桑原 聡

Purpose Cutaneous sympathetic pathophysiology in complex regional pain syndrome type 1 (CRPS-1) is not yet completely understood. To evaluate cutaneous sympathetic dysfunction in CRPS-1, we evaluated sympathetic sweat response (SSwR) and skin vasomotor reflex (SkVR) in CRPS-1 patients. Methods We studied 10 CRPS-1 patients (age 41 +/- A 13 years; 5 females and 5 males; disease duration 20 +/- A 22 months) and 10 healthy subjects (age 44 +/- A 13 years; 3 females and 7 males). SkVRs and SSwRs to several sympathetic activating procedures were recorded on the palms of the CRPS-1 patients (affected side) and controls (right side). Results There were no significant differences in the baselines of sweat output and skin blood flow between the CRPS-1 and control groups. SSwR and SkVR amplitudes were significantly lower in the CRPS-1 group than in the control group. There was no significant correlation between disease duration and SSwR or SkVR amplitudes among the patients. Conclusions The reduced SSwRs and SkVRs in the affected limb of our CRPS-1 patients may reflect underlying damage to the sympathetic postganglionic fibres.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) not only induces the differentiation of hematopoietic cells into granulocytes and macrophages but also exerts immunomodulatory functions. GM-CSF promotes experimental autoimmune encephalomyelitis, multiple sclerosis, and rheumatoid arthritis. Conversely, GM-CSF ameliorates some type 2 helper T cell-dominant diseases, including experimental autoimmune myasthenia gravis, experimental autoimmune thyroiditis, Crohn's disease, type 1 diabetes mellitus, autoimmune neutropenia, and juvenile systemic lupus erythematosus. However, the contribution of GM-CSF to the pathogenesis of neuromyelitis optica (NMO) has not been studied. In this article, we review GM-CSF roles in the central nervous system and report evidence that GM-CSF may positively affect the pathogenesis of NMO. We have previously reported (i) that patients with NMO expressing antinuclear antibodies (ANA-positive) have less severe disease activity and a better prognosis than ANA-negative patients and (ii) an analysis of the cytokine/chemokine profiles of 24 patients with NMO. We investigated associations between cytokine expression, ANA-positivity, and disease severity. Among the 24 patients, the six who were ANA positive had significantly elevated serum GM-CSF concentrations than the ANA-negative patients (medians: 7.0 vs 0.27 pg/mL, respectively P = 0.001) and higher cerebrospinal fluid GM-CSF concentrations (medians: 53.7 vs 47.0 pg/mL, respectively P = 0.068). Although no other cytokine/chemokine profiles were different based on ANA status, cerebrospinal fluid GM-CSF concentrations at relapse were negatively correlated with Kurtzke Expanded Disability Status Scale scores (R2 = 0.26, P = 0.009). Therefore, GM-CSF may play a protective role in the pathogenesis of NMO.

Peripheral nerve diseases are traditionally classified as demyelinating or axonal. It has been recently proposed that microstructural changes restricted to the nodal/paranodal region may be the key to understanding the pathophysiology of antiganglioside antibody mediated neuropathies. We reviewed neuropathies with different aetiologies (dysimmune, inflammatory, ischaemic, nutritional, toxic) in which evidence from nerve conductions, excitability studies, pathology and animal models, indicate the involvement of the nodal region in the pathogenesis. For these neuropathies, the classification in demyelinating and axonal is inadequate or even misleading, we therefore propose a new category of nodopathy that has the following features: (1) it is characterised by a pathophysiological continuum from transitory nerve conduction block to axonal degeneration; (2) the conduction block may be due to paranodal myelin detachment, node lengthening, dysfunction or disruption of Na+ channels, altered homeostasis of water and ions, or abnormal polarisation of the axolemma; (3) the conduction block may be promptly reversible without development of excessive temporal dispersion; (4) axonal degeneration, depending on the specific disorder and its severity, eventually follows the conduction block. The term nodopathy focuses to the site of primary nerve injury, avoids confusion with segmental demyelinating neuropathies and circumvents the apparent paradox that something axonal may be reversible and have a good prognosis.

Fisher syndrome has been regarded as a peculiar inflammatory neuropathy with ophthalmoplegia, ataxia, and areflexia, whereas Bickerstaff brainstem encephalitis has been considered a pure central nervous system disease characterized by ophthalmoplegia, ataxia, and consciousness disturbance. Both disorders share common features including preceding infection, albumin-cytological dissociation, and association with Guillain-Barré syndrome. The discovery of anti-GQlb IgG antibodies further supports the view that the two disorders represent a single disease spectrum. The lesions in Fisher syndrome and Bickerstaff brainstem encephalitis are presumably determined by the expression of ganglioside GQlb in the human peripheral and central nervous systems. Bickerstaff brainstem encephalitis is likely to represent a variant of Fisher syndrome with central nervous system involvement.

Objective Fatigue is a major disabling symptom in multiple sclerosis (MS) patients. The Modified Fatigue Impact Scale (MFIS) is generally approved for evaluating fatigue in MS patients. However, a Japanese version of MFIS has not been established. The aims of the present study were to validate the Japanese MFIS and to investigate its relationship with pain in Japanese MS patients. Methods The MFIS was translated into Japanese by a professional translator. The Japanese version of MFIS was carried out for 30 relapsing-remitting MS patients during remission, and 30 age- and sex-matched healthy controls. MFIS for MS patients was repeated within 4 days to show the reliability. The Japanese version of the Multidimensional Fatigue Inventory and Pain Effects Scale were also carried out. Results No significant difference in MFIS score was found between the first and second assessments. Total scores were higher for the patients than for controls (P &lt 0.001) they correlated with those of the Kurtzke's Expanded Disability Status Scale (P &lt 0.001), Multidimensional Fatigue Inventory (P = 0.031) and Pain Effects Scale (P &lt 0.001). Positive correlations were found among subscales of the Japanese version of the MFIS in the patients. Conclusions A Japanese version of the MFIS validated fatigue evaluation in these patients.

Objective: To investigate the diagnostic performance of brain acetylcholinesterase (AChE) activity measurement using N-[C-11]-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 k(3) values, an index of AChE activity, in each voxel were estimated by nonlinear least squares analysis. Volumes of interest (VOIs) were identified on parametric k(3) 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 k(3) 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. Copyright (C) 2015 John Wiley & Sons, Ltd.

The study was conducted to determine whether serum vascular endothelial growth factor (VEGF) levels are significantly correlated with subfoveal choroidal thickness (CT) and foveal thickness (FT) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. In this cross-sectional observational case series, we studied 31 eyes of 16 treatment-na < ve patients with POEMS syndrome with no evidence of fundus abnormalities. Subfoveal CT and FT were measured using enhanced depth imaging optical coherence tomography (EDI-OCT), and correlations between serum VEGF levels and subfoveal CT and FT were determined. The mean subfoveal CT was 417.9 +/- 73.5 mu m (right eye, 416.7 +/- 81.2 mu m; left eye, 419.0 +/- 68.1 mu m), and the mean FT was 243.8 +/- 35.2 mu m (right eye, 248.8 +/- 22.0 mu m; left eye, 239.1 +/- 44.6 mu m). There was a significant positive correlation between the serum VEGF level and subfoveal CT (right eye, r = 0.58, p = 0.021; left eye, r = 0.60, p = 0.012), but the correlation between the level of serum VEGF and FT was not significant (right eye, r = 0.007, p > 0.05; left eye, r = 0.25, p > 0.05). The significant correlation between the serum VEGF level and subfoveal CT in patients with POEMS syndrome suggests that choroidal thickness is influenced by the level of serum VEGF. These results not only aid in an understanding of the pathogenesis of ocular changes in patients with POEMS syndrome, but also offer clues regarding the pathogenesis of other choroidal diseases.

Background Chronic inflammatory demyelinating polyneuropathy (CIDP) is currently classified into 'typical' CIDP and 'atypical' subtypes such as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Objectives To assess the frequency of CIDP subtypes, and to elucidate clinical and electrophysiological features, and treatment response in each subtype. Methods We reviewed data from 100 consecutive patients fulfilling criteria for CIDP proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society. The Kaplan-Meier curve was used to estimate long-term outcome. Results Patients were classified as having typical CIDP (60%), MADSAM (34%), demyelinating acquired distal symmetric neuropathy (8%) or pure sensory CIDP (1%). Compared with patients with MADSAM, patients with typical CIDP showed more rapid progression and severe disability, and demyelination predominant in the distal nerve segments. MADSAM was characterised by multifocal demyelination in the nerve trunks. Abnormal median-normal sural sensory responses were more frequently found for typical CIDP (53% vs 13%). Patients with typical CIDP invariably responded to corticosteroids, immunoglobulin or plasmapheresis, whereas patients with MADSAM were more refractory to these treatments. The Kaplan-Meier analyses showed that 64% of patients with typical CIDP and 41% of patients with MADSAM had a clinical remission 5 years later (p=0.02). Conclusions Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. In typical CIDP, the distal nerve terminals and possibly the nerve roots, where the blood-nerve barrier is anatomically deficient, are preferentially affected, raising the possibility of antibody-mediated demyelination, whereas cellular immunity with breakdown of the barrier may be important in MADSAM neuropathy.

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.

Objective: POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating neuropathy with upregulation of vascular endothelial growth factor (VEGF). This study aimed to elucidate axonal excitability properties and their relation to VEGF levels and nerve edema in POEMS neuropathy. Methods: Axonal excitability measurement and nerve ultrasound were performed in the median nerve of 33 patients with POEMS syndrome. Serum VEGF levels were measured by ELISA. Results: Compared with normal subjects (n = 87), POEMS patients showed longer strength-duration time constant, fanning-out of threshold electrotonus curves, and greater threshold changes in a hyperpolarizing current-threshold relationship. Nerve ultrasound showed significant enlargement in POEMS patients. Serum VEGF levels and the extent of nerve edema partly correlated with nerve conduction slowing, as well as persistent sodium currents and inward rectification. Conclusions: In POEMS syndrome, patterns of changes in excitability properties could suggest increased persistent sodium currents, and impaired potassium and inward rectifying channels. The findings were not consistent with depolarization due to nerve edema and compression ischemia. Significance: In addition to demyelination, nerve edema induced by upregulated VEGF, and upregulated inflammatory cytokines could modulate profiles of POEMS neuropathy. (C) 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of "typical" CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients. (C) 2015 Elsevier B.V. All rights reserved.

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.

Objective: The duration of the distal compound muscle action potential (DCMAP) is a useful index to detect demyelination in the distal nerve segments. However in published electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), the cut-off values of DCMAP duration are defined using an EMG low frequency filter of only 20 Hz. We aimed to provide widely-available reference data using several low cut filters. Methods: In 13 Japanese and European tertiary centers, DCMAP duration data using 2, 5, 10, and 20 Hz low frequency filters were prospectively collected from 147 normal controls, 59 patients with typical CIDP, and 100 with diabetic polyneuropathy. Optimal cut-off values were calculated with receiver-operating characteristic curves, offering 100% specificity versus normal controls. Results: The higher low frequency filter was associated with significantly shorter DCMAP duration in all groups. For CIDP diagnosis, the calculated cut-off values had a sensitivity ranging from 51% to 66%, and a specificity versus diabetic neuropathy from 96% to 98%. Conclusions: Our results show that DCMAP duration is largely dependent on low frequency filter settings, but is a useful index for CIDP diagnosis when the cut-off values are properly determined at each filter setting. Significance: Our data provide the systematic reference values of DCMAP duration for CIDP diagnosis available for most EMG laboratories. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Aims Although subthalamic nucleus deep brain stimulation (STN-DBS) is effective in patients with advanced Parkinson's disease (PD), its physiological mechanisms remain unclear. Because STN-DBS is effective in patients with PD whose motor symptoms are dramatically alleviated by L-3,4-dihydroxyphenylalanine (L-DOPA) treatment, the higher preoperative catecholamine levels might be related to the better clinical outcome after surgery. We aimed to examine the correlation between the preoperative catecholamine levels and postoperative clinical outcome after subthalamic nucleus deep brain stimulation. The effectiveness of STN-DBS in the patient who responded well to dopaminergic medication suggest the causal link between the dopaminergic system and STN-DBS. We also examined how catecholamine levels were modulated after subthalamic stimulation. Methods In total 25 patients with PD were enrolled (Mean age 66.2 +/- 6.7 years, mean disease duration 11.6 +/- 3.7 years). Mean levodopa equivalent doses were 1032 +/- 34.6 mg before surgery. Cerebrospinal fluid and plasma catecholamine levels were measured an hour after oral administration of antiparkinsonian drugs before surgery. The mean Unified Parkinson's Disease Rating Scale scores (UPDRS) and the Parkinson's disease Questionnaire-39 (PDQ-39) were obtained before and after surgery. Of the 25 patients, postoperative cerebrospinal fluid and plasma were collected an hour after oral administration of antiparkinsonian drugs during on stimulation at follow up in 11 patients. Results Mean levodopa equivalent doses significantly decreased after surgery with improvement in motor functions and quality of life. The preoperative catecholamine levels had basically negative correlations with postoperative motor scores and quality of life, suggesting that higher preoperative catecholamine levels were related to better outcome after STN-DBS. The preoperative plasma levels of L-DOPA had significantly negative correlations with postoperative UPDRS-III score in off phase three months after STN-DBS. The preoperative cerebrospinal fluid (CSF) 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxytryptamine (5-HT) levels had significantly negative correlations with postoperative UPDRS-III score in off phase one year after STN-DBS and the preoperative CSF homovanilic acid (HVA) levels had significant negative correlations with postoperative UPDRS-III score in on phase three months after STN-DBS. In PDQ-39 SI (summary index), preoperative plasma dopamine (DA) level had significantly negative correlations with postoperative PDQ-39 SI one year after STN-DBS suggesting that higher preoperative plasma DA level resulted in better quality of life (QOL) one year after STN-DBS. The stepwise multiple linear regression study revealed that higher preoperative plasma HVA levels had negative influence on the postoperative motor symptoms (i.e., increase in the score of UPDRS), whereas higher preoperative CSF L-DOPA levels had positive influence on the postoperative motor symptoms and QOL (decrease in the score of UPDRS and PDQ-39 SI) The catecholamine levels were not significantly reduced postoperatively in 11 patients despite the significant reduction in levodopa equivalent doses. Unexpectedly, CSF HVA levels significantly increased from 0.00089 +/- 0.0003 ng/mu l to 0.002 +/- 0.0008 ng/mu l after STN-DBS. Conclusion The preoperative catecholamine levels might affect the postoperative motor symptoms and quality of life. The catecholamine levels were not significantly reduced postoperatively despite the significant reduction in levodopa equivalent doses.

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.

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were -7.0 +/- 7.1 and -0.04 +/- 0.1, respectively, in the riluzole group and -6.9 +/- 6.4 and 0.04 +/- 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future.

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.

Abstract Objective Combined nerve/muscle biopsy is widely carried out to improve the diagnostic sensitivity for vasculitic neuropathy. However, an additional yield of muscle biopsy is modest. Therefore, we investigated whether skin biopsy in combination with nerve/muscle biopsy increases the detection rate of vasculitis. Methods A total of 25 combined nerve/muscle/skin biopsy samples from patients with biopsy-proven necrotizing vasculitis (n = 16) or clinically probable vasculitic neuropathy (n = 9) were reviewed. Specimens from the sural nerve, peroneus brevis muscle and skin were obtained simultaneously by a single incision. Results Skin biopsy substantially contributed to diagnosis of vasculitic neuropathy. Additional skin biopsy enhanced diagnostic sensitivity from 88% to 100% in patients with pathologically confirmed vasculitis (n = 16). Vasculitis was detected only in skin specimens from two of the entire cohort (n = 25). There were no complications related to skin collection, such as anastomotic leakage or wound infection. Conclusion Combined nerve/muscle/skin biopsy could be a less invasive option to improve the diagnostic sensitivity for vasculitis.

Abstract Autoimmune polyendocrine syndromes (APS), a group of autoimmune-mediated multiple endocrine gland failure, type 3 is composed of autoimmune thyroid disease with endocrinopathy, including type 1 diabetes mellitus (DM), other than adrenal insufficiency. Only a few cases of multiple sclerosis (MS) with APS type 3 have been reported. We present the case of a 37-year-old Japanese man diagnosed with MS and Graves' disease at 22 years-of-age. Interferon-β-1b therapy, which he had previously discontinued for 10 years, was restarted for MS at 35 years-of-age. After the therapy, he complained of thirst and rapid bodyweight loss (15 kg/6 months), and developed type 1 DM. At onset of DM and before the restart of interferon-β-1b therapy, antiglutamic acid decarboxylase antibody findings had been positive. He was diagnosed as having APS type 3, associated Graves' disease and type 1 DM in addition to MS. Our case suggested that MS can be concomitant with APS type 3, and that interferon-β-1b therapy for a MS patient with a specific genetic background could induce onset of type 1 DM.

The purpose of this study was to evaluate the incidence and clinical features of muscle haematoma in ischaemic stroke patients. Muscle haematomas are rare complications that occur during antithrombotic treatment for acute ischaemic stroke. Clinical and laboratory records of ischaemic stroke patients with muscle haematomas in the last 3.5 years were retrospectively reviewed. Muscular haematoma developed in three of 694 (0.4%) consecutive patients with acute ischaemic stroke who were admitted to our institution. In addition, one outpatient presenting with muscle haematoma was found during the same period. The types of haematomas were rectus sheath haematoma in two patients and iliopsoas haematoma in the remaining two. All three acute patients received both antiplatelet and anticoagulant therapies. The outpatient was treated with warfarin. Initial symptoms of haematoma included pain (n = 3) and syncope (n = 1). No patient was correctly diagnosed at the onset of muscle haematoma. At initial examination of muscle haematoma, no patients showed skin lesions. An ecchymosis developed in the abdominal area at an average of 3 days after the initial symptoms. Mean decrease in haemoglobin was 6.8 g/dL from baseline. None required surgery whereas two patients required blood transfusion. Muscle haematomas in stroke patients receiving antithrombotic therapy are rare complications that are difficult to diagnose at onset. The possibility of muscle haematoma should be considered in patients with ischaemic stroke undergoing antithrombotic therapy and presenting with acute pain and syncope, even if skin manifestations or a palpable mass are lacking. (C) 2015 Elsevier Ltd. 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: Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K+ channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost-and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. Methods: Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. Results: Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K+ current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. Conclusions: This study showed that patients with CFS might have abnormal kinetics in a slow K+ current. Significance: Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K+ channel openers. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. 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.

Our objective was to elucidate the clinical factors affecting functional decline and survival in Japanese amyotrophic lateral sclerosis (ALS) patients. We constructed a multicenter prospective ALS cohort that included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and determined the timing of introduction of a tracheostomy for positive-pressure ventilation and death. A joint modelling approach was employed to identify prognostic factors for functional decline and survival. Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper limb weakness (p = 0.010), lower limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in the ALSFRS-R score was correlated with a shortened survival time (p < 0.001). In conclusion, the factors affecting functional decline and survival in ALS were common in part but different to some extent. This difference has not been previously well recognized but is informative in clinical practice and for conducting trials.

A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option.

Objective: Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K&lt sup&gt +&lt /sup&gt channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling. Methods: Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology. Results: Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses) excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K&lt sup&gt +&lt /sup&gt current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes. Conclusions: This study showed that patients with CFS might have abnormal kinetics in a slow K&lt sup&gt +&lt /sup&gt current. Significance: Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K&lt sup&gt +&lt /sup&gt channel openers.

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.

Objective: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. Methods: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. Results: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 9 10(-3)). Interpretation: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

To study distribution and patterns of nerve hypertrophy in chronic inflammatory demyelinating polyneuropathy (CIDP), magnetic resonance neurography with 3-dimensional reconstruction of short tau inversion recovery images was performed in 33 patients. This technique clearly showed longitudinal morphological changes from the cervical roots to the nerve trunks in the proximal arm. Nerve enlargement was detected in 88% of the patients. According to the clinical subtype of CIDP, typical CIDP patients showed symmetric and root-dominant hypertrophy, whereas Lewis-Sumner syndrome patients had multifocal fusiform hypertrophy in the nerve trunks. The patterns of nerve hypertrophy presumably reflect the different pathophysiology of each CIDP subtype. Ann Neurol 2014.

Objective: To identify useful MRI abnormalities in the putamen for diagnosing multiple system atrophy. Methods: Patients with multiple system atrophy (n = 15), Parkinson's disease (n = 16), or progressive supranuclear palsy (n = 9) and healthy controls (n = 10) were enrolled. Using a visual analog scale, 4 examiners independently rated high-intensity signals along the lateral putamen on T2-weighted and T2*-weighted images, low-intensity signals within the putamen on T2-weighted and T2*-weighted images, and putaminal atrophy. Receiver operating characteristic analyses were performed, and the area under the receiver operating characteristic curve was calculated. Results: For differentiating multiple system atrophy from progressive supranuclear palsy, Parkinson's disease, and healthy controls, the mean area under the curve values was the highest for low-intensity signals within the putamen on T2*-weighted images (0.797, 0.867, 0.896, respectively). Variations in the area under the curve values among the 4 examiners were the smallest in low-intensity signals within the putamen on T2*-weighted images. Good inter-rater reliability was achieved for low-intensity signals within the putamen on T2*-weighted images and high-intensity signals along the lateral putamen on T2*-weighted images. Conclusion: Low-intensity signals within the putamen on T2*-weighted images is the most useful MRI abnormality for diagnosing multiple system atrophy. (C) 2015 Elsevier B.V. All rights reserved.