The 32nd Annual Meeting of Japan Stroke Society was held in Fukuoka city during March 22-23, 2007. The main thema was “Resure the brain and keep up with the given life span”. Finally 766 papers were accepted, and 7 symposia, 12 luncheon and 8 evening seminors were convened altogether. Professor Heistad and professor Donnan presented their outstanding works, respectively. Athersclerosis is most responsible for the development of circulatory disturbance in the brain. Hypertension is the major factor to precipitate atherosclerosis of cerebral arteries. In recent years, the prevalence of diabete mellitus is increased, and atherosclerosis in the extra- and intracranial arteries in normotensives with diabetes mellitus has become more severe than ever. In hypertensives, cerebral blood flow (CBF) is reduced, and cerebral metabolic rate of oxygen (CMR2) are maitained by increased oxygen extraction fraction (OEF). In cases with severe atherosclerosis, perfusion pressure in the brain is decreased and both CBF and CMRO2 are reduced despite of the elevated OEF. Prevention of the developmenet of cerebral and carotid atherosclerosis are of great use to protect patients against ischemic stroke.
Four years ago, when I was nominated as the 4th president of the Japan Stroke Society (JSS), I put forward a list of 20 important points that I wanted to address during my presidency (Table 1). So far, eleven of them have been completely or almost completely resolved, and progress has been made on several others. One of the most important issues was the establishment of an age-limit system, which has been a long-standing problem for the JSS. Within the next 5 years, an age-limit of 65 years will be introduced for members of the board of directors and councillors in JSS. Another milestone was the 2nd examination for JSS-verified stroke specialists : as a result, 81 new specialists were accepted, making a total of 2,540 stroke specialists in Japan. Our journals in Japanese (Nousotchuu) and in English (J Stroke CVD) are progressing very well, and J Stroke CVD will be included in the National Library of Medicine from next year. In addition, t-PA seminars were held 166 times throughout Japan, with 9,093 participants in total. Several issues remain, including: 1) the question of publicity for stroke specialists; 2) the updating of the Guidelines for the Management of Stroke, in which the JSS is playing a key role; 3) establishment of the “brainattack” campaign committee; 4) improvement of international cooperation, particularly with Asian countries; 5) better stroke education for the general population, ambulance people, general physicians, young residents and students; 6) cooperation with other medical professionals, including scientific meetings and so on. I hope that, with the further cooperation of the JSS members, we will soon see considerable progress in these areas too.
Background and Purpose: The Middle Cerebral Artery Embolism Local Fibrinolytic Intervention Trial (MELT) Japan was organized to determine the safety and clinical efficacy of intra-arterial infusion of urokinase (UK) in patients with ischemic stroke within 6 hours of onset. Methods: Patients with ischemic stroke presenting within 6 hours of onset and displaying occlusions of the M1 or M2 portion were randomized to the UK or control groups. Clinical outcome was assessed by the modified Rankin Scale (mRS). Results: A total of 114 patients underwent randomization, 57 patients in each group. The primary end-point (mRS 0-2) at 90 days was somewhat more frequent in the UK group than in the control group (49.1% and 38.6%) but did not reach significant level. However, excellent functional outcome (mRS 0-1) at 90 days, a preplanned secondary endpoint, was more frequent in the UK group than in the control group (42.1% and 22.8%, p=0.045). Conclusions: The trial was aborted prematurely and the primary end point did not reach statistical significance. Nevertheless, the secondary analyses suggested that intra-arterial fibrinolysis has the potential to increase the likelihood of excellent functional outcome.
Background and purpose: We estimated the incidence of heparin-induced thrombocytopenia (HIT) in acute ischemic stroke and investigated clinical features of the HIT patients. Methods: Of 1,078 consecutive patients with acute ischemic stroke, 392 were treated with intravenous unfractionated heparin (UFH). Ten of them showed prominent thrombocytopenia without evident causes and were suspected to have HIT. We studied these 10 patients retrospectively. Clinical diagnosis of HIT was made according to the two scoring systems. Antibodies against heparin-platelet factor 4 complexes in plasma were detected by enzyme-linked immunosorbent assay (ELISA) and were confirmed by 14C-serotonin release assay. Results: Eight patients were clinically suspected of having HIT according to both the scoring systems. Of them, serological tests were positive in 2 patients only by ELISA and in 2 by both the assays. Amount of UFH administered was larger in 4 patients with positive serological findings than the others. Three patients developed thromboembolic events. Two patients were died and the remaining 6 patients were dependent at the time of hospital discharge. Clinical severity and outcome of all the 8 patients were unfavorable regardless of serological findings. Conclusions: Prevalence of HIT was 0.5% after ascertainment by serological assays. One should never neglect this serious complication when treating stroke.
This study was undertaken to evaluate indication and efficacy of intra-arterial thrombolysis for 20 consecutive patients with vertebrobasilar artery occlusion by stroke MRI findings, including diffusion weighted imaging (DWI) and MR angiography in the acute stage. The age ranged from 41 to 87 years old (a mean of 69.0). National Institutes of Health Stroke Scale (NIHSS) distributed between 1 and 28 (a mean of 11.4). All patient underwent stroke MRI examination before the treatment. We established new DWI scoring, depending on the infarction size and location, from one to five points. One point was given for brain stem infarction less than 0.5cm, two points between 0.5cm and 1cm, and three points for more than 1cm in greatest diameter of brain stem blight signal. If the infarcts were located cerebellum, thalamus or occipital lobe, one point was given for single ischemic lesion and two points for two or more lesions. Revascularization was obtained in 12 of 14 patients by intra-arterial thrombolysis, urokinase administration with or without balloon angioplasty in the acute stage. One patient who failed to have recanalization deceased. Average DWI score before treatment was 2.4 in 12 patients with recanalization group, 2.0 in 2 patients with non-recanalization group, and 1.7 in 5 patients with conservative treatment group. In 14 patients with endvascular treatment group, average DWI score in patients with modified Rankin Scale (mRS) 0-2 at 90 days was 1.17±1.07, whereas the score in patients with mRS3-6 was 3.25±1.09 (p=0.006). Our results suggest that the new DWI score could be the good predictor to evaluate the indication and efficacy of intra-arterial thrombolysis for occlusion of vertebrobasilar artery in the acute stage.
We have studied the relation of polymorphisms to the prevalence of stroke in a total of 3,151 Japanese individuals: 1,141 stroke patients (636 with atherothrombotic cerebral infarction, 282 with intracerebral hemorrhage, and 223 with subarachnoid hemorrhage) and 2,010 controls. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hypercholesterolemia revealed that eight polymorphisms were related to the prevalence of atherothrombotic cerebral infarction, nine polymorphisms with intracerebral hemorrhage, and 10 polymorphisms with subarachnoid hemorrhage. A personalized prevention system for atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage was then developed independently. Conventional risk factors are evaluated by laboratory examination. In addition, genetic factors are evaluated by genotyping of various polymorphisms. The risk diagnosis system predicts the future risk for each type of stroke in each individual by calculating the prediction probability from the results of both laboratory examination and genetic analysis. Furthermore, this system predicts how the risk level will decrease if conventional and treatable risk factors, including hypertension, diabetes mellitus, hyperlipidemia, and smoking, are reduced or eliminated. This system may thus be expected to contribute to personalized prevention of each type of stroke.
Warfarin is the most widely prescribed oral anticoagulant, but there is greater than 10-fold interindividual variability in the dose required to attain a therapeutic response. Pharmacogenetic analysis of two genes, the warfarin metabolic enzyme CYP2C9 and warfarin target enzyme, vitamin K epoxide reductase complex 1 VKORC1, confirmed their influence on warfarin maintenance dose. The contribution to inter-individual variation in warfarin dose in our patients on stable anticoagulation with a target International Normalized Ratio of 1.6-2.6 was 5.9% for VKORC1-1639G>A and 5.2% for CYP2C9 42613A>C. Recent studies have shown that VKORC1 haplotype and CYP2C9 genotypes predicted about 40% of the individual variations of warfarin dose. Including non-genetic factors such as age, sex, weight and drug interactions with genotype information predicted more than 50% of warfarin dosing variability. Aspirin reduces the risk of cardiovascular events in patients with atherosclerotic diseases. However, its effectiveness is limited because a significant portion of the patients with arterial thrombosis who are treated with aspirin has a recurrent event. This is designated as aspirin resistance. To understand aspirin resistance and to develop the effective monitoring system of aspirin effectiveness, we are conducting the Study on Profile and Genetic factors of Aspirin Resistance: ProGEAR Study.
Gender differences in locomotion activity after stroke were investigated in 2,344 consecutive patients with stroke who were admitted to our hospital between January 1986 and December 2000. They included 625 patients with brain hemorrhage and 1,719 patients with brain infarction. The brain infarction was classified according to criteria based on the clinical findings into thrombotic infarction (n=594), lacunar infarction (n=608), and cardiogenic embolism (n=441). The locomotion activity evaluated at the time of discharge was classified into the following 5 categories: (1) no significant disability; (2) slight disability to walk; (3) assisted with cane or braces; (4) using a wheelchair; (5) bedridden. After brain hemorrhage, women showed worse ability to walk than men at discharge (P<0.05). After brain infarction, female patients also showed worse locomotion activity than male patients. Multiple regression analysis revealed that locomotion activity after brain infarction was influenced by gender in addition to age, size of lesion and systolic blood pressure on admission. These findings suggest that gender differences in locomotion activity exist after stroke, particularly after brain infarction.
Gene transfer technique may be applicable to the treatment of serious types of brain infarction. Recently the neurovascular unit is proposed as an important target for brain infarction. Therefore, we examined usefulness of gene transfer approach for neurovascular protection in brain ischemia. Focal brain ischemia was produced by photothrombotic occlusion of the distal middle cerebral artery in spontaneously hypertensive rats. Candidate genes, such as midkine, dominant negative MCP-1, interleukin 10 or soluble Flt-1 (sFlt-1) were transferred using adenoviral vectors into the lateral ventricle 90 minutes after induction of ischemia. Marked expression of transgene was detected at the periventricular area from 6 hours to 7 days after gene transfer and ischemia. Postischemic gene transfer of midkine reduced infarct volume with marked attenuation of apoptosis. Overexpression of anti-inflammatory genes attenuated leukocytes and microglia/macrophages infiltrations with marked reduction of infarct volume. Gene transfer of sFlt-1 provided prominent reduction of blood brain barrier permeability that lead to reduction of brain edema and infarction. Postischemic gene transfer approach was useful for neurovascular protection, and the novel molecular approaches may have potentials for treatment of brain nfarction.
Gene therapy is crucial to salvage neuron, glia and astrocyte in ischemic stroke, not only in the acute phase but also in the chronic phase. It may have a bright future, as they are now used in the clinic in the world for treating cancer and are under administrative review for the treatment of ischemic stroke. Cumulative evidence revealed that apoptosis plays a pivotal role in neuronal cell death after cerebral ischemia in various experimental models, including gene therapy. The time-dependent molecular and biochemical sequelae that lead to apoptotic cell death after the interruption of cerebral blood flow have been established. Therefore, various kinds of anti-apoptotic protein or growth factor have been developed for gene therapy. In this symposium, we introduced the benefit or side effect of many kinds of vectors for gene therapy, and also we showed our experimental on several kinds of brand-new neuroprotective compounds focused on the anti-apoptosis pathway after focal ischemia. Furthermore, we showed the gene-transferred Bcl-2, anti-apoptotic protein or GDNF, neurotrophic factor, have dramatically ameliorated the infarcted volume after focal ischemia. These present data suggested that these newly developed gene therapy are effective for neuroprotection and neurorestoration after acute cerebral ischemia. We strongly hope this gene therapy will be adapted in clinical medical care for the patients with cerebral infarction, and these patients will be getting better in Quality of Life (QOL) after gene therapy in near future.
Brain ischemia stimulates neurogenesis. Previous studies have focused on proliferation of neural stem cells. However, newborn neurons show a progressive decrease in number over time. First, we have shown that apoptosis could be involved in decrease of newborn neurons by TUNEL staining and Bcl-2 transgenic mouse. Then, we examined the involvement of cAMP responsive element binding protein (CREB) and CRE-mediated pathway in the survival of newborn neurons. Newborn neurons shows strongly positive signal for CREB phosphorylation. When we inhibited CRE-mediated gene expression, the number of newborn neurons decreased. In contrast, survival of newborn neurons was enhanced by administration of rolipram, inhibitor of phosphodiesterase IV, which could increase the level of cAMP. Our findings demonstrated the potential value of strategy for enhancing survival of newborn neurons after ischemia.
The JELIS (Japan EPA Lipid Intervention Study) was conducted with a PROBE design to examine the preventive effects of eicosapentaenoic acid (EPA) on coronary heart diseases (CHD) and other vascular events including stroke. In JELIS, patients with a total cholesterol of 250mg/dL or greater were recruited throughout Japan between 1996 and 1999. Patients were randomly assigned to receive 1,800mg of EPA daily with statin (EPA group; n=9,326) or statin only (control group; n=9,319) with a 5-year follow-up. One of the major findings was a significant suppression of CHD by 19% in the EPA group as compared to the control group. There were no statistically significant differences between the two groups in total stroke incidence. In patients with the past history of stroke, stroke recurrence was detected in 6.8% of patients in the EPA group as compared with 10.5% of patients in the control group, indicating a significant 20% relative reduction of stroke recurrence by EPA (p=0.047). The mean EPA concentrations on treatment in all patients were divided in tertile. Incidence of stroke was significantly lower in the highest tertile by 14% than in the lowest tertile (p=0.042). When only the patients with good compliance for test drug were selected for analysis, these patients in the EPA group showed a significantly lower incidence of stroke by 14% than those in the control group (p=0.048). The patients with the past history of stroke and good compliance for test drug showed a significantly lower incidence of stroke recurrence in the EPA group by 36% than in the control group (p=0.004). These data indicate that EPA is a promising treatment for prevention of stroke, especially for the secondary prevention of ischemic stroke in Japanese hypercholesterolemic patients.
REACH Registry is a large international observatioal study in patients with symptomatic atherothrombosis including cerebrovascular disease (CVD), coronary artery disease (CAD), and peripheral artery disease (PAD) as well as asymptomatic patients with multiple risk factors for atherothrombosis. We analyzed the baseline and one-year follow-up data on the risk of CVD in 5,197 Japanese patients enrolled in the REACH Registry. Except advanced age, hypercholesterolemia and diabetes under drug treatment as well as carotid plaque were frequent risk factors even more than uncontrolled hypertension in the Japanese CVD patients. One-year follow-up data showed that cardiovascular (CV) death and total CV events were highest in CVD patients and lowest in CAD patients. The incidence of CV events was higher in patients with CVD plus PAD than CVD alone. The incidence of CVD was very high in patients with carotid stenosis or plaque, PAD, and diabetic nephropathy. We clarified in this study that in CVD patients the risks of death and CV events are highest among patients with atherothrombosis. In order to reduce these risks, we may need strict management of not only hypertension but also hyperlipidemia and diabetes as well as strategies against carotid disease and PAD.
Information on the background and status of recurrence realities of lacunar infarction(LI) is still limited. We investigated 856 patients started to treat from 1997 to 2000, in whom a diagnosis of first-ever symptomatic LI was detected by MRI were enrolled, excluding possible cardiogenic embolic stroke or branch atheromatous disease using medical records in 14 institutions in Kanagawa, retrospectively. Recurrent cerebrovascular events (CVEs) occurred in 96 patients (11%) and the annual incidence was 4.8%. The mean systolic blood pressure (SBP) just before recurrence of CVEs was significantly higher than the mean SBP at final follow-up in recurrence-free patients (P<0.001). As the result of multivariate analysis performed after adjusting for following risk factors, antiplatelet therapy, a high SBP just before the end of follow-up, the presence of diabetes mellitus, and a modified Rankin scale ≥5 were independent prognostic factors related to recurrence of CVEs. The recurrence rates of CVEs or LI were decreased by lowering of the SBP and DBP just before the end of follow-up. Our analyses provide no evidence of a J-curve relationship between BP level and a recurrence after first-ever symptomatic LI.
Object: We analyzed relations between stroke and hyper tension or the therapy with resent elder Japanese data. Methods: 1) We performed a case control study by comparing rates of hypertension or the therapy with the data of patients in JSSRS and a general population. 2) We performed a open cohort study to analyze a relation between blood pressure revel and total mortality with a general population. The analysis repeated in each gender and each generation (40-59 years, 60-69 years, 70-79 years, 80-89 years). 3) We performed a open cohort study to calculate the risks of hypertension therapy in the same blood pressure revels with another general population. Results: Hyper tension showed significant risk to cerebral infarction in people less than 60 years old, but did not in people more than 60 years old. Hyper tension therapy showed significant risk to cerebral infarction in all generation. Blood pressure showed did not show significant risk to total mortality until 160/100 (systolic/diastolic) in both gender and all generations of the general population. Hyper tension therapy showed significant risk to total mortality at the revel of blood pressure over 180/110. The reason is assumed as the patients with higher blood pressure were treated with hard therapy. Discussion: Hypertension therapy is aiming to decrease blood pressure less than 140/90 now. This study shows the goal is not adequate for elder people. Cerebral infarction may result from the hard treatment.
At the time of approval of alteplase for treatment of acute ischemic stroke by MHLW, they required the companies 1) to present results of post-marketing efficacy and safety survey on 3,000 cases or more within 2 years, and 2) to confirm if i.v. dose of 0.6 mg/kg alteplase can recanalize or reopen the occluded artery. During the period of October, 2005 and September, 2006, the number of patients treated with alteplase was estimated to be 3,200. Among 2,867 patients registered to the post-marketing survey, data sheets were obtained from 2,069. These data were used for analysis of patients' characteristics and adverse effects. Symptomatic intracranial hemorrhage (sICH) within 36 hours was seen in 4.7%, slightly less than those of J-ACT, 5.8%. Death due to sICH was the same as those in J-ACT (1.0% each). Total efficacy rate of the post-marketing survey, mRS 0 & 1 at 3 months, was 32.7%, slightly worse than those of J-ACT, 36.9%. But, it was apparently better than historical observational data from JSSRS and J-MUSIC. These results may be explained by the fact that 121 patients (10%) with age ≥75 years and NIHSS score ≥23/JCS ≥100 were included. Proportion of favorable outcome in those 121 patients was only 6.0%, while those in 1,266 patients without such conditions were 37.0%. Mortality in each group was 42% and 16%, respectively. The above results suggest that we have to ask physicians/surgeons to keep the treatment guidelines more strictly (to avoid those patients with older age and high NIHSS score).
Role of endogenous tissue-type plasminogen activator (tPA) on focal cerebral ischemic injury (FII) after middle cerebral artery occlusion (MCAo) was studied by using tPA deficient mice (KO) and wild type mice (WT). FII size in KO was smaller than that in WT in permanent MCAo whereas larger in transient MCAo. These findings suggest that endogenous tPA protected FII through its thrombolytic action on transient MCAo, but deteriorated by neurotoxicity of tPA on persistent occlusion. Cerebral hemorrhage associated with antithrombotic and thrombolytic therapy in acute stroke is a major clinical problem. We demonstrated that heparin administration after the MCAo caused cerebral hemorrhage in WT, but not in KO. We observed an induction of MMP9 and its mRNA expression by heparin administration in WT but not in KO. We also investigated about hemorrhage induced by tPA administration using MMP3 deficient mouse. The hemorrhage is induced by tPA in wild type mice, but not in MMP3 deficient mice. Our findings suggest that endogenous tPA plays an important role in heparin-produced cerebral hemorrhage via MMP9 induction and activation and that hemorrhage induced by tPA administration is related with MMP3.
We investigated the treatment outcome of revascularization for acute ischemic stroke and reviewed therapeutic strategy of endovascular therapy and intravenous rt-PA therapy. The purpose of this study is to assess the safety and effectiveness our experiences of intravenous (IV) rt-PA and endovascular therapy for acute ischemic stroke patients who had main trunk (M1) occlusion of middle cerebral artery (MCA). Revascularization with thrombolytic therapy was performed in 57 acute ischemic stroke patients who had MCA (M1) occlusion. since 2002. IV rt-PA and endovascular therapy were performed in 27 and 30 patients, respectively. IV rt-PA therapy was indicated for patients of less than 3 hours from symptom onset. Endovascular therapy was indicated for patients beyond three hours that had DWI/PWI mismatch and for contraindication of rt-PA. Mean time from onset to treatment was 2.2 hours in rt-PA group and 5.3 hours in endovascular group. Recanalization rate were 56% in rt-PA group and 90% in endovascular group. Symptomatic intracranial hemorrhagic transformation was observed in 7.4% in rt-PA group and 3.3% in endovascular group. Good outcome (mRS 0-2) at 3 months was observed in 52% in rt-PA group and 53% in endovascular group. Neuroendovascular therapy after patients' selection by DWI/PWI MRI indicates an important role for acute ischemic stroke patients who have occlusions of main trunk of middle cerebral artery.
Over an 18-month period, 511 patients with ischemic stroke were admitted to our hospital; 18 were treated with intravenous recombinant tissue plasminogen activator (rt-PA, alteplase 0.6mg/Kg). After rt-PA treatment, symptomatic intracranial hemorrhages (SIH) developed in 5 patients (age range, 58-85 years; time to treatment, 84-175 minutes; baseline NIHSS, 16-21); 3 had a hemorrhagic infarction; 1 had an intracranial hematoma; and 1 had a subarachnoid hemorrhage. Development of SIH related to NIHSS and antithrombotic medications. Three months after onset, their modified Rankin scale (mRS) scores were 2 in 1 patient and 5 in 4 patients. One patient had a cardioembolic stroke (CE) in the middle cerebral artery (MCA) territory that did not affect the perforating area and recovered functionally (mRS, 2), while 2 patients who had a CE in the entire MCA territory became bedridden (mRS, 5). In 2 patients not treated with anticoagulants, the hemorrhagic infarction kept enlarging until 2 weeks. In one patient who developed a subarachnoid hemorrhage after rt-PA, no aneurysms had been noted on MR angiography at the time of arrival. In conclusion, the risks and benefits of rt-PA need to be carefully considered in stroke patients, especially, those with severe neurological deficits.
Thrombolysis with intravenous rt-PA for acute cerebral infarction was approved in Japan in 2005. The approval was so late among advanced countries in the world that we need to study hard to solve problems, not only of the therapy itself but also of those proper to our country. To help this task, on-going clinical trials on this therapy in the world were surveyed via internet at http://clinicaltrails.gov/ and www.strokecenter.org/ and from the information at international congress of stroke in USA this year. As the result, 29 on-going trials were found and divided in 8 groups, prolongation of time window, evaluation of tPA effect, combination with other drugs or therapy, intra-arterial therapy, drugs other than Alteplase, combination with ultrasound, application to the community and the data base. Essential information of each study was shown.