Recent studies have emphasized that endothelial cells produce mediators which control vascular tone not only in the systemic circulation but also in the cerebral circulation. The aim of the present study was to clarify the role of the endothelium in the cerebral vasodilatory response to hypercapnia. An experimental model for cerebral endothelial injury was prepared using monocrotaline (MCT), a pyrrolizidine alkaloid, which causes endothelial damage to the pulmonary and other vascular systems. The regional cerebral blood flow (r-CBF) was measured by the hydrogen clearance method, being monitored in the right and the left frontal white matter. MCT (240 mg/kg) was infused continuously into the left carotid artery. Endothelium-derived vasodilation by ACh (1.7 μg/kg/min) was tested before and after the MCT administration. The dilatory response to hypercapria was also measured during inhalation of 5% CO₂ in air before and after the MCT administration. Following MCT infusion, the endothelium-derived vasodilation in response to ACh in the left frontal white matter was decreased (from 12.7% to -4.4%), but the resting r-CBF did not change significantly (from 30.2 to 29.2 ml/100 g brain/min). The vasodilatory response to hypercapnia also showed a significant decrease in the left frontal white matter (from 2.18 to 0.79%/mmHg). The data obtained suggest that MCT produces functional injury of the vascular endothelium, and the cerebral endothelium may play some role in the vasodilatory response to hypervapnia.

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The purpose of the present study was to clearfy the risk factors for asymptomatic lacunar infarction and also to evaluate the relative importance of each risk factor. The subjects studied comprised 882 healthy males and 376 healthy females without a past history of cerebrovascular diseases, with mean ages ± S.D. of 51± 10 years and 53 ± 10 years, respectively, who visited our institute for the detection of asymptomatic brain diseases. Lacunar infarction was diagnosed from T₁-weighted, T₂-weighted and proton density images obtained by magnetic resonance imaging. Age, past history, medication, blood pressure, body weight, complete blood count, blood chemistry, alcohol and smoking habit were correlated with the presence of lacunar infarction. Overall, lacunar infarctions were found in 84 males (9.5%) and 22 females (5.9%), with a statistically significant difference (p < 0.05) in incidence between the sexes. In males, age and blood pressure were independent risk factors for lacunae, whereas only age was a risk factor in females. In males, hypertension accelerated the occurrence of lacunar infarction by almost 10 years. The relative risk for having lacunae was 3.24.2 in males in the 6th decade.

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We evaluated the usefulness of single photon emission computed tomography (SPECT) using ^99mTc-hexamethyl-propylene-amine-oxime (HMPAO) for classification of the stroke subtype in elderly patients with acute ischemic stroke. The association between the asymmetric index (AI) calculated from the HMPAO SPECT findings on admission and the diagnosed stroke subtype on discharge in 47 cases with supratentorial cerebral infarction (mean age ±1 SD, 78.7 ± 7.8 years; cerebral embolism, 19 cases; cerebral thrombosis, 28 cases) was studied retrospectively. The Al was determined as the percentage of decreased radioactivity in the ischemic lesion with respect to the symmetrical region in the contralateral hemisphere. The values were significantly higher in the embolic group than in the thrombotic group (means ± 1 SD) : embolic group, 51.7 ± 16.3%; thrombotic group, 19.0 ± 10.0%, and classification was possible. This finding suggests that noninvasive HMPAO SPECT can be of value for classifying stroke subtype in aged patients with acute ischemic stroke.

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Thrombomodulin (TM) is a thrombin receptor on endothelial cells. Endothelial damage allows TM to be degraded and released into the blood stream. From this standpoint, we examined whether or not the plasma level of TM represents an endothelial cell marker which can reflect the endothelial damage associated with cerebral thrombosis. The plasma levels of TM were studied in age-matched healthy subjects and in cerebral thrombosis patients during the chronic stage with and without diabetes mellitus (DM). In the control, group, a significant correlation was noted between TM (Y) and age (X) as follows : Y = 0.190X + 8.299, r =0.718, p <0.01. The basal concentrations of TM were significantly elevated in the group with cerebral thrombosis (26.18 ± 12.000 U/ml) as compared to the controls (18.79 ± 4.43 U/ ml).
Furthermore, among the patients with CVD, those with DM showed higher levels of TM (34.85 ± 21.03 U/ml) than those without DM (23.73 ± 6.31 U/ml). Thus, high TM levels could well reflect the presence of endothelial damage. In conclusion, the level of TM in the plasma is considered to be a potential marker of the presence of endothelial injury associated with cerebral thrombosis.

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We investigated the characteristic clinical findings of so-called crescendo TIA in relation to the etiology of TIA. Forty-eight patients who underwent cerebral angiography were divided into the following 5 groups according to the etiology of TIA : a perforator lesion group (P group), microembolism group (M group), cerebrovascular insufficiency group (I group), cardiogenic embolism group (E group), and unknown group. The following definition of crescendo TIA was adopted; TIA attack which repeated 3 or more times within 72 hours before evaluation, or which repeated 2 or more times within 24 hours after evaluation. The number of patients in each group was 17 (35%) in the P group, 15 (31%) in the M, 5 (10%) in the I, 5 (10%) in the E, and 6 (13%) in the unknown group. Among all TIA cases, the number with crescendo TIA was only 7 (14%), comprising 6 cases of the P group (35% of 17 cases in the P group) and 1 case of the M group (7% of 15 cases in the M group). There was no definite difference in clinical picture between the crescendo and non-crescendo cases of the P group. However the occurrence rate of cerebral infarction (%/person month) in the P group was higher in the crescendo cases than in the non-crescendo cases, i.e. 1.6 vs 0.6. Moreover, the cerebral infarction observed in the crescendo cases occurred within 3 days after the initial TIA attack despite the application of intensive drug therapies including heparin administration. Cerebral infarction was, in contrast, not experienced in the crescendo case of the M group. The present data suggest that crescendo TIA in Japan is rare, and is liable to be observed in TIA cases, whose etiology can be explained by perforator lesions, such as lipohyalinosis. Cases of crescendo TIA belonging to the P group are also liable to develop into cerebral infarction soon after the initial TIA attack.

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Endothelin-1 (ET-1) is known to be a vasocontractor peptide derived from the endothelium and to be involved in the pathogenesis of cerebrovascular disease (CVD). Plasma thrombomodulin (TM) is an endothelial cell marker which may reflect endothelial damage. In order to examine whether or not the antiplatelet agent, Cilostazol, could reduce the endothelial damage in CVD during the chronic stage, 25 patients with cerebral thrombosis at the chronic stage were given 400 mg of Ciloatazol every day for 2 weeks. We measured the levels of ET-1 and TM in the plasma before and after the administration. The plasma ET-1 level was significantly decreased from basal values of 2.16 ± 0.68 pg/ml to 1.75 ± 0.80 pg/ ml (p < 0.05). In addition, the reductions of the plasma levels of ET-1 following Cilostazol administration were significantly higher in CVD with diabetes mellitus (0.78 ± 0.51 pg/ml, p <0.05) than in CVD without diabetes mellitus (0.10 ± 0.28 pg/m1). On the other hand, no significant change in TM was noted between the values of 2.86 ± 0.72 FU/ml before and 2.85 ± 0.77 FU/ml after Cilostazol and administration. CVD with diabetes mellitus revealed significantly higher levels of TM (2.33 ± 0.75 FU/ml, P <0.05) than those without diabetes mellitus (1.91 ± 0.49 FU/ml). Cilostazol significantly reduced the plasma level of ET-1 in CVD. It is concluded therefore that Cilostazol did not exert a protective effect on thrombotic damage of the endothelium, but may reduce the induction of ET-1 from the endothelium through its inhibition of cyclic adenosine monophosphate hydrolysis.

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We examined the efficacy of intravenous sodium ozagrel, a selective thromboxane A₂ synthetase inhibitor, and heparin in elderly patients with acute thrombotic and hemodynamic stroke. A total of 84 consecutive patients admitted within 72 hours from the onset of symptoms were allocated randomly into 3 groups. Forty-seven cases were treated with intravenous sodium ozagrel and heparin (OH group), 16 cases underwent only sodium ozagrel administration (O group) and 21 cases received only glycerol (G group). The neurological scores improved significantly in the OH group as compared to the O group (p< 0.05) and G group (p <0.01) over the first 3 and 7 days. Hemorrhagic complications including hemorrhagic infarction were not observed in both the OH group and O group. We conclude that combined therapy with intravenous sodium ozagrel and heparin was more effective than their sole administration for acute thrombotic and hemodynamic cerebral ischemia in aged patients.

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Use of the International Normalized Ratio (INR) for the monitoring of warfarin therapy has been strongly recommended, but it is still not widely employed even in the United States. Inaccuracy of the international Sensitivity Index (ISI) for commercially available thromboplastin has also been suggested. It is imperative to use an “exact” therapy in multicenter trials. We designed a study to clarify whether utilization of the INR was popular in Japan and whether the ISI value for commercial thromboplastin was accurate or not. We surveyed the monitoring system for warfarin therapy in 29 hospitals, and compared the ISI values of each thromboplastin provided by the manufacture (manufacturer's ISI) with the standardized ISI value calibrated according to the WHO reference thromboplastin equivalent (ISI-1.0). Among the 29 hospitals, the INR was employed routinely in only 10 (34%), and their manufacturer's ISI ranged from 1.0 to 2.2 The manufacturer's ISI value was not always equal to the standardized ISI value. The difference from the standardized ISI (range, 0.15 to 0.37) was particularly large in the case of a manufacturer's ISI of 2.0 to 2.2. We conclude that the INR is also not yet widely employed in Japan, and the value of the manufacturer's ISI is not always accurate. To avoid inappropriate warfarin therapy, we should utilize the INR, particularly with thromboplastins of low ISI values. Suppliers of thromboplastin should label their thromboplastins with accurate ISI values. Based on results for the standardization of the ISI, we are carrying out a multicenter cooperative study (Japanese Nonvalvular Atrial Fibrillation (NVAF) Embolism Secondary Prevention Study) to evaluate the efficacy of low-intensity warfarin in the prevention of recurrence of cardioembolic stroke in NVAF patients.

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A rare case of spontaneous cerebellar hemorrhages from tentorial dural AVM is described. A 48-year-old man, who had suffered two cerebellar hemorrhages at 1 and 7 months previously, respectively, was admitted to our hospital with headache and vertigo. Vertebral angiography demonstrated a tentorial dural AVM fed by meningeal branches from the left vertebral artery. The AVM was successfully resected by a combined occipital-suboccipital approach. In the literature, we found 62 other patients with tentorial dural AVM. Of the total of 63 patients, 38 presented with intracranial bleeding. We infer that dural AVM at this location is more likely to bleed when compared with those at other intracranial locations except for the anterior cranial fossa.

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We describe two patients in whom a unilateral lesion of the midbrain produced vertical gaze palsy, and discuss the mechanism of vertical gaze palsy in relation to the rostral interstitial nuclei of the medial longitudinal fasciculus (riMLF). Case 1 displayed left oculomotor nerve nucleus syndrome, contralateral vertical gaze palsy, and right coordination disturbance. MRI revealed a paramedian dorsal infarction including nuclear involvement of the oculomotor nerve on the left side of the middle mesencephalic tegmentum. Case 2 displayed isolated upward and downward gaze palsy. MRI revealed a small hematoma extending from the anterior part of the supperior colliculus on the right side into the pretectum past the posterior commissure. In case 1, ipsilateral superior and inferior rectus palsy and contralateral superior rectus palsy were produced by the nuclear involvement of the oculomotor nerve. Upward gaze palsy in case 2 was also produced by damage to the supranuclear tracts which was caused by a unilateral lesion of the right posterior commissure. It was possible that contralateral inferior rectus palsy in case 1 and downward gase palsy in case 2 could have been produced by damage to the supranuclear tracts mediating downgaze. Based on experimental data and clinicopathological studies, it is considered that isolated paralysis of downward gaze may be caused by bilateral lesions in the riMLF. However, downward gaze palsy in our cases could have been produced by supranuclear palsy from the unilateral lesion of the riMLF.

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Two cases of cerebral infarction with slowly progressive paresis are reported. Case 1 was a 54-year-old woman with slow progression of sensory disturbance and paresis in the left upper extremity over 2.5 months. Brain CT and MRI demonstrated cortical infarction in the right precentral and postcentral gyrus, and cerebral angiography disclosed delayed filling of the right Rolandic artery. Case 2 was a 62-year-old man with slow progression of paresis in the right hand over 3 weeks. Brain CT and MRI demonstrated infarctions in the left precentral gyrus, anterior and posterior watersheds on the left side. Cerebral angiography disclosed occlusion of the M2 portion in the left middle cerebral artery, and good collateral circulation except for the rolandic artery. The causes of the progressing ischemic stroke in the two cases were as follows : 1) delay of diagnosis and therapy, 2) lesions of the branch of the middle cerebral artery, and 3) poor collateral circulation to the Rolandic artery.
These represent very rare cases of progressing ischemic stroke in the distribution of the branch of the middle cerebral artery resembling brain tumor.

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