Daisuke Shimbo

Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia reperfusion injury.

Despite successful revascularization, reperfusion after prolonged ischemia causes ischemia reperfusion (I/R) injury. Recruitment and activation of neutrophils is thought to be a key event causing I/R injury. We examined whether post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin (LEH), an artificial oxygen carrier without neutrophils, could reduce I/R injury in a rat transient middle cerebral artery occlusion (MCAO) model. Male Sprague-Dawley rats were subjected to 2-h MCAO and then were divided into three groups: (1) LEH group (n=7) infused with LEH (Hb concentration of 6g/dl, 10ml/kg/h) through the recanalized internal carotid artery for 2h, (2) vehicle group (n=8) infused with saline (10ml/kg/h) in the same manner as the LEH group, and (3) control group (n=9) subjected to recanalization only. After 24-h reperfusion, all rats were tested for neurological score and then sacrificed to examine infarct and edema volumes, myeloperoxidase (MPO) expression, matrix metalloproteinase-9 (MMP-9) expression and activity, and reactive oxygen species (ROS) production. Compared with the control group and the vehicle group, the LEH group showed a significantly better neurological score and significantly smaller infarct and edema volumes. MPO expression, MMP-9 expression and activity, and ROS production in the LEH group were also significantly lower than those in the control and vehicle groups. The results in the present study suggest that post-ischemic intra-arterial infusion of LEH can reduce I/R injury through reducing the effect of MMP-9, most likely produced by neutrophils. This therapeutic strategy may be a promising candidate to prevent I/R injury after thrombolysis and/or thromboectomy.

Transarterial Regional Brain Hypothermia Inhibits Acute Aquaporin-4 Surge and Sequential Microvascular Events in Ischemia/Reperfusion Injury.

BACKGROUND Although transarterial regional hypothermia is an attractive alternative to general hypothermia, its efficacy and underlying mechanisms remain unclear. OBJECTIVE To confirm transarterial regional hypothermia therapeutic effects on ischemia/reperfusion (I/R) injury and to elucidate the mechanisms responsible. METHODS The therapeutic effects of transarterial regional hypothermia were initially investigated in 2-hour middle cerebral artery occlusion rats regionally infused with 10°C saline (cold saline group) or 37°C saline (warm saline group) and untreated rats (control group) just before the onset of 24 hours of reperfusion. The time course of infarct and edema progression, inflammatory reactions, microvascular morphological changes, and aquaporin-4 (AQP4) expression was analyzed after 0, 2, 6, and 24 hours of reperfusion. RESULTS Cold saline infusion only lowered brain temperatures for 30 minutes but mediated strong neuroprotective effects with infarct volume reductions of less than one-third. The time-course analysis revealed the following sequence of ischemia/reperfusion injury-related events in the control group: upregulated expression of AQP4 (2 hours); microvascular narrowing resulting from swollen astrocytic end-feet (2-6 hours); infarct and edema progression, blood-brain barrier disruption, and upregulated expression of intracellular adhesion molecule-1 (6-24 hours); and the activation of other inflammatory reactions (24 hours). These sequential events were inhibited in the cold saline group. CONCLUSION Transarterial regional hypothermia initially inhibited the acute AQP4 surge and then attenuated microvascular narrowing, blood-brain barrier disruption, and activation of other inflammatory reactions, leading to strong neuroprotective effects. More direct and intensive cooling of the endothelium and its surroundings may contribute to these effects. ABBREVIATIONS AQP4, aquaporin-4BBB, blood-brain barrierIba1, ionized calcium-binding adapter molecule 1ICA, internal carotid arteryICAM-1, intracellular adhesion molecule-1I/R, ischemia/reperfusionMCAO, middle cerebral artery occlusionMMP-9, matrix metalloproteinase-9.

Reappraisal of Microsurgical Revascularization for Anterior Circulation Ischemia in Patients with Progressive Stroke.

BACKGROUND Intravenous thrombolysis using tissue plasminogen activator and endovascular treatment for acute ischemic stroke is becoming an established standard therapy. However, there is no consensus in the treatment of patients who are suffering from progressive neurologic symptoms in the later stages. The purpose of this study was to evaluate the safety and efficacy of microsurgical revascularization in such patients with progressive stroke. METHODS We retrospectively reviewed the clinical and radiological records of 14 consecutive patients with progressive stroke who underwent emergency open surgery for anterior circulation occlusion within 7 days after onset. Surgical candidates were carefully selected on the basis of symptom severity, diffusion-weighted imaging, and perfusion study. Superficial temporal artery to middle cerebral artery bypass was applied for atherosclerotic occlusion, and microsurgical embolectomy was applied for embolic occlusion. RESULTS Superficial temporal artery to middle cerebral artery bypass was performed in 12 patients, microsurgical embolectomy in 1, and the combination of these modalities in 1. As a result, complete revascularization was achieved in all patients. The National Institutes of Health Stroke Scale scores significantly improved after surgery (at third postoperative day, P < 0.05; at 14th postoperative day, P < 0.01). A favorable outcome (modified Rankin Scale 0-2) was achieved in 12 of the 14 (85.7%) patients. Minor intracerebral hemorrhage occurred in 1 patient and hyperperfusion syndrome occurred in 1 patients; however, the patients subsequently recovered without additional treatment. CONCLUSIONS Microsurgical revascularization is a feasible treatment option for patients with progressive stroke due to anterior circulation major vessel occlusion.

[Metronidazole-Induced Encephalopathy during Brain Abscess Treatment:Two Case Reports].

Metronidazole is a widely used antibiotic against anaerobic bacteria and protozoa. We report two cases of metronidazole-induced encephalopathy(MIE)during treatment of a brain abscess with metronidazole. The patients developed mental disturbance, and brain MRI showed reversible signals on DWI, FLAIR, and T2. Case 1: A 48-year-old woman was admitted to our hospital with a cerebellar abscess. We initiated treatment with oral metronidazole. After taking the medication, she developed mental disturbance, and her brain MRI showed a hyperintensity within the corpus callosum. We suspected metronidazole toxicity and discontinued metronidazole treatment. The symptoms resolved rapidly within a week, and the hyperintensity on the MRI disappeared. Case 2: A 22-year-old man was admitted to our hospital with a brain abscess. We initiated treatment with oral metronidazole. On day 38, he developed mental disturbance, and his MRI showed hyperintensities within the bilateral dentate nuclei and corpus callosum. These symptoms were consistent with MIE. After cessation of metronidazole, his symptoms and abnormal MRI signals completely disappeared.

Superficial Temporal Artery–Superior Cerebellar Artery Bypass with Anterior Petrosectomy

BACKGROUND Superficial temporal artery (STA) to superior cerebellar artery (SCA) bypass is associated with a relatively high risk of surgical complications, such as hematoma and/or edema caused by temporal lobe retraction. Therefore, the right side is typically used to avoid retraction of the left temporal lobe. In this report, we present a case of left STA-SCA bypass with anterior petrosectomy to avoid retraction of dominant-side temporal lobe and describe the surgical technique in detail. CASE DESCRIPTION A 69-year-old man presented with gradual worsening of dysarthria and gait disturbance. Magnetic resonance imaging showed no signs of acute infarction, but digital subtraction angiography showed severe stenosis of basilar artery and faint flow in the distal basilar artery. On 3-dimensional computed tomography angiography, posterior communicating arteries were not visualized; we could identify the left SCA, but not the right SCA. Despite dual antiplatelet therapy, a small fresh brainstem infarct was detected 10 days after admission. To avert fatal brainstem infarction and further enlargement of the infarct, we performed left STA-SCA bypass with anterior petrosectomy to avoid retraction of the dominant-side temporal lobe. Postoperative imaging revealed no new lesions, such as infarction or temporal lobe contusional hematoma, and confirmed the patency of the bypass. Postoperative single-photon emission computed tomography demonstrated improved cerebral blood flow in the posterior circulation. The patient was transferred to another hospital for rehabilitation. CONCLUSIONS This method helps minimize the risk of injury to the temporal lobe, especially that of the dominant side.

Impact of Antiplatelets and Anticoagulants on the Prognosis of Intracerebral Hemorrhage

BACKGROUND Intracerebral hemorrhage (ICH) associated with antithrombotic therapy (AT) is becoming more common as the use of those medications increases in the aging population. METHODS This study included 490 consecutive patients hospitalized for nontraumatic ICH in a single center during an 8-year period, which was subdivided into former (2008-2011) and latter (2012-2015). Patients were classified into those with no antithrombotic drugs (NATs) and those with AT. The AT group was divided into 4 subgroups according to medications: antiplatelet (AP1), multiple antiplatelets (AP2), anticoagulant (AC), and antiplatelet and anticoagulant (APC). We evaluated the clinical characteristics and prognosis and compared the number of patients on AT between the former and latter groups. RESULTS There were 125 patients treated with AT (25.5%), including 50 (10.2%) on AP1, 14 (2.9%) on AP2, 32 (6.5%) on ACs, and 29 (5.9%) on APCs. Compared with the former group, the latter group had a higher number of patients on AT (19.3% versus 31.7%), AP1 (9.8% versus 10.6%), AP2 (1.6% versus 4.1%), ACs (4.9% versus 8.1%), and APCs (2.90% versus 8.9%). Compared with the NAT group, the patients in the AT group had a larger ICH volume, more frequent hematoma expansion, and higher rate of poor outcome, particularly for those on APCs. CONCLUSION The number of ICH patients on AT has increased; these patients were more likely to have a poor prognosis than those who were not on AT. Care should be taken when giving a combination of antiplatelets and anticoagulants in ICH.

Superior Microvascular Perfusion of Infused Liposome-Encapsulated Hemoglobin Prior to Reductions in Infarctions after Transient Focal Cerebral Ischemia

BACKGROUND The development of cerebral infarction after transient ischemia is attributed to postischemic delayed hypoperfusion in the microvascular region. In the present study, we assessed the microvascular perfusion capacity of infused liposome-encapsulated hemoglobin (LEH) in a therapeutic approach for transient middle cerebral artery occlusion (tMCAO). METHODS Two-hour middle cerebral artery occlusion rats were immediately subjected to intra-arterial infusion of LEH (LEH group) or saline (vehicle group) or no treatment (control group), and then to recanalization. Neurological findings, infarct and edema progression, microvascular endothelial dysfunction, and inflammatory reactions were compared between the 3 groups after 24 hours of reperfusion. Microvascular perfusion in the early phase of reperfusion was evaluated by hemoglobin immunohistochemistry and transmission electron microscopy. RESULTS The LEH group achieved significantly better results in all items evaluated than the other groups. Hemoglobin immunohistochemistry revealed that the number of hemoglobin-positive microvessels was significantly greater in the LEH group than in the other groups (P < .01), with microvascular perfusion being more likely in narrow microvessels (≤5 µm in diameter). An electron microscopic examination revealed that microvessels in the control group were compressed and narrowed by swollen astrocyte end-feet, whereas those in the LEH group had a less deformed appearance and contained LEH particles and erythrocytes. CONCLUSION The results of the present study demonstrated that the infusion of LEH reduced infarctions after tMCAO with more hemoglobin-positive and less deformed microvessels at the early phase of reperfusion, suggesting that the superiority of the microvascular perfusion of LEH mediates its neuroprotective effects.