A 79-year-old woman was referred to our institution with a 1-year history of tearing, blurry vision, pain, photophobia, and redness in her right eye. Past medical history was significant for breast cancer, which required right lumpectomy 14 years prior and left lumpectomy plus radiation that was completed about 1 year prior to referral. The patient’s symptoms in the right eye had begun about 1 month following the completion of the radiation treatment for breast cancer, at which point she was diagnosed with nodular scleritis inferotemporally in the right eye, and she was found to have elevated perinuclear accentuated anti-neutrophil cytoplasmic antibodies (p-ANCA), leading to suspicion for granulomatosis with polyangiitis. She was managed by multiple ophthalmologists and rheumatologists. Medical history also included insulin-dependent diabetes, hypertension, hyperlipidemia, anemia, and colon cancer about 16 years prior. There was a history of maxillary and sphenoid sinusitis, for which the patient had right mastoid surgery, as well as a history of bilateral ear tubes. The patient also had, at the time of presentation, bilateral renal oncocytomas treated with cryoablation, but renal function was normal. Past ocular history included open-angle glaucoma initially well-controlled with topical therapy alone but later exacerbated by an inflammatory/corticosteroid-induced component in the right eye. Prior to referral, the patient had been treated with oral prednisone, with good response, but experienced recurrences whenever the dose was tapered. She had also been treated with cyclophosphamide and indomethacin but had a history of poor response to azathioprine. Upon referral to our institution, best corrected visual acuity (BCVA) was 20/80 in the right eye. Slit-lamp examination demonstrated 360° of conjunctival and scleral injection, nodules in the temporal sclera, and 1+ nuclear sclerotic cataract. Dilated fundus examination and B-scan ultrasound showed panuveitis and serous retinal detachment associated with subretinal fluid (Fig. ). A “T” sign was also noted on ultrasound, consistent with posterior scleritis. Left eye exam was unremarkable. The differential diagnosis included inflammatory sclero-uveitis and intraocular lymphoma but favoring a diagnosis of inflammatory anterior/posterior scleritis and uveitis. An extensive work-up for sclero-uveitis was only positive for p-ANCA with a titer of >1:640 (normal <1:10). Pertinent negatives included rheumatoid factor, rapid plasma reagin, fluorescent treponemal antibody, and angiotensin converting enzyme. The leading diagnosis was granulomatosis with polyangiitis, and the patient was treated with oral prednisone, cyclophosphamide, and indomethacin and showed clinical improvement, with vision improving to 20/40.\nNine months later, our patient was referred again with an exacerbation of her inflammation after cataract surgery in the right eye (performed at an outside institution). Her BCVA was 20/200. Slit-lamp examination showed mild scleral injection with a fibrotic-appearing lesion adherent to the medial sclera. Dilated fundus examination demonstrated chorioretinal scars with subretinal fibrosis and pale optic nerve. The infiltrative fibrotic lesion on the sclera was biopsied, and histologic examination revealed mixed chronic inflammatory infiltrate with fibrosis consistent with orbital inflammatory pseudotumor (Fig. b–d). Although no actively necrotizing vasculitis was seen, a portion of the inflammation exhibited a vasculo-centric pattern, with hyalinization of vessels, raising the possibility that these findings represented the late stage of a vasculitic process, and accordingly, granulomatosis with polyangiitis remained in the differential diagnosis (Fig. b, c).\nTreatment subsequently included methotrexate and infliximab infusions, but the patient continued to have recurrent eye pain and eventually developed a blind, painful right eye with end-stage glaucoma and persistent vitritis, besides evidence of optic nerve sheath inflammation on imaging, leading to an enucleation. The histopathology of the globe showed necrotizing and fibrotic granulomatous scleritis and granulomatous panuveitis (Fig. ). Of note, microbial stains were negative. Chronic optic neuritis was also noted, with optic cupping and atrophy (Fig. a, e). There was serous detachment of the retina with subretinal protein, correlating with the clinical appearance (Fig. a). The retina exhibited severe atrophy, with chronic vasculitis seen in some of the retinal vessels (Fig. f), and a neovascular epiretinal membrane was appreciated overlying the pars plana. There were no atypical lymphocytes or any evidence of lymphoma on immunohistochemistry, with T cells (CD3-positive) far outnumbering the B cells (CD20-positive), and with in situ hybridization demonstrating a relatively even mixture of kappa- and lambda-positive plasma cells (not shown). Many of the plasma cells stained positive with IgG4 (Fig. g), i.e., about 70 per high-power field, comprising over 50 % of the total plasma cell population. (The total plasma cells were assessed with CD138 immunostain, not shown.) The previous episcleral/orbital biopsy was then retrospectively also stained with IgG4 immunostain, which likewise revealed positivity in >50 % of the plasma cell population (Fig. d). (Serum IgG4 was not obtained.)
A 54-year-old man with a 4-month history of recurrent sinusitis, 100-lb unintentional weight loss, gait instability, and generalized weakness presented with headache and painless, bilateral visual loss. Bilateral temporal artery biopsies were performed and showed no arteritis. Magnetic resonance imaging (MRI) of the brain revealed mild meningeal enhancement and a chronic subdural hematoma causing mild midline shift. Following surgical drainage, visual acuity remained unchanged, and his headaches worsened. Pertinent clinical findings were no light perception in both eyes, amaurotic pupils, and bilateral mild, temporal optic disc pallor. Ocular coherence tomography (OCT) of both optic nerves demonstrated normal nerve fiber layer thickness. Laboratory tests failed to suggest an etiology of his vision loss. Lumbar puncture showed lymphocytic pleocytosis but cytology and flow cytometry were negative for lymphoma. Repeat brain MRI was performed and demonstrated diffuse pachymeningeal enhancement (Fig. a) with possible involvement of the optic nerve sheath (Fig. b); a dural biopsy was performed.\nHistopathology demonstrated a dense infiltrate of lymphocytes and plasma cells, with no definite vasculitis or granulomatous inflammation (Fig. c, d). The possibility of marginal zone lymphoma was considered but was ruled out by immunohistochemistry, with T cells (CD3-positive) outnumbering B cells (CD20-positive), and with in situ hybridization revealing a kappa:lambda ratio of <4:1 among the plasma cells (not shown). In situ hybridization for Epstein-Barr virus was negative (not shown). Additionally, molecular genetic studies did not show any evidence of a clonal IgH gene rearrangement by polymerase chain reaction (PCR). However, IgG4 immunostain was markedly positive, with 40 IgG4-positive cells per high-power field (HPF), comprising over 40 % of the total plasma cell population (Fig. e, f). (The total plasma cell population was assessed with CD138 immunostain, and IgG immunostain was also obtained, showing that all IgG-positive cells were also IgG4-positive, i.e., IgG4:IgG ratio of 1, not shown). Subsequent bone marrow biopsy also showed no evidence of lymphoma (small CD19-positive B-cell population with normal kappa:lambda light chain ratio), and fine-needle aspiration biopsy of a left supraclavicular lymph node showed similar findings negative for lymphoma.\nOn his systemic work-up, p-ANCA was borderline positive, and serum IgG showed elevated IgG4 subclasses (148.0; normal range 2.4–121.0). Accordingly, the diagnosis of IgG4-related meningeal disease was made. The patient was started on aggressive immunosuppression with high-dose corticosteroids to be followed by either cyclophosphamide or rituximab. However, due to insurance issues, he was able to receive only methotrexate. There was near-total resolution of meningeal enhancement on repeat MRI, but his visual acuity improved to only bare light perception in both eyes. He remains stable on methotrexate almost 1 year from his diagnosis.