Hemodynamic occurrence of cerebral ischemia is a recognized but poorly described entity. The aim of this study was to define the effect and hemodynamic significance of orthostatic hypotension and severe cerebral major artery stenosis as a cause of cerebral ischemia. The study group consisted of 161 patients admitted to our hospital from 1977 through 1995 with a clinical diagnosis of TIA or cerebral infarction that met the following requirement : that each patient was studied by cerebral arteriography and the upright tilt-table test. Twenty-three patients developed focal neurological signs in the standing position, and most of them had cerebral infarction with TIAs. Eighteen of the patients (78.3%) demonstrated orthostatic hypotension, and 2 of them developed focal neurological signs during the upright tilt-table test. Seventeen patients (73.9%) exhibited cerebral major artery stenosis of greater than 50%. Although stroke of orthostatic occurrence was related to orthostatic hypotension, transient hypotension that occurred immediately after standing was not related to patients with stroke of orthostatic occurrence, and continuous hypotension that occurred during standing was related to patients with stroke of orthostatic occurrence. Patients who had both orthostatic hypotension and severe cerebral major artery stenosis were related to stroke of orthostatic occurrence, but others who had either orthostatic hypotension or severe cerebral artery stenosis were not related to stroke of orthostatic occurrence. Patients who had both orthostatic hypotension and severe cerebral artery stenosis were related to stroke of orthostatic occurrence.

View full abstract

Fourteen patients with aculc cerebral thrombosis were divided into 2 groups. One group (n=7) was treated with 100 mg/day of CV-4151, a thromboxane A₂ synthase inhibitor, for 14 days (group C), and the other group (n=7) was treated with 160 mg/day of sodium ozagrel for 14 days (group O), to study the comparative effects on prostanoid metabolism, clinical efficacy and safety profiles, and also to examine the pharmacokinctics of CV-4151 in group C. The following results were obtained.
1) The formation of serum thromboxane (TX) B₂ was inhibitcd in both groups C and O, and the inhibitory effect on the serum TXB₂ formation was more marked and persised for longer in group C than in group O. At 24 hours after the drug administration, the serum TXB₂ formation in group C was still significantly inhibited, but that in group O was increascd to approximately 3 times more than the predrug value. Serum 6-keio-PGF_1α formation was stimulated in both groupos.
2) The transient urine excretion of 11-dehydro-TXB₂ in the early morning and 24-hour pooled urine was suppressed in both groups C and O, while the 2, 3-dinor-PGF_1α cxcretion tended to be increascd in both groups.
3) The pharmacokinecties of CV-4151, in terms of the changes in blood concentrations of CV-4151 and its metabolites, were compared between one-day administration and 14-day consecutive administration. CV-4151 was not accumulated in the blood by the consecutive administration.
4) CV-4151 was comparable to sodium ozagrel in terms of its clinical efficacy and safety profiles.
These results suggest that CV-4151 may be usefulin the treatment of patients with acute cerebral thrombosis.

View full abstract

Ischemic lesions in the cerebral white matter tend to be asymptomatic and to be detected before the onset of symptomatic cerebral infarction. Lesions in the basal ganglia or thalamus, on the other hand, are more frequently symptomatic. We conducted a pathological study on 111 autopsied specimens to evaluate the arteriolosclerotic changes in these areas. The type of arteriolosclerosis common to all areas was fibrotic adventitial proliferation, being most advanced in the white matter and progressing with age. When compared to the controls, patients with lacunar infarction in the basal ganglia or thalamus had advanced arteriolosclerosis not only in those areas but also in the white matter. The degree of arteriolar adventitial proliferation in the white matter was significantly correlated with that in the basal ganglia in the controls and cases of lacunar infarction. It is concluded that arteriolar adventitial proliferation may be an indicator of progressive ischemia in the brain. Since arteriolosclerosis in the white matter precedes that in other areas, it would appear that asymptomatic lesions in the white matter are followed by symptomatic ones.

View full abstract

Based on clinical experience, many neurosurgeons have the vague impression that patients with subarach-noid hemorrhage tend to be admitted in clusters. The present investigation was undertaken to ascertain whether or not this is true for datd collected at Showa-Inan Hospital in the southern part of Nagano Prefecture. Judging from a study of 632 cases out 835 whose onset of stroke was identified, from 1972 to 1991, it appeared that clustering was evident because multiple onsets within a day were observed (on 27 occasions, 2 cases in a day; on 4 occasions, 3 cases in a day; on 57 occasion, 2 patients in a day or a couple of days : on 10 occasions, 3 patients on the same day or within the next 2 days; on 3 occasions, 4 patients in a day or within 2 or 3 days). 40.5% of all cases were admitted within the first 3 days, and 55.1% were clustered within 6 days, instead of the average of one case in 11 days. On the other hand, the present investigation showed clearly that significant differences between clustered and solitary attack groups in terms of sex, age, location of the aneurysm involved, barometric pressure and tendency for barometric changes before the onset of subarachnoid hemorrhage, could not be recognized.

View full abstract

To investigate the effects of various factors derived from vascular endothelial cells on the pathology of cerebral thrombosis, we measured the blood levels of the putative thrombogenic factor, endothelin-1 (ET-1), the fibrinolytic factor, tissue plasminogen activator (t-PA), and its inhibitor, plasminogen activator inhibitor (PAI-1). Determinations were made at both the acute and chronic phases in patients with lacunar stroke (LAC) or atherothrombotic stroke (ATH). Venous occlusion tests were also carried out in these patients during the chronic phase. In patients with cerebral thrombosis, the ET-1 level decreased from the lower limit of normal over the course of the first 7 days after thrombosis, whereas the t-PA level tended to increase in the patients over the same time period. The changes were more significant in patients with ATH, in whom the t-PA level was higher than those measured in a group of normal healthy subjects and patients with LAC. The total PAI-1 level was high in patients with LAC or ATH; however, no temporal fluctuation was noted. The changes in ET-1 and t-PA levels in patients with LAC or ATH can be explained by a tendency for ET-1 release to decrease and t-PA release from vascular endothelial cells to increase during the venous occlusion test, when there is high basal release of PAT-1. The t-PA level increases as an adjustment reaction, and subsequent release of ET-1 is inhibited. In order to clarify the significance of vascular endothelial cells in the pathophysiology of cerebral thrombosis, it is important to determine the temporal relationships of these factors.

View full abstract

Endothelin-1 (ET-1) has been shown to be a vasconstrictor peptide related to the function of the endothelium, but the site of ET-3 synthesis has not yet been determined. No systematic evaluation of ET-3 has ever been attempted during the acute stage of cerebrovascular disease (CVD). We determined the ET-3 concentrations of the cerebrospinal fluid (CSF) in CVD. The subjects comprised 15 patients including 7 cases with hemorrhagic CVD and 8 cases with occlusive CVD. We found that the CSF level of ET-3 on day 1 (68.9 ± 21.4 pg/ml) was significantly increased in hemorrhagic CVD as compared to that on day 14 (57.6 ± 7.1 pg/ml). Occlusive CVD also demonstrated a higher level of ET-3 on day 1 (54.8 ± 9.8 pg/ ml), followed by a substantial decrease on day 14 (47.0± 6.8 pg/ml). The value on day 1 was significantly higher than that on day 14. In addition, patients who underwent repeated measurement of the ET-3 in their CSF showed a gradeal decrease in ET-3 throughout the study (on day 1, day 14 and day 28). We have reported that elevated concentrations of ET-1 in both the plasma and CSF were noted during the acute stage of CVD in a previous study. Thus, the ET-3 concentration in the CSF is thought to increase in association with a raised concentration of ET-1. Considering its potent vasodilator effect, ET-3 may play an important role in the pathophysiology of CVD.

View full abstract

The effects of defibrination with batroxobin (Bx) on the middle cerebral artery blood flow velocity (MCA-V) and its CO₂ reactivity during hypocapnia were examined in 12 patients with chronic cerebral infarction (S group), and compared with those in 25 healthy volunteers (C group). The MCA · V was measured with a transcranial Doppler flowmeter, and we calculated the corrected blood flow velocity (MCA ·V₄₀) at 40 mm Hg of end-tidal carbon dioxide tension, and the CO₂ reactivity during hypocapnia. In accordance with the significant decrease in plasma fibrinogen occurring after administration of Bx, the MCA·V at rest, MCA·V₄₀, and CO₂ reactivity during hypocapnia underwent significant increases in the C group and also in the S group (p<0.01, respectively), which suggested improvement of the cerebral microcirculation. A significant negative relationship (r =-0.583, p = 0.0001) existed between the plasma fibrinogen concentration and CO₂ reactivity in the S group. In association with the decrease in plasma fibrinogen, the CO₂ reactivity improved significantly in chronic cerebral infarction.

View full abstract

To clarify the role of lipoprotein (a) [LP (a)] and remnant-like particles (RLP-ch) in extracranial carotid lesions and ischemic stroke, the serum levels of Lp (a) and RLP-ch were studied in 216 elderly subjects, who underwent ultrasonography (US) examination of their carotid artery and brain computerized tomography (CT). In the US findings, both occlusion and plaque were considered to be carotid lesions. Plaque, defined as a thickened intima-media complex of 2.1 mm or more in height, was divided into 2 types based on the ratio between the heigth (a) and length (b) : mural plaque (b≥ 3a) and nodular plaque (b <3a). It was also divided into 3 types based on its echogenicity : hypoechoic, hyperechoic, and heterogeneous plaque. In addition, the extent of the carotid lesions was semiquantitatively assessed from their distribution and given a score : 2 (bilateral), 1 (unilateral), and 0 (absent). According to the CT findings, infarcted areas were classified into 2 groups : small-vessel disease (SVD), which included lacunae, brainstem infarction, and leuko-araiosis, and large-vessel disease (LVD), which included cortical infarction and watershed infarction. Employing blood samples obtained during fasting, Lp (a) and RLP-ch were determined by the latex fixation method and immunosorbent assay, respectively. US revealed no lesion in 90 subjects (NL group), a unilateral lesion in 54 patients (UL group), and bilateral lesions in 72 patients (BL group). Compared to the mean Lp (a) level in the NL group, the LP (a) levels in the UL and BL groups were significantly high. Moreover, the mean Lp (a) levels of hypoechoic (n = 39) and heterogeneous (n =15) plaques were significantly elevated among the lesions. A high carotid lesion score was frequently observed in cases with high Lp (a) levels of ≥20 mg/dl and thickened plaque in addition in cases with higher Lp (a) levels of ≥ 40 mg/dl. CT demonstrated no vascular change in 81 subjects (NVC group), SVD in 86 patients (SVD group), and LVD in 49 patients (LVD group). The mean Lp (a) levels in the SVD and LVD groups were both significantly higher than that in the NVC group. In contrast, no difference in US findings was noted according to the serum RLP-ch levels, although the mean RLP-ch levels of the SVD and LVD groups on CT were lower than that of the NVC group. Multivariate analysis revealed that carotid lesions were strongly affected by ageing, serum Lp (a) level, and smoking, in that order. These findings indicate, therefore, that Lp (a) is a strong risk factor for carotid lesions and all types of ischemic stroke in the elderly, whereas the significance of RLP-ch in cerebrovascular disease remains unclear. High Lp (a) levels in cases with thickened plaques or hypoechoic plaques on US suggest that LP (a) could promote the formation of athermatous plaque with or without intraplaque hemorrhage or superimposed thrombi.

View full abstract

The identification of atrial natriuretic peptide (ANP) in the cardiac atrium has disclosed a new functional role for the heart as an endocrine organ regulating body fluid homeostasis and blood pressure control. Recently, endothelin-1 (ET-1) has been shown to be a potent vasoconstrictor peptide which plays an important role in the pathogenesis of cerebrovascular disease. However, no simultaneous measurements of ANP and ET-1 have ever been attempted during the acute stage of cerebral thrombosis. The present study focuses on an evaluation of the changes in both ANP and ET-1 in the plasma over a period of 2 weeks following an episode of cerebral thrombosis. The AVP levels were also measured in the plasma samples. The plasma ANP concentration in the patients during the acute stage was elevated to 70.5 ± 80.9 pg/ml on day 1 (acute stage), followed by a significant decrease to 56.1 ± 7.0 pg/ml on day 14 (subacute stage). In addition, the level of ET-1 was 5.19 ± 1.91 pg/ml during the acute stage, and that during the subacute stage had declined to 2.79 ± 1.65 pg/ml. The ET-1 level at the acute stage was significantlt higher, when compared with that at the subacute stage. During the acute stage, the following relationship between the level of ET-1 (Y) and ANP (X) was obtained : Y = 0.019X + 3.864. The correlation between them was significant (r = 0.789, P <0.01). During the subacute stage also, the increased level of ET-1 (Y) showed an excellent linear relation ship with age (X) : Y = 0.015X + 1.979 X (r = 0.667, P < 0.01). The time course of induction of ET production is evidently consistent with elevated concentrations of ANP, and the data suggest that ANP release may be positively modulated by ET-1. The results of the present study support the hypothesis that ET-1 may be a potent secretagogue for ANP in the pathogenesis of cerebral thrombosis in vivo.

View full abstract

Several abnormal breathing patterns have been observed in patients with cerebrovascular disorders during sleep. In this study, the respiratory rates and patterns were investigated in patients with cerebral infarction. Polysomnography (PSG) was performed in 45 patients with brainstem infarction mean age, 60.9 years including 5 patients with midbrain, 20 patients with pontine, 16 patients with medullary, and 4 patients with cerebellar infarction, and in 5 normal subjects mean age, 53.8 years. PSG was also carried out in patients with cortical (MCA) infarction mean age, 71.3 years. Sleep apnea syndrome (SAS) was noted in 18 to 23 patients (78.3%) with cortical, in 1 of 5 (20.0%) with midbrain, in 5 of 20 (25.0%) with pontine and in 6 of 16 (37.5%) with medullary infarction. As regards the type of sleep apnea, predominantly central sleep apnea was observed in cortical and medullary infarction. Although Cheyne-Stokes type respiration was seen in 18 patients with cortical, 1 patient with midbrain and 2 patients with pontine infarction, cluster type breathing was found in 6 patients with lateral medullary infarction (LMI).
To evaluate the regularity of respiration, we calculated the kurtosis. This parameter is usually employed to evaluate the pattern of distribution in statistics. A higher value of kurtosis denotes regular breathing. The kurtosis is lower in patients with LMI than in those with cerebral infarction without LMI during all stages of sleep. In LMI with Horner's syndrme, much lower values of kurtosis were observed. In addition, a lower value of kurtosis with tachypnea was found in the case of “near miss” patient with LMI. The above data suggest that quantitative analysis of respiratory rate and pattern during sleep employing PSG can be of use in the clinical diagnosis and prognosis of patients with brainstem and cerebellar infarction.

View full abstract

One case of progressive thrombotic thrombocytopenic purpura (TTP) after ticlopidine therapy is reported. A 55-year-old woman was started on ticlopidine therapy for transient ischemic attack. Three weeks after commencing the therapy, the patient was hospitalized because of a relapse of right hemiparesis and dysarthria. Three days after admission, her platelet count was 1.4 × 10⁴, and the peripheral blood film showed a little red cell fragmentation. The prothrombin time, activated partial thromboplastin time, fibrinogen, and FDP levels were normal. On the following day, she suffered vomiting and abdominal pain. The patient became apathetic and drowsy. Six days after admission, generalized convulsions attaclked the patient, and she was transferted to an intensive care unit. Laboratory testing revealed : hemoglobin, 7.4 g/dl; plate count, less than 1.0 × 10⁴; and serum creatinine, 1.6 mg/dl. The peripheral blood film revealed abundant red cell fragmentation. A diagnosis of TTP was confirmed on the basis of thrombocytopenia, fever, renal failure, the neurologic symptoms and microangiopathic hemolytic anemia. Treatment was initiated by plasma infusion with plasma exchange, but the patient died. This is the first case of thrombotic thrombocytopenic purpura (TTP) probably related to the use of ticlopidine in Japan.

View full abstract

A case of spontaneous thrombosis of an unruptured middle cerebral artery aneurysm with parent artery occlusion is described. The patient was a 57-year-old male with a cerebral infarct in the putaminal region. Cerebral angiography revealed no evident occluded artery and a non-thrombosed large aneurysm in the left middle cerebral artery. A radical operation on the aneurysm was scheduled. However, while waiting for the operation, the patient developed motor aphasia and, on reperformed cerebral angiography, spontaneous thrombosis of the aneurysm and occlusion of the M₂ branch of the left middle cerebral artery were found. The operation was therefore postponed. The patient was started on volume expansion, induced hypertension and administration of anti-platelet agents, but the occlusion of the origin of the M₁segment, leaving behind severe motor aphasia and right hemiparesis. After receiving rehabilitation treatment, the right hemiparesis became minimal and the aphasia demonstrated slight improvement. The patient was able to return to his previous employment. In this case, we belive that the mechanism of parent artery occlusion was related to retrograde thrombosis originating within the aneurysm, stretching and compression of the middle cerebral artery by the thrombosed aneurysm, and arteriosclerosis in the peripheral vessels.

View full abstract