Hiroyuki Kinouchi

Diffusion tensor tractography predicts motor functional outcome in patients with spontaneous intracerebral hemorrhage.

OBJECTIVEWe prospectively investigated the predictive value of diffusion tensor tractography for motor functional outcome in a case series of patients with intracerebral hemorrhage. METHODSDiffusion tensor tractography was performed in 17 patients with intracerebral hemorrhage (putamen, nine patients; thalamus, seven patients; combined, one patient) within 5 days after onset. Mean fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values along the corticospinal tracts at the level of the hematoma were measured bilaterally, and the ratios of values (hematoma side/contralateral side) were determined as FA and ADC ratios, respectively. Patients were evaluated for motor function on admission and at 3 months after onset using the manual muscle test score and then divided into good (manual muscle test, 4–5) and poor (manual muscle test, 0–3) motor function groups. RESULTSFA ratio measured shortly after the onset of intracerebral hemorrhage correlated well with motor functional outcome at 3 months (P < 0.05) but not with motor function on admission. FA ratios in the group with good motor functional outcome were significantly higher than those in the group with poor motor functional outcome (P < 0.01). The ADC ratio did not correlate with motor function either on admission or at 3 months. All patients with an FA ratio greater than 0.8 had a good motor functional outcome. In three patients, however, motor functional outcomes were favorable even though FA ratios were not high; in these patients, ADC ratios tended to be elevated. CONCLUSIONMotor functional outcome in patients with intracerebral hemorrhage can be predicted by measuring FA values using diffusion tensor tractography.

Expression of indoleamine 2,3-dioxygenase and correlation with pathological malignancy in gliomas.

BACKGROUNDn: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme involved in immune tolerance and tumor immune escape processes. Recently, IDO expression has been found to correlate with the prognosis of malignant tumors, but the implication of IDO in glioma progression remains unknown.nnnOBJECTIVEn: To investigate the relationship between IDO expression and histological malignancy in gliomas.nnnMETHODSn: IDO expression was examined in a total of 75 surgical specimens obtained from 68 patients with glioma using immunohistochemical staining. The 75 specimens included 15 diffuse astrocytomas, 21 anaplastic astrocytomas, and 39 glioblastomas. Six of 39 glioblastomas were secondary glioblastomas, transforming from grade II or III gliomas that had been determined at the first surgery. IDO expression rate was compared in each histological grade, and patient survival was analyzed.nnnRESULTSn: Expression of IDO was found in 72 of 75 gliomas at varying intensities. Stronger expression of IDO was more likely to be observed in malignant gliomas compared with low-grade gliomas. IDO expression in the 6 cases of secondary glioblastoma was stronger than in the initial low-grade glioma. Survival analysis using the Kaplan-Meier method revealed that grade IV patients with strong IDO expression had significantly worse overall survival rates (P = .04) than patients with weak IDO expression.nnnCONCLUSIONn: IDO is expressed more strongly in both primary and secondary glioblastoma tissue than low-grade glioma and may affect clinical outcome. If IDO promotes glioma cells to escape from the immune system, IDO may be a crucial therapeutic target for malignant gliomas.

Astrocyte-Mediated Ischemic Tolerance

Preconditioning (PC) using a preceding sublethal ischemic insult is an attractive strategy for protecting neurons by inducing ischemic tolerance in the brain. Although the underlying molecular mechanisms have been extensively studied, almost all studies have focused on neurons. Here, using a middle cerebral artery occlusion model in mice, we show that astrocytes play an essential role in the induction of brain ischemic tolerance. PC caused activation of glial cells without producing any noticeable brain damage. The spatiotemporal pattern of astrocytic, but not microglial, activation correlated well with that of ischemic tolerance. Interestingly, such activation in astrocytes lasted at least 8 weeks. Importantly, inhibiting astrocytes with fluorocitrate abolished the induction of ischemic tolerance. To investigate the underlying mechanisms, we focused on the P2X7 receptor as a key molecule in astrocyte-mediated ischemic tolerance. P2X7 receptors were dramatically upregulated in activated astrocytes. PC-induced ischemic tolerance was abolished in P2X7 receptor knock-out mice. Moreover, our results suggest that hypoxia-inducible factor-1α, a well known mediator of ischemic tolerance, is involved in P2X7 receptor-mediated ischemic tolerance. Unlike previous reports focusing on neuron-based mechanisms, our results show that astrocytes play indispensable roles in inducing ischemic tolerance, and that upregulation of P2X7 receptors in astrocytes is essential.

Intra-arterial injection fluorescein videoangiography in aneurysm surgery.

BACKGROUND: To visualize blood flow in the arteries and aneurysm during surgery, intravenous fluorescence videoangiography has been used. However, the image contrast with this procedure is diminished by repeated study because the dye remains for about 10 minutes after injection. OBJECTIVE: To determine the optimal dye concentration and to clarify the usefulness of fluorescein videoangiography by intra-arterial dye injection. METHODS: In the pilot study, fluorescein sodium dissolved at various concentrations was illuminated with excitation light, and fluorescence was detected by cameras. The fluorescence of 0.001% fluorescein sodium solution mixed with plasma at various concentrations was then examined. In 13 aneurysm patients, dye solution was administered through the catheter for intraoperative digital subtraction angiography. The intravenous injection method was also performed, and the findings were compared. RESULTS: Dye was clinically used at a concentration of 0.005% to 0.1% on the basis of the results of the pilot study. Fluorescence emission from the vessels and aneurysms was clearly observed by both methods; however, arterial injection provided brighter emission, resulting in clearer demonstration of the bloodstream than venous injection. Dye clearance was also quicker, which allowed repeat injections without delay. Dye filling in the aneurysm indicating incomplete occlusion was detected in 2 cases, and occlusion of the perforating artery was observed in 2 cases. CONCLUSION: Intra-arterial fluorescein videoangiography provides brighter and clearer imaging of blood flow with a smaller dose of dye than intravenous videoangiography. It can be repeated within a short time and is useful for detecting incomplete clipping or unexpected obstruction of arteries. ABBREVIATIONS: AcomA, anterior communicating artery DSA, digital subtraction angiography ICA, internal carotid artery ICG, indocyanine green MEP, motor evoked potential

Transplantation of neural stem cells that overexpress SOD1 enhances amelioration of intracerebral hemorrhage in mice.

Previous studies have shown that intraparenchymal transplantation of neural stem cells (NSCs) ameliorates neurologic deficits in animals with intracerebral hemorrhage (ICH). However, massive grafted cell death after transplantation, possibly caused by a hostile host brain environment, lessens the effectiveness of this approach. We focused on the effect of oxidative stress against grafted NSCs and hypothesized that conferring antioxidant properties to transplanted NSCs may overcome their death and enhance neuroprotection after ICH. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted NSCs and accelerates amelioration of ICH. Neural stem cells that overexpress SOD1 were administered intracerebrally 3 days after ICH in a mouse model. Histologic and behavioral tests were examined after ICH. Copper/zinc-superoxide dismutase overexpression protected the grafted NSCs via a decrease in production of reactive oxygen species. This resulted in an increase in paracrine factors released by the NSCs, and an increase in surviving neurons in the striatum and a reduction in striatal atrophy. In addition, SOD1 overexpression showed progressive improvement in behavioral recovery. Our results suggest that enhanced antioxidative activity in NSCs improves efficacy of stem cell therapy for ICH.

Rapid Reduction of Acute Subdural Hematoma and Redistribution of Hematoma

An 88-year-old woman presented with acute subdural hematoma (ASDH) which showed rapid resolution on computed tomography (CT) and magnetic resonance (MR) imaging. She was transferred to our hospital after falling out of bed. On admission, she was comatose with Japan Coma Scale score of 200 and Glasgow Coma Scale score of E1V1M2. Brain CT showed a thick left frontotemporal ASDH. Conservative treatment consisted of 200 ml of glycerol administered intravenously twice a day, and maintenance in the approximately 20 degree head-up position to reduce intracranial pressure. Three days later, her consciousness recovered to Japan Coma Scale score of 30 and Glasgow Coma Scale score of E2V4M5. CT showed obvious reduction of the hematoma without brain or scalp swelling. Spinal MR imaging detected no redistribution of hematoma to the spine. The present case illustrates that rapid spontaneous reduction of ASDH may occur by redistribution of hematoma, mainly to the supratentorial subdural space because of brain atrophy.

Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice.

Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.

In-stent Thrombosis after Carotid Artery Stenting Despite Sufficient Antiplatelet Therapy in a Bladder Cancer Patient

In-stent thrombosis (IST) after carotid artery stenting (CAS) is a rare but potentially devastating complication. We present a case of early IST after CAS despite sufficient antiplatelet therapy in a patient with bladder cancer. A 77-year-old man under preventive triple antiplatelet therapy underwent CAS without any intra- or periprocedural complications. However, the patient developed a large asymptomatic IST 6 days after CAS. Anticoagulant therapy with argatroban was reintroduced to treat IST concomitant with antiplatelet agents. Subsequently, the IST shrank and disappeared without any thrombotic symptoms. Malignancy is regarded as an acquired thrombophilic condition associated with a significant risk of thrombosis. In the field of coronary stents, cancer is associated with a significant increasing risk of IST. The cause of IST in our case was possibly related in hypercoagulable state because of the patients cancer. Attention for IST should be paid in CAS cases with these risk factors, and repeated examination is recommended.

Giant Serpentine Aneurysm of the Distal Anterior Cerebral Artery

We report a case of a 38-year-old man with a giant serpentine aneurysm arising from the distal anterior cerebral artery. This aneurysm grew from a fusiform aneurysm to a huge aneurysm within 5 months before manifesting as a mass lesion. The aneurysm was largely filled with thrombus, and 4 distal branches arose from the aneurysm dome. Selective balloon test occlusion of the distal anterior cerebral artery using an intravascular technique was performed to confirm the tolerance of the brain tissue. The balloon test occlusion elicited adequate leptomeningeal collateral circulation and no neurologic symptoms; thus, the aneurysm was treated with trapping and resection. The patient had no ischemic complications after the surgery and returned to his job 1 month later. No ischemia developed in the 2 years after surgery. Selective balloon test occlusion of the distal cerebral artery using an intravascular technique can be a very useful tool in planning the therapeutic strategy for a complicated distal cerebral aneurysm.

Neuroprotective effects of group II metabotropic glutamate receptor agonist DCG-IV on hippocampal neurons in transient forebrain ischemia.

Activation of group II metabotropic glutamate receptor (mGluR) inhibits the excessive release of glutamate that may be crucial in the pathogenesis of cerebral ischemia. This study investigated the protective effects of the group II mGluR agonist (2S,2R,3R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), against cerebral ischemia by examining extracellular glutamate concentration ([Glu]e) and neuronal damage in a rat model of transient forebrain ischemia. Cerebral ischemia was induced by 5 min of bilateral carotid artery occlusion and hypotension. DCG-IV (10, 100, or 250 pmol) was administered into the lateral ventricle four times every 12 h from 36 h before the start of ischemia, or administered intraperitoneally (40 micromol/kg) 24 h before ischemia, and the effect of the group II mGluR antagonist (LY341495) was also examined. [Glu]e in the CA1 subfield was measured by microdialysis during the peri-ischemic period, and the survival rate of CA1 neurons was evaluated 5 days after ischemia. [Glu]e increased significantly after cerebral ischemia and reached the maximum at 1 min after reperfusion, then gradually decreased and returned to the preischemic level in the vehicle group. The intraventricular injection of DCG-IV (250 pmol) significantly attenuated the [Glu]e increase and significantly increased the survival rate of CA1 neurons. Co-injection of LY341495 reversed the protective effects of DCG-IV. These results suggest that pretreatment with DCG-IV has neuroprotective effects against ischemic neuronal injuries through the inhibition of the glutamate release via the activation of group II mGluR.