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 38-year-old Asian man with a history of sinusitis status presented at the Ophthalmology outpatient department following a surgical intervention at another hospital 3 months previously, with complaints of gradual painless blurred vision and proptosis for 6 months. There was no periocular sensory change or recent trauma. His family history was unremarkable.\nOn ophthalmic examination, best-corrected visual acuity (BCVA) was 20/30 on the right eye (OD) and 20/40 on the left eye (OS). Slit-lamp and funduscopic examination results were normal. The pupil reacted sluggishly without a relative afferent pupillary defect. Color vision was normal. Ocular motility was intact without diplopia, but exophthalmometry measurements were 21.5 mm with base 112 mm using one accurately calibrated Inami exophthalmometer (Hertel K-0161; Inami & Co., Ltd., Bunkyo-ku, Tokyo, Japan) on both eyes (OU). There was neither periocular sensory change nor palpated mass in the lower eyelid.\nThyroid function tests revealed normal free thyroxine and thyroid-stimulating hormone levels, but serological studies showed extremely high serum concentrations of IgG4 (2650 mg/dL; normal range < 135 mg/dL); elevated serum concentrations of IgG (2630 md/dL; normal range 751.0–1560.0 mg/dL); abnormal erythrocyte sedimentation rate (31 mm/h; normal range < 15 mm/1 h); and high levels of total IgE (1903.00 IU/dL; normal range < 87.00 IU/mL). The calculated serum IgG4/IgG ratio was 100% (normal range < 6%). No eosinophilia was found in the blood.\nPostcontrast T1-weighted fat-saturated magnetic resonance imaging (MRI) images showed a “doughnut” sign encircling the right optic nerve, and inferior sheath enhancement surrounding the left optic nerve was visible on the coronal MRI images (Fig. a). Bilateral “tram-track” signs were evident on the axial images (Fig. b). Bilateral enhancing lesions at the pterygoid plate, pterygomaxillary fissure, and sella region, with involvement of both maxillary nerves, were visualized using gadolinium-enhanced T1-weighted MRI (Fig. c, d). Bilateral infraorbital nerve involvement was also evident on the MR images (Fig. d, e). Enlargement of extraocular muscles, especially severe at the bilateral inferior rectus, right medial rectus, bilateral superior rectus, and bilateral lateral rectus muscles, was noted on coronal MRI images (Fig. e). Mucosal thickening in the ethmoid, maxillary, sphenoid, and frontal sinuses was also visible.\nWe referred this patient to the Department of Otolaryngology in our hospital for surgical biopsy. Biopsy with functional endoscopic sinus surgery was performed, and a tissue specimen measuring 0.5 × 0.3 × 0.2 cm was sent to the Department of Pathology for further testing. The result revealed chronic sinusitis with dense infiltrate of lymphocytes and plasma cells. Chronic inflamed granulation tissue, aggregates of foamy histiocytes, and fibrosis of sinonasal tissue were also noted (Fig. a–c). Organisms were not identified in the Periodic Acid-Schiff stain and the Acid-fact stain tests. Immunhistochemistry revealed CD138 accentuated plasma cells (Fig. d) and highlighted numerous IgG4-positive plasma cells (> 50 IgG4-positive plasma cells per high-power field), of which over 40% were IgG-positive plasma cells (Fig. e, f).\nThe patient underwent a treatment regimen comprising oral systemic corticosteroids (prednisolone 1 mg per kg body weight daily) for 2 weeks followed by slow tapering. Visual acuity improved to 20/25 (OU) 1 month after initiating treatment. Four months after the initial treatment, the vision got worse again, with the BCVA dropping to 20/30 (OD) and 20/50 (OS), respectively. Visual field test showed parafoveal scotoma (OD) and an enlarged blind spot (OS). Visual evoked potentials indicated bilateral delayed P100 latency (Fig. f). No active lesions were found after systemic screening. Based on the combined clinical, radiographic, and histopathologic findings, the final diagnosis was IgG4-RD with bilateral optic perineuritis, branches of trigeminal nerves involvement, and pansinusitis.\nThe patient underwent another course of oral prednisolone daily for 2 weeks with gradually tapering of dosage. This was followed by treatment with the immunosuppressive agent azathioprine (50 mg, twice daily). The final BCVA was 20/20 (OD) and 20/25 (OS) during the follow-up period of 2 years.