News in autoimmune myelitis in the oncological context.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating disease of the central nervous system (CNS) with the presence of conformation-sensitive antibodies against MOG. The spectrum of MOGAD includes monophasic/relapsing optic neuritis, myelitis, neuromyelitis optica spectrum disorder (NMOSD) phenotype without aquaporin 4 (AQP4) antibodies, acute/multiphasic demyelinating encephalomyelitis (ADEM/MDEM)-like presentation, and brainstem and cerebral cortical encephalitis. There is no apparent female preponderance in MOGAD, and MOGAD can onset in all age groups (age at onset is approximately 30 years on average, and approximately 30% of cases are in the pediatric age group). While prevalence and incidence data have been available for AQP4+ NMOSD globally, such data are only beginning to accumulate for MOGAD. We reviewed the currently available data from population-based MOGAD studies conducted around the world: three studies in Europe, three in Asia, and one joint study in the Americas. The prevalence of MOGAD is approximately 1.3-2.5/100,000, and the annual incidence is approximately 3.4-4.8 per million. Among White people, the prevalence of MOGAD appears to be slightly higher than that of AQP4+ NMOSD. No obvious latitude gradient was observed in the Japanese nationwide survey. The data available so far showed no obvious racial preponderance or strong HLA associations in MOGAD. However, precedent infection was reported in approximately 20-40% of MOGAD cases, and this is worthy of further investigation. Co-existing autoimmune disorders are less common in MOGAD than in AQP4+ NMOSD, but NMDAR antibodies may occasionally be positive in patients with MOGAD. More population-based studies in different populations and regions are useful to further inform the epidemiology of this disease.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated inflammatory central nervous system (CNS) disease that has been gradually recognized in recent years and is currently considered as a distinct disease entity distinguished from multiple sclerosis and neuromyelitis optica spectrum disorder. Lately, the new diagnostic criteria for MOGAD proposed by the International MOGAD Panel were published.1 The new criteria cover six core clinical phenotypes (optic neuritis, myelitis, acute disseminated encephalomyelitis, cerebral monofocal or polyfocal deficits, brainstem or cerebellar deficits, and cerebral cortical encephalitis often with seizures), emphasize the positive serum MOG-immunoglobulin G (IgG) test (determined using cell-based assay) and exclusion of alternative causes, and include supporting clinical/neuroimaging features to offset possible deficiencies in antibody detection, aiming to provide precise diagnosis of MOGAD and avoid overdiagnosis. MOGAD, with diverse clinico-radiological manifestations, is deemed to be the “great mimic”. While the new diagnostic criteria may be relatively strict in clinical practice, we are concerned that some patients suffering from MOGAD may be omitted according to the current standards. For instance, some patients, who clearly tested positive for serum MOG-IgG, presented with fever, headache, and leptomeningeal enhancement on brain magnetic resonance imaging (MRI). In this clinical setting, MOG antibody-associated aseptic meningitis is the most reasonable diagnosis.2, 3 However, these patients are unlikely to be diagnosed with MOGAD according to the new criteria, given that meningitis does not fit into any of the six defined phenotype classifications. In another scenario, a few patients with seizures (a relatively common presentation in MOGAD4) may have normal brain MRI (especially at the disease onset),5 and may not sufficiently fulfil the new criteria, which can affect the early diagnosis of MOGAD, thus delaying immunotherapy. In addition, short segment myelitis (SSM, < 3 contiguous vertebral segments in length) is not uncommon in MOGAD. Ciron et al. evaluated 73 patients with MOGAD and found 28 (38.4%) had short lesions and 45 (61.6%) had long lesions at the first episode of myelitis.6 Moreover, the occurrence of conus medullaris involvement varied in different populations, which seems to be more uncommon in patients presenting in China (2/59 [3.4%]7), than those in Europe (22/73 [30.1%]6) and North America (21/51 [41.2%]8). Similarly, in our center with recent 5-year data, conus medullaris injury was observed in 2/17 [11.8%] cases with myelitis as the onset manifestation. SSM, with eccentric lesions and without conus medullaris involvement, can occur with low positive serum MOG-IgG. These patients would also fail to meet with the current criteria, but their clinical findings may still be relevant to MOG-IgG. Furthermore, MOG-IgG associated myelitis with negative initial spinal cord MRI occurred in 7/73 patients with MOGAD.9 For the patients with MRI-negative myelitis, if detected with low positive serum MOG-IgG, also challenge the diagnosis of MOGAD according to the new criteria, which may lead to the therapeutic dilemma. Moving forward, detailed studies of MOGAD are likely to identify additional clinico-radiological phenotypes, and the frequency of existing phenotypes will also change, and the diagnostic criteria need to be revised and updated with the times. Although there is still room for improvement, the publication of the 2023 criteria is a key step towards unifying and standardizing the diagnosis of MOGAD, pushing its research into a new era. We expect that the next version of MOGAD criteria will include the uncommon clinical phenotypes, which would allow clinicians to be more vigilant in identifying patients with MOGAD that are presenting with atypical manifestations. Furthermore, we suggest it would be beneficial to define levels of diagnostic certainty (such as possible/probable/definite MOGAD), similar to the diagnostic criteria for autoimmune encephalitis and paraneoplastic neurological syndromes. We believe that these approaches may be more advantageous in clinical diagnosis and management strategies, compensating for lower sensitivity from the current strict diagnostic criteria in the pursuit of higher specificity, so as to decrease underdiagnosis. Given that MOGAD is a treatable disease, but therapeutic regimens are still different from those for other inflammatory CNS diseases, early identification can facilitate timely and optimal treatment, thus improving the prognosis. Not applicable. The authors declare no conflict of interest. Not applicable. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Aim/backgroundThe concept of neuromyelitis optica spectrum disorder (NMOSD) is changing, with a disease spectrum emerging that includes aquaporin 4 (AQP4) IgG-seropositive NMOSD, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), and double-seronegative NMOSD. The past years have seen important advances in understanding rare demyelinating central nervous system (CNS) disorders associated with AQP4-IgG and MOG-IgG antibodies. Most of the recent literature has focused on the identification of clinical and magnetic resonance imaging (MRI) features that help distinguish these diseases from each other, simultaneously highlighting major diagnostic pitfalls that may lead to misdiagnosis. The present study aims to understand the epidemiology and disease characteristics of NMOSD and MOGAD in our population and compare them with previously published reports.Materials and methodsThis was a prospective, single-center, comparative, observational study conducted over 18 months. Thirty patients were recruited and categorized into two groups: NMOSD and MOGAD. Each group consisted of 15 patients. Data regarding neurological assessment, neuroimaging, treatment, and outcome were collected. These patients were followed at one, three, six, and 12 months for treatment response, residual disability, and relapse. Disease severity and disability were assessed by using the Expanded Disability Status Scale (EDSS) and modified Rankin scale (mRS).ResultsThe average age at presentation of the NMOSD group of patients was 34.67 ± 15.66 years, which was significantly higher compared to the 26 ± 5.74 years seen for the MOGAD group (p < 0.0001). The MOGAD group of patients had a significantly higher proportion of men compared to the NMOSD group (66.67% in MOGAD versus 0% in NMOSD). Optic neuritis was seen in a significantly higher proportion of MOGAD patients compared to the NMOSD group of patients (p = 0.0061). Bilateral optic neuritis was more common in the MOGAD group (26.67% vs. 6.67% in the NMOSD group). Isolated myelitis was higher in the NMOSD group. A higher proportion of patients in the NMOSD group received steroids along with rituximab (26.67%) compared to the MOGAD subgroup of patients. In terms of the rescue treatment, intravenous immunoglobulin (IVIG) or plasma exchange (PLEX) therapy was required more in the NMOSD group than the MOGAD group. The EDSS and mRS scores of both groups were comparable at baseline. However, on follow-up, the EDSS and mRS levels were significantly lower for the MOGAD group compared to the NMOSD group (p < 0.05). The overall relapse rate was 33.33% in the NMOSD group compared to 20% in the MOGAD group at 12 months.ConclusionNMOSD and MOGAD are two distinct CNS demyelinating disorders having different demographics, clinical profiles, treatment responses, relapse rates, and short-term outcomes. MOGAD patients appear to have younger age at onset, male predominance, less severe clinical presentation, good response to first-line treatment, fewer relapses, and better one-year functional outcomes whereas NMOSD has female predominance, more severe clinical attacks of myelitis and optic neuritis, less response to first-line management of acute attack requiring rescue therapy more often, less response to conventional immunosuppressive treatment with more relapses requiring escalation of maintenance therapy with rituximab, and significant visual and locomotor residual disability at 12 months.

To clarify T-cell responses in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we cultured the peripheral blood mononuclear cells of 24 patients with MOGAD and 20 with aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), and those of 17 healthy controls (HCs), in the presence of fourteen MOG peptides covering the full-length MOG, five AQP4 peptides, two myelin basic protein peptides, or two proteolipid protein peptides. Then, we measured T-cell activation markers, such as cell surface CD69 and the intracellular production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-γ in CD4-positive T-cells, with a flow cytometer. The expression of CD69 in response to MOG p16-40 and MOG p181-205 was significantly higher (Stimulation Index > 2) in MOGAD than in HCs. Also, CD69 for AQP4 p21-40, AQP4 p211-230, and MOG p166-190 were significantly increased in NMOSD than in HCs. Intracellular GM-CSF production responding to MOG p16-40 was significantly higher in MOGAD than in HCs (p < 0.05), although intracellular interferon-γ was not elevated. None of the responses to the other peptides were different between the groups. The present study showed subtle CD4-positive T-cell activation elicited by some MOG peptides alone in patients with MOGAD. Further studies of cytokines or other stimulation and alternative assay markers and metrics are needed to delineate the immunopathological roles of T-cells in MOGAD.

Although the causes and pathophysiologies of many neurological diseases are still poorly understood, the number of neurological diseases in which autoantibodies are suggested to be involved in pathogenesis has been increasing every year. Thus, the range of neuroimmunological diseases has expanded to date, including myasthenia gravis, neuromyelitis optica spectrum disorder (NMOSD), Guillain–Barré syndrome, paraneoplastic syndromes, stiff-person syndrome, autoimmune encephalopathies, Hashimoto's encephalopathy, cerebellar ataxia, autoimmune epilepsy, autoimmune autonomic neuropathies, and so on. In this focused review series, experts in myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), Hashimoto's encephalopathy, autoimmune epilepsy, and autoimmune autonomic ganglionopathy will provide an overview of each of these diseases. Misu et al reviewed MOG antibody-associated disease (MOGAD).1 MOGAD is a newly proposed disease concept, while the pathogenicity of anti-MOG antibodies has been debated for many years. The diagnostic criteria for MOGAD were published in 20232; however, qualified diagnosis is often confounded because the clinical features of MOGAD share similarities with NMOSD or multiple sclerosis (MS). In addition, the variety of clinical phenotypes that MOGAD can take, including optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, make it more difficult to diagnose. The authors provide an up-to-date overview of anti-MOG antibody assays, clinical characteristics of the various forms of MOGAD, pathology, and treatment. Matsunaga et al reviewed disorders associated with anti-NH2-terminal of alpha-enolase (NAE) antibodies (NAEAD).3 Anti-NAE antibodies have been used as a useful biomarker for the diagnosis of Hashimoto's encephalopathy. The clinical forms of Hashimoto's encephalopathy include acute encephalopathy, psychosis, cerebellar ataxic form, and Creutzfeldt-Jakob disease-mimic form. Recently, anti-NAE antibodies have been detected in autoimmune encephalopathies, including limbic encephalitis, autoimmune cerebellar ataxia, autoimmune psychosis including dementia, and some neurodegenerative diseases in addition to Hashimoto's encephalopathy, and a new concept of NAE antibody-associated diseases (NAEAD) has been proposed. The authors discuss the measurement system of NAE antibodies, various clinical features, and the development of the concept of NAEAD. Koto et al reviewed autoimmune epilepsy.4 Autoimmune epilepsy is characterized as a subtype of autoimmune encephalitis in which epileptic seizures are the sole or primary symptom. Early diagnosis of autoimmune encephalitis targeting cell surface antigens is important because early immunological intervention is effective in improving the prognosis. The authors describe representative autoantibodies such as against glutamic acid decarboxylase (GAD), N-methyl-d-aspartate receptor (NMDAR), gamma-aminobutyric acid (GABA)-A/B receptors, and voltage-gated potassium channels (VGKC). They also provide an overview of the immune background of autoimmune epilepsy in terms of plasmablasts and follicular helper T-cells. Nakane et al reviewed autoimmune autonomic ganglionopathy (AAG).5 It has been about two decades since the discovery of ganglionic acetylcholine receptor (gAChR) antibodies. Although it seems clear that they are involved in the pathogenesis of autoimmune autonomic neuropathy, the pathogenesis and diagnostic criteria are still unclear. It is important to establish a method for measuring gAChR antibodies as an adjunctive biomarker for clinical diagnosis, to elucidate the mechanism using animal models to help clarify the pathogenesis of autonomic neuropathy, and to develop therapeutic methods. The authors review the recent development of gAChR antibody assays in AAG and the development of animal models. These four review articles by the experts will contribute to a further understanding of neurologic disorders caused by autoantibodies. None. Approval of the Research Protocol: N/A. Informed Consent: N/A. Registry and the Registration No. of the Study/Trial: N/A. Animal Studies: N/A. The author declares no conflicts of interest. Yuji Nakatsuji is a current Editor of Clinical and Experimental Neuroimmunology. None.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.

Granulocytes play a well-established role in the pathogenesis of brain tissue damage in neuromyelitis optica spectrum disorder (NMOSD). The release of granulocyte activation markers (GAM) into CSF has recently been shown to distinguish NMOSD from multiple sclerosis (MS) with high accuracy. However, their pathogenetic role in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear, and their usefulness for diagnostic differentiation is unknown. This observational cohort study by eight tertiary centres in Europe and Japan included 244 CSF samples from patients with MOGAD (n = 71), NMOSD (n = 48), MS (n = 125) and control persons (n = 19). CSF levels of GAM [neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-8 and 9 (MMP-8, MMP-9)], astrocyte damage markers [ADM: glial fibrillary acidic protein (GFAP), S100B], and complement factors C5 and C5a were analysed by capillary ELISA (Ella™) or Luminex®. The primary outcome was the capacity of these markers to differentiate MOGAD, NMOSD and MS in the acute (≤21 days post-exacerbation) stage, and the correlation of GAM with C5 and C5a. Secondary analyses included the correlations of these markers with disability severity, measured by the Expanded Disability Status Scale (EDSS). GAM (except for MMP-9), ADM and C5/C5a levels peaked at onset of disease exacerbation of MOGAD and NMOSD (regardless of aquaporin-4 antibody status), and were significantly higher than in MS. MMP-9 levels were continuously increased in MS over MOGAD and NMOSD, both in acute and subacute/chronic stages. C5 and C5a were equally increased over MS in acute stages of MOGAD and NMOSD. A logistic model and receiver operating characteristics analyses incorporating GAM and C5 displayed high discriminatory power between MOGAD/NMOSD versus MS [area under the curve (AUC) = 0.880], NMOSD versus MS (AUC = 0.837) and MOGAD versus MS (AUC = 0.925) in acute stages. Accordingly, increased ADM levels in NMOSD differentiated NMOSD from MS and MOGAD (AUC = 0.897 and 0.843, respectively). GAM levels correlated with EDSS scores in MOGAD and NMOSD, but not in MS, while those of ADM correlated with disability in NMOSD, but not in MOGAD and MS. Determining CSF levels of GAM and C5/C5a, and of ADM provide a biology-driven approach to differentiate MOGAD, NMOSD and MS. Their measurement can be processed faster and with similar accuracy than with most autoantibody assays, enabling timely initiation of appropriate therapy in acute presentations. The correlation between GAM and C5/C5a levels with neurological impairment in MOGAD and NMOSD corroborates their role as effectors of neural damage, supporting the acute stage use of inhibitors of C5 activation.

Optic neuritis (ON) can present as the first demyelinating attack in both multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), which may require different treatment depending on the final diagnosis. We present 2 young Hispanic women who presented with ON during pregnancy, one of whom was diagnosed with MS and the other with MOGAD. We describe key clinical features to help differentiate between MS and MOGAD including ON features, brain and spinal MRI, CSF profiles, and serum MOG and aquaporin-4 (AQP-4) antibodies, which all can help guide clinicians to an ultimate diagnosis. Pregnancy is usually considered an immunotolerant state because complex immunologic shifts arising to support tolerance of the developing fetus seem to decrease the risk of relapses. However, relapses may still occur during pregnancy, and relapse rates increase immediately postpartum. Our cases raise the possibility that young Hispanic patients may face increased risk of demyelinating disease activity even during the relatively immunotolerant state of pregnancy. A high index of suspicion for demyelinating disease should be maintained to accelerate diagnosis and prevent disability.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in the serum and cerebrospinal fluid (CSF). Initially considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), it is now widely recognized as a separate entity, supported by converging evidence from serological, pathological, and clinical studies. Patients with MOGAD often exhibit better recovery from acute attacks; however, their clinical and pathological features vary based on the immunological role of MOG-IgG via antibody- or complement-mediated perivenous demyelinating pathology, in addition to MOG-specific cellular immunity, resulting in heterogeneous demyelinated lesions from vanishing benign forms to tissue necrosis, even though MOGAD is not a mild disease. The key is the immunological mechanism of devastating lesion coalescence and long-term degenerating mechanisms, which may still accrue, particularly in the relapsing, progressing, and aggressive clinical course of encephalomyelitis. The warning features of the severe clinical forms are: (1) fulminant acute multifocal lesions or multiphasic ADEM transitioning to diffuse (Schilder-type) or tumefactive lesions; (2) cortical or subcortical lesions related to brain atrophy and/or refractory epilepsy (Rasmussen-type); (3) longitudinally extended spinal cord lesions severely affected with residual symptoms. In addition, it is cautious for patients refractory to acute stage early 1st treatment including intravenous methylprednisolone treatment and apheresis with residual symptoms and relapse activity with immunoglobulin and other 2nd line treatments including B cell depletion therapy. Persistent MOG-IgG high titration, intrathecal production of MOG-IgG, and suggestive markers of higher disease activity, such as cerebrospinal fluid interleukin-6 and complement C5b-9, could be identified as promising markers of higher disease activity, worsening of disability, and poor prognosis, and used to identify signs of escalating treatment strategies. It is promising of currently ongoing investigational antibodies against anti-interleukin-6 receptor and the neonatal Fc receptor. Moreover, due to possible refractory issues such as the intrathecal production of autoantibody and the involvement of complement in the worsening of the lesion, further developments of other mechanisms of action such as chimeric antigen receptor T-cell (CAR-T) and anti-complement therapies are warranted in the future.

Optic neuritis (ON) is the most common cause of subacute optic neuropathy in young adults. Although most cases of optic neuritis (ON) are classified as typical, meaning idiopathic or associated with multiple sclerosis, there is a growing understanding of atypical forms of optic neuritis such as antibody mediated aquaporin-4 (AQP4)-IgG neuromyelitis optica spectrum disorder (NMOSD) and the recently described entity, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). Differentiating typical ON from atypical ON is important because they have different prognoses and treatments. Findings of atypical ON, including severe vision loss with poor recovery with steroids or steroid dependence, prominent optic disc edema, bilateral vision loss, and childhood or late adult onset, should prompt serologic testing for AQP4-IgG and MOG-IgG. Although the traditional division of typical and atypical ON can be helpful, it should be noted that there can be severe presentations of otherwise typical ON and mild presentations of atypical ON that blur these traditional lines. Rare causes of autoimmune optic neuropathies, such as glial fibrillary acidic protein (GFAP) and collapsin response-mediator protein 5 (CRMP5) autoimmunity also should be considered in patients with bilateral painless optic neuropathy associated with optic disc edema, especially if there are other accompanying suggestive neurologic symptoms/signs. Typical ON usually recovers well without treatment, though recovery may be expedited by steroids. Atypical ON is usually treated with intravenous steroids, and some forms, such as NMOSD, often require plasma exchange for acute attacks and long-term immunosuppressive therapy to prevent relapses. Since treatment is tailored to the cause of the ON, elucidating the etiology of the ON is of the utmost importance.

Differentiating multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), especially in seronegative cases, remains challenging due to overlapping clinical and imaging features. High-level Epstein-Barr virus (EBV)-derived Epstein-Barr nuclear antigen 1 (EBNA-1) peptide antibody titers may be an MS-specific biomarker that could the improve differential diagnosis. To determine whether longitudinal EBNA-1 peptide antibodies can distinguish MS from MOGAD and NMOSD. This was a retrospective, multicenter, longitudinal, case-control study with patients from Austria, Germany, and the US. This study assessed samples from 2 independent retrospective cohorts. A test cohort and a validation cohort assessed longitudinal plasma samples from patients with MS, MOGAD, or NMOSD. Patients were recruited between 2001 and 2023 and followed up for 2 years. A combined analysis of both cohorts was conducted in January 2025. Plasma EBNA-1 peptide immunoglobulin G (IgG) titers measured by enzyme-linked immunosorbent assay after diagnosis and in 3 follow-up samples. Diagnostic utility of persistent EBNA-1 peptide antibody levels across 4 time points in patients with MS compared with patients with MOGAD and NMOSD. This study included the plasma samples of 2091 patients (mean [SD] age, 31.0 [16.9] years; 1137 female [54.4%]) with neuroinflammatory disease and 1976 healthy controls (mean [SD] age, 39.8 [16.2] years; 1120 male [56.7%]) recruited between 2001 and 2023. The test cohort (310 patients; 54.8% female) included 184 patients with MS, 65 with MOGAD, and 61 with NMOSD (including 12 who were seronegative for aquaporin 4 [AQP4] IgG). The validation cohort (183 patients; 126 female [68.8%]) included 142 patients with MS, 24 with MOGAD, and 17 with NMOSD. In the test cohort, 177 patients with MS (96.2%) had high-level titers in 2 or more of 4 follow-up samples compared with 5 patients (7.7%) with MOGAD (odds ratio [OR], 303.4; 95% CI, 94.4-908.6) and 11 patients (18.0%) with NMOSD (OR, 114.9; 95% CI, 43.0-280.0). Among patients with NMOSD who were seronegative for AQP4-IgG, only 1 (11.1%) had persistent high-level EBNA-1 peptide antibody titers compared with 61 matched patients (96.7%) with MS (OR, 236.0; 95% CI, 18.6-2588.0). In the validation cohort, 135 patients (95.1%) with MS had high-level titers in 2 or more of 4 follow-up samples compared with 4 patients (16.7%) with MOGAD (OR, 96.4; 95% CI, 26.6-293.0) and 3 patients (17.6%) with NMOSD (OR, 90.0; 95% CI, 19.7-319.7). Results of this case-control study reveal that persistent high-level EBNA-1 peptide antibody titers may serve as a reliable biomarker for differentiating MS from MOGAD, and NMOSD.

Diagnosing neuromyelitis optica spectrum disorder (NMOSD) may be challenging owing to overlapping clinical features with multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), particularly in AQP4-IgG seronegative NMOSD patients. We evaluated cerebrospinal fluid (CSF) biomarkers, specifically glial fibrillary acidic protein (GFAP) and albumin quotient (QAlb), to improve diagnostic accuracy in NMOSD. In this retrospective study, we analyzed CSF samples for biomarkers GFAP, QAlb, neurofilament light, and total-Tau, from patients with AQP4-NMOSD, DNNMOSD, MOGAD, and MS in the Region Västra Götaland, Sweden. Receiver operating characteristic (ROC) analysis with calculation of the area under the curve (AUC) was used to identify optimal cut-off levels for discriminating AQP4-NMOSD from the other groups. Logistic regression models assessed the diagnostic power of GFAP and QAlb combined. Patients with AQP4-NMOSD (N = 19) had significantly higher CSF GFAP levels than the others: median 2470 ng/L vs 330 ng/L (p < 0.001). The GFAP cutoff >715 ng/L gave a sensitivity of 81 % and specificity of 92 %. Combining GFAP and QAlb further increased the diagnostic accuracy (AUC = 0.96). MOGAD patients (N = 29) had the highest CSF lymphocyte counts, with elevated lymphocyte counts correlating with polyphasic MOGAD (R = 0.63; p = 0.016). CSF GFAP is a valuable biomarker for distinguishing AQP4-NMOSD from other demyelinating diseases: Combining GFAP with QAlb enhances diagnostic precision.

To present a case of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) following atezolizumab and bevacizumab therapy and systematically review the literature on immune checkpoint inhibitor (ICI)-associated antibody-mediated central nervous system (CNS) inflammatory demyelinating diseases. While ICIs have transformed cancer treatment, they can trigger diverse neurological immune-related adverse events. Autoimmune demyelinating disorders remain uncommon, with sparse published cases linking ICIs to MOGAD. We report a novel case of MOGAD developing after administration of atezolizumab plus bevacizumab. We conducted a retrospective chart review of the index case and performed a systematic literature review (January 1, 2001, to April 30, 2025) of reported antibody-mediated CNS demyelinating disorders associated with ICIs. This represents the first documented MOGAD case during atezolizumab and bevacizumab treatment for hepatocellular carcinoma. The patient achieved a favorable response to intravenous methylprednisolone and immunoglobulin therapy. Further research is warranted to elucidate the pathogenesis underlying ICI-associated MOGAD.

In patients with myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), acute disease activity is generally identified through medical history, neurologic examination, and imaging. However, these may be insufficient for detecting disease activity in specific conditions. This study aimed to investigate the dynamics of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) after clinical attacks and to assess their utility in discriminating attacks from remission in patients with MOGAD. We conducted a multicenter, retrospective, longitudinal study including 239 sera from 62 MOGAD patients assessed from 1995 to 2023 in a discovery and validation setup. Sera were measured for sNfL and sGFAP with a single-molecule array assay and for MOG-IgG with a live cell-based assay. sNfL and sGFAP Z scores and percentiles adjusted for age, body mass index, and sex (sGFAP) were calculated from a healthy control normative database. Mixed-effects regression models were used to characterize biomarkers' dynamics and to investigate associations between serum biomarkers, clinical variables, and disease activity status. Among the 62 study participants, 29 (46.8%) were female, with a median age at baseline of 40.0 years (interquartile range [IQR] 29.5-49.8) and a median duration of follow-up of 20.0 months (IQR 3.0-62.8). sNfL and sGFAP Z scores were nonlinearly associated with time from attack onset (p < 0.001 and = 0.002, respectively). During attacks, both biomarkers presented higher median values (sNfL Z score 2.9 [IQR 1.4-3.5], 99.8th; sGFAP Z score 0.4 [IQR -0.5 to 1.5], 65.5th) compared with remission (sNfL Z score 0.9 [IQR -0.1 to 1.6], 81.6th, p < 0.001; sGFAP Z score -0.2 [IQR -0.8 to 0.5], 42.1th; p < 0.001) across all clinical phenotypes. sNfL values consistently discriminated disease activity status in the discovery and validation cohorts, showing a 3.5-fold increase in the odds of attacks per Z score unit (odds ratio 3.5, 95% confidence interval 2.3-5.1; p < 0.001). Logistic models incorporating sNfL Z scores demonstrated favorable performance in discriminating disease activity status across both cohorts. sNfL Z scores may serve as a biomarker for monitoring disease activity in MOGAD.

BackgroundDespite rigorous confirmation with reliable assays, some individuals showing the neuromyelitis optica spectrum disorder (NMOSD) phenotype remain negative for both aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies.ObjectiveWe aimed to investigate whether double seronegative NMOSD (DN-NMOSD) and NMOSD with AQP4 antibody (AQP4–NMOSD) share the same pathophysiological basis, astrocytopathy, by measurement of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) levels as a marker of astrocyte damage.MethodsSeventeen participants who (1) satisfied the 2015 diagnostic criteria for NMOSD, and (2) tested negative for AQP4 and MOG antibodies confirmed with repeated cell-based assays, and (3) had available CSF samples obtained at the point of clinical attacks, were enrolled from 4 medical centers (South Korea, Germany, Thailand, and Denmark). Thirty age-matched participants with AQP4–NMOSD, 17 participants with MOG antibody associated disease (MOGAD), and 15 participants with other neurological disorders (OND) were included as controls. The concentration of CSF GFAP was measured using enzyme-linked immunosorbent assay.ResultsCSF GFAP levels in the DN-NMOSD group were significantly lower than those in the AQP4–NMOSD group (median: 0.49 versus 102.9 ng/mL; p < 0.001), but similar to those in the OND (0.25 ng/mL) and MOGAD (0.39 ng/mL) control groups. The majority (90% (27/30)) of participants in the AQP4–NMOSD group showed significantly higher CSF GFAP levels than the highest level measured in the OND group, while no participant in the DN-NMOSD and MOGAD groups did.ConclusionsThese results suggest that DN-NMOSD has a different underlying pathogenesis other than astrocytopathy, distinct from AQP4–NMOSD.