桑原 聡

Objective To classify the patterns of functional decline in patients with sporadic amyotrophic lateral sclerosis (ALS) and explore the genetic backgrounds that modified these patterns. Methods We included 465 patients with sporadic ALS in the analysis and clustered the longitudinal functional scores in the registered patients, using a mixture approach of a non-linear mixed-effects model. We conducted a genome-wide analysis of 572 983 single nucleotide polymorphisms (SNPs). We then assessed the association between the clusters of longitudinal functional scores and SNPs. Results We identified the following four clusters of longitudinal functional decline in the cases: a rapid decline cluster, an intermediate decline cluster, a sigmoidal decline cluster and a moderate decline cluster. We identified seven SNPs associated with the rapid decline cluster, using a recessive model (p=3.47-8.34x10(-8)). The OR for the probabilities of the rapid decline cluster ranged from 5.5 to 5.84. Homozygosity for the minor alleles in the seven SNPs, which constituted a linkage disequilibrium (LD) block, was associated with decreased expression of TTN (encoding Titin, a large sarcomere protein) in the expression quantitative trait loci database of a large-scale Japanese genetic variation database (p= 8.6x10-10-1.1x10-7). TTN expression in immortalised lymphocyte lines was decreased in patients who were homozygous for the minor alleles compared with those who were homozygous for the major alleles (n=19 in each group, p=0.002). Conclusions We detected an LD block associated with a rapid functional decline in patients with sporadic ALS, which is linked to decreased expression of TTN.

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.

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.

Aims To determine whether there is a significant correlation between the peripapillary retinal thickness (pRT) and the serum level of vascular endothelial growth factor (VEGF) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. Methods This was a cross-sectional, observational case series. We studied 34 eyes of 17 treatment-naive patients with POEMS syndrome whose intracranial pressure was within the normal range. The spectral-domain optical coherence tomographic (SD-OCT) examinations consisted of circle scans of 3.45 mm diameter around the optic disc. The pRT was automatically measured in the SD-OCT images and was used for the statistical analysis. The serum level of VEGF was measured by ELISAs, and the correlation between the pRT and the serum level of VEGF was determined. Multivariable logistic regression analyses were used to identify independent factors that were correlated with the pRT. Results There was a significant positive correlation between the serum levels of VEGF and the average pRT of the two eyes of each patient (r=0.81, p<0.0001). There was a significant correlation between the pRT of the right and left eyes with an intraclass correlation coefficient of 0.839. Multiple regression analysis showed that the serum levels of VEGF were independent contributors to the pRT (standard regression coefficient=0.59, p=0.012). Conclusions The significant correlation between the pRT and the serum level of VEGF suggests that the higher serum level of VEGF might be associated with the development of the optic disc oedema in patients with POEMS syndrome.

Objective: To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) and to propose a novel modification so as to enhance sensitivity based on results of individual patient data (IPD). Methods: Individual patient data were available from 8 studies comparing the diagnostic accuracy of Awaji and revised El Escorial (rEEC) criteria. The sensitivity of a novel updated Awaji criteria, incorporating a "probable-laboratory supported" category, was also tested. Results: Individual patient data were available from 1086 patients, consisting of 881 ALS and 205 patients with disorders mimicking ALS. Summary sensitivities based on random effects logistic regression modelling disclosed a higher sensitivity of the Awaji criteria (0.70, 95% confidence interval [CI] 0.51-0.83) and updated Awaji criteria (0.73, 95% CI 0.56-0.85) when compared to rEEC (0.58, 95% CI 0.48-0.68). Paired analysis revealed higher sensitivities of Awaji criteria in 4 studies, and of updated Awaji criteria in 7 studies, when compared to rEEC. Conclusion: Individual patient data analysis established a higher sensitivity of Awaji criteria when compared to rEEC. The updated Awaji criteria enhanced the diagnostic sensitivity in limb-onset ALS. Significance: The updated Awaji criteria should be considered in clinical practice and future therapeutic trials. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.

The clinical courses of sporadic amyotrophic lateral sclerosis (ALS) show extensive variability. Our objective was to elucidate how age of onset influences the progression of regional symptoms and functional losses in sporadic ALS. We included 648 patients with sporadic ALS from a multicenter prospective ALS cohort. We investigated the distribution of initial symptoms and analyzed the time from onset to events affecting activities of daily living (ADL) as well as the longitudinal changes in each regional functional rating score among four groups with different ages of onset. The frequencies of dysarthria and dysphagia as initial symptoms were higher in the older age groups, whereas weakness of upper limbs was the most common initial symptom in the youngest age group. The survival times and the times from onset to loss of speech and swallowing were significantly shorter in the older age group (p < 0.001), although the times from onset to loss of upper limb function were not significantly different among the age groups. According to joint modeling analysis, the bulbar score declined faster in the older age groups (< 50 vs. 60-69 years: p = 0.029, < 50 vs. a parts per thousand yen70 years: p < 0.001), whereas there was no significant correlation between the age of onset and decline in the upper limb score. Our results showed that age of onset had a significant influence on survival time and the progression of bulbar symptoms, but had no influence on upper limb function in sporadic ALS.

Background and purpose: Fisher syndrome (FS) may overlap with Guillain-Barre 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.

Background: MSA is clinically classified into two phenotypes: parkinsonism predominant (MSA-P) and cerebellar ataxia predominant (MSA-C). However, little is known about the differences in urinary dysfunctions between MSA-C and MSA-P. We investigated the differences in urinary and cardiovascular dysfunctions between MSA-C and MSA-P.Methods: We retrospectively reviewed the medical records of patients with MSA diagnosed as having probable or possible MSA according to Gilman's second consensus criteria from January 2007 to September 2013 in our hospital. Data regarding the initial symptoms, onset of urinary symptoms, and results of urodynamic (including anal sphincter electromyography) and head-up tilt tests were collected.Results: A total of 100 patients with MSA, including 59 patients with MSA-C and 41 with MSA-P, were reviewed. Initial symptoms were autonomic (n = 12) and cerebellar (n = 47) in the MSA-C phenotype and were autonomic (n = 14) and parkinsonian (n = 27) in the MSA-P phenotypes. Urodynamic study indicated that bladder contraction was more severely impaired in patients with MSA-P than in those with MSA-C. In the head-up tilt test, the decrease in diastolic blood pressure was significantly larger in the MSA-P phenotype than that in the MSA-C phenotype. Acontractile bladder during the pressure flow study increased likelihood that the phenotype is MSA-P (odds ratio: 6.67; 95% confidence interval: 1.004-44.284; P = 0.050).Conclusions: Urinary dysfunctions were more severe in MSA-P compared with MSA-C. Detailed urodynamic study was helpful for detecting subtle differences between MSA-C and MSA-P.

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.

We describe two cases of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome patients with deteriorated extravascular volume overload without increased levels of vascular endothelial growth factor after the administration of cyclophosphamide + granulocyte colony-stimulating factor for stem cell mobilization. We then measured the serum levels of 27 cytokines from these cases using a multiplex suspension array system. The analysis revealed the changes of cytokine profiles before cyclophosphamide + granulocyte colony-stimulating factor and after the development of capillary leak symptoms in both cases. This may improve our current level of understanding of the pathogenesis of POEMS syndrome not driven by vascular endothelial growth factor. (C) 2015 Elsevier Ltd. All rights reserved.

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.

Background: Calciphylaxis is a syndrome consisting of vascular calcification, thrombosis, and skin necrosis. The syndrome develops often in chronic hemodialysis patients. However, there have been several case reports on calciphylaxis in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome, a systemic disease associated with plasma cell dyscrasia and upregulation of vascular endothelial growth factor (VEGF). Methods: In 76 POEMS patients and 86 age- and gender-matched disease controls, we studied abnormal small vessel calcification by computed tomography (CT) of the soft tissues. Clinical and laboratory profiles were compared between POEMS patients with and without calciphylaxis. Histological examination was performed in six autopsy cases. Results: Small vessel calcification on CT was found in 17 % of POEMS patients and in none of the controls (P < 0.001). Autopsy confirmed calciphylaxis in 2 (33 %) patients. Among POEMS patients, higher disease activity, including more severe neuropathy and ascites, higher serum levels of interleukin-6, and lower serum albumin levels, was associated with the development of calciphylaxis. Serum levels of creatinine, calcium, and phosphate were not related to the presence of calciphylaxis. Conclusions: Calciphylaxis is often present in patients with POEMS syndrome. Upregulation of multiple inflammatory cytokines such as VEGF and interleukin-6 may contribute to the development of calciphylaxis, by entirely different mechanism from that in chronic dialysis. POEMS syndrome should be recognized as a potential cause of calciphylaxis.

We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients. (C) 2016 Elsevier Inc. All rights reserved.

BackgroundAutonomic urinary dysfunction affects patients with progressive supranuclear palsy (PSP); however, the severity and prevalence of urinary dysfunctions in these patients compared with those observed in patients with Parkinson's disease (PD) and multiple system atrophy (MSA) are unknown.ObjectiveWe compared urinary dysfunction characteristics in patients with PSP, PD, and MSA.Patients and MethodsForty-seven patients who satisfied the probable or possible criteria of the National Institute for Neurological Diseases and Stroke and Society for PSP were assessed using the urinary symptoms questionnaire and the urodynamic study at Chiba and Toho Universities (n = 26 and 21, respectively). The results were compared with those of patients with PD and MSA (n = 218 and 193, respectively).ResultsThe mean disease duration of PSP and the mean age were 2.97 +/- 0.26 and 71.4 +/- 0.88 years, respectively. The mini-mental state examination and frontal assessment battery scores were 22.6 +/- 0.70 and 10.7 +/- 0.49, respectively. Urinary storage and voiding symptoms were observed in 57% and 56% of patients with PSP, respectively. Detrusor overactivity in the urodynamic study was detected in 81% of patients with PSP, which was slightly more than that found in patients with PD (69%) and MSA (67%); however, this was not statistically significant. Postvoid residual volume in patients with PSP was significantly more than that in patients with PD (P < 0.01), but was equivalent to that in patients with MSA.ConclusionsThe present study demonstrated that patients with PSP experienced various urinary dysfunctions. Urinary storage dysfunction in patients with PSP was not different from that in patients with PD or MSA, whereas urinary voiding dysfunction in patients with PSP was milder than that in patients with MSA and more severe than that in patients with PD. These features should be taken into account for the differentiation of PSP from PD and MSA.

© 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&lt;0.001, and 21% vs. 3%, P&lt;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 &lt; 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.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by segmental vasospasm and it is often accompanied by either posterior reversible encephalopathy syndrome or stroke. However, other MRI abnormalities have rarely been reported. A 28-year-old woman presented with a thunderclap headache immediately after delivery; MRI showed segmental vasoconstriction and an abnormal signal in the splenium of the corpus callosum. Neuroimaging abnormalities normalized 20 days after the first examination. Only two cases of RCVS with transient splenial lesions (TSL) have so far been reported. Both cases occurred postpartum like ours, indicating that delivery may be a trigger for the development of both TSLs and RCVS.

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal neuropathy and multi-organ involvement, associated with plasma cell dyscrasia and upregulation of serum levels of vascular endothelial growth factor (VEGF). The pathogenesis of the disorder is not well understood, but increased vascular permeability and neovascularization mediated by VEGF and other inflammatory cytokines are likely to play an important role in most of the characteristic symptoms. However, the pathogenesis of peripheral neuropathy is unclear VEGF may affect the blood-nerve barrier and allow neurotoxic substances to access the nerve parenchyma, resulting in nerve structural damages. POEMS syndrome is a potentially fatal disease, and there is no established treatment regimen for this syndrome. In appropriate candidates, high-dose chemotherapies with autologous peripheral blood stem cell transplantation are recommended, because this treatment can lead to obvious and rapid clinical improvement in neuropathy as well as other symptoms, with a significant decrease in serum VEGF levels. The indication for this treatment has not yet been established, and the long-term prognosis is unclear. Potential future therapies include the administration of thalidomide, lenalidomide, bortezomib, and anti-VEGF monoclonal antibody (bevacizumab). Prognosis of POEMS syndrome has been substantially improved by these novel interventions, whereas randomized control trials are required to establish a proper therapeutic guideline. This review focuses on recent advances in diagnosis and treatment of POEMS syndrome and discusses future perspectives of therapeutic strategy.

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&lt;0.05, p&lt;0.001, respectively). There was a significant difference in mean cortical AChE activities between AD and DLB patients (p&lt;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 &lt; 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 &gt; 0.05; left eye, r = 0.25, p &gt; 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 &lt; 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.