The Japanese Society of Neurological Therapeutics is pleased to announce the launch of an electronic version of the Society's journal. Beginning in 2016, the Society's journal will be open access and all manuscripts will be accessible in both PDF and HTML (XML) format on J–STAGE (Japan Science and Technology Information Aggregator, Electronic). Each manuscript will have a unique digital object identifier (doi) that provides a permanent link to the manuscript and facilitates citation by researchers anywhere in the world. Members of the Japanese Society of Neurological Therapeutics will receive regular emails that include the table of contents of new issues as well as other important information about the journal.

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Autoimmune encephalopathies are clinically and immunologically heterogeneous disorders. Over time, many different types of autoimmune encephalopathy have been discovered. In such clinical situations, we often recognize that patients with autoimmune encephalopathy are often misdiagnosed as exhibiting functional psychogenic movement, conversion, or somatoform disorders. We clinically analyzed 63 patients (14 males and 49 females; age range, 15–79 years) diagnosed with autoimmune encephalopathy in our hospital from 2013 to 2015. Throughout this period we diagnosed almost no conversion disorders in our department. These patients were diagnosed using the diagnostic criteria for each disease, following clinical features showing neurological symptoms of brain origin, responsiveness to immunosuppressive therapy, the existence of known pathological antibodies, and/or history of human papilloma virus (HPV) vaccination. Fourty–two patients showed motor disturbance (weakness, paresis of extremities, or slower pinching) and 35/42 (83.3％) patients showed give–way weakness, indicating disruption of continuous muscle contraction. Fourty–four patients showed sensory abnormalities such as strong pain, deep muscle pain, dysesthesia, paresthesia, or fast neurologic pain. Surprisingly, most pain was distributed in manner that was not explainable anatomically, while some patients also showed patchy, stocking–glove, or localized pain. Seventeen patients exhibited involuntary movements such as tremor entrainment, dystonia, or coarse involuntary movement. In most patients, such motor, sensory, or involuntary movements were markedly improved with immunosuppressive therapies such as prednisolone, azathioprine, or immune adsorption therapy. We observed memory loss, PNES (psychogenic non–epileptic seizure), dissociative amnesia, hyperventilation, opsoclonus, epilepsy, or autonomic symptoms amongst our patients. Although give–way weakness, anatomically unexplainable pain/abnormal sensation, and strange involuntary movements were thought to be psychogenic, the presence of one of these three symptoms was indicative of autoimmune encephalopathy. As autoimmune encephalitis exhibits diffuse involvement with the whole brain, these symptoms were entirely understandable. Except for the presence of organic disease, most patients were classified into somatoform disorders (DSM–IV, ICD–10) or functional movement disorders. Without first excluding autoimmune encephalopathy, we propose that physicians should not diagnose somatoform disorders. Since autoimmune encephalopathy patients often possess so–called psychogenic signs, it is possible that such signs might be generated by autoimmune encephalopathy instead of somatoform disorders. In conclusion, we propose that give–way weakness and anatomically unexplainable pain/abnormal sensation are key symptoms of autoimmune encephalopathy. We hope that many patients with autoimmune encephalopathy will now be identifiable using our new neurological examination and that each patient can be given an exact diagnosis and therefore be administered with the appropriate treatments.

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A. Non–herpetic acute limbic encephalitis & anti–NMDAR encephalitis
 Non–herpetic acute limbic encephalitis is diagnosed with the characteristic onset symptom of limbic system and absence of herpes simplexes virus in CSF. Anti–NMDAR encephalitis is diagnosed with presence of antibodies to complex of NMDA–type GluR subunits by cell–based assay. Non–herpetic acute limbic encephalitis & anti–NMDAR encephalitis are causally related with antibodies to NMDA–type GluR, which internalize complex of NMDA–type GluR subunits on neural cell surface. Internalization may lead to protection from apoptosis by excitotoxicity related with increased glutamate and cytokines, and less phosphorylation of Akt in these encephalitides. Passive transfer of rabbit antibodies to n–terminal of human GluN2B into hippocampi of mice caused probable excited behavior and impairment of memory in behavioral analysis, and decreased expression of pam gene in microarray analyses and quantitative analyses of gene expression. In non–herpetic acute limbic encephalitis, factors including granzyme B, glutamate, etc., other than antibodies are causally related with neuronal cell death.
B. Encephalitis mediated by antibodies to voltage–gated potassium channel (VGKC)
 In encephalitides mediated by antibodies to VGKC, patients with antibodies to leucine–rich glioma–inactivated 1 (LGI1) show characteristics of limbic encephalitis, and patients with antibodies to contactin–associate protein (Caspr) 2 show Morvan's syndrome with thymoma.
C. Acute disseminated encephalomyelitis (ADEM)
 ADEM is the most common immune–mediated encephalitis, and its immune–mediated pathophysiology was not revealed. Recently, antibodies to myelin–oligodendrocyte glycoprotein were found in a few pediatric patients.

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Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease that is distinct from myxedema encephalopathy, based on an autoimmune mechanism associated with Hashimoto's thyroiditis, and steroid treatment was successfully administrated. Recently, we discovered the serum autoantibodies (Abs) against the NH₂–terminal of α–enolase (NAE) as a highly specific diagnostic biomarker for HE. We analyzed the serum anti–NAE Abs and the clinical features in 80 cases of HE from institutions over Japan and other countries. About a half of HE patients carried anti–NAE Abs. Most of HE patients were in euthyroid states, and all patients had anti–thyroid (TG) Abs and/or anti–thyroid peroxidase (TPO) Abs. HE consists of various clinical phenotypes such as acute encephalopathy form, chronic psychiatric form and other particular clinical forms including limbic encephalitis, progressive cerebellar ataxia and Creutzfeldt–Jakob disease (CJD)–like form. Such a wide clinical spectrum in HE easily leads to mis– or under–diagnosis of the disease. The differential diagnosis varied among viral myxedema, encephalitis, non–herpetic limbic encephalitis, spinocerebellar degeneration, schizophrenia, front–temporal lobe dementia, Alzheimer's disease, CJD and other toxic/metabolic conditions. The common neuropsychiatry features are consciousness disturbance and psychosis, followed by cognitive dysfunction, involuntary movements, seizures and ataxia. Abnormalities on EEG and decreased cerebral blood flow on the brain single photon emission computed tomography (SPECT) are common findings whereas abnormalities on brain MRI are rare. Cerebellar ataxic form of HE clinically mimics spinocerebellar degeneration (SCD), and is characterized by absence of nystagmus, absent or mild cerebellar atrophy.
The serum from a HE patient with anti–NAE Abs immunologically reacted with cultured human brain vascular endothelial cells, and merged with α–enolase in the cytoplasm. In contract, a patch–clump study using a patient's CSF containing anti–NAE Abs in rat cerebellar slices demonstrated defective glutamate release, which suggests that the Abs' target is neurons in HE.
Taken together, we should provide an attention to the possibility of Hashimoto's encephalopathy, and should search for the pathogenesis.

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A relatively high incidence of chronic limb pain, frequently complicated by violent, tremulous involuntary movements, has been noted in Japanese girls following human papillomavirus (HPV) vaccination. The average incubation period after the first dose of the vaccine was 5.47±5.00 months. Frequent manifestations included headaches, general fatigue, coldness of the legs, limb pain and weakness. The skin temperature examined in the girls with limb symptoms exhibited a slight decrease in the fingers and a moderate decrease in the toes. Digital plethysmograms revealed a reduced height of the waves, especially in the toes. The limb symptoms of the affected girls were compatible with the diagnostic criteria for complex regional pain syndrome (CRPS). The Schellong test identified a significant number of patients with orthostatic hypotension and a few patients with postural orthostatic tachycardia syndrome. Electron–microscopic examinations of the intradermal nerves showed an abnormal pathology in the unmyelinated fibers in two of the three girls examined. The symptoms observed in this study can be explained by abnormal peripheral sympathetic responses. The most common previous diagnosis in the studied girls was psychosomatic disease. Additionally delayed manifestation of cognitive dysfunction in the post–vaccinated girls has been paid much attention: memory loss, difficulty in reading textbooks and/or calculation.

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Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that inflammation in the CNS is involved in the pathophysiology of CFS/ME, there were no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia and/or astrocytes is related to neuroinflammation. Our recent PET study successfully demonstrated that neuroinflammation (activation of microglia and astrocytes) is present in widespread brain regions in patients with CFS/ME, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with CFS/ME may be essential for understanding the core pathophysiology, as well as for developing the objective diagnostic criteria and effective medical treatments for CFS/ME. We here describe related pathophysiological findings and topics, and mention the diagnostic and therapeutic attempts through these findings in Japan.

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筋萎縮性側索硬化症の病態に酸化ストレスが関係していると考えられている．フリーラジカルスカベンジャー，edaravoneを用いamyotrophic lateral sclerosis（ALS）に対するプラセボ対象二重盲検比較試験を行った．ALS患者40例を2群に分け，実薬群20例にedaravone 30mgを4週間の中で20日投与し，プラセボ群は生理食塩水を投与した．両群とも2週間の休薬期間をおいたのち，14日間edaravone 30mgを投与した．主要評価項目のALS機能評価尺度（ALSFRS–R）の変化量および努力性肺活量（％FVC）の変化量ともに有意差はなかった．二次評価項目の髄液中3–nitrotyrosine（3NT）は実薬群で有意に低下した．探索的解析では，重症度分類がI・II度の患者群では％FVCは実薬群で有意に進行抑制効果がみられた．ALSFRS–Rが41点以上のさらに比較的障害が軽度の患者群では，ALSFRS–R変化量，％FVCいずれも実薬群はプラセボ群に比し，有意な進行抑制効果がみられた．この効果は実薬投与が終了した8週間後も続いていた．安全性には大きな問題は認めなかった．Edaravone 30mgを連日投与することでも障害が軽度のALS患者には，呼吸機能及び運動機能障害の進行抑制に有効である可能性が示唆された．

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持続性片側頭痛（hemicrania continua；HC）はindomethacinが絶対的に反応する三叉神経・自律神経性頭痛の1型である．HCはindomethacinを中止すると再発し，長期投与を必要とする症例が多いが，indomethacinの連用により，めまい，胃腸障害などの副作用による忍容性の低下や長期投与に伴う胃腸障害や腎障害などの重篤な副作用も指摘されている．われわれは国際頭痛分類第3版β版で診断されたHC患者8例のindomethacinまたはindomethacin farnesilによる寛解後の症状の推移およびこれらの薬剤の投与量や併用薬につき検討した．2例は経過中に中止することができた．減量困難な6例に対して，本邦で神経障害性疼痛や片頭痛予防薬として使用されているpregabalinやtopiramateを併用し，indomethacinまたはindomethacin farnesilを1例で中止，4例で減量することができた．本邦でのindomethacin投与量は欧米よりも少量であるが，indomethacinの長期投与が必要であるHCに対して，忍容性の低下や重篤な副作用の回避をするため，pregabalinやtopiramateなどの併用投与を検討していく必要があると考えられた．

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