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.
【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 4th 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．
［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．