Cases of AQP4 ‐Antibody‐Positive Neuromyelitis Optica Spectrum Disorder Successfully Discontinuing Steroids With Satralizumab Treatment: Considerations on the Method of Tapering for Steroids After the Introduction of Satralizumab

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

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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

Comparison of clinical characteristics, therapeutic responses and outcomes in myelin-oligodendrocyte-glycoprotein-mog associated nmosd versus AQP4 associated NMOSD in a consecutive cohort of Sri Lankan patients

Serum glial fibrillary acidic protein correlates with retinal structural damage in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), “bright spotty” (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

In this article, we present our previous research, which highlighted adenosine triphosphate (ATP) as the cause of neuropathic pain during the acute phase of neuromyelitis optica spectrum disorder (NMOSD). In NMOSD pathology, damage-associated molecular patterns (DAMPs), including ATP, are released from damaged astrocytes, triggering the activation of innate immune cells. ATP is a central mediator of acute pain in NMOSD. We delve into the mechanisms of ATP in peripheral neuropathic pain, drawing comparisons with our findings in NMOSD. Additionally, we address the intricacies of chronic pain associated with NMOSD. Neuromyelitis optica spectrum disorder and neuropathic pain: NMOSD is an inflammatory disease characterized by optic neuritis and long cord transverse myelitis. It was classified as a form of multiple sclerosis (MS), that is, optic spinal MS, before autoantibody discovery. The presence of autoantibodies against astrocytes in the sera of patients was recognized, and the antigen on astrocyte surfaces was identified to be aquaporin-4 (AQP4). Subsequently, the pathogenicity of the AQP4 antibody was revealed, and the concept of NMOSD was established. Physicians treat NMOSD patients with steroid pulse and plasma exchange in the acute phase, and oral steroids and immunosuppressants in the chronic phase to prevent a relapse. Recently, various biological antibody drugs such as eculizumab, satralizumab, and inebilizumab have become available. However, the treatment for residual symptoms is insufficient. Neuropathic pain is a residual symptom that is difficult to treat and significantly reduces quality of life. More than 70% of NMOSD patients experience neuropathic pain, which is severe and often difficult to control, even with more than two analgesics or opioids (Ayzenberg et al., 2021). Although the clinical characteristics of neuropathic pain in NMOSD are known to be severe and drug-resistant, the underlying mechanisms are poorly understood. However, little research has been conducted on NMOSD pain. In this article, we introduce our research on the role of ATP in acute NMOSD pain. NMOSD pathology and innate immunity: NMOSD is characterized by inflammatory demyelinating lesions with necrotic changes in the optic nerve and spinal cord. In the acute stage, neutrophils and eosinophils are prominent, and noticeable necrotic changes are observed with thickening and hyalinization of the vessel walls. Extensive AQP4 disappearance and astrocyte degeneration are observed in acute phase lesions, which are observed around vessels where immunoglobulin and activated complement are deposited. Pathogenic AQP4 antibodies, which are essential in the pathogenesis of NMOSD, bind to the astrocyte surface and enhance the migration of neutrophils and macrophages, triggering antibody-dependent cellular cytotoxicity and complement recruitment, inducing astrocyte damage via complement-dependent cellular cytotoxicity mechanism. Astrocytic damage leads to secondary neuronal loss. The high complement activation potential of pathogenic AQP4 autoantibodies and neutrophil NETosis contribute to more severe tissue destruction compared to MS. In addition, microglia activation around the lesion and the infiltration of certain macrophages are reported, with monocytic cells secreting inflammatory cytokines such as interleukin-1β (IL-1β). Activation of microglia is also believed to be a key factor in neuropathic pain, and the nature of NMOSD pathology is presumed to be an essential factor in causing NMOSD neuropathic pain. Damage-associated molecular patterns and diseases: When cells undergo necrosis, they release DAMPs, which are intracellular molecules with a high capacity for immunostimulatory effects. DAMPs are paired with pathogen-associated molecular patterns such as lipopolysaccharides (LPS) in the cell walls of gram-negative bacilli. Lipopolysaccharide binds to toll-like receptor 4 on monocytes activating NOD-like receptor pyrin domain-containing protein 3 inflammasome pathway and inducing the release of proinflammatory cytokines such as IL-1β and interleukin-18 (IL-18). In contrast, DAMPs are self-molecules released because of necrosis due to ischemia, trauma, or autoimmunity. They also trigger monocytic cells and induce the release of inflammatory cytokines, leading to tissue damage. Gout attacks are caused by the reaction of monocytes with uric acid crystals in the joint cavity. In cerebral ischemic stroke lesions, dead cells secrete DAMPs such as ATP and high mobility group box 1 (HMGB1), stimulating monocytes and triggering auto-inflammation, worsening the infarction pathology (Shichita et al., 2023). In the cerebrospinal fluid of NMOSD patients, elevated levels of HMGB1, mitochondrial deoxyribonucleic acid (DNA), and ATP have been reported. This may be due to their release from the damaged astrocytes (Uzawa et al., 2013; Yamashita et al., 2018; Ishikura et al., 2021). Therefore, DAMPs may affect the central nervous system and cause neuroinflammation in NMOSD patients. In particular, the role of ATP in neuropathic pain has been the subject of basic research, and its detailed mechanisms have been elucidated. Peripheral neuropathic pain and ATP: Peripheral neuropathic pain can be caused by various diseases including diabetes, autoimmune diseases, traumatic bone compression, infections, and malignancies. In a model of peripheral neuropathic pain, known as spared nerve injury (SNI), microglia are activated in response to peripheral neuropathy and extracellular ATP stimulation, causing the production and release of cytokines and neurotrophic factors and inducing dorsal horn neuronal excitation. Thus, the detailed mechanism of peripheral neuropathic pain has been elucidated (Inoue and Tsuda, 2018). In the SNI model, ATP released from injured nerves and astrocytes triggers the activation of spinal cord microglia and upregulates the expression of interferon regulatory factor 8, which subsequently upregulates the expression of interferon regulatory factor 5 and a purinergic receptor P2RX4. ATP binding to P2X4R on activated microglia stimulates the synthesis and release of brain-derived neurotrophic factor (BDNF). BDNF in turn, downregulates the neuronal chloride transporter KCC2, leading to changes in the transmembrane anion gradient in a subpopulation of neurons in the posterior horn layer I. Several studies have shed light on these underlying mechanisms. Another mechanism involves the release of proinflammatory cytokines by microglia. The activation of nuclear factor-κB through P2RX7 receptors, another type of purinergic receptor on microglia, triggers the NOD-like receptor pyrin domain-containing protein 3 inflammasomes, promoting the release of IL-1β. IL-1β acts on spinal cord dorsal horn neurons and contributes to neuropathic pain. ATP causes neuropathic pain in the NMOSD rat model acute phase: Several DAMPs have been reported to be elevated in NMOSD cerebrospinal fluid. Among these DAMPs, ATP, a key molecule in peripheral neuropathic pain, has been identified. In this context, we hypothesized that ATP released from astrocytes induces neuropathic pain in NMOSD. To investigate this hypothesis, we established a rat spinal cord AQP4 antibody injection model and demonstrated that ATP released from astrocytes causes acute phase pain (Ishikura et al., 2021). We administered recombinant AQP4 antibody derived from the cerebrospinal fluid plasmablasts of NMOSD patients and control IgG to the spinal cord at the level of the 10th thoracic vertebra in Lewis rats. The von Frey test revealed significant mechanical pain hypersensitivity in the AQP4 antibody group, but only during the acute phase, compared to the Control IgG group. Transcriptome analysis of the spinal cord demonstrated increased expression of several ATP receptor genes, including P2RX4, in the AQP4 antibody-treated group compared to that in the Control IgG group. Furthermore, we demonstrated that administration of TNP-ATP, a receptor inhibitor of P2RX4, alleviated neuropathic pain in an NMOSD rat model. Additionally, we confirmed that administration of AQP4 antibody to human embryonic kidney (HEK293) cells with forced expression of AQP4 and to primary rat astrocytes resulted in complement-dependent release of ATP. Furthermore, our findings indicate that NMOSD patients in the acute phase have remarkably higher ATP levels in their cerebrospinal fluid compared to individuals with MS in the acute phase or other neurological conditions. Notably, we also observed an increase in ATP levels among NMOSD patients in the chronic phase. The transcriptome and quantitative polymerase chain reaction results also showed elevated levels of IL-1β, a typical cytokine gene released by monocytic cells when stimulated by DAMPs, in the spinal cord of rats treated with AQP4 compared to the control IgG-treated group. Previous studies have established that in models of SNI, ATP released from injured nerves interacts with activated microglia expressing ATP receptors, such as P2RX4, and triggers the release of neurotrophic factors such as BDNF and IL-1β via P2RX7. However, there are reports that IL-1β release is partially stimulated by P2RX4 in spinal cord injury models (de Rivero Vaccari et al., 2012). We speculate that the effectiveness of ATP receptors may vary from model to model and that the P2RX4-IL-1β axis may have been stronger in our NMOSD model. Puregenic receptors and downstream cytokines are known to overlap. P2RX4 downstream cytokines may vary in different models, with IL-1β being associated with central pain conditions like SCI and NMOSD, and BDNF with peripheral pain. Our results suggest that in NMOSD, ATP released due to the binding of AQP4 antibodies to astrocytes may be intercepted by activated microglia, leading to the subsequent release of IL-1β, contributing to the development of neuropathic pain (Figure 1).Figure 1: NMOSD acute pain and ATP, compared with peripheral neuropathic pain.In acute NMOSD pain, AQP4 antibodies bind to astrocytes, cause cell necrosis with complement and neutrophils, and promote the release of ATP as DAMPs, which bind to P2RX4 in activated microglia. In peripheral neuropathic pain, ATP released from injured nerves and astrocytes binds to P2RX7 in activated microglia. In both pathological conditions, microglial mediators including IL-1β released from activated microglia, promote neuroexcitation of SDH neurons and cause neuropathic pain. Ab: Antibody; AQP4: aquaporin-4; ATP: adenosine triphosphate; DAMPs: damage-associated molecular patterns; DRG: dorsal root ganglion; IL: interleukin; NMOSD: neuromyelitis optica spectrum disorder; P2RX4, P2RX7: purinergic receptors; SDH: superficial dorsal horn.NMOSD chronic pain and treatment: Our results indicated that ATP plays a key role in acute pain in NMOSD. Although many NMOSD patients experience chronic pain, there has been almost no basic research that elucidates chronic pain in NMOSD. There is only one publication that reports the administration of an anti-repulsive guidance molecule (RGMa) antibody to an NMOSD animal model, which prevents neutrophil infiltration from the acute phase and can prevent chronic pain (Iwamoto et al., 2022). NMOSD lesions predominantly occur in regions characterized by high AQP4 expression, including the hypothalamus, optic nerve, ventral medulla around the third and fourth ventricles, and the central canal of the spinal cord. The descending pain inhibitory system begins in various areas of the brainstem, particularly in the periaqueductal gray matter of the midbrain and rostral ventromedial medulla, and descends via the dorsolateral cord to all levels of the spinal cord. The pain inhibitory pathway is often involved in NMOSD lesions. Therefore, lesions in NMOSD may inhibit the descending pain inhibitory system. Furthermore, AQP4 loss in astrocytes has been noted in the first layer of the cortex in NMOSD brain autopsies (Kawachi and Lassmann, 2017). It is speculated that astrocyte dysfunction is associated with chronic pain. In the intact central nervous system, AQP4 is co-expressed with the excitatory amino acid transporter 2 and facilitates glutamate uptake into astrocytes. Glutamate, an excitatory neurotransmitter, is converted to glutamine, a precursor of amino acid neurotransmitters, within astrocytes. This glutamine is then released from astrocytes and taken up by neurons by active transport. In GABAergic neurons, glutamine is hydrolyzed to glutamate, which is then partially decarboxylated to gamma-aminobutyric acid (GABA), replenishing the synaptic neurotransmitter pool. Astrocyte death interrupts the glutamine-glutamate-GABA pathway, possibly leading to a delicate balance between the excitation and inhibition of the nociceptive pathway. Elevated extracellular glutamate concentration also affects the vulnerable inhibitory alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, as well as GABA neurons. Astrocytes also release endogenous cannabinoid 2-arachidonoylglycerol, which potently activates GABAergic inhibition (Bradl et al., 2014). A recent study has revealed a link between allodynia symptoms in SNI models and the formation of pain nerve circuit spines in the sensory cortex, a process regulated by astrocytes. We speculate that astrocytopathy in the sensory cortex, a region not typically predisposed to NMOSD lesions, may also be associated with enhanced or reduced NMOSD chronic pain (Takeda et al., 2022). These are the current opinions on the mechanisms of NMOSD chronic pain, and it is unclear if and how the release of DAMPs, such as ATP, is related to NMOSD chronic pain. However, in the SNI model, the autonomous secretion of ATP by excited neurons via nucleotide transporters, such as the vesicular nucleotide transporter, is the maintenance mechanism of chronic pain, which is a potential target of pain treatment (Kato et al., 2022). The release of ATP as a DAMP possibly triggers NMOSD chronic pain. Nevertheless, more basic research on NMOSD chronic pain is required. This perspective has highlighted the role of ATP in NMOSD acute pain, in comparison to that in PNI pain. We hope that advanced basic research will discover new insights into the pathogenesis, revealing further NMOSD pain mechanisms including NMOSD chronic pain. We are grateful to Dr. Makoto Kinoshita (Osaka University, Japan) for proposing the concept of ATP-induced NMOSD acute pain. C-Editors: Zhao M, Sun Y, Qiu Y; T-Editor: Jia Y

Comparison of clinical features of aquaporin-4 positive neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein associated disorder (MOGAD), and double seronegative NMOSD - A single center experience.

Central nervous system (CNS) involvement can occur in primary Sjögren's syndrome (pSS) due to co-existing neuromyelitis optica spectrum disorder (NMOSD) which has a highly relapsing course requiring indefinite immunosuppression, and if not diagnosed early, damage accrual occurs over time leading to permanent disability and morbidity. In this review, we describe and outline the clinical course and outcomes of anti-aquaporin 4 (AQP4) antibody seropositive NMOSD with pSS overlap cases. To investigate the co-existence of AQP4 + NMOSD with pSS, we conducted a review of individual patient data from case reports and case series found in major databases. The study extracted clinico-demographic features, imaging and laboratory profiles, treatment approaches, and outcomes of these patients. Inclusion criteria for the review required patients to have positivity for anti-AQP4 or NMO-IgG autoantibodies in the blood and/or cerebrospinal fluid (CSF) and exhibit at least one manifestation of both pSS and NMOSD. In this overlap between AQP4 + NMOSD and pSS, 44 patients were included of whom 41 (93.2%) were females. The mean age of pSS onset was 44.8 ± 18.4years and NMOSD onset was 43.2 ± 19.8years. In 20 (45.5%) patients, NMOSD preceded pSS onset, 13 (29.5%) NMOSD occurred after pSS onset, and 11 (25%) patients had a simultaneous presentation. 31 (70.5%) patients experienced acute transverse myelitis, 21 (47.7%) optic neuritis, 14 (31.8%) cerebral syndrome, 10 (22.7%) acute brainstem syndrome, 5 (11.4%) area postrema syndrome, and 2 (4.5%) diencephalic clinical syndromes. For the treatment of acute phase, 40 (90.9%) patients received intravenous methylprednisolone, 15 (34.1%) received plasma exchange, and 10 (22.7%) received intravenous immunoglobulin; and for the induction/maintenance therapy, 16 (36.4%) patients received cyclophosphamide, 6 (13.6%) received rituximab, 16 (36.4%) received azathioprine, and 10 (22.7%) received mycophenolate mofetil. Disease course was monophasic in 2 (4.5%) and relapsing in 27 (61.4%) patients. At median (IQR) follow-up duration of 2.4 (6) years, 39 (88.6%) patients showed improvement, 3 (6.8%) showed stabilization and 2 (4.5%) showed worsening of their NMOSD manifestations. In this overlap syndrome of AQP4 + NMOSD and pSS, patients have a neurologically disabling disorder that can mimic neurological manifestations of pSS, frequently occurs prior to the onset of pSS, has a relapsing course, responds well to immunosuppressants, and necessitates indefinite treatment. Collaborative multicentre studies are needed to clarify the natural history and outcomes of this rare overlap syndrome.

Asymptomatic or persistent optic nerve enhancement in aquaporin-4 (AQP4)-immunoglobulin G (IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) is thought to be rare. Improved understanding may have important implications for assessment of treatment efficacy in clinical trials and in clinical practice. Our objective was to characterize NMOSD interattack optic nerve enhancement. This was a retrospective cohort study performed between 2000 and 2019 (median follow-up 5.5 [range 1-35] years) of patients with AQP4-IgG-positive optic neuritis (ON) evaluated at Mayo Clinic. MRI orbits were reviewed by a neuroradiologist, neuro-ophthalmologist, and neuroimmunologist blinded to the clinical history. Interattack optic nerve enhancement (>30 days after attack) was measured. The correlation between interattack enhancement and Snellen visual acuity (VA), converted to logarithm of the minimum angle of resolution (logMAR), at attack and at follow-up were assessed. A total of 198 MRI scans in 100 patients with AQP4-IgG+ NMOSD were identified, with 107 interattack MRIs from 78 unique patients reviewed. Seven scans were performed before any ON (median 61 days before attack [range 21-271 days]) and 100 after ON (median 400 days after attack [33-4,623 days]). Optic nerve enhancement was present on 18/107 (16.8%) interattack scans (median 192.5 days from attack [33-2,943]) of patients with preceding ON. On 15 scans, enhancement occurred at the site of prior attacks; the lesion location was unchanged, but the lesion length was shorter. Two scans (1.8%) demonstrated new asymptomatic lesions (prior scan demonstrated no enhancement). In a third patient with subjective blurry vision, MRI showed enhancement preceding detectable eye abnormalities on examination noted 15 days later. There was no difference in VA at preceding attack nadir (logMAR VA 1.7 vs 2.1; p = 0.79) or long-term VA (logMAR VA 0.4 vs 0.2, p = 0.56) between those with and without interattack optic nerve enhancement. Asymptomatic optic nerve enhancement occurred in 17% of patients with NMOSD predominantly at the site of prior ON attacks and may represent intermittent blood-brain barrier breakdown or subclinical ON. New asymptomatic enhancement was seen only in 2% of patients. Therapeutic clinical trials for NMOSD require blinded relapse adjudication when assessing treatment efficacy, and it is important to recognize that asymptomatic optic nerve enhancement can occur in patients with ON.

Follow-up of retinal thickness and optic MRI after optic neuritis in anti-MOG antibody-associated disease and anti-AQP4 antibody-positive NMOSD

Application of the 2015 neuromyelitis optica spectrum disorders diagnostic criteria in a cohort of Chinese patients

Short transverse myelitis (STM; <3 vertebral segments) is considered noncharacteristic of neuromyelitis optica (NMO) spectrum disorders (NMOSDs). Nonappreciation of the potential for STM to occur in NMOSD may lead to increased disability from delay in diagnosis and appropriate treatment. To determine the frequency of short lesions at the initial myelitis manifestation of NMOSD and to compare the demographic, clinical, and radiological characteristics of aquaporin-4-IgG (AQP4-IgG) seropositive and seronegative STM. We reviewed the records and images of patients at the Mayo Clinic who were identified as AQP4-IgG positive from 1996 to 2014. Inclusion criteria were first STM episode, magnetic resonance imaging performed 90 days or less from symptom onset, spinal cord T2-hyperintense lesion less than 3 vertebral segments, AQP4-IgG seropositivity, and a final diagnosis of NMO or NMOSD. Patients with an initial longitudinally extensive transverse myelitis were excluded (n = 151). Patients with STM who were seronegative for AQP4-IgG among an Olmsted County population-based cohort of inflammatory demyelinating disorders of the central nervous system were used as a control group. Delay to diagnosis in months, clinical and radiological characteristics, and disability measured by ambulatory status. Twenty-five patients who were AQP4-IgG seropositive with an initial STM represented 14% of initial myelitis episodes among patients with NMOSD. The STM episode was defined as the first manifestation of NMOSD in 10 patients (40%) preceded by optic neuritis in 13 patients (52%) and preceded by a nausea and vomiting episode in 2 patients (8%). In comparison with the excluded patients with NMOSD who had an initial longitudinally extensive transverse myelitis, delay to diagnosis/treatment was greater when initial lesions were short (P = .02). In AQP4-IgG-positive STM cases, subsequent myelitis episodes were longitudinally extensive in 92%. Attributes more common in patients with AQP4-IgG-positive STM than in 27 population-based patients with AQP4-IgG-negative STM included the following: nonwhite race/ethnicity; tonic spasms; coexisting autoimmunity; magnetic resonance imaging (central cord lesions, T1 hypointensity, and a brain inconsistent with multiple sclerosis); and cerebrospinal fluid (oligoclonal bands lacking). Short transverse myelitis is not uncommon in NMOSD and, when it is present, delays diagnosis and treatment. Clinical and radiological characteristics identified in this study may help select patients with STM who are at the highest risk for an NMOSD. Short transverse myelitis does not exclude consideration of AQP4-IgG testing or NMOSD diagnosis.

Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune-mediated central nervous system (CNS) inflammatory demyelinating disease characterized by 6 major clinical syndromes, including myelitis, optic neuritis, area postrema syndrome, symptomatic cerebral syndrome, brainstem syndromes, and acute diencephalic clinical syndrome. A 32-year-old female, complaining of numbness in her right limb for 1 month, was diagnosed with aquaporin-4 antibody (AQP4-IgG)-positive NMOSD. She developed acute pancreatitis (AP) during disease relapse, representing a rare extra-neurological manifestation of NMOSD. Spinal contrast-enhanced magnetic resonance imaging scan indicated hyperintense lesions on the T2-weighted sequence in the spinal cord at C2/C4 at the initial onset and extending from C2 to C6 vertebral levels at the recurrence of the disease. Serological profiling demonstrated a significant rise in AQP4-IgG titers (from 1:100 to 1:1000). During the recurrence of NMOSD, the patient manifested acute gastrointestinal symptoms, including severe epigastric pain with emesis. Laboratory tests revealed profound hyperamylasemia (amylase, 2293.8 U/L; pancreatic amylase, 1843.6 U/L). Abdominal computed tomography scan demonstrated definitive signs of AP, confirming the diagnosis. She received methylprednisolone and mycophenolate mofetil for NMOSD treatment. When AP occurred, she was placed on nil per os status and treated with gabexate and esomeprazole. The patient was discharged with relief of neurological dysfunction symptoms and maintained on nasojejunal tube feeding for nutritional support. Three months after discharge, clinical assessment revealed stable myelitis symptoms. There was no evidence of pancreatitis recurrence during the follow-up period. This case suggests that AQP4-IgG-mediated immune damage may not be confined to the CNS. There may be a possible association between NMOSD and AP in the pathophysiological mechanisms. AP may be a rare extra-CNS complication of NMOSD. Our case expands the spectrum of potential systemic complications in NMOSD, highlighting the need for increased clinical vigilance.

Differentiating multiple sclerosis (MS) from other relapsing inflammatory autoimmune diseases of the central nervous system such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is crucial in clinical practice. The differential diagnosis may be challenging but making the correct ultimate diagnosis is critical, since prognosis and treatments differ, and inappropriate therapy may promote disability. In the last two decades, significant advances have been made in MS, NMOSD, and MOGAD including new diagnostic criteria with better characterization of typical clinical symptoms and suggestive imaging (magnetic resonance imaging [MRI]) lesions. MRI is invaluable in making the ultimate diagnosis. An increasing amount of new evidence with respect to the specificity of observed lesions as well as the associated dynamic changes in the acute and follow-up phase in each condition has been reported in distinct studies recently published. Additionally, differences in brain (including the optic nerve) and spinal cord lesion patterns between MS, aquaporin4-antibody-positive NMOSD, and MOGAD have been described. We therefore present a narrative review on the most relevant findings in brain, spinal cord, and optic nerve lesions on conventional MRI for distinguishing adult patients with MS from NMOSD and MOGAD in clinical practice. In this context, cortical and central vein sign lesions, brain and spinal cord lesions characteristic of MS, NMOSD, and MOGAD, optic nerve involvement, role of MRI at follow-up, and new proposed diagnostic criteria to differentiate MS from NMOSD and MOGAD were discussed.