Mayumi Muto

Cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels are increased during initial neuromyelitis optica attacks.

BACKGROUND The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, however this criteria seemed to be insufficient at early stage of NMO. Hence, the development of diagnostic marker besides anti-aquaporin 4 antibody at early stage of NMO may be required. Our main aim of this study is to test the usefulness of measuring cerebrospinal fluid (CSF) interleukin (IL)-6 and glial fibrillary acidic protein (GFAP) concentrations as early diagnostic markers during initial NMO attacks. METHODS We investigated CSF IL-6 and GFAP concentrations in 13 NMO spectrum disorder (NMOSD) patients at initial attacks, 24 idiopathic central nervous system inflammatory disease patients (9 optic neuritis, 9 myelitis and 6 encephalitis) and 20 other non-inflammatory neurological disorders (ONNDs) patients, retrospectively. RESULTS The mean CSF IL-6 and GFAP concentrations during the initial NMOSD attack were 91.4 pg/ml and 369.3 ng/ml, respectively, and were significantly higher than in ONNDs, idiopathic optic neuritis and myelitis patients (P<0.01). The sensitivity of high CSF IL-6 during initial NMO attack was 76.9% and that of high CSF GFAP was 84.6%, respectively. CONCLUSION Our data suggests that CSF IL-6 and GFAP may be useful early diagnostic markers of NMOSD.

CSF high-mobility group box 1 is associated with intrathecal inflammation and astrocytic damage in neuromyelitis optica

Objective High-mobility group box 1 (HMGB1) acts as a proinflammatory mediator when released by cells. Recent studies implicate extracellular HMGB1 in the pathogenesis of various autoimmune diseases. Our main aim of this study is to determine whether HMGB1 is involved in the neuromyelitis optica (NMO) inflammatory process. Methods Cerebrospinal fluid (CSF) and serum HMGB1 levels in 42 NMO patients were compared with those in 30 multiple sclerosis (MS) patients, and 30 patients with other noninflammatory neurological disorders (ONNDs). We also tested the possible correlation between CSF HMGB1 levels and the clinical and laboratory variables in NMO patients. Results CSF HMGB1 levels in NMO patients were higher than those in MS and ONNDs patients (p<0.001), and these levels in MS patients were higher than those in ONNDs patients (p<0.001). After treatment, the CSF HMGB1 levels in NMO patients decreased to normal. In addition, CSF HMGB1 levels correlated with CSF cell counts, CSF protein levels, CSF interleukin-6 levels, CSF glial fibrillary acidic protein levels, and CSF/serum albumin ratio (p≤0.001). Serum HMGB1 levels in MS patients were significantly higher than those in ONNDs patients (p=0.002). Conclusions HMGB1 could play a key role in central nervous system inflammation in NMO patients.

Anti-high mobility group box 1 monoclonal antibody ameliorates experimental autoimmune encephalomyelitis

High mobility group box 1 (HMGB1) is an established inflammatory mediator when released from cells. Recent studies have implicated extracellular HMGB1 in the pathogenesis of various autoimmune diseases. The objective of this study was to determine whether HMGB1 could be a therapeutic target for experimental autoimmune encephalomyelitis (EAE). In this study, an anti‐HMGB1 monoclonal antibody was injected intraperitoneally into a mouse model of EAE. We also measured serum cytokines levels in EAE and anti‐HMGB1 monoclonal antibody‐treated EAE. As a result, intraperitoneal injection of an anti‐HMGB1 monoclonal antibody ameliorated the clinical and pathological severity of EAE and attenuated interleukin‐17 up‐regulation in serum. In conclusion, HMGB1 is involved in EAE pathogenesis and could trigger inflammation in the central nervous system. The novel aspect of this study is the demonstration that anti‐HMGB1 ameliorates EAE. HMGB1 may be a novel therapeutic strategy for multiple sclerosis.

Serum antinuclear antibody may be associated with less severe disease activity in neuromyelitis optica.

Antinuclear antibody‐positive multiple sclerosis (MS) patients have shorter disease duration and lower Expanded Disability Status Scale (EDSS) scores. The aim of this study was to compare clinical and laboratory features between MS and neuromyelitis optica (NMO) patients with and without autoantibodies and to investigate the prognosis of NMO in patients with and without autoantibodies.

Current symptomatology in multiple sclerosis and neuromyelitis optica

Several symptoms and signs are characteristic of multiple sclerosis (MS) such as Lhermittes sign, Uhthoffs phenomenon and painful tonic seizure. Neuromyelitis optica (NMO) is another inflammatory disease of the central nervous system, and most of the opticospinal form of MS is thought to be NMO. This study aimed to investigate the frequencies of symptoms and signs, previously regarded as characteristic of MS, in NMO and MS patients.

Increased cerebrospinal fluid metalloproteinase-2 and interleukin-6 are associated with albumin quotient in neuromyelitis optica: Their possible role on blood–brain barrier disruption:

Background: Inflammation in neuromyelitis optica (NMO) is triggered by a serum antibody against the aquaporin-4 (AQP4). This process requires antibody penetration of the blood–brain barrier (BBB), but the mechanisms for BBB disruption in NMO remain unknown. Objective: We examined whether changes in cerebrospinal fluid (CSF) and serum matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and cytokines are associated with BBB disruption in NMO. Methods: The concentrations 9 MMPs, 4 TIMPs, and 14 cytokines were measured by multiplex assay in CSF and serum samples from 29 NMO patients, 29 relapsing-remitting multiple sclerosis (MS) patients, and 27 patients with other neurological disorders. We also performed immunohistochemistry for MMP-2 and TIMP-1 expression in post-mortem brain tissues from NMO patients. Results: NMO patients exhibited significantly elevated MMP-2, TIMP-1, interleukin-6, and MMP-2/TIMP-2 ratio in CSF (but not sera) than the other groups. The CSF/serum albumin ratio, an index of BBB permeability, was most strongly correlated with CSF MMP-2 concentration, which in turn correlated with CSF interleukin-6 levels. Immunohistochemistry revealed MMP-2- and TIMP-1-positive cells surrounding vessels in NMO lesions. Conclusion: In NMO, increased CSF MMP-2, likely induced by interleukin-6 signaling, may disrupt the BBB and enable serum anti-AQP-4 antibodies migration into the central nervous system (CNS).

Epstein-Barr virus persistence and reactivation in neuromyelitis optica

Objective Epstein-Barr virus (EBV) infection has been thought to be a key environmental factor in the development of multiple sclerosis (MS). The aim of this study is to investigate the association of EBV infection with neuromyelitis optica (NMO). Methods We measured levels of serum antibodies against EBV antigens, including anti-viral capsid antigen (VCA) IgM, anti-VCA IgG, anti-early antigen (EA) IgM, anti-EA IgG and anti-EBV nuclear antigen-1 IgG, in 50 patients with NMO (including 12 partial form with antiaquaporin 4 antibodies), 51 patients with MS, and 52 healthy controls, and cerebrospinal fluid (CSF) antibodies in 37 patients with NMO and 33 patients with MS with ELISA. Result Compared with patients with MS and normal participants, patients with NMO more frequently had serum anti-EA IgG antibodies (52%), indicating more active viral replication than patients with MS (26%) and controls (25%). The antibody titres were significantly higher in the NMO group than in the MS (p=0.005) and control (p=0.005) groups. The CSF antibody titres were also higher in patients with NMO than in those with MS (p=0.03). Conclusions Our results raise the hypothesis that persistent, active EBV replication is present in NMO, and may contribute to the immunological alterations that play a pathogenetic role in the disorder.

Identification of Cerebral Infarction-Specific Antibody Markers from Autoantibodies Detected in Patients with Systemic Lupus Erythematosus

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease which may be caused by development of the autoantibodies. On the other hand, SLE is a high-risk group of atherosclerosis, so it is possible that some of autoantibodies in SLE are the result of atherosclerosis-related diseases such as cerebral infarction (CI), cardiovascular disease (CVD) and diabetes mellitus (DM). Methods: The initial screening of autoantibodies was performed using the protein array method. AlphaLISA was used to analyze the serum antibody levels using synthetic polypeptides as antigens. Results: After the initial screening using protein array, we identified 67 antigens that were recognized by IgG antibodies in sera of patients with SLE. In the second screening, 170 peptides derived from amino acid sequences of 67 antigens were synthesized and used as antigens for analysis of serum antibody levels by AlphaLISA. The antibody levels for ten peptides were significantly higher in the sera of patients with SLE than in those of healthy donors. Further AlphaLISA analysis of sera of patients with CI, CVD or DM revealed that the serum antibody levels for four peptides derived from SOSTDC1, CTNND1, CLDND1 and CCNG2 were elevated in patients as compared to those of healthy donors. Conclusions: Serum antibody levels against peptide antigens of SOSTDC1, CTNND1, CLDND1 and CCNG2 are useful markers for diagnosis of the progression of CI, CVD and/or DM.

Seasonality of multiple sclerosis and neuromyelitis optica exacerbations in Japan

Dear Sir A meta-analysis of the seasonality of multiple sclerosis (MS) exacerbations showed that relapse occurred more frequently in spring and summer.1 However, the seasonality of MS relapse has been rarely reported from regions other than Western countries. Moreover, few studies have addressed the seasonality of neuromyelitis optica (NMO) relapse. To investigate the seasonality of MS/NMO relapse in Japan, medical records documenting relapse onset and initial hospital visits during relapse were collected from consecutive patients with relapsing–remitting MS or relapsing NMO diagnosed according to the revised diagnostic criteria.2,3 Records documenting the hospital visits of patients with other neurological disorders (ONDs) including Parkinsonian syndrome, motor neuron diseases, and cerebrovascular diseases were also collected as control. All patients were evaluated at the neurology outpatient clinic at Chiba University Hospital between October 2004 and September 2011. Our hospital is the only regional center specializing in MS/NMO; thus, we believe that all regional MS/NMO patients experiencing a relapse have visited our hospital during the study period. We compared seasonal variations of MS/NMO exacerbations and those of ONDs. Seasons were defined as spring (April–June), summer (July–September), fall (October–December), and winter (January–March). Significant differences and deviation in hospital visit rates of MS/NMO patients and those of controls were evaluated monthly using the Fisher’s exact test and Walter–Elwood test, respectively.4 There were 295 MS exacerbations (54 males and 241 females), 131 NMO exacerbations (3 males and 128 females), and 117,829 visits for ONDs (54,950 males and 62,879 females) over the study period. Comparison of total visits for MS/NMO exacerbations with those for ONDs according to seasons revealed a significant peak in MS exacerbation in summer (MS: 95 in summer versus 200 in other seasons; ONDs: 30,133 in summer versus 87,696 in other seasons; p = 0.011) and a nadir in winter (MS: 56 in winter versus 239 in other seasons; ONDs: 29,377 in winter versus 88,452 in other seasons; p = 0.018). In analysis by gender, a similar significant seasonal difference existed between visits for MS exacerbations and those for ONDs in females but not in males. No significant seasonal difference (total and by gender) in NMO exacerbations existed. In monthly analysis, no significant seasonal difference (total and by gender) existed between visits for MS/NMO exacerbations and control visits (Fisher’s exact test), and no significant effect of seasonality on MS/NMO exacerbations was observed (Walter–Elwood test). However, seasonal deviations with an excess of exacerbations in August and a nadir in March was observed in female MS patients (p = 0.054). We examined the relationship between seasonal distribution of MS relapse and publicly available meteorological and viral infection data from Chiba city. Mean, maximum and minimum daily temperatures, relative humidity, and vapor pressure as well as coxsackievirus and enterovirus infection rates showed similar seasonal variations, with peak in summer and nadir in winter. Other factors including UV radiation and mumps virus infections showed a different pattern. In conclusion, seasonal variations in exacerbations were observed for MS but not for NMO in Japan.

Trigeminal root entry zone involvement in neuromyelitis optica and multiple sclerosis

Trigeminal root entry zone abnormality on brain magnetic resonance imaging has been frequently reported in multiple sclerosis patients, but it has not been investigated in neuromyelitis optica patients. Brain magnetic resonance imaging of 128 consecutive multiple sclerosis patients and 46 neuromyelitis optica patients was evaluated. Trigeminal root entry zone abnormality was present in 11 (8.6%) of the multiple sclerosis patients and two (4.3%) of the neuromyelitis optica patients. The pontine trigeminal root entry zone may be involved in both multiple sclerosis and neuromyelitis optica.