桑原 聡

Background POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) syndrome, a rare cause of demyelinating neuropathy associated with multiorgan involvement, has been increasingly recognised. Polyneuropathy is often an initial manifestation and therefore the disorder can be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Objective To elucidate whether POEMS syndrome and CIDP are differentiated based on profiles of neuropathy. Methods Clinical and electrophysiological data were reviewed in consecutive POEMS syndrome (n=51) and typical CIDP (n=46) patients in a single Japanese hospital between 2000 and 2010. Results Both POEMS and CIDP patients showed symmetric polyneuropathy, physiological evidence of demyelination (70% of POEMS patients fulfilled the electrodiagnostic criteria for definite CIDP) and albuminocytological dissociation; 49% of the POEMS syndrome patients had neuropathy onset and 60% of them were initially diagnosed as having CIDP by neurologists. Clinically, POEMS neuropathy more frequently showed severe leg pain (76% vs 7%; p < 0.001), muscle atrophy (52% vs 24%; p=0.005) and distal dominant muscle weakness. Electrophysiologically, POEMS syndrome was characterised by less prolonged distal motor latency (mean 5.6 ms vs 8.1 ms; p < 0.001) and higher terminal latency index (0.42 vs 0.33; p=0.006) in the median nerves, and unrecordable tibial and sural responses (p < 0.001), suggesting demyelination predominant in the nerve trunk rather than in the distal nerve terminals, and axonal loss in the lower limb nerves. Conclusions Before development of typical systemic manifestations, POEMS neuropathy can be distinguished from CIDP by the clinical profile and patterns of nerve conduction abnormalities. Recognition of these features leads to early diagnosis and proper treatment for POEMS syndrome.

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (CO2)-C-13 excretion (T-max) in the C-13-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (CO2)-C-13 excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (CO2)-C-13 excretion (T-max) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 +/- 22.7 min and 42.5 +/- 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (CO2)-C-13 excretion (T-max) values without and with subthalamic deep brain stimulation after surgery were 44.0 +/- 17.5 min and 30.0 +/- 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (CO2)-C-13 excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (CO2)-C-13 excretion (T-max) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (delta ghrelin) and changes in T-max values (delta T-max) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and delta T-max post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.

In amyotrophic lateral sclerosis (ALS), hand muscle wasting preferentially affects the 'thenar (lateral) hand', including the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles, with relative sparing of the hypothenar muscles (the abductor digiti minimi (ADM)). This peculiar pattern of dissociated atrophy of the intrinsic hand muscles is termed the 'split hand' and is rarely seen in diseases other than ALS. The muscles involved in the split hand are innervated through the same spinal segments (C8 and T1), and FDI and ADM, which are differentially affected, are both ulnar nerve innervated. The physiological mechanisms underlying the split hand in ALS are incompletely understood but both cortical and spinal/peripheral mechanisms are probably involved. Motor potentials evoked by magnetic stimulation are significantly smaller when recorded from the thenar complex, compared with the hypothenar muscles, supporting a cortical mechanism. But peripheral axonal excitability studies have suggested that APB/FDI motor axons have more prominent persistent sodium currents than ADM axons, leading to higher axonal excitability and thereby more ready degeneration. Pincer or precision grip is vital to human hand function, and frequent use of thenar complex muscles may lead to greater oxidative stress and metabolic demands at both upper and lower motoneurons innervating the APB and FDI. The split hand is a useful diagnostic sign in early ALS, and recent objective studies indicate that the sign has a high degree of specificity.

Objective: The aim of this study is to establish reference values for single-fibre electromyography (SFEMG) using concentric needles in a prospective, multicentre study. Methods: Voluntary or stimulated SFEMG at the extensor digitorum communis (EDC) or frontalis (FRO) muscles was conducted in 56-63 of a total of 69 normal subjects below the age of 60 years at six Japanese institutes. The cut-off values for mean consecutive difference (MCD) of individual potentials were calculated using +2.5 SD or 95% prediction limit (one-tail) of the upper 10th percentile MCD value for individual subjects. Results: The cut-off values for individual MCD (+2.5 SD) were 56.8 mu s for EDC-V (voluntary SFEMG for EDC), 58.8 mu s for EDC-S (stimulated SFEMG for EDC), 56.8 mu s for FRO-V (voluntary SFEMG for FRO) and 51.0 mu s for FRO-S (stimulated SFEMG for FRO). The false positive rates using these cut-off values were around 2%. Conclusions: The +2.5 SD and 95% prediction limit might be two optimal cut-off values, depending on the clinical question. The obtained reference values were larger than those reported previously using concentric needles, but might better coincide with conventional values. Significance: This is the first multicentre study reporting reference values for SFEMG using concentric needles. The way to determine cut-off values and the statistically correct definition of the percentile were discussed. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to alpha-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis.

Objective: To assess whether Awaji criteria improve the sensitivity of diagnosis for amyotrophic lateral sclerosis (ALS). In Awaji ALS criteria, fasciculation potentials are regarded as evidence of acute denervation in the presence of chronic neurogenic changes on needle electromyography. Methods: We reviewed clinical and neurophysiological data of 113 consecutive patients who were suspected as suffering ALS. The six muscles (trapezius, biceps, first dorsal interosseous, T10-paraspinalis, vastus lateralis, and tibialis anterior muscles) were examined by EMG, focusing on the presence of fasciculation potentials. The sensitivity of revised El Escorial (R-EEC) and Awaji criteria was compared. Results: Probable or definite ALS was diagnosed in 61% of the patients by R-EEC and 71% by Awaji criteria. By applying Awaji criteria; (1) 17 of the 44 patients categorized as possible ALS by R-EEC reached to probable/definite ALS, 11 of whom had bulbar onset, (2) in 48 patients with bulbar onset, the proportion of probable/definite ALS increased from 59% to 82%, (3) in 62 patients with limb onset, the proportion of probable/definite ALS was 61% (63% by R-EEC). Conclusions: Awaji criteria improve the sensitivity of ALS diagnosis in patients with bulbar onset, but not in those with limb onset. Significance: Accepting fasciculation potentials as evidence of acute denervation increases the diagnostic sensitivity of ALS, particularly in patients with bulbar onset, and contributes to early diagnosis. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Objective: To report the clinical features and recovery patterns of patients with non-thyrotoxic acquired hypokalemic paralysis. Methods: The clinical and laboratory records of 11 consecutive patients with acquired non-thyrotoxic hypokalemic paralysis were reviewed and compared with those of 3 patients with thyrotoxic periodic paralysis (TPP). The causes of potassium wasting were diarrhea (n = 4), alcohol abuse (n = 2), pseudoaldosteronism (n = 2), primary aldosteronism (n = 1), distal renal tubular acidosis associated with Sjogren's syndrome (n = 1) and an unknown cause (n = 1). Results: Three of the 11 patients had prominently asymmetric limb weakness, and 2 had predominant upper limb weakness. On admission, mean serum potassium and creatine kinase (CK) levels of patients with acquired hypokalemic paralysis on admission were 1.8 mEq/L and 4,075 U/mL, respectively, and the mean duration between admission and independent walking was 6.8 days (range, 2-31 days). Despite clinical recovery, 10 patients still presented with increased CK levels after several days (mean of maximum levels, 10,519 U/mL). In addition, normalization of serum potassium levels in patients with acquired hypokalemic paralysis patients was much slower compared to that in patients with TPP. One patient with acquired hypokalemic paralysis developed ventricular fibrillation, whereas all 3 patients with TPP had symmetric proximal and lower limb-dominant weakness and exhibited complete recovery from paralysis as well as normalized serum potassium levels within 24 h. Conclusions: In patients with acquired non-thyrotoxic hypokalemic paralysis, asymmetric or upper limb-dominant weakness of the extremities is observed. Despite clinical improvement after treatment, normalization of serum potassium and CK levels is often delayed, and therefore, careful monitoring for cardiac and renal complications is required. (C) 2011 Elsevier B.V. All rights reserved.

A pivotal role of c-jun N-terminal kinase (INK) on neuronal apoptosis has been demonstrated in a rodent stroke model. MAP kinase phosphatase 1 (MKP-1) is an archetypal member of the dual-specificity protein phosphatase (DUSP) family, which inactivates mitogen-activated protein kinase (MAPK) including JNK through dephosphorylation. MKP-1, one of immediate early genes in stress conditions, was induced at transcriptional level in hypoxia/re-oxygenation (H/R) in neuroblastoma N1E115 cells, however the activation of JNK was not suppressed in the acute phase of re-oxygenation. Small interference RNA-mediated knock-down of MKP-1 enhanced phospho-JNK and neuronal death that is rescued by INK inhibitor in H/R. Conversely, conditional over-expression of MKP-1 suppressed phospho-JNK, the expression of proapoptotic genes, and neuronal death in H/R. Further the immunoreactivity of MKP-1 was detected in the neurons and partially co-localized with that of phospho-JNK in the surrounding zone of ischemia in rat MCA-O (middle cerebral artery occlusion) reperfusion model. These findings indicate that over-expression of MKP-1 could suppress neuronal death possibly through regulating JNK signaling in vitro and be a prominent neuroprotective target for the treatment of acute cerebral infarction. (C) 2011 Elsevier B.V. All rights reserved.

A 58-year-old immunocompetent man gradually developed loss of appetite, cognitive decline, gait disturbances, and personality changes over 4 months. Brain magnetic resonance imaging (MRI) revealed bilateral diffuse leukoencephalopathy without mass formation on admission. His condition progressively deteriorated, and we treated him with intravenous high-dose steroids. His symptoms improved rapidly, but exacerbated when therapy was withdrawn. A brain biopsy was performed, and the diagnosis of primary central nervous system lymphoma (PCNSL) was confirmed. He was successfully treated with high-dose methotrexate therapy. Although it is difficult to diagnose PCNSL without mass formation in the early stages, steroid responsiveness is important and brain biopsy is essential for the correct diagnosis of PCNSL.

Background POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome is a rare cause of demyelinating and axonal mixed neuropathy with monoclonal plasma cell proliferative disorder and multiorgan involvement. The pathogenesis of POEMS syndrome is not well understood, but overproduction of vascular endothelial growth factor (VEGF), probably secreted by plasmacytomas, is likely to be responsible for most of the characteristic symptoms. POEMS syndrome is a potentially fatal disease, and patients' quality of life deteriorates because of progressive neuropathy, massive pleural effusion or ascites, or thromboembolic events. There is a need for efficacious therapy to improve prognosis. This is the first update of a review first published in 2008. Objectives To assess the effects of treatment for POEMS syndrome. Search methods We searched the Cochrane Neuromuscular Disease Group Specialized Register (23 February 2012), CENTRAL (2012, Issue 2), MEDLINE (January 1966 to February 2012), EMBASE (January 1980 to February 2012) and CINAHL Plus (January 1937 to February 2012) for all papers on POEMS syndrome Selection criteria We sought all randomized and quasi-randomized controlled trials, and non-randomized controlled studies. Since we discovered no such clinical trials, we assessed and summarized all retrospective case series including five or more patients in the 'Discussion' section. Data collection and analysis Two review authors independently reviewed and extracted details of all potentially relevant trials with any treatment for POEMS syndrome. We then collated and summarized information on the outcome. Main results We found no randomized or non-randomized prospective controlled trials of treatment for POEMS syndrome. We summarized the results of retrospective case series containing five or more patients in the 'Discussion' section. Authors' conclusions There are no randomized or quasi-randomized controlled clinical trials of treatment for POEMS syndrome on which to base practice.

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of &lt sup&gt 13&lt /sup&gt CO2 excretion (Tmax) in the &lt sup&gt 13&lt /sup&gt C-acetate breath test and was assessed in patients with and without administration of 100-150mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of &lt sup&gt 13&lt /sup&gt CO2 excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of &lt sup&gt 13&lt /sup&gt CO2 excretion (Tmax) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6±22.7min and 42.5±13.6min, respectively (P=not significant), thus demonstrating levodopa resistance. The peak time of &lt sup&gt 13&lt /sup&gt CO2 excretion (Tmax) values without and with subthalamic deep brain stimulation after surgery were 44.0±17.5min and 30.0±12.5min (P&lt 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the &lt sup&gt 13&lt /sup&gt CO2 excretion curve was also significantly improved relative to surgery with no stimulation (P=0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of &lt sup&gt 13&lt /sup&gt CO2 excretion (Tmax) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in Tmax values (ΔTmax) in the subthalamic deep brain stimulation trial after surgery (r=-0.20), and no association between changes in other characteristics and ΔTmax post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease. © 2012 The Author.

Objective: The aim of this study is to develop a novel method to assess activity-dependent hyperpolarization in human single motor axons at a constant stimulus frequency by using intra-muscular axonal stimulating single fiber electromyography (s-SFEMG). Methods: We performed s-SFEMG in the extensor digitorum communis (EDC) muscle of 10 normal subjects, and measured changes in latencies for single muscle fiber action potentials (MAPs) during 500 stimuli delivered at 5, 10 and 20 Hz. The data were analyzed with a repeated measurement analysis, and multiple comparisons were performed. Results: A total of 585 MAPs were examined at 5 Hz (n = 190), 10 Hz (n = 210), and 20 Hz (n = 185) steady stimulation. There was a progressive linear prolongation of latencies, as the stimulus rate increased (F = 95.6, p < 0.001); the least square means (SEM) of latency change were 100.7 (0.28)% at 5 Hz, 102.3 (0.27)% at 10 Hz and 105.3 (0.28)% at 20 Hz. There were statistically significant differences between frequencies by Tukey-Kramer's method. Despite the significant latency prolongation, no activity-dependent conduction block developed. A 20 Hz electric stimulation to intramuscular axons was well-tolerated in all the subjects. Conclusions: Tetanic stimulation at a constant rate results in significant latency increase in single human motor axons, the extent of which depends on the stimulus frequency. The findings imply that physiological discharge rates will activate the Na(+)/K(+) pump and thereby produce axonal hyperpolarization in single motor axons. Significance: This technique may detect activity-dependent conduction block if the safety margin of impulse transmission is significantly reduced by demyelination or increased branching due to collateral sprouting in a variety of neuromuscular disorders. (C) 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Background Urinary dysfunction is common in Parkinson's disease (PD); however, little is known about urinary dysfunction in early and untreated PD patients.Methods Fifty consecutive untreated PD patients (mean age, 66.7; mean disease duration, 23.6 months; and mean Hoehn & Yahr scale, 1.9) were recruited; those with other conditions that might have influenced urinary function were excluded. Patients were evaluated using a urinary questionnaire and urodynamic studies.Results Sixty-four per cent complained of urinary symptoms (storage, 64.0%; voiding, 28.0%). Urodynamic studies showed abnormal findings in the storage phase in 84%, with detrusor overactivity (DO) and increased bladder sensation without DO in 58.0% and 12.0% of patients, respectively. In the voiding phase, detrusor underactivity, impaired urethral relaxation such as detrusor sphincter dyssynergia, and bladder outlet obstruction were present in 50.0%, 8.0% and 16% of patients, respectively. In patients with both storage and voiding phase abnormalities, DO+detrusor underactivity was the most common finding. Few patients experienced urge incontinence and/or quality-of-life impairment owing to urinary dysfunction; none had low-compliance bladder or abnormal anal-sphincter motor unit potential. These urinary symptoms and urodynamic findings were not correlated with gender, disease severity or motor symptom type.Conclusion Urinary dysfunction, manifested primarily as storage disorders with subclinical voiding disorders and normal anal-sphincter electromyography, occurs in early and untreated PD patients. In cases with severe voiding disorder and/or abnormal anal-sphincter electromyography, other diagnoses should be considered.

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), suggesting abnormally increased excitability of motor axons. Previous nerve excitability studies have shown reduced axonal potassium currents in ALS patients that may contribute to the hyperexcitability and thereby generation of fasciculations. To clarify changes in axonal ion channel expression in motor axons of ALS, we performed immunohistochemistry of potassium and sodium channels in the C7 and L5 ventral/dorsal roots obtained from five autopsy cases of sporadic ALS. Compared to controls, the immunoreactivity of potassium channels (Kv1.2) was markedly reduced in the ventral roots, but normal in the dorsal roots of all the ALS patients. Nodal sodium channel expression was not significantly different in ALS patients and control subjects. Our results show prominently reduced expression of axonal potassium channels, and provide the neuropathological and biological basis for decreased accommodative potassium currents in motor axons of ALS patients. The axonal hyperexcitability would lead to generation of fasciculations, and possibly enhances motor neuron death in ALS. (C) 2011 Elsevier Inc. All rights reserved.

Neuromyelitis optica (NMO) is an acute inflammatory disease that preferentially involves the optic nerves and spinal cord. Although many infectious agents, including mumps virus, are postulated to have a role in the pathogenesis of multiple sclerosis (MS), the relationship between NMO and infectious agents remains uncertain. To investigate the relationship between NMO and viruses that have special affinity for the central nervous system, we performed a nested polymerase chain reaction (PCR) to detect mumps virus or enterovirus RNA in cerebrospinal fluid samples from 13 patients with MS, 8 with NMO and 20 with other neurological diseases (ONDs). Nested PCR was positive for mumps virus in 2 (25%) of NMO patients, but in none of those with MS and ONDs. Moreover, nested PCR results became negative in the remission phase in the two PCR-positive NMO patients. Mumps virus may have some role in the pathogenesis of NMO.

Objectives: To study the utility of muscle ultrasound (US) for detection of fasciculations and its contribution to diagnosis in amyotrophic lateral sclerosis (ALS). Fasciculations are characteristic features of ALS, and US can detect them easily and reliably. New diagnostic criteria for ALS, the Awaji algorithm, reintroduced fasciculations as evidence of acute denervation equivalent to that of fibrillations and positive sharp waves. Methods: In 81 consecutive patients with sporadic ALS, we prospectively performed needle EMG and US in 6 muscles (tongue, biceps brachii, first dorsalis interosseous, paraspinalis, vastus lateralis, and tibialis anterior), and diagnostic category were determined by revised El Escorial criteria and Awaji criteria. Results: Fasciculations were much more frequently detected by US than by EMG in the tongue (60% vs 0%), biceps brachii (88% vs 60%), and tibialis anterior muscles (83% vs 45%). The proportion of the patients with definite or probable ALS was 48% by revised El Escorial criteria and 79% by Awaji criteria using US. Conclusions: Muscle US is a practical and efficient tool to detect fasciculations, particularly in the tongue. A combination of US and EMG substantially increases the diagnostic sensitivity of ALS. Neurology (R) 2011;77:1532-1537

Objective: Sweating on the palms of the hands and soles of the feet, so-called emotional sweating, is considered to be mediated by the limbic system, including the amygdala and anterior cingulate cortex. To reveal involvement of the limbic system in emotional sweating, we evaluated emotional sweating on the palms in patients with limbic encephalitis. Methods: Sweat and skin vasoconstriction responses to arousal stimuli were recorded on the palms of 7 patients with limbic encephalitis caused by viral infection (n = 3) or immune-mediated encephalitis (n = 4). All patients had amnesia, and magnetic resonance imaging revealed mesial temporal lobe lesions, including those on the amygdala, in 6 of these patients. Results: Sweat responses were absent or markedly reduced in patients with limbic encephalitis compared to normal controls following deep inspiration (p<0.05), mental arithmetic (p<0.01), exercise (p<0.05), and tactile stimulation (p<0.01). Skin vasoconstriction responses in these patients were also impaired, but the extent of such impairment was mild compared to that of the sweating reductions. Conclusion: Sweating on the palm was significantly impaired in patients with mesial temporal lesions. Sweating on the palm could be a useful index of limbic function. (C) 2011 Elsevier B.V. All rights reserved.

Objective: To evaluate the degree of blood-brain barrier disruption in patients with neuromyelitis optica (NMO) and to clarify whether the levels of soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) in patients with NMO can be useful biomarkers for blood-brain barrier breakdown. Design: Descriptive historical cohort. Setting: Department of Neurology, Graduate School of Medicine, Chiba University. Patients: The levels of sICAM-1 and sVCAM-1 in 25 patients with NMO, 21 patients with multiple sclerosis, and 20 patients with other noninflammatory neurologic disorders in the serum and cerebrospinal fluid (CSF) were measured using a multiplexed fluorescent magnetic bead-based immunoassay. Main Outcome Measures: Levels of the soluble adhesion molecules in serum and CSF and their associations with blood-brain barrier disruption. Results: The CSF levels of sICAM-1 and sVCAM-1 increased in patients with NMO compared with patients with multiple sclerosis and other noninflammatory neurologic disorders (P < .001), and serum levels of sICAM-1 increased in patients with NMO compared with healthy control individuals (P = .003). The CSF sICAM-1 levels from patients with NMO were correlated with the albumin quotient (P = .02) and the presence of lesions detected via gadolinium-enhanced magnetic resonance imaging. Conclusions: Severe blood-brain barrier breakdown occurs in patients with NMO. Measuring adhesion molecules is useful to evaluate this barrier disruption.

The neuromuscular junction (NMJ) is a specialized synapse with a complex structural organization. Muscle contraction involves several steps: (1) nerve conduction to depolarize the motor nerve terminals, (2) opening of voltage-gated calcium channels (VGCCs) in the presynaptic membrane, (3) generation of endplate potential in the postsynaptic membrane via acetylcholine receptors, (4) depolarization of muscle sodium channels, and (5) excitation-contraction (E-C) coupling. Each step can be affected by various diseases. Guillain-Barre syndrome involves distal axons and possibly the presynaptic NMJ. The abnormalities can be detected by nerve conduction studies and single-fiber electromyography (SFEMG). Myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) antibodies, is the most common NMJ disorder, and ∼5% of myasthenia patients are positive for anti-muscle specific kinase (MuSK) antibodies. Patterns and severity of neuromuscular transmission failure detected by repetitive nerve stimulation test and SFEMG are somewhat different in AChR-MG and MuSK-MG. Excitation-contraction (E-C) coupling can be affected by MG, possibly via antibodies against ryanodine receptors. The E-C coupling time can be assessed with an accelerometer. Lambert-Eaton myasthenic syndrome is caused by antibodies against presynaptic VGCCs. This review will focus on neurophysiological testing, including SFEMG, and measurements of E-C coupling time with an accelerometer. In addition to confirming or excluding the diagnosis, these techniques can provide new insights into the pathophysiology of a variety of neuromuscular disorders.

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

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is currently classified into "typical CIDP" and other variants, such as "multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)". Typical CIDP is a classic form, clinically characterized by symmetric proximal and distal muscle weakness and motor-dominant manifestation. In typical CIDP, demyelination predominantly affects the distal nerve terminals and nerve roots, presumably because of the lack of the blood-nerve barrier in these regions, and this could be responsible for the "non-nerve length-dependent" distribution of muscle weakness. Furthermore, the safety factor of impulse transmission is physiologically lowered by axonal branching in the intramuscular motor nerves, and therefore, conduction block develops more readily in motor axons than in sensory axons, leading to motor-dominant polyneuropathy in typical CIDP. These findings suggest the importance of humoral immunity in typical CIDP. In contrast, MADSAM is characterized by multifocal demyelination in the intermediate nerve trunks with preservation of the nerve terminals/roots, and such distribution of lesions should result in multiple mononeuropathy or asymmetric polyneuropathy. In MADSAM neuropathy, cellular immunity might be predominantly involved in the breakdown of the blood-nerve barrier at the site of the conduction block. Clinical features are likely to be determined by the distribution of demyelinative lesions, and probably reflect the different immunopathogenesis of each CIDP subtype. This review focuses on clinical-electrophysiological correlation in the subtypes of CIDP. © 2011 Japanese Society for Neuroimmunology.

Objective: Pathological studies showed both pontine transverse (cortico-ponto-cerebellar) and longitudinal (corticospinal) fibers degenerate in MSA. The objective was to investigate the association between the development of cross sign, degenerations of pontine fibers, and the frequency of pyramidal signs in MSA. Methods: Patients with MSA (n = 26) and healthy subjects (n = 27) were enrolled in this study. Whole pontine transverse and longitudinal fibers were individually traced by diffusion tensor tractography. FA was calculated along each entire tractography. Cross sign was graded as: 0, no cross sign; 1, anterior-posterior line only; and 2, complete cross sign. T2-hyperintense MCPs was graded as: 0, no change; 1, slight signal change; and 2, severe signal change. FA of pontine fibers in MSA patients and that in healthy subjects was statistically evaluated by ANOVA with an overall statistical significance level of 0.05. The frequency of pyramidal signs in MSA was compared between each cross and MCP grade. Results: FA of pontine transverse fibers in MSA patients decreased with the development of cross sign. FA of Cross 2 was significantly lower than that of healthy subjects (p = 0.003). As regards pontine longitudinal fibers, FA decreased when cross sign was completed. The frequency of pyramidal signs in MCP 2 and 1 was higher than that in MCP 0. Conclusion: Pontine transverse fibers degenerate as cross sign develop, and degenerations of pontine longitudinal fibers begin, or even accelerate when cross sign becomes apparent. Pyramidal signs are frequently present when T2-hyperintense MCPs are clearly observed. (C) 2011 Elsevier B.V. All rights reserved.

In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.

TAR DNA binding protein of 43 kDa (TDP-43) is likely to be the major pathogenetic protein in amyotrophic lateral sclerosis (ALS). A previous study has shown that levels of TDP-43 in CSF measured by an ELISA are significantly higher for ALS patients than for controls. The aim of this study was to investigate whether elevated CSF TDP-43 levels are specific to ALS, and are associated with clinical profiles in ALS patients. We measured CSF TDP-43 levels by the same ELISA in 27 ALS patients and 50 neurodegenerative or inflammatory disease controls such as Parkinson's disease, multiple sclerosis, and Guillain-Barre, syndrome. Results showed that the CSF TDP-43 levels were increased only in ALS patients. Receiver operating characteristic (ROC) analyses showed a sensitivity of 59.3% and a specificity of 96.0%. We also found that lower CSF TDP-43 levels may be associated with shorter survival time. In conclusion, the CSF TDP-43 is a potential biomarker that supports a diagnosis of ALS. Moreover, among ALS patients, lower levels of CSF TDP-43 may reflect the accumulation of TDP-43 in the cortical and spinal motor neurons and thereby shorter survival time, although this should be confirmed in larger prospective studies.

Nerve conduction slowing in amyotrophic lateral sclerosis (ALS) is usually caused by loss of fast motor axons. We studied the frequency, extent, and distribution of prominently prolonged distal motor latencies in ALS. We reviewed results of median, ulnar, and tibial nerve conduction studies in 91 patients with ALS, 24 with lower motor neuron disorders, and 36 with axonal neuropathy. Coincidental carpal tunnel syndrome was found for 4 (4.4%) of the ALS patients who were excluded from analyses. Markedly prolonged distal latencies (>125% of the upper limit of normal) were found only in the median nerve of ALS patients (9%), and in none of the disease controls. Excitability studies suggested membrane depolarization in some ALS patients. Our results show that approximately 10% of ALS patients shows prominently prolonged median distal latency, which cannot be explained by axonal loss and carpal tunnel lesion. The distal nerve conduction slowing may partly be caused by membrane depolarization possibly due to motor neuronal degeneration in ALS. We suggest that recognition of the pattern of distal motor axonal dysfunction predominant in the median nerve is clinically important, and could provide additional insights into the pathophysiology of ALS. (C) 2010 Elsevier B.V. All rights reserved.

Fisher syndrome is characterized by the clinical triad of ophthalmoplegia, ataxia, and areflexia. It is considered a variant form of Guillain-Barre syndrome, which is associated with anti-GQ1b antibodies. During initial examinations of patients, physicians must rule out other neurologic disorders or conditions that resemble Fisher syndrome, such as vitamin B1 deficiency (Wernicke's encephalopathy), vascular disease, multiple sclerosis, collagen disease, Behcet disease, sarcoidosis, neoplasm of the brainstem, and infectious diseases such as diphtheria, botulism, and viral infections (eg, herpes encephalitis). The acute phase of Fisher syndrome should be carefully observed to see if it occurs concomitantly with Guillain-Barre syndrome or if there is development to Bickerstaff brainstem encephalitis, as these require specific immune treatments. Typically, Fisher syndrome has a fairly good natural course. Although several reports have suggested the possible efficacy of immunotherapies such as plasmapheresis and intravenous immunoglobulins (IVIg) in treating Fisher syndrome, there have been no randomized controlled studies. Large retrospective studies have suggested that neither plasmapheresis nor IVIg alters the clinical outcome of patients with Fisher syndrome, probably because of the good spontaneous recovery in these patients. Therefore, Fisher syndrome alone does not necessarily require immunotherapy. To accelerate the start of recovery, IVIg can be given, but it is important to first obtain informed consent from patients after the potential risks of blood products are explained. When overlap with Guillain-Barre syndrome or development to Bickerstaff brainstem encephalitis occurs, plasma exchange or IVIg should be administered as early as possible because Guillain-Barre syndrome can cause respiratory failure or severe weakness with axonal degeneration, and Bickerstaff brainstem encephalitis may not have as good a natural course as Fisher syndrome alone. There have been no prospective, controlled studies (randomized or nonrandomized) of the use of immunotherapy to treat Fisher syndrome. To evaluate the efficacy of immunotherapies used to treat Fisher syndrome, large prospective studies are required.