Orbital Inflammation in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: A Case Report and Review of the Literature

Background: To present 2 patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease with unilateral orbital inflammation, optic nerve head edema, and abnormalities of the optic nerve and nerve sheath on imaging. We review the most current literature on this important and uncommon clinical phenotype. Methods: A case report of 2 patients and a comprehensive review of the relevant literature on orbital inflammation in MOG antibody-associated disease (MOG-AD). Results: Two patients presented with decreased vision and unilateral orbital inflammation. Both had optic nerve head edema and abnormalities of the optic nerve and nerve sheath on imaging. The patients were treated with immunosuppressants and had improvement of vision changes as well as their orbital inflammatory signs. MOG antibody was positive in high titers in both patients. Only 3 other cases of orbital inflammation associated with MOG antibody have been described. In all cases, orbital signs responded rapidly to intravenous methylprednisolone, but the improvement in visual acuity was variable and less robust. Conclusion: Orbital inflammation is a unique and underrecognized phenotype of MOG-AD with only a few reports in the literature. In patients who present with vision loss and orbital inflammation, MOG-AD should be considered in the differential.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Orbital Inflammation in Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease: A Case Report and Review of the Literature Victor D. Liou, MD, Michael K. Yoon, MD, Mary Maher, MD, Bart K. Chwalisz, MD Background: To present 2 patients with myelin oligodendrocyte glycoprotein (MOG) antibody–associated disease with unilateral orbital inflammation, optic nerve head edema, and abnormalities of the optic nerve and nerve sheath on imaging. We review the most current literature on this important and uncommon clinical phenotype. Methods: A case report of 2 patients and a comprehensive review of the relevant literature on orbital inflammation in MOG antibody–associated disease (MOG-AD). Results: Two patients presented with decreased vision and unilateral orbital inflammation. Both had optic nerve head edema and abnormalities of the optic nerve and nerve sheath on imaging. The patients were treated with immunosuppressants and had improvement of vision changes as well as their orbital inflammatory signs. MOG antibody was positive in high titers in both patients. Only 3 other cases of orbital inflammation associated with MOG antibody have been described. In all cases, orbital signs responded rapidly to intravenous methylprednisolone, but the improvement in visual acuity was variable and less robust. Conclusion: Orbital inflammation is a unique and underrecognized phenotype of MOG-AD with only a few reports in the literature. In patients who present with vision loss and orbital inflammation, MOG-AD should be considered in the differential. Journal of Neuro-Ophthalmology 2022;42:e56–e62 doi: 10.1097/WNO.0000000000001400 © 2022 by North American Neuro-Ophthalmology Society Ophthalmic Plastic Surgery (VDL, MKY), Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts; Department of Radiology (MM), Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; Neuro-ophthalmology (BKC), Department of Ophthalmology, Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts; and Department of Neurology (BKC), Massachusetts General Hospital / Harvard Medical School, Boston, Massachusetts. The authors report no conflicts of interest. Address correspondence to Bart K. Chwalisz, MD, Neuroophthalmology Service, 243 Charles Street, Boston, MA 02114; E-mail: [e-mail] e56 M yelin oligodendrocyte glycoprotein (MOG) is a protein expressed on the outermost surface of myelin sheaths. More recently, MOG antibody–associated disease (MOG-AD) has been implicated in demyelinating disorders, such as optic neuritis and transverse myelitis. However, the understanding of MOG-AD continues to evolve, and heterogeneous disease presentations have been reported including with brainstem and cortical involvement as well as seizures (1). Distinguishing MOG-AD from related disorders such as multiple sclerosis (MS) and neuromyelitis optica (NMO) associated with aquaporin-4 antibodies (AQP4-Ab) is important because MOG-AD may have different treatment implications and overall prognosis. In this report, we describe 2 patients with primary findings of optic neuritis accompanied by prominent orbital inflammation. Both patients had positive antibodies to MOG. To the best of the authors’ knowledge, this clinical phenotype of MOG-AD has only been previously described 3 times and these reports are reviewed. METHODS Case One A 79-year-old man with a previous medical history of dyslipidemia, smoking, and prostate cancer presented to the emergency department with progressive vision loss in the right eye for 3 days. Additional symptoms included right temple pain and right periorbital edema. His examination was significant for no light perception vision in the right eye, 6 mm of right proptosis by Hertel exophthalmometry, a right relative afferent pupil defect (rAPD), and abduction and supraduction deficits (Fig. 1). There was also inferotemporal chemosis but no anterior chamber inflammation. A dilated eye examination was significant for right optic nerve edema. MRI of the brain and orbits showed evidence of significant enhancement and thickening of the right optic Liou et al: J Neuro-Ophthalmol 2022; 42: e56-e62 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. External photograph demonstrating right eyelid edema, erythema, and conjunctival chemosis (Frontal view, A). There is evidence of right eye proptosis in worm’s-eye view (B). nerve and nerve sheath with orbital fat stranding (Fig. 2). The lacrimal gland and extraocular muscles were symmetric compared with the left. There was no spinal inflammation on MRI of the spine. A lumbar puncture was performed, and the patient’s cerebrospinal fluid (CSF) showed slight inflammation: 116 mg/dL total protein (range 5–55 mg/ dL), glucose 92 mg/dL (50–75 mg/dL), and 2 nucleated cells (0–5 mL). To assess for metastatic prostate cancer, whole-body positron emission tomography/computed tomography (PET/CT) was performed, which was negative for malignancy. To rule out giant cell arteritis, temporal artery ultrasound and erythrocyte sedimentation rate analysis were performed and were normal. Finally, an incisional biopsy of the right lacrimal gland showed no inflammation or tumor. One week after admission, serum MOG antibody returned positive at 1:1,000 titer. The results of additional inflammatory workup including angiotensin-converting enzyme (ACE), antineutrophil cytoplasmic antibodies (ANCAs), and NMO/AQP4-IgG antibody were negative. The patient underwent admission and treatment with 5 days of intravenous methylprednisolone 1 g daily, followed by a slow oral prednisone taper. He also received rituximab (Rituxan, Genentech, San Francisco, CA). Before discharge, his vision had improved to hand motion and his orbital inflammatory signs and symptoms were resolving (Fig. 3). His visual acuity was 20/125 in the right eye at his most recent follow-up visit 1 year after the onset of vision loss. Case Two A 33-year-old man with no previous medical history presented to the emergency department with 2 days of left eye pain with eye movement and 1 day of inferior visual Liou et al: J Neuro-Ophthalmol 2022; 42: e56-e62 field loss. On initial examination, his visual acuity was 20/ 20 in the right eye and 20/25 in the left eye with red desaturation. There was a left rAPD. Externally, there was evidence of left eyelid edema and mild proptosis. Slit-lamp examination was significant for left conjunctival injection with follicles (Fig. 4A). A dilated eye examination was significant for 360-degree disc edema and extensive macular dot-blot hemorrhages (Fig. 4B). Testing with automated visual field showed a left dense inferior arcuate defect. Serologic inflammatory markers were normal. MRI of the orbits showed enhancement of the left optic nerve, nerve sheath, and surrounding orbital fat (Fig. 5). CSF was normal. Given the feature of follicular conjunctivitis and orbital inflammation, an infectious etiology was initially considered. Serological tests for Lyme disease, Bartonella, Leptospira, and syphilis were negative. The patient was treated with intravenous ceftriaxone as well as empiric ivermectin to prevent possible reactivation of strongyloidiasis, given a history of overseas travel. Intravenous methylprednisolone 1 g daily was started to treat the patient’s optic neuritis, papillophlebitis, and orbital inflammation. The patient responded to treatment with completely resolved pain in the left eye and improved visual field defect. Around 2 weeks after his presentation, serum MOG antibody returned with 1:1,000 titer. NMO/AQP4-IgG antibody was negative. The patient stopped all antibiotics and given his rapid improvement was not recommended to take additional steroids. At his most recent visit 5 months after initial presentation, visual acuity was 20/15 with a small paracentral scotoma visual field defect. RESULTS In this case report, the current 2 patients in conjunction with 3 other well-documented cases of prominent orbital inflammation in MOG-AD were assessed (Table 1). Of the 5 patients, 4 were male (80%) and 1 was female (20%). The mean age of diagnosis was 61.2 years (range 33–87 years). Symptoms were unilateral in 4 patients (80%) and asymmetrically bilateral in 1 patient (20%). Vision loss was the most common presenting symptom (100%), and it was HM in 1 patient (20%) and NLP in 3 patients (60%). Two of 3 patients with NLP vision had improved visual acuity with treatment. Universal findings included optic nerve head edema and MRI evidence of inflammation of the nerve, nerve sheath, and/or surrounding orbital tissues. Treatment initially consisted of intravenous methylprednisolone ranging from 500 mg to 1 g per day followed frequently by an oral prednisone at 1 mg per kg per day taper. All cases which documented response of eyelid and orbital inflammation to corticosteroids mentioned that it occurred within a handful of days with vision improvement occurring much later. There was 1 recurrent case of optic neuropathy that was successfully treated with an additional course of corticosteroids. e57 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Postcontrast axial (A and B) coronal fat-saturated MRI images demonstrating a severe right optic neuritis as longitudinally extensive enhancement and enlargement of the right retrobulbar and intracanalicular optic nerve (arrowhead). There is perineuritis with enhancement of the optic nerve sheath complex (thin arrow). Stranding in the orbital fat (thick arrow) is associated with right proptosis. CONCLUSIONS MOG-AD is well-described as a cause of optic neuritis. The optic neuritis can be bilateral during an attack and is associated with optic nerve edema and retrobulbar involvement (5,6). In children, disease presentation is commonly with acute disseminated encephalomyelitis (ADEM) with features such as pyramidal signs, ataxia, and hemiparesis (1). Adults more often experience an opticospinal phenotype with optic neuritis along with myelitis or less commonly an encephalitis or brainstem syndrome (1). Rarely, adults can also have an ADEM-like presentation with seizures, and this can result in permanent cognitive deficits (1,7). FIG. 3. Patient had significant improvement of orbital inflammatory signs after initiation of corticosteroids and rituximab (Frontal view, A). There is improved proptosis in worm’s-eye view (B). e58 Compared with patients with NMO/AQP4-Ab, patients with MOG-AD have been reported to have fewer relapses and overall better clinical outcomes. Some patients with MOG-AD develop a chronic relapsing inflammatory optic neuritis phenotype that is characterized by frequent optic neuritis relapses necessitating repeat or continuous administration of corticosteroids or other immunosuppressants (1,5). Although most patients recover well, 45% can be left with severe disability, mostly a result of the onset attack (1). MOG-AD-associated optic neuritis more commonly has radiologic features of an optic perineuritis with contrast enhancement of the optic nerve sheath and surrounding FIG. 4. A. Slit-lamp findings included conjunctival follicles and injection. B. Posterior segment findings were significant for optic nerve head edema and macular dot-blot hemorrhages. Liou et al: J Neuro-Ophthalmol 2022; 42: e56-e62 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. Postcontrast axial (A and B) coronal fat-saturated MRI images demonstrating a severe left optic neuritis as longitudinally extensive enhancement and enlargement of the left retrobulbar nerve (arrowhead). Perineuritis is present with extensive enhancement of the optic nerve sheath (thin arrow) at the optic nerve insertion. There is also mild orbital fat stranding (thick arrow). orbital fat, as seen in the cases we presented (6,8). Apart from being uncommon in demyelinating disorders other than MOG-AD, perineural enhancement can be an important clue to the presence of an optic neuropathy associated with systemic connective tissue disorders such as sarcoidosis, infection, or paraneoplastic disease (9–11). These pathologies may otherwise have clinical and imaging features that are not substantially different from demyelinating ON. It is thus arguably the single radiological feature that is most likely to expand the differential diagnosis of ON. In all the cases presented, patients’ vision or visual field loss occurred in conjunction with orbital signs such as orbital apex syndrome and proptosis or preseptal inflammatory findings such as eyelid edema, chemosis, and follicular reaction. These findings were so prominent as to cause initial diagnostic confusion and prompt additional workup. These signs and symptoms improved robustly with the initiation of steroids. It is unlikely that the orbital inflammation occurred because of a separate infectious or inflammatory etiology given normal serologies and inflammatory markers. In addition, the sensitivity and specificity of the MOG cell-based assay with MOG expressed in its native conformation is very high (12). Although it is possible that the patients with this phenotype had concomitant MOG-AD optic neuritis and idiopathic orbital inflammation (IOI) or some other disease process, we believe this to be less likely given the absence of clinical or radiographic evidence of dacryoadenitis or myositis which have been shown to be 2 common subtypes of IOI (13,14). The precise functions of MOG are unknown, but some data have suggested that it functions as an adhesion molecule, regulates the classical complement pathway, or contributes to oligodendroglial signaling processes (15,16). Its location on the outer surface of myelin sheaths may trigger T-cell and B-cell responses. It is also conceivable that this location may lead to a greater likelihood of the inflam- Liou et al: J Neuro-Ophthalmol 2022; 42: e56-e62 mation of MOG antibody–associated optic neuritis to extend to the optic nerve sheath, and in exuberant cases, “spill over” into the adjacent orbital soft tissues, specifically the orbital fat. There also may be MOG-like targets within the orbit that may be involved based on titer levels. Future research will help to determine whether such receptors exist and targeted local treatments could compound systemic therapies. As supported by the cases presented, acute onset of inflammatory symptoms and prominent orbital signs tend to be associated with poor visual outcomes. A more robust orbital inflammation over a short period could result in additional vascular compromise leading to dramatic vision loss at presentation with only partial recovery of vision after treatment. The relatively younger patients in this literature review (aged 33 and 47 years) with conceivably less cardiovascular risk factors had better treatment outcomes. MOG-AD is frequently managed with a variety of immunosuppressing and immunomodulatory therapies such as corticosteroids, plasma exchange, intravenous immunoglobulin, and rituximab to both acutely decrease inflammation and reduce annual relapse rates in recurrent disease (1). However, as this is a relatively new entity, no randomized controlled trials have been completed to suggest the optimal treatment. As the understanding of MOG-AD continues to evolve, so does the physicians’ ability to provide more immediate treatment to improve overall outcomes. Orbital inflammation in association with optic neuritis is an uncommon manifestation of this disease. However, such a presentation, especially with vision loss in the context of optic nerve, nerve sheath, and orbital fat enhancement on imaging should prompt health care providers to consider ordering anti-MOG antibody testing to facilitate efficient diagnosis and treatment. e59 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Documented cases of MOG-AD with orbital inflammation in the literature Author (year) Age/Sex Eye Chief Complaint Clinical Findings Imaging Characteristics Treatment Outcome Orbital signs MRI with extensive IV methylpre T2 hyperintensity dnisolone 1g per improved on day day for 5 days 2, vision in the followed by improved to intraorbital, 1 mg/kg/day 20/160 over intracanalicular, 12 days; lost to prechiasmal, and oral prednisone follow-up chiasmal parts of the right optic nerve with abnormal enhancement of the surrounding orbital tissues at the orbital apex After 3 months, IV methylpre Wagley 47, Right Vision loss, Right eye HM vision,MRI revealed right eye acuity enhancement of dnisolone rAPD, eyelid (2020) (3) female eyelid the right optic 1g daily followed by improved to edema and erythema, 20/20 with and edema, erythema, ptosis, nerve, sheath, 2 rituximab resolution of infusions 14 days and adjacent ptosis, pain conjunctival optic disc edema orbital fat. No apart, oral chemosis and with eye despite prednisone signs of movements injection, 2-mm 80 mg/day tapered persistent rAPD; relative proptosis, extraocular down by 10 mg/day recurrence of muscle supraduction optic neuropathy deficit, decreased enlargement or each week. at month 4 which other white sensation in the was successfully matter lesions on trigeminal (V2) treated with imaging. distribution to steroids light touch, anterior vitreous cells, and optic disc edema with optic nerve hemorrhages Deschamps 87, maleBilateralTwo days of Left eye NLP vision, The brain and IV corticosteroid at Orbital signs orbital MRI (2020) (4) orbital pain rAPD, proptosis, 500 mg daily for resolved in a few followed by lid edema, days; after 5 days followed showed chemosis, and sudden 2 months, vision by oral extensive optic disc edema; bilateral optic vision loss improved to prednisone right eye visual OS 9/10 (20/25+) 1 mg/kg/day neuritis, acuity 4/10 in the right eye and 5 sessions associated with (20/50) but remained of diffuse softNLP in the left tissue infiltration plasmapheresis eye; no every other day affecting the additional followintraconal and up presented extraconal fat on the left side Kurathong 60, maleRight (2019) (2) e60 Orbital pain, Right eye NLP diplopia, vision, rAPD, blurry vision ptosis, motility for 1– restriction, and 2 weeks optic nerve edema Liou et al: J Neuro-Ophthalmol 2022; 42: e56-e62 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (Continued ) Author (year) Age/Sex Eye Liou (2020) 79, maleRight 33, maleLeft Chief Complaint Clinical Findings Imaging Characteristics Treatment Outcome Orbital signs days of IV improved in the methylpre first 3–4 days dnisolone 1 g with no orbital daily followed pain reported by by a slow oral prednisone taper day 5, VA improved to with concurrent 20/125 after rituximab for 3 8 months without infusions recurrence for 1 year IV methylpre Orbital signs began MRI with Inferior visual Left eye 20/25 to improve on visual acuity with enhancement of dnisolone 1 g field loss daily for 5 days day 3 with the left optic red desaturation and pain complete nerve, nerve and a dense with eye resolution by day sheath, and movements inferior arcuate 5, left eye visual surrounding defect, eyelid for 1– acuity improved orbital fat edema, mild 2 days at 5 months to proptosis, 20/15 with conjunctival residual injection with paracentral follicles, 360scotoma; lost to degree disc follow-up edema, and extensive macular dot-blot hemorrhages MRI with significant5 Progressive Right eye NLP enhancement of vision, 6-mm vision loss relative proptosis, the right optic OD, right nerve and nerve rAPD, abduction temple and supraduction sheath, overall pain, and bulkiness of the deficits, right optic nerve, and inferotemporal periorbital orbital fat edema over chemosis, and stranding optic nerve head 3 days edema IV, intravenous; NLP, no light perception; rAPD, relative afferent pupillary defect. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. Liou, M. Yoon, M. Maher, and B. Chwalisz; b. Acquisition of data: V. Liou, M. Yoon, M. Maher, and B. Chwalisz; c. Analysis and interpretation of data: V. Liou, M. Yoon, M. Maher, and B. Chwalisz. Category 2: a. Drafting the manuscript: V. Liou, M. Yoon, M. Maher, and B. Chwalisz; b. Revising it for intellectual content: V. Liou, M. Yoon, M. Maher, and B. Chwalisz. Category 3: a. Final approval of the completed manuscript: V. Liou, M. Yoon, M. Maher, and B. Chwalisz. REFERENCES 1. Reindl M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat Rev Neurol. 2019;15:89–102. 2. Kurathong S, Sanpatchayapong A, Apiwattanakul M. Case Report: anti-myelin oligodendrocyte glycoprotein (MOG) positive in a patient presented with orbital apex syndrome. Neuroophthalmology. 2019;44()255–257. 3. Wagley S, Wang Y, McClelland CM, Chen JJ, Lee MS. 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