The relationship between apolipoprotein E (apo E) genotype and ischemic cerebrovascular disease (CVD) was investigated to evaluate the putative role of the apo E genotype, especially the ε4 allele. The apo E genotype of 31 subjects with asymptomatic lacunar stroke and 25 subjects with asymptomatic stenosis of the intracranial arteries was determined by the PCR-RFLP method. Classification of the CVD was performed based on the clinical symptoms, magnetic resonance imaging (MRI) findings and magnetic resonance angiography (MRA). The relative frequency of the apo E alleles was estimated in 200 control subjects without any MRI or MRA abnormalities. The frequency of the ε4 allele in the asymptomatic intracranial stenosis group (36%) was higher than that in the control group (15.5%) (p=0.022). Multiple logistic regression analysis showed this difference to be significant (p=0.042; 95%CI, 1.04-6.84; odds ratio, 2.66). However, no asociation between the ε4 allele and asymptomatic lacunar stroke was observed. The ε4 allele appears to be a susceptible genetic locus for intracranial atherosclerosis, but not for lacunar stroke. Our data suggest the ε4 allele could be a predisposing factor for atherosclerosis.

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To evaluate the outcome in patients with low-grade stenotic lesions of the extracranial carotid artery, 347 consecutive outpatients aged 60 years or older were studied with regard to outcome after performing examinations by carotid ultrasonography and platelet function tests. They had a variety of disease, including 107 patients with cerebrovascular disease and 77 patients with dizziness, although patients with high-grade carotid artery stenosis of more than 70% of the vessel diameter were excluded. The mean age was 77.5 years, and the patients consisted of 161 men and 186 women. Based on the ultrasonographic findings, carotid lesions were defined as having plaque or stenosis of 50-70% of the vessel diameter. Plaques, defined as thickened intimamedia complexes of 2.1 mm or more in height, were classified into 2 types according to their morphometric dimensions (nodular and mural plaques). The patients were divided into 3 groups based on the number of carotid artery lesions: the no lesion group (n=153), which had no carotid lesion; the unilateral lesion group (n=103), which had a unilateral carotid lesion; and the bilateral lesion group (n=91), which revealed carotid lesions bilaterally. The patients were also divided into 4 groups on the basis of the plaque morphometry: the nodular plaque group (n=66), which had nodular plaque only; the mural plaque group (n=118), which had mural plaque with or without nodular plaque; the stenotic group (n=10), which revealed stenosis of 50-70 % of the vessel diameter ; and the no lesion group. Platelet function was assessed using a platelet aggregometer with adenosine-5' -diphosphate. At baseline, the mean age as well as the incidence of advanced thrombotic diseases and total dependence in the ADL status was higher in the bilateral lesion group and mural plaque group than in the no lesion group. The mean follow-up period was 3.9 years. A total of 66 patients died, and the most common cause of death was pneumonia, followed by vascular events. The annual mortality rate due to vascular events was 0.5% in the no lesion group and 1.7% in the unilateral lesion group, while the rate was 4.0% in the bilateral lesion group. Furthermore, the annual mortality rate due to vascular events was 1.8% in the nodular plaque group, 3.6% in the mural plaque group, and 0% in the stenotic group. Log-rank statistics derived from Kaplan-Meier survival curves showed these rates to be significantly higher in both the bilateral lesion group and the mural plaque group than in the no lesion group. The Cox proportional hazards model for death due to vascular events demostrated a significantly high hazard ration in the bilateral lesion group, the mural plaque group, and the accelerated platelet function group. These findings suggested that, in addition to undertaking further assessments of vascular lesions and control of vascular risks, antiplatelet therapy should be performed in those patients with bilateral carotid lesions or mural plaque to prevent vascular events.

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PURPOSE: We investigated the effects of ticlopidine and aspirin on platelet aggregation in post-thrombotic stroke patients using a novel whole blood aggregometer by a screen filtration pressure method. METHODS: The subject comprised 51 ticlopidine (200 mg/day)-medicated post-thrombotic stroke patients, 34 aspirin (330 mg/day) -medicated post-thrombotic stroke patients and 25 normal controls. The ADP-and collagen-induced platelet aggregability was determined with a whole blood aggregometer employing a screen filtration pressure method. The aggreometer measures the resistance of flow of whole blood samples through the screen of a microsieve with 30-micrometer square openings. To evaluate lpatelet aggregability, the platelet aggrega-tory threshold index (PATI) was determined using a grading curve obtained by plotting four concentrations of the inducers (ADP or collagen) along tha horizontal axis and plotting their pressure rate (%) along the longitudinal axis. The PATI was defined as the concentration of inducer producing a pressure rate of 50%. We also measured platelet aggregability by the conventional optical method, and compared the results of this method with those obtained by the screen filtration pressure method. RESULTS : (1) In comparison with the normal controls, the PATI obtained with ADP or collagen was increased in both the ticlopidine-and aspirin-medicated patients, indicating that the whole blood platelet aggregability was significantly reduced in the ticlopidine-and aspirin-medicated patients. (2) The ADP-induced whole blood platelet aggregability was increased at 60 min after blood collection as compared to the aggregability at 5 min in the controls and ticlopidine-medicated patients.(3) The PATI obtained with ADP showed a significant negative correlation with the platelet aggregability measured by the optical method. CONCLUSION: The present platelet aggre-gometer may be useful for monitoring the whole blood platelet aggregability in patients receiving anti-platelet medication.

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Adhesion molecules of circulating leukocytes and endothelial cells play an important role in the pathogenesis of acute cerebral infarction. We reported previously that the expression of lymphocyte adhesion mole-cules, LFA-la. β(CDI la bright and CD18 bright), increases from the acute phase to chronic phase of the disease. In the present study, 40 patients with chronic lacunar infarction and 25 age-mathed controls were inves-tigated, employing immunofluorescence flow cytometry and ELISA to measure the lymphocyte membrane expression of LFA-lα(CD11a bright), LFA-1β (CD18 bright), VLA-4α(CD49d) and VLA-4β(CD29 bright), and the plasma levels of soluble (s) ICAM-1 and sVCAM-1, which are ligands for LFA-1 and VLA-4. The rela-tionships between the adhesion molecules and risk factors of cerebrovascular disease were analyzed. The ex-pression of LFA-la, R and the level of sICAM-1 showed a significant increase in the patients as compared to the controls (p<0.01, p<0.05, and p<0.001, respectively). Although there was no siginificant difference in the case of VLA-4, the level of sVCAM-1 was significantly higher in the patients than in the controls (p<0.0001). The expression of LFA-la, R tended to be increased in smokers, as was the level of sVCAM-1 in diabetics and smokers. It seems likely that the local vascular lesions are chronically affected by repetition of ischemic reper-fusion in the chronic phase of cerebral infarction, so that the expression of adhesion molecules of endothelial cells (ICAM-1, VCAM-1) increases and, thereby, the expression of adhesion molecule of lymphocytes (LFA-1) increases.

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A 68-year-old man suddenly suffered from right-sided hypesthesia, dysesthesia and hemiparesis. His neurological findings on admission consisted of right-sided loss of position, light touch and vibratory sense and diminished sensation to all modalities from C2 to C4, right-sided hemiparesis and urinary retention. MRI revealed a right-sided infarct extending from the lower medulla to upper cervical spinal cord in the territones of the posterior spinal artery. A T2-weighted image showed an intimal flap in the right vertebral artery. Right vertebral angiography demonstrated a tapering occlusion of the right vertebral artery. This is a rare case of posterior spinal artery syndrome due to vertebral artery dissection.

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A 74-year-old woman exhibiting drowsiness, conjugate deviation and left-sided hemiparesis was transferred to the author's institution at 4 days after symptomatic onset. Her NIHSS was 15. Magnetic resonance (MR) images on admission revealed an infarction in the territory of the right deep border zone, and an MR angiogram demonstrated poor visualization of the right internal carotid artery (ICA). Cerebral angiograms showed a high-grade stenosis of the right ICA. After the patient and her family gave written informed consent, she was treated by percutaneous transluminal cerebral balloon angioplasty (PTCBA) on the admission day. Her neurological symptoms were not improved immediately after the PTCBA, and hyperbaric oxygenation (HBO) was started. Her NIHSS improved up to 6 when the HBO was ended 12 days later. These results suggest that combination therapy by PTCBA and HBO can improve the neurological symptoms even at 4 days after progressing stroke has occurred due to a high-grade stenosis.

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Recent changes in lifestyle have caused an increase in extracranial internal carotid artery (ICA) lesions in Japan. The prevalence of severe ICA atherosclerosis with>50% stenosis in the Suita City was 4.4% (7.9% in men and 1.3% in women), being almost equal to that reported in developed western countries. Several clini-cal studies also indicated that atherothrombotic brain infarction particularly due to extracranial ICA lesions has rapidly been increasing in frequency in Japan. The ICA lesions have strong relationships to cardiovascu-lar risk factors and coronary heart diseases.
Carotid ultrasonography is a rapid, noninvasive and accurate way to examine ICA lesions. Diffusion MRI studies will provide new knowledge how ICA lesions produce infarcts particularly in borderzone areas.
The efficacy of carotid endarterectomy (CEA) in the management of severe ICA stenosis was established in US, Canada, and Europe, but not in Japan. Carotid artery stenting remains a matter of investigations. Clini-cal evidence on the effectiveness and limitations of such surgical interventions and medicla management with antithrombotic agents and HMG-CoA blockers should be collected for Japanese patients with ICA lesions.

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We have experienced 188 carotid endarterectomies for symptomatic and asymptomatic carotid stenosis. From those experiences we proposed issues as indicated above. Pathological features of the Japanese plaque are similar to those of the American Caucasians. The Japanese plaques are rather early stage of the disease. Pathological feature of familial hypercholesterolemia in Japanese patients is identical of the Americans, suggesting importance of diet. Discussion on evidence-based medicine (EBM) is focused on carotid endarterectomy. Surgical indication for asymptomatic carotid stenosis is a matter of issue and we should be careful for EBM data reading. Post endarterectomy restenosis is not a rare condition and we should pay attention to this pathology. Our experience is presented. Endarterectomy versus endvascular stent placement is a matter of issue and we discussed indications for those procedures. Finally, request from neurosurgeon to internist is listed.

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Atherosclerosis in cervico-cephalic arteries is a lesion responsible for atherothrombotic brain infarcts. The pathological studies on the diversity of brain infarcts found in the autopsy cases with significant athero- sclerosis of the carotid arteries are summarized. All five autopsy cases with occlusive carotid thrombosis showed arterial territorial infarcts and no borderzone infarcts. Fifteen autopsy cases with atheromatous embolism in the brain, however, showed two types of brain infarcts (6 with arterial territorial infarct, 9 with bor-derzone infarct). This diversity of the lesion appeared to be correlated with histological features of the embolic materials (cholesterol crystal with or without other atheromatous components, especially fibrin). These variation in the components of the emboli may determine the size and location of the lodged arteries and feasibility of re-opening and hemorrhagic transformation. Recent development of transcranial Doppler and diffusion-weighted MRI enabled us to betect and follow-up very early stage of brain embolism and their silent recurrence, and may be valuable for clarifying the pathophysiology of brain embolism which occur based on the carotid atherosclerosis.

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Oxidized LDL (Ox-LDL) has been suggested as a key factor in atherogenesis. Ox-LDL can be specifically bound and internalized by Ox-LDL receptors, which transforms macrophages into foam cells and induces proinflammatory responses in vascular cells. These play crucial roles in the formation and deatabilization of atherosclerotic plaques. LOX-1 is a 40-50 kDa type II membrane glycoprotein, which acts as a cell surface receptor for Ox-LDL, in vascular endothelial and smooth muscle cells as well as macrophages. Ox-LDL uptake by LOX-1 down-regulates Bcl-2 expression, uprgulates Bax expression, and thereby induces apoptosis of cultured vascular smooth muscle cells. In addition, expression of Bax and LOX-1 was colocalized in atherosclerotic lesions of human carotid arteries. SR-PSOX, a novel class of Ox-LDL receptor in macrophages, is a type I membrane glycoprotein whose molecular weight is appoximately 30kDa. SR-PSOX is abundantly expressed by macrophages, but not smooth muscle or endothelial cells, accumulated in the intima of human carotid atherosclerotic plaques. Ox-LDL receptors, such as LOX-1 and SR-PSOX, may play key roles in atherosclerotic plaque formation including human carotid arteries.

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Carotid endarterectomy has been established as the gold standard for the treatment of carotid stenosis. However, patients with high risk characteristics including advanced age, heart/lung diseases, diabetes mellitus, and vascular co-morbidities represent a large segment of the perioperative morbidity and mortality reported from endarterectomy trials. Carotid stenting has been presented as an alternative treatment especially for these high risk patients for several years. Recently, Wholey et al. repoted the outcome of carotid stenting collecting from a large number of hospitals. The initial success rate of stent implantation was 98.4%, and the complication rate within 30 days after the procedure were as follows ; transient ischemic attack : 2.82 %. minor stroke : 2.72%, major stroke : 1.49%, death: 0.86%. According to this report, carotid stenting seems feasible and safe. However, carotid stenting has two major problems to be solved, distal embolization and restenosis. Distal embolization of atherosclerotic debris as a consequence of stent implantation was the major reason of neurological complications, however recent investigations showed that distal protection devices can reduce the complication caused by distal embolization markedly. Restenosis, renarrowing of the lesion, was another problem, however the newest technology and knowledge developed in the field of cardiovascular interventions will solve this problem.

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Stroke patients have longer length of hospital stay. After the introduction of 3 types of critical pathway dedicated for various severity of acute ischemic stroke in 1995, the average length of hospital stay of both stroke and non-stroke patients declined from 30.0 days (1993) to 14.9 days (1999) in our hospital. Rehabilitation in the recovery stage could be done in the specialized rehabilitation hospitals within Kumamoto due to inter-hospital cooperation. Our acute stroke team can concentrate on the treatment of stroke in the acute stage (within 2-3 week from the onset). We have been developing this stroke management system based on an acute stroke unit with referral to a rehabilitation unit in other hospital (inter-hospital referral model) in contrast to the conventional system with a combined acute and rehabilitation stroke unit in a single hospital (intra-hospital referral model). Eight-hundred and six patients (459 male, 347 female, 71.0±12.2 years old) with acute ischemic stroke were admitted to three hospitals between May 1999 and April 2000. The average NIHSS was 8.2 (median 5). 41.3% of the patients admitted within 3 hours of stroke onset. The length of hospital stay was 17.3±17.4 (median 14) days. Two-fifth of all patients discharged to their home, and 76.6% of them discharged within 14 days. Another 2/5 patients were transferred to rehabilitation hospitals, and 62.1% of them discharged within 21 days. The reduction of length of hospital stay was achieved by the use of critical pathway and the inter-hospital cooperation.

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Recent advances of diagnosis and therapy have been promoting the improvement of clinical outcomes in stroke patients. However, procedures for diagnosis and therapy have been complicated according to the advance, and the sufficient knowledge and medical ability are required in the stroke treatment. Stroke care unit (SCU) has been introduced to emergency medical centers in Japan, but its criterion has not been fully established especially for medical staffs. The guideline for stroke management will be published by the joint committee in the next year. For acute stroke patients, it is desirable that the medical specialist carry out the treatment according to the established guideline in SCU. Applying SCU for the improvement of the clinical outcome, the medical specialist is necessary for carrying out the complicated stroke treatment and the management of medical team in SCU.
For the stroke management in a local community, the medical specialist in SCU is suitable for the role of establishing the cooperative medical care system with hospitals and pre-hospital teams.
In the present time, stroke patients are treated in neurosurgical department, neurological department, cardiological department, emergency medical department or other departments. Only a small number of hospitals have SCU. Therefore, the level of stroke treatment should be standardized between those departments. For this purpose, the system of medical specialist for stroke treatment is available.
The establishment of the board qualified system for medical specialist for stroke treatment is required to improve the clinical outcome of stroke patients and necessary in the effective management of SCU. The name of board qualified strokologist is appropriate for such a medical specialist.

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In the begining of this century, a dramatic increase of stroke patients is expected in concomitant with continuous increase of older-age population in the developed countries. There are three major phases for stroke management: primary prevention, treatment at acute and chronic phases of stroke. First, we focused on the importance of effective population approach for reducing the mean level of causative risk factors. Selfrating stroke risk scoring system should be developed and prevailed by using modern information technology. Among people at particularly high risk of stroke, genome-based tailor-made prevention strategy should be established. Through the basic research on 'ischemic tolerance', vaccination against stroke should also be developed in the future. Second, we focust on effective treatment of brain attack by establishing primary stroke centers, where other than thrombolytic therapy neuroprotective approaches such as mild hypothermia and gene theapies would become possible. Finally, we focused on the importance of secondary prevention based on pathophysiological mechanism of each patient and well-organized comprehensive rehabilitation based on the promotion of understanding of molecular mechanism of neuronal prasticity. Regenerative medicine such as stem cell seeding and promotion of neurogenesis in the damaged brain should be developed for chronic phase of patients in the near future.

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