Thrombolytic therapy for acute ischemic stroke was established in 1995, when the National Institutes of Neurological Disorders and Stroke recombinant tissue–type Plasminogen Activator Stroke Study (NINDS rt–PA stroke study) group revealed the efficacy of intravenous alteplase infusion at 0.9mg/kg. The drug, alteplase, was introduced to Japan in 2005 after Japan Alteplase Clinical Trial (J–ACT) showed identical efficacy and safety to NINDS study using a reduced dose of 0.6mg/kg. The time allowance for the use of the drug was extended from 3 hours to 4.5 hours in 2012 in Japan. This therapy is still being investigating in several ways : 1) Optimal dosing, 0.6mg/kg vs. 0.9mg/kg, was investigated on the Enhanced Control of Hypertension and Thrombolysis Stroke Study, 2) extending time window over 4.5 hours using advanced brain imaging, 3) Introduction of mobile stroke unit that enables field administration, 4) Developing new–generation thrombolytic drugs that have more fibrin specificity, better plasminogen activator inhibitor resistance and longer half–life than alteplase.

Streptokinase, alteplase, duteplase, desmoteplase, and tenecteplase are the previously or currently tested drugs as for the use of acute thrombolytic therapy. Among them, alteplase is the only drug approved to use in clinical settings. Other drugs except for tenecteplase were failed to proceed to clinical application. Tenecteplase is currently the only drug that has possibility to replace alteplase in the future. Several phase III studies comparing tenecteplase with alteplase are currently ongoing. In Japan, however, tenecteplase is officially not available currently, even for acute myocardial infarction. The most advanced study, Tenecteplase versus Alteplase for Stroke Thrombolysis Evaluation (TASTE), is targeting more than 1,000 stroke patients who have targeted mismatch on advanced brain imaging within 4.5 hours. Should tenecteplase proved better efficacy and safety over alteplase, international standard drug will be replaced to tenecteplase.

The cerebral small vessel disease (CSVD) is a pathological condition commonly observed in elderly population and causes cognitive impairment and gait disturbance. Despite the importance of the disease, little is known about its molecular pathogenesis. The discovery of causative genes for hereditary CSVD has opened up new ways of understanding the molecular pathogenesis of CSVD. COL4A1 and COL4A2 for COL4A1/2–related small vessel disease, NOTCH3 for autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and HTRA1 for autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) are the representative. The current topic from recent advances of the hereditary CSVD study is the matrisome, which is a term of the repertoire of extracellular matrix (ECM) proteins. ECM proteins fill the extracellular space and create tissue–specific microenvironment cooperatively. Most of the hereditary CSVD involves the matrisome in small vessels, suggesting that the tissue–specific microenvironment is not harmonious. Here we discuss the molecular mechanisms of the hereditary CSVD in terms of the disturbance of the matrisome. The concept helps us understand the CSVD pathogenesis.

Cerebral small vessel disease (SVD), which affects small arteries, arterioles, venules, and capillaries in the brain, has long been associated with cognitive impairment and dementia. Pathologically, characteristic features include (1) vasculopathy of the small cerebral vessels, (2) lacunar infarcts, (3) microbleeds (lobar or deep), (4) widened perivascular spaces (Virchow–Robin spaces), (5) focal or diffuse white matter (WM) changes (often seen as hyperintensities on magnetic resonance imaging), and (6) microinfarcts. SVD is a spectrum of abnormalities, with the majority of patients experiencing symptoms from both ischemic and hemorrhagic changes in varying degrees as the disease progresses. WM damage is commonly found in SVD, and enlarged perivascular spaces, lacunar infarction, and deep microbleeds coexist with lipohyalinosis, whereas cortical microinfarcts and lobar microbleeds are more frequently found in cerebral amyloid angiopathy. Such pathological changes also frequently accompany the hallmarks of Alzheimer's disease and previously were only evident by postmortem histopathological examinations but now often visible with modern neuroimaging. Despite improvements in clinical/radiological markers available for the characterization of SVD, none are specific for SVD and there remain other factors yet to be identified. There are at least 4 important factors involved in the pathogenesis of the endothelial dysfunction that leads to blood–brain barrier (BBB) disruption in SVD. The 4 factors include (1) hypertension and salt intake, (2) infection and inflammation, (3) large and small artery cross talk, and (4) cell–cell interaction in the BBB. Therefore, a promising strategy for SVD would involve targeting such contributing factors for restoration of BBB integrity. Salt restriction, normalization of brain–gut interaction with probiotics, antibiotics, and oral care, exercise, and drugs such as matrix metalloproteinases and angiotensin receptor blockers may focus on rescuing BBB disruption through multiple but interrelated pathways.

The acute stroke treatment dramatically changes for a last decade. Regarding hyper acute stroke, first line is intravenous thrombolytic therapy with recombinant tissue–type plasminogen activator (IV rt–PA). Randomized controlled studies and meta–analysis shows an efficacy and safety of IV rt–PA. Although it is difference of rt–PA dosage among countries, non–inferiority of low dosage (0.6mg/kg, Japanese standard) was nearly confirmed. In hyper acute stroke with occluded artery just after IV rt–PA, endovascular therapy (EVT) is recommended. The occluded artery can be recanalized at a higher rate compared with rt–PA alone, and ischemic penumbra can be relieved with performing EVT. The benefit of EVT was, confirmed by several clinical trial and meta–analysis, to reduce disability for patients with ischemic stroke of anterior circulation irrespective of eligibility for rt–PA. In the current situation, it should be noted that it is necessary to carry out the case selection strictly.

In order to prevent a stroke recurrence, acceptable medication by using antiplatelet and anticoagulant agents should be considered. In Japanese guidelines for the management of stroke 2015, aspirin (160～300mg/day) monotherapy is recommended to reduce the risk of recurrent stroke for patients with noncardioembolic ischemic stroke in acute phase (Grade A). The combination of antiplatelet therapy, mostly aspirin and clopidogrel, is also recommended as lower evidence for those in acute phase (Grade B). Recent meta–analysis shows that combination therapy within 3 months compared to monotherapy significantly reduces the recurrent stroke without increases the risk of hemorrhage event.

For anticoagulation therapy, there is no substantial evidence about secondary prevention in acute phase of stroke occurrence. It is reasonable to initiate oral anticoagulation within 14 days after the onset of index stroke, when a patient has no risk of hemorrhagic infarction, such as large infarct, hemorrhagic transformation in initial neuroimaging, hypertension, and bleeding tendency. Multicenter–randomized study to investigate the advantage of direct oral anticoagulants for acute phase of stroke should be needed.

Stoke is one of the leading cause of death in the world. Although the mortality rate after stroke decreased, there are increasing number of patients who needs daily life support after stroke. The Hisayama study demonstrated the recurrence rate of ischemic stroke was 49.7% in ten years after first ever stroke. In addition to the traditional risk factors for stroke recurrence such as age, hypertension, diabetes, smoking, there are increasing evidence the another potential risk factors including infection, insulin resistance, visceral fat, gut dysbiosis, air pollution. These potential risk factors are associate with systemic chronic inflammation that promote artherosclerosis and myocardial injury that result in recurrence of stroke. Cognitive decline is one of the critical problems after stroke. Alzheimer's pathology is frequently related to the onset of dementia after stroke and recurrence of stroke is significant risk for the dementia. The strategy to attenuate the recurrence of stroke is also effective to reduce post stroke dementia. The use of antithrombotics is main treatment for the secondary prevention. Furthermore, strict risk factor control is also able to reduce the risk of stroke recurrence. One of the long term observational study demonstrated both antithrombotic treatment and the strict risk factor control attenuated cognitive decline after stroke. We discussed these topics of chronic stage of ischemic stroke in this section.

We had been shown that circulating hematopoietic stem cells contributes to the maintenance of vasculature in patients with microvascular diseases and local transplantation of hematopoietic stem cell activates angiogenesis in patients with limb ischemia. In experimental stroke model, we had been shown that intravenous administration of bone marrow–derived hematopoietic stem cell after stroke improves neurogenesis and functional recovery through enhancing angiogenesis. Based on these observations, we have started phase 1/2a clinical trial of intravenous autologous bone marrow–derived mononuclear cell transplantation in 10 days after onset of stroke for patients with cardiogenic cerebral embolism. Our results indicated that autologous bone marrow–derived mononuclear cell transplantation is feasible and safe even in patients with severe stroke, and patients with cell transplantation have significant better neurological outcomes, compared with historical control. These findings indicated that activation of angiogenesis by hematopoietic stem cell transplantation at sub–acute period after stroke can contribute to improvement of functional recovery, as well as the immunomodulation of inflammation by mesenchymal stem cell transplantation at acute period and activation of remodeling by neuronal stem cell transplantation at chronic period.

【目的】本邦人では報告のない脳卒中後にみられるうつ状態（post stroke depression：PSD）の有症率，発症時期および経過，危険因子について多施設共同研究を実施して，本邦のPSDの実態を把握することを目的とした．

【対象，方法】脳卒中亜急性期–慢性期（脳卒中発症から1カ月～1年）373例，急性期（脳卒中発症から2週間～1カ月）159例，内因性うつ病12例それぞれに対しDiagnostic and Statistical Manual of Mental Disorders 4^th text revision（DSM–IV–TR）診断基準及びHamilton depression rating scale（HAM–D）を用いた評価を行い，亜急性期–慢性期におけるPSDの有病率・病態・危険因子を解析した．

【結果】急性期及び亜急性期～慢性期脳卒中において，それぞれ18.2%および24.1%がPSDと診断された．また亜急性期～慢性期において，女性患者におけるPSDの危険が有意に高いことが示されたが，他は有意な発症危険因子は検出できなかった．HAM–Dサブ解析にてPSDにおける抑うつ気分，自殺企図の重症度は内因性うつ病に比較して低かったのに対して，PSDにおける意欲低下の重症度は内因性うつ病と同等であった．

【結論】慢性期のPSDは内因性うつとは異なる病態を呈し，また従来の欧米の報告と比較し低頻度であり，PSD発症と病変部位に明確な相関はみられない事を診断・治療の際，留意すべきだと思われた．

［目的］筋萎縮性側索硬化症（amyotrophic lateral sclerosis：ALS）の病態として筋肉の萎縮と筋力低下が挙げられる．筋力評価においては徒手筋力検査法（Manual Muscle Testing：MMT）等が行われるが，微細な症状の変化をとらえるには不十分である．今回，Edaravone点滴およびリハビリテーションの複合治療において本疾患の上肢機能を客観的に数値化する評価方法を検討したので報告する．

［方法］対象はEdaravoneを6クール施行したALS患者5例のうち，簡易上肢機能検査（Simple Test for Evaluating Hand Function：STEF）が測定可能であった2例．Edaravone点滴1クールごとに，リハビリテーションを行い，各クールの点滴開始前後にSTEF，MMT，ALSFRS（ALS Functional Rating Scale）–R等にて本症例の上肢機能を評価した．

［結果］Edaravone点滴1クール目と6クール目の評価結果比較では，1例目は右81点，左83点より右97点，左97点に改善した．2例目も右26点，左64点より右32点，左72点に改善した．MMTやALSFRS–Rでは変化を認めなかった．

［結論］ALS患者における上肢機能評価方法についてSTEFを用いて検討したところ，MMTやALSのスコアリングでは検出できない改善をSTEFで評価することで数値化し把握することができた．

症例は69歳の男性である．右耳介の発赤腫脹の後，活動性の低下，パーキンソニズムを呈し，頭部MRIにて両側対称性に大脳基底核に高信号を認めた．その後，精神症状が亜急性に進行し，髄液中の細胞と蛋白の増加があり，造影効果も認め，自己免疫性脳炎と考えてステロイドパルス療法を実施した．改善を認め転院となったが，その後辺縁系を含め広範囲に病変を呈し当院へ再入院となった．ステロイドパルス療法を実施し症状，頭部MRI画像での改善が再度得られた．後に抗N–methyl–D–aspartate（NMDA）受容体抗体が陽性と判明，経過を通じて悪性腫瘍の合併も明らかではなく非典型的な経過ではあるが，抗NMDA受容体脳炎と考えられた．パーキンソニズムで発症し，病初期の画像は基底核病変のみで，緩徐に進行する脳炎でも抗NMDA受容体脳炎を考慮し，精査する必要があると考えられる．

目的：脳梗塞後はじめて発作を発症した場合，てんかんと診断できるか検討するため，有事率とそのリスク，非誘発性発作の再発率等について多数例を後ろ向きに調査した．方法：当院に入院した脳梗塞急性期（transient ischemic attack；TIAを除く）患者2071名を対象に，けいれん発作発症例を抽出した．年齢，性，皮質病変，Oxford分類，MRIでの深部白質病変等を評価項目とした．結果：脳梗塞発症後，急性症候性発作（acute symptomatic seizure；ASS）は43例で過半数は発症当日であった．非誘発性発作（unprovoked seizure；US）は，100～300日でピークとなるがその後も増加を続け，5年間で73例であった．ASSのリスクは，皮質病変・total anterior circulation infarction；TACI（Oxford分類），USのリスクは，皮質病変・TACI・partial anterior circulation infarction；PACI（Oxford分類）・deep and subcortical white matter hyperintensity；DSWMH（グレード3・4）・75歳未満（多重ロジスティック回帰法）であった．再発性USは，US群74%，ASS群9%と有意にUS群で高かった．初発より抗てんかん薬（antiepileptic drugs；AEDs）を投与すると有意に再発率が減少した．非誘発性発作の重積発作発生率は，AEDs投与群19.6%，非投与群34.3%と有意にAEDs投与群が少なかった．結論：脳梗塞慢性期に初発発作を発症した場合は，てんかんと診断できる．AEDsは，US再発およびてんかん重積状態の予防に有効であり初発USより投与開始を検討する必要がある．