植田 晃広

A 47-year-old man with a subdural abscess was initially diagnosed with endogenous depression at another hospital. He presented with a chronic illness, but without any typical symptoms, such as headache and fever. Antidepressants were ineffective and brain magnetic resonance imaging showed areas of abnormal high-signal intensity along the surface of the bilateral frontoparietal lobes. We diagnosed him with a subdural abscess based on magnetic resonance imaging and cerebrospinal fluid findings, which was successfully managed with antibiotic treatment alone. This case highlights the possibility that depressive state can be an initial symptom of a subdural abscess.

Background: Although most patients with Parkinson's disease (PD) show decreased cardiac I-123-metaiodobenzylguanidine (MIBG) uptake, some exhibit normal uptake. We evaluated the clinical characteristics of such patients. Methods: We enrolled 154 non-demented patients showing parkinsonism with normal cardiac MIBG uptake and had been clinically followed up during 29.9 +/- 27.6 months. We defined the patients who did not fit the exclusion criteria for PD and demonstrated >= 30% reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score after anti-Parkinson agent administration as probable PD. We compared clinical characteristics and the cardiac MIBG heart-to-mediastinum (H/M) ratio between the probable PD group (N = 37) and other groups (N = 117). Results: The probable PD group showed significantly higher UPDRS motor scores and greater incidence of tremor/rigidity than those of other groups. In addition, they showed a significantly lower cardiac MIBG HIM ratio in the delayed phase (delayed, p < 0.0001). Washout-rate (WR) was significantly higher in probable PD cases (p < 0.0001). Among 16 probable PD patients undergoing serial cardiac MIBG scintigraphy, the delayed phase cardiac MIBG H/M ratio showed a significant decrease and WR significantly increased during follow-up periods. Conclusions: An increase in WR and lower delayed phase cardiac MIBG uptake were found to be characteristics of such patients. (C) 2015 Elsevier B.V. All rights reserved.

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

A 74-year-old woman was hospitalized due to dysuria, weakness and dysesthesia of the lower extremities. She was in an immunosuppressed state following the administration of methylprednisolone therapy for idiopathic interstitial pneumonia. Cerebrospinal fluid and blood cultures were negative, and no infectious biomarkers were found. A gadolinium (Gd)-enhanced T1-weighted image of magnetic resonance imaging (MRI) revealed disseminated nodular lesions along the spinal cord. We suspected a diagnosis of seronegative deep mycosis and initiated anti-fungal therapy with voriconazole, which subsequently alleviated all of the patient's symptoms and MRI findings. Therefore, the presence of Gd-enhanced disseminated nodules on spinal MRI may be a good marker of deep meningeal mycosis.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are presumed to be an autoimmune disease in the central nervous system (CNS). Although lipids are most abundant components in the nervous system, it has been believed that cellular and/or humoral immunity to various myelin proteins causes these neuroinflammatory diseases. Recent research advances enable us to study lipids in the membranes and some key molecules involved in various neurological disorders including Guillain-Barre syndrome, Alzheimer's disease, Parkinson's disease, and prion disease, are localized in lipid rafts. In MS and NMO, the key molecules for the pathogenesis or the target molecules for the treatments of MS and NMO are also localized in lipid rafts. Here in this article, we highlight on the possible involvement of lipid rafts in the pathogenesis and treatment of MS and NMO and introduce our recent observation of aquaporin 4 regarding NMO.

Activation of the high-affinity nerve growth factor (NGF) receptor Trk occurs through multiple processes consisted of translocation and clustering within the plasma membrane lipid rafts, dimerization and autophosphorylation. Here we found that a nonprotein extract of inflamed rabbit skin inoculated with vaccinia virus (Neurotropin (R)) enhanced efficiency of NGF signaling. In rat pheochromocytoma PC12 cells overexpressing Trk (PCtrk cells), Neurotropin augmented insufficient neurite outgrowth observed at suboptimal concentration of NGF (2 ng/mL) in a manner depending on Trk kinase activity. Cellular exposure to Neurotropin resulted in an accumulation of Trk-GM1 complexes without affecting dimerization or phosphorylation states of Trk. Following NGF stimulation, Neurotropin significantly facilitated the time course of NGF-induced Trk autophosphorylation. These observations provide a unique mechanism controlling efficiency of NGF signaling, and raise the therapeutic potential of Neurotropin for various neurological conditions associated with neurotrophin dysfunction. (C) 2014 Elsevier B.V. All rights reserved.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system and is considered to be caused by the binding of NMO-IgG to aquaporin 4 (AQP4) on astrocytes, which initiates complement-dependent cytotoxicity. AQP4 has two isoforms, i.e., M1 and M23. AQP4 is considered to form heterotetramers containing both isoforms in vivo. Most of the previous studies were performed using either one of the isoforms expressing cell lines. In this study, we generated a fluorescent epitope-tagged AQP4 M1 and M23 co-expressing astrocyte cell line and examined the subcellular targeting of AQP4. In this cell line, AQP4 was targeted mostly to membrane lipid rafts fraction evidenced by sucrose density gradient ultracentrifugation followed by Western blotting with anti-AQP4 antibody. Cholesterol depletion with methyl-beta-cyclodextrin or simvastatin resulted in the dislocation (relocation) of AQP4 from lipid rafts to non-rafts fraction of the membrane and AQP4 was not internalized intracellularly. This change in the localization of AQP4 on membrane significantly reduced complement-dependent cytotoxic effects of NMO-IgG obtained from patients with NMO without affecting AQP4 orthogonal arrays. Thus, these data strongly suggest that the targeting of AQP4 in the lipid rafts is closely related to the pathogenic effects of NMO-IgG. (C) 2014 Elsevier B.V. All rights reserved.

我々は、亜急性軸索障害型ニューロパチーの一部の患者の血清中にNGFの高親和性受容体であるTrk蛋白に対する抗体が出現してくる事を報告した。現在まで、当科で経験した自験2例は、共に非Hodgkin B細胞リンパ腫の既往があり、亜急性にの感覚障害を中核症状とする軸索型ニューロパチーが出現し、IVIg療法に程度の差はあるものの一定の効果を認めた。抗Trk抗体の検出は、PC12細胞にTrkを高発現させたPCtrk細胞のcell-free lysateを市販の抗Trk抗体で免疫沈降し、患者血清でWestern blot(WB)し陽性バンドを検出した。また、細胞のcell-free lysateを治療前後の患者血清で免疫沈降し、その免疫沈降物を市販の抗Trk抗体でWBしで陽性バンドを検出した。亜急性軸索障害型ニューロパチーで原因が明らかでない場合、特に非Hodgkin B細胞リンパ腫の既往のある場合には、抗Trk抗体の検索も考慮すべきと考えられた。(著者抄録)

Objective:The aim of this study was to review 4 patients with encephalomyeloradiculoneuropathy (EMRN) and assess for autoantibodies against neutral glycolipids.Methods:We studied the progression of clinical, radiologic, neurophysiologic, and CSF findings, as well as anti-neutral glycolipid antibodies in sera.Results:All patients developed acute or subacute motor weakness and impaired consciousness. Their CSF showed pleocytosis and high immunoglobulin G concentrations. MRI revealed lesions in the brain and spinal cord. Neurophysiologic examinations indicated dysfunction of the spinal cord, nerve roots, and peripheral nerves. Steroid pulsed immunotherapy and/or high dose of IV immunoglobulin replacement therapy resulted in clear and often dramatic clinical improvements. Reactivity to anti-neutral glycolipid antibodies was positive in all patients with acute EMRN but not in the recovery phase. Forty-seven age-matched patients with other neurologic disorders and 28 age-matched healthy volunteers tested negative for reactivity to anti-neutral glycolipid antibodies.Conclusion:The resolution of radiologic and neurologic abnormalities and altered autoantibody titers against neutral glycolipids after immunotherapy suggest that EMRN is caused by an immune-mediated mechanism. These autoantibodies may be useful biomarkers for EMRN.

要旨：61歳の右利き男性で，漢字にほぼ限局した漢字失書の1例を経験したので報告した．左角回から側頭葉にかけての深部白質の脳梗塞の発症約1カ月後と考えられる初診時には，ほぼ純粋な漢字失書を呈していた．発症1カ月後と6カ月後に小学校1，2学年で習得する漢字を用いて失書の程度と回復の過程を評価した．本例では，発症6カ月後には漢字失書はほとんど回復していた．また，漢字失書の分類では既報の左側頭葉後部障害例に認められているように想起困難が多く，次いで類形性錯書を認めた．漢字失書は画数の多い漢字に強い傾向が認められた．本例は，既報例と異なり語形認知領域(visual word form area)とされている左側頭葉後部から側頭葉底面の紡錘状回よりやや離れた頭頂葉よりの部分の白質での脳梗塞で漢字失書を認めており，漢字失書の発症機序を考える上で重要な症例と考えられた．

Viral encephalitis is still a life-threatening disease occurring at any age. It is critical to make a rapid and correct diagnosis for a better outcome of the disease. Accumulating evidence has suggested that MRI is a powerful tool for the detection of any lesion of the CNS caused by viral infections and helps to initiate the timely treatment. In this review, we summarize the current understanding of MRI findings of viral encephalitis, especially related to HSV, HIV, varicella zoster, Japanese encephalitis, John Cunningham, and influenza viruses. With these considerations, we learnt that the inclusion of diffusion-weighted image sequences on routine MRI examination would have a significant value in detecting the pathologic changes that occur following viral invasion of the CNS.

Hypertrophic pachymeningitis (HP) is thought to have an autoimmune etiology but its precise cause and treatment remains to be elucidated. Here, we report the clinical details and therapeutic responses of 3 patients with HP and reviewed 66 previously reported cases in the literature. Among these patients, headache was the most frequent complaint. Cranial nerve involvement was also frequently observed, with the optic nerve being the most frequently impaired followed by the oculomotor, trochlear, and abducens nerves in frequency. Elevated C-reactive protein levels and erythrocyte sedimentation rates were found in approximately 97% of the patients. Steroids were the most commonly prescribed therapy, but no definite protocols for the standard dose and duration in HP have been proposed thus far. The average initial dose of prednisolone (PSL) was 42.7 mg/day, and the average maintenance dose was 12.4 mg/day in the chronic stage. Recurrence occurred in many patients when the dose of PSL was reduced to under 20 mg/day. Therefore, steroids should be tapered extremely slowly.

POEMS症候群は形質細胞の増殖異常と多発神経炎を中核とした多臓器病変を伴う疾患である．症例は32歳男性．倦怠感を機に副腎皮質機能低下症と診断されコートリルが投与されたが，諸症状の改善を認めず精査入院となった．その後POEMS症候群と診断，自己末梢血幹細胞移植を施行された．内分泌障害を機に診断されたPOEMS症候群の1例であり移植後軽快状態にあり，現在内分泌障害の改善を経過観察中である.<br>

A 26-year-old man was admitted to our hospital because of high fever, drowsiness, memory disturbance, and disorientation due to H1N1 influenza virus-associated encephalitis/encephalopathy. All of his symptoms rapidly improved following methylprednisolone pulse therapy. The diffusion-weighted image of brain magnetic resonance imaging (MRI) revealed a large transient hyperintense signal lesion on the central splenium of the corpus callosum. This MRI finding in conjunction with a complete clinical recovery has been previously observed in cases of clinically mild seasonal influenza-associated encephalitis/encephalopathy, and can be also a useful clue for the diagnosis of new type of influenza, H1N1 influenza virus infection complicated by encephalitis/encephalopathy.

Background: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. Methods: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. Results: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p &lt; 0.001 and p &lt; 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. Conclusion: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection. Copyright (C) 2011 S. Karger AG, Basel

Previous studies have shown that patients with the axonal form of Guillain-Barre syndrome (CBS) develop autoantibodies against GM1 ganglioside (GM1) Nerve growth factor (NGF) is essential for neuronal survival in vivo and its functional receptor is Trk-tyrosine kinase Here we examined the biological effects of sera from patients with the axonal form of GBS on the morphology and the phosphorylation state of Trk-tyrosine kinase in PC12 cells Furthermore we examined the effect of the sera on the integrity of membrane lipid rafts biochemically The data show that anti GM1 antibodies found in patients sera but not control sera inhibit NGF-induced Trk autophosphorylation Most intriguingly the autoantibodies alter the distribution of Trk in lipid rafts without shifting the distribution of a rafts marker protein These data strongly suggest that anti GM1 antibodies directly influence the integrity of the signaling platform lipid rafts implicating the importance of lipid rafts in the development of this disorder (C) 2010 Elsevier Inc All rights reserved

Innate immunity, especially that involving macrophage function, reportedly diminishes with advancing age and in patients with Alzheimer&apos;s disease (AD). In this study, we tried to elicit the non-specific activation of peripheral macrophages by oral administration of the herbal medicine Juzen-taiho-to (JTT), to assess its effect as a possible treatment for AD patients. Amyloid-beta protein precursor transgenic mice were used as a model of AD to clarify the effect of JTT. Activated macrophages derived from bone marrow cross the blood-brain barrier, and then develop into microglia, which phagocytose aggregated amyloid-beta (A beta) in senile plaques. Here we show that orally administered JTT increased the number of CD11b-positive ramified microglia in the mouse brain. The immunohistochemical examination of brain sections stained with polyclonal anti-A beta antibody showed reduced A beta burden, and A beta levels were also decreased in the insoluble fractions of brain homogenates, as determined by ELISA. Thus, the activation of peripheral macrophages by JTT might be a potential new therapeutic strategy for AD.

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. To investigate the mechanism of neurotoxicity of clioquinol, we used PC12 cell line and focused on nerve growth factor (NGF) signaling through Trk receptor, which is essential for survival and differentiation of neuronal cells. Clioquinol inhibited NGF-induced Trk autophosphorylation in a dose-dependent manner. This inhibitory activity was further confirmed by the data of the inhibition of NGF-induced mitogen-activated protein kinase (MAPK) phosphorylation, which is located in the down stream of NGF-Trk intracellular signaling pathway. Clioquinol also caused neurite retraction induced by NGF and cell death. NGF-stimulated (differentiated) cells were more vulnerable than naive cells. These results strongly suggest that choquinol may cause the perturbation of the intracellular survival pathway by inhibiting Trk-initiated signaling pathway. (C) 2009 Elsevier B.V. All rights reserved.

Acute autonomic, sensory and motor neuropathy (AASMN) is a rare peripheral nerve disorder characterized by prominent dysautonomia with somatic sensory and motor impairment. Dysautonomia in AASMN is intractable even with corticosteroid therapy or plasmapheresis. Here we report a case of AASMN with severe orthostatic hypotension. Although the effectiveness of corticosteroid was insufficient, high dose intravenous immunoglobulin therapy (IVIg) was effective for not only sensorimotor symptoms but also autonomic symptoms. This is the first case of AASMN showing favorable responses to IVIg treatment, suggesting that IVIg should be considered when corticosteroid therapy or plasmapheresis is ineffective or insufficient.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder dividing into two forms, early onset familial and late onset sporadic forms. Early onset genetic cases (familial AD (FAD)) constitute about 10% of all AD cases. Heretofore, highly fibrillinogenic and pathological Abeta peptide formation is regarded as the fundamental molecular basis for this disorder. Recent enormous efforts to find out a pathogenesis, however, have revealed that this disorder has a multiplicity of causes such as glycosphingolipids abnormalities, impairment of neurotrophin signaling, protein trafficking, and protein turnover. Most of these aspects were disclosed by the studies on FAD-related presenilin. In this review, we will focus on the current knowledge of many abnormal aspects of cellular lipids, especially glycosphingolipids other than a pathogenic Abeta production caused by the mutant presenilins as a model system. Moreover, we will discuss how these glycosphingolipids abnormalities cause the pathological conditions found in this disorder.