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.

[Objective] We aimed at ascertaining the actual situation of post stroke depression (PSD) in Japan by implementing a multicenter study on prevalence, the time of onset and course, and risk factors for PSD, an area of research not previously reported, in Japanese patients.

[Subject and Methods] We assessed each of 373 subjects in the subacute–chronic phase of stroke (1 month to 1 year after the onset of stroke), 159 subjects in the acute phase (2 weeks to 1 month after the onset of stroke), and 12 subjects with endogenous depression based on the criteria for DSM–IV–TR diagnoses and the HAM–D (Hamilton Depression Rating Scale). We also analyzed the prevalence, pathological state, and risk factors for PSD in the subacute–chronic phase.

[Results] PSD was diagnosed in 18.2% of the patients in the acute phase and 24.1% of those in the subacute–chronic phase. The risk of PSD in female patients in the subacute–chronic phase was shown to be significantly higher than that in men, but there were no detectable risk factors in other groups. While rates of depressed mood and the severity of the suicide ideation in PSD patients were lower than in those with endogenous depression in the HAM–D sub–analysis, the severity of loss of motivation in those with PSD was comparable to that associated with endogenous depression.

[Conclusion] PSD in the chronic phase shows a different pathology from that of endogenous depression and has a low incidence as compared to the frequencies described in previous reports from the West. Furthermore, it is noteworthy that, in diagnosis and treatment, there is no clear correlation between the onset of PSD and lesion location.

Introduction:

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which results in muscle atrophy and weakness. Although manual muscle testing (MMT) has been applied to patients with ALS as a subjective evaluation of muscle strength, it is not enough to detect the slight changes in symptoms. We herein reported the objective evaluation of arm function in ALS patients after administering the combinative therapy with intravenous (IV) edaravone and rehabilitation.

Method:

Two out of five ALS patients who have received the six IV edaravone courses were included in this study as they met the criteria for evaluation of upper extremity function known as simple test for evaluation hand function (STEF). Rehabilitation was applied in these patients with every course of IV edravone treatment. The evaluations with STEF, MMT and ALS Functional Rating Scale (ALSFRS)–R were made in these patients before and after administrating the each IV edaravone course.

Result:

The STEF score of case 1 and case 2 on right and left sides of arms before giving the first course of IV edaravone were 81/83 and 26(right)/64(left). After giving the 6^th course of IV edaravone, the score of case 1 was improved to 99/97 and case 2 was ameliorated to 32/72. However, both MMT and ALSFRS–R showed no changes with IV edaravone treatment.

Conclusion:

We assessed the upper extremity function test in patients with ALS using STEF. The STEF was able to quantify the improvement in the ALS patients which could not be detected by both MMT and ALS scoring test.

A 69–year–old man developed gait disturbance and apathy. He had mild cognitive impairment, apathy, and parkinsonism at the first admission followed by subacute cognitive dysfunction. T2 weighted brain magnetic resonance imaging (MRI) showed high intensity lesions in bilateral basal ganglia with partial gadolinium enhancement. Steroid pulse therapy was performed under the diagnosis of autoimmune encephalitis and cognitive function was improved. However, he relapsed after 1 month. Brain MRI showed enlarged lesions including limbic system. Then, he hospitalized again and steroid pulse therapy was performed, followed by the improvement in both clinically and MRI findings. Seizure was not exhibited during the clinical course. CSF anti–NMDA receptor antibody turned out to be positive after discharge. Although anti–NMDAR antibody encephalitis is usually presented with psychiatric symptoms and seizure, the main symptom was parkinsonism in our case. Our atypical case suggests that anti–NMDAR antibody should be measured even if the symptom is mild cognitive impairment and parkinsonism without seizure.

We retrospectively studied the occurrence of convulsive seizure after first–ever cerebral infarction to elucidate whether a single unprovoked seizure (US) can be diagnosed as poststroke epilepsy. The subjects were 2071 patients who were admitted to our hospital for acute first–ever cerebral infarction. We ascertained all episodes of convulsive seizure in our 5–year observation. Data on age, gender, status epilepticus (SE), cortical lesion, Oxford classification and deep white matter lesion on MRI and subsequent episodes of recurrent US were collected. The cumulative risk at 3 months and 1, 2, and 5 years were 2.0% (95% CI ; 2.0–2.6), 4.4% (3.9–4.9), 5.2% (4.7–5.7), and 7.7% (7.0–8.4), respectively. The occurrence rate of recurrent US in patients with US without anti–epileptic drug (AED) treatment was 74%, which was significantly higher than those with AED treatment. The occurrence rate of SE in patients without AED treatment was significantly higher than in those with AED treatment. On multivariate analysis, cortical lesion (OR＝4.0 ; CI 1.2–13.6), TACI (OR＝9.0 ; 2.9–28.7), PACI (OR＝3.6 ; 1.3–10.6), DSWMH (grade 3 or 4) (OR＝3.9 ; 1.6–5.5), and age＜75 (OR＝0.55 ; 0.35–0.96) remained the significant predictors of US. These findings demonstrate that a single US after cerebral infarction can be diagnosed as poststroke epilepsy. Moreover, AEDs do not only prevent recurrent US but also reduce the risk of SE when recurrent US occurs.