Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis-A Review

Our understanding of demyelinating optic neuritis has substantially evolved over the past 2 decades. With advancements in serological testing, antibodies against myelin oligodendrocyte glycoprotein (MOG) have been recently discovered in a distinct subset of demyelinating neuroinflammatory disease. Although MOG-immunoglobulin G (IgG)-associated disorder (MOGAD) has previously been seen as a component of neuromyelitis optica spectrum disorder (NMOSD), evidence increasingly suggests that it should be distinguished as a separate condition. The dis- tinction of MOGAD from aquaporin-4 IgG NMOSD is impera- tive as treatment plans need to be tailored to its unique disease course and prognosis. The purpose of this review is to explore the nature and outcomes of MOGAD optic neuritis to help guide acute and long-term immunosuppressive treatment decisions.

Trainees’ Corner Section Editors: Vivek R. Patel, MD Prem Subramanian, MD, PhD Myelin Oligodendrocyte Glycoprotein Antibody– Associated Optic Neuritis—A Review Megha Kaushik, MBBS, Michael A. Burdon, MBBS Abstract: Our understanding of demyelinating optic neuritis has substantially evolved over the past 2 decades. With advancements in serological testing, antibodies against myelin oligodendrocyte glycoprotein (MOG) have been recently discovered in a distinct subset of demyelinating neuroinflammatory disease. Although MOG-immunoglobulin G (IgG)–associated disorder (MOGAD) has previously been seen as a component of neuromyelitis optica spectrum disorder (NMOSD), evidence increasingly suggests that it should be distinguished as a separate condition. The distinction of MOGAD from aquaporin-4 IgG NMOSD is imperative as treatment plans need to be tailored to its unique disease course and prognosis. The purpose of this review is to explore the nature and outcomes of MOGAD optic neuritis to help guide acute and long-term immunosuppressive treatment decisions. Journal of Neuro-Ophthalmology 2021;41:e786–e795 doi: 10.1097/WNO.0000000000001234 © 2021 by North American Neuro-Ophthalmology Society O ver the past 2 decades, our understanding of demyelinating optic neuritis has substantially evolved. Since the Optic Neuritis Treatment Trial in 1992, we have learnt that ‟typical” optic neuritis, idiopathic or multiple sclerosis (MS) associated, tends to spontaneously improve within 4 weeks, and a short course of corticosteroid can hasten the recovery but does not alter overall outcomes (1). However, the natural progression and treatment response of ‟atypical” cases of optic neuritis have shown to be vastly disparate. In 2004, the aquaporin-4 (AQP4) antibody was discovered as the cause of a discrete subset of neuroinflammatory disease, neuromyelitis optica spectrum disorder (NMOSD) (2). Its features have since been well delineated, and we now underNeuro-Ophthalmology, Department of Ophthalmology, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham, United Kingdom. The authors report no conflicts of interest. Address correspondence to Megha Kaushik, MBBS, Department of Ophthalmology, Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2TH; E-mail: [e-mail] e786 stand that patients with AQP4-immunoglobulin G (IgG)– positive optic neuritis tend to have a poor visual prognosis and hence require high-dose corticosteroid followed by plasma exchange and long-term immunotherapy (3). More recently, another antibody associated with a previously unclassified subset of ‟atypical” optic neuritis has been rediscovered against the myelin oligodendrocyte glycoprotein (MOG), a transmembrane protein expressed on outer myelin sheaths (4,5). Although MOG-IgG– associated disorder (MOGAD) has previously been seen as a component of NMOSD, evidence increasingly suggests that it should be distinguished as a separate condition. This distinction is important as MOGAD seems to exhibit a unique course and prognosis that requires a tailored treatment plan. However, its characterization is still evolving. The purpose of this review is to explore what is known about the nature and outcomes of MOGAD optic neuritis to date to help guide clinical decision making on its treatment. We also present a case to illustrate the necessity of clinical acumen to distinguish MS, AQP4-IgG NMOSD, and MOGAD optic neuritis because the results of serological tests for the AQP4-IgG and MOG-IgG antibodies can be delayed for weeks, and early treatment decisions are crucial to maximize long-term visual outcomes. CLINICAL SPECTRUM OF MYELIN OLIGODENDROCYTE GLYCOPROTEIN-IgG– ASSOCIATED DISORDER MOGAD causes primary demyelination, contrasting to AQP4-IgG NMOSD, which is a water-channel astrocytopathy with secondary demyelination. It is idiopathic, but there are reports that it can be triggered by vaccination and infection (6,7). MOGAD optic neuritis has not shown to have a predilection for a specific ethnic population, with a prevalence between 2% and 12% in optic neuritis cohorts in North America, Korea, and Europe (8–11). However, relapse rates may be higher in Caucasian than in Asian Kaushik and Burdon: J Neuro-Ophthalmol 2021; 41: e786-e795 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner populations (12,13). MOGAD has a more equal distribution between men and women (1:1 to 1:2) in contrast to AQP4-IgG NMOSD, which has 9-fold higher incidence in women (3,14,15). Unlike AQP4-IgG NMOSD and MS, MOGAD is the most common cause of optic neuritis in children and accounts for up to 50% of acute demyelinating events in children (16). MOGAD is a spectrum of central nervous system disease affecting the brain, spine, and/or optic nerve. The diagnostic criteria are under ongoing development (17). It can manifest as optic neuritis, myelitis, encephalitis, brainstem encephalitis, and acute demyelinating encephalomyelitis (ADEM). Its unique clinical features can help distinguish it from AQP4-IgG NMOSD and MS while antibody tests are pending (Table 1). The most common form of MOGAD in children is ADEM, which is particularly common in younger children (18,19). Optic neuritis is a more frequent manifestation in older children especially above the age of 9 years (18,20). Optic neuritis is the most common site affected in MOGAD, ranging between 54% and 61% of large mixed adult and pediatric cohorts (6,21,22). It is also the most common site for relapse (6,21). MOGAD optic neuritis presents bilaterally in around 50% of cases (6,11). It tends to cause long lesions in the anterior and intraorbital components of the optic nerve, leading to optic disc edema compared with AQP4-IgG NMOSD, which has a predilection for the posterior nerve and chiasm (14,21). Perineural sheath involvement is also a prominent feature in MOGAD optic neuritis, and enhancement can even extend to the perioptic orbital tissue (6,23). INVESTIGATIONS WHEN SUSPECTING MYELIN OLIGODENDROCYTE GLYCOPROTEIN-IgG– ASSOCIATED DISORDER The relevance of antibodies against MOG to disease was unclear for many years until advancements were made in the methodology of serological testing for human antibodies against full-length native conformational MOG (17). Fulllength MOG-transfected live human embryonic kidney 293 cells are usually used. This live cell–based assay with flow cytometry or immunofluorescence has significantly improved sensitivity and specificity than earlier techniques, such as western blot or enzyme-linked immunosorbent assays (15). The assay has been recently validated across international centers but lacks reproducibility for low positive titer samples (24). Despite such high specificity, MOG-IgG serological testing is not indicated in all cases of optic neuritis. Jarius et al (17) developed recommendations for testing in all cases of recurrent optic neuritis and cases of monophasic optic neuritis with atypical clinical features such as bilateral disease or associated myelitis. Kaushik and Burdon: J Neuro-Ophthalmol 2021; 41: e786-e795 As MOG-IgG results can take weeks to return, neuroimaging and cerebrospinal fluid (CSF) analysis can aid diagnosis to guide treatment. Magnetic resonance imaging (MRI) findings in MOG-IgG disease are distinct to MS and AQP4-IgG NMOSD. It can cause poorly demarcated, fluffy, white–grey matter lesions especially around the cerebral peduncles, thalamus, and pons, diffuse leukodystrophic-like white matter changes, optic nerve and chiasmal enhancement, and optic nerve perineuritis (25,26). The transverse myelitis in MOGAD is usually longitudinally extensive ($3 vertebral segments) like in AQP4IgG NMOSD but can be short and multifocal as well (21,23,27). Spinal lesions commonly affect the conus medullaris and grey matter creating a ‟H pattern” on T2weighted MRI (27). In MOGAD, CSF analysis can reveal MOG-IgG antibodies (28–30), raised white cell count (marked pleocytosis in 50%) (6,7,14,31–33), raised protein, and raised L-lactate (32,34). Recent literature reports a striking absence of oligoclonal bands in most adult and pediatric cases (7,14,32–34). Changes in the CSF are more likely with acute myelitis and brain lesions than isolated optic neuritis (32,33). The clinical sensitivity of MOG-IgG serum testing surmounts CSF testing because intrathecal levels are often low and transient (32,35). However, CSF may improve the overall sensitivity because it can be positive when serum is negative (35). Other antibodies can coexist with MOG-IgG, including antiglycine receptor antibody (28,36). Coexistence with AQP4-IgG is rare to none (30). However, some cases of dual positivity exist (37–39). INSTRUCTIVE CASE REPORT We present a vignette of a 66-year-old woman who developed progressive visual blur over 2 weeks in both eyes. She had headaches and pain on eye movements for 3 days before presentation. She had no significant medical or ocular history. Her best-corrected visual acuity was 20/80 in the right eye and 20/600 in the left eye. She identified only 4 of 17 Ishihara color plates with the right eye and 1 of 17 with the left eye. There was evidence of bilateral moderate optic disc swelling with hyperemia (Fig. 1). MRI showed evidence of long, bilateral, optic nerve enhancement and dilated optic nerve sheaths but no chiasmal involvement (Fig. 1). There were no brain lesions. She was commenced on intravenous methylprednisone 1000 mg for 5 days. Due to clinical features of bilateral optic neuritis with long lesions and rapid improvement in visual function after 5 days of treatment (visual acuity 20/40 in the right eye and 20/20 in the left eye), a provisional diagnosis of MOGAD optic neuritis was made. With this provisional diagnosis and response to glucocorticoids, it was decided that plasma exchange was not essential but a slow taper of oral prednisolone was indicated over 3 months. After 6 weeks, e787 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner TABLE 1. Clinical features to help distinguish between MOG-IgG–associated disorder (MOGAD), AQP4-IgG Neuromyelitis optica spectrum disorder (NMOSD), and multiple sclerosis associated optic neuritis MOGAD Age Children—30s Sex (male: 1:1 female) Nil Ethnicity with higher prevalence Bilateral optic Common neuritis Visual outcome Good Relapsing optic Frequent neuritis Disease Frequent relapses course Can be monophasic Optic nerve Long, anterior MRI findings lesion Perineuritis Brain MRI Indistinct whitefindings grey matter lesions Diffuse white matter changes Long lesions Spinal MRI findings Rarely short lesions Cerebrospinal Can have fluid findings prominent pleocytosis Rare oligoclonal bands AQP4-IgG NMOSD Multiple Sclerosis $40 1:9 20–30 1:2 Asian Caucasian Common Rare Poor Frequent Good Less frequent Frequent relapses Can be monophasic Relapsing remitting Chronic progressive Long, posterior lesion Chiasmal and optic tract involvement Rare Nonspecific changes around hypothalamus, corpus callosum, brainstem Short lesion Long lesions Short lesions Can have prominent pleocytosis Rare oligoclonal bands Oligoclonal bands Mild pleocytosis serological results confirmed MOG-IgG positivity. By 3 months, her vision was 20/20 in both eyes, visual fields were restored, and color vision normalized. RECURRENCE MOGAD optic neuritis can be monophasic or relapsing. Studies have reported moderate to high relapse rates (Table 2) (6,21,22). However, most children with MOGAD have monophasic disease, with reports up to 80% (18). The highest risk of relapse is within the first 1 year (22,23), and most relapses occur within 5 years (14). Relapse most commonly occurs with steroid weaning, especially when the daily dose is less than 10 mg and when the steroid treatment lasts for less than 3 months (6). Initially, some early studies suggested that the risk of relapse was lower in MOGAD than in AQP4-IgG NMOSD, but these studies had a short follow-up period (40,41). Studies in Table 2 reveal higher relapse rates in MOGAD than in AQP4-IgG NMOSD. However, this apparent difference may not be true due to influence from e788 Distinct ovoid lesions in periventricular, juxtacortical, cortical, infratentorial regions Dawson fingers selection bias because these studies were conducted in large tertiary centers where severe relapsing cases are usually managed. Jurynczyk et al conducted a wider cohort study and identified a low annual relapse rate of 0.2 for MOGAD (21). MYELIN OLIGODENDROCYTE GLYCOPROTEIN-IgG SERUM TITERS Studies have assessed the relationship between MOG-IgG seropositivity and relapse. Titers at first episode do not correlate with relapse rate, a specific disease phenotype, or disability (18,42–45). The absolute titer level is highly variable between subjects and appears less relevant than a change in titer (30). Persistence of serum MOG-IgG may increase the risk of relapse but does not guarantee relapse (21,38). Higher titers have been measured during relapse compared with remission (19,30), and titers tend to be negative in remission (7). Duration until MOG-IgG seronegative conversion is shorter in those who do not relapse (12 months) compared with those with multiple relapses Kaushik and Burdon: J Neuro-Ophthalmol 2021; 41: e786-e795 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner FIG. 1. Imaging in a patient with myelin oligodendrocyte glycoprotein-IgG–associated disorder (MOGAD) optic neuritis. A. Fatsuppressed T1-weighted coronal (right) and axial (left) MRI with gadolinium showing long enhancement of the optic nerves and dilated optic nerve sheaths. (B) Optical coherence tomography (OCT) showing thickening of the nerve fiber layer at presentation. (C) Reduction of nerve fiber layer thickness 3 months after presentation. (D) Normal ganglion cell layer at presentation. (E) Reduction of ganglion cell layer thickness 3 months post presentation. Kaushik and Burdon: J Neuro-Ophthalmol 2021; 41: e786-e795 e789 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Study Armangue et al (28) (prospective) Number of Number of Time to Poor Visual MOG-IgG– Subset of Median People Average First Outcome Positive MOG-IgG Follow-up Who Number of Relapse Final Visual (20/200 or Final Disability Patients Adults/Children Disease (m) Relapse Relapses (m) Outcome Worse) Score 116 Children Optic 42 neuritis ADEM Encephalitis Myelitis 28% — — Brayo et al (37) (retrospective) 11 Adults Optic neuritis — 65% Alshamrani et al (42) (retrospective) Pedapati et al (43) (retrospective) 9 Adults Optic — neuritis Myelitis Optic 22 neuritis Encephalitis Myelitis 78% 3 75% 2.5 4.7 — 3 — — — — — — Kaushik and Burdon: J Neuro-Ophthalmol 2021; 41: e786-e795 20 Children Adults Liu et al (29) (retrospective) 31 Adults Optic 38 68% neuritis (mean) Cobo Calvo et al (22) (retrospective multicentre) 125 Adults Optic 54 neuritis ADEM Encephalitis Myelitis 84% Waters et al (18) (prospective) 84 Children Optic 82 neuritis ADEM Myelitis 38% 0.5 annual11 relapse rate Chen et al (14) (retrospective) 87 Children Adults Optic 35 neuritis 82% 3 4 Ramanathan et al (6) (retrospective) 59 Children Adults Optic 61 neuritis ADEM Myelitis 100% 3 Most in Visual acuity first 6 loss (24%), mon no VA ths results 90% VA 20/ 20-20/60 Maintenance Treatment 85% modified First-line treatment Relapse risk did not differ rankin (steroid/IVIG/PLEX) score ,2 vs Second-line immunotherapy (rituximab) — Rituximab No recurrence with rituximab. Mycophenolate One patient without long term immunotherapy did not relapse Median EDSS Azathioprine Patients without long term 2 Mycophenolate treatment did not have more recurrences 71% modified Mycophenolate Annual relapse rate reduced rankin Rituximab for all treatments except score #3 Azathioprine mycophenolate Cyclophosphamide IVIG — Corticosteroid Steroid dependency 36% (AQP4 3%) 1.14 — 76% VA $ 14% annual 20/40 relapse (AQP4 rate 32%) 2 56% in Visual 18% severe 70% Mycophenolate first disability visual EDSS #2.5Rituximab year mild 61%, disability Azathioprine moderate Methotrexate 21% Mitoxantrone Cyclophosphamide Good (visual function score of 0 at 4 years) Median VA 6% 20/20 — EDSS 0 at 4 years — — Treatment Outcome — Mycophenolate Rituximab Azathioprine EDSS 1.08 Maintenance children, prednisone Azathioprine 1.56 Mycophenolate adults, 42% scored 0 Rituximab IVIG Annual relapse rate reduced only with mycophenolate, rituximab, and azathioprine 9 patients started immunotherapy before 1st relapse but EDSS did not change — 61% received immunotherapy Treatment reduced relapses. Steroid dependency shown Less relapses with maintenance steroid than other immunotherapy (5% vs 38%) Trainees’ Corner e790 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Major studies on MOGAD optic neuritis including visual and treatment outcomes Higher relapse for corticosteroid ± immuno therapy ,3 months (46 months) (28). In children, 38% relapsed if still seropositive, but only 13% relapsed if they had seronegative conversion (18). As seropositivity may increase the risk of relapse, it has been suggested that serial testing may be beneficial; however, as the relationship is not concrete, it should not solely guide whether to give long-term immunotherapy (18). Importantly, patients can still get positive titers and episodes of disease after converting to seronegativity (18,20,21). However, it should be noted that falsepositives are a significant problem with low titers of serum MOG-IgG (24). VISUAL/DISABILITY OUTCOME e791 16% VA ,6/ 120 — 0.2 annual27 relapse rate 36% Optic 16 neuritis ADEM Myelitis Adults 75 100% 1.6 (vs 3 (vs 6.7VA LogMAR 12% (vs 59% inclus0.7 AQP4) 0.1 (vs 1.7 AQP4) ion AQP4) AQP4) criterion Recurrent 45 optic neuritis 24 Jitprapaikulsan et al (60) (retrospective) Adults — — 6 100% 2 inclusion criterion Optic 66 neuritis Myelitis ADEM Brainstem encephalitis Children 102 Hacohen et al (20) (prospective, multicentre) Study (Continued ) — Kaushik and Burdon: J Neuro-Ophthalmol 2021; 41: e786-e795 31% with EDSS 0 Studies as detailed in Table 2 show that recovery of visual acuity is good for MOGAD, especially compared with AQP4-IgG NMOSD (36,38,44,46,47). Some studies show that visual disability is worse with more relapses (21,48), but others demonstrate no difference in visual disability at onset compared with relapse (22). The relationship to MOG-IgG titers is not well demonstrated (44), but some studies have shown that high visual disability at onset is linked to higher MOG-IgG titers (45). Visual outcomes may be better in younger patients (38,49), but some studies contradict this (21). Only 6%–14% of patients with MOGAD optic neuritis have a final visual outcome worse than 20/200 (Table 2), compared with over one-third with AQP4-IgG NMOSD optic neuritis (26). Some case series report poor visual outcomes with MOGAD optic neuritis. Jelcic et al reported 3 cases with poor visual outcome, but these cases were difficult to treat despite immunosuppression and their poor visual outcome after the initial attack was a clue to the visual prognosis (50). Choi et al reported relapsing cases that reduced with rituximab (51). Again, incomplete visual recovery after the first episode was a clue to relapse and poor visual prognosis. There are limited studies focusing on optical coherence tomography (OCT) changes following MOGAD optic neuritis. There is less peripapillary nerve fiber and ganglion cell complex loss in MOGAD than in AQP4-IgG NMOSD (29,52). The retinal nerve fiber layer (RNFL) is relatively preserved despite the frequency of optic neuritis attacks in MOGAD optic neuritis (53,54). However, patients with MOGAD optic neuritis can still get severe optic atrophy despite good visual outcomes, with a mean RNFL of 59– 65 mm in some studies (47,48,55). Pache et al showed no difference in RNFL and ganglion cell layer (GCL) thickness between MOGAD and AQP4-IgG NMOSD cases, and furthermore, due to more relapses, the MOGAD cases resulted in more severe RNFL loss (12.8-mm loss after the first episode of optic neuritis vs an additional 37.8-mm loss after the second episode). But unlike many other studies, this group did not find a difference in visual acuity between MOG-IgG–positive and AQP4-IgG–positive optic neuritis Number of Number of Time to Poor Visual MOG-IgG– Subset of Median People Average First Outcome Positive MOG-IgG Follow-up Who Number of Relapse Final Visual (20/200 or Final Disability Patients Adults/Children Disease (m) Relapse Relapses (m) Outcome Worse) Score czyk et al Juryn (21) (retrospective, multicentre) Mycophenolate Rituximab Azathioprine Methotrexate Cyclophosphamide 47% EDSS . Corticosteroid 4.5, 7% Azathioprine EDSS $4 Methotrexate Higher relapse in immunotherapy group Reduced relapses and EDSS with IVIG Smaller reduction in relapse rate with rituximab, mycophenolate, and azathioprine Better outcomes may be due to more aggressive immunosuppression Mycophenolate Rituximab Azathioprine Cyclophos-phamide Cyclosporine MS disease modifiers IVIG Maintenance Treatment Treatment Outcome Trainees’ Corner Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Trainees’ Corner patients, and thus, the more severe cases may be overrepresented. In our case presentation, there was evidence of RNFL thinning and substantial GCL loss 3 months after the initial episode, despite excellent functional recovery (Fig. 1). High nonvisual disability occasionally can occur (21,22). Expanded disability status scale is worse in patients with higher serum titers and more relapses (22,45). ACUTE TREATMENT There is consensus in the literature that the acute treatment for MOGAD optic neuritis is high-dose methylprednisone. The disease is often steroid responsive and dependent, relapsing with steroid taper more than in AQP4-IgG NMOSD (6,21,29). Thus, a slow taper of oral prednisone is recommended (6). Early steroid treatment, before 7 days, has also been associated with better visual outcomes, but most of the patients in this study were AQP4-IgG positive rather than MOG-IgG positive (53). Second-line acute treatment entails plasma exchange or intravenous immunoglobulin, but this is typically reserved for attacks that do not respond to steroids (6,20,23,56). LONG-TERM IMMUNOSUPPRESSION The rationale for long-term immunosuppression in MOGAD optic neuritis for maintenance therapy has not been well developed. As relapse does not occur in all cases, most experts only consider long-term immunosuppression in relapsing disease. Some studies recommend to use immunosuppression early due to high relapse rates, OCT changes, and accumulated visual disability (14). However, it is not clear if long-term visual disability is influenced by the level of recovery of an episode or number of relapses. The duration of immunosuppression is also unclear. One should be mindful of the adverse effects with long-term immunotherapy, and it may not be necessary in all patients as most have good visual outcomes and have highly steroid responsive disease. Also, there are many cases that continue to relapse and thus fail multiple long-term immunosuppressive treatments (20,23). Factors that would influence the decision include the number of relapses, visual outcome, response to first-line therapy in the first episode, patient age and comorbidities, and MOG-IgG status and titer during follow-up. In the demonstrative case report, it was decided not to initiate any long-term immunosuppression due to factors, including older age, first episode of disease, and level of visual recovery with high-dose glucocorticoids. For MOGAD patients with relapsing disease that require long-term immunosuppression, the treatments are wide ranging and include mycophenolate mofetil, azathioprine, rituximab, cyclophosphamide, and methotrexate. Regular intravenous immunoglobulin has shown to be effective in children and may have a role in recalcitrant cases (20). MS e792 disease modifying treatments, such as beta-interferon, have not shown to be effective (20). While these MS therapies are associated with higher disease recurrence in AQP4-IgG NMOSD, this has not been seen in MOGAD (57–59). CONCLUDING REMARKS The unique spectrum and prognosis of MOGAD optic neuritis are still being delineated. 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