Aquaporin 4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) is an autoimmune astrocytopathic disease pathologically characterized by the massive destruction and regeneration of astrocytes with diverse types of tissue injury with or without complement deposition. However, it is unknown whether this diversity is derived from differences in pathological processes or temporal changes. Furthermore, unlike for the demyelinating lesions in multiple sclerosis, there has been no staging of astrocytopathy in AQP4-IgG+NMOSD based on astrocyte morphology. Therefore, we classified astrocytopathy of the disease by comparing the characteristic features, such as AQP4 loss, inflammatory cell infiltration, complement deposition and demyelination activity, with the clinical phase. We performed histopathological analyses in eight autopsied cases of AQP4-IgG+NMOSD. Cases comprised six females and two males, with a median age of 56.5 years (range, 46–71 years) and a median disease duration of 62.5 months (range, 0.6–252 months). Astrocytopathy in AQP4-IgG+NMOSD was classified into the following four stages defined by the astrocyte morphology and immunoreactivity for GFAP: (i) astrocyte lysis: extensive loss of astrocytes with fragmented and/or dust-like particles; (ii) progenitor recruitment: loss of astrocytes except small nucleated cells with GFAP-positive fibre-forming foot processes; (iii) protoplasmic gliosis: presence of star-shaped astrocytes with abundant GFAP-reactive cytoplasm; and (iv) fibrous gliosis: lesions composed of densely packed mature astrocytes. The astrocyte lysis and progenitor recruitment stages dominated in clinically acute cases (within 2 months after the last recurrence). Findings common to both stages were the loss of AQP4, a decreased number of oligodendrocytes, the selective loss of myelin-associated glycoprotein and active demyelination with phagocytic macrophages. The infiltration of polymorphonuclear cells and T cells (CD4-dominant) and the deposition of activated complement (C9neo), which reflects the membrane attack complex, a hallmark of acute NMOSD lesions, were selectively observed in the astrocyte lysis stage (98.4% in astrocyte lysis, 1.6% in progenitor recruitment, and 0% in protoplasmic gliosis and fibrous gliosis). Although most of the protoplasmic gliosis and fibrous gliosis lesions were accompanied by inactive demyelinated lesions with a low amount of inflammatory cell infiltration, the deposition of complement degradation product (C3d) was observed in all four stages, even in fibrous gliosis lesions, suggesting the past or chronic occurrence of complement activation, which is a useful finding to distinguish chronic lesions in NMOSD from those in multiple sclerosis. Our staging of astrocytopathy is expected to be useful for understanding the unique temporal pathology of AQP4-IgG+NMOSD.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients. The contribution of T cells to the formation of astrocyte destructive lesions is currently unclear. However, active human NMO lesions contain CD4+ T-lymphocytes expressing the activation marker Ox40, and the expression is more profound compared to that seen in MS lesions of comparable activity. Therefore, we analyzed the role of T-cell activation within the CNS in the initiation of NMO lesions in an experimental model of co-transfer of different encephalitogenic T-cells and human AQP4 antibody containing NMO immunoglobulin (NMO IgG). We further studied the expression of the T-cell activation marker Ox40 in NMO and multiple sclerosis lesions in different stages of activity.

Objective To elucidate the differences in the source and in the level of intrathecal synthesis between anti–aquaporin-4 antibodies (AQP4-IgG) and anti-myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Methods Thirty-eight patients with MOG-IgG–associated disease and 36 with AQP4-IgG–positive neuromyelitis optica spectrum disorders (NMOSD) were studied for the antibody titers in the sera and CSF simultaneously collected in the acute attacks. The quotients between CSF and serum levels of albumin, total immunoglobulin G, and each disease-specific antibody were calculated. Intrathecal production level in each disease-specific antibody was evaluated by calculating the antibody index from these quotients. Results Eleven of the 38 patients with MOG-IgG were positive for the antibody only in the CSF, while no patient with AQP4-IgG showed CSF-restricted AQP4-IgG. Blood-brain barrier compromise as shown by raised albumin quotients was seen in 75.0% of MOG-IgG–positive cases and 43.8% of AQP4-IgG–positive cases. Moreover, MOG-IgG quotients were >10 times higher than AQP4-IgG quotients (effect size r = 0.659, p < 0.0001). Elevated antibody index (>4.0) was confirmed in 12 of 21 with MOG-IgG, whereas it was seen only in 1 of 16 with AQP4-IgG (φ = 0.528, p < 0.0001). The CSF MOG-IgG titers (ρ = 0.519, p = 0.001) and antibody indexes for MOG-IgG (ρ = 0.472, p = 0.036) correlated with the CSF cell counts but not with clinical disability. Conclusions Intrathecal production of MOG-IgG may occur more frequently than that of AQP4-IgG. This finding implies the different properties of B-cell trafficking and antibody production between MOG-IgG–associated disease and AQP4-IgG–positive NMOSD.

The spectrum of myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD) includes optic neuritis (ON), myelitis (MY), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, cerebral cortical encephalitis (CE), and aquaporin-4-IgG (AQP4-IgG)-negative neuromyelitis optica spectrum disorder (NMOSD). In MOGAD, MOG-IgG are usually detected in sera (MOG-IgG_SERUM), but there have been some seronegative MOGAD cases with MOG-IgG in CSF (MOG-IgG_CSF) and its diagnostic implications remains unclear. In this cross-sectional study, we identified patients with paired serum and CSF sent from all over Japan for testing MOG-IgG. Two investigators blinded to MOG-IgG status classified them into suspected MOGAD (ADEM, CE, NMOSD, ON, MY and Others) or not based on the current recommendations. The MOG-IgG_SERUM and MOG-IgG_CSF titres were assessed with serial two-fold dilutions to determine endpoint titres [≥1:128 in serum and ≥1:1 (no dilution) in CSF were considered positive]. We analysed the relations between MOG-IgG_SERUM, MOG-IgG_CSF, and the phenotypes with multivariable regression. A total of 671 patients were tested (405 with suspected MOGAD, 99 with multiple sclerosis, 48 with AQP4-IgG-positive NMOSD, and 119 with other neurological diseases [OND]) before treatment. In suspected MOGAD, 133 patients (33%) tested MOG-IgG-positive in serum and/or CSF; 94 (23%) double-positive (ADEM 36, CE 15, MY 8, NMOSD 9, ON 15, and Others 11), 17 (4.2%) serum-restricted-positive (ADEM 2, CE 0, MY 3, NMOSD 3, ON 5, and Others 4), and 22 (5.4%) CSF-restricted-positive (ADEM 3, CE 4, MY 6, NMOSD 2, ON 0, and Others 7) cases. None of AQP4-IgG-positive NMOSD, multiple sclerosis, or OND cases tested positive for MOG-IgG_SERUM but two with multiple sclerosis were MOG-IgG_CSF-positive; the specificity of MOG-IgG_SERUM and MOG-IgG_CSF in suspected MOGAD were 100% (95%CI 99%–100%) and 99% (97%–100%), respectively. Unlike AQP4-IgG-positive NMOSD, the correlation between MOG-IgG_SERUM and MOG-IgG_CSF titres in MOGAD was weak. Multivariable regression analyses revealed MOG-IgG_SERUM were associated with ON and ADEM, whereas MOG-IgG_CSF were associated with ADEM and CE. The number needed to test (NNT) of MOG-IgG_CSF to diagnose one additional MOGAD case was 13.3 (14.3 for ADEM, 2 for CE, 19.5 for NMOSD, infinite for ON, 18.5 for MY, and 6.1 for Others). In the status of MOG-IgG_SERUM/CSF, most cases were double-positive, while including either serum-restricted (13%) or CSF-restricted (17%). These statuses were independently associated with clinical phenotypes, especially with ON in serum and CE in CSF, suggesting these pathophysiologic implications and the utility of preferential diagnostic testing. Further studies are warranted for the clinical and pathological significance of compartmentalized MOG-IgG.