There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multiple sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1β (MIP-1β), were measured simultaneously in CSF supernatants from 40 patients with relapsing–remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-γ and IL-4 in CSF CD4⁺ T cells. In CSF supernatants relative to controls, IL-17, MIP-1β, IL-1β and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-α was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS-multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-γ⁺IL-4⁻ T-cell percentage and intracellular IFN-γ/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patients showed not only a significantly greater percentage of IFN-γ⁺IL-4⁻ T cells than controls but also a significantly higher percentage of IFN-γ⁻IL-4⁺ T cells than C-multiple sclerosis patients. Among the cytokines elevated in multiple sclerosis, only IL-8 showed a significant positive correlation with the Expanded Disability Status Scale of Kurtzke score. Both the length of the spinal cord lesions on MRI and the CSF/serum albumin ratio had a significant positive correlation with IL-8 and IL-17 in multiple sclerosis, in which the spinal cord lesions were significantly longer in OS-multiple sclerosis than in C-multiple sclerosis. Three of six spinal cord specimens from autopsied OS-multiple sclerosis cases demonstrated numerous myeloperoxidase-positive neutrophils infiltrating necrotic lesions. These findings strongly suggest that in OS-multiple sclerosis, in addition to the Th1 cell upregulation seen in C-multiple sclerosis, intrathecal activation of the IL-17/IL-8 axis inducing heavy neutrophil infiltration contributes to extensive spinal cord lesion formation.

Differences in cytokine/chemokine profiles among patients with neuromyelitis optica (NMO), relapsing remitting multiple sclerosis (RRMS), and primary progressive MS (PPMS), and the relationships of these profiles with clinical and neuroimaging features are unclear. A greater understanding of these profiles may help in differential diagnosis. We measured 27 cytokines/chemokines and growth factors in CSF collected from 20 patients with NMO, 26 with RRMS, nine with PPMS, and 18 with other non-inflammatory neurological diseases (OND) by multiplexed fluorescent bead-based immunoassay. Interleukin (IL)-17A, IL-6, CXCL8 and CXCL10 levels were significantly higher in NMO patients than in OND and RRMS patients at relapse, while granulocyte-colony stimulating factor (G-CSF) and CCL4 levels were significantly higher in NMO patients than in OND patients. In NMO patients, IL-6 and CXCL8 levels were positively correlated with disability and CSF protein concentration while IL-6, CXCL8, G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-γ were positively correlated with CSF neutrophil counts at the time of sample collection. In RRMS patients, IL-6 levels were significantly higher than in OND patients at the relapse phase while CSF cell counts were negatively correlated with the levels of CCL2. Correlation coefficients of cytokines/chemokines in the relapse phase were significantly different in three combinations, IL-6 and GM-CSF, G-CSF and GM-CSF, and GM-CSF and IFN-γ, between RRMS and NMO/NMOSD patients. In PPMS patients, CCL4 and CXCL10 levels were significantly higher than in OND patients. Our findings suggest distinct cytokine/chemokine alterations in CSF exist among NMO, RRMS and PPMS. In NMO, over-expression of a cluster of Th17- and Th1-related proinflammatory cytokines/chemokines is characteristic, while in PPMS, increased CCL4 and CXCL10 levels may reflect on-going low grade T cell and macrophage/microglia inflammation in the central nervous system. In RRMS, only a mild elevation of proinflammatory cytokines/chemokines was detectable at relapse.

Objective To test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD). Methods Levels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined. Results For both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p = 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of 75.8%. Conclusions sGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.

Objective: To investigate anti‐neurofascin 155 (NF155) antibody‐positive chronic inflammatory demyelinating polyneuropathy (CIDP).Methods: Sera from 50 consecutive CIDP patients diagnosed in our clinic, 32 patients with multiple sclerosis, 40 patients with other neuropathies including 26 with Guillain–Barré syndrome (GBS)/Fisher syndrome, and 30 healthy controls were measured for anti‐NF antibodies by flow cytometry using HEK293 cell lines stably expressing human NF155 or NF186. Four additional CIDP patients with anti‐NF155 antibodies referred from other clinics were enrolled for clinical characterization.Results: The positivity rate for anti‐NF155 antibodies in CIDP patients was 18% (9/50), who all showed a predominance of IgG4 subclass. No other subjects were positive, except one GBS patient harboring IgG1 anti‐NF155 antibodies. No anti‐NF155 antibody carriers had anti‐NF186 antibodies. Anti‐NF155 antibody‐positive CIDP patients had a significantly younger onset age, higher frequency of drop foot, gait disturbance, tremor and distal acquired demyelinating symmetric phenotype, greater cervical root diameter on magnetic resonance imaging neurography, higher cerebrospinal fluid protein levels, and longer distal and F‐wave latencies than anti‐NF155 antibody‐negative patients. Marked symmetric hypertrophy of cervical and lumbosacral roots/plexuses was present in all anti‐NF155 antibody‐positive CIDP patients examined by neurography. Biopsied sural nerves from two patients with anti‐NF155 antibodies demonstrated subperineurial edema and occasional paranodal demyelination, but no vasculitis, inflammatory cell infiltrates, or onion bulbs. Among anti‐NF155 antibody‐positive patients, treatment responders more frequently had daily oral corticosteroids and/or immunosuppressants in addition to intravenous immunoglobulins than nonresponders did.Interpretation: Anti‐NF155 antibodies occur in a subset of CIDP patients with distal‐dominant involvement and symmetric nerve hypertrophy.

In order to clarify the relationship between the clinical phenotype and the human leucocyte antigen (HLA) in multiple sclerosis in Asians, 93 Japanese patients with clinically definite multiple sclerosis underwent clinical MRI and HLA-DPB1 gene typing studies. According to a neurological examination, 29 patients were classified as opticospinal multiple sclerosis, 17 as spinal multiple sclerosis and 47 as Western type multiple sclerosis showing the involvement of multiple sites in the CNS including either the cerebrum, cerebellum or brainstem. The opticospinal multiple sclerosis showed a significantly higher age of onset, higher expanded disability status scale scores and higher CSF cell counts and protein content than the Western type multiple sclerosis. On brain and spinal cord MRI, the opticospinal multiple sclerosis showed a significantly lower number of brain lesions, but a higher frequency of gadolinium-enhancement of the optic nerve and a higher frequency of spinal cord atrophy than in Western type multiple sclerosis. The frequency of the HLA-DPB1*0501 allele was found to be significantly greater in opticospinal multiple sclerosis (93%) than in healthy controls (63%, corrected P value = 0.0091 and relative risk = 7.9), but not in Western type multiple sclerosis (66%) or spinal multiple sclerosis (82%). The marked differences in the clinical and MRI findings as well as in the immunogenetic backgrounds between the opticospinal multiple sclerosis and Western-type multiple sclerosis together suggest that HLA-DPB1*0501-associated opticospinal multiple sclerosis is a distinct subtype of multiple sclerosis.