Journal of Neuro-Ophthalmology, March 2014, Volume 34, Issue 1

Bilateral Optic Nerve Involvement in Immunoglobulin G4Related Ophthalmic Disease

To describe a presumptive case of immunoglobulin G4-related ophthalmic disease (IgG4-ROD) with bilateral optic nerve involvement and to review the clinical features of this entity. A 62-year-old man presented with bilateral blurred vision. He had a history of sinus surgery, and a biopsy specimen showed dense infiltration of IgG4-positive plasma cells. His visual acuity was 20/25, right eye, and 20/125, left eye. Serologies demonstrated elevated serum levels of IgG and IgG4, and computed tomography showed masses surrounding both optic nerves at the orbital apices and bilaterally enlarged infraorbital nerves. The patient underwent 2 cycles of intravenous pulse steroid therapy followed by a taper of oral steroids Three months later, vision was 20/20 in each eye and, while the serum level of IgG was within normal limits, the IgG4 level remained elevated. IgG4-ROD may involve the optic nerves resulting in vision loss. Although steroid administration is the primary treatment for this entity, slow tapering is essential to avoid relapse.

Bilateral Optic Nerve Involvement in Immunoglobulin G4-Related Ophthalmic Disease Yasuhiro Takahashi, MD, PhD, Atsuko Kitamura, MD, PhD, Hirohiko Kakizaki, MD, PhD Background: To describe a presumptive case of immuno-globulin G4-related ophthalmic disease (IgG4-ROD) with bilateral optic nerve involvement and to review the clinical features of this entity. Methods: Case report. Results: A 62-year-old man presented with bilateral blurred vision. He had a history of sinus surgery, and a biopsy specimen showed dense infiltration of IgG4-positive plasma cells. His visual acuity was 20/25, right eye, and 20/125, left eye. Serologies demonstrated elevated serum levels of IgG and IgG4, and computed tomography showed masses surrounding both optic nerves at the orbital apices and bilaterally enlarged infraorbital nerves. The patient underwent 2 cycles of intravenous pulse steroid therapy followed by a taper of oral steroids Three months later, vision was 20/20 in each eye and, while the serum level of IgG was within normal limits, the IgG4 level remained elevated. Conclusion: IgG4-ROD may involve the optic nerves result-ing in vision loss. Although steroid administration is the primary treatment for this entity, slow tapering is essential to avoid relapse. Journal of Neuro-Ophthalmology 2014;34:16-19 doi: 10.1097/WNO.0b013e3182a304f4 © 2014 by North American Neuro-Ophthalmology Society Immunoglobulin G4-related ophthalmic disease (IgG4- ROD) is a distinct clinicopathological entity characterized by elevated serum IgG4 levels and IgG4-positive lymphoplas-macytic orbital infiltration (1-4). The lacrimal gland is most commonly involved but other orbital structures affected include the extraocular muscles and the supraorbital and infraorbital nerves (3,5-7). Painless eyelid swelling, mild prop-tosis, and diplopia are common symptoms (1,2) and approx-imately 70% of reported cases affect both orbits (5). Both unilateral (2,3,8) and bilateral (7) optic nerve involvement have been reported with IgG4-ROD and, at times, visual impairment is severe (8). We report a presump-tive case of IgG4-ROD with bilateral optic nerve involvement that was treated successfully and review the clinical features of this entity. CASE REPORT A 62-year-old man reported a 1-year history of blurred vision in both eyes. Ten months previously he had undergone surgery for maxillary and ethmoidal sinusitis. Histopathological examination of the excised paranasal polyps disclosed infiltra-tion of lymphocytes, plasma cells, and eosinophils (Fig. 1A). Although fibrosis was present, it was not in a storiform pattern with obliterative phlebitis. There was no histopathological evi-dence of sarcoidosis, Castleman disease, Wegener granuloma-tosis, or malignancy. Immunostaining for IgG and IgG4 demonstrated intensely stained IgG4-positive plasma cells, with the IgG4/IgG plasma cell ratio .40% and .10 IgG4 plasma cells per high-power field (Fig. 1B). Vision initially improved after surgery but soon worsened again. His medical history was otherwise unremarkable. At our initial evaluation of the patient, visual acuity was 20/20, right eye, and 20/125, left eye. Pupils reacted normally without a relative afferent pupillary defect. Ocular motility was intact, and Hertel exophthalmometry measurements were 16.5 mm bilaterally (base, 100 mm). Slit-lamp and fundu-scopic examinations were unremarkable. Kinetic perimetry showed bilaterally enlarged blind spots and pericecal scotomas in the left eye. There was no facial numbness. Hematological studies revealed elevated serum levels of: IgG 3,550.3 mg/dL (normal: 870.0-1,700.0 mg/dL), IgG4 1,850.0 mg/dL (normal: ,135 mg/dL), and IgE 1,400 IU/mL (normal: ,170 IU/mL). The IgG4/IgG ratio was 52.1% (nor-mal: ,6%). Results of other blood tests that were within normal limits included anti-myeloperoxidase and anti-proteinase 3, antineutrophil cytoplasmic antibodies, rheu-matoid factor, angiotensin-converting enzyme, soluble Department of Ophthalmology (YT, HK), Aichi Medical University, Nagakute, Aichi, Japan; and Department of Pathology (AK), Aichi Medical University Hospital, Nagakute, Aichi, Japan. The authors report no conflicts of interest. Address correspondence to Hirohiko Kakizaki, MD, PhD, Depart-ment of Ophthalmology, Aichi Medical University, Nagakute, Aichi 480-1195, Japan; E-mail: [e-mail] 16 Takahashi et al: J Neuro-Ophthalmol 2014; 34: 16-19 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. interleukin-2 receptor, b2-microglobulin, C-reactive protein, and b-D-glucan. Antinuclear antibody titer was 1:80 (normal: ,1:40). Computed tomography demonstrated masses sur-rounding the optic nerve at the orbital apices (Fig. 2A) and enlarged infraorbital nerves bilaterally (Fig. 2B). There was soft tissue swelling in the maxillary, ethmoidal, and frontal sinuses. The patient underwent 2 cycles of pulse steroid therapy each consisting of 10 mg/kg/d of intravenous methylprednisolone for 3 days. After the first cycle, his vision improved to 20/20 in each eye. Kinetic perimetry was normal after the second cycle of pulse steroids, with a decline in the serum levels of IgG (2071.0 mg/dL) and IgG4 (973 mg/dL). The patient was treated with 30 mg of oral prednisolone daily for 2 weeks and the dose was gradually reduced by 5 mg every 2 weeks. One month after starting oral medication, there was a significant reduction in the size of the lesions on magnetic resonance imaging (Fig. 3). Three months after completion of steroid therapy, visual function was stable and Hertel exophthalmometry measurements decreased to 13.0 mm, right eye, and 14.0 mm, left eye (base, 100 mm). Serum IgG returned to within normal limits (1,343.1 mg/dL), although IgG4 (382.0 mg/dL) and the IgG4/IgG ratio (28.4%) remained elevated. DISCUSSION According to the proposed diagnostic criteria, our patient had "possible" IgG4-ROD (4) (Table 1). He had masses at the apex of each orbit with optic nerve involvement and elevated serum level of IgG4. We were unable to biopsy the tumor masses, given their proximity to the optic nerves. However, histopathological findings of the nasal polyps, elevation of serum IgE, involvement of the infraorbital nerves, and improvement of symptoms immediately after steroid admin-istration are supportive of the diagnosis (1,4,6). Histopatho-logical findings of the nasal polyps showed dense infiltration FIG. 1. Nasal polyp histopathology. A. There is infiltration with lymphocytes, plasma cells, and eosinophils (hematoxylin- eosin, ·400). B. Immunostaining for IgG4 is positive in the majority of plasma cells (·400). FIG. 2. Axial (A) computed tomography shows masses (arrows) surrounding the optic nerves at the orbital apices and soft tissue swelling in the ethmoid sinuses. The coronal scan (B) demonstrates enlargement of the infraorbital nerves bilaterally (arrows) and mucosal thickening in the maxillary sinuses. Takahashi et al: J Neuro-Ophthalmol 2014; 34: 16-19 17 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. of IgG4-positive plasma cells and eosinophils with a ratio of IgG4+ cells/IgG+ cells .40% and .10 IgG4+ cells/high-power field. Although fibrosis in a storiform pattern and obliterative phlebitis, which are the major histopathological features of IgG4-related disease, were not demonstrated, these findings occasionally are lacking (9). Often the functions of the involved orbital structure, such as lacrimal gland, extraocular muscle, or trigeminal nerve, are relatively maintained in cases of IgG4-ROD (1,2,10,11). Yet our patient had optic nerve involvement with severe visual impairment in the left eye. In cases with severe vision loss, IgG4-ROD lesions always involve the orbital apex (8). The optic neuropathy leading to vision impairment may be due to a compressive or inflammatory process or both. Reports of involvement of a variety of orbital structures have been described in IgG4-ROD with optic nerve involvement. The infraorbital nerves were affected in our patient and other cases as well (2,3). Other reported sites include lacrimal gland (3,7), extraocular muscles, and supraorbital nerve (3). One case showed panorbital inflammation, including the extraocular muscles (8). All reported IgG4-ROD cases with optic nerve involvement affect single or multiple additional orbital struc-tures (2,3,7), which may be a typical feature of IgG4-ROD cases with optic nerve involvement. Systemic involvement has been described in 3 patients with IgG4-ROD and optic nerve involvement. Lesions were detected in the pancreas and inguinal lymph nodes (7), and salivary gland lesion and skin (3). Our patient had bilateral sinusitis with nasal polyps. This indicates that systemic evaluation is warranted in patients with IgG4-ROD. Steroid administration is the primary treatment for IgG4- ROD. Yet the optimal dose and length of treatment have yet to be established. Treatment of IgG4-ROD often consists of oral predonisolone at a dose of 30-40 mg/d (12). Pulse steroid therapy followed by oral steroid administration has been used for IgG4-ROD with optic nerve involvement (3,11). Both regimens are initially effective, but recurrence often occurs after short-term administration (1-3). Gradual tapering of steroid treatment is an essential step to avoid relapse. Rituximab has shown promise in the treatment of IgG4-related diseases (13), but there are no reports of its use in IgG4-ROD with optic nerve involvement. FIG. 3. T2 magnetic resonance imaging with fat suppression 1 month after starting oral prednisone. There is a reduction in size of the orbital apex lesions (arrows) on the axial scan (A) and of the infraorbital nerves (arrows) on the coronal scan (B). TABLE 1. Proposed comprehensive diagnostic criteria for IgG4-related disease 1. Clinical examination reveals characteristic diffuse/localized swelling or masses in single or multiple organs. 2. Hematological examination shows elevated serum IgG4 concentration (.135 mg/dL). 3. Histopathological examination demonstrates: (a) Marked lymphocytic and plasmacytic infiltration and fibrosis. (b) Infiltration of IgG4 + plasma cells: ratio of IgG4 + cells/IgG4 cells .40% and .10 IgG4 + plasma cells/HPF. Definite disease: 1 + 2 + 3 Probable disease: 1 + 3 Possible disease: 1 + 2 It is important by histopathological examination differentiating IgG4-related disease of each organ from neoplasm (e.g., carcinoma, lymphoma) and other inflammatory conditions Modified from Umehara et al (4). HPF, high-power field. Modified with permission from Umehara H, Okazaki K, et al. Mod Rheumatol 2012. 18 Takahashi et al: J Neuro-Ophthalmol 2014; 34: 16-19 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. REFERENCES 1. Andrew N, Kearney D, Selva D. IgG4-related orbital disease: a meta-analysis and review. Acta Ophthalmol. 2012 September 11 (epub ahead of print). doi: 10.1111/j. 1755-3768.2012.02526.x. 2. Kubota T, Moritani S. Orbital IgG4-related disease: clinical features and diagnosis. ISRN Rheumatol. 2012;2012:412896. 3. TakahiraM, Ozawa Y, Kawano M, Zen Y, Hamaoka S, Yamada K, Sugiyama K. Clinical aspects of IgG4-related orbital inflammation in a case series of ocular adnexal lymphoproliferative disorders. Int J Rheumatol. 2012;2012:635473. 4. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, Matsui S, Yoshino T, Nakamura S, Kawa S, Hamano H, Kamisawa T, Shimosegawa T, Shimatsu A, Nakamura S, Ito T, Notohara K, Sumida T, Tanaka Y, Mimori T, Chiba T, Mishima M, Hibi T, Tsubouchi H, Inui K, Ohara H. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-R). Mod Rheumatol. 2012;22:21-30. 5. Sato Y, Ohshima K, Ichimura K, Sato M, Yamadori I, Tanaka T, Takata K, Morito T, Kondo E, Yoshino T. Ocular adnexal IgG4- related disease has uniform clinicopathology. Pathol Int. 2008;58:465-470. 6. Ohshima K, Sogabe Y, Sato Y. The usefulness of infraorbital nerve enlargement on MRI in clinical diagnosis of IgG4-related orbital disease. Jpn J Ophthalmol. 2012;56:380-382. 7. Plaza JA, Garrity JA, Dogan A, Ananthamurthy A, Witzig TE, Salomão DR. Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4 systemic disease. Arch Ophthalmol. 2011;129:421-428. 8. Pasquali T, Schoenfield L, Spalding SJ, Singh AD. Orbital inflammation in IgG4-related scleroging disease. Orbit. 2011;35:258-260. 9. Deshpande V, Zen Y, Chan JK, Yi EE, Sato Y, Yoshino T, Klöppel G, Heathcote JG, Khosroshahi A, Ferry JA, Aalberse RC, Bloch DB, Brugge WR, Bateman AC, Carruthers MN, Chari ST, Cheuk W, Cornell LD, Fernandez-Del Castillo C, Forcione DG, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Lauwers GY, Masaki Y, Nakanuma Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani DV, Smyrk TC, Stone JR, Takahira M, Webster GJ, Yamamoto M, Zamboni G, Umehara H, Stone JH. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181-1192. 10. Takahira M, Kawano M, Zen Y, Minato H, Yamade K, Sugiyama K. IgG4-related chronic sclerosing dacryadenitis. Arch Ophthalmol. 2007;125:1575-1578. 11. Higashiyama T, Nishida Y, Ugi S, Ishida M, Nishio Y, Ohji M. A case of extraocular muscle muscle swelling due to IgG4-related sclerosing disease. Jpn J Ophthalmol. 2011;55:315-317. 12. Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H. A novel concept of Mikulicz's disease as IgG4-related disease. Auris Nasus Larynx. 2012;39:9-17. 13. Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4- related disease: lessons from 10 consecutive patients. Medicine. 2012;91:57-66. Takahashi et al: J Neuro-Ophthalmol 2014; 34: 16-19 19 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.