Roles of cytokines and T cells in the pathogenesis of myasthenia gravis.

Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti-AChR antibody-positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (Treg ) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of Treg cells have been reported in patients with anti-AChR antibody-positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)-17; a Th17-related cytokine, IL-21 (a Tfh-related cytokine), the B-cell-activating factor (BAFF; a B cell-related cytokine) and a proliferation-inducing ligand (APRIL; a B cell-related cytokine) have been reported to be up-regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future.

Changes in serum complements and their regulators in generalized myasthenia gravis.

OBJECTIVE: To investigate changes in serum complements and their regulators in the pathogenesis of myasthenia gravis (MG). METHODS: Forty-four patients with acetylcholine receptor antibody-positive MG, as well as 20 patients with non-inflammatory neurological disorders were enrolled. Serum complements (C3, C4 and soluble C5b-9) and complement regulators (vitronectin, clusterin and properdin) were extensively analysed by enzyme-linked immunosorbent assay and their associations with clinical profiles of MG were examined. RESULTS: Serum C3, C4 and clusterin levels were not significantly different between patients with MG and controls. The patients with MG had higher soluble C5b-9 (P = 0.09) and vitronectin (P = 0.001) levels than the controls; moreover, vitronectin levels decreased after treatment (P = 0.09). Serum properdin (P = 0.03) levels were lower in the patients with MG than in the controls, and negatively correlated with the MG Activities of Daily Living score (rs = -0.26, P = 0.09) and with the presence of bulbar palsy (P = 0.04). CONCLUSION: Our results show that activation of complements and an altered complement network could contribute to the inflammatory pathogenesis of MG.

Peroxiredoxins are involved in the pathogenesis of multiple sclerosis and neuromyelitis optica spectrum disorder.

Peroxiredoxins (PRXs) are intracellular anti-oxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5 and PRX6) in the cerebrospinal fluid (CSF) and serum of 16 patients with MS, 16 patients with NMOSD and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1-6) in the central nervous system (CNS) were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (P < 0·05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood-brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD.

Serum level of soluble urokinase plasminogen activator receptor (suPAR) as a disease severity marker of myasthenia gravis: a pilot study.

Myasthenia gravis (MG) is an autoantibody-mediated inflammatory disease of the neuromuscular junction. Biomarkers indicating disease activity in MG are warranted. Recently, the soluble urokinase plasminogen activator receptor (suPAR) has been reported to be associated with inflammation, tissue damage, disease activity and prognosis in various diseases, including autoimmune diseases. In this study, serum suPAR levels were measured in 40 patients with anti-acetylcholine receptor antibody-positive MG and 30 controls, and their correlations with clinical variables and severity scale scores were investigated. We identified that serum suPAR levels significantly correlated with MG activities of daily living scale (Spearman's ρ = 0·45; P = 0·004) and MG Foundation of America classification (Spearman's ρ = 0·37; P = 0·02) at serum sampling, but not with anti-acetylcholine receptor antibody titers. In conclusion, serum suPAR levels can be a candidate for a novel biomarker of disease activity in anti-acetylcholine receptor antibody-positive MG.

Comparison of brain atrophy in patients with multiple sclerosis treated with first- versus second-generation disease modifying therapy without clinical relapse.

BACKGROUND AND PURPOSE: The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease-modifying drugs (DMDs) in patients with MS during their relapse-free period. METHODS: Patients with relapsing-remitting MS were classified into two groups on the basis of clinical records, i.e. a first-generation DMD group treated with interferon-beta-1a, interferon-beta-1b or glatiramer acetate and a second-generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12. RESULTS: A total of 45 patients with relapsing-remitting MS were enrolled in the first-generation (n = 22) or second-generation (n = 23) DMD group. The annualized relapse rate was lower in the first-generation than in the second-generation DMD group (median 0.26 vs. 0.59; P < 0.001). The annualized atrophy rate of the normalized brain volume was not different between the first- and second-generation DMD groups after analysis of covariance (median 0.13% vs. 0.59%; P = 0.17). CONCLUSIONS: The median annualized atrophy rate of normalized brain volume in the first-generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first-generation DMD need not be changed when patients with MS are clinically inactive.

Cranial nerve involvement in typical and atypical chronic inflammatory demyelinating polyneuropathies.

BACKGROUND AND PURPOSE: Cranial nerve palsy is occasionally present in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), but its prevalence, characteristics and relations with the CIDP subtypes have rarely been investigated. The aim of this study was to systematically assess cranial nerve involvement in typical and atypical CIDP. METHODS: Clinical data were reviewed in 132 consecutive patients with CIDP, including typical CIDP (n = 89), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) (n = 31), distal acquired demyelinating symmetric (DADS) (n = 9) and others (n = 3). RESULTS: The frequency of cranial nerve palsy was 11% in typical CIDP, 48% in MADSAM and 11% in DADS. Facial and bulbar palsy was most frequently present (9%), followed by ocular motor nerve palsy (5%). Bilateral involvement was seen in all typical CIDP and DADS patients, whereas 80% of MADSAM patients had unilateral palsy. The presence of cranial nerve involvement was associated with more severe limb muscle weakness in typical CIDP, but not in MADSAM. Cranial nerve palsy fully recovered in 90% of typical CIDP and in 67% of MADSAM patients. CONCLUSION: Amongst the CIDP subtypes, cranial palsy is frequent and unilateral in MADSAM, and less frequent and bilateral in typical CIDP and DADS. In typical CIDP, facial and bulbar palsy reflects more severe and extensive inflammation.

Frequency and features of myasthenia gravis developing after thymectomy.

BACKGROUND AND PURPOSE: Thymectomy is an effective treatment for myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) antibodies. We rarely encounter patients who develop MG after surgery for thymic tumors. This study aimed to investigate the characteristics and frequency of post-thymectomy onset (PostTx) MG. METHODS: We reviewed the clinical information of thymoma-associated MG in 158 patients. Of these, 18 (11%) patients with PostTx MG were identified. RESULTS: The presence of anti-AChR antibodies (82%) and electrophysiological abnormalities (50%) was confirmed before thymectomy in patients with PostTx MG. The clinical characteristics of PostTx MG were similar to those of pre-thymectomy onset (PreTx) MG. In PostTx MG, the duration between thymectomy and MG onset were distributed as < 6 months (early-onset PostTx MG) and ≥ 6 months (late-onset PostTx MG). Notably, some patients with late-onset PostTx MG were associated with thymoma relapse. CONCLUSION: Our results suggest that approximately 11% of patients with thymoma-associated MG were PostTx MG and pre-surgical assessment of anti-AChR antibody titer or electrophysiological testing may predict PostTx MG development. However, no difference in clinical manifestation and prognosis was observed between PreTx MG and PostTx MG.

Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Recombinant thrombomodulin ameliorates experimental autoimmune encephalomyelitis by suppressing high mobility group box 1 and inflammatory cytokines.

Recombinant thrombomodulin (rTM) has pleiotrophic properties, including anti-coagulation and anti-inflammation; however, its effectiveness as a treatment for multiple sclerosis (MS) has not been evaluated fully. High mobility group box 1 (HMGB1) and proinflammatory cytokines, working as inflammatory mediators, are reportedly involved in the inflammatory pathogenesis of MS. The aim of this study was to determine whether rTM can be a potential therapeutic agent for experimental autoimmune encephalomyelitis (EAE). EAE mice received rTM treatment (1 mg or 0·1 mg/kg/day) from days 11 to 15 after immunization. The clinical variables, plasma levels of inflammatory cytokines and HMGB1 and pathological findings in EAE were evaluated. rTM administration ameliorated the clinical and pathological severity of EAE. An immunohistochemical study of the spinal cord showed weaker cytoplasmic HMGB1 staining in the rTM-treated EAE mice than in the untreated EAE mice. Plasma levels of inflammatory cytokines and HMGB1 were suppressed by rTM treatment. In conclusion, rTM down-regulated inflammatory mediators in the peripheral circulation and prevented HMGB1 release from nuclei in the central nervous system, suppressing EAE-related inflammation. rTM could have a novel therapeutic potential for patients with MS.

Adequate tacrolimus concentration for myasthenia gravis treatment.

BACKGROUND AND PURPOSE: A 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. METHODS: The 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. RESULTS: The 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. CONCLUSIONS: An adequate tacrolimus concentration is required for better MG prognosis.

Amyotrophic lateral sclerosis and motor neuron syndromes in Asia.

While the past 2 decades have witnessed an increasing understanding of amyotrophic lateral sclerosis (ALS) arising from East Asia, particularly Japan, South Korea, Taiwan and China, knowledge of ALS throughout the whole of Asia remains limited. Asia represents >50% of the world population, making it host to the largest patient cohort of ALS. Furthermore, Asia represents a diverse population in terms of ethnic, social and cultural backgrounds. In this review, an overview is presented that covers what is currently known of ALS in Asia from basic epidemiology and genetic influences, through to disease characteristics including atypical phenotypes which manifest a predilection for Asians. With the recent establishment of the Pan-Asian Consortium for Treatment and Research in ALS to facilitate collaborations between clinicians and researchers across the region, it is anticipated that Asia and the Pacific will contribute to unravelling the uncertainties in ALS.

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

BACKGROUND AND PURPOSE: 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. METHODS: The frequencies of antinuclear, anti-Sjögren's syndrome A (SSA)/Ro, anti-Sjögren'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). RESULTS: More 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). CONCLUSIONS: Autoantibodies possibly modulate the pathophysiology of NMO. Antinuclear antibody may be associated with less severe disease activity or less disability in NMO.

How often and when Fisher syndrome is overlapped by Guillain-Barré syndrome or Bickerstaff brainstem encephalitis?

BACKGROUND AND PURPOSE: Fisher syndrome (FS) may overlap with Guillain-Barré syndrome (GBS), in particular the pharyngeal-cervical-brachial variant form (PCB-GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS. METHODS: Sixty consecutive patients with FS were studied. FS/PCB-GBS was diagnosed when the patients developed pharyngeal, cervical and/or brachial weakness. Patients with flaccid tetraparesis were diagnosed as having FS/conventional GBS. FS/BBE was defined as the development of consciousness disturbances. RESULTS: All 60 patients initially developed the FS clinical triad alone (pure FS). Of these, 30 (50%) patients had pure FS throughout their course, whereas the remaining 50% of patients showed an overlap: PCB-GBS in 14 (23%) patients, conventional GBS in nine (15%) patients and BBE in seven (12%) patients. The median (range) durations from FS onset to progression to FS/PCB-GBS, FS/GBS or FS/BBE were 5 (1-7), 3 (1-4) and 3 (1-5) days, respectively. Patients with overlap syndromes more frequently received immune-modulating treatment, and the outcomes were generally favourable. The frequencies of positivity for anti-GQ1b, GT1a, GD1a, GD1b, GalNAc-GD1a and GM1 antibodies were not significantly different amongst the four groups. CONCLUSIONS: Of the patients with pure FS, 50% later developed an overlap with PCB-GBS, conventional GBS or BBE. The overlap occurred within 7 days of FS onset; thus, physicians should pay attention to the possible development of this overlap during the first week after FS onset.

Current symptomatology in multiple sclerosis and neuromyelitis optica.

BACKGROUND AND OBJECTIVES: Several symptoms and signs are characteristic of multiple sclerosis (MS) such as Lhermitte's sign, Uhthoff's 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. METHODS: Consecutive Japanese NMO-plus patients [NMO (n = 30) or partial NMO (n = 18)] and MS patients (n = 128) seen at Chiba University Hospital between 2011 and 2012 were investigated for the frequencies of symptoms and signs characteristic of MS. Logistic regression analyses were used to identify factors that distinguished NMO-plus from MS. RESULTS: Univariate analyses revealed that tonic seizures, Lhermitte's sign, persistent pain, fatigue and girdle sensation were more frequent in NMO-plus patients than in MS patients. Multivariate logistic regression analysis showed that paroxysmal itching, Uhthoff's phenomenon, Lhermitte's sign and girdle sensation were more characteristic of NMO-plus than of MS. CONCLUSIONS: Several classical MS symptoms and signs are more frequent in NMO patients than MS patients, which may be caused by the differences in the severity of inflammation, and localization and extensiveness of demyelinated lesions.

Dementia with Lewy bodies can be well-differentiated from Alzheimer's disease by measurement of brain acetylcholinesterase activity-a [11C]MP4A PET study.

OBJECTIVE: To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[(11) C]-methyl-4-piperidyl acetate (MP4A) and PET in patients with dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: Participants were 14 DLB patients, 25 AD patients and 18 age-matched healthy controls (HC). All subjects underwent PET scans and MP4A to measure regional brain AChE activity. We performed anatomical standardization of each brain image, and k3 values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k3 images in frontal, temporal, parietal and occipital cortices, and in anterior and posterior cingulate gyri (ACG and PCG). In each VOI, the differential diagnostic performance between AD and DLB of k3 values was assessed by area under the curve (AUC) of the receiver-operating characteristic. Voxel-based statistical analyses were also performed. RESULTS: Mean cortical AChE activities in AD patients (-8.2% compared with normal mean) and DLB patients (-27.8%) were lower than HCs (p < 0.05, p < 0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p < 0.001). All regional brain AChE activities of defined VOIs except ACG were able to well discriminate DLB from AD, and notably performance was the most significant in PCG (AUC = 0.989, 95% CI: 0.965-1.000). CONCLUSIONS: Brain cholinergic deficit is consistently prominent in DLB compared with AD. PET measurement of brain AChE activity may be useful for the differential diagnosis between DLB and AD.

Modulation of the kallikrein/kinin system by the angiotensin-converting enzyme inhibitor alleviates experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Bradykinin is the end-product of the kallikrein/kinin system, which has been recognized as an endogenous target for combating CNS inflammation. Angiotensin-converting enzyme (ACE) inhibitors influence the kallikrein/kinin system and reportedly have immunomodulatory characteristics. The objectives of this study were to determine whether bradykinin is involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and whether bradykinin control by the ACE inhibitor could be a therapeutic target in MS. The ACE inhibitor enalapril (1·0 or 0·2 mg/kg/day) was administered orally to EAE mice and the serum levels of bradykinin and cytokines in EAE mice were analysed. As a result, the administration of enalapril increased serum bradykinin levels, decreased the clinical and pathological severity of EAE and attenuated interleukin-17-positive cell invasion into the CNS. Additionally, bradykinin receptor antagonist administration reduced the favourable effects of enalapril. Our results suggest that bradykinin is involved in the pathomechanism underlying CNS inflammation in EAE, possibly through inhibiting cell migration into CNS. Control of the kallikrein/kinin system using ACE inhibitors could be a potential therapeutic strategy in MS.

Serum cytokine and chemokine profiles in patients with myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune-mediated inflammatory disease of the neuromuscular junction. Previous studies of animal MG models have suggested important roles of cytokines in MG pathogenesis, but adequate studies on cytokines in human MG are lacking. Using a multiplex suspension array system, we measured the serum levels of 27 cytokines/chemokines in 47 anti-acetylcholine receptor antibody-positive patients with MG and 20 normal controls (NC) to investigate the contribution of cytokines/chemokines toward MG pathogenesis. Correlations between clinical parameters and cytokine/chemokine levels in patients with MG were also examined. The serum levels of interleukin (IL)-15 (mean ± standard deviation: 6·85 ± 6·97 pg/ml) and vascular endothelial growth factor (VEGF) (96·21 ± 71·60 pg/ml) significantly increased, whereas IL-4 levels (3·57 ± 0·86 pg/ml) decreased in patients with MG compared with NC (IL-15: 4·42 ± 1·55 pg/ml; VEGF: 63·51 ± 32·95 pg/ml; IL-4: 4·15 ± 0·81 pg/ml, P < 0·05). In addition, eight cytokines (IL-4, IL-8, IL-15, eotaxin, macrophage inflammatory protein-1α, macrophage inflammatory protein-1ß, VEGF and IL-1b) were significantly changed among MG patients with thymoma, MG patients without thymoma and NC (P < 0·05). Some cytokines, such as IL-4, IL-15, and VEGF, may play roles in the pathogenesis of MG.

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.

POEMS syndrome with Guillan-Barre syndrome-like acute onset: a case report and review of neurological progression in 30 cases.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare cause of demyelinating neuropathy with monoclonal plasma cell proliferation, and POEMS neuropathy is usually chronically progressive. Herein, the authors report a 34-year-old woman with POEMS syndrome presenting as acute polyneuropathy. Within 2 weeks of disease onset, she became unable to walk with electrodiagnostic features of demyelination and was initially diagnosed as having Guillan-Barré syndrome. Other systemic features (oedema and skin changes) developed later, and an elevated serum level of vascular endothelial growth factor led to the diagnosis of POEMS syndrome. She received high-dose chemotherapy with autologous peripheral blood stem cell transplantation, resulting in good recovery. The authors also reviewed patterns and speed of progression of neuropathy in the 30 patients with POEMS syndrome; 22 (73%) of them were unable to walk independently with the median period of 9.5 months from POEMS onset (range 0.5-51 months). Whereas the speed of neuropathy progression varies considerably among patients, some POEMS patients can show acute or subacute polyneuropathy. The early diagnosis and treatment could result in rapid improvement as shown in the present patient.

Pelvic organ dysfunction is more prevalent and severe in MSA-P compared to Parkinson's disease.

AIMS: It is usually difficult to distinguish between idiopathic Parkinson's disease (PD) and parkinsonian-type multiple system atrophy (MSA-P) in the early stage. However, it is important to make a careful early-stage diagnosis. Therefore, we determined whether an examination of pelvic organ dysfunction would be helpful to distinguish between PD and MSA-P. METHODS: We recruited 61 patients with PD and 54 patients with MSA-P who were examined at our neurology clinic. The mean ages of the patients with PD and MSA-P were 67 and 64 years, respectively. The mean disease duration of both groups was 3.2 years. We administered a questionnaire on pelvic organ dysfunction to the PD and MSA-P groups. The questionnaire had sections focusing on bladder, bowel, and sexual function. Dysfunction, as described in the responses, was evaluated as normal, mild (>once a month), moderate (>once a week), or severe (>once a day). The Mann-Whitney U-test was used for statistical analysis. RESULTS: Compared with the PD group, the prevalence and severity of pelvic dysfunction in the MSA-P group was significantly higher for urinary urgency (MSA-P 76%, PD 58%, P<0.05), retardation in initiating urination (79%, 48%, P<0.05), prolongation in urination (79%, 72%, P<0.05), and constipation (58%, 31%, P<0.05). The quality-of-life index among pelvic organ dysfunctions indicated that urinary and bowel function was significantly more impaired in the MSA-P group than in the PD group. CONCLUSIONS: Urinary urgency, retardation in initiating urination, prolongation in urination, and constipation are more prevalent and severe in MSA-P compared to PD.