Search

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.

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.

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.

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.

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.

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.

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.

Background and Purpose— Recent studies have shown that selective inhibition of specific subsets of intercellular adhesion molecules protects the brain during ischemia. We studied selective inhibition of integrin αvβ3 with cyclo [Arg-Gly-Asp- d -Phe-Val] (cRGDfV) in the rat middle cerebral artery occlusion model (MCAO). Methods— Rats were treated before and after MCAO with cRGDfV. Physiological parameters, expression of integrin αvβ3, infarction volume, brain water content, Evans Blue exudation, IgG exudation, histology, immunohistochemistry, and western blotting were studied in 4 groups of animals: sham operation (n=13), untreated (n=18), nonfunctioning peptide treatment (n=19), and cRGDfV treatment (n=27). Results— Treatment with cRGDfV reduced infarction, reduced brain edema, reduced exudation of Evans blue and IgG, and prevented fibrinogen deposition. Western blotting showed reduction of phosphorylated Flk-1 (a vascular endothelial growth factor [VEGF] receptor), reduction of phosphorylated FAK (an intracellular kinase phosphorylated in the presence of VEGF), reduction of VEGF, and reduction of fibrinogen in the cRGDfV treatment group. Conclusions— The selective integrin αvβ3 inhibitor cRGDfV improves outcomes in the MCAO model by preserving the blood-brain barrier, which mechanistically may occur in a VEGF- and VEGF-receptor–dependent manner.

An 18-year-old male suffered a penetrating skull base injury caused by a metal rod. We made translucent three-dimensional (3D) computed tomography (CT) for clearing the injury site. This method has revealed that right carotid artery was compressed directly by the foreign body, and internal carotid artery trapping was carried out based on hemodynamics as revealed by angiography. This patient achieved modified Rankin scale score of 1 at discharge. Cases of trauma involve a variety of circumstances and therefore require a case-by-case evaluation that depends on the patient's condition. Translucent 3D CT was useful in considering the treatment strategy of the penetrating skull base injury.

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.

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.

Object. The strategy to treat asymptomatic angiographic vasospasm following subarachnoid hemorrhage (SAH) is controversial. In this study we review our consecutive vasospasm series and discuss an adequate treatment strategy for asymptomatic vasospasm.Methods. From January 2007 to December 2012 we treated 281 aneurysmal SAH cases, with postoperative angiography performed 9 ± 2 days after the onset of SAH. Four asymptomatic cases received intra-arterial (IA) injection of vasodilator due to angiographic vasospasm. All cases improved vasospasm immediately following intervention. But all cases turned symptomatic within 48 hours. We retrospectively analyzed the time-density angiography curve and calculated the time to peak (TTP), mean transit time (MTT), and relative blood flow (rBF). Relative blood flow was calculated as follows. The integration of the value of the time-density curve for the artery was divided by the same value for the internal carotid artery multiplied by the MTT.Results. The decrease in TTP and MTT for the etiologic artery was similar to that of the nonetiologic artery. But the improvement in rBF for the etiologic artery and nonetiologic artery was 10% and 17%, respectively. Blood supply to the spastic artery decreased due to iatrogenic steal.Conclusion. Prophylactic IA injection of vasodilator in cases of asymptomatic vasospasm can produce symptomatic vasospasm.

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.

We developed a novel trans‑femoral artery approach to the rat middle cerebral artery occlusion model (TF‑MCAO) without sacrifi cing the external carotid artery (ECA) with/without the pterygopalatine artery which is important for chewing food. To make the TF‑MCAO we fi rst 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 sacrifi ce the ECA branch. A 24‑gage catheter is inserted into the left femoral artery. We insert a slightly bent 0.014 inch 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 17 mm from the bifurcation of the CCA until slight resistance is encountered. The guide wire and temporary occlusion clips are withdrawn after 90 minutes. Rats were sacrifi ced 24 h 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 94.4 ㎣ ± 9.4 se and mean infarction volume of the cerebral cortex was 124.2 ㎣ ± 21.6 se. No rat died due to cerebral infarction and no rat suff ered subarachnoid hemorrhage. We conclude that TF‑MCAO was useful for producing a cerebral infarction. Hirosaki Med.J. 61 Supplement:S142―S146,2010

A 32-year-old female presented with a rare case of pituitary abscess manifesting as homonymous hemianopsia. Serum prolactin level was slightly high (40.8 ng/ml). Magnetic resonance (MR) imaging showed the content of the lesion as homogeneously isointense on the T1-weighted images and hyperintense on the T2-weighted images. The capsule of the lesion, which appeared thin and smooth, was enhanced by gadolinium. Dural enhancement around the sella turcica was also recognized. Thallium-201 single photon emission computed tomography (201Tl SPECT) showed homogeneous high accumulation in the pituitary region on both the early and delayed images. The lesion was treated via a transnasaltranssphenoidal approach. The cystic lesion contained pus and the capsule consisted of normal pituitary gland with inflammatory changes. The patient was treated with antibiotics for 3 weeks and the pituitary abscess was cured completely. Pituitary abscess can be differentiated from pituitary adenoma as lesion with a homogeneous high uptake on 201Tl SPECT on both the early and delayed images, and no enhancement of the central portion on MR images.

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