桑原 聡

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.

Background: Callosal lesions in multiple sclerosis (MS) are usually focal, involving the inferior aspect of the corpus callosum on brain magnetic resonance imaging (MRI), but little is known about callosal lesions in neuromyelitis optica (NMO). Objective: To clarify MRI abnormalities in callosal lesions of NMO. Methods: Japanese patients with NMO (n=28) or MS (n=22) were assessed. The distributions and appearances of callosal lesions were evaluated on a brain mid-sagittal T2-weighted image (T2WI) or a fluid-attenuated inversion recovery image with a I.5T MRI scanner. Logistic regression analysis identified which characteristics of the callosal lesions were useful for discriminating NMO from MS. Results: Callosal lesions were present in 79% of NMO and 82% of MS patients. Callosal abnormalities of NMO, including splenial lesions (57% in NMO versus 27% in MS, odds ratio (OR)=4.23, p=0.04), diffusely spreading lesions from the lower to upper edges of the corpus callosum (71% versus 23%, 0R=7.18, p=0.0024), and heterogeneous T2 hyperintense lesions (71% versus 9%, 0R=44.3, p=0.0006), were feasible for discriminating NMO from MS. Conclusion: Diffuse and heterogeneous T2 hyperintense splenial lesions were characteristic of NMO. These findings could help distinguish NMO from MS on MRI.

Postprandial hypotension (PPH) is a major clinical problem in patients with autonomic failure such as that observed in multiple system atrophy (MSA). The pathophysiology of PPH remains unclear, although autonomic dysfunction and gastrointestinal vasoactive peptides have been suspected to participate in its pathogenesis. We measured blood pressure and plasma levels of glucose, insulin, noradrenaline, neurotensin, glucagon-like peptide (GLP)-1 and GLP-2 before and after meal ingestion in 24 patients with MSA to reveal the roles of the autonomic nervous system and gastrointestinal vasoactive peptides in PPH. We performed a second meal-ingestion test by administering acarbose to evaluate the effects of acarbose (an alpha-glucosidase inhibitor) on PPH and vasoactive peptides in 14 patients with MSA and PPH. We also evaluated blood pressure responses to the head-up tilt test and heart rate variability in all the patients. Severities of PPH and orthostatic hypotension were significantly correlated. Patients with PPH had significantly worse orthostatic hypotension and lower heart rate variability than those without PPH. Postprandial GLP-1 secretion was higher in patients with PPH than in those without PPH. No significant differences were observed in the postprandial increases in plasma levels of glucose, insulin, noradrenaline, neurotensin or GLP-2. Acarbose significantly attenuated postprandial hypotension and tended to decrease GLP-2 secretion. Our results indicate that autonomic failure is involved in the pathogenesis of PPH and confirm that acarbose has a preventive effect against PPH in patients with MSA. Decreased postprandial secretion of GLP-2, which increases intestinal blood pooling, may attenuate PPH in patients with MSA.

STUDY DESIGN.: Retrospective clinical study. OBJECTIVE.: To report the surgical outcomes of patients with cervical myelopathy associated with athetoid cerebral palsy and to assess whether a halo vest is necessary for postoperative external immobilization. SUMMARY OF BACKGROUND DATA.: Although a halo vest has remained the first choice for postoperative external immobilization of patients with cervical myelopathy associated with cerebral palsy, simplification of this method has been attempted in recent years. Studies focusing on postoperative external immobilization are rare. METHODS.: Since 2001, 20 patients underwent surgery with posterior instrumented fusion or posterior fixation and anterior decompression with fusion with a year or longer follow-up. Before 2004, all patients were given a halo vest for postoperative external immobilization. After 2004, halo vests were not used, and when abnormal involuntary neck movements were severe, an intramuscular injection of botulinum toxin was administered before and after surgery. Surgical outcomes, surgical methods and complications were compared between the group that used a halo vest and the group that did not use a halo vest. RESULTS.: In the halo vest group, the average Japanese Orthopedic Association score was 6.9 points before surgery and 9.3 points at 1-year follow-up. The average recovery rate was 25.0%. In the group without halo vest use, the average Japanese Orthopedic Association score was 5.8 points before surgery and 9.9 points at 1-year follow-up. The average recovery rate was 35.7%. The group without halo vest use achieved outcomes equal to those achieved in the group with halo vest use. The frequency of complications was less without halo vest use than with halo vest use. CONCLUSION.: No inferiority in clinical outcomes was seen if postoperative halo vest use was omitted. Progress in surgical instrumentation and injection of botulinum toxin may explain this result. © 2013, Lippincott Williams &amp Wilkins.

Background A GGGGCC hexanucleotide repeat expansion in C9ORF72 occurs on a chromosome 9p21 locus that is linked with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in white populations. The diseases resulting from this expansion are referred to as 'c9FTD/ALS'. It has been suggested that c9FTD/ALS arose from a single founder. However, the existence of c9FTD/ALS in non-white populations has not been evaluated. Results We found two index familial ALS (FALS) patients with c9FTD/ALS in the Japanese population. The frequency of c9FTD/ALS was 3.4% (2/58 cases) in FALS. No patients with sporadic ALS (n=110) or control individuals (n=180) had the expansion. Neuropathological findings of an autopsy case were indistinguishable from those of white patients. Although the frequency of risk alleles identified in white subjects is low in Japanese, one patient had all 20 risk alleles and the other had all but one. The estimated haplotype indicated that the repeat expansion in these patients was located on the chromosome with the risk haplotype identified in white subjects. Conclusions C9ORF72 repeat expansions were present in a Japanese cohort of ALS patients, but they were rare. Intriguingly, Japanese patients appear to carry the same risk haplotype identified in white populations.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum levels of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vasopermeability, are considered to be responsible for the characteristic symptoms such as angiomata, pleural effusion/ascites, edema, and organomegaly in the disorder. To study whether other angiogenetic factors are upregulated in POEMS syndrome, we measured serum levels of basic fibroblast growth factor and hepatocyte growth factor (HGF), as well as VEGF, in 17 patients with POEMS syndrome. All these factors were significantly upregulated in the POEMS syndrome patients. After the treatment with anti-VEGF antibody, the levels of HGF did not change, suggesting that elevation of HGF levels is not secondary to VEGF overproduction. These results suggest that different angiogenetic factors might contribute to the pathogenesis of POEMS syndrome, and this fact might contribute to the insufficient clinical effects obtained by suppression of VEGF alone.

Pseudoperipheral palsy can be caused by cerebral cortical infarctions; however, it is rarely caused by lacunar infarctions, including those in the posterior limb of the internal capsule. Meanwhile, the somatotopic localization of the corticospinal tract in the posterior limb of the internal capsule remains unknown. We herein report the case of an 81-year-old Japanese woman who presented with a left hand drop. Brain magnetic resonance imaging revealed an acute infarction as the causative lesion at the inferior level of the anteromedial portion of the posterior limb of the right internal capsule. This case report indicates the topography of hand fibers in the internal capsule.

Objective The autoimmune mechanism is considered to play an important role in the development of acquired idiopathic generalized anhidrosis (AIGA), and muscarinic M3 receptors (M3Rs) on eccrine glands are possible autoimmune targets. We investigated the existence of autoantibodies against M3Rs in AIGA patients. Methods We immunostained M3R-expressing cultured cells with the serum of 12 AIGA patients (mean age: 35.0 +/- 11.7 years, mean disease duration: 26.6 +/- 25.8 months) and 10 healthy subjects (mean age: 32.4 +/- 10.4 years). Results The surface of the M3R-expressing cells was stained by the serum obtained from one of the 12 AIGA patients but not by the serum obtained from the remaining 11 patients or healthy subjects. Conclusion The presence of M3R autoantibodies may therefore be related to the underlying mechanism of disease in a subset of AIGA patients.

Objective: To study dynamic postural balance for Parkinson's disease patients, axial mobility and center of foot pressure (COP) were recorded simultaneously during movements of a head or chest. Materials and Methods: Fifteen patients with treated Parkinson's disease and age matched 15 volunteers with no neurological disease participated in this study. Head movements were monitored with a gyroscope on the head, and COP was monitored on a force platform. The subjects were standing upright on the platform and they were asked to rotate the head only alternatively repetitively, and then asked to rotate the chest and head synchronized alternatively repetitively. Both movements were asked to do at own pace for 20 sec, respectively, gazing at a cue synchronized to the head movements. Results: Head angular velocity showed significant differences for ratios of the peak power of the power spectra by the integrated power without the peak power between groups with PD and of volunteers (P &lt 0.0001), and between movements with the head only and with the head-thorax synchronized (P &lt 0.05). COP showed significant differences for the integrated power between groups with PD and of volunteers (P &lt 0.0001) and between movements with the head only and with the head-thorax synchronized (P &lt 0.0001). Conclusion: This simple and useful measurement might give numerical evaluation of axial rigidity for Parkinson's disease patients. © 2013 Japan International Cultural Exchange Foundation &amp Japan Health Sciences University.

Fisher syndrome has been regarded peculiar inflammatory neuropathy with ophthalmoplegia, ataxia, and areflexia, whereas Bickerstaff brainstem encephalitis has been considered pure central nervous system disease characterized with ophthalmoplegia, ataxia, and consciousness disturbance. Both disorder share common features including preceding infection, albumin-cytological dissociation, and association with Guillain-Barre syndrome. The discovery of anti-GQ1b IgG antibodies further supports the view that the two disorder represent a single disease spectrum. Currently Bickerstaff brainstem encephalitis can be regarded as a variant of Fisher syndrome with central nervous system involvement.