In the 1980s, the brain-protecting effet of mild hypothermia therapy in which the brain temperature was maintained at 33-35°C was demonstrated using a global brain ischemic model or traumatic brain injury model, and this technique is currently being applied clinically. In the 1990s, reports providing confirmation of the brain-protecting effect of mild hypothermia above 30°C in focal brain ischemic models have been published, reaching a total of 19 reports to date. Eleven experimental groups among these studies were classified into a transient middle cerebral arterial occlusion (MCAO) group and the other 11 into a permanent MCAO group. In the transient MCAO group, the duration of MCA occlusion was 1 to 3 hours. The brain or body temperature during hypothermia was 30-34°C and the duration of hypothermia was from the start until within 1 hour after ischemia in most cases. Evaluations were performed by comparing the infarct volume after 1 day with that up to after 1 week. The CBF, SEP, T1-T2 relaxation time, development of cortical spreading depression and NO synthesis were also assessed in some studies. In the transient MCAO group, the effectiveness of hypothermia was confirmed by all of the authors, whereas in the permanent occlusion group, effectiveness was confirmed in 8 studies out of 11, and no brain-protecting effect was noted in the remaining 3. These findings clarified that when mild hypothermia was commenced during ischemia or within 1 hour after focal brain ischemia, the infarct volume was reduced in most experiments, mainly with rodents. Howerve, it is unclear whether or not this effect is continuously observable at the chronic stage such as several months after ischemia. In the present review, we discuss the efficacy and the problems of mild hypothermia therapy for human focal brain ischemia.

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We studied the serum lipoprotein profile among healthy subjects (239 cases), and patients with silent brain infarction (78 cases) and symptomatic brain infarction (lacunar infarction, 75 cases ; atherothrombotic infarction, 42 cases). The following results were obtained. 1) Patients with lacunar and atherothrombotic infarctions had significantly lower serum HDL-cholesterol concentrations than did patients with silent brain infarction and healthy subjects. 2) There were no differences in mean values of the serum total cholesterol, triglyceride, and LDL-cholesterol concentration. 3) Female patients with atherothrombotic infarction revealed a significantly lower serum total cholesterol concentration and a lower proportion of hypercholesterolemia than did patients with silent brain infarction and healthy subjects. 4) There were no significant differences in mean values of the four lipoprotein concentrations and in the proportion of dyslipoproteinemia between healthy subjects and patients with silent brain infarction. A decreased HDL-cholesterol level is closely associated with symptomatic (lacunar or atherothrombotic) brain infarction rather than silent brain infarction.

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The purpose of the present study was to elucidate risk factors for vascular dementia in stroke patients. Among 400 patients examined at the chronic stage of stroke, 112 were diagnosed as dementia (group D1; age, 69 ± 9 years old; men/women, 73/39) and 288 as non-dementia (group ND1; 63 ± 10 years old; men/women, 225/63) by the Cross Cultural Cognitive Examination (CCCE), which is a screening examination for dementia. When the number of failed tasks on the CCCE exceeded “3”, the patient was diagnosed as being demented. The differences in values of the blood pressure (BP), body mass index (BMI), and routine laboratory assessments [hematocrit (Ht), total cholesterol (T-Ch), triglyceride (TG), HDL-Ch, total protein (TP), fasting blood sugar (BS), and HbAlc] at the chronic stage were analyzed between the two groups. Age was higher and the educational background was lower to a significant extent in group D1 than in group ND1, but the history of diabetes mellitus and the duration of hypertension were not related to cognitive impairment. The number and size of lesions on CT were significantly larger, and the brain was significantly more atrophic in group Dl than in group ND1. Significant differences between both groups were found in the systolic and diastolic blood pressure, Ht, BMI, T-Ch and TG at the chronic stage. By multiple logistic regression analysis, the cognitive decline was related to advanced age, high diastolic blood pressure, low T-Ch, and low educational background. To assess whether or not the factors at the acute stage of stroke affected the impairment of cognition at the chronic stage, we examined the 165 patients out of the 400, who were admitted to our clinic at the acute stage. 55 patients developed dementia later (group D2; age 68 ± 11 years old), and 110 patients were regarded as non-dementia (group ND2; age, 62 ± 10 years old) at the chronic stage. Significant differences between both groups at the acute stage were found for age, BMI, educational background, Ht, T-Ch, and TG. By multiple logistic regression analysis, cognitive decline was associated with advanced age, low BMI, and low educational background. The present results demonstrate that a decrease of cognitive function after stroke was caused by the size and number of brain lesions, as well as additional contributions from demographic and nutritional factors.

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Seventy-four cases of primary pontine hemorrhage were diagnosed by CT scan from January 1981 to December 1994. The subjects comprised 56 males and 18 females. Their ages ranged from 31 to 94 years with a mean of 60.3 years. We studied the relationship between outcome and clinical symptoms or CT findings. The cases were divided into six groups according to their outcome evaluated at 6 months after onset. The 16 cases in the 1st group showed a full recovery of good ADL. The 10 cases in the second group recovered to a daily life with partial assistance. The 11 cases in the 3rd group recovered to a daily life with almost complete assistance. The 2 cases in the 4th group were severely disabled with prolonged coma or “locked-in” syndrome. The 30 cases n the 5th group died within a few hours to days after onset. The 5 cases in the 6th group died with complications within 6 months after onset. We assessed the disturbance of consciousness (evaluated by the Japan Coma Scale), abnormal pupils (anisocoria, pinpoint pupils and mydriasis), respiratory disturbance (Cheyne-Strokes respiration, gasping respiration or ataxic respiration), tachycardia (over 90/min), hyperthermia (over 39°C) and motor disturbance (hemiplegia, tetraplegia or decerebrate posture) on admission. The horizontal extension of the hematoma was measured from the diameter of the hematoma on transverse sections of CT scans through the pons, and the vertical extension was assessed according to whether the hematoma extended into the midbrain and/or the basal ganglia. Rupture of the hematoma into the fourth, the third or the lateral ventricles and hydrocephalus were also examined. Among the various factors for predicting the outcome, it was found that respiratory distur-bance, abnormal pupils, hyperthermia and rupture of the hematoma into the ventricles were significantly correlated with the outcome using multiple analysis of variance.

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Sequential changes in cerebral blood flow (CBF) were investigated in patients with surgicallyevacuated hypertensive intracerebral hematoma (ICH). The subjects comprised 14 patients with subcortical ICH. CBF was studied by means of stable xenon-enhanced computed tomography (xenon CT) before and after surgery, and during the chronic stage. The pre-operative CBF and its response to acetazolamide (AZ) on the hematoma side declined in accordance with an increase in hematoma volune. Not only the global CBF levels on the hematoma side but also the regional CBF surrounding the hematoma were distinctly improved after evacuation of the hematoma in all cases. These findigns suggest that surgical evacuation, in cases of hypertensive subcortical hematoma, might be useful for improving the CBF.

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The purpose of the present study was to evaluate the long-term prognosis of silent cerebral infarciton patients, based on consecutive patients with lacunar lesions detected by cranial CT. Of a series of patients who had undergone CT between 1983 and 1989, 3006 patients without apparent lesions on CT were extracted. Among them, 279 patients who were found to have lacunar lesions and survived for at least 3 months or longer were selected for this study. The subjects were divided into two groups : those with no clinical stroke episodes (silent group), and those with stroke episodes (infarct group). After the clinical profiles of each patient had been investigated, the patients were followed up to assess the prognosis comparatively. Detailed analyses were conducted on 267 patients (follow-up rate, 95.7%) and the mean follow-up period was 57 months. During the follow-up period, stroke occurred in 11 patients (1.73%/year; 9 infarctions and 2 hemorrhages) in the silent group and 16 patients (2.53%/year, 10 infarctions and 6 hemorrhages) in the infarct group. Futhermore, in the silent group, stroke did not occur in the patients (n = 40) who had no risk facotrs, while among the patients (n=80) who did have risk factors, even just one factor, stroke occurred in 10 patients (2.78%/year), which represented approximately the same incidence as in the infarct group. There was no difference between the two groups in the mortality or causes of death during the follow-up period. In conclusion, it can be said that in patients with silent cerebral infarction, stroke occurred less often among patients who had no risk factors and occurred in patients who had any risk factor at approximately the same rate as in patients with symptomatic cerebral infarction.

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Endothelin-1 (ET-1) exerts powerful vasoconstrictuve and blood pressure elevating effects through endothelial cells. Plasma thrombomodulin (TM) is an endothelial cell marker which may reflect endothelial damage. Argatroban, a synthetic selective thrombin inhibitor, has been shown to exhibit a potent anti-thrombotic effect in experimental thrombosis models using animals. However, the influences of argatroban on the levels of ET-1 and TM, and markers of coagulation and fibrinolysis have not been examined precisely.
In this study, we investigated the effects of argatroban using 16 patients with acute cerebral thrombosis. The plasma level of ET-1 in the argatroban group was significantly decreased from 4.5 ± 1.7 pg/ml to 2.9 ± 1.4 pg/ml on day 1 as compared to that in the control group. On the other hand, no significant changes in TM were noted in both the argatroban group and control group. The plasma level of TM in the cerebral thrombosis patients was significant higher than the TM level in age-matched controls. The level of D-dimer in the argatroban group revealed lower values throughout the study as compared to those in the controls. It is concluded that argatroban may reduce the induction of ET-1 from the endothelium and may have a therapeutic effect on human thrombotic disease through selective and potent inhibition of thrombin.

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Adrenomedullin (AM) is a potent hypotensive peptide newly discovered in pheochromocytoma tissue by monitoring its elevating effect on platelet cAMP. However, the possibility of AM acting as a new circulating hormone which participate in the pathogenesis of cerebrovascular disease (CVD) has never been investigated. We measured the plasma concentration of AM in patients with CVD by our recently established highly sensitive and specific RIA. The study population consisted of 22 patients with occlusive CVD and 8 patients with hemorrhagic CVD. The plasma AM during the acute stage was increased in the patients with occlusive CVD (37.0 ± 56.9 fmol/ml) as compared to those with hemorrhagic CVD (10.7 ± 6.2 fmol/ml). The increase in plasma AM during the acute stage was more prominent in patients with a Japan Coma Scale (JCS) of 100-300 than in patients with a JCS of 0-30. The time course of the AM levels in both occlusive CVD and hemorrhagic CVD indicated that that the values during the subacute stage were higher than those during both the acute stage and chronic stage. In conclusion, based on its potent vasodilator effect. AM may be involved in the pathogenesis of CVD.

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A 71-year-old man was admitted to our neurological service due to clouding of consciousness and right-sided weakness. Neurological examinations on admission revealed a semicomatous state, tetraplegia and bilateral pyramidal tract signs. The computed tomographic (CT) findings demonstrated bilateral infarctions of the anterior cerebral artery territory. Cerebral angiography revealed bilateral occlusion of the internal carotid artery, and a well-developed collateral circulation. The bilateral anterior cerebral artery was recognized via anastomosis from a branch of the left external carotid artery. The infarction in this patient resulted from artery-to-artery embolism from the distal part of the left internal carotid artery. The pathogenesis of bilateral internal carotid artery occlusion is discussed with special reference to the blood supply of the anterior cerebral artery.

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We report the case of a 24-year-old man with isolated angiopathy of the central nervous system (IACNS) which progressed to large-vessel arterial occlusion. At two months after experiencing difficulty in walking, the patient suddenly developed severe headache and progressive paralysis of the left extremities and was admitted to hospital. A brain CT scan disclosed cerebral infarction. His left hemiparesis rapidly improved without treatment. One month later, however, left hemiparesis recurred. He was then transferred to Kinki Medical University Hospital for evaluation. Physical examination on adminission whowed left hemiparesis with left facial paresis. The results of general laboratory work-up were unremarkable. No abnormalities were detected in serological and immunological tests. The patients cardiac echogram and ECG were normal Brain MRI demonstrated multiple infarctions in the area o the right internal capsule, caudate and parietal lobe. Cerebral angiography revealed multiple segmental stenosis, irregularity and narrowing of the right anterior callosomarginal artery and anterior cerebral artery. These data suggested IACNS. Leptomeningeal biopsy was negative. The patient was treated with high-dose steroids, but complete left hemiplegia progressed during the next two months. Brain MRI at that time showed high-intensity signals within the areas of the anterior cerebral and middle cerebral arteries. On cerebral angiography, the right anterior and middle cerebral arteries were found to be completely obstructed. The typical angiographic abnormalities of IACNS include multiple localized areas of narrowing, and occlusions of vessels, reflecting the predominance of small-vessel inflammation. Our case was unusual in its progression to large-vessel arterial occlusion.

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We describe two cases of ischemic cerebrovascular disease associated with hereditary protein C deficiency. Patient 1 was a 34-year-old man who developed sudden onset of dysarthria and weakness of both hands. Cerebral magnetic resonance imaging (MRI) studies and angiography demonstrated no abnormalities. Three days later, the patient's clinical manifestations completely disappeared. His plasma levels of protein C antigen and functional activity were 53% and 51%, respectively. His father, who had had his left leg amputated due to arterial thrombosis, and his sister also revealed protein C deficiency. Patient 2 was a 62-year-old women who was admitted with progressive right hemiparesis. MRI disclosed an infarction in the left corona radiata. On admission, her protein C antigen level and functional activity were found to be reduced to 48% and 43%, respectively. Investigation of her family members revealed protein C deficiency in her two children as well. Warfarin was used for long-term propbylaxis in conjunction with short-term heparin administration to prevent warfarin-induced skin necrosis. Subsequently, there have been no arterial thrombotic events. We conclude that protein C deficiency should be examined for in patients with an unexplained cerebral infarction, even if they are relatively old, in order to treat them and possibly other family members at risk.

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Proton magnetic resonance spectroscopy (H-1 MRS) is a useful technique for performing noninvasive chemical analysis. N-Acetyl aspartate (NAA) is localized only in neurons, and the NAA peak is considered to be a neuronal marker. A 32-year-old man who had sustained a closed fracture of the femur 6 hours previously, developed sensory aphasia. After excluding other causes of brain infarction, we diagnosed him as having cerebral fat emgbolism. We performed H-1 MRS on the 4th and 30th hospital days, selecting a volume of interest from the infarcted area. We demonstared reduction of the NAA peak, although the findings of SPECT and the patient's neurological improvement might have indicated recanalization of the brain blood flow. It was considered that irreversible ischemic neuronal damage had occurred. We conclude that H-1 MRS is an available method for detecting neuronal loss in cerebral far embolism.

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