Akira Munakata

Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVEIt is hypothesized that cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is induced by free radicals released from a subarachnoid clot. This study therefore investigated the effect of a new free radical scavenger, edaravone, in the treatment of patients with aneurysmal SAH. METHODSNinety-one patients with aneurysmal SAH participated in this study and were randomized into a control group (n = 42) and an edaravone-treated group (n = 49). The difference between the 2 groups in terms of incidence of delayed ischemic neurological deficits (DINDs) and cerebral infarction caused by vasospasm, and Glasgow Outcome Scale score at 3 months after SAH were statistically analyzed. RESULTSThe incidence of DINDs was 21% in the control group and 10% in the edaravone-treated group, yet there was no statistically significant difference between the 2 groups (P = 0.118). In patients with DINDs, the incidence of cerebral infarction caused by vasospasm was 66% in the control group and 0% in the edaravone-treated group (P = 0.028), whereas the incidence of poor outcome caused by vasospasm was 71% in the control group and 0% in the edaravone-treated group (P = 0.046). CONCLUSIONWe found a trend toward a lesser incidence of DINDs and a lesser incidence of poor outcome caused by cerebral vasospasm in edaravone-treated patients. It might therefore be suggested that edaravone is a useful agent for the treatment of aneurysmal SAH.

Suppression of the Rho/Rho-Kinase Pathway and Prevention of Cerebral Vasospasm by Combination Treatment with Statin and Fasudil After Subarachnoid Hemorrhage in Rabbit

The Rho/Rho-kinase pathway is considered important in the pathogenesis of sustained smooth muscle cell contraction during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The aims of this study were to investigate whether combination treatment, with pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevents the cerebral vasospasm. SAH was simulated using the double-hemorrhage rabbit model, and pitavastatin, or fasudil, or both (combination treatment) were administrated. The basilar artery (BA) cross-sectional area only in the combination treatment group was statistically larger than in the SAH group (p < 0.05). BA Rho-kinase, as measured by ELISA, was statistically reduced only in the combination treatment group compared with the SAH group (p < 0.05). In the other two treatment groups, pitavastatin or fasudil treatment group showed larger BA cross-sectional areas and lower value for BA Rho-kinase, but there were no statistically significant differences compared with the SAH group. The expression of endothelial nitric oxide synthase (eNOS), evaluated by immunohistochemistry in the pitavastatin group and the combination group, was higher than in the SAH group. Results indicate that combination treatment could extensively prevent cerebral vasospasm due to the synergic effect of combining pitavastatin and fasudil on the Rho/Rho-kinase pathway and on eNOS.

Decompressive hemi-craniectomy is not necessary to rescue supratentorial hypertensive intracerebral hemorrhage patients: consecutive single-center experience.

OBJECTIVE A consensus on decompressive surgery for hypertensive intracranial hemorrhage (ICH) has not been reached. We retrospectively analyzed our single-center experience with ICH. MATERIAL AND METHODS From January 2004 to August 2009, 65 consecutive supratentorial ICH patients underwent surgery in our institute. Supratentorial ICHs that exhibited a hematoma volume of over 50 mL according to the xyz/2 method were included in this study. We compared a hematoma removal plus decompressive craniectomy group (DC) and a hematoma removal group (HR) with regard to GCS, preoperative hematoma volume, shift from the midline, time from the ictus to surgery, post-surgical hematoma volume, brain swelling, hospitalization periods, and m-RS after 3 months. Statistical analysis was done using the t-test or χ2 test, and the odds ratio was calculated. RESULTS Twenty-five patients participated in this study. The DC group included 5 male patients, and the HR group 20 patients (F/M=8/12). Mean DC group age was 44.2 years, and 56.8 years for the HR group (p<0.05). GCS, preoperative hematoma volume, shift from the midline, time from the ictus to surgery, and postoperative hematoma volume were similar between both groups. Brain swelling on post-operative [corrected] CT was demonstrated to be mild and delimited within the cranium in the DC group, similar to the HR group. Hospitalization periods increased in the DC group (p<0.05). The m-RS after 3 months was similar for both groups. The factors relevant for m-RS were age, postoperative hematoma volume, and GCS at 24 h after surgery. CONCLUSION Decompressive craniectomy is not necessary for rescue in ICH if the hematoma can be removed completely.

Abducens Nerve Pareses Associated with Aneurysmal Subarachnoid Hemorrhage

Background: This study was performed to reveal the incidence and the etiology of abducens nerve pareses associated with aneurysmal subarachnoid hemorrhage. Methods: At the time of admission, CT scan was carried out, and the thickness of the prepontine subarachnoid clot was measured. Results: In total 101 patients met the study requirements and abducens nerve pareses was apparent in 6 patients (5.9%). There were significant differences between the group with abducens nerve pareses and the group without in regard to the thickness of the prepontine subarachnoid clot on CT scan. Conclusions: The prepontine subarachnoid clot seemed to be the factor inducing the abducens nerve pareses.

Role of Cyclooxygenase-2 in Relation to Nitric Oxide and Endothelin-1 on Pathogenesis of Cerebral Vasospasm After Subarachnoid Hemorrhage in Rabbit

Endothelial dysfunctions that include decreased nitric oxide (NO) bioactivity and increased endothelin-1 (ET-1) bioactivity have been considered to be involved in the pathogenesis of cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (SAH). Recent cardiovascular studies have revealed that cyclooxygenase-2 (COX-2) is involved in a disturbance in cross-talk between NO and ET-1. COX-2 expression was detected in the endothelial cells of a spastic artery after experimental SAH; however, the pathophysiological significance of COX-2 in relation to CVS remains unclear. The aim of this study was to investigate the role of COX-2 in relation to NO and ET-1 in the pathogenesis of CVS by using the COX-2 selective inhibitor, celecoxib. In the SAH group, SAH was simulated using the double-hemorrhage rabbit model. In the celecoxib group, SAH was simulated and celecoxib was administered. The basilar artery was extracted on day 5 and examined. The cross-section area of the basilar artery in the celecoxib group was significantly larger than in the SAH group. An increased expression of COX-2, ET-1, and ETA receptor (ETAR), and a decreased expression of endothelial NO synthase (eNOS) were seen in the SAH group. In the celecoxib group compared to the SAH group, expression of COX-2, ET-1, and ETAR were statistically significantly decreased, and eNOS expression was significantly increased. COX-2 might be involved in the pathogenesis of CVS due to up-regulation of ET-1 and ETAR and down-regulation of eNOS, and celecoxib may potentially serve as an agent in the prevention of CVS after SAH.

EFFECT OF A FREE RADICAL SCAVENGER, EDARAVONE, ON FREE RADICAL REACTIONS ― RELATED SIGNAL TRANSDUCTION AND CEREBRAL VASOSPASM IN THE RABBIT SUBARACHNOID HEMORRHAGE MODEL ―

OBJECTIVE it is hypothesized that free radical reactions evoked by oxyhemoglobin (oxyHb) cause cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), even though the detailed mechanisms have not yet been fully established. The aims of this study were thus to investigate, through the use of the double-hemorrhage rabbit model, the possibility that free radical reactions play a role in cerebral vasospasm and to delineate the mechanism of signal transduction that causes cerebral vasospasm. METHODS in the SAH group, SAH was simulated using the double-hemorrhage rabbit model. In the treatment group, edaravone (0.6 mg/kg), a potent free radical scavenger, was injected into the central ear vein twice a day. Four days after SAH, the basilar artery was excised. The degree of cerebral vasospasm was evaluated by measuring the diameter of each basilar artery, and the expression of Rho-kinase in the vascular wall was examined by western blotting. RESULTS the diameter of the basilar artery in the edaravone-treated group was 0.64 ± 0.06 mm, which was statistically significantly larger than that in the nontreated SAH group (0.50 ± 0.03 mm; p < 0.01). The expression of Rho-kinase in the edaravone-treated group was statistically significantly reduced in comparison to that of the nontreated SAH group. CONCLUSION results from this study have indicated for the first time that free radical reactions mediated by oxyHb may play an important role in the pathogenesis of cerebral vasospasm through the expression of Rho-kinase.

Role of oxidized LDL and lectin-like oxidized LDL receptor-1 in cerebral vasospasm after subarachnoid hemorrhage

OBJECT Cerebral vasospasm after subarachnoid hemorrhage (SAH) is a serious complication. Free radicals derived from subarachnoid clotting are recognized to play an important role. Oxidized low-density lipoprotein (ox-LDL) and lectin-like oxidized LDL receptor-1 (LOX-1) have been shown to be related to the pathogenesis of atherosclerosis and may increase in cerebral arteries after SAH, due to the action of free radicals derived from a subarachnoid clot. These molecules may also affect the pathogenesis of vasospasm, generating intracellular reactive oxygen species and downregulating the expression of endothelial NO synthase (eNOS). If so, apple polyphenol might be effective in the prevention of vasospasm due to an abundant content of procyanidins, which exhibit strong radical scavenging effects, and the ability to suppress ox-LDL and LOX-1. The purposes of this study were to investigate changes in levels of ox-LDL and LOX-1 after SAH and whether administering apple polyphenol can modify cerebral vasospasm. METHODS Forty Japanese white rabbits were assigned randomly to 4 groups: an SAH group (n = 10); a shamoperation group (n = 10), which underwent intracisternal saline injection; a low-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 10 mg/kg per day from Day 0 to Day 3; and a high-dose polyphenol group (n = 10) with SAH and oral administration of apple polyphenol at 50 mg/kg per day. At Day 4, the basilar artery and brain was excised from each rabbit. The degree of cerebral vasospasm was evaluated by measuring the cross-sectional area of each basilar artery, and the expression of ox-LDL, LOX-1, and eNOS was examined for each basilar artery by immunohistochemical staining and reverse transcriptase polymerase chain reaction. In addition, neuronal apoptosis in the cerebral cortex was evaluated by TUNEL. RESULTS Compared with the sham group, the expression of ox-LDL and LOX-1 in the basilar arterial wall was significantly increased in the SAH group, the expression of eNOS was significantly decreased, and the cross-sectional area of basilar artery was significantly decreased. Compared with the SAH group, the cross-sectional area of basilar artery was increased in the polyphenol groups, together with the decreased expression of ox-LDL and LOX-1 and the increased expression of eNOS. In the high-dose polyphenol group, those changes were statistically significant compared with the SAH group. In the low-dose polyphenol group, those changes were smaller than in the high-dose polyphenol group. No apoptosis and no changes were seen in the cerebral cortex in all groups. CONCLUSIONS This is the first study suggesting that ox-LDL and LOX-1 increase due to SAH and that they may play a role in the pathogenesis of vasospasm. It is assumed that procyanidins in apple polyphenol may inhibit a vicious cycle of ox-LDL, LOX-1, and ROS in a dose-dependent manner. Apple polyphenol is a candidate for preventive treatment of cerebral vasospasm.

Current Management of Subarachnoid Hemorrhage in Advanced Age

PURPOSE we focused on the recent management of aneurysmal subarachnoid hemorrhage (SAH) in patients over 70 years old (advanced age). METHODS from January 2001 through July 2009 we treated 372 aneurysmal SAH cases including 123 patients of advanced age. Since 2006 we have been selecting primarily interventional treatment in advanced age. We divided patients into two groups: from 2001 to 2005 and from 2006 to 2009. We analyzed Hunt-Kosnik (HK) grade, treatment methods, rate of vasospasm, Glasgow Outcome Scale at 30 days after onset of SAH, and the ratio of shunt operations. Statistical analyses were done with chi-square analysis or the t-test. RESULTS the ratio of procedures in advanced age increased statistically from 28% (51/183) to 38% (72/189). Mean age of patients increased from 76.2 to 77.7. HK grade and proportion of radical surgeries were similar. But the proportion of acute stage surgery and coil embolization increased significantly from 79 to 95% and from 8 to 24%, respectively. Incidence of symptomatic vasospasm increased from 35 to 37%, while asymptomatic vasospasm decreased from 4.7 to 3.2%. Rate of angioplasty increased significantly from 22 to 76%. The proportion of shunt surgeries decreased from 33 to 19% and favorable outcomes increased from 47 to 51%. CONCLUSIONS mean age and proportion of procedures in advanced age are increasing, but outcomes have improved. These results depend on radical surgery for aneurysm in the acute stage and aggressive prevention and treatment of vasospasm. Interventional treatment is necessary to improve the outcome in cases of advanced age.

Augmentation index is related to white matter lesions

The augmentation index (AIx) is a measure of pulse wave reflection from peripheral muscular conduit arteries, and is assumed to increase with stiffened arteries. A white matter lesion (WML) is generally regarded as a chronic ischemic lesion, which is associated with cerebral small-vessel arteriosclerosis. The aim of this study is to elucidate the effect of pulse wave reflection on the brain. Carotid AIx was measured in a total of 205 neurologically normal adults. The correlations between AIx and WML were investigated. Two categories of WML were evaluated, periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH). On univariate analysis, AIx was significantly correlated with the grades of PVH and DSWMH (P=0.0001, respectively). On multivariate analysis, AIx was correlated with PVH and DSWMH, independent of other risk factors such as age or blood pressure. Pulse wave reflection from small vessels may influence the genesis of WML.

An infant case of intracranial peripheral-type primitive neuroectodermal tumor with long-term survival

Abstract Supratentorial primitive neuroectodermal tumors (S-PNET) that develop in children have recently been classified into two types: central-type PNET (C-PNET), which has been reported over the years, and peripheral-type PNET (P-PNET), which develops intracranially and was referred to as Ewings sarcoma in the past. P-PNET is fundamentally a malignant tumor, but the patient reported here represents a case of long-term survival from onset without recurrence. At the age of 21 months, a male infant developed a cranial bone deformity and symptoms of high intracranial pressure. A CT scan revealed a cystic tumor attaching to the falx, and cyst drainage operation was immediately performed. The intracranial tumor was then resected. The tumor was an intradural extramedullary tumor, and it was totally excised with the falx attachment. The tumor was initially diagnosed as a neuroblastoma, and postoperative treatment consisted of administration of radiotherapy and chemotherapy using cyclophosphamide and vincristine. Twenty years have now passed without any recurrence. Recent repeated performance of histopathological analysis resulted in a diagnosis of P-PNET. In recent years, studies in molecular biology have demonstrated that P-PNET involves the EWS-FLI1 chimeric gene, and immunohistochemical staining has shown P-PNET to be MIC2 positive. P-PNET also differs from C-PNET with regard to prognosis, and for this reason it is believed that P-PNET and C-PNET should be considered separate entities. That is, in spite of the fact that P-PNET is a malignant tumor, patient survival can be comparatively long. Because P-PNET originates intracranially, it is fundamentally an intradural extramedullary tumor. For this reason, treatment should consist of surgical excision that is as complete as possible, followed by appropriate radiotherapy and chemotherapy. This approach can be expected to result in the patients long-term survival.