Naoya Matsuda

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.

Early ambulation produces favorable outcome and nondemential state in aneurysmal subarachnoid hemorrhage patients older than 70 years of age.

BACKGROUND We analyzed consecutive subarachnoid hemorrhage (SAH) cases in patients older than 70 years of age who underwent aneurysm surgery. We report the influence of early ambulation on outcome in advanced-age SAH. METHODS From 2005 through 2010, 71 aneurysmal SAH cases whose Hunt-Hess grades ranged from 1 to 3 were included. All cases underwent clip ligation or coil embolization. Male to female ratio was 8/63; median age was 76 years (range, 70-87). We routinely have patients become ambulatory the day after surgery. The ambulation date was used to determine four groupings: 0-5 days, 6-10 days, 11-15 days, and 16 days and longer. We analyzed the relationship between ambulation date and the Glasgow Outcome Scale (GOS) or dementia at 30 days after the SAH. Favorable outcome was defined as good recovery and moderate disability according to the GOS. Dementia was screened by use of the revised-Hasegawa dementia scale. The chi-square test was used and a P < 0.05 was considered statistically significant. RESULTS Mean days to ambulation was 10.7 ± 9.3 SD days. Forty-eight cases (66%) achieved favorable outcome, and 27 cases (38%) reached a nondemential state. Early ambulation positively correlated with favorable GOS and postoperative nondemential state. CONCLUSIONS Elderly SAH patients with good Hunt-Hess grades should have a clip ligation or endovascular coiling. Early ambulation produces favorable outcome and a nondemential state in elderly SAH patients.

The Role of Arterioles and the Microcirculation in the Development of Vasospasm after Aneurysmal SAH

Cerebral vasospasm of the major cerebral arteries, which is characterized by angiographic narrowing of those vessels, had been recognized as a main contributor to delayed cerebral ischemia (DCI) in subarachnoid hemorrhage (SAH) patients. However, the CONSCIOUS-1 trial revealed that clazosentan could not improve mortality or clinical outcome in spite of successful reduction of relative risk in angiographic vasospasm. This result indicates that the pathophysiology underlying DCI is multifactorial and that other pathophysiological factors, which are independent of angiographic vasospasm, can contribute to the outcome. Recent studies have focused on microcirculatory disturbance, such as microthrombosis and arteriolar constriction, as a factor affecting cerebral ischemia after SAH. Reports detecting microthrombosis and arteriolar constriction will be reviewed, and the role of the microcirculation on cerebral ischemia during vasospasm after SAH will be discussed.

Effect of Cilostazol on Cerebral Vasospasm and Outcome in Patients with Aneurysmal Subarachnoid Hemorrhage: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Several clinical studies have indicated the efficacy of cilostazol, a selective inhibitor of phosphodiesterase 3, in preventing cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). They were not double-blinded trial resulting in disunited results on assessment of end points among the studies. The randomized, double-blind, placebo-controlled study was performed to assess the effectiveness of cilostazol on cerebral vasospasm. Methods: Patients with aneurysmal SAH admitted within 24 h after the ictus who met the following criteria were enrolled in this study: SAH on CT scan was diffuse thick, diffuse thin, or local thick, Hunt and Hess score was less than 4, administration of cilostazol or placebo could be started within 48 h of SAH. Patients were randomly allocated to placebo or cilostazol after repair of a ruptured saccular aneurysm by aneurysmal neck clipping or endovascular coiling, and the administration of cilostazol or placebo was continued up to 14 days after initiation of treatment. The primary end point was the occurrence of symptomatic vasospasm (sVS), and secondary end points were angiographic vasospasm (aVS) evaluated on digital subtraction angiography, vasospasm-related new cerebral infarction evaluated on CT scan or MRI, and clinical outcome at 3 months of SAH as assessed by Glasgow Outcome Scale, in which poor outcome was defined as severe disability, vegetative state, and death. All end points were evaluated with blinded assessment. Results: One hundred forty eight patients were randomly allocated to the cilostazol group (n = 74) or the control group (n = 74). The occurrence of sVS was significantly lower in the cilostazol group than in the control group (10.8 vs. 24.3%, p = 0.031), and multiple logistic analysis showed that cilostazol use was an independent factor reducing sVS (OR 0.293, 95% CI 0.099-0.568, p = 0.027). The incidence of aVS and vasospasm-related cerebral infarction were not significantly different between the groups. Poor outcome was significantly lower in the cilostazol group than in the control group (5.4 vs. 17.6%, p = 0.011), and multiple logistic analyses demonstrated that cilostazol use was an independent factor that reduced the incidence of poor outcome (OR 0.221, 95% CI 0.054-0.903, p = 0.035). Severe adverse events due to cilostazol administration did not occur during the study period. Conclusions: Cilostazol administration is effective in preventing sVS and improving outcomes without severe adverse events. A larger-scale study including more cases was necessary to confirm this efficacy of cilostazol.

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.

Safety of preprocedural antiplatelet medication in coil embolization of ruptured cerebral aneurysms at the acute stage.

Preoperative antiplatelet medication for aneurysm coil embolization during acute subarachnoid hemorrhage (SAH) is not common. However, recent advances in neurointerventional devices make antiplatelet medication necessary for SAH surgery. We tested the hypothesis that preprocedural antiplatelet therapy in the acute stage of SAH prevents complications due to ischemia or induced bleeding. We retrospectively reviewed 35 consecutive ruptured cerebral saccular aneurysms that underwent coiling at our institute. Two hundred milligrams of aspirin and 150 mg of clopidogrel were administered to the patients at least two hours before coiling. Systemic heparinization was given after sheath insertion. Procedure-related thrombus formation on digital subtraction angiography, and clinical evidence of ischemia and procedure-related stroke on CT were reviewed. The median patient age was 69 years. Five males and 30 females were included. Seventy-seven percent of patients were Hunt-Hess grades 1 to 3. Assist techniques were used in 20 cases (57%). We inserted one extracranial internal carotid artery stent, but no intracranial stent. Intraoperative thrombosis occurred in one case (2.9%), with no clinical symptoms. Postoperative cerebrospinal fluid drainage was done in three cases, but we experienced no bleeding complications. Preoperative antiplatelet therapy leads to a low rate of thromboembolic events in coiling during acute stage SAH, and this strategy had no adverse influence on bleeding complications.

Analysis of Factors That Influence Long-Term Independent Living for Elderly Subarachnoid Hemorrhage Patients

BACKGROUND The number of elderly subarachnoid hemorrhage (SAH) patients has been increasing. The aim of this study was to analyze long-term outcome for elderly (≥75 years) SAH patients and to establish a treatment strategy. METHODS From January 2005 to December 2013, 86 consecutive cases were treated. We used a modified Rankin Scale (mRS) at the outpatient clinic or a telephone interview of patients and/or families. Kaplan-Meier plots were done for mortality and independent (mRS 0 ∼ 2) state. Multivariate analysis was done to distinguish factors that influence on outcome. RESULTS Median age was 79, Hunt-Kosnik grade 1 ∼ 3 was 79%, and the radical intervention (clipping or coiling) rate was 78%. Mean follow-up period was 28.7 ± 3.4 standard error months. Half of deaths occurred during the first two months. The number of cases of independent living gradually decreased to 50% at 28 months after SAH. Half of patients lived independently for 36 months at HK grades 1 to 3, and 3 months at HK grades 4 to 5 (p < 0.05). Half of patients lived independently for 40 months in the radical intervention group, and 14 months in the conservative treatment group (p < 0.05). Multivariate analysis for independent living revealed that gender, pre-morbid condition, HK grade, and postoperative complication were significant (p < 0.05). CONCLUSIONS Good-grade elderly SAH cases that were independent pre-stroke should have radical intervention performed for aneurysm. Avoiding perioperative complications have a positive influence on long-term independent living.

Rehabilitation and the Neural Network After Stroke

Stroke remains a major cause of disability throughout the world: paralysis, cognitive impairment, aphasia, and so on. Surgical or medical intervention is curative in only a small number of cases. Nearly all stroke cases require rehabilitation. Neurorehabilitation generally improves patient outcome, but it sometimes has no effect or even a mal-influence. The aim of this review is the clarification of the mechanisms of neurorehabilitation. We systematically reviewed recently published articles on neural network remodeling, especially from 2014 to 2016. Finally, we summarize progress in neurorehabilitation and discuss future prospects.

A rare case of primary bone xanthoma of the clivus

Primary bone xanthoma is a rare type of tumor, and those developing primarily within the skull are even more unusual. In this case, a primary bone xanthoma of the clivus without endocrine or metabolic complications represents the first of this type to be reported. The patient, a 24-year-old woman, initially experienced frequent headaches. Subsequent skull tomography and bone-window computed tomography (CT) revealed a clearly demarcated osteolytic lesion in the clivus. T1-weighted magnetic resonance imaging (MRI) exhibited low intensity, and T2-weighted MRI showed iso-high intensity and a heterogeneously faint contrast effect. The tumor was completely resected, after which the patient’s headaches disappeared completely. Because xanthoma is devoid of neoplastic features, it does not necessarily require aggressive therapy. Therefore, it is very important to understand the characteristics of its clinical symptoms and to give due consideration to differential diagnosis based on pathological presentations and imaging features. This study introduces information regarding a bone xanthoma originating within the skull, together with a review of bone xanthoma literature.

NOVEL RAT MIDDLE CEREBRAL ARTERY OCCLUSION MODEL: TRANS- FEMORAL ARTERY APPROACH COMBINED WITH PRESERVATION OF THE EXTERNAL CAROTID ARTERY

We developed a novel trans-femoral artery approach to the rat middle cerebral artery occlusion model (TF-MCAO) without sacrificing the external carotid artery (ECA) with/without the pterygopalatine artery, which is important for chewing food. To make the TF-MCAO we first dissect the left common carotid artery (CCA), ECA, and internal carotid artery (ICA). Transient occlusion clips are applied to the proximal ECA and the pterygopalatine artery; we never sacrifice the ECA branch. A 24-gage catheter is inserted into the left femoral artery. We insert a slightly bent 0.014in. hydrophilically coated guide wire via a haemostasis valve. Anatomically, the left common carotid artery is located rostral to the descending aorta, permitting a straight-forward, blind approach to the CCA. The guide wire is gently advanced about 17mm from the bifurcation of the CCA until slight resistance is encountered. The guide wire and temporary occlusion clips are withdrawn after 90min. Rats were sacrificed 24h after reperfusion. Eleven rats were examined. One rat died before occlusion due to deep anesthesia. The success rate for producing infarction was 80%. The mean infarction volume of the basal ganglia was 94.4mm(3)+/-9.4 se and mean infarction volume of the cerebral cortex was 124.2mm(3)+/-21.6 se. No rat died due to cerebral infarction and no rat suffered subarachnoid hemorrhage. We conclude that TF-MCAO was useful for producing a cerebral infarction.