We review and discuss the scientific basis for the treatment of experimental cerebral ischemia with glutamate receptor antagonists. Ischemia induces a massive increase in extracellular concentration of glutamate, which is neurotoxic. One of the most compelling pieces of evidence for excitotoxicity in cerebral ischemia and stroke is the fact that selective glutamate receptor antagonists such as MK-801 or NBQX reduced infarct volume in almost all studies on focal ischemia produced by middle cerebral artery occlusion. However, MK-801 attenuated incomplete but not complete infarction in a thrombotic middle cerebtral artery occlusion model in the rat (Stroke 24 : 864-871, 1993; Brain Res. 642 : 117-122, 1994). In preclinical drug trials, many confounding factors such as drug-induced changes in physiological variables, brain temperature and cerebral blood flow should be controlled or at least monitored. Although treatment with glutamate antagonists has theoretical benefits in both global and focal (stroke) ischemia, whether or not glutamate antagonists attenuate infarction by actual blockade of glutamate receptor, and not by secondary or non-specific effects (e.g., drug-induced hypothermia), should be confirmed. The precise mechanism by which glutamate receptor antagonists attenuate not only selective necrosis (incomplete infarction) but also complete infarction needs to be clarified by future studies.

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Nitric oxide (NO) was first found as an endothelium-derived relaxing factor, but has also been shown to affect cerebral blood flow and cell signal transduction. It is important that NO itself is not so toxic or reactive in vivo, and that rapid reaction with superoxide forms a more powerful biological species, peroxynitrite. It is suggested that reaction of peroxynitrite with superoxide dismutase (SOD) nitrates protein tyrosine, so facilitating cell degeneration after ischemia. This mechanism could also explain the reason for motor neurron death in farmilial amyotrophic lateral sclerosis, in which SOD point mutations were recently found.

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A total of 160 patients (114 males and 46 females; average age, 63.4 years old) with cerebral infarction were classified according to the cerebrovascular disease classification III proposed by NINDS, U.S.A. Since the NINDS classification does not specify detailed diagnostic criteria, we adapted our own test findings to establish a precise diagnosis. Patients with classic lacunar syndrome, who were found to have lesions of less than 15 mm in diameter or no lesiion, were diagnosed as lacunar infarction. Patients with a cardioembolic source and sudden onset were diagnosed as cardioembolic infarction, while 24 patients (15.0%) with vascular lesion that were determined to be the cause of infarction were diagnosed as atherothrombotic infarction. Furthermore, 55 patients (34.4%) who were diagnosed as having small lesions based on neurological examinations and correlative tomographic findings were added to the group of lacunar infarction, and 32 patients (20.0%) who were found to have a cardioembolic source and were diagnosed as cardiac embolization based on the manner of onset and tomographic findings were added to the group of cardioembolic infarction. At the final count, 49 patients (30.6%) were unable to be classified. The incidence of lacunar infarction in our patients was slightly higher than that reported in the U.S.A., while the incidence of other subtypes was similar to that in the U.S.A. There was a tendency towards a reverse correlation between the incidence of atherothrombotic infarction and that of unclassified infarction, which could probably be explained by the inability to determine the exact nature of the vascular lesions. Further development of clinical test method should decrease the incidence of unclassified cases of infarction.

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This study examined a simple method for measuring the regional cerebral blood flow (rCBF) using ^99mTc-HM-PAO SPECT. The mean CBF (mCBF) was determined by the Patlak plot method and rCBF was calculated with Lassen's correction algorithm, as reported by Matsuda et al. The cerebral hemisphere was employed as the reference region for Lassen's correction. The reference RI count rate was calculated from the left cerebral hemisphere at the basal ganglia level and the correction factor a was fixed at 2.0. As a result, rCBF could be measured more easily than by Matsuda's method. The contributions of age, laterality and gender to the CBF of normal subjects were studied.
The mCBF value of 26 normal subjects was 53.8 ± 6.4 ml/100 g/min and showed a significant correlation with advancing age (R = 0.644, p= 0.0004, n=26). The mean values for rCBF of the cerebellum, frontal area, temporal area, occipital area and parietal area were 77.3 ± 6.6 ml/100 g/min, 70.2 ± 9.1 ml/100 g/min, 72.3 ± 7.5 ml/100 g/min, 71.8 ± 6.2 ml/100 g/min and 73.8 ± 8.6 ml/100 g/min, respectively. There were no gender or laterality differences in the mCBF or respective rCBF values. Each of the above listed regions, except for the occipital area, demonstrated a significant correlation with advancing age. The most remarkable decrease in rCBF with age was noted in the frontal area (R = 0.757, p=0.001, n=26).

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The authors confirmed the expression of bcl-2 protein within the infarcted brain in rats by the methods of the immunohistochemistry and Western blot analysis. Immunohistochemical reaction with anti-bcl-2 protein antibody introduced positive production of bcl-2 protein in neurons surrounding the infarction 4 days after making ischemia. Immunohistochemical reaction for bcl-2 protein showed positive in neuronal axons of cerebral cortex, internal capsule, cerebral peduncles, corpus callosum and other pyramidal tracts related to damaged cortex 21 days after making infarction. Western blot analysis proved the existence of bcl-2 protein with molecular weight of 26 kD (bcl-2 α) in the infarcted brain while no detectable bcl-2 protein in the intact brain. The authors suggest bcl-2, a proto-oncogene known as blocking apoptosis in haematopoietic tumors, expresses in neurons around cortical infarction to protect from neuronal death.

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We studied hemispatial neglect in 16 patients with cerebrovascular disease. Twelve patients had a lesion in the territory of the middle cerebral artery (MCA group, mean age 70 y.o.) and 4 patients in the territory of the posterior cerebral artery (PCA group, mean age 72 y.o.). The MCA lesions were centered in the parieto-temporo-occipital junction, and the PCA lesions included the medial aspect of the occipital lobe or temporal lobe. In the MCA group, all cases denied hemianopia (anosognosia) and most cases showed extinction of stimuli on double simultaneous stimulation (DSS) in somatosensory and auditory modalities. In the PCA group, all cases showed awareness of hermianopia without extinction on DSS and topographical disorientation. The hemispatial neglect lasted longer and its recovery was worse in the MCA group than in the PCA group. These findings suggest that different mechanisms may be involved in the hemispatial neglect caused by MCA and PCA lesions.

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We examined the effects of 3-isobutyryl-2-isopropylpyrazolo- [1, 5-a] -pyridine (Ibudilast) on hypoxic injury in fetal rat cortical cells. Primary cortical cell cultures (embryonic day 18) were established and maintained. After 72 h in culture, Ibudilast was added to the serum-free medium. Cultures were divided into two groups : the normoxia group was in culture for another 48 h, and the hypoxia group was exposed to 24 h of hypoxia follwed by continuation of culture for another 24 h. As a quantitative measure of cell death, the lactate dehydrogenase (LDH) activity was estimated in the culture medium. The LDH activity, released by the hypoxic insult, was significantly smaller with Ibudilast treatment at 2 × 10^-5, and 2 × 10^-6 M (p <0.05) as compared to the control. The protective effect of Ibudilast did not differ from that of prostaglandin El. We conclude that Ibudilast can protect rat cortical neurons against hypoxic insult.

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The prognosis of intracranial hemorrhage in patients with leukemia is poor. We made a retrospective analysis of 601 patients with leukemia admitted to Kitasato University Hospital during the period from April, 1979 to September, 1993. Thirty-two patients suffered from intracranial hemorrhage. They included 19 men and 13 women, with a mean age of 46.2 ± 22.8 and 45.3 ± 23.1 years, respectively. The incidence of intracranial hemorrhage among the patients with leukemia was 5.3%. The mortality was 87.5%. As many as 12.5% of the patients presented with hemorrhage occurring at two locations, such as brain hemorrhage combined with subarachnoid hemorrhage or subdural hemorrhage. The most frequent initial symptoms at onset were headache and disturbance of consciousness. Cerebral focal signs were seen in only a few patients. Intracranial hemorrhage occurred more frequently in myelocytic leukemia than in lymphocytic leukemia. The most frequent type of leukemia complicated by intracranial hemorrhage was acute myelocytic leukemia. There was no significant difference in the frequency of intracranial hemorrhage between acute leukemia and chronic leukemia. Thrombocytopenia at the time of admission was noted more in patients who died than in those who survived. Thrombocytopenia was considered to be a sign of a poor prognosis.

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We investigated the effects of nimodipine as a pre-, mid-, or post-ischemic treatment on the cerebral blood flow (CBF) and brain energy metabolism during forebrain ischemia and reperfusion using a laser-Doppler flowmeter and in vivo ³¹phosphorus nuclear magnetic resonance (³¹P NMR) spectroscopy in 112 adult male Mongolian gerbils. Nimodipine (1 μg/kg/min), or an equal volume of vehicle or saline, was administered continuously by intravenous infusion over 60 min during the pre-, mid-, or post-ischemia period. The sequential changes in phosphocreatine (PCr) /inorganic phosphate (Pi) ratio, β-ATP/Pi ratio, and intracellular pH (pHi) were determined by ³¹P NMR spectroscopy. CBF was measured continuously with a laser-Doppler flowrneter throughout the study. In the case of pre-ischemic treatment with nimodipine, the PCr/Pi and β-ATP/Pi ratios were significantly higher at all times of measurement after reperfusion than those in the mid-ischemic treatment group, and higher at 180 and 240 min after reperfusion than those in the post-ischemic treatment group. Nimodipine improved the brain energy metabolism during reperfusion when administered during the pre- or post-ischemia period, which could imply a direct protective effect against ischemic brain damage.

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We carried out one-stage superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis to prevent symptomatic vasospasm during aneurysmal clipping in 2 of 5 patients with significant occlusive lesions in the carotid system. Due to well-developed collateral circulation via the circle of Willis, 2 patients with occlusion of the common/internal carotid artery did not underg one-stages STA-MCA anastomosis. They did not suffer symptomatic vasospasm, although SPECT studies revealed mild hypoperfusion in the ipsilateral hemispheres at the acute stage. Of 3 patients with severe stenosis of the middle cerebral artery (MCA), 2 underwent one-stage STA-MCA aanastomosis, and did not suffer symptomatic vasospasm. However, symptomatic vasospasm caused severe consciousness disturbance and left hemiparesis in the one patient with severe MCA stenosis who did not undergo one-stage bypass surgery. In conclusion, one-stage STA-MCA anastomosis could prevent symptomatic vasospasm in certain groups of patients with subarachnoid hemorrhage and significant occlusive disease in the carotid system.

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We report a 67-year-old female presenting with only eyelid ptosis on the left side and diplopia. On neurological examination, there was only left-sided infranuclear oculomotor palsy with pupillary dilatation. Other neurological abnormalities such as hemiplegia, nystagmus, etc. were not detected. Head CT examinations showed a high density area in the left paramedian portion of the tegmentum of the midbrain. The pathogenesis of unilateral infranuclear oculomotor palsy is usually considered to involve extramedullary lesions. Intramedullary lesions associated with unilateral infranuclear oculomotor palsy are often accompanied by a variety of other neurological signs and symptoms. We suggest that it is necessary to consider the possibility of midbrain hemorrhage in patients presenting with only unilateral infranuclear oculomotor palsy.

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A 57-year-old male was admitted to our hospital because of right facial numbness, dysphagia and gait disturbance. Since neurological examinations revealed right Horner's syndrome, right cerebellar ataxia, paralysis of the right soft palate and pharynx, and MRI demonstrated right dorsolateral medullary infarction, we diagnosed right Wallenberg's syndrome. In addition, the patient showed left paralysis of the tongue, right pyramidal signs, and decreased tactile and vibration sense of the right half of the body with facial sparing, which suggested left Dejerine's syndrome. This case is the first to demonstrate Wallenberg's syndrome associated with contralateral Dejerine's syndrome. The pathogenesis is discussed with special reference to the vascular supply of the brain stem.

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