Characterizing double seronegative neuromyelitis optica spectrum disorder: A distinct subgroup or part of the continuum?

Myelin oligodendrocyte glycoprotein (MOG-IgG) antibodies have been associated with a variety of demyelinating neurologic disorders, including optic neuritis. It remains unclear whether the presence of MOG-IgG represents a distinct syndrome or is simply a marker for central demyelination. Two experts, John J. Chen, MD, PhD, and Clare L. Fraser, MBBS, MMed, debate this topic. Pro: John J. Chen, MD, PhD Opening Statement In medicine, physicians and other providers often adopt the preference of being either a "lumper" or "splitter" when it comes to disease processes with overlapping characteristics. However, once a molecular basis is identified that reliably distinguishes one disease entity from another, particularly in a situation for which such a distinction affects treatment, being a "lumper" could lead to delays in our diagnosis, initiation of best therapies, and understanding of the disease process. The understanding of neuromyelitis optica spectrum disorder (NMOSD) is a perfect example of how serologic diagnosis has advanced characterization of demyelinating disease. Just over a decade ago, there was debate as to whether neuromyelitis optica (NMO) was a separate entity from multiple sclerosis (MS) (1). However, the discovery of antibodies to aquaporin-4 (AQP4-IgG) in 2004 cemented NMOSD as a separate disorder and revolutionized our understanding of the pathophysiology, clinical characteristics, and treatment of the disease (2,3). More recently, antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have emerged as a reproducible marker for a subset of patients with optic neuritis and other demyelinating event phenotypes. While there is some clinical overlap with other demyelinating disorders, MOG-IgG–associated demyelinating disease is now becoming recognized as its own disease entity that is distinct from classic MS and AQP4-IgG–positive NMOSD (4,5). Characteristics suggestive of myelin oligodendrocyte glycoprotein disease The most common phenotype of MOG-IgG–positive demyelinating disease is optic neuritis, particularly when recurrent, followed by myelitis, acute disseminating encephalomyelitis (ADEM), and brainstem encephalitis (4–9). There are some characteristics of MOG-IgG–positive demyelinating disease that should alert the clinician to this possibility. Compared to other forms of acute demyelinating optic neuritis, MOG-IgG–positive optic neuritis has a higher likelihood of being recurrent, bilateral, and associated with prominent disc edema. Recurrent optic neuritis is seen in between 50% and 80% of cases of MOG-IgG–positive optic neuritis (6,7,9). This condition can sometimes be steroid responsive and dependent, thus meeting the criteria for what has previously been termed chronic relapsing inflammatory optic neuropathy (9–11). Bilateral simultaneous involvement occurs in almost 50% of cases of MOG-IgG–positive optic neuritis (6,7,9,12,13). Optic disc edema at onset is present in up to 86% (4,9,12–15). The disc edema can be severe, with peripapillary hemorrhages; these are a feature that is rarely seen in other forms of demyelinating optic neuritis. The vision loss is usually severe at the nadir, but recovery is typically better than that seen with AQP4-IgG–positive optic neuritis (7,9). On MRI, there is often longitudinally extensive enhancement of the optic nerve in those with MOG-IgG–positive optic neuritis (4,9,14,16,17). Perineural enhancement of the optic nerve sheath and peribulbar structures is seen in up to 50% of cases and is a fairly specific sign of this disorder, which is not typically seen with MS or AQP4-IgG–positive optic neuritis (9,15,16,18,19). Patients with longitudinally extensive transverse myelitis (≥3 contiguous vertebral segments) and negative AQP4-IgG antibody testing should be evaluated for MOG-IgG status; this is the case because such extensive spinal cord involvement is rarely seen in patients with classic MS. Transverse myelitis involves the conus medullaris in MOG-IgG disease more commonly than in other demyelinating diseases (including AQP4-IgG–positive transverse myelitis) (4,7,20). A recent study also found that the T2-signal abnormalities in the spinal cord are often restricted to the grey matter, forming a hallmark "H-sign" on axial images (20). An accompanying brainstem encephalitis and/or an ADEM-like presentation should also raise suspicion for MOG-IgG disease. These phenomena are less commonly seen in patients with AQP4-IgG–positive disease or in those with classic MS. Myelin oligodendrocyte glycoprotein–positive demyelinating disease is distinct from multiple sclerosis Although antibodies to myelin oligodendrocyte glycoprotein (MOG) were initially associated with MS based on nonspecific solid phase assay results (21), recent studies using transfected cell-based assays have found that MOG antibodies are almost never seen in patients with typical MS. In the process of optimizing the MOG-IgG assay at the Mayo Clinic, 50 patients with classic MS were tested, and none of them were positive for MOG-IgG (22). A follow-up study evaluating 86 patients with MOG-IgG–positive optic neuritis found only 1 patient with MS; this patient had a minimally elevated MOG-IgG binding index of 2.8 (laboratory cutoff of 2.5). In addition, none of the patients in that study had oligoclonal bands in the cerebral spinal fluid (CSF) (9). Many other groups have also found that patients with MOG-IgG–associated demyelinating disease do not have oligoclonal bands in the CSF and do not follow a classic MS disease course (5,7). Finally, a multicenter study of 200 patients and review of the literature found only 1 single borderline-positive MOG-IgG result among 290 patients with MS (23). The lack of coexisting MOG antibodies in patients with classic MS indicates that MOG-IgG disease is a distinct and separate process. Myelin oligodendrocyte glycoprotein–positive demyelinating disease is distinct from AQP4-IgG–positive neuromyelitis optica spectrum disorder Patients with antibodies to MOG can develop optic neuritis and longitudinally extensive transverse myelitis and thus fulfill the criteria for NMOSD, the disease process classically associated with AQP4-IgG. Approximately 30% of patients with NMOSD are seronegative for AQP4-IgG; recent studies have suggested that MOG-IgG is positive in approximately one-third of these patients (5,24,25). Much like MOG antibodies are rare in patients with MS, MOG-IgG is almost never seen in patients who have antibodies to AQP4 (26). This supports the concept that MOG-IgG disease and AQP4-IgG–positive NMOSD are separate entities (5). While there is clinical overlap between MOG-IgG–mediated and AQP4-IgG–mediated disease, the pathophysiologies are very different. Pathologic specimens from patients with AQP4-IgG–positive NMOSD show astrocyte destruction and secondary demyelination (27). In contrast, MOG-IgG–positive inflammatory disease tissue shows primary demyelination with preserved astrocytes; this was previously designated as Pattern II demyelination (5,26,28,29). Therefore, AQP4-IgG and MOG-IgG appear to be fundamentally distinct entities with different underlying pathophysiological bases. The importance of testing for myelin oligodendrocyte glycoprotein and recognizing myelin oligodendrocyte glycoprotein–positive demyelinating disease as a separate entity Testing for MOG antibodies, and recognizing MOG-IgG–positive demyelinating disease as a separate entity, truly matter because these distinctions influence our diagnostic ability, prognostication, and ultimately, our treatment of the patient. MOG-IgG disease can present with widespread central nervous system (CNS) inflammation that can be concerning for a vasculitic or infectious process. Much of what we know about the pathology for MOG-IgG disease was derived from brain biopsies performed because of diagnostic uncertainty; these were obtained before the advent of reliable cell-based assays for MOG-IgG. Now that we have a better understanding of the phenotype of MOG-IgG disease and have specific assays for MOG antibodies, diagnosing MOG-IgG disease with a simple serum test can lead to the correct diagnosis and exclude the necessity of a brain biopsy. As our understanding of MOG-IgG disease improves, formal diagnostic criteria will be developed and further refined in order to reliably diagnose this disorder. In addition, separating MOG-IgG disease from other demyelinating diseases will improve our understanding of the natural course. This will enhance our abilities to prognosticate and counsel our patients. Presumably because of the differences in pathogenesis, MOG-IgG–associated inflammation has better outcomes than AQP4-IgG disease even among patients who meet the current criteria for NMOSD. Despite a tendency to cause recurrent severe optic neuritis, the majority of patients with MOG-IgG–positive optic neuritis have meaningful recovery of vision and retain functional vision (7,9,30). This is unlike patients with AQP4-IgG–positive optic neuritis, for whom over one-third have poor visual outcomes (31–33). Recognizing MOG-IgG–demyelinating disease not only is helpful in diagnosis and prognosis but also may have a substantial impact on treatment. Recent studies have shown that MS disease-modifying agents are not effective in preventing relapses in the setting of MOG-IgG–associated disease (18,34,35). Treatment with MS disease-modifying agents could lead to the accumulation of CNS lesion burden from continued relapses; this could unwittingly lead to addition or escalation of what are actually ineffective disease-modifying agents, thus subjecting patients to unnecessary side effects. In addition, it is possible that MS disease-modifying agents could even worsen MOG-IgG–associated disease; this phenomenon has been seen in the setting of AQP4-IgG–positive NMOSD (4,5,18,36–38). The optimal treatments for AQP4-IgG and MOG-IgG diseases may be different as well. A recent multicenter study suggested that rituximab reduces relapse rates in MOG-IgG disease but not as effectively as it does for patients AQP4-IgG–positive NMOSD (39). Therefore, in the future, it will be important for patients with demyelinating disease to be classified according to their underlying molecular diagnosis rather than by a set of clinical criteria alone. Appreciating MOG-IgG–associated disease as its own entity will allow us to better understand the disease pathogenesis. This will be important because it will ultimately lead to directed therapies. Such a paradigm is being tested in ongoing clinical trials for AQP4-IgG–positive NMOSD. Lumping MOG-IgG–positive disease with other forms of demyelinating processes will hamper advancements that can be made for this unique entity. Con: Clare L. Fraser, MBBS, MMed, FRANZCO MOG is expressed exclusively in the CNS as a minor component of myelin. The protein structure of MOG is classified as an immunoglobulin and is found preferentially at the extracellular surface; MOG thus serves as a marker of oligodendrocyte maturation (40). MOG is also thought to serve in myelin adhesion, integrity, and cellular interactions (41). It is therefore studied as a target in CNS demyelinating disease. The potential role for MOG-IgG antibodies in AQP4-negative NMOSD was first suggested in 2007 (6). Following this, in vitro and patient cohort studies have pursued this link. Taking this line of thought one step further, it is suggested that MOG-IgG positivity may denote a disease entity in its own right. However, some of the studies have been limited by the assay type used, small patient numbers, limited diversity of the patients reviewed, and the lack of long-term follow-up data. Identification of MOG-IgG antibodies using cell-based assays (transfected or transduced with native human MOG in its conformational state and analyzed by flow cytometry or microscopy) have demonstrated the presence of this antibody in pediatric patients with ADEM or a relapsing demyelinating (MS-like) disease. Further studies using cell-based assays have shown MOG-IgG positivity in patients with NMOSD. Therefore, the data must be reviewed carefully before we decide if MOG antibody–associated optic neuritis is indeed a distinct entity. Consequence, not cause? To place MOG antibodies in the context of the current clinical literature, and thus this debate, it is important to review the animal studies. Experimental autoimmune encephalomyelitis (EAE) is an animal model of CNS demyelination. Induction of EAE requires immunizing the animal with CNS tissue homogenates or purified myelin components (42). This results in a complex immune response, including a strong T-cell–driven component. Transfer of encephalitogenic T cells can also initiate demyelination and EAE in animals. While MOG antibodies are part of this response, they alone do not necessarily result in the transfer of disease and are not required for severe clinical disease (40,43). This implies that immune system exposure to neurological tissue may result in MOG-IgG as a secondary consequence of preexisting damage; this is similar to the way in which antiretinal antibodies are found in conditions like retinitis pigmentosa. When the mouse IgG monoclonal antibody (mAb) equivalent of anti-MOG, known as 8-18C5 mAb, was transferred into animals that already had EAE, a hyperacute inflammatory response and extensive demyelinating plaques were seen. This suggests that perhaps MOG antibodies amplifies and modifies preexisting demyelinating pathology (44). Furthermore, this effect was dependent on the T cells having weakened the blood–brain barrier; there was no correlation between the antibody titers and the clinical disease (43). In mice, MOG-IgG only causes temporary damage of myelin and axons. More importantly, it does not produce inflammatory cell infiltration, axonal loss, neural degeneration, or astrocyte death (45). It could therefore be argued that perhaps MOG antibodies amplify preexisting disease rather than being a direct and separate pathological entity. The early published clinical research also points toward MOG antibodies being a broader consequence of neurological disease. In 1991, one group reported MOG-IgG in the CSF of 7 patients with MS, in 2 patients with "other inflammatory neurological disease" (OIND), and in 1 patient with tension headaches (46). Larger studies found MOG-IgG in 14%–33% of MS patients, 19%–55% of OIND, and in 3%–8% of noninflammatory neurological disease patients; this included all cases of neurosarcoid tested (47,48). MOG-IgG was also found in 10% of rheumatoid arthritis patients who had no neurological disease (47). Studies from this era are limited by the use of enzyme-linked immunosorbent assay (ELISA), which is less reliable than the newer assays. Even the newer cell-based assays are not without problems. In one study that used full-length human MOG, 48% of epilepsy control patients had a positive test result for MOG-IgG, which reduced to 5.8% when an IgG1-specific secondary antibody was used (49). These results would argue that MOG-IgG is a more generalized marker of inflammation, rather than a disease-causing antibody, in many forms of neurological disease. Chronic inflammatory CNS disease may induce autoantibodies by virtue of epitope spreading. In the MS literature, one study of 103 patients with clinically isolated syndrome found that 21% of patients were positive for both MOG-IgG and myelin basic protein IgM antibodies; 41% were positive for MOG antibodies alone. Those with antibodies to one or both myelin components were more likely to have relapses and to meet the criteria for clinically definite MS (21). The authors went on to emphasize that they could not prove whether the measured antibodies had demyelinating capacity or whether they represented an epiphenomenon of myelin destruction. Postmortem studies also showed higher levels of MOG antibodies within the MS lesions, compared to CSF and serum, suggesting local production as a consequence of disease (50). The authors also reported similar tissue findings in a patient with CNS aspergillosis. While most studies since this time have found MOG-IgG exclusively in patients with optic neuritis and/or myelitis who are AQP4-IgG negative, some concerns have been raised about the data (18). The cohorts included a median of 9 patients with only 24-month median follow-up; long-term follow-up was not available (6). Some cohorts contained no Caucasian patients or were genetically mixed. This may be of relevance as genetic (HLA-DRB-1 types) and infectious (Chlamydia pneumoniae, Helicobacter pylori) factors are thought to contribute to the pathogenesis of NMOSD (51). Finally, some control cohorts were too small to assess the specificity of the tests (6). Lumper or splitter? NMOSD is a demyelinating disorder of the CNS, typically presenting with optic neuritis or transverse myelitis (3). Since the discovery of AQP4 antibodies, it is now distinguishable from MS. However, 10%–25% of clinical NMOSD patients are negative for the AQP4 antibody. Therefore, assuming that MOG-IgG seropositivity does not per se constitute an "alternative diagnosis" from MS, then MOG-related conditions could still fit the 2015 diagnostic criteria for NMOSD (3). Jarius et al (18) found that 32% of patients with MOG-IgG met the 2015 NMOSD criteria, while 44% fulfilled the McDonald criteria for MS at the time of their study. However, AQP4-IgG–positive NMOSD is a disease of astrocytes, whereas MOG-IgG targets oligodendrocytes and therefore might be classified as a form of opticospinal MS (52). Perhaps, there are several routes to characterizing the final common pathways of the diseases we know as MS and NMOSD. Indeed, NMOSD may have 3 subtypes: AQP4-IgG–positive, MOG-IgG–positive, and dual positive cases. In a study of 174 patients, 2 cases tested positive to both MOG-IgG and AQP4-IgG antibodies (53). These 2 patients were women in their 50s who presented with bilateral simultaneous optic neuritis and longitudinally extensive transverse myelitis. Both patients tested positive for MOG-IgG and AQP4-IgG in both the serum and CSF. Mader et al (54) found that one-third of MOG-IgG–positive patients who fulfilled the diagnostic criteria for NMOSD also were AQP4-IgG positive. Dual serum positivity has also been reported in 1 patient with isolated optic neuritis in Japan and in 1 patient in China (55,56). In another study of recurrent optic neuritis (2 episodes separated by more than 1 month), 6 of 23 patients tested positive for both antibodies (57). Of these 6 patients, 50% failed to respond to high-dose corticosteroids and plasmapheresis, with visual acuity remaining poor. Using fluorescence-activated cell sorting, one group reported 10 patients (8%) with dual positivity to MOG-IgG and AQP4-IgG from a group of 125 patients with NMOSD (58). The majority of these patients have MS-like brain lesions on MRI, severe edematous multifocal changes on spine MRI, and pronounced loss of retinal nerve fiber layer thickness on optical coherence tomography, even in clinically unaffected eyes. The disease was typically multiphasic, with a high annual relapse rate and severe residual disability by Expanded Disability Status Scale and visual acuity testing. Yan et al (58) argue that a lack of similar findings in other studies was consequence of laboratory techniques that only allowed for the detection of antibodies in the extracellular or cell-surface domains. To date, I have not found any reports of double-positive antiacetylcholine receptor and muscle-specific kinase antibodies antibodies in myasthenia gravis, yet both forms of the disease are called myasthenia gravis! Why create 2 separate entities for AQP4 antibody and MOG antibody–positive demyelinating disease? Finally, the term MOG-IgG optic neuritis may be a misnomer because 80%–93% of such patients develop a relapsing disease; in addition, 52% develop more widespread neuroinflammatory changes, including myelitis, brainstem encephalitis and cerebellitis (6). Therefore, it seems more appropriate to say MOG-IgG–associated disease (new acronym—MAD?) spectrum disorder rather than MOG-IgG optic neuritis. Rebuttal: John J. Chen, MD, PhD Dr. Fraser has brought up several points that advance discussion of the importance of MOG antibodies in demyelinating disease. Dr. Fraser mentioned that prior studies on MOG-IgG were limited by small patient numbers. However, there are now many recent reports from large cohorts of patients spanning multiple ethnicities, with studies being published in Asia, Australia, the United Kingdom, France, the United States, Brazil, and many other countries (6,7,9,12,13,59,60). These larger studies have provided great insight into MOG-IgG–positive disease and have further shown that this is a distinct entity. I agree with Dr. Fraser that the early studies on MOG-IgG were fraught with difficulties and a lack of specificity; this incorrectly led to the notion that MOG-IgG was associated with MS. However, as Dr. Fraser mentioned, studies in this era were limited by the use of ELISA, which did not evaluate antibodies to MOG in its native form, leading to the poor specificity (61). The new cell-based assays use MOG in its native form which, in conjunction with optimization of the secondary antibodies, have led to very good to MOG are not found in patients, those with classic MS, patients with other optic or in those with other autoimmune disease While there are rare cases of simultaneous MOG and AQP4 antibody positivity in the these are rare with the use of the new cell-based assays and are limited to case In all of the large recent published on MOG-IgG, there have not been any cases of dual positivity for both MOG-IgG and AQP4-IgG While Dr. Fraser reported several of patients with MOG-IgG and these studies were and assays that were either not cell based or not with to the secondary There are likely rare cases of positivity because both MOG-IgG and AQP4-IgG demyelinating disease are autoimmune disorders, but this is an rather than the Therefore, autoantibodies to MOG are specific for a unique subset of patients with demyelinating disease and are not seen in other disease In addition, they are not an epiphenomenon of inflammatory CNS or optic nerve disease. It is still unclear whether MOG antibodies are or a marker of disease. A recent study demonstrated that MOG antibodies derived from with MOG-IgG disease were in demyelination on in 2 different EAE et al other potential that are distinct from AQP4-IgG–mediated disease. Even if antibodies to MOG up not being it is that MOG-IgG is a good marker of a specific disease process that is distinct from AQP4-IgG–mediated disease and from MS. This distinction has clinical and be because of the for prognosis and treatment. While some cases of MOG-IgG disease will meet the current criteria for NMOSD or the McDonald criteria for MS, these the lack of specificity in the diagnostic criteria rather than of MOG-IgG disease not being its own entity. There are unique to MOG-IgG disease that it from its MS and AQP4-IgG As MOG-IgG disease has a different presentation and MOG-IgG disease is seen in and unlike MS and AQP4-IgG disease that both have a The CSF for MOG-IgG–positive disease is distinct from that of MS As the pathology found on brain for MOG-IgG is different than what is found in AQP4-IgG disease. The best treatment for MOG-IgG has yet to be but it is that disease-modifying agents used to MS are not Therefore, MOG-IgG–positive disease has a different pathogenesis, and treatment. Lumping MOG-IgG into the disease process will hamper the understanding of this unique demyelinating process. to how distinct from MS over a decade with the discovery of the now that we have a specific and reliable marker for MOG-IgG disease, it will also its own separate disease. I agree with Dr. Fraser that MOG-IgG optic neuritis is not the most appropriate because MOG-IgG–positive disease can have a neuroinflammatory This has been called MOG-IgG encephalomyelitis according to a group of While the will likely its relevance as a distinct disease will Recognizing MOG-IgG disease as its own distinct entity will allow us to better understand the disease process and improve treatments for this disease. Rebuttal: Clare L. Fraser, MBBS, MMed, FRANZCO the the of is toward MOG-IgG optic neuritis being a distinct entity, which Dr. has I that we agree that it does more to a broader to the disease entity, such as MOG-IgG rather the condition to MOG-IgG optic neuritis this is particularly in Some of own in 1 were from the literature, with less for antibody testing than we now have In one of the early showed that patients with MOG antibody–associated demyelination to have a unique and the more clinical has led to and MOG-IgG–positive patients as having a separate disease process to MS and of MOG-IgG–associated demyelination was published The clinical response, and outcomes of patients were The that there remains diversity in associated with MOG-IgG–associated demyelination and that some overlap may be present between patients with clinically definite MS and MOG However, the literature on the clinical and phenotype and of treatment response, I agree with Dr. that this condition as a separate clinical entity from MS and NMOSD. In the that MOG-IgG antibody testing could be restricted to patients with a clinical and phenotype for MS, particularly in the event of isolated or recurrent optic neuritis While MOG-IgG–associated demyelination as an optic neuritis in the majority of patients, there is a clinical spectrum that to be broader than simply patients with NMOSD. the high of MOG-IgG positivity in it seems to test for MOG antibodies in all particularly if relapsing MD, and The to suggests that MOG-IgG–associated demyelinating disease may a distinct disorder with and that it from both MS and NMOSD. one is a or a the clinical spectrum of MOG is still It remains to be seen whether MOG antibodies are a marker for demyelination or whether these are per This may have for treatment and prognosis for MOG-IgG–associated demyelinating disease. Further studies and clinical the several will our understanding of this important

Objectives:Study was conducted with aim of comparing subtypes types of NMOSD based on serology.Methods:In this retrospective study, patients ≥18 years were included satisfying IPND 2015 criteria. Three groups were created based on seropositivity for AQP4 antibody, MOG antibody or double seronegative. Demographic, clinical and imaging were compared using regression analysis.Results:Forty-six patients, 28 (60.9%) AQP4+, 11 (23.9%) MOG + and remaining 7 (15.2%) double seronegative were included. Thirty-seven patients (80.4%) had presenting symptoms localized to optic nerve and/or cord [AQP4 + 22 (78.5%), MOG + 9 (81.8%) and double seronegative 6 (85.7%)]. Presentation with bilateral optic neuritis was more common in AQP4- patients. Twenty (86.8%) out of the 23 patients who had relapsing disease localized to optic nerve and/or spinal cord [AQP4 + 13/14 (92.8%), MOG + 3/5 (60%) and double seronegative 4/4 (100%)]. Relapses were more common in AQP4+ (77% vs 12% vs10%). In AQP4 negative group disability (EDSS 4.2 vs 3.3) and progression index was relatively less (1.6 vs 1.1). CSF pleocytosis (38.8% vs 17.9%) and raised proteins (66.6% vs 32.1%) were also more common. Optic nerve MRI (>50% optic nerve and chiasma involvement) was more commonly abnormal in AQP4 negative (52.9% vs 31.2%). Regression analysis revealed females to be significantly higher in AQP4 positive NMOSD (89.3%) when compared to MOG positive (36.4%) and double seronegative (42.9%).Conclusion:Gender was the only significant difference between the three groups. There was trend towards greater disability and more relapses in AQP4 + groups.

To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies. Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells. Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack. Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.

The clinical phenotypes of myelin oligodendrocyte glycoprotein (MOG) antibody disease, its disease course, and treatment are poorly understood and much work needs to be done towards this. To characterize the clinico-radiologic spectrum and treatment outcomes of MOG antibody disease and differentiate it from aquaporin-4 (AQP-4) antibody positive neuromyelitis optica spectrum disorders (NMO-SD). A single-center, observational study from Western India during 2017-2019, of 48 patients with either MOG antibody positive (21 patients) or AQP-4 antibody positive (27 patients) central nervous system demyelination. MOG antibody group had median age 32.2 years, no gender bias, median disease duration 40 months, relapses in 9 patients (43%), and median 2.5 (1-16) episodes per patient. Onset phenotypes included isolated bilateral optic neuritis (ON) (43%), isolated unilateral ON (19%), acute brainstem syndrome (19%), simultaneous ON with myelitis (9%), isolated myelitis (5%), and acute disseminated encephalomyelitis optic neuritis (ADEM-ON) (5%). Characteristic neuroimaging abnormalities were anterior segment longitudinally extensive ON, upper brainstem, and thoracic cord involvement (both short and long segment lesions). Most patients (86%) responded well to steroids, only 3/21 required rescue immunotherapy. In total, 6 out of 46 eyes affected developed permanent visual disability, while one patient had motor disability. The features differentiating MOG from AQP-4 antibody group were: no female predilection, preferential optic nerve involvement, characteristic neuroimaging abnormalities, and favorable therapeutic response and outcome. MOG disease commonly presents as severe ON, myelitis, acute brainstem syndrome, ADEM or their combinations. Early identification, treatment, and maintenance immunosuppression are necessary. It can easily be differentiated from NMO-SD using clinico-radiological features and therapeutic response.

Background:More and more cases of myelin oligodendrocyte glycoprotein (MOG) antibody are being diagnosed with the availability of laboratory tests helping us to know the differing patterns from AQP-4 antibody disease and we need to understand the natural course, treatment, and prognosis in a better way.Objectives:Neuromyelitis optica spectrum disorder (NMOSD) and anti-MOG syndromes are immune-mediated inflammatory demyelinating conditions of the central nervous system (CNS) that mainly involve the optic nerves and the spinal cord. We conducted this study to compare demographic, clinical, laboratory, and radiological features of AQP-4 antibody and MOG antibody positive patients.Methods:A single-centre retrospective observational study from a large tertiary care university centre of Northwest India conducted during 2019--2021. We screened all patients presenting with acute CNS demyelinating attacks and recruited total 47 patients of which 25 were positive for AQP4 antibody and 22 were positive for MOG antibody. No patient tested positive for both antibodies. Data were collected using a standardized format including demographic, clinical, laboratory, and neuroimaging data.Results:In our study, total 47 patients were included, amongst which 25 patients were AQP4 antibody and 22 patients were MOG antibody positive. Though there was no gender preponderance, pediatric patients were more frequently affected in MOG antibody positive group. In AQP-4 antibody positive patients, myelitis was most common presenting clinical feature followed by optic neuritis (ON), simultaneous ON with myelitis, and brainstem syndrome. In MOG antibody positive group, myelitis was the commonest phenotype followed by ON, brainstem syndrome, and cerebral syndrome. The neuroimaging revealed involvement of medulla mainly area postrema, cervicodorsal spinal cord and extension of cervical lesion up to brainstem more commonly in AQP4 antibody group, on the other hand involvement of upper brainstem (midbrain and pons), cortex, and conus was more common in MOG antibody group.Conclusion:We have made an attempt to find differentiating features in AQP-4 vs. MOG antibody positive cases but they were of no statistically significance value as the numbers were small. Further larger studies may prove helpful in planning better strategies in two groups.

Diagnostic algorithm for relapsing demyelinating syndromes of the CNS in children

Role of serostatus in pediatric neuromyelitis optica spectrum disorders: A nationwide multicentric study.

Optic neuritis (ON) represents the most common optic neuropathy in young adults; however, longitudinal data on visual recovery, particularly in autoimmune ON subtypes, remain limited. This study aimed to assess long-term visual outcomes in patients with severe ON without multiple sclerosis stratified by autoantibody status: aquaporin-4 (AQP4)-IgG positive, myelin oligodendrocyte glycoprotein (MOG)-IgG positive and double seronegative (DN). A retrospective cohort analysis was conducted at a tertiary neurology center in southern India, including severe ON patients (best-corrected visual acuity [BCVA] ≤1.0 logMAR) between January 2016 and April 2024. Serological testing for AQP4 and MOG antibodies was performed via cell-based assays. Visual outcomes were categorized as "good recovery" (≥66.77% improvement in BCVA) and "complete recovery" (return to baseline BCVA). Among 42 patients, 17 were AQP4-IgG positive, 10 MOG-IgG positive and 15 DN. The median BCVA at nadir was 1.7 logMAR. Compared with that in the MOG-IgG group, the likelihood of complete visual recovery was lower in both the AQP4-IgG (hazard ratio [HR]: 0.18; p = 0.16) and DN (HR: 0.56; p = 0.34) groups. For good recovery, the AQP4-IgG (HR: 0.16; p = 0.001) and DN (HR: 0.24; p = 0.001) groups had significantly lower HR. All MOG-IgG-positive patients achieved good recovery, compared with fewer than half in the other groups. Antibody status predicted long-term visual outcomes in patients with isolated ON, with MOG-IgG conferring the best recovery, AQP4-IgG the worst and DN intermediate, underscoring the importance of early, antibody-guided management.

Comparison of clinical characteristics and prognoses in patients with different AQP4-Ab and MOG-Ab serostatus with neuromyelitis optica spectrum disorders

The present study aimed to detect myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) antibodies in serum specimens of patients with recurrent optic neuritis (RON) through establishing 293 cells with stable expression of MOG and the complete genomic sequence as the substrate using a cell-based assay (CBA). Furthermore, the clinical features of MOG antibody-positive recurrent optic neuritis (MOG-RON) were assessed. A total of 43 RON patients admitted to Beijing Tongren Hospital from December 2014 to May 2015 were enrolled, including 11 males and 32 females. The serum was collected from all patients, and the MOG and AQP4 antibodies were detected via the CBA. According to the results, the 43 patients were divided into four groups, namely the MOG antibody-positive group (n=11), the AQP4 antibody-positive group (n=20), the MOG/AQP4 antibody-positive group (n=1) and the MOG/AQP4 antibody-negative group (n=11). Clinical data were collected and all patients were followed up for 6 months, with parameters observed including the visual acuity, visual field and ocular fundus. The differences in the demographics, clinical features, characteristics of imaging examination, vision at onset and visual function recovery at 6 months after treatment were compared among the different groups. The characteristics of MOG antibody-positive RON were summarized. Of the 43 RON patients, 2.33% was both MOG and AQP4 antibody-positive, 27.91% were MOG antibody-positive. Compared with the AQP4-RON patients, there were relatively less MOG-RON patients (63.6 vs. 95.0%) and the canal segment and intracranial segment of the optic canal were less involved (P<0.05). The visual acuity at onset of MOG-RON was not inferior to that of AQP4-RON, and the visual recovery degree of MOG-RON was better (P<0.05). MOG antibody may be detected in the serum of certain RON patients, which have unique and different characteristics from AQP4 antibody-positive RON patients, so it may be used as a prognostic biomarker for RON. Furthermore, MOG antibody is present in the serum of patients with neuromyelitis optica spectrum disorders and may be a potential biomarker for these conditions.

Optic neuritis (ON) is an inflammatory disease of the optic nerve characterized by pain and visual lossand often associated with multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD).Autoantibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patientswith inflammatory central nervous system disorders including isolated optic neuritis (ON).Objective: To investigate the differences of clinical features, cerebrospinal fluid (CSF), MRI findings andresponse to steroid therapies between patients with optic neuritis (ON) who have myelin oligodendrocyteglycoprotein (MOG) antibodies and seronegative group. This study was done in a period between June2015 and July 2018, 65 patients were included in this study with ON who ophthalmologists had diagnosedas having or suspected to have ON with acute visual impairment and declined critical flicker frequency,abnormal findings of brain MRI, optical coherence tomography and fluorescein fundus angiography at theironset or recurrence. After exclusion of all patients who fulfilled the diagnostic criteria of neuromyelitisoptica (NMO)/NMO spectrum disorders (NMOSD), MS McDonald’s criteria, we defined 40 patients withidiopathic ON (12 males, 28 females, age range 15-60 years). Sera from patients were tested for antibodiesto MOG and aquaporin-4 (AQP4) with a cell-based assay.Results: 37.5% (15/40) were positive for MOG antibodies, 2.5% (1/40) were positive for AQP4 and 25(62.5%) were seronegative. Among the 15 patients with MOG antibodies, four had optic pain (p=0.007) andfive had prodromal infection (p=0.05). Two of the 15 MOG-positive patients showed significantly high CSFlevels of myelin basic protein (p=0.05) and none were positive for oligoclonal band in CSF. On MRIs, fiveMOG-positive patients showed high signal intensity on optic nerve, four had a cerebral lesion and two had aspinal cord lesion. Six of the eight MOG-positive patients had a good response to steroid therapy.Conclusions: The present results indicate that Patients with NMOSD and MOG positive antibodies havedistinct clinical features, fewer attacks and better recovery than seronegative patients.

Objective To compare the changes of spontaneous brain activity in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) positive and Aquaporin 4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorder (NMOSD) by using resting-state functional magnetic resonance imaging (fMRI). Methods A case control study was designed.A total of 11 NMOSD patients with positive MOG-Ab and 21 NMOSD patients with positive AQP4-Ab were enrolled from October 2006 to May 2017 in PLA General Hospital.Thirty-four healthy controls closely matched in age, sex and education were recruited and underwent resting-state fMRI scans.The amplitude of low-frequency fluctuation (ALFF) was extracted to investigate the spontaneous brain activity.This study was approved by Ethics Committee of PLA General Hospital (S2019-111-01). All subjects enrolled signed informed consent. Results Two patients in the MOG-Ab positive group had seizure history, and no seizure history was observed in AQP4-Ab positive group and healthy control group.Compared with healthy control group, all patients in MOG-Ab positive group and AQP4-Ab positive group had significantly increased ALFF values of prefrontal gyrus.The ALFF values of bilateral anterior central gyrus and bilateral posterior central gyrus in AQP4-Ab positive group were 1.89±0.56 and 2.10±0.69, respectively, which were lower than 3.32±1.15 and 3.61±1.23 in MOG-Ab positive group, the differences were statistically significant (both at P<0.001, AlphaSim correction). Conclusions Resting-state fMRI could provide new evidence of possibly multi-focal disease mechanisms.Hyperactivity in prefrontal cortex, motor cortex and somatosensory cortex might reflect differences in pathological processes between MOG-Ab positive and AQP4-Ab positive NMOSD patients. Key words: Optic neuritis; Resting-state functional magnetic resonance imaging; Amplitude of low frequency fluctuation; Neuromyelitis optica spectrum disorder; Aquaporin 4 antibody; Myelin oligodendrocyte glycoprotein antibody

Implications of Low-Titer MOG Antibodies

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Introduction: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease is a recently described central nervous system (CNS) inflammatory disorder with phenotypic overlap with Neuromyelitis Optica Spectrum Disorder (NMOSD). NMOSD seronegative patients, and those with limited forms of the disorder, become suspects for MOG antibody-associated disease. We describe a multi-ethnic population with MOG antibody seropositivity from the University of British Columbia MS/NMO clinic.Methods: AQP4-antibody seronegative patients presenting 2005–2016 with CNS inflammatory disease suspicious for NMOSD, as well as 20 MS controls, were retrospectively tested for MOG-IgG1 antibodies by live cell-based assay at Oxford Autoimmune Neurology Diagnostic Laboratory (UK) and by a commercial fixed cell-based assay at MitogenDx (Calgary, Canada). Additional MOG seropositive cases were identified through routine clinical interaction (2016–2018) using one of these laboratories. Clinical data was reviewed retrospectively.Results: Retrospective testing identified 21 MOG seropositives (14 by live assay only, 3 by fixed assay only and 4 by both) representing 14% of the “NMOSD suspects” cohort. One multiple sclerosis (MS) control serum was MOG seropositive. Twenty additional MOG positive cases were identified prospectively. Of 42 patients (27 female), median disease onset age was 29 years (range 3–62; 9 pediatric cases), 20 (47%) were non-Caucasian, and 3 (7%) had comorbid autoimmune disease. Most common onset phenotypes were optic neuritis (23, 55%; 8 bilateral) and myelitis (9, 21%; 6 longitudinally extensive) Three of the patients in our cohort experienced cortical encephalitis; two presented with seizures. Onset was moderate-severe in 64%, but 74% had good response to initial steroid therapy. Cumulative relapse probability for the MOG positive group at 1 year was 0.428 and at 4 years was 0.628. Most had abnormal brain imaging, including cortical encephalitis and poorly demarcated subcortical and infratentorial lesions. Few “classic MS” lesions were seen. Optic nerve lesions (frequently bilateral) were long and predominantly anterior, but 5 extended to the chiasm. Spinal cord lesions were long and short, with involvement of multiple spinal regions simultaneously, including the conus medullaris.Conclusions: Our MOG seropositive patients display phenotypes similar to previous descriptions, including cortical lesions with seizures and conus medullaris involvement. Many patients relapsed, predominantly in a different CNS location from onset. Serologic data from two different cell-based antibody assays highlight the discrepancies between live and fixed testing for MOG antibodies.