鵜沢 顕之

Objective Brain regions responsible for cognitive dysfunction in MS and neuromyelitis optica spectrum disorder (NMOSD) are not known. Our aim of this study was to investigate whether cognitive function and brain volume differed between MS and NMOSD in Japanese patients. Methods Brain MRI and neuropsychological tests including the Wechsler Adult Intelligence Scale-III (WAIS-III), Wechsler Memory Scale-Revised (WMS-R), Trail Making Test (TMT) and Clinical Assessment for Attention (CAT) were performed. Parametric grey matter (GM) and white matter (WM) volumes determined from lesion-filled T1-weighted images using wholebrain voxel-based morphometry (VBM) were compared by two-tailed t test. Results Twenty relapsing-remitting MS and sixteen NMOSD patients were included. MS patients were younger than NMOSD patients. Processing speed intelligence quotient (IQ), general memory, verbal memory and delayed recall were significantly worse in MS patients than in NMOSD patients. Furthermore, left superior temporal gyrus (STG) GM volume was smaller in MS patients than in NMOSD patients (P < 0.05, family-wise error [FWE] corrected, Zmax = 4.97, 62 voxel). The left STG GM volume tended to be positively correlated with delayed recall in MS patients. Conclusions Despite being younger, MS patients demonstrated worse performance in certain cognitive variables than NMOSD patients, which might be associated with left STG GM volume loss.

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).

Introduction: In this study we sought to clarify the effects of early fast-acting treatment (EFT) strategies on the time course for achieving the treatment target in generalized myasthenia gravis (MG). Methods: This retrospective study of 923 consecutive MG patients analyzed 688 generalized MG patients who had received immunotherapy during the disease course. The time to first achieve minimal manifestations (MM) or better while receiving prednisolone at <= 5 mg/day for >= 6 months (MM-or-better-5mg) up to 120 months after starting immunotherapy was compared between EFT and non-EFT patients. Results: Achievement of MM-or-better-5mg was more frequent and earlier in the EFT group (P = 0.0004, Wilcoxon test; P = 0.0001, log-rank test). Multivariate Cox regression analysis calculated a hazard ratio of 1.98 (P < 0.0001) for utilization of EFT. Dosing regimens of oral steroids in EFT produced no differences in the time course. Conclusions: EFT strategies are advantageous for early achievement of MM-or-better-5mg.

Background: Elevation of cerebrospinal fluid (CSF) interleukin (IL)-6 has been reported in various neurological disorders but has never been systematically analyzed. Our main objectives are to compare the CSF IL-6 levels among various neurological disorders and to evaluate the significance of CSF IL-6 measurements for the diagnosis of neuromyelitis optica (NMO). Methods: We retrospectively investigated the IL-6 levels of 572 consecutive CSF samples in patients with various neurological disorders. Additionally, the associations between clinical manifestations in NMO patients and CSF IL-6 levels were closely investigated. Results: Among the neurological disorders, patients with NMO had the highest CSF IL-6 level. Receiver operating characteristic analysis found the optimal cutoff CSF IL-6 value for diagnosing NMO as 7.8 pg/ml, and the sensitivity and specificity were 0.7317 and 0.7694, respectively. In NMO, CSF IL-6 levels were correlated with the length of the spinal cord lesion and anti-aquaporin-4 antibody-positivity and decreased after treatment. Conclusion: CSF IL-6 can be high in various inflammatory and non-inflammatory CNS disorders, but its upregulation appears to be the most remarkable in NMO. (C) 2017 Elsevier B.V. All rights reserved.

Soluble CD40 ligand (sCD4OL) is reported to disrupt the blood-brain barrier (BBB). Cerebrospinal fluid (CSF) and serum sCD4OL levels were measured in 29 multiple sclerosis (MS), 29 neuromyelitis optica spectrum disorder (NMOSD), and 27 disease control (DC) patients. In MS, serum sCD4OL levels were higher than in DCs and positively correlated with the CSF/serum albumin ratio (Qalb). In NMOSD, CSF sCD4OL levels were significantly increased compared to DCs, and were correlated to Qalb, CSF cell counts, protein concentrations, and interleukin-6 levels. sCD4OL could be involved in BBB disruption in MS, whereas it may contribute to CNS inflammation in NMOSD. (C) 2017 Elsevier B.V. All rights reserved.

Previously, we identified anti-Talin-1 antibodies in the serum of MS. In this case, we measured the serum soluble Talin-1 (sTalin-1) levels by enzyme-linked immunosorbent assay. The serum sTalin-1 levels were significantly higher in 40 patients with MS than in 43 normal controls and in the acute phase of disease than in the remission phase. Interestingly, serum sTalin-1 levels were associated with a sustained increase in disability after MS attack but not with serum anti-Talin-1 antibody levels. sTalin-1 may be a biomarker for the acute phase of MS and may be used for the short-term prognosis of MS. (C) 2017 Elsevier B.V. All rights reserved.

Background and purposeA single, oral dose of 3 mg/day tacrolimus, approved for myasthenia gravis (MG) treatment in Japan, was shown to reduce steroid dose and anti-acetylcholine receptor (AChR) antibody titers as well as to improve MG symptoms. However, no studies have investigated the association between tacrolimus concentration and its clinical efficacy in MG. In this study, we aimed to determine the optimal tacrolimus concentration for MG treatment. MethodsThe trough tacrolimus concentration in 51 patients with MG (positive for anti-AChR antibody, n = 48; negative for anti-AChR and anti-muscle-specific tyrosine kinase antibodies, n = 3) who received 3 mg/day tacrolimus for more than 1 year was measured using a chemiluminescent enzyme immunoassay. The clinical characteristics of patients with MG as well as the dose of prednisolone used before and after tacrolimus treatment were evaluated retrospectively. ResultsThe median trough tacrolimus concentration was 5.4 (range, 2.9-7.6) ng/mL, which was correlated with minimal manifestation or better status' (P = 0.0190, r = 0.3273) and the reduction in anti-AChR antibody 1 year after tacrolimus initiation (P = 0.0170, r = 0.3465). When the cut-off value for tacrolimus was defined as 4.8 ng/mL using a receiver operating characteristic curve, patients with adequate tacrolimus concentration (4.8 ng/mL) showed more reduction in anti-AChR antibody titers and more improvement in MG-related activities in daily life scores. More patients with adequate tacrolimus concentration achieved minimal manifestation or better status' compared with those with low tacrolimus concentration. ConclusionsAn adequate tacrolimus concentration is required for better MG prognosis.

Objectives: To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. Design: Cross-sectional study. Setting and participants: We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. Outcome measures: All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose >= 20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at <= 5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry. Results: We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was >= 50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. Conclusions: Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.

Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG. The effects of AChR-Fc in vivo were also examined using rat MG models. AChR-Fc bound to anti-AChR antibodies and exhibited cytotoxicity against patient-derived antibody-producing B cells. Additionally, a dose-dependent improvement in the clinical signs of disease was observed in a rat MG model. AChR-Fc can diminish signs of MG by neutralizing anti-AChR antibodies and enhancing cytotoxicity against autoantibody-producing B cells. Thus, AChR-Fc can be a novel therapeutic biomolecule for patients with MG.

Objective: Damage-associated molecular patterns (DAMP) and cytokines can play a crucial role in inflammation at neuromuscular junctions in myasthenia gravis (MG). However, the relationship between DAMP and cytokine levels in MG pathogenesis remains unknown. To clarify this, we examined the relationship between serum levels of DAMP and cytokines in MG patients. Methods: Using serum data from 26 patients with anti-acetylcholine receptor antibody-positive MG, we investigated the relationship between the levels of DAMP (high-mobility group box 1 [HMGB1] and peroxiredoxin 5) and cytokines (interleukin [IL]-4, IL-15, IL-19, IL-20, IL-28A, IL-35, a proliferation-inducing ligand [APRIL] and vascular endothelial growth factor), which were reported to be significantly elevated in MG. Results: Serum levels of APRIL (r = 0.4789, P = 0.0133), IL-19 (r = 0.5496, P = 0.0036) and IL-35 (r = 0.5396, P = 0.0044) were correlated with those of HMGB1, but no cytokine levels were correlated with peroxiredoxin 5 levels. When we carried out multivariate analyses, only APRIL (P = 0.0244) and IL-19 (P = 0.0009) levels were correlated with HMGB1 levels. Conclusions: HMGB1 might be related with upregulation of IL-19 and APRIL levels in MG immunopathogenesis. These molecules could play a key role in controlling autoimmune inflammatory response, and represent a potent therapeutic target in MG.

Background: We have previously reported using two-step cluster analysis to classify myasthenia gravis (MG) patients into the following five subtypes: ocular MG; thymoma-associated MG; MG with thymic hyperplasia; anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; and AChR-Ab-positive MG without thymic abnormalities. The objectives of the present study were to examine the reproducibility of this five-subtype classification using a new data set of MG patients and to identify additional characteristics of these subtypes, particularly in regard to response to treatment. Methods: A total of 923 consecutive MG patients underwent two-step cluster analysis for the classification of subtypes. The variables used for classification were sex, age of onset, disease duration, presence of thymoma or thymic hyperplasia, positivity for AChR-Ab or anti-muscle-specific tyrosine kinase antibody, positivity for other concurrent autoantibodies, and disease condition at worst and current. The period from the start of treatment until the achievement of minimal manifestation status (early-stage response) was determined and then compared between subtypes using Kaplan-Meier analysis and the log-rank test. In addition, between subtypes, the rate of the number of patients who maintained minimal manifestations during the study period/that of patients who only achieved the status once (stability of improved status) was compared. Results: As a result of two-step cluster analysis, 923 MG patients were classified into five subtypes as follows: ocular MG (AChR-Ab-positivity, 77%; histogram of onset age, skewed to older age); thymoma-associated MG (100%; normal distribution); MG with thymic hyperplasia (89%; skewed to younger age); AChR-Ab-negative MG (0%; normal distribution); and AChR-Ab-positive MG without thymic abnormalities (100%, skewed to older age). Furthermore, patients classified as ocular MG showed the best early-stage response to treatment and stability of improved status, followed by those classified as thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; by contrast, those classified as AChR-Ab-negative MG showed the worst early-stage response to treatment and stability of improved status. Conclusions: Differences were seen between the five subtypes in demographic characteristics, clinical severity, and therapeutic response. Our five-subtype classification approach would be beneficial not only to elucidate disease subtypes, but also to plan treatment strategies for individual MG patients.

Background: Recently, new diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD) were published. Objective: Our primary aim was to evaluate the usefulness of the new diagnostic criteria in anti-aquaporin 4 (AQP4) antibody-negative cases. Methods: Consecutive 471 patients whose anti-AQP4 antibody was measured at Chiba University were reviewed. Results: Four anti-AQP4 antibody negative-patients, who fulfilled the new diagnostic criteria for NMOSD but not 2006 diagnostic criteria for neuromyelitis optica (NMO), were identified. They showed high cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels, an absence of oligoclonal bands and/or cloud-like enhancement on magnetic resonance imaging, which are compatible findings for NMO. Conclusion: The new diagnostic criteria are clinically useful in seronegative NMOSD.

Background: Both neuromyelitis optica spectrum disorder (NMOsd) and multiple sclerosis (MS) patients experience optic neuritis (ON) attacks characterized by rapidly reduced best-correct visual acuity (BCVA) and slow recovery. Prognosis and effects of recurrence on recovery may differ between disorders but remain unclear. Objective: To compare ON severity, time and degree of recovery and effects of previous ON between NMOsd and MS patients. Methods: Retrospective chart review was performed. BCVA measurements acquired before ON, at nadir and during recovery were retrospectively reviewed. Records were obtained on 69 ON attacks in 36 NMOsd patients and 43 attacks in 28 MS patients, including first episodes and recurrences. Results: NMOsd patients exhibited significantly lower BCVA values at all time points after attack (P <0.05), reached nadir earlier (P = 0.014) and regained a smaller fraction of baseline BCVA than MS patients (P < 0.001). In NMOsd, relapsed ON resulted in worse recovery and tended to reach nadir earlier than first-episode ON (P = 0.030 and 0.059, respectively). In MS, relapsed ON also reached nadir earlier (P = 0.042); however, there was no difference in recovery. Conclusions: Recovery from ON was poorer in NMOsd than in MS and was negatively affected by previous ON attacks. (C) 2016 Elsevier B.V. All rights reserved.

Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation- inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late- onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.

Background: Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients. Methods: We included 58 MG patients with anti-acetylcholine receptor antibody (AChR + MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK + MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers. AChR + MG was classified into the three subgroups: early-onset MG (EOMG; n = 11), late-onset MG (LOMG; n = 20), and thymoma-associated MG (n = 27). Healthy volunteers (n = 100) served as controls. Results: A significant positive association was observed between MuSK + MG with the DRB1*14 [57.1%, MuSK + MG vs. 18.0%, healthy controls (HC); odds ratio (OR): 6.1] and DQB1*05 [78.6%, MuSK + MG vs. 30.0%, HC; odds ratio (OR): 8.5]. We found a negative association between LOMG and DQB1*04 [5.0%, LOMG vs. 37.0%, HC; OR: 0.09]. There was no association between other MG subgroups and HLA alleles. Conclusion: HLA-DRB1*14 and DQB1*05 were associated with MuSK + MG, therefore these alleles may play important roles in developing MuSK + MG across the races. (C) 2016 Elsevier B.V. All rights reserved.

© 2015 Japanese Society for Neuroimmunology. Objective It is well-known that bladder dysfunction is common in patients with multiple sclerosis (MS). Voiding dysfunction is remarkable in neuromyelitis optica (NMO). However, the difference in the urinary symptoms between MS and NMO remain unknown. We planned to elucidate the differences between the two conditions using a urinary symptoms questionnaire. Methods We recruited 34 patients with MS and 14 patients with NMO, who were examined at the Department of Neurology, Chiba University Hospital. We administered the following urinary symptom questionnaires: (i) Overactive Bladder Symptom Score (OABSS); and (b) International Prostate Symptom Score (IPSS). Neurological (Evaluation of the Expanded Disability Status Scale) and neuroradiological examinations were also carried out. Results The mean score of OABSS and IPSS tended to be higher in patients with NMO without statistical significance. The score of IPSS quality of life was significantly higher in patients with NMO. A positive correlation was found between the Evaluation of the Expanded Disability Status Scale and IPSS scores in patients with MS, whereas a negative correlation was found between the Evaluation of the Expanded Disability Status Scale and IPSS scores in patients with NMO. Multiple linear regression analysis showed that the presence of a cervical spinal cord lesion and the central lesion involving gray matter was associated with the severity of urinary symptoms. Conclusions The urinary symptoms tended to be more severe in patients with NMO as compared with patients with MS. The urinary symptoms and neurological disabilities seemed to be differentially correlated between patients with MS and those with NMO. The urinary symptoms and neurological disabilities seemed to be differentially correlated between patients with MS and those with NMO. Cervical spinal cord lesions and the central lesion involving gray matter are responsible for the urinary symptoms in patients with MS and NMO.

Background and purposeAntinuclear 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. MethodsThe frequencies of antinuclear, anti-Sjogren's syndrome A (SSA)/Ro, anti-Sjogren's syndrome B (SSB)/La and anti-thyroid peroxidase (TPO) antibodies in the sera of 75 NMO patients and 131 MS patients were compared. Clinical and laboratory profiles were also compared between NMO patients with and without autoantibodies, including annual relapse rate and time from onset of NMO to EDSS scores of 4.0 (limited walking but without aid) and 6.0 (walking with unilateral aid). ResultsMore NMO than MS patients had antinuclear and anti-SSA/Ro antibodies (31% vs. 10%, P<0.001, and 21% vs. 3%, P<0.001, respectively). Antinuclear antibody-positive NMO patients had a lower annual relapse rate from disease onset to serum sampling compared with antinuclear antibody-negative NMO patients, independent of treatment regimen. Antinuclear antibody-negative NMO patients reached an EDSS score of 6.0 earlier than antinuclear antibody-positive NMO patients (P=0.026). Cerebrospinal fluid cell counts were higher in anti-SSA/Ro-positive than in anti-SSA/Ro-negative NMO patients. More anti-TPO antibody-positive than anti-TPO antibody-negative NMO patients had oligoclonal immunoglobulin G bands (60% vs. 11%, P=0.048). ConclusionsAutoantibodies possibly modulate the pathophysiology of NMO. Antinuclear antibody may be associated with less severe disease activity or less disability in NMO. Click to view the accompanying paper in this issue.

Background: Complement activation is important in multiple sclerosis (MS) and is essential for anti-aquaporin 4 antibodies to damage the central nervous system in neuromyelitis optica (NMO). Little is known about the role of cerebrospinal fluid (CSF) regulators of complement activation in NMO and MS. We determined whether CSF CD59, which is a complement regulator and C5b-9 formation inhibitor, is involved in the pathogenesis of NMO and MS. Methods: We analyzed CSF levels of CD59 in 30 patients with NMO, 22 patients with MS, and 24 patients with non-inflammatory neurological disorders (NINDs). Possible correlations between CSF CD59 levels and the clinical and laboratory variables in patients with NMO and MS were also reviewed. Results: CSF CD59 levels in patients with NMO and MS were higher than those in patients with NINDs (p < 0.001), and those in patients with NMO decreased after treatment. No significant correlations were found between CSF CD59 levels and clinical and laboratory parameters in NMO and MS. Conclusion: High CSF CD59 levels in NMO and MS may reflect inflammation, damage, and/or complement activation in the central nervous system. (C) 2015 Elsevier B.V. All rights reserved.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that favors the cerebrum and typically occurs in immunosuppressed patients. We herein report the case of a 66-year-old man with PML, idiopathic CD4(+) T lymphocytopenia (ICL), and chronic renal failure. Cranial magnetic resonance imaging (MRI) showed a crescent-shaped lesion in the left cerebellum, brainstem, and middle cerebellar peduncle. Although the patient did not present with HIV infection, collagen diseases, or tumors, JC virus DNA was detected in the cerebrospinal fluid. Clinicians should consider PML and ICL in the differential diagnosis if the patient develops progressive ataxia and a crescent-shaped cerebellar lesion on MRI.

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.

Extracellular peroxiredoxin 5 (PRX5) is known to be an inflammatory mediator. The serum PRX5 levels of 40 patients with anti-acetylcholine receptor antibody-positive MG and those of 40 controls were measured. PRX5 levels in patients with MG were higher than those in the controls (P = 0.045). Thymoma-associated MG patients showed higher PRX5 levels than late-onset MG patients and controls (P < 0.05). There were significant associations between the serum PRX5 levels and high mobility group box 1 levels. PRX5 elevation in MG could be related to the neuromuscular junction breakdown and plays a pivotal role in the pathogenic inflammation of MG. (C) 2015 Elsevier B.V. All rights reserved.

Good-outcome neuromyelitis optica (NMO) is defined as an Expanded Disability Status Scale (EDSS) score of 3.0 at 10 years after onset. The clinical courses of 80 consecutive patients with NMO were analyzed to identify the frequency and features of Japanese patients with good-outcome NMO. Of the 80 patients, 37 had a disease duration of >10 years; of these, eight (21.6%) presented a good outcome. These cases presented lower EDSS scores during the early phase of disease compared with those with conventional NMO. However, half of these patients developed severe disabilities later on, indicating that truly benign NMO is rare.

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 (43%) of the neuromyelitis optica patients. The pontine trigeminal root entry zone may be involved in both multiple sclerosis and neuromyelitis optica. (C) 2015 Elsevier B.V. All rights reserved.

In the pathogenesis of multiple sclerosis (MS), B cell/antibody-related mechanisms have recently received attention. To investigate the role of autoantibody in MS, we performed SEREX which can identify autoantibody cyclopedically. We identified serum antibodies against cytoskeletal protein talin1, and the levels of whom were remarkably higher in 39 MS than 43 normal controls (P<0.01) and 35 disease controls (P = 0.06), and in MS patients without oligoclonal bands than ones with them. Moreover, we found negative-correlations between serum anti-talin1 antibody and IgG index in MS (P = 0.03). Anti-talin1 antibody exists in MS patients' sera, which may have some protective factor. (C) 2015 Elsevier B.V. All rights reserved.

Objective High mobility group box 1 (HMGB1) functions as an inflammatory mediator and is implicated in the pathogenesis of various autoimmune diseases. Our primary aim is to determine whether HMGB1 is involved in the pathogenesis of myasthenia gravis (MG). Methods Serum HMGB1 levels of 60 patients with anti-acetylcholine receptor (AChR) antibody-positive MG without immunosuppressive treatment and of 10 patients with anti-muscle-specific receptor tyrosine kinase (MuSK) antibody-positive MG were compared with those in 40 controls. We also investigated the potential correlation between serum HMGB1 levels and the clinical variables in patients with MG. Results Serum HMGB1 levels in patients with antiAChR antibody-positive MG were higher than those in controls (7.80 +/- 7.47 vs 4.13 +/- 2.55 ng/mL, p=0.004) and were decreased after treatment (p=0.051). Although not significant, patients with anti-MuSK antibody-positive MG showed higher serum HMGB1 levels than the controls (p=0.178). There were correlations between serum HMGB1 levels and phenotypes of anti-AChR antibody-positive MG: patients with generalised MG showed higher HMGB1 levels than those of patients with ocular MG (p=0.059) and controls (p=0.002); patients with thymoma showed higher HMGB1 levels than those without thymoma (p=0.094) and controls (p=0.001). Conclusions Serum HMGB1 is elevated in patients with MG and may play a key role in the inflammation of the neuromuscular junction.

Thymectomy is an effective treatment for myasthenia gravis (MG). However, there is limited data on its effectiveness in non-thymomatous late-onset MG (LOMG). The aim of this study was to analyze the effects of thymectomy in LOMG. We retrospectively reviewed the 2-year post-thymectomy prognosis in 39 consecutive patients with non-thymomatous, anti-acetylcholine receptor antibody positive, and generalized LOMG (age at onset a parts per thousand yen50 years). The MG foundation of America (MGFA) classification, MGFA post-intervention status, dosage of prednisolone and pyridostigmine, and anti-acetylcholine receptor antibody titers were evaluated. Among the 39 LOMG patients, thymic hyperplasia was seen in 5 (12.8 %). MGFA classification and prednisolone dosage before thymectomy were similar between the LOMG with thymic hyperplasia group (n = 5) and the LOMG with involuted thymus group (n = 34). Two years after thymectomy, the LOMG patients with thymic hyperplasia showed higher proportion of remission (60 vs. 26 %) and received lower prednisolone dosage compared to patients with involuted thymus (0.8 vs. 4.0 mg/day). Notably, the proportion of patients with minimal manifestation or better status with receiving a parts per thousand currency sign5 mg/day prednisolone was much higher in the thymic hyperplasia group than in the involuted thymus group (100 vs. 62 %). In conclusion, thymectomy could have beneficial effects in generalized LOMG, particularly in patients with thymic hyperplasia.

Background: Spinal magnetic resonance imaging (MRI) finding of longitudinally extensive spinal cord lesions (LESCL) extending over three vertebral segments and involvements of spinal central gray matter have been reported in patients with neuromyelitis optica (NMO). Objectives: We aimed to review spinal MRI findings in NMO and multiple sclerosis (MS), and to determine whether the "bright spotty lesions" (BSLs) are a discriminative finding of NMO. Methods: For this study, 24 consecutive patients with NMO and 34 patients with MS were enrolled. BSLs were defined as very hyperintense spotty lesions on axial T2WI. We also studied the length, distribution, signal homogeneity, size, and presence of contrast-enhanced lesions. Results: BSLs were more frequently found in patients with NMO (54%) than in those with MS (3%; p < 0.01). LESCL were found in 67% of the NMO patients. BSLs were seen in 63% of the patients without LESCL. BSLs or LESCL were found in 88% of the NMO patients. Inhomogeneous lesions, transversally extensive lesions, and central lesions were more frequently seen in NMO than in MS. Conclusions: BSLs are a newly defined spinal MRI finding specifically seen in NMO. In combination with LESCL, BSLs can help differentiate patients with NMO from those with MS with higher sensitivity than LESCL alone.

Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system (CNS) that predominantly affects the optic nerves and spinal cord. Previously, it has been considered to be a severe variant of multiple sclerosis (MS), especially common in Asia. However, the finding that most NMO patients have autoantibodies against aquaporin-4 (AQP4) has improved our knowledge of its pathogenesis and led to the concept that NMO is a disease distinct from MS. Although the 2006 NMO revised criteria are useful for diagnosing NMO, their usefulness in the diagnosis of early-stage NMO is limited. Hence, there is an urgent need for new and more precise diagnostic methods. Interleukin-6 may play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in the peripheral circulation and in the enhancement of inflammation in the CNS. Severe blood-brain barrier disruption in NMO allows the anti-AQP4 antibody to access the astrocytic endfeet. The anti-AQP4 antibody causes astrocytic damage through complement activation. Thus, NMO is an astrocytopathic, rather than a demyelinating, disease. Some brain lesions specific to NMO have recently been reported. Significant advances in the understanding of NMO pathogenesis are beginning to improve existing treatment strategies and will help develop new treatments. This review focuses on the current advances in NMO research and its clinical characteristics, immunological findings, neuroimaging and pathophysiology. (C) 2013 Elsevier Ltd. All rights reserved.

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extensive transverse myelitis. The discovery of an NMO-specific autoantibody to the aquaporin-4 (AQP4) water channel has improved knowledge of NMO pathogenesis. Many studies have focused on inflammatory and pathological biomarkers of NMO, including cytokines and chemokines. Increased concentrations of T helper (Th)17- and Th2-related cytokines and chemokines may be essential factors for developing NMO inflammatory lesions. For example, interleukin-6 could play important roles in NMO pathogenesis, as it is involved in the survival of plasmablasts that produce anti-AQP4 antibody in peripheral circulation and in the enhancement of inflammation in the central nervous system. Therefore, assessment of these useful biomarkers may become a supportive criterion for diagnosing NMO. Significant advances in the understanding of NMO pathogenesis will lead to the development of novel treatment strategies. This review focuses on the current advances in NMO immunological research, particularly that of cytokines and chemokines.

Upbeat nystagmus (UBN) is relatively rare. Little is known about UBN in acute central nervous system inflammatory disorders, including multiple sclerosis (MS), neuromyelitis optica (NMO) and related disorders. We investigated two patients with MS, one with clinically isolated syndrome and one with brainstem inflammation possibly related to NMO who developed UBN because of brainstem lesions. Three of the four patients presented caudal medulla lesions and one presented a caudal pontomesencephalic lesion on magnetic resonance imaging. Caudal brainstem lesions may cause UBN in these disorders, probably by impairing the ventral tegmental tract. © 2013 Japanese Society for Neuroimmunology.

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.

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&lt;0.001), and these levels in MS patients were higher than those in ONNDs patients (p&lt;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 &lt;= 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.