It has been postulated that hemostatic molecular markers become increased in acute ischemic stroke. For example, TAT and D-dimer, which are indices of coagulation and fibrinolytic activation, are significantly increased in cardioembolic stroke, whereas βTG and PF4, which are indices of platelet activation, are significantly increased in atherothrombotic stroke. No significant changes in hemostatic molecular markers are observed in lacunar stroke. Atherothrombotic stroke involves various stroke mechanisms. However, no systematic investigation of the relationships between the mechanisms of atherothrombotic stroke and hemostatic molecular markers has yet been performed. The present study was therefore designed to examine the levels of hemostatic molecular markers in different subtypes of atherothrombotic stroke.
A total of 237 patients with acute ischemic stroke were investigated within 2 days of onset of stroke. The study group included 95 patients with lacunar stroke, 51 with atherothrombotic stroke, and 91 with cardioembolic stroke. Patients with lacunar stroke were classified into two groups according to infarct size as determined by MRI : (1) small lacuna type (61 patients with MRI lesions of less than 15 mm in diameter), and (2) giant lacuna type (34 with MRI lesions of 15 mm or more). Atherothrombotic stroke patients were classified into two stroke subtypes besed on the stroke mechanisms : (1) 15 patients with artery to artery embolism, and (2) 36 with non-artery to artery embolism. The hemostatic molecular markers were measured within 2 days of onset.
The plasma levels of TAT and D-dimer were significantly higher in the cardioembolic stroke patients than in the atherothrombotic stroke and lacunar stroke patients (p<0.005 and p<0.0001, respectively). The plasma levels of TAT, D-dimer, βTG and PF4 in the lacunar stroke patients were significantly higher in patients with giant lacunae than in those with small lacunae (p<0.05). Among the atherothrombotic stroke patients, the plasma levels of TAT and PF4 were higher in artery to artery embolism patients than in nonartery to artery embolism patients, the plasma levels of D-dimer and βTG displayed no significant differences among the subtypes of atherothrombotic stroke patients.
Our results suggest that different mechanisms of coagulation may underlie the different subtypes of atherothrombotic stroke. Anticoagulation therapy could be recommended for artery to artery embolism as well as cardioembolic embolism. In lacunar infarcts, coagulation and platelet activation differed between small lacuna infarcts and giant lacuna infarcts. Coagulation and platelet activation were significantly increased in giant lacuna infarcts, suggesting that combination therapy involving antiplatelet and anticoagulation should be considered in the treatment of giant lacuna infarcts.

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We quantitated the function of walking in 34 patients with severe ischemic lesions in the white matter, clarifying the association with other staging markers (intellectual function, orthostatic blood pressure change, and periventricular hyper-intensity on T₂-weighted MRI). The necessary time to 10-meter walking showed an inverse correlation with the numbers on the Kana pick-up test, and the average steps per day was correlated with the Kana pick-up test data. The orthostatic blood pressure decline was more marked in patients who took under 5, 000 steps per day than in those taking over 5, 000 steps. Furthermore, an inverse correlation was noted between the average steps per day and the severity of periventricular hyperintensity. Gait disturbance is an important symptom of lesions of the white matter, so that analysis of gait, especially of the average steps per day, is thought to be useful as a quantitative marker of the severity of this condition.

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The effects of Oren-Gedoku-To (TJ-15) and Toki-Shakuyaku-San (TJ-23) on cerebral ischemic changes were analyzed in Wistarrats. TJ-15 (group A), TJ-23 (group B) or distilled water (group C) was given through a catheter inserted into the stomach every day for 14 days. Under general anesthesia, the common carotid arteries were tied and cut bilaterally. Drug or distilled water was given every day until 30 days after the surgery. Overall, 6/13, 5/12, and 5/12 rats in groups A, B, and C, respectivery, died. In group A, 3/6 died within 2 days after the surgery (early phase) and the other 3 animals died within 11-14 days after the surgery (late phase). In groups B and C, each of the 5 animals died within a few days. The death rate at the early phase in groups A, B and C was 23, 42, and 42%, respectively, and the rate was significantly low in group A. In surviving animals, infarction was seen in the cortices and/or hippocampus. The rates of appearance of infarction were 0/7 (0%), 1/7 (14%), and 5/7 (71%) in groups A, B, and C, and the rates in groups A and B were significantly low compared to group C. VEGF positive cells were apparent in the surrounding area of infarction, but there were no significant differences in their rate of appearance or distribution in the animals with infarction in the three groups. bFGF positive cells were also significantly increased in the surrounding area of infarction and no significant differences were noted among the animals with infarction in the three groups. Both ER (estrogen receptor) positive cells and PgR (progesterone receptor) positive cells were observed in the hypothalamus of all animals. There were no changes in numbers of ER and PgR positive cells in the three groups. The concentrations of estrogen (estrone, estriol and estradiol) in the blood showed no differences in the three groups. Based on our results, it is suggested that TJ-15 exerted, a protective effect against ischemic changes in the acute and chronic phases, while TJ-23 exerted a protective effect against ischemic changes in the chronic phase.

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Stroke is both a leading cause of death and a major cause of severe neurologic disability in Korea. According to the records of the National Health Insurance Corporation and the Korea National Statistical Office, 64.7% of stroke cases were due to cerebral infarction, and 35.3% to cerebral hemorrhage in 2000; and the stroke mortality rate was 72.9 per 100, 000 of the population per annum.
We have two unique features in terms of stroke management in Korea, namely, the presence of traditional herbal medicine and a complicated medical referral system. Historically traditional oriental medicine has been the first-line of stroke management, but after the introduction of western medicine its position has been gradually eroded. In Korea, the referral of stroke patients tends to be influenced by the initial presumptive diagnosis and the level of consciousness of the patients. Alert patients with ischemic stroke are apt to go to an oriental-medicine hospital, and hemorrhagic stroke patients or stuporous or comatose patients tend to be referred to a western-medicine hospital. In addition, our complex medical referral system has often resulted in delayed arrival at appropriate medical centers, and has contributed to mortality and morbidity rates. Intense public education is required to provide the public with more information about stroke. The introduction of a systematic medical referral system is also imperative for maximizing the effectiveness of stroke management in Korea.

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Objective : Thrombolytic therapy for acute ischemic stroke was implemented into clinical routine 4 years ago. Unfortunately, at present less than 2% of eligible patients receive thrombolytic therapy. We present an overview of all hitherto completed trials of intravenous and intraarterial thrombolytic therapy for carotid and vertebrobasilar artery storoke including recommendations for therapy and diagnostic procedures and their impact on patient selection and meta-analyses. New imaging techniques such as MRI diffusion- and perfusion-weighted imaging and their impact on patient selection are discussed. Finally, phase IV trials of thrombolysis in general and cost efficacy analyses are presented. Data Sources : We performed an extensive literature search not only to identify the larger and well-known randomized trials but also to identify smaller pilot studies and case series. Trials included in this review, among others, are the NINDS study, ECASS I and II, and ATLANTIS A and B, PROACT I and II and two large meta-analyses, including the Cochrane Library report. In addition, we inclue our own experience with more than 500 thrombolysis patients over the past 20 years where appropriate. Conclusion : Intravenous thrombolytic therapy with rt-PA has demonstrated a significant benefit and have proven to be safe for patients who can be treated within 3-6 hours after symptom onset. This benefit is at the cost of an increased rate of symptomatic intracranial hemorrhage without a significant effect on overall mortality. In general, the benefit of thrombolysis decreases and the risks increase with progressing time after symptom onset. Intraarterial thrombolytic therapy significantly improves outcome if administered within 6 hours after stoke onset. Vertebrobasilar occlusion has a grim prognosis and intra-arterial thrombolytic therapy to date is the only life-saving therapy that has demonstrated benefit with regard to mortality and outcome, albeit not in a randomized trial. New MRI-techniques may facilitate and improve the selection of patients for thrombolytic therapy. Presently, thrombolytic therapy is still underutilized because of problems with clinical and time criteria, and lack of public and professional education to regard stroke as a treatable emergency. If applied more widely, thrombolytic therapy may result in profound cost savings in healthcare and reduction of longterm disability of stroke patients.

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In order to assess the present condition of the Brain Dock, questionnaires were sent to 565 medical facilities enrolled in the Japanese Society for Dectection of Asyptomatic Brain Disease and 235 out of them responded to the questionaires. The results were as follows : MRI and MRA was performed almost at 100% of the facilities ; the higher cortical function test was performed only at 31.3% of them ; magnetic field strength of MRI was over 1.0 tesla at 70% of them ; the average fee was about Y50, 000; and 58% of the examinees were members of either the health insurance or the local self-governing bodies with which each facility has a contact.
Persons categorized as the high-risk group are highly suggested to be screened at the Brain Dock. Both accountability and transparency is reqested at the Brain Dock.

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Unruptured cerebral aneurysm study in Japan (UCAS Japan) is conducted to clarify natural course and treatment risks of unruptured cerebral aneurysms (UCA), and build national data bank. This is a prospective cohort study and enrolled patients are cases with newly diagnosed UCA after Jan. 1, 2001. Data of all patients with UCA, either treated or observed, are registered through internet. All cases are scheduled to have periodic follow-up at 3 months, 12 months and 36 months after the diagnosis. During the last l7months, 2, 979 new patients with UCA are registered from 385 institutions. Male-female ratio was 1 :2. The most frequent reason for imaging, which leaded diagnosis of UCA, was ill-defined symptoms such as headache or dizziness. Multiple aneurysms were found in 18% of cases. Size of aneurysm ranged 3-45mm (median 5mm) and the most frequent location of aneurysm was internal cerebral artery. At the first registration, craniotomy was indicated in 35% and endovascular treatment in 4% of casese. Three months follow-up were reported in 2, 327 cases and 12 months report in 579 cases. Treatment was performed in 943 cases with 1, 074 aneurysms. We are planning to call for further patient's enrollment and conform reliable data source to direct future management of UCA.

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To obtain relevant data on "silent" lesions found in health screening of the brain, we analyzed findigns on magnetic resonance imaging in 539 community dwelling elderly subjects with a mean age of 66 years. The prevalence of silent brain infarction and deep white matter lesions were 12.4% and 32.1%, respectively. Multivariate analysis with a logistic regression model revealed that silent brain infarction was significantly associated with age, male gender, and hypertension. Recently, elevated plasma homocysteine levels were suggested to be an independent risk factor for silent brain infarction. Particular attention should be payed to such potentially treatable or modifiable factors for ischemic lesions in the setting of health screening of the brain. With regard to deep white matter lesions, data on prevalence or pathogenetic factors are often controversial. One source of conflicting results in white matter hyperintensities on magnetic resonance imaging would be the differences in visual rating scale. In our experience, multivariate analysis revealed that deep white matter lesions were significantly associated with age, hypertension, total cholesterol, and decreased plasma tryptophan concentrations. A further important point in health screening of the brain is an early detection of cognitive decline at its mild stage to prevent the future development of dementia. Based on the clinical evidence accumulated in health screening of the brain, we need to work out a better strategy of preventing subsequent symptomatic stroke or vascular cognitive impairment.

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Gradient-echo or echo-planar gradient-echo T2^*weighted MR imaging frequently detected hypointense lesions in symptomatic patients with lacunar infarction and intra-cerebral hematoma with high sensitivity. The lesions were increasingly found in neurologically normal elderly patients. The histopathological studies revealed that hypointense lesions on T2^*weighted MR imaging mainly represented hemosiderin depositionin in the brain tissue and hemosiderin-containing macrophages. The distribution of hypointensity on gradientecho T2^*weighted MR imaging was similar to that of hypertensive cerebrovascular diseases. High incidence of the lesion was associated with hypertension, lacunar infarction, intracerebral hematoma, leukoaraiosis and increasing age. Some cases indicated that hemorrhagic infarction was associated in patients with T2^* weighted MR hypointensity than those without after acute thrombolytic therapy. Anti-coagulant therapy induced high incidence of gradient-echo T2^*weighted MR hypointensity. The accumulating data suggested that the lesions detected by gradient-echo T2^*weighted MR imaging is an indicator of potential risk of cerebral hemorrhage and hypertensive cerebrovascular diseases.

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Based on the currently available evidence, we estimated cost-effectiveness of brain check-up with MRI/ MRA to diagnose and treat asymptomatic unruptured cerebral aneurysm.
In this simulation analysis using a medical decision analysis model, we estimated costs and effectiveness under two different strategies ; one is asymptomatic 100, 000 Japanese population, aged mid-50's, receive brain check-up (Screen group), and another is nobody receive brain check-up (No Screen group). Costs included those for brain check-up (JPY 30, 000), diagnostic work-up (JPY 200, 000), treatment of unruptured aneurysm (JPY 2, 000, 000), treatment of ruptured aneurysm (JPY 4, 000, 000), and for long-term care ranging from JPY 1, 000, 000 to 5, 000, 000 per year according to the severity of disability. Effectiveness of brain check-up, in this analysis, was defined as the gain of life-years of survival, which is calculated as the difference of total life-years between the Screen group and the No Screen group.
Based on the currently available evidence in Japan, we assumed the prevalence of asymptomatic unruptured aneurysm in the Japanese population aged mid-50's as 5%, sensitivity of brain check-up as 87%, its specificity as 92%. Likewise, we estimated the distribution of aneurysm size and the probability of spontaneous rupture according to the size, and the life and functional prognosis of the cases (see Text).
The results indicated that mortality from subarachnoid hemorrhage would be decreased in the Screen group by about 80% than in the No Screen group. The cost for saving the life of one case with asymptomatic unruptured aneurysm was estimated to be JPY 74.4 × 10⁶, and the cost for one life-year suvival was estimated to be JPY 2.4×10⁶.

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Neural stem cells form fuctional synapses, and differntiate into neurons in the hippocampus of the ischemic rats. The possibility of treating stroke patients by using these cells will be discussed.

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The adult brain has generally been thought to be incapable of significant self-repair. Recently, the adult mammalian brain has been shown to harbor neural stem cells that retain the potential for both neural production and differentiation in the experimental animal models. These findings offer the prospect of the potential use of neural stem cells for regenerative strategy. In the present report, the possible therapeutic strategy of the neural stem cell transplantation for the stroke is discussed.
Self-renewing and multipotential properties of human neural stem cells were demonstrated in vitro. Histological examination of the ischemic lesion following transplantation revealed that the transplanted human neural stem cells differentiated into both neuronal and glial lineages. In addition, transplantation of neural stem cells into the stroke models resulted in the reduced ischemic volume. Behavior studies also demonstrated the functional benefits following transplantation. These findings reveal that human neural stem cells seem to be useful to establish a cell therapy for stroke.

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Nerve injured peripheral motor neurons are able to survive and regenerate, however the potential for regeneration is not high in neurons of the central nervous system (CNS). Using motor nerve injury model, we have collected several genes associated with the survival and regeneration, and suggested some possible molecular mechanisms underlying the survival and regeneration in injured motor neurons. The fate of injured motor neurons seems to be decided by the balance between survival and death signals elicited by injury. Some of these survival signals are not seen in CNS injury model such as the middle cerebral artery (MCA) occlusion model. This might be a reason why CNS neurons are fragile.

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Involuntary movements are not uncommon consequences of stroke, which limit patients' daily activity greatly. Ablative neurosurgical procedures, such as thalamotomy and pallidotomy, for control of involuntary movements always carry a risk associated with creating additional lesions in an already damaged brain, and the results of these procedures are not always satisfactory. Due to the unpredictability of the effects and the irreversibility of the procedures, most physicians have been reluctant to recommend ablative neurosurgical treatments to their patients whose brain is already damaged by stroke. In contrast, there is not such a risk in deep brain stimulation (DBS) therapy. Based on our experience with 25 patients with post-stroke involuntary movements, clinical values of DBS are summarized. A quadripolar DBS electrode is placed in such a way that the most distal contact is located on the ventral part of thalamic VIM nucleus and the most proximal contact in the dorsal part of VOP nucleus. Complete control of involuntary movements has been achieved by DBS in many patients (76%) with hemiballism, hemichoreo-athetosis, jerky dystonic unsteady hand, distal resting and/or action tremor and proximal postural tremor. The effects have continued to be seen for the entire follow-up period ranging 1-9 years in our series. DBS is an ideal therapeutic option to control post-stroke involuntary movements due to the reversibility of the procedure, and alterability of anatomical location and extent of stimulation.

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The mechanisum of the functional recovery by repetitive transcranial magnetic stimulation (rTMS) is not studied fully yet. In this study we analysed the memory and behavior, and with changes of the neurotransmitters, by using tha passive avoidance method and elevated plus-maze test, and microdialysis methed. As the results, rTMS does not change the memory compared with electric convulsive test. And the serotonin level in group of rTMS is correlated with anxiolytic effect, compared with the group of sham and control in small animals. rTMS might induce the slow EEG in human, which might be related with anxiolytic effect by rTMS. Apparenty rTMS has the effect on the brain, and it has the great possibility to make the neural reorganization.

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For prolonged consciouseness disorder patient under persistent vegetative state, the music-exercise therapy which is applied in the early stage of sickbed would be effective to these lost cerebral function as a whole body activating rehabilitation. As the purpose of medical verification of the music-exercise therapy, some bio-electrical measurement was done. That is the two autonomic nervous activities and the change of the emotion or some feeling by the method of analysis of heart rate variability as the unconscious bio-reply signals reflectively from the patient brain recognition.
The Vital Index including emotion was induced from the heart rate variability analysis by LRR-3/Mem-Calc system which can be measured a calculated the signals to the slope of the power law relation between the power and the frequency of R-R interval variation from the whole frequency range (0.01-0.6) of each 30 second during all course of a therapy analyzed.
It was shown that the consciousness disorder level of persistent vegetative state could be diagnosed from the graph divided in 9 areas (IA-IIIC) that arranged from the clinical scale of 'three step scoring table (score 0-40)' and 'Vital Index' including emotion.
In addition, the good therapeutic result was also obtained by the case of early apply of music-exercise therapy, which is showed from the data of the 16 cases with above therapy repeated.

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