.

Examination

Best corrected visual acuity was 20/20 in both eyes. Pupils were equally reactive to light with no afferent pupillary defect. IOP was 9 mm Hg in the right eye and 11 mm Hg in the left eye. Extraocular movements were intact and confrontation visual fields were full bilaterally. External examination showed left ptosis and mild periorbital edema (Figure 1a). There was no proptosis or facial paralysis. Notably, the facial edema had resolved after the last course of steroids. Ocular examination showed left conjunctival hyperemia with no perilimbal flush and a prominent, irregular mass at the location of the lacrimal gland (Figure 1b). There was no apparent feeder vessel or abscess collection. No signs of scleritis, keratitis, conjunctival ulceration or anterior chamber cells were noted. Dilated fundus exam was unremarkable.

What is your diagnosis?

The initial differential diagnosis can be quite broad for superotemporal orbital masses that can cause ptosis, periorbital edema and ocular redness.

These mainly include infectious causes such as herpes zoster, which could explain the hearing loss and facial/periorbital swelling. However, vesicular rash and pain are the hallmark signs whereas an orbital mass is not typical of its clinical presentation. Bacterial facial and periorbital cellulitis were initially considered, which was why the patient was treated with the antibiotic and prednisone taper by the outside provider. In cases of orbital cellulitis, patients typically present with pain with extraocular movement, proptosis, restriction of extraocular movement or decreased vision. Of note, clinical signs may be more pronounced in the setting of orbital abscess formation. Both orbital and preseptal cellulitis can present with periorbital edema and erythema; however, orbital mass formation is uncommon. Neoplasms, such as lacrimal gland adenoid cystic carcinoma, pleomorphic adenoma, orbital fibrous histiocytoma or metastatic carcinoma, are also high on the differential. Given the patient’s positive family history for autoimmune diseases, one should also consider systemic inflammatory diseases such as sarcoidosis, amyloidosis and vasculitis. Idiopathic orbital inflammation is also possible, although unlikely in the absence of ocular pain.

Management

To investigate the superotemporal mass, CT of the orbits, sinus and head with contrast was performed. A well-circumscribed 22-mm enhancing mass in the left superolateral extraconal orbit was noted in the expected location of the left lacrimal gland (Figure 2). There were no signs of optic nerve compression, extraocular muscle involvement or periorbital bone erosion. Partial opacification of the left mastoid air cells and middle ear cavity was also noted. Otherwise, the paranasal sinuses and the right mastoid air cells were clear.

The patient’s laboratory workup was notable for an elevated C-reactive protein (CRP) of 52.3, positive antineutrophil cytoplasmic antibodies (ANCA) with positive anti-proteinase 3 (PR3) and negative myeloperoxidase, blood in the urine, and an elevated protein/creatinine ratio of 0.4 (normal 0.3). The remaining laboratory studies, including red and white blood cell count, platelets, ACE and lysozyme, were within normal range. Infectious workup, including FTA-ABS, QuantiFERON Gold, and hepatitis B and C serologies, was negative. Additionally, ANA, anti-SSA, anti-SSB and IgG4 tests were negative.

The constellation of hearing loss, periorbital swelling, ptosis and a lacrimal gland/orbital mass in the setting of elevated CRP and ANCA positive testing suggested a vasculitic process, specifically granulomatosis with polyangiitis (GPA). She was subsequently started on 60 mg of oral prednisone. An external lacrimal gland biopsy via the conjunctiva was performed. Pathology showed several lymphoid aggregates with occasional plasma cells with no evidence of granulomas or vasculitis.

2. Computerized tomography of head and orbit with contrast shows an enhancing 22 mm mass lesion in the left supero-temporal extraconal orbit, in the expected location of the left lacrimal gland. No signs of EOM, globe or optic nerve involvement.

A repeat lacrimal gland biopsy via an anterior orbitotomy was performed for a larger tissue sample, which similarly showed no evidence of GPA or lymphoma. At this point, the patient had established care with a rheumatologist, who started the patient on a rituximab induction treatment and a slow prednisone taper. In this case, the clinical suspicion was high enough for PR3-ANCA positive vasculitis with lacrimal gland and inner/middle ear involvement despite inconclusive pathohistology results. Two months after the initial diagnosis, the patient was tolerating the maintenance rituximab without issues and reported improvement of her ocular hyperemia and left-sided hearing loss, whereas her right hearing loss persisted. In addition, further testing by nephrology confirmed microhematuria, elevated protein/creatinine ratio and atypical red blood cells, suggesting an early manifestation of renal involvement.

Discussion

ANCA-associated vasculitides are a heterogeneous group of rare autoimmune diseases of unknown cause, characterized by inflammatory cell infiltration of small blood vessels, with or without necrosis. Clinical presentation can range from a focal skin rash to fulminant multisystem involvement. ANCA-associated diseases are comprised mainly of GPA (formerly known as Wegener’s granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). The disease is more common in patients older than 60 years. Despite significant advances in early diagnosis, specifically with ANCA testing, and treatments such as immunosuppressive therapy, mortality for GPA is still high if untreated. The estimated 5-year survival rate for GPA is 74% to 91%. Diagnosis is often delayed by more than 6 months in 33% of patients, highlighting the importance of detailed history-taking, diagnostic testing and systems-based investigation.

For ANCA-positive patients with systemic manifestation, a combination of glucocorticoids with rituximab or cyclophosphamide is indicated for induction therapy. Cyclophosphamide was the first immunosuppressive drug that significantly decreased the mortality of the disease (which was more than 80% if left untreated). Currently, there is an overall preference for rituximab due to its safe side effect profile, noninferiority to cyclophosphamide in clinical trials, and increased effectivity in relapsing disease. After successful remission post-induction, maintenance therapy, such as rituximab, azathioprine or methotrexate, is generally indicated for at least 18 to 24 months.

Orbital involvement as the presenting feature can occur in up to 16% of GPA cases in either limited or systemic disease. More specifically, lacrimal gland involvement of the disease is rare but has been reported as the presenting feature of GPA in a few case reports. In these cases, diagnosis can be more difficult due to nonspecific clinical features. Interestingly, Kalina and colleagues showed in a case series that the classic triad of vasculitis, tissue necrosis and granulomatous inflammation is present in only 25% to 50% of orbital biopsies. This highlights the importance of clinical correlation, ANCA testing and extraorbital biopsy whenever available and feasible.

A retrospective study by Tan and colleagues compared clinical and imaging features of 247 patients who had undergone orbital biopsy to help distinguish GPA with lacrimal gland involvement from other types of orbital inflammation. There were 69 cases of confirmed GPA; the mean age at presentation was 36.7 ± 16.7 years, and the interval between presentation and diagnosis ranged from 3 months to 20 months. In this study, signs of sinonasal involvement and bone erosion on imaging were considered distinguishing features in patients with GPA compared with those without GPA (P < .05). Imaging signs of sinonasal involvement included mucosal thickening, opacification of the sinuses, and changes of the mucosal walls or turbinates; bone erosion included destruction of the nasal septum, cavity and turbinates, and orbital walls. Our patient showed none of these imaging findings, and the biopsy revealed nonspecific inflammatory changes without GPA confirmation.

One could speculate on whether our case was a very early presentation of ANCA-associated vasculitis or GPA with no classic clinical signs and an inconclusive lacrimal gland biopsy. It is worth nothing that it has been previously reported that lacrimal gland biopsies often have a low biopsy-positive yield. The previous steroid courses could have also masked the biopsy results or a possible sinonasal involvement on imaging studies. Nevertheless, we highlight the importance of early immunosuppressive therapy when the clinical suspicion is high and of a multidisciplinary approach to prevent permanent vision loss or other serious systemic outcomes, including death.