Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Over the past few years, new-generation cell-based assays have demonstrated a robust association of autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis and brainstem encephalitis, as well as with acute disseminated encephalomyelitis (ADEM)-like presentations. Most experts now consider MOG-IgG-associated encephalomyelitis (MOG-EM) a disease entity in its own right, immunopathogenetically distinct from both classic multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorders (NMOSD). Owing to a substantial overlap in clinicoradiological presentation, MOG-EM was often unwittingly misdiagnosed as MS in the past. Accordingly, increasing numbers of patients with suspected or established MS are currently being tested for MOG-IgG. However, screening of large unselected cohorts for rare biomarkers can significantly reduce the positive predictive value of a test. To lessen the hazard of overdiagnosing MOG-EM, which may lead to inappropriate treatment, more selective criteria for MOG-IgG testing are urgently needed. In this paper, we propose indications for MOG-IgG testing based on expert consensus. In addition, we give a list of conditions atypical for MOG-EM (“red flags”) that should prompt physicians to challenge a positive MOG-IgG test result. Finally, we provide recommendations regarding assay methodology, specimen sampling and data interpretation.

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of <1/million population. Among East Asians, the prevalence is higher, at ~3.5/100,000 population, while the prevalence in Blacks may be up to 10/100,000 population. For MOG-antibody disease, hospital-based studies largely do not observe any significant racial preponderance so far. This disorder comprises a significant proportion of NMOSD cases that are AQP4-antibody-seronegative. A recent Dutch nationwide study reported the annual incidence of MOG-antibody disease as 1.6/million population (adult: 1.3/million, children: 3.1/million). Clinical and radiological differences between AQP4-antibody and MOG-antibody associated diseases have led to interest in the revisions of NMOSD definition and expanded stratification based on detection of a specific autoantibody biomarker. More population-based studies in different geographical regions and racial groups will be useful to further inform the prevalence and incidence of NMOSD and their antibody-specific subgroups. Accessibility to AQP4-antibody and MOG-antibody testing, which is limited in many centers, is a challenge to overcome. Environmental and genetic studies will be useful accompaniments to identify other potential pathogenetic factors and specific biomarkers in NMOSD.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that preferentially affects the spinal cord and optic nerve. Most patients with NMOSD experience severe relapses that lead to permanent neurologic disability; therefore, limiting frequency and severity of these attacks is the primary goal of disease management. Currently, patients are treated with immunosuppressants. Interleukin-6 (IL-6) is a pleiotropic cytokine that is significantly elevated in the serum and the CSF of patients with NMOSD. IL-6 may have multiple roles in NMOSD pathophysiology by promoting plasmablast survival, stimulating the production of antibodies against aquaporin-4, disrupting blood-brain barrier integrity and functionality, and enhancing proinflammatory T-lymphocyte differentiation and activation. Case series have shown decreased relapse rates following IL-6 receptor (IL-6R) blockade in patients with NMOSD, and 2 recent phase 3 randomized controlled trials confirmed that IL-6R inhibition reduces the risk of relapses in NMOSD. As such, inhibition of IL-6 activity represents a promising emerging therapy for the management of NMOSD manifestations. In this review, we summarize the role of IL-6 in the context of NMOSD.

Objective To evaluate cerebrospinal fluid (CSF) cytokine profiles in myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) disease in adult and paediatric patients. Methods In this cross-sectional study, we measured 27 cytokines in the CSF of MOG-IgG+ disease in acute phase before treatment (n=29). The data were directly compared with those in aquaporin-4 antibody-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) (n=20), multiple sclerosis (MS) (n=20) and non-inflammatory controls (n=14). Results In MOG-IgG+ disease, there was no female preponderance and the ages were younger (mean 18 years, range 3–68; 15 were below 18 years) relative to AQP4-IgG+ NMOSD (41, 15–77) and MS (34, 17–48). CSF cell counts were higher and oligoclonal IgG bands were mostly negative in MOG-IgG+ disease and AQP4-IgG+ NMOSD compared with MS. MOG-IgG+ disease had significantly elevated levels of interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor and granulocyte macrophage-colony stimulating factor, interferon-γ, IL-10, IL-1 receptor antagonist, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α as compared with MS. No cytokine in MOG-IgG+ disease was significantly different from AQP4-IgG+ NMOSD. Moreover many elevated cytokines were correlated with each other in MOG-IgG+ disease and AQP4-IgG+ NMOSD but not in MS. No difference in the data was seen between adult and paediatric MOG-IgG+ cases. Conclusions The CSF cytokine profile in the acute phase of MOG-IgG+ disease is characterised by coordinated upregulation of T helper 17 (Th17) and other cytokines including some Th1-related and regulatory T cells-related ones in adults and children, which is similar to AQP4-IgG+ NMOSD but clearly different from MS. The results suggest that as with AQP4-IgG+ NMOSD, some disease-modifying drugs for MS may be ineffective in MOG-IgG+ disease while they may provide potential therapeutic targets.