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DS-1040 is a novel inhibitor of the activated form of thrombin-activatable fibrinolysis inhibitor that may have therapeutic potential in thromboembolic diseases, such as acute ischemic stroke (AIS) or pulmonary embolism. We undertook a Phase I clinical trial to investigate the safety, pharmacokinetics, and pharmacodynamics of DS-1040 in Japanese patients who were eligible for thrombectomy following AIS.The trial enrolled patients with AIS due to large vessel occlusion, who were planned for thrombectomy within 8 h of symptom onset. Subjects were randomized to receive a single intravenous infusion of placebo or DS-1040 (0.6, 1.2, 2.4 or 4.8 mg) in a sequential-cohort design. The primary endpoints were the incidence of intracranial hemorrhage (ICH) and major extracranial bleeding within 36 and 96 h, respectively, of treatment initiation. Treatment-emergent adverse events (TEAEs) and pharmacokinetic/pharmacodynamic parameters were also assessed.Nine patients received placebo and 32 patients received DS-1040. There were no cases of symptomatic ICH or major extracranial bleeding with either placebo or DS-1040 after 36 and 96 h. One patient, who received DS-1040 0.6 mg, experienced a subarachnoid hemorrhage that was considered to be drug-related. Three patients died (2 placebo, 1 DS-1040), but no deaths were adjudicated as study drug-related. In vivo exposure to DS-1040 increased in proportion to dosage, but no clear dose-response relationship was seen for D-dimer levels and thrombin-activatable fibrinolysis inhibitor activity.Single doses of DS-1040 0.6-4.8 mg were well tolerated in Japanese patients with AIS undergoing thrombectomy.NCT03198715; JapicCTI-163164.

Some aneurysmal subarachnoid hemorrhage (SAH) patients are delayed in their presentation. This can cause a washout of the subarachnoid hematoma and a potential misdiagnosis. As a result, they may suffer re-rupture of the aneurysm and preventable deterioration. We investigated the factors that influence delayed SAH presentation.Aneurysmal SAH patients treated at nine stroke centers from 2002 to 2020 were included. Age, gender, pre-SAH modified Rankin scale (mRS), World Federation of Neurological Surgeons (WFNS) grade, Fisher group, day of presentation, aneurysm treatment method, past history of cerebral stroke, comorbidity of hypertension and/or diabetes mellitus, and mRS at discharge were assessed retrospectively. We formed two groups based on the day of presentation after the onset of SAH: day 0 ∼ 3 (early) and other (delayed). Logistic regression analyses detected the factors that influenced the day of presentation and outcome for SAH. A p-value0.05 was considered significant.Delayed presentation comprised 282 cases (6.3%) of 4,507 included cases. Logistic regression analyses showed that patients in an urban area, of male gender, low WFNS grade, and low Fisher group correlated significantly with a delayed presentation. But delayed presentation did not influence outcome at discharge.Area of residency and gender correlated with delayed presentation after SAH in Japan. Urbanization, male gender and mild SAH lead patients to delay presentation. The factors underlying these tendencies will be analyzed in a future prospective study.

Various techniques have been performed to reduce subarachnoid clotting during aneurysmal neck clipping surgery. We considered that maintaining the physiologic cerebrospinal fluid circulation by performing arachnoid plasty after clipping during surgery would lead to the accelerated clearance of the subarachnoid clot.Patients in a prospectively maintained aneurysmal subarachnoid hemorrhage (aSAH) database at our institution and with aSAH that fulfilled the criteria were selected for this study. The incidence of delayed cerebral ischemia, angiographic vasospasm, 3-month functional outcome, and the amount of subarachnoid clot on computed tomography were compared between the 2 groups after matching.From 2006 through 2016, 228 clipping cases met the inclusion criteria. Using propensity score matching, 89 cases of clipping without arachnoid plasty were matched to 89 cases of clipping with arachnoid plasty. Univariate analyses showed that arachnoid plasty significantly reduced the occurrence of hydrocephalus and incidence of poor outcome. Arachnoid plasty statistically significantly reduces the occurrence of hydrocephalus (odds ratio 0.267, 95% confidence interval 0.074-0.963, P0.05). Multivariate analysis also showed that arachnoid plasty was the factor reducing poor outcome at 3 months after aSAH (odds ratio 0.222, 95% confidence interval 0.075-0.661, P0.01).The present study suggests that good hematoma clearance due to arachnoid formation reduced brain damage, cerebral vasospasm, and hydrocephalus, resulting in significantly fewer cases with poor functional prognosis. It therefore follows that procedures such as arachnoid plasty should be taken into consideration in order to improve outcome in surgical clipping.

Background The most uncontrollable complication during coil embolization of a ruptured cerebral aneurysm is thromboembolic ischemia. We analyzed whether thromboembolic complications could be reduced by using preoperative antiplatelet medications for acute subarachnoid hemorrhage in multicenter fashion. Methods We selected antiplatelet medicines according to an official protocol: a combination of 200 mg aspirin, 150 or 300 mg clopidogrel, and 200 mg cilostazol. Systemic heparinization was done after sheath insertion in all cases. One hundred and ten consecutive, ruptured cerebral saccular aneurysms that underwent coiling at our institute were analyzed. Procedure-related thrombus formation on digital subtraction angiography and clinical evidence of ischemia and procedure-related stroke on computed tomography scan were reviewed. Results Eighty cases (73%) were medicated with multiple antiplatelet medications, 22 cases (20%) were treated with a single medication, and 8 cases (7%) were treated without antiplatelet medication. Thromboembolic complications were reduced in an inverse relationship with the number of antiplatelet medications. Hemorrhagic complications because of antiplatelet medications did not occur. Postoperative symptomatic vasospasm tended to decrease, and outcome also tended to improve in the multiple medications groups. Reduction of thromboembolic complications significantly improved clinical outcome in logistic regression analysis. Conclusions Preoperative multiple antiplatelet medication reduced thromboembolic events in coiling during acute stage subarachnoid hemorrhage and improved clinical outcomes.

The initiation of anticoagulant administration after large vessel occlusion (LVO) or stenosis with nonvalvular arterial fibrillation (NAVF) is controversial. We evaluate the timing of anticoagulation and its relationship with clinical factors.We enrolled 595 anterior circulation LVO or stenosis with NAVF cases from 38 stroke centers. Laboratory data; activities of daily living; the Alberta Stroke Program Early CT Score (ASPECTS); the National Institutes of Health Stroke Scale (NIHSS) score; occluded artery; treatment methods; date of the initiation of apixaban administration and outcome were recorded. Multivariate analyses were performed after univariate analysis.The median start of apixaban administration after the stroke was 2 days (interquartile range, 1-5; range, 0-14). Multivariate analysis of variance showed that non-internal carotid artery occlusion (F value 4.60), reperfusion therapy (31.1), high ASPECTS (6.27) before anticoagulant intake, and absence of intracranial hemorrhage (12.9) were significantly correlated with early apixaban administration. Multiple logistic regression analysis for independent living at 90 days after the stroke showed significant factors: aging (odds, 0.94; 95% confidence interval [CI], 0.91-0.97); male (odds, 0.46; 95% CI, 0.26-0.79); prestroke independence (odds, 20.7; 95% CI, 6.48-93.9); number of white blood cells (odds, 0.99; 95% CI, 0.97-1.00); non-internal carotid artery occlusion; NIHSS score at 72 hours after the stroke (odds 0.92; 95% CI, 0.89-0.96); ASPECTS before apixaban intake (odds, 1.15; 95% CI, 1.00-1.31) and initiation of apixaban (odds, 0.91; 95% CI, 0.83-0.99).Early administration of apixaban is induced by nonsevere infarction, reperfusion therapy or none of intracranial hemorrhage and it correlates with an independent long-term outcome.

Early brain injury (EBI) is considered an important cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). As a factor in EBI, microcirculatory dysfunction has become a focus of interest, but whether microcirculatory dysfunction is more important than angiographic vasospasm (aVS) remains unclear. Using data from 128 cases, we measured the time to peak (TTP) in several regions of interest on digital subtraction angiography. The intracerebral circulation time (iCCT) was obtained between the TTP in the ultra-early phase (the baseline iCCT) and in the subacute phase and/or at delayed cerebral ischemia (DCI) onset (the follow-up iCCT). In addition, the difference in the iCCT was calculated by subtracting the baseline iCCT from the follow-up iCCT. Univariate analysis showed that DCI was significantly increased in those patients with a prolonged baseline iCCT, prolonged follow-up iCCT, increased differences in the iCCT, and with severe aVS. Poor outcome was significantly increased in patients with prolonged follow-up iCCT and increased differences in the iCCT. Multivariate analysis revealed that increased differences in the iCCT were a significant risk factor that increased DCI and poor outcome. The results suggest that the increasing microcirculatory dysfunction over time, not aVS, causes DCI and poor outcome after aneurysmal aSAH.

A successful microsurgical neck clipping of cerebral aneurysm is one of the milestones for neurosurgeons. However, a 'complete clip closure of aneurysm without neurological deficit' is not enough for the patient, as esthetic problems can occur several months after the surgery. In this paper, we describe a series of surgical tips concerning the surgical steps starting from skin incision to craniotomy to minimize the esthetic impact. First, the skin incision should be oriented perpendicular to the fall pattern of hair follicles in the temporal area so that the hair covers the scar line and the scalpel is tilted about 50° to face in the frontal area for preservation of hair roots. After minimum coagulation and skin clip application, interfascial fat pad is dissected at 2 cm dorsal to McCarty keyhole to root of zygomatic process, in order to protect facial nerve. Subgaleal connective tissue with periosteum is harvested as a flap for reconstruction of the calvarial defect. The temporal muscle should be dissected from the caudal to rostral position to avoid delayed muscular atrophy. Central dural tenting sutures are placed at the dural incision. The craniotomy line should be filled with bone crust and covered by subgaleal connective tissue with the periosteum. Single, short-distance galeal sutures, and loose skin sutures can reduce post-operative granulation. From the day after surgery, the patient can shampoo his/her head.

Pathophysiological findings of early brain injury in humans have not permitted conclusive determinations. We explored the essence of this phenomenon by taking intraoperative cortical specimens of Hunt-Kosnik grades IV~V (poor-grade) subarachnoid hemorrhages (SAH). From 2013 to 2017, we treated 39 consecutive poor-grade patients in 226 cases of aneurysmal SAH. Fourteen of the 39 patients agreed to this study following written informed consent. We took specimens from untouched areas prior to surgical intervention: cortex near the ruptured aneurysm for clipping, convexity cortex for cerebral ventricular drainage. Cortical specimens were stained with hematoxylin-eosin, anti-cleaved caspase-3, and anti-DNA/RNA damage staining. Positive signals were calculated in six random, high-power fields for quantitative assessment. Double immunofluorescence was done to evaluate neural damage. Chi-square analyses were carried out to assess the correlation between the Glasgow Outcome Scale at 90 days after the ictus and the number of positive cells. Cortical specimens were taken at 12.7 ± 7.00 h after the first ictus. All 14 cases showed dense nuclei, with the appearance of acidic and shrunken cytoplasms. Diffuse positivity of anti-cleaved caspase-3 and anti-DNA/RNA damage was detected. Cleaved caspase-3 was detected in 68% of neurons, and DNA/RNA damage was detected in 64% of neurons. Positive reactions of both antibodies indicated poor outcome. With poor-grade cases, irreversible ischemic, apoptotic, and oxidative changes were detected in the cerebral cortex within several hours after the ictus. Those changes occurred far from the aneurysm. Our findings suggest that a revolution is needed in the treatment strategy for poor-grade SAH.

Oxidative stress influences many kinds of diseases. Our hypothesis is that oxidative stress and antioxidant potentials correlate with cognitive function, activities of daily life and white matter injury. (UMIN-CTR R000016770) Thirty-two consecutive patients participated to this study after informed consent. A routine biochemical analysis, modified-Rankin Scale (m-RS), revised Hasegawa Dementia Scale (HDS-R), Mini-Mental State Examination (MMSE) and fluid-attenuated-inversion-recovery imaging (FLAIR) were performed before admission. Derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) were measured photometrically using arterial blood. Statistical analyses were done by analysis variance or logistic regression analysis. Median age was 72 (IQR: 64.3 -- 75.8). The d-ROMS were 367 ± 55.4, and BAP was 1967 ± 284. HDS-R and m-RS deteriorated with d-ROMs elevation (p 0.05). Uric acid and creatinine decreased with d-ROMs elevation (p 0.05). Both periventricular hyperintensity grade and deep and subcortical white matter hyperintensity grade worsened with BAP reduction (p 0.05). Oxidative stress correlates negatively with cognitive function and activities of daily life. Low antioxidative potentials correlate with aggravation of white matter injury. We should control both oxidative stress and antioxidative potential to maintain healthy lives.

Case Vertebral artery injury is a low-frequency but high-mortality injury. The surgical approach to a bleeding vertebral artery injury is one of the most difficult procedures in trauma surgery.A 64-year-old woman was transported to our emergency department after being stabbed in the middle side of the right neck with a large kitchen knife. Her initial hospital examination indicated a shock state, and computed tomography images revealed a right vertebral artery injury. We undertook angiography and transcatheter arterial embolization before the surgical operation. Outcome The patient suffered right upper extremity paralysis due to brachial plexus injury and was transferred to another hospital for rehabilitation on the 24th hospital day. Conclusion Computed tomography angiography for diagnosis and interventional radiology treatment are useful for the management of penetrating neck trauma. Transcatheter arterial embolization for vertebral artery injury is safe and allows for easy control of bleeding compared to a surgical procedure.

We analyzed acute ischemic stroke by thromboembolism in the early period after lung cancer surgery. A retrospective review of the clinical records of patients who underwent lung resection for primary lung cancer was performed. Patients who underwent lobectomy, bilobectomy, and pneumonectomy were included. The clinical characteristics of the patients, the incidence of atrial fibrillation (Af) after surgery, and the incidence of acute ischemic stroke were analyzed. The clinical courses of patients having acute ischemic stroke were also reviewed. In 4 (0.6%) of 696 patients, acute ischemic stroke occurred in the early period during hospitalization after lung cancer surgery. Acute ischemic stroke occurred within 4 days in three cases and after 4 days in one case. The resection site of the lung was the left side in all cases, and there were three cases of left upper lobectomy and one case of left lower lobectomy. As for the two recent patients, thrombus removal was performed by a neurosurgeon, and both cases achieved successful recanalization. The time between symptom detection and recanalization was 205 and 170 min, respectively. One patient was cured without any residual effect of disease, and the other patient’s hemiplegia resolved and aphasia improved. Since cerebral infarction impairs the patient’s quality of life, thrombus removal should be considered if possible.

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11–0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

The number of elderly patients with an aneurysmal subarachnoid hemorrhage (aSAH) has been increasing in aging- or aged societies in many countries. A treatment strategy for the elderly with aSAH has not been established, although many studies have been published emphasizing poor outcome for aSAH. The aim of this study was to analyze the factors and treatments affecting outcome in aSAH in the elderly in a systematic review of the literature by investigating patients over age 75. A literature search was done for "elderly aSAH" in PubMed and Embase. Literature with a clear description of treatment measures for aneurysmal occlusion and outcome was selected. Twelve studies, consisted of 816 cases, met the eligibility criteria. Patient characteristics included 83.2% female, 33.8% poor clinical grade on admission, 57.1% Fischer group 3, and 41% internal carotid artery aneurysm. As complications, symptomatic vasospasm was seen in 25.5% of patients, hydrocephalus in 31.1%, and medical complication in 38.4%. Favorable outcome was 35.0% in total, 45.3% for clipping, 36.3% for coiling, and 9.0% for conservative treatment. Several studies by multivariate analysis indicated that poor clinical grade on admission could be a risk factor for neurological outcome and mortality. Advanced age and selection of conservative treatment without aneurysmal occlusion could be a risk factor for mortality. Patients under age 85 with good clinical grade on admission can be candidates for treatment of aneurysm repair. However, treatment for patients over age 85 or with poor clinical grade should be carefully determined.

Vascular tortuosity is associated with various disorders and is being increasingly detected through advances in imaging techniques. The underlying mechanisms for vascular tortuosity, however, remain unclear. Here, we tested the hypothesis that oxidative stress mediates the generation of tortuous vessels. We used the bilateral common carotid artery (CCA) ligation model to induce vascular tortuosity. Both young and adult rats showed basilar artery tortuous morphological changes one month after bilateral CCA ligation. These tortuous changes were permanent but more pronounced in the adult rats. Microarray and real-time PCR analysis revealed that these tortuous changes were accompanied by the induction of oxidative stress-related genes. Moreover, the indicated model in rabbits showed that tortuous morphological changes to the basilar artery were suppressed by antioxidant treatment. These results are highly suggestive of the significance of oxidative stress in the development of vascular tortuosity. Although further studies will be needed to elucidate the possible mechanisms by which oxidative stress enhances vascular tortuosity, our study also points toward possible prophylaxis and treatment for vascular tortuosity.

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.

Oxidative stress was shown to play a crucial role in the diverse pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Microcirculatory dysfunction is thought to be an important and fundamental pathological change in EBI. However, other than blood-brain barrier (BBB) disruption, the influence of oxidative stress on microvessels remains to be elucidated. The aim of this study was to investigate the role of oxidative stress on microcirculatory integrity in EBI. SAH was induced in male Sprague-Dawley rats using an endovascular perforation technique. A free radical scavenger, edaravone, was administered prophylactically by intraperitoneal injection. SAH grade, neurological score, brain water content, and BBB permeability were measured at 24 h after SAH induction. In addition, cortical samples taken at 24 h after SAH were analyzed to explore oxidative stress, microvascular mural cell apoptosis, microspasm, and microthrombosis. Edaravone treatment significantly ameliorated neurological deficits, brain edema, and BBB disruption. In addition, oxidative stress-induced modifications and subsequent apoptosis of microvascular endothelial cells and pericytes increased after SAH induction, while the administration of edaravone suppressed this. Consistent with apoptotic cell inhibition, microthromboses were also inhibited by edaravone administration. Oxidative stress plays a pivotal role in the induction of multiple pathological changes in microvessels in EBI. Antioxidants are potential candidates for the treatment of microvascular disturbances after SAH.

The relatively high rate of post-operative recurrence in the treatment of chronic subdural hematoma (CSDH) is a significant problem. Goreisan is an herbal medicine that exhibits a hydragogue effect by inhibiting the expression of aquaporins, and its efficacy in preventing post-operative CSDH recurrence has been suggested by several case trials. This multi-center prospective randomized controlled trial was performed to investigate the preventative effect of goreisan on post-operative CSDH recurrence. Patients with symptomatic CSDH over 60 years old undergoing burr hole surgery were enrolled in this study. The patients were randomly allocated to the control group or the goreisan group, in which oral administration of goreisan (7.5 g daily) was continued for 12 weeks. The primary end-point was the post-operative recurrence rate at 12 weeks and the secondary end-point was hematoma volume reduction rates on computed tomography scan at 12 weeks. The analyses were performed not only on patients of all ages older than 60 years, but also on patients divided into those over or under 75 years old. One hundred and eighty patients were followed and analyzed (the control group, n = 88; the goreisan group, n = 92). The recurrence rates considering patients of all ages and patients under 75 years old were relatively low in the goreisan group but without a significant difference. The hematoma volume reduction rates showed no significant difference. Based on the results of the present study, a larger-scale study including more cases is necessary in future to confirm the efficacy of goreisan.

Stroke remains a major cause of disability throughout the world: paralysis, cognitive impairment, aphasia, apraxia and so on. Surgical or medical intervention is curative in only a small number of cases. Stroke cases with morbidity require rehabilitation. Neurorehabilitation generally improves patient outcome, but the involved mechanisms have not been clarified. Recent advancements in technology are revealing the mechanisms of neurorehabilitation from the gene and up to neural network remodeling. Rehabilitation in clinical application, however, should be guided by convincing evidence. In this chapter we review the evidence for the regeneration of the neural network after stroke.

Background and purposeCarotid plaque contains biologically active substances released into the blood during carotid artery stenting (CAS). The main purpose of this prospective study was to analyse sequential changes in oxidative stress during CAS and their relationship to clinical factors.MethodsTwenty-two consecutive CAS procedures were performed between May 2014 and April 2016. Arterial blood was collected four times: (1) after the sheath insertion without edaravone; (2) pre-angioplasty with edaravone from the carotid artery; (3) after post-stenting angioplasty from an occluded carotid artery; and (4) before sheath removal. Derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) were measured photometrically. The relationship between d-ROMs or BAP and preoperatively investigated biochemical parameters, cognitive function, and number of diffusion-weighted image (DWI) high spot lesions was analysed using one-way ANOVA and the Tukey–Kramer HSD test.ResultsThe d-ROM values for CAS were 355±58.8 Carratelli Units at sheath insertion, 315±57.2 after edaravone infusion, 328±56.8 after post-stenting angioplasty, and 315±53.0 just before sheath removal. The d-ROM values were reduced significantly after edaravone infusion (PConclusionOxidative stress is correlated negatively with cognitive function and positively with postoperative ischemic lesions. Antioxidant potential decreases with ageing.

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.

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.

We developed a novel model of a rat embolic cerebral infarction with a quantifiable autologous arterial blood clot. The left femoral artery had 0.15 ml of blood withdrawn and mixed with 10 units of thrombin in 50 μl saline. After 30 min, the clot was suctioned into a 4-French polyvinyl chloride tube. A 24-gage catheter was inserted up through the internal carotid artery via the external carotid artery stump. The 1-cm clot, at a volume of 7.2 mm3, was pushed and inserted into the internal carotid artery via the catheter. After withdrawing the catheter, the ICA blood flow recovered. We checked neurological status after 24 h (neurological free was 15, and worst was 1) and measured the infarction volume by the TTC method. Twelve rats were examined, and five sham-operated rats were included. Two rats were not able to achieve an 80% reduction in CBF. One rat died due to cerebral infarction. The success rate in producing infarction was 83%. The total infarction volume was 368.5 mm3±61.2 se. Median neurological score was 6. Hemorrhagic transformation was not detected. Sham-operated rats revealed no infarction and no neurological deficit. The volume of infarction correlated significantly with the neurological score. We conclude that this embolic stroke model is useful in producing a human, severe cardioembolic cerebral infarction.

Different types of tumor have been reported in the pineal gland, but pleomorphic xanthoastrocytoma (PXA) in this region is extremely rare. A 61-year-old man had gait disturbance and dementia for 1 month. Radiological examination revealed a 22 × 26 × 22-mm-diameter mass in the pineal gland and remarkable hydrocephalus. Biopsy of the tumor was performed and histological examination confirmed diagnosis of PXA with anaplastic features. Radiation therapy with concomitant temozolomide was performed, and tumor reduction was achieved. We report the first case of PXA with anaplastic features in the pineal gland. This case indicates that temozolomide and radiation therapy are effective for treating PXA with anaplastic features.

Treatment strategy of malignant congenital brain tumor is controversial. We report a congenital embryonal tumor case with various pathological components. A normally delivered male infant had an enlarged head circumference at 1 month after birth. The abnormality of the right side of the head was also noted during the routine 4-month health check. The head circumference was 45.1 cm (+2.25, SD); neurological status, however, was normal, with a pediatric GCS of 9 and body weight of 6,370 g (−0.85, SD). Magnetic resonance imaging (MRI) revealed right brain tumor whose size was 99 × 91 × 86 mm. The tumor was enhanced homogeneously with central necrosis, and the margin of the tumor was well circumscribed. We performed a subtotal removal of the tumor. The pathological diagnosis was meningioma (MIB-1 index was 2 %). The residual tumor gradually shrank, and we performed monthly MRI follow-up. The tumor abruptly recurred 7 months after the operation. The level of patient consciousness deteriorated, and emergency removal surgery was performed. The histological examination showed various types of embryonal components without meningioma-like parts. The pathological diagnosis was an embryonal tumor. The MIB-1 index was 48 %. One month after the second operation, dissemination of the tumor occurred at the right temporal lobe, cerebellum, and in subcutaneous tissue. Chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide) was initiated following radiation therapy (3 Gy/day, 8×). Adjuvant therapies were effective, and no tumor recurrence was detected during 34 months follow-up. Treatment strategies for malignant indefinite diagnosed tumor need to be discussed.

Objective: Ischemic stroke and hyperperfusion (HP) are the most frequent and important complications in carotid artery stenosis surgery. Carotid artery stenting (CAS) has replaced carotid endarterectomy in high medical risk patients. Prior to CAS, initial angiographic findings disclose a small caliber internal carotid artery (IC) due to stenosis, but after the stenosis is relieved, the diameter of the IC becomes enlarged. We investigated whether a change in the IC diameter was related to ischemic complication and HP using cerebral blood flow single photon emission computed tomography (SPECT). Methods: From February 2008 to December 2009 we consecutively performed 39 CAS on 35 patients. We retrospectively analyzed the relationship between changes at the level before the entry to the petrous bone canal of the IC and stenosis of the etiological artery, improvement in stenosis, HP and postintervention diffusion-weighted image high-intensity lesions. Statistical analyses comprised Wilcoxon/Kruskal-Wallis analysis, analysis of variance and a multivariate logistic analysis. Results: A total of 9 cases showed HP in SPECT. Severity of IC stenosis and change in the IC at the level before the entry to the petrous bone canal were related with statistical significance to HP. Other factors did not correlate with HP. Conclusion: Procedure-related dilation of the IC at the level before the entry to the petrous bone canal occurred due to release of the etiological stenosis. This finding can also support the prediction of HP.

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.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.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 (p0.05). Half of patients lived independently for 40 months in the radical intervention group, and 14 months in the conservative treatment group (p0.05). Multivariate analysis for independent living revealed that gender, pre-morbid condition, HK grade, and postoperative complication were significant (p0.05).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.

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.

Aesthetics must be considered in surgery for unruptured cerebral aneurysms, since it is a prophylactic treatment and a good-quality postoperative life should be maintained. We introduce several of our attempts to this end. To prevent postoperative alopecia, scalp clips are not used, and a skin incision is made perpendicular to the hairline and parallel to the hair-growing angle. Prevention of postoperative atrophy of the temporal muscle is attempted by not using keyholes, not using incision in the anterior part of the muscle, and preserving deep temporal arteries and veins. Any craniotomy lines and burr holes should be covered by artificial devices or autologous bone powder obtained during craniotomy and tightly covered by subgaleal connective tissue or temporal muscle with periosteum. In bald-headed patients, keyhole surgery is effective to make the scar ambiguous. Otherwise, a craniotomy under a skin incision on a wrinkle of the forehead, which can offer a larger operative field than keyhole surgery, effectively obscures the skin incision postoperatively. These attempts have resulted in satisfactory aesthetic effects both subjectively and statistically.

Vertebrobasilar artery dissection began to attract attention as a cause of subarachnoid hemorrhage (SAH) in the late 1970s. Although reports on this disease have gradually increased, the natural history of vertebrobasilar artery dissection remains obscure, and long-term follow-up of patients without surgical treatment is necessary to determine appropriate treatment. We describe the long-term clinical course of ruptured vertebrobasilar artery dissection treated non-surgically. Fourteen subjects with ruptured vertebrobasilar artery dissection were treated conservatively in 7 neurosurgical departments. We reviewed their clinical outcomes, image findings and the chronological changes at the dissection site from their charts. The modified Rankin Scale was Grade 0 in 13 of 14 cases, and Grade 2 in 1 case. The configuration of dissection did not change during the follow-up period in 12 of 14 cases, but occlusion and restoration were recognized in a single case each. Good prognosis was common in the patients with ruptured vertebrobasilar artery dissection who were treated non-surgically. It is essential to accumulate more data on the clinical course and changes in image findings of long-term survival cases to establish a definite strategy for ruptured vertebrobasilar artery dissection.

A 42-year-old male patient presented with an anterior cerebral artery (ACA) dissection manifesting as sudden onset of severe headache. Initial computed tomography revealed faint subarachnoid hemorrhage in the frontal region. Initial angiography showed tapering stenosis at the A(2) segment of right ACA. The patient was admitted to our hospital and treated conservatively. Magnetic resonance (MR) imaging and angiography did not detect intramural hematoma, intimal flap, or double lumen at the stenotic right A(2) segment. The ACA dissection was difficult to confirm based on the findings on day 0. ACA dissection was confirmed by improvement of the right ACA stenosis on follow-up angiography on day 14. On the other hand, MR cisternography revealed a fusiform dilatation of the vascular outer contour at the right A(2) on day 0, which had resolved on day 14. Cerebral angiography and MR cisternography similarly suggested asymptomatic contralateral (left) A(2) dissection on day 14. Fusiform dilatation of the vascular outer contour at the affected segment on MR cisternography may be indicative of arterial dissection in the acute phase.

Chronic subdural hematoma (CSH) is a disease frequently seen in the neurosurgical department. CSH also has a high rate of recurrence. Our hypothesis is that thrombin solution irrigation reduces recurrence in high-risk CSH patients. We define high risk as follows: use of anti-platelets, use of anticoagulants, recurrent CSH, renal failure, liver cirrhosis, and hematological disease. From January 1, 1998, to March 31, 2008, we compared a saline solution irrigation group (43 patients) and a thrombin solution (100 unit/ml) irrigation group (36 patients) prospectively and randomly. Surgical procedures were the same: one burr hole craniostomy, drainage of hematoma, irrigation of cavity, frontal insertion of silicon tube, replacement of air with solution, and removal of tube at 24 h after surgery. We define recurrence as an additional drainage operation due to neurological deficit within six months of surgery. Recurrences of CSH arose in two patients (5.5%) with thrombin irrigation and in 11 patients (25.6%) with saline irrigation (p0.05). Saline irrigation patients with anti-platelet medication experienced recurrence in five of 19 patients, although no thrombin-irrigated side recurred with the same drug. No complication occurred in relation to thrombin irrigation. Irrigation of CSH with thrombin solution is an effective treatment option for high-risk cases of CSH without complication.

OBJECTIVE: It 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. METHODS: Ninety-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. RESULTS: The 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). CONCLUSION: We 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.

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.

An insult due to intracerebral hemorrhage (ICH) is critical to patients. So, breakthroughs in ICH treatment are very important.Advances in the stem cell treatment of stroke have been remarkable. And stem cell experimentation on ischemic stroke, however, preceded such work on ICH and did not emphasized ICH therapy.We review recent stem cell treatments for ICH, an experimental model of ICH, the medical care of ICH, and several stem cell therapies for ICH along with future prospects.Stem cell therapy for ICH is effective in rodent or animal models. For humans, only a small number of clinical trials have been done, and significant functional recovery was recorded.We need to reveal the mechanism of stem cell therapy and develop a reliable, definitive treatment strategy for treatment of ICH. In the future, several types of stem cells will be available for the treatment of ICH.