桑原 聡

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

Background: The features of acute aortogenic embolic stroke on magnetic resonance diffusion-weighted imaging (DWI) have not been fully elucidated, so we compared patients with acute aortogenic embolic stroke and those with acute cardioembolic stroke. Methods and Results: This study included 40 consecutive patients with acute aortogenic embolic stroke, and 40 age- and sex-matched patients with acute cardioembolic stroke. The diagnosis of aortogenic embolic stroke was made when patients met 5 criteria: (1)acute neurologic event lasting >24h; (2) positive signals on DWI; (3) atherosclerotic lesions >= 3.5-mm thick at the aortic arch on transesophageal echocardiography; (4) neuroradiologic features suggesting embolic stroke, such as lesions involving the brain cortex or the re-opening phenomenon of previously occluded vessels on Magnetic Resonance Angiography (MRA); and (5) absence of other embolic sources, including heart disease and carotid stenosis. The number, site, and maximal diameter of the infarct lesions on DWI were compared between the aortogenic and cardiogenic groups. The aortogenic patients more frequently had >= 3 lesions (25.0% vs. 2.5%, P<0.01), lesions with a maximal diameter <30 mm (77.5% vs. 20.0%, P< 0.001), and vertebrobasilar system lesions (55.0% vs. 10.0%, P< 0.001) than the cardiogenic patients. Conclusions: Acute aortogenic embolic stroke is characterized by multiple (>= 3) and small lesions, and involvement of the vertebrobasilar system.

Introduction: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. Methods: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. Results: The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. Conclusions: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers. Muscle Nerve49:357-361, 2014

Objective: Bortezomib is a proteasome inhibitor with high efficacy for multiple myeloma but with severe peripheral neurotoxicity, leading to dose modification and severe neurological disability. This study aimed to investigate the pathophysiology of bortezomib-induced neuropathy. Methods: Threshold tracking was used to assess the excitability of sensory and motor axons. Measurements were sequentially performed before and after bortezomib treatment in nine patients with newly diagnosed multiple myeloma. Results: In total, 67% of patients finally developed symptomatic neuropathy. Changes in sensory axonal excitability indices readily occurred after the first course of administration. Patterns of changes in excitability indices suggest membrane depolarization (decreased superexcitability, P < 0.001; decreased depolarizing threshold electrotonus 90-100 ms, P = 0.02). Abnormalities in nerve conduction parameters suggestive of axonal degeneration appeared after the second course of treatment. Conclusions: Bortezomib induces a depolarizing shift in resting membrane potential prior to the development of neuropathy. Membrane depolarization could be associated with impairment of electrogenic Na+-K+-ATPase-dependent pump caused by toxic effects of bortezomib on mitochondria. Significance: Axonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Background: Cases of transient myoclonus without other neurological manifestations in the elderly have very rarely been reported. Objective: To report clinical features of elderly people with isolated transient myoclonus. Methods: Clinical and laboratory features of 11 consecutive patients with isolated transient myoclonus (six men and five women; mean age, 75 years) were reviewed. Transient myoclonus was defined as an acute onset of tremulous myoclonus with/without asterixis in adults without other neurological symptoms. Results: Preceding infections were recorded in five patients (pneumonia, two; upper respiratory tract infection, two; and septic arthritis of the shoulder, one). Myoclonus predominantly affected the head and/or neck (n = 10) and upper extremities (n = 11), compared with the trunk (n =2) and lower extremities (n = 6). Asterixis was observed in six patients. Laboratory testing, neuroimaging, and electroencephalograms revealed no specific abnormalities. With or without treatment using benzodiazepines, myoclonus in all patients resolved completely within 1-4 days, although five had recurrence 2-19 months after their first episodes. Among these five patients, the accompanying asterixis patterns (presence or not) in four were different in the first and subsequent episodes. Conclusions: Isolated transient myoclonus with or without asterixis may be more common than generally believed, and it could be a clinical entity or disease spectrum. Transient myoclonus is a benign condition in the elderly, but can be under-reported or misdiagnosed. Therefore, it is important to recognize that the elderly may have this syndrome. (C) 2013 Elsevier B.V. All rights reserved.

Aims: Not all the mechanisms by which subthalamic nucleus deep brain stimulation (STN-DBS) alleviates parkinsonian symptoms have been clarified as yet. The levels of striatal monoamine and the subthalamic beta activity might contribute to its efficacy. However, their direct relationship is unclear. We aimed to examine the correlation between the striatal monoamine and the STN beta activity induced by STN-DBS. Experimental procedures: Experiments were performed under urethane anesthesia in normal (n = 4) and 6-hydroxydopamine hemi-lesioned Parkinson's disease (PD) model rats (n = 5). STN-DBS was applied to the left STN, and local field potential (LFP) was recorded before and after STN-DBS. Striatal extracellular fluid was collected before, during, and after STN-DBS. Spectral analysis of STN-LFP was performed, and the levels of monoamine were measured. Results: The levels of 3-4-dihydroxyphenylacetic acid (DOPAC) were significantly decreased after the cessation of stimulation in PD model rats. The levels of none of the monoamines were significantly affected in normal rats. The STN beta power was significantly elevated after the cessation of stimulation in normal rats but was significantly decreased in PD model rats. Results: The STN beta power and the levels of DOPAC and 5-HT was positively correlated in PD model rats, whereas the levels of dopamine and 5-HT showed positive correlation and the levels of DOPAC and Homovanillic acid (HVA) showed negative correlation in normal rats. Conclusion: STN-DBS could decrease the levels of DOPAC and the STN beta power in a PD model rat. The STN beta power and the levels of striatal monoamine might be differentially correlated between normal and PD model rats. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

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

Objective To investigate whether or not the lesions in sporadic amyotrophic lateral sclerosis (ALS) originate from a single focal onset site and spread contiguously by prion-like cell-to-cell propagation in the rostrocaudal direction along the spinal cord, as has been hypothesised (the 'single seed and simple propagation' hypothesis). Methods Subjects included 36 patients with sporadic ALS and initial symptoms in the bulbar, respiratory or upper limb regions. Abnormal spontaneous activities in needle electromyography (nEMG)-that is, fibrillation potentials, positive sharp waves (Fib/PSWs) or fasciculation potentials (FPs)-were compared among the unilateral muscles innervated by different spinal segments, especially between the T10 and L5 paraspinal muscles, and between the vastus medialis and biceps femoris. Axon length and the proportion of muscle fibre types, which are both related to motoneuronal vulnerability in ALS, are similar in the paired muscles. Results Fourteen of 36 patients showed a non-contiguous distribution of nEMG abnormalities from the onset site, with skipping of intermediate segments. In eight of them, the non-contiguous pattern was evident between paired muscles with the same motoneuronal vulnerability. The non-contiguously affected lumbosacral lesions involved motoneuron columns horizontally or radially proximate to one another, appearing to form a cluster in four of the eight patients. FPs, known to precede Fib/PSWs, were shown more frequently than Fib/PSWs in all the lumbosacral segments but L5, suggesting that 2nd hits occur at L5 and then spread to other lumbosacral segments. Conclusions In sporadic ALS, the distribution of lower motoneuron involvement cannot be explained by the 'single seed and simple propagation' hypothesis alone. We propose a 'multifocal hits and local propagation' hypothesis instead.

Helicobacter cinaedi, a gram-negative spiral bacillus that inhabits the intestinal tracts of rodents and primates, is associated with gastroenteritis in humans. H. cinaedi infection has been commonly reported in immunocompromised individuals such as human immunodeficiency virus-infected patients, but rarely in immunocompetent individuals. Prior contact with animals has attracted attention as a possible Source of H. cinaedi infection. We report a case of meningitis in an immunocompetent 34-year-old woman who had daily contact with a kitten for a month. She developed acute headaches, fevers, and chills. Neurological examination revealed neck stiffness and her cerebrospinal fluid (CSF) exhibited polymorphonudear pleocytosis and a decreased concentration of glucose. Blood and CSF cultures were negative; however, the pathogen responsible for her condition was identified as H. cinaedi by polymerase chain reaction in CSF. This is the first adult case of meningitis caused by H. cinaedi. Thus, this bacillus should be considered a possible causative agent of bacterial meningitis in healthy adults. (C) 2013 Published by Elsevier B.V.

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

Background: According to Braak staging of Parkinson's disease (PD), detection of autonomic dysfunction would help with early diagnosis of PD. Objective: To determine whether the autonomic nervous system is involved in the early stage of PD, we evaluated cardiovascular and sudomotor function in early untreated PD patients. Methods: Orthostatic blood pressure regulation, heart rate variability, skin vasomotor function, and palmar sympathetic sweat responses were examined in 50 early untreated PD patients and 20 healthy control subjects. Results: The mean decrease in systolic blood pressure during head-up tilt in PD patients was mildly but significantly larger than in controls (p = 0.0001). There were no differences between the 2 groups in heart rate variability, with analysis of low frequency (LF; mediated by baroreflex feedback), and high frequency (HF; mainly reflecting parasympathetic vagal) modulation. However, LF/HF, an index of sympatho-parasympathetic balance, was lower in the PD group than in controls (p = 0.02). Amplitudes of palmar sweat responses to deep inspiration (p = 0.004), mental arithmetic (p = 0.01), and exercise (p = 0.01) in PD patients were lower than in controls, with negative correlations with motor severity. Amplitudes of palmar skin vasomotor reflexes in PD patients did not differ from controls. Conclusions: Our study indicates impairment of sympathetic cardiovascular and sudomotor function with orthostatic dysregulation of blood pressure control, reduced LF/HF and reduction in palm sweat responses even in early untreated PD patients.

Objective No clinically effective treatment for promoting peripheral axonal regeneration has yet been established. Several experimental studies in vitro and in vivo have shown that a high dose of methylcobalamin (MeCbl), an analogue of vitamin B12, promotes axonal growth in peripheral nerve injury. We herein assessed the safety and efficacy of an ultra-high dose MeCbl treatment for patients with peripheral neuropathy and chronic axonal degeneration. Methods Fourteen patients with immune-mediated or hereditary neuropathy in the chronic progressive or stable phase were enrolled. MeCbl, 25 mg/day for 10 days followed by monthly 25 mg for 5 months, was intravenously administered. The patients were evaluated before and 1 year following treatment. The primary endpoints were safety and improvement in the Medical Research Council (MRC) sum score in at least two muscles of the 20 muscles. This trial is registered with the University Hospital Medical Information Network (UMIN) Center in Japan under the ID: UMIN000009359. Results There were no adverse effects in twelve of the patients, whereas treatment was discontinued in two patients who had seborrheic dermatitis at 3 months and respiratory tract infection at 2 months, respectively. Therefore, twelve patients were evaluated for the primary outcomes; the MRC sum score was improved in seven of the patients and unchanged or worsened in the remaining five patients. Conclusion Intravenous ultra-high dose MeCbl treatment is a safe and potentially efficacious therapy for patients with peripheral neuropathy and chronic axonal degeneration.

Guillain-Barré syndrome (GBS) is the most frequent peripheral neuropathic cause of acute flaccid paralysis. GBS is currently classified into two major forms on the basis of the following pathological and electrophysiological criteria acute inflammatory demyelinating polyneuropathy (AIDP), and acute motor axonal neuropathy (AMAN). AIDP is the most commonly encountered variant except in East Asia, (China and Japan), where the AMAN variant predominates. AMAN is characterized by electrophysiological and pathological changes that may reflect axonal degeneration of the motor nerves, functional conduction failure or other pathophysiology. An important cause of AMAN is the molecular mimicry between human gangliosides and bacterial lipo-oligosaccharides, possibly associated with anti-ganglioside antibodies. In particular, IgG antibodies to the gangliosides GM1, GM1b, GD1a and GalNAc-GD1a may be induced by infectious agents such as Campylobacter jejuni or Haemophilus influenza. In contrast, target molecules have not yet been identified for AIDP. Although AMAN and AIDP appear similar in their clinical features, there are important differences. AMAN presents clinically as a predominantly motor syndrome, with infrequent and mild involvement of the autonomic nervous system. When sensory fibers are also affected, this axonal subtype is designated acute motor and sensory axonal neuropathy (AMSAN). Patients with AMAN may manifest hyperreflexia during the recovery phase. AMAN progresses rapidly in its early stage and has an earlier nadir than AIDP. AMAN has two distinct patterns of clinical recovery rapid and prolonged. This contrasts with the relatively uniform recovery observed in AIDP. Irrespective of the variant, electrophysiological evidence of axonal degeneration is thought to be an indicator of poor prognosis. However, even the most severely disabled patients with AMAN may walk independently within a few years, indicating that a diagnosis of AMAN in and of itself does not always imply a poor recovery. The efficacy of plasma exchange and intravenous immunoglobulin (IVIg) has been established in large international randomized trials. Nonetheless, IVIg is preferred because of its greater availability, comparative ease of administration and relatively lower complication rates. In contrast, corticosteroid treatments are ineffective. This review provides an update on the clinical features, pathogenesis and treatment of GBS.

This review described current status and perspectives of treatment for immune-mediated neuropathies, such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, and demyelinating neuropathy with anti-MAG neuropathy. corticosteroids, immunoglobulin therapy, and plasmapheresis are conventional treatments for these neuropathies, but the responsiveness to the treatments significantly differ among the disorders. Promising new treatment options include anti-complement monoclonal antibody (Eculizumab, anti-C5) for Guillain-Barre syndrome, and rituximab (anti-CD20) for anti-MAG neuropathy. For CIDP, different treatments would be required according to the clinical subtypes typical CIDP and asymmetric variabt). For multifocal neuropathy, maintainance treatment with immunoglobulin is necessary.

Wide-spread fasciculations are prominent clinical features in patients with amyotrophic lateral sclerosis (ALS), specifically seen in ALS among disorders with neurogenic muscle atrophy. Fasciculations frequently arise from the motor nerve terminals, and the hyperexcitability of motor axons appears to constitute the pathophysiology of the disease. Neurophysiologic investigations of the upper and lower motor neurons/axons have shown increased excitability. The altered excitability is supposed to relate to motor neuron death. Based on these findings, a clinical trial of mexiletine (non-selective sodium channel blocker) is ongoing.

Objective Vascular endothelial growth factor (VEGF) plays an essential role in the pathophysiology of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome. Anti-VEGF antibody (bevacizumab) appears to be an attractive therapeutic option. The aim of this study is to investigate the effects of bevacizumab for patients with POEMS syndrome. Methods We reported six POEMS patients treated with bevacizumab and reviewed the literature. Results The serum VEGF levels decreased immediately after bevacizumab administration in all six patients. However, four patients had entirely no clinical response, and two of them died. The remaining two showed improvement that could be explained by combined treatments. We also reviewed the literature and found 11 patients treated with bevacizumab; of these, only one was treated with bevacizumab alone. 10 had combined treatments, and four died without any response. Conclusions Both our experience and the literature suggest ambiguous effects of bevacizumab; inhibition of VEGF alone may be insufficient because multiple cytokines are upregulated, or aberrant neo-vascularization may have already fully developed in the advanced stage of POEMS syndrome.

The influenza A (H1N1) 2009 vaccination program was the largest mass vaccination initiative in the USA, including 23 million people. A report published in The Lancet shows that the vaccination was associated with a very small increased risk of Guillain-Barré syndrome (GBS), and suggests that the benefits of influenza A (H1N1) vaccines outweighed the risks. Another recent large study has shown that none of the 550 people with a history of GBS had its recurrence after vaccination. At present, there is no evidence that modern vaccination is associated with recurrent GBS. © 2013 Japanese Society for Neuroimmunology.

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS Crow-Fukase) syndrome is a devastating disorder related to plasma cell dyscrasia, characterized by polyneuropathy, organomegaly, edema/effusion, M-protein and skin changes. Novel therapeutic approaches can substantially improve the prognosis. Diagnosis of POEMS syndrome is often challenging because of a combination of clinical presentations. To facilitate precise and early diagnosis, a comprehensive systemic survey is essential, and we propose that current diagnostic criteria should be modified. The current first-line therapy is high-dose chemotherapy with autologous stem cell transplantation, whereas patients who are not eligible for transplantation because of older age or poor general condition, are treated with immunomodulatory drugs, such as thalidomide or lenalidomide. The prognosis of POEMS syndrome has been substantially improved by these novel interventions. However, how to treat very young patients and those with a relapse after autologous stem cell transplantation is controversial. Until the 2000s, therapeutic approaches initially aimed at lifesaving (or short-term improvement), but recent treatment advances could achieve long-term remission of the disease. A treatment algorithm should be decided from the viewpoint of disease control over a decade. Elucidation of the natural history of the disease and well-conducted randomized control studies are fundamental to establish a proper therapeutic guideline. The present review focuses on recent advances in the diagnosis and treatment of POEMS syndrome, and discusses future perspectives of therapeutic strategies. © 2013 Japanese Society for Neuroimmunology.

Background In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed split hand'. Previous axonal excitability studies have suggested increased nodal persistent sodium current and reduced potassium current in motor axons in ALS, but the extent of excitability changes in APB and ADM axons in ALS has never been compared. Objective To elucidate the peripheral axonal pathophysiology of split hand. Methods In both APB and ADM motor axons of 21 patients with ALS and 17 age-matched normal controls, threshold tracking was used to measure excitability indices such as strength-duration time constant (SDTC; a measure of persistent sodium current) and threshold electrotonus. Results In normal controls, SDTC was significantly longer for APB than ADM axons, suggesting that axonal excitability is physiologically higher in APB axons. Compared with normal controls, patients with ALS had longer SDTC and greater threshold changes in depolarising threshold electrotonus in both APB and ADM axons. Furthermore, the difference in extent of SDTC prolongation between normal subjects and patients with ALS was greater in APB than ADM axons. Conclusions APB axons have physiologically higher excitability than ADM axons, and, in ALS, the hyperexcitability is more prominent in APB axons. Although cortical mechanisms would also be involved, more prominent hyperexcitability of APB axons may contribute to development of split hand, and the altered axonal properties are possibly associated with motor neuronal death in ALS.

Objectives: To clarify whether patients with spinal muscular atrophy (SMA) or spinal and bulbar muscular atrophy (SBMA) suffer disabling muscle fatigue, and whether activity-dependent conduction block (ADCB) contributes to their fatigue. ADCB is usually caused by reduced safety factor for impulse transmission in demyelinating diseases, whereas markedly increased axonal branching associated with collateral sprouting may reduce the safety factor in chronic lower motor neuron disorders. Methods: We assessed the fatigue severity scale (FSS) in 22 patients with SMA/SBMA, and in 100 disease controls (multiple sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDP), and axonal neuropathy). We then performed stimulated-single fibre electromyography (s-SFEMG) in the extensor digitorum communis (EDC) muscle of 21 SMA/SBMA patients, 6 CIDP patients, and 10 normal subjects. Results: The FSS score was the highest in SMA/SBMA patients [4.9 +/- 1.1 (mean +/- SD)], with 81% of them complaining of disabling fatigue, compared with normal controls (3.5 +/- 1.0), whereas patients with multiple sclerosis (4.3 +/- 1.6), myasthenia gravis (4.0 +/- 1.6) or CIDP (4.3 +/- 1.4) also showed higher FSS score. When 2000 stimuli were delivered at 20 Hz in s-SFEMG, conduction block of single motor axons developed in 46% of patients with SMA/SBMA, and 40% of CIDP patients, but in none of the normal controls. Conclusion: SMA/SBMA patients frequently suffer from disabling fatigue presumably caused by ADCB induced by voluntary activity. Significance: ADCB could be the mechanism for muscle fatigue in chronic lower motor neuron diseases. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Retinol palmitate, an analog of vitamin A, plays multiple roles in the nervous system, including neural differentiation, axon outgrowth, and neural patterning, and is also an antioxidative agent and thereby potential neuroprotectant for brain ischemia. The present study aimed at investigating the protective effects of retinol palmitate against ischemia-induced brain injury in a bilateral common carotid artery occlusion (BCCAO) model in mice. Ischemia induced by 20-min BCCAO resulted in significant neuronal morphological changes and reactive astrocyte proliferation in the hippocampus, particularly in the CA1 region, and these changes were accompanied by increased Notch1 expression. Intraperitoneal retinol palmitate administration before ischemia reduced ischemic neurons with Notch1 expression the differences were statistically significant in both the 1.2. mg/kg group and 12. mg/kg group. These results show that retinol palmitate prevents brain ischemia-induced neuronal injury with Notch1 expression and that Notch1 signaling could be involved in the neuroprotective mechanism. Retinol palmitate could be a treatment option for human brain infarction. © 2013 Elsevier Inc.

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

Neuromyelitis optica (NMO) is an inflammatory disorder of the central nervous system that predominantly affects the optic nerves and spinal cord. NMO is characterized by anti-aquaporin 4 (AQP4) antibody-mediated astrocytopathy. Recent studies have improved our knowledge of NMO. Interleukin-6 presumably plays an important role in the immunopathogenesis of NMO, because it is involved in the production of anti-AQP4 antibody in the peripheral circulation and in the enhancement of inflammation in the central nervous system. Significant advances in the understanding of the pathogenesis of NMO will help develop new treatments. The present review focuses on the current research addressing the role of interleukin-6 in NMO. © 2013 Japanese Society for Neuroimmunology.

Objective We carried out a retrospective study to define clinical features in a large series of patients with multifocal motor neuropathy (MMN) and to assess the diagnostic spectrum of MMN. Methods The study consisted of 46 patients with MMN between 2005 and 2009 from 19 major neuromuscular centers in Japan. The 2006 European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) criteria (hereafter, original criteria) and the efficacy of intravenous immunoglobulin (IVIg) therapy were taken into consideration in the diagnosis of MMN. The main parameters were clinical features and electrophysiological findings. The Japanese MMN Study Group designed a set of recommended criteria to reduce the frequency of underdiagnosis. Furthermore, we verified the diagnostic spectrum of MMN using both the original criteria and the recommended criteria. Results Clinical features were similar to those of previous studies. A total of 25 of the 46 patients (54.3%) showed conduction block (CB) that is, nearly half of the patients did not satisfy the original criteria. The Japanese MMN Study Group included findings indicative of focal demyelination, namely, activity-dependent CB and asymmetric abnormality of F-waves in the electrophysiological test, in the recommended criteria. By doing so, the diagnostic sensitivity of the recommended criteria was increased by 17.4% compared with that of the original criteria. Conclusions The recommended criteria designed by the Japanese MMN Study Group showed higher diagnostic sensitivity than the original criteria, but no significant difference was found between them. A prospective study using the recommended criteria might reduce the frequency of underdiagnosis in patients with MMN. © 2013 Japanese Society for Neuroimmunology.

OBJECTIVE: In contrast to tactile inputs, the organization and processing of nociceptive inputs in the primary somatosensory cortex (S1) remain largely unexplored. Few studies have examined the arrangement of nociceptive inputs in S1. The aim of this study was to investigate the representation of nociceptive inputs in the human cortex, including the somatosensory and posterior parietal cortices, from widely separated cutaneous sites. METHODS: We examined the somatotopic organization of the nociceptive system in S1, opercular and posterior parietal cortices by measuring the magnetoencephalographic responses (somatosensory-evoked magnetic fields) of four healthy controls in response to intraepidermal electrical stimulation applied to the face, neck, back, elbow, wrist, hand, finger, knee, and foot, which selectively activated the Aδ fibers. RESULTS: Magnetoencephalography demonstrated clear somatotopy in the S1 responses to noxious stimuli, with the foot representation in the extreme posteromedial position of S1 and the facial area in the extreme anterolateral position. There was little evidence of any clear somatotopic organization in the secondary somatosensory and posterior parietal cortices. CONCLUSION: These findings suggest that the nociceptive system uses the large body surface map in S1. SIGNIFICANCE: This is the first MEG study to demonstrate the cortical representation of nociceptive inputs in the human S1. We showed that widely separated cutaneous sites clearly supported Penfield's homunculus.

Objective: To elucidate the features of sensory nerve involvement in Fisher syndrome (FS), this study extensively investigated sensory electrophysiology. Methods: In 47 consecutive FS patients, results of sensory nerve conduction studies in the median, ulnar and sural nerves, soleus H-reflexes, and median or tibial somatosensory-evoked potentials (SEP) were reviewed. Because of the large effects of age on amplitude of sensory nerve action potentials (SNAP), we strictly defined reduction of SNAP amplitudes by using a nomogram which age and amplitude obtained from 87normal subjects. Results: In routine nerve conduction studies, SNAP amplitude was reduced only in 32% of the patients, and conduction velocity was decreased in 2%. In contrast, soleus H-reflexes were frequently absent or reduced (67%). SEPs were abnormal only in 17%. Conclusions: In FS, absent soleus H-reflexes are the most frequent electrophysiologic abnormalities, whereas SNAPs amplitudes are rarely affected. The pattern is characterized by predominant involvement of group Ia afferents with relatively preserved cutaneous afferents without evidence suggestive of demyelination. Significance: The major targets of immune attack by anti-GQ1b antibodies in FS appear to be group Ia neurons in the dorsal root ganglia, and this is presumably responsible for ataxia and areflexia in FS. (C) 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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

Gangliosides, GM1 and GQ1b, are respectively major immunological target molecules in Guillain-Barré syndrome and Fisher syndrome. In enzymelinked immunosorbent assay, the addition of acidic phospholipids increases the activities of anti-GM1 antibodies, but not of anti-GQ1b antibodies, suggesting different physicochemical properties of GM1 and GQ1b. On the axolemma, gangliosides form clusters termed "rafts", and the environment surrounding the clusters possibly modulates the activity of the autoantibodies. © 2013 Japanese Society for Neuroimmunology.

Background: Ischemic stroke can occur in patients with an underlying or undiagnosed malignancy. We aim to report the clinical features of ischemic stroke patients in whom a previously undiagnosed cancer was detected after stroke onset. Methods: Clinical and laboratory records of 28 consecutive ischemic stroke patients with cancer were reviewed retrospectively. The analysis was made focused on the differences between patients who were already diagnosed as having cancer before ischemic stroke (Group A) and those in whom a previously undiagnosed cancer was detected after ischemic stroke onset (Group B). Results: There were 18 patients in the Group A and 10 in the Group B. In Group B patients, the indicators that led to the detection of cancer were as follows: ascites (n=2), liver enzyme elevation (n=2), anemia (n=2), hematemesis (n=1), hematochezia (n=1), and sore throat (n=1), and autopsy (n=1). Nine of the 10 patients (90%) in Group B, and 6 of the 18 (33%) in Group A had a gastrointestinal cancer. In Group B, 8 of the 9 patients showed elevated serum carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9). Stroke relapse, prognosis, diffusion-weighted imaging patterns and laboratory findings were not different between the 2 groups. Conclusions: Gastrointestinal cancer was frequent in ischemic stroke patients with newly diagnosed malignancy after stroke onset in this study among Japanese patients. Physicians should be aware that underlying cancer may be present particularly in ischemic stroke patients whose stroke etiology is unclear or who have anemia or liver dysfunction. In such cases, measurements of CEA and CA19-9 levels are easy and useful screening for the detection of occult malignancies.

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

Aim: A previous study on a small number of patients showed that low skin temperature of the hands, the so called "cold hands sign", may be useful for distinguishing multiple system atrophy (MSA) from Parkinson's disease (PD). We have further investigated skin temperature of the hand in a larger number of patients. Methods: Skin temperature on the palm was measured in 50 MSA (11 MSA-P and 39 MSA-C patients) and 50 PD patients, and 25 normal healthy subjects. Results: Palm skin temperature was significantly lower in MSA patients (32.0 +/- 2.7 degrees C) than in controls (34.1 +/- 0.9 degrees C, p = 0.0002), but was not different compared with the PD group (32.9 +/- 1.8 degrees C, p = 0.06). Temperatures of &lt;28 degrees C were observed in 3 MSA patients (6%) and none of the PD patients and controls. There was no significant difference in palm skin temperature between patients with and without orthostatic hypotension for each patient group, or between MSA-P and MSA-C patients. Conclusion: The cold hand (&lt;28 degrees C) is a useful marker for distinguishing MSA from PD, but it is not common in MSA patients, and its sensitivity may be low for differentiating between MSA and PD. (C) 2013 Elsevier Ltd. All rights reserved.

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.