Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by degeneration of the anterior horn of the spinal cord and muscle atrophy, most commonly caused by the survival motor neuron 1 (SMN1) on chromosome 5 (5q13). The severity ranges according to time of onset and is classified as type 0–4. SMN2 is paralogous to SMN1, and the copy number of the SMN2 is an important determinant of SMA severity. That is, a greater number of SMN2 copies can generate more SMN protein and presents milder SMA phenotypes. A series of novel therapies have been approved for SMA in recent years, which include nusinersen, a nucleic acid drug using antisense oligonucleotides ; onasemnogene abeparvovec–xioi, a gene therapy drug ; and risidiplam, a small molecule drug. Each has different routes and intervals of administration, but all are designed to increase SMN protein. Clinical trials have shown positive effect on survival, respiratory function, as well as motor function. In order to achieve higher efficacy, evidences have shown that initiation of the treatment as early as possible is essential. In this term, a newborn screening system is being developed for early diagnosis. The further accumulation of data to assess the long–term efficacy and safety of these drugs are needed.

Advance in acute recanalization therapy: The most significant topic in 2021 was the validation of the significance of pre–intravenous administration of alteplase in patients of large vessel occlusion (LVO) planned to mechanical thrombectomy. An integrated analysis of 1,633 patients from DIRECT–MT, DEVT, SKIP, and MR CLEAN–NO IV studies, was performed. The risk difference for functional independence was 1% (95% CI −4–5%) and for symptomatic intracranial bleeding 1% (95% CI −1–3%), suggesting non–inferiority of MT alone to MT plus alteplase in several respects. Another meta–analysis of 433 patients in 4 trials of tenecteplase (TNK) found that effective recanalization with TNK was increased 3.05 (95% CI 1.73–5.40) times compared to those with alteplase. TNK also reduces the time required to recanalize the occluded vessel.

Advance in antithrombotic therapy: Dabigatran did not prove efficacy over aspirin among east Asian patients with ESUS (Embolic Stroke of Undetermined Source). Sub–group analysis of CSPS.com study revealed that add–on effect of cilostazol is greater with patients treated with clopidogrel than those with aspirin. Dual antiplatelet therapy (DAPT) using cilostazol might be a potential solution to the genetic polymorphisms in CYP2C19 poor metabolizer.cover poor metabolizer. Cilostazol based DAPT is effective for non–cardioembolic ischemic stroke patients with intracranial arterial stenosis.

Blood pressure control: Hypertension is the most powerful risk factor of stroke, even for the patients with ischemic stroke. A meta–analysis of Boncorago et al. revealed that anti–hypertensive therapy reduces the risk of ischemic stroke/TIA (HR 0.79, 95%CI 0.66–0.94). A post–hoc analysis of ATACH–2 reaffirmed that the blood pressure drop should not exceed 90mmHg to avoid acute kidney injury.

New desease associated with COVID–19: It is the Thrombosis with Thrombocytopenia Syndrome (TTS). Similar to Heparin–induced Thrombocytopenia, heparin aggravates TTS. Intravenous immunoglobulin and non–heparin anticoagulants should be started as soon as possible.

For those of us involved in dementia care, 2021 was a big year. In June, the U.S. Food and Drug Administration (FDA) conditionally approved aducanumab. It is the first disease–modifying drug to be approved. Meanwhile, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a negative opinion in December. Subsequently, in Japan, where a review was conducted at the end of the same year, the decision was made to “continue deliberations,” resulting in a split decision in each country.

In addition, there was the pandemic of the new coronavirus (SARS–CoV–2) infection, which affected not only acute care facilities but also all medical and nursing care facilities, including those for dementia.

Although it has been an eventful year, this report focuses on the results of relatively large clinical studies on dementia treatment reported in 2021. As far as we could find, most of them were related to Alzheimer disease, and only a few were related to dementia with Lewy bodies. Here we report a summary of these studies.

COVID–19, which has been raging in Japan since 2020, has been reported to cause various syndromes and neurological disorders, including stroke, Guillain–Barré syndrome (GBS), encephalitis/encephalopathy, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as sequelae. These mechanisms are mainly immune–mediated mechanisms rather than direct viral effects, and GBS and encephalitis/encephalopathy have slightly different characteristics from the conventional COVID–19 non–associated course. In addition, in stroke, not only neurological damage but also multi–organ damage may occur, and rehabilitation may be time–consuming. Furthermore, 14.3% of patients with sequelae of COVID–19 infection develop ME/CFS. Since no treatment for ME/CFS has been established, patients are forced to seek treatment by hand, such as rTMS therapy and carnitine replacement, and future treatment methods are awaited.

In infectious meningoencephalitis, Multiplex PCR, although not approved by insurance in Japan, has the potential to rapidly identify the pathogen and is expected to be utilized in clinical practice as soon as possible. Although no new drugs have been introduced, meta–analysis has shown the usefulness of naloxone combination therapy for viral meningitis, dexamethasone combination therapy for tuberculous meningitis, and a single high–dose amphotericin B liposome regimen for HIV–positive cryptococcal meningitis, respectively.

The recent widespread use of biologics for neuroimmune diseases has focused attention on progressive multifocal leukoencephalopathy (PML), a serious complication of some agents. However, since this therapy may result in brain damage, it is no longer recommended, and the focus is on discontinuation of the causative agent and symptomatic treatment.

In HTLV–1–associated myelopathy (HAM), the pathogenesis has become clearer over the years, and CXCL–10 and neopterin are already established biomarkers of disease activity. Oral steroids and interferon–alpha have been shown to improve motor function and are already being utilized in clinical practice, but the development of HAM–specific therapeutic agents that affect CXCL–10 and neopterin levels is also underway daily, and we look forward to future drug discovery efforts.

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 DMT initiation strategy and MS disability progression, the real world data on MS DMT and pregnancy, the association between expansion of chronic lesions and disease progression in relapsing–remitting MS, the efficacy of prednisolone monotherapy for neuromyelitis optica spectrum disorder (NMOSD), the clinical features and risk of relapse in children and adults with myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), and the brain structural alterations in MOGAD measured by multimodal MRI.

We review reports published in 2021 providing new information on the management of Parkinson disease (PD) and its related disorder. Several clinical trials of drugs for disease–modifying therapy (DMT) are also underway, but no drug has yet been reported that has clearly demonstrated efficacy in either PD or secondary parkinsonism.

We would like to review the recent therapeutic advances of spinocerebellar degeneration (SCD) that were published in 2021. Currently, SCD treatment is limited only to symptomatic mitigation, and no therapy is available to stop or delay the disease progression. Various pre–clinical and clinical trials were carried out in 2021. Some interesting trials have been reported, and further developments are expected. This article introduces the outline of therapies with rovatirelin, riluzole/troriluzole, leriglitazone, sodium valproate, CRISPR/Cas9 gene editing, antisense oligonucleotides (ASOs), mesenchymal stem cells (MSCs), and cerebello–spinal transcranial direct current stimulation (tDCS). We expect that these treatments will benefit the patients with SCD.

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 2021, results of open–label extension study of sodium phenylbutyrate–taurursodiol and long–term observational study of masitinib were published, which both studies proved the positive effects for survival of ALS. As for SMA, risdiplam was approved in Japan. And 5 years observational study of onasemnogene abeparvovec showed lasting effect.

This review provides an overview of clinical advances in MND research and summarizes selected key literature on therapeutic approaches in 2021.

In recent years, new treatments such as molecular targeted drugs and tumor vaccine therapy have appeared and progressed rapidly. However the treatment of brain tumors and granulomatous disease in the brain represents serious unmet needs due to lethal progression and the blood–brain barrier. The improvements in clinical trial designs and therapeutic drugs overcome these problems. In this article we will focus on glioma, brain metastases and neurosarcoidosis and introduce the promising results in clinical trials of new–targeted therapies with some reports published in 2021.

Peripheral neuropathies are very common neurological disorders that are caused by various etiologies. This review focuses on four neuropathies where substantial advances have been made recently. In Guillain–Barré syndrome, treatment for severe cases is still a challenge. Unfortunately, the efficacy of immunoglobulin re–administration has not been proven. Clinical trials of several anti–complement drugs are currently underway and results are awaited. In CIDP (chronic inflammatory demyelinating polyneuropathy), European Academy of Neurolog/Peripheral Nerve Society published updated guidelines. The classification of CIDP subtypes has been changed and autoimmune nodopathies are divided from CIDP. Subcutaneeous immunoglobulin has been added as a standard maintainace therapy. In addition, knowledge is accumulation regarding optimization of globulin dosing for maintenance therapy and the efficacy of rituximab for autoimmune nodopathies has been investigated. For ATTR amyloidosis, remarkable treatment progress has been made. In addtion to stabilizers of transthyretine, RNA interference therapeutic agents have become the main treatment. Chemotherapy induced peripheral neuropathy (CIPN) is a very common complication of anti–cancer treatment. However, no drugs have been successfully developed for CIPN treatment. Researches on new drugs such as GM1 and calmangafodipir are ongoing and non–pharmacologic interventions have been investigated. With advances in cancer treatment and the increasing number of cancer survivors, CIPN patients are increasing and future developments are expected.

We reviewed articles on the novel development of treatment for autonomic disorders published in 2021. Thigh–length elastic pressure socks may prevent orthostatic hypotension (OH) that could develop after spinal surgery. A randomized double–blind and controlled study indicated that ampreloxetine improved OH. A meta–analysis revealed that commonly prescribed drugs causing sympathetic inhibition were associated with significantly increased odds of OH. Caffeine might be a treatment option for OH if other evidence–based treatments are ineffective. Abdominal and lower body compression, high dietary sodium intake, and ivabradine reduced heart rate and improved symptoms during standing in adult patients with postural orthostatic tachycardia syndrome. Acarbose may avoid the occurrence of postprandial hypotension. For patients with recurrent vasovagal syncope (VVS), there is a possibility that yoga exercise improves postural symptoms and QOL. Increased salt and water intake may reduce syncope recurrence rates in pediatric patients with VVS. Tibial nerve stimulation may be as effective as anticholinergic drugs for overactive bladder (OBA) and more tolerable. Transcutaneous tibial nerve stimulation may be as effective as percutaneous tibial nerve stimulation for OAB. Sacral neuromodulation may be effective as well as onabotulinumtoxin A for OAB, and safety. A randomized double–blind and controlled study indicated that vibegron (75mg/day) was more effective for OAB than tolterodine (4mg/day). Treatment with a cinnamon patch might improve OAB. Tenapanor may improve irritable bowel syndrome with constipation symptoms. A randomized double–blind and controlled study showed that plecanatide relieved the symptoms of chronic idiopathic constipation with a relatively low incidence of diarrhea. Probiotics treatment may be effective for constipation in patients with Parkinson disease. Rhubarb, a Chinese traditional medicine, may be effective for chronic idiopathic constipation.

We reviewed treatments for headaches (migraine and cluster headaches) and epilepsy, mainly published in 2021. Headache is the most common neurological disorder and the third leading cause of disability worldwide. Recently, calcitonin gene–related peptide (CGRP) has been highlighted for its role in the pathophysiology of migraine headaches. Therefore, since 2021, monoclonal anti–CGRP antibodies have been approved in Japan. They have been shown to improve the frequency of headache attacks compared with placebo or previous medications. Furthermore, they did not show significant adverse effects in the clinical trials. In addition to these antibodies, a selective 5–HT1F receptor agonist (ditans) was also approved in 2021 and was shown to resolve pain in the acute phase of migraine.

Recently, one study showed a difference in survival between patients treated with enzyme–inducing antiseizure medications and lamotrigine or levetiracetam for post–stroke epilepsy. These results can be due to the increased metabolism of drugs used in secondary prevention after stroke or directly associated with markers of vascular diseases, such as lipid abnormalities. The mechanistic target of rapamycin (mTOR) is a ubiquitous regulator of cell metabolism, growth, proliferation, and survival. Pathogenic variants of genes associated with mTOR cause epilepsy or neurodevelopmental disorders, such as tuberous sclerosis. In addition, focal cortical dysplasia type II results from somatic brain mutations of mTOR pathway activators. Therefore, substances associated with mTOR can be therapeutically used to treat drug–resistant seizures.

【目的】高齢COVID–19患者の回復期の摂食機能療法の効果と社会的意義について検討する．

【方法】高齢者施設を感染経路とし，急性期治療後に当院へ転入院したCOVID–19連続14例の経過を後方視的に検討した．摂食機能療法は医師と看護師，理学療法士で開始し，隔離解除後に言語聴覚士が携わった．

【結果】14例は年齢86±7（mean±SD, range 72–95）歳で，8例は認知症，2例は神経変性疾患を有した．COVID–19は86%で肺炎像を呈し，64%で酸素吸入を要した．発症から18.2±5.6（11–33）日経過した当院入院時，9例（63%）が摂食不能であった．入院後，5例は体力や意欲，認知機能が回復し摂食が回復したが，神経変性疾患2例は摂食嚥下機能が回復せず，認知症1例は先行期の問題が回復せず，残る1例は死亡した．

【結論】神経変性疾患以外でCOVID–19から回復した高齢者の83%は摂食嚥下機能が回復した．神経難病診療を生かした隔離下での嚥下評価と摂食機能療法が高齢COVID–19患者の摂食嚥下機能回復に寄与し，予後の改善につながった．

目的：脊髄小脳変性症（Spinocerebellar degeneration：SCD）の小脳失調症状の改善目的にprotirelinやtaltirelinが使用されるが，症状の改善の程度をScale for the Assessment and Rating of Ataxia（SARA）およびInternational Cooperative Ataxia Rating Scale（ICARS）で半定量化した報告は少ない．protirelinの静脈内投与による小脳失調症状の改善効果についてSARA，ICARSを用いて検討した．

方法：当院で小脳失調症状に対してprotirelinを静脈内投与し，SARAおよびICARSを評価したSCD10例について投与前後におけるSARAおよびICARSのスコアの変化を評価し，Wilcoxonの符号順位検定を用いて解析した．

結果：10例においてSARAは治療前平均16.25から治療後平均12.90（p＝0.0176），ICARSは治療前平均41.50から治療後平均32.75（p＝0.0020）とスコアの改善を認めた．四肢失調，姿勢および歩行障害においては有意なスコアの改善が認められたが，言語障害，眼球運動障害には有意な改善を認められなかった．

結論：protirelinの静脈注射によるSCD患者の小脳失調症状の改善の程度をSARA，ICARSを用いて評価し，有意なスコアの改善が認められた．

［目的］Parkinson病（Parkinson disease：PD）への脳深部刺激療法（Deep Brain Stimulation：DBS）において，術後の薬剤使用に決まった方法は確立されていない．治療1年後における薬剤使用状況とその予後の関連を検討し術後の薬剤治療の最適化を図ること．［方法］視床下核（Subthalamic nucleus：STN–）DBSを施行したPD症例23例を対象とした．1年後の使用薬剤と運動機能の変化について検討した．［結果］平均年齢および罹病期間がそれぞれ62.7歳，13.4年であり．平均L–DOPA，L‐DOPA equivalent daily doseが各々470mgおよび897mgであった．1年後のMAO–B阻害薬の有無（有9；selegiline 5，rasagiline 4），無（14）で検討したところ，1年後のMovement Disorder Society–Sponsored Revision of the Unified Parkinson's Disease Rating Scale part IIIスコアの改善率（77 vs. 35%, p＝0.012）に有意差を認めた．［考察］PDのSTN–DBS後は，MAO–B阻害薬を併用した方がOff状態の改善が良い可能性がある．

症例は29歳女性．肺炎球菌性肺炎に対してceftriaxone sodium（CTRX）を投与後に，妄想，幻覚，支離滅裂な会話などの統合失調症様症状と，興奮，昏迷，無言症，常同症，姿勢保持などのカタトニア症状を来した．CTRXの中止によりこれらの所見が改善したことから，同剤による脳症と診断した．本症では精神症状や意識障害や痙攣，ミオクローヌスなどの神経症状がみられるが，前者の詳細は明らかにされていない．我々は既報告を含めた検討から，本症では統合失調症様症状とカタトニアがみられることを指摘した．統合失調症とカタトニアの病態にはgamma–amino butyric acid（GABA）系の機能障害が関与しており，これらの症状はCTRXが有するGABA_A受容体の阻害作用により生じると考えられた．CTRX投与中に精神症状を認めた際には，同剤による脳症を考慮する必要がある．

Lewy小体型認知症（dementia with Lewy bodies：DLB）80歳男性例の発作性の意識障害（disturbance of consciousness：DOC）再発予防にamantadine（AD）を投与し，有効な結果を得たので報告する．患者は4年前から歩行困難で車椅子を使用していた．当院入院8ヶ月前に1回目の原因不明のDOC発作を起こした．その後2回目のDOC発作を起こし当院に入院した．入院後に数時間持続する急性のJapan Coma Scale（JCS）Ⅱ–30程度の原因不明のDOCを一日に2回起こしたが無治療で回復した．DLBに合併したDOC発作と診断し，DOCの予防に1日量50mgの経口ADを投与した．その結果，経過が追えた約4ヶ月間はDOC発作の再発は認めなかった．限られた期間の1例だけの観察であるが，ADがDLBのDOC発作に有効であった可能性が示唆される．DLBのDOC発作再発予防にADのドーパミン賦活作用とN–methyl–D–asparate（NMDA）受容体拮抗作用に加えて，ADのニコチン性アセチルコリン受容体機能抑制作用が有効性を示した機序を推測した．