Japan's population is aging at a rate never before experienced by humankind. In this context, neurologists are expected to have a wide range of skills, including ability to comprehensively understand and deal with patients who has multimorbidity, complex decision support, promotion of drug discovery and clinical trials, and medical care that supports patients who live, all of which have not been covered in undergraduate education to date. I have looked ahead to the next 20 years as a neurology department that is more useful to society.

Among patients with emergent large vessel occlusion (LVO), mechanical thrombectomy (MT) is now become first–line therapy. It is unclear whether preceding alteplase is mandatory or not. DIRECT–MT study showed non–inferiority of MT alone in terms of achieving good clinical outcome compared to combined therapy with alteplase and MT. This clinical question will be answered when other ongoing similar trials' data become available.

New generation P2Y₁₂ antagonists, ticagrelor and prasugrel, announced promising results in 2020. Dual antiplatelet therapy (DAPT) using ticagrelor reduced stroke or death in patients with minor ischemic stroke or high–risk TIA. Although overall benefit was cancelled by increase of severe bleeding. Prasugrel showed good safety profile among Japanese high risk patients (age ＞75y or weight ＜50kg) with lacunar and atherothrombotic stroke.

The concept of embolic stroke of undetermined source (ESUS) is now entered re–consideration phase. Japanese subgroup analysis of RE–SPECT ESUS disclosed that dabigatran significantly reduced the risk of recurrent stroke (HR 0.55, 95%CI 0.32–0.94). Furthermore, no difference was observed about the risk of major bleeding. Japanese subgroup was older and more CKD patients are enrolled. Prevalence of covert atrial fibrillation may be higher than the other.

Treat Stroke to Target (TST) trial investigated whether aggressive LDL lowering (＜70mg/dL) result in reduction of cardiovascular events among patients with recent ischemic stroke with atherosclerotic plaque. Indeed, lower–target group (LDL ＜70mg/dL) revealed 22% risk reduction compared to higher–target group (LDL 90–110mg/dL).

Finally, COVID–19 pandemic dramatically changed our stroke triage and emergency protocol. Top priority is the perfect defense of medical staff from COVID–19 infection. Making each hospital's own Protected Code Stroke is essential. COVID–19 itself seems to cause stroke. ESUS, LVO, young stroke, and hypercoagulable state are the key words of COVID–19 related stroke.

With the aging of society, the number of dementia patients in Japan continues to increase, with the Ministry of Health, Labor and Welfare predicting 4.62 million dementia patients in 2012 and another 4 million patients with mild cognitive impairment. In other words, about 8.6 million people have dementia or are in the preliminary stages of the disease. When this number is compared with the number of patients with other diseases announced by the ministry in 2014, it is not as high as the number of patients with hypertension (10.1 million), but it is much higher than the number of patients with diabetes (3.16 million). This increase is not limited to Japan, the same trend is observed worldwide, and many research results have been reported in response to this trend.

We summarized and reported the results of the relatively large–scale studies on dementia treatment reported in 2020.

Recent advances and new findings relating to multiple sclerosis (MS) and other inflammatory disorders in the central nervous system were reviewed. The following topics were discussed : the association between disease modifying therapy (DMT) of MS and coronavirus infectious disease–19 (COVID–19), the association between initial DMT and MS disability progression, the efficacy of extended interval dosing of rituximab in treatment for RRMS, the efficacy and safety of ofatumumab for RRMS, the characteristic relapse patterns of neuromyelitis optica spectrum disorder (NMOSD), the efficacy and safety of satralizumab monotherapy for relapse prevention of NMOSD, the characteristic MRI findings of myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), the pathological characteristics of MOGAD, and the use of rituximab for relapse prevention of NMOSD and MOGAD.

We review reports published in 2020 providing new information on the management of Parkinson disease (PD) and its related disorder.

Motor neuron diseases (MND) are devastating neurodegenerative disorder which primary affects motor neurons : amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (SBMA), and spinal muscular atrophy (SMA). In 2020, positive results of several clinical trials including novel antisense oligonucleotide treatment on SOD1–ALS (tofersen) were published. As for SMA, novel gene–replacement treatment (zolgensma) was approved in Japan. These novel drugs will bring a promising future for MND patients.

This review provides an overview of clinical advances in MND research and summarizes selected key literature on therapeutic approaches in 2020.

The treatment of brain tumors and granulomatous disease in the brain represents a serious unmet medical need in the field of neuro–oncology. Even though many effective compounds have demonstrated success in treating peripheral tumors with targeted agents, one aspect of this lack of success in the brain may be related to poor delivery of otherwise effective compounds. This review discusses some issues that are pertinent to precision medicine for glioma, brain metastases and neurosarcoidosis with some reports published in 2020. In addition, we introduce the promising results in clinical trials of new–targeted immunotherapies for these diseases.

Evidence is being generated and new treatments are being developed in various neuropathies. This paper discusses about recent progresses that clinicians should be aware of : In Guillain–Barré syndrome, a randomized controlled trial failed to show the efficacy of a second administration of immunoglobulin. Development of new therapies to inhibit complement activation is underway. European Association of Neurological Societies/Peripheral Nerve Society published updated guidelines of CIDP. Clinical subtypes have been organized and subcutaneous immunoglobulin has been added as a recommended treatment. For POEMS syndrome, thalidomide was approved after an investigator–led clinical trial. Moreover, ELISA kit for vascular endotherial growth factor was also approved for diagnosis and evaluation of therapeutic response. ATTRv amyloidosis is an autosomal dominant inherited disorder for which innovative treatments have been implemented. Although ATTRv amyloidosis is rare, it should be kept in mind as a differential diagnosis to provide patients with appropriate treatment as early as possible.

We reviewed articles on novel development of neurological treatment published in 2020. Atomoxetine improved orthostatic blood pressure changes as much as midodrine and was better in terms of ameliorating orthostatic hypotension symptoms. One meta–analysis provides low–quality evidence of a short–term improvement in orthostatic intolerance with increased salt intake. Another meta–analysis showed no significant effect to orthostatic hypotension of resistance exercise, electrical stimulation, and lower limb compression bandaging. Splanchnic venous compression alone did not improve tachycardia or symptoms, but the combination with propranolol was more effective in improving symptoms than either alone. Pharmacological norepinephrine transporter inhibition prevented severe vasovagal reactions and syncope induced by head up–tilt testing in patients with vasovagal syncope. Overactive bladder (OAB) symptoms were significantly improved in older adults with Parkinson's disease under fesoterodine fumarate treatment. One meta–analysis indicated that the safety and efficacy profile of mirabegron remains favorable compared with anti–muscarinics among older adults. Vibegron provided significant reductions in micturitions, urgency episodes and urge incontinence in patients with OAB. Daily consumption of sterilized probiotic containing L. helveticus with or without polydextrose alleviated constipation–related symptoms. Flaxseed flour was more effective at increasing defecation frequency than lactulose, patients with chronic functional constipation. Linaclotide significantly improved opioid–induced constipation symptoms. Electro–acupuncture could effectively improve bowel function, mental states and QOL of functional constipation patients. Plecanatide, tenapanor and minesapride were well–tolerated and effective treatment option for patients with constipation–predominant irritable bowel syndrome or functional constipation.

We reviewed treatments for headaches (migraine and cluster headaches) and epilepsy, mainly published in 2020. Headache is the most common neurological disorder and the third leading cause of disability worldwide. Recently, Calcitonin gene–related peptide (CGRP) has been shed light on because of its role in the pathophysiology of migraine headaches. In 2020, the monoclonal anti–CGRP antibodies were approved in Japan. They were shown to improve the frequency of headache attacks compared to the placebo or previous medications. Furthermore, they did not show significant adverse effects in the clinical trials. Other than these antibodies, selective 5–HT_1F receptor agonist (ditans) or CGRP antagonists (gepants) are also under clinical trials. Cluster headache is one of the most painful disorders. Although the precise protocols were not determined, one study showed that the gradual decrement protocols of prednisolone improve the frequency of headache attacks.

Recently, the number of patients with epilepsy in the elderly has been gradually increasing because of the aging society. Since the cause of late–onset epilepsy was mainly cerebrovascular diseases and dementia, the cross–talks between epilepsy and dementia were reported. Patients with Alzheimer's disease had a 6–times higher odds ratio of complications of seizures. Meanwhile, cognitive functions of minimal cognitive impairment cases with epileptic seizures worsened compared to those without epileptic seizures. Autoimmune encephalitis is one of the crucial causes of late–onset epilepsy. However, autoimmune encephalitis such as anti LGI1 antibody–associated encephalitis was often misdiagnosed because it mimics epilepsy or dementia. It responses to immunological treatments like methylprednisone pulse or IVIg.

Other advances were reported below. 1) The use of continuous electroencephalogram (cEEG) was revealed to improve the prognosis of critical care patients. As a result, the American Clinical Neurophysiology Society recommended its use to diagnose nonconvulsive seizures in the neuro–intensive care unit. 2) Oromucosal solution containing the active substance midazolam was approved in Japan to treat prolonged, acute convulsive seizures in children and adolescents less than 18 years of age. 3) The treatment with responsive neurostimulation (RNS) in the USA was shown to provide significant reductions in the frequency of focal onset seizures through 9 years of follow–up. In addition, there could be longer–term neuromodulatory effects of neurostimulation that resulted in continued improvement in outcomes.

症例は統合失調症の48歳女性．定期のaripiprazole投与後に昏迷，無動，無言，一点凝視などのカタトニア症状を来した．その後，常用していた抗精神病薬とbenzodiazepineが中断され，発熱と筋強剛が悪化した．悪性症候群の診断基準を満たしたが，dantrolene, bromocriptineの効果がなく，diazepam静注により劇的に改善し，悪性カタトニアと診断された．悪性カタトニアは，カタトニアに発熱や自律神経症状を合併する状態である．抗精神病薬による悪性カタトニアは，悪性症候群に類似した症状を呈するが，その発症機序は明らかにされていない．本例の検討から抗精神病薬とbenzodiazepineの中断により，ドパミン系，gamma–amino butyric acid（GABA）系，および両者の間のフィードバック回路が障害され，悪性カタトニアを発症すると推測した．抗精神病薬とbenzodiazepineは併用されることが多く，悪性カタトニアは悪性症候群と診断され，見過ごされている可能性がある．

症例は56歳男性．2016年から重症アトピー性皮膚炎で当院皮膚科を通院していた．2017年に左不全片麻痺が出現後，activity of daily livingが階段状に低下し2018年末には独歩困難となった．2019年1月自宅で倒れているところを発見され緊急入院した．来院時，意識障害，左錐体路徴候，全身の苔癬化を呈し，採血では高度脱水とIgE 81,399U/mlと上昇を認めた．MRIで大脳皮質および白質，小脳，脳幹に急性期病変と陳旧性病変が混在する多発脳梗塞を認めた．明らかな血管病変や心内塞栓源なく，凝固系異常や膠原病関連抗体も認めず，アトピー性皮膚炎症の関連した多発脳梗塞と診断した．cilostazol，rupatadine，ステロイド軟膏を開始後，皮膚症状は著明に改善し脳梗塞の臨床的再発を1年間認めなかった．アトピー性皮膚炎は脳梗塞リスクと指摘されており，血栓傾向や皮膚感染による塞栓子形成を呈した例が報告されている．アトピー性皮膚炎治療が脳梗塞予防に繋がることを示唆する貴重な症例と考えられ報告した．

16歳女性．発熱，頭痛が出現した2週間後より変動する意識障害，独語，従命不良が出現した．頭部MRIで異常なく，卵巣腫瘍の合併はなかった．経過から腫瘍非合併の抗n–methyl–D–aspartate（NMDA）受容体脳炎と考え，ステロイドパルス，単純血漿交換，免疫グロブリン静注療法，免疫抑制薬を併用した集学的免疫療法を実施した．最重症時は挿管，ICU管理が必要な状態まで増悪がみられたが，早期より各免疫療法を繰り返し行ったことで，意識障害の出現から2か月程度の経過で機能予後良好なレベルまで症状改善が得られた．抗NMDA受容体脳炎の長期予後調査で81%は24か月後の機能予後良好（modified Rankin Scale：mRS 0–2）と報告されたが，回復するまでに時間を要することが示されている．抗NMDA受容体脳炎において早期の積極的な集学的免疫療法が奏効する可能性が示唆された．