Kazuaki Aoki

Background: Intravenous administration of clazosentan, a selective endothelin receptor subtype A antagonist, has been used as an anti‐vasospastic agent. This study aimed to investigate whether intrathecal administration of clazosentan prevents neuroinflammation and affects lymphatic clearance of hemoglobin in a mouse model of acute subarachnoid hemorrhage (SAH). Methods: Male C57BL/6 mice (n=109) underwent prechiasmatic cisternal injection models of SAH or sham models. From 30 minutes post‐modeling, mice randomly received a continuous intracerebroventricular infusion of saline or clazosentan (1, 0.2, and 0.04 μg in 192 μL of saline; defined as 50%, 10%, and 2% of the clinically achievable blood concentration, respectively) at a rate of 8 μL/h for 24 hours. The intervention effects were assessed by neurobehavioral testing, SAH grading, and immunohistochemical staining at 24 and 48 hours, and Western blotting at 24 hours post‐modeling. Results: Clazosentan treatment did not influence SAH grading but showed a dose‐dependent trend toward improved survival in SAH mice. A comparison of saline treatment and 50% clazosentan treatment revealed that clazosentan significantly suppressed post‐SAH neurological deterioration, hemoglobin infiltration into the brain, and induction of ionized calcium‐binding adapter molecule 1 and tenascin‐C in the brain, and significantly upregulated vascular endothelial growth factor receptor‐3 in the brain without affecting vascular endothelial growth factor‐C levels. When comparing the effects of different clazosentan doses, an inhibitory effect on neuroinflammation was observed up to 10% clazosentan. At 48 hours post‐modeling, clazosentan administration dose‐dependently inhibited neurological deterioration, hemoglobin infiltration into the brain and activation of perivascular macrophages and microglia, and increased hemoglobin deposition in the deep cervical lymph nodes of SAH mice without intracranial lymphatic vessel proliferation. Conclusions: This study first showed that intrathecal administration of clazosentan can suppress early brain injury in terms of neuroinflammation at cerebrospinal fluid concentrations one‐tenth of the clinically achievable blood concentrations, associated with enhanced lymphatic drainage of hemoglobin.

Background/Objectives: The outcome for aneurysmal subarachnoid hemorrhage (SAH) remains poor, particularly for patients presenting with World Federation of Neurological Surgeons (WFNS) grades IV–V. This study was designed to identify independent prognostic factors in this group of patients with poor-grade SAH. Methods: We prospectively analyzed 357 SAH patients with admission WFNS grades IV–V enrolled in nine primary stroke centers in Mie prefecture, Japan, from 2013 to 2022. This study compared clinical variables, including treatments for angiographic vasospasm and delayed cerebral ischemia (DCI), between patients with favorable (modified Rankin Scale [mRS] scores 0–2) and unfavorable (mRS scores 3–6) outcomes at 90 days post-onset. Multivariate analyses were then performed to identify independent determinants of favorable 90-day outcomes, followed by propensity score matching analyses. Results: The median age was 68 years, and 53.5% of patients had admission WFNS grade V. DCI occurred in 12.9% of patients, and 66.9% had unfavorable outcomes. Independent variables related to unfavorable outcomes were older age, admission WFNS grade V, ventricular drainage, edaravone administration, and delayed cerebral infarction, while those for favorable outcomes were spinal drainage (adjusted odds ratio [aOR] 6.118, 95% confidence interval [CI] 2.687–13.927, p < 0.001), modified Fisher grade 3 (aOR 2.929, 95% CI 1.668–5.143, p < 0.001), and triple prophylactic anti-DCI medication consisting of cilostazol, fasudil hydrochloride and eicosapentaenoic acid (aOR 1.869, 95% CI 1.065–3.279, p = 0.029). Nimodipine is not approved in Japan, and statin and cerebral vasospasm did not influence outcomes. As spinal drainage and the triple prophylactic anti-DCI medication were intervenable variables, propensity score matchings were performed, and they confirmed that both spinal drainage and the triple prophylactic anti-DCI medication were useful to achieve favorable outcomes. Conclusions: In poor-grade SAH, spinal drainage and the triple prophylactic anti-DCI medication may be effective in improving outcomes, possibly by suppressing DCI pathologies other than cerebral vasospasm.

Osteopontin (OPN), a matricellular protein, is produced as a full-length OPN (FL-OPN) and cleaved by thrombin, thus generating the N-terminal half of OPN (OPN N-half) with new functions. Although plasma FL-OPN levels have been associated with neurovascular events after aneurysmal subarachnoid hemorrhage (SAH), plasma OPN N-half levels have never been investigated. In this study, prospective clinical data and plasma samples were collected from 108 consecutive SAH patients with ruptured aneurysms undergoing acute treatment via surgery, and FL-OPN and OPN N-half levels were measured in plasma with a particular focus on delayed cerebral infarction (DCIn), which has the greatest impact on outcomes. Plasma FL-OPN and OPN N-half levels were intercorrelated and significantly higher in patients with DCIn at days 10–12 post-SAH; a greater area under the receiver-operating characteristic curve was observed for OPN N-half levels, with a cut-off value of 70.42 pmol/L. Multivariate analyses revealed that plasma OPN N-half levels of ≥70.42 pmol/L at days 10–12 were independently associated with DCIn development (adjusted odds ratio, 5.65; 95% confidence interval, 1.68–18.97; p = 0.005). Based on the findings of this study and previous reports, an increase in the OPN N-half level may be indicative of a protective mechanism against DCIn development, and, thus, it holds promise as a new therapeutic target against DCIn after aneurysmal SAH.

症例は82歳男性. 頭痛, 意識障害で救急搬送となり, 頭部CTで右後頭葉の脳出血と急性硬膜下血腫を認めた. 脳血管撮影で出血部に一致してpiral AVFとnon-sinus type dural AVFの併存を疑う所見を認めた. 直達手術で確認したところ, 両者が併存しており, 異なるシャントポイントから同一単独の脳皮質静脈に流出しており, 根治には位置関係を見極めて処置する必要があった. このような症例においては, 複数のシャントポイントを直視下に確認して確実に処置できる直達手術の優位性が高い.

Objective: The risk of embolization to distal territory or to new territory in mechanical thrombectomy remains a major issue despite advancements in technological device. This condition can be caused by a large and firm dropped thrombus without passing through a guiding catheter during stent retriever or aspiration catheter withdrawal. This report introduced a novel technique referred to as retrograde angiography to detect dropped thrombus. Methods: The retrograde angiography to detect dropped thrombus technique is a kind of retrograde angiography that consists of a contrast medium injection via a distal microcatheter and aspiration through an inflated balloon-guiding catheter. This method was used to detect dropped thrombus at the balloon-guiding catheter tip when back flow was blocked from the balloon-guiding catheter after stent retriever or aspiration catheter withdrawal. We retrospectively reviewed four consecutive patients who underwent the retrograde angiography to detect dropped thrombus technique during mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion in the anterior circulation between January 2018 and January 2021. Results: Three of four patients had dropped thrombus, which was diagnosed with the technique and retrieved completely with subsequent procedures while maintaining the balloon-guiding catheter inflated. None of the patients experienced embolization to distal territory/embolization to new territory, and a successful reperfusion was achieved in all four cases. Conclusions: The retrograde angiography to detect dropped thrombus is a technique to detect a dropped thrombus at the balloon-guiding catheter tip and allows us to retrieve it with subsequent mechanical thrombectomy procedures while maintaining the balloon-guiding catheter inflated and it may be useful for reducing the risk of embolization to distal territory/embolization to new territory.