Hirokazu Koseki

A sphingosine‐1‐phosphate receptor type 1 agonist, ASP4058, suppresses intracranial aneurysm through promoting endothelial integrity and blocking macrophage transmigration

Intracranial aneurysm (IA), common in the general public, causes lethal subarachnoid haemorrhage on rupture. It is, therefore, of utmost importance to prevent the IA from rupturing. However, there is currently no medical treatment. Recent studies suggest that IA is the result of chronic inflammation in the arterial wall caused by endothelial dysfunction and infiltrating macrophages. The sphingosine‐1‐phosphate receptor type 1 (S1P1 receptor) is present on the endothelium and promotes its barrier function. Here we have tested the potential of an S1P1 agonist, ASP4058, to prevent IA in an animal model.

An S1P1 agonist, ASP4058, suppresses intracranial aneurysm through promoting endothelial integrity and blocking macrophage transmigration.

Intracranial aneurysm (IA), common in the general public, causes lethal subarachnoid haemorrhage on rupture. It is, therefore, of utmost importance to prevent the IA from rupturing. However, there is currently no medical treatment. Recent studies suggest that IA is the result of chronic inflammation in the arterial wall caused by endothelial dysfunction and infiltrating macrophages. The sphingosine‐1‐phosphate receptor type 1 (S1P1 receptor) is present on the endothelium and promotes its barrier function. Here we have tested the potential of an S1P1 agonist, ASP4058, to prevent IA in an animal model.

T cell function is dispensable for intracranial aneurysm formation and progression

Given the social importance of intracranial aneurysm as a major cause of a lethal subarachnoid hemorrhage, clarification of mechanisms underlying the pathogenesis of this disease is essential for improving poor prognosis once after rupture. Previous histopathological analyses of human aneurysm walls have revealed the presence of T cells in lesions suggesting involvement of this type of cell in the pathogenesis. However, it remains unclear whether T cell actively participates in intracranial aneurysm progression. To examine whether T cell is involved in aneurysm progression, intracranial aneurysm model of rat was used. In this model, aneurysm is induced by increase in hemodynamic force loaded on bifurcation site of intracranial arteries where aneurysms are developed. Deficiency in T cells and pharmacological inhibition of T cell function were applied to this model. CD3-positive T cells were present in human aneurysm walls, whose number was significantly larger compared with that in control arterial walls. Deficiency in T cells in rats and pharmacological inhibition of T cell function by oral administration of Cyclosporine A both failed to affect intracranial aneurysm progression, degenerative changes of arterial walls and macrophage infiltration in lesions. Although T cells are detectable in intracranial aneurysm walls, their function is dispensable for macrophage-mediated inflammation and degenerative changes in arterial walls, which presumably leads to intracranial aneurysm progression.

Macrophage Imaging of Cerebral Aneurysms with Ferumoxytol: an Exploratory Study in an Animal Model and in Patients

OBJECTIVE The purpose of this study is to assess the validity and feasibility of macrophage imaging using an ultrasmall superparamagnetic iron oxide nanoparticle, ferumoxytol, in the cerebral aneurysmal wall in an animal model and in humans. MATERIALS AND METHODS Engulfment of ferumoxytol by primary culture of macrophages and RAW264.7 cells was assessed. Uptake of ferumoxytol was evaluated histologically in a cerebral aneurysmal model in rats. In an exploratory clinical study of magnetic resonance macrophage imaging, 17 unruptured aneurysms in 17 patients were imaged using thin-slice gapless magnetic resonance images of 2D-gradient-recalled echo (2D-GRE) and 3D-T1-fast-spin echo sequences on day 0 and of the same sequences with infusion of ferumoxytol 24 hours after the first imaging. Pre- and postinfusion images were evaluated independently by 2 medical doctors. RESULTS Engulfment of ferumoxytol was confirmed in vitro, but the amount of ferumoxytol uptake was independent of the activation state or the differentiation state. Ferumoxytol uptake in CD68-positive cells was observed in the cerebral arterial walls of 4 out of 15 (26.7%) experimentally induced aneurysms in rats. In a clinical study, 17 aneurysms were enrolled and 2 aneurysms were not assessed because of incomplete images. Eleven aneurysms without oral intake of recent anti-inflammatory agents of the remaining 15 aneurysms showed ferumoxytol uptake on 2D-GRE subtraction images, and the size of the aneurysms was significantly related to positive images. CONCLUSIONS Ferumoxytol uptake was confirmed in cultured macrophages and in the cerebral aneurysmal wall in rats. Thin-slice gapless magnetic resonance imaging with ferumoxytol in human cerebral aneurysmal walls may reflect macrophages in the cerebral aneurysmal wall, but its application to small-sized lesions may be restricted.

Direct Microsurgical Embolectomy for Acute Occlusion of the Internal Carotid Artery and Middle Cerebral Artery

BACKGROUND Surgical embolectomy is the most promising therapy for physically removing emboli from major cerebral arteries. However, it requires an experienced surgical team, time-consuming steps, and is not incorporated into acute stroke therapy. METHODS We established seamless collaboration between services, refined surgical techniques, and conducted a prospective trial of emergency surgical embolectomy. Surgical indications included the presence of acute hemispheric symptoms, absence of low-density area on computed tomography, evidence of internal carotid artery terminus or proximal middle cerebral artery occlusion, and availability of resources to start surgery within 3 hours of symptom onset. The indications were confirmed by an interdisciplinary team. We assessed revascularization rates, time from admission to surgery and from surgery to recanalization, procedural complications, and clinical outcomes. RESULTS Between 2005 and 2014, 14 consecutive patients with acute proximal middle cerebral artery or internal carotid artery terminus occlusion underwent emergency surgical embolectomy. All patients showed complete recanalization. Twelve patients survived and 7 had fair functional outcome (Rankin Scale score, ≤3). No significant procedural adverse events occurred. The mean times from admission to start of surgery, from surgery to recanalization, and from onset to recanalization were 14 minutes, 79 minutes, and 223 minutes, respectively. CONCLUSIONS Our results suggest that microsurgical embolectomy can rapidly, safely, and effectively retrieve clots and deserves reappraisal, although the choice largely depends on local institutional expertise.

Intraoperative and Postoperative Bleeding in Microvascular Decompression for Trigeminal Neuralgia

OBJECTIVE The surgical approach for the trigeminal nerve involves veins connected to the superior petrosal and tentorial sinus, and we should pay special attention to these veins. We investigated intraoperative and postoperative bleeding using our database. METHODS A prospectively accumulated database of 247 microvascular decompression surgeries for trigeminal neuralgia over the past 10 years was analyzed. Intraoperative and postoperative bleeding was confirmed with surgical records, videos, and computed tomography. Of 235 patients, 161 were female; 85 patients were >70 years old at the time of surgery; 96 surgeries involved the left side. RESULTS Intraoperative venous bleeding was encountered in 29 surgeries (12%): from the superior petrosal vein/sinus in 18 and the hemispheric bridging vein/tentorial sinus in 11. Massive bleeding occurred from the superior petrosal sinus owing to tear of the entrance of the superior petrosal vein in 4 surgeries and from the tentorial sinus in 3; bleeding was controlled by Surgicel with fibrin glue. Postoperative bleeding occurred in 11 surgeries (4%): intracerebellar hematoma in 2, subarachnoid hemorrhage in 3, subdural hemorrhage in 3, supratentorial subdural hemorrhage in 2, and supratentorial epidural hematoma in 1. These lesions were associated with intraoperative bleeding in 1 case, a trans-horizontal fissure approach in 1 case, coagulation of the petrosal vein in 2 cases, and unknown reasons in 7 cases. Cure without medication was achieved in 218 surgeries at an average follow-up of 4.2 years. CONCLUSIONS Microvascular decompression for trigeminal neuralgia involves potential risks of intraoperative and postoperative bleeding.

Nonspastic hemifacial spasm confirmed by abnormal muscle responses

Background: Hemifacial spasm is usually diagnosed by inspection which mainly identifies involuntary movements of orbicularis oculi. Assessing abnormal muscle responses (AMR) is another diagnostic method. Case Description: We report a case of left hemifacial spasm without detectable involuntary facial movements. The patient was a 48-year-old man with a long history of subjective left facial twitching. On magnetic resonance imaging (MRI), the left VIIth cranial nerve was compressed by the left anterior inferior cerebellar artery (AICA), which was in turn compressed by the left vertebral artery. We initially treated him with botulinum toxin. We were able to record AMR, and hemifacial spasm occurred after AMR stimulation, although no spasm was detectable by inspection. Subsequently, we performed microvascular decompression with transposition of the AICA that compressed the VIIth cranial nerve. His hemifacial spasm resolved by 5 weeks after surgery and was not induced by AMR stimulation. Conclusion: Hemifacial spasm can sometimes be diagnosed by detecting AMR rather than by visual inspection. We propose that such hemifacial spasm should be termed nonspastic hemifacial spasm.

Population of inflammatory cells in intracranial aneurysm with the special insight to the development of novel diagnostic and therapeutic approaches

1Center for Innovation in Immunoregulation Technologies and Therapeutics (AK project), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. 2Department of Neurosurgery, Tokyo Women’s Medical University Medical Center East, Tokyo 116-8567, Japan. 3Core Research for Evolutional Science and Technology (CREST) from Japan Agency for Medical Research and Development (AMED), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.