Analysis of vascular perfusion territory using selective intraarterial injection CT angiography before and after revascularization surgery in patients with moyamoya disease.

OBJECTIVE: In moyamoya disease (MMD), blood flow to the internal carotid artery (ICA) system is supplied via the basal fine vascular network, leptomeningeal anastomoses, and transdural collateral vessels from the external carotid artery (ECA). After revascularization, there is a dramatic change in cerebral perfusion to the ECA system. Understanding this shift in blood supply is important for evaluating treatment efficacy and elucidating the postoperative pathophysiology. However, anatomical and quantitative methods for doing so have not yet been established. In the present study, selective intraarterial injection CT angiography (iaCTA) was performed in patients with MMD, and blood supply changes in each arterial system before and after revascularization surgery were evaluated. METHODS: This study included 10 hemispheres in 10 patients who underwent combined revascularization surgery for adult MMD. Digital subtraction angiography was performed before and 3 months after surgery, and selective iaCTA was performed from the ICA, ECA, and vertebral artery (VA) at the same times in a hybrid CT/digital subtraction angiography suite. The anatomical distribution of each vessel was determined and perfusion volume was measured quantitatively on contrast-enhanced axial CT images. RESULTS: Selective iaCTA clearly depicted the anatomical distribution of perfusion for each vessel. Conversion of blood supply from the ICA and VA to the ECA system was observed in the cerebral cortices and insulae but not in the basal ganglia. The mean volume of perfusion territories of the ECA (preoperative 0.9 cm3, postoperative 98.8 cm3); ICA (preoperative 225.7 cm3, postoperative 159.3 cm3); and VA (preoperative 244.0 cm3, postoperative 163.6 cm3) in the cerebral hemispheres changed significantly after revascularization. There was a correlation between increase in the ECA territory volume and decrease in the VA territory volume due to revascularization (R = -0.84, p < 0.005). CONCLUSIONS: Selective iaCTA enabled clear visualization of anatomical changes in each vascular perfusion territory and quantitative measurement of each perfusion volume. Perfusion conversion to the ECA system after bypass surgery was observed in the cortical regions and in the insulae on the bypass operation sides, but not in the basal ganglia. Combined revascularization promoted the development of ECA-perfused territory, which correlated with a decrease in hemodynamic burden of the posterior cerebral artery.

Blood Blister-Like Aneurysms at the Junction of the Internal Carotid and Posterior Communicating Artery: Characteristics and Treatment Strategies.

BACKGROUND: Blood blister-like aneurysms (BBAs) usually arise from the anterior walls of the internal carotid artery, and such lesions at the junction of the internal carotid artery and posterior communicating artery (PCoA) have not been reported to date. Here, we report our experiences of BBAs at PCoA. We studied their clinical and angiographical characteristics including the internal carotid-PCoA angle, an indicator of hemodynamic stress at the bifurcation. METHODS: Three patients with BBAs located at the origin of PCoA were studied. Wrap-clipping was adopted as the first-line therapy, but direct clipping was conducted when difficult. RESULTS: All patients were elderly females (mean age 81.3 years), and BBAs were small in size (mean maximum diameter 1.5 mm), which arose at the origins of wide-angled fetal-type PCoAs (mean internal carotid-PCoA angle 37.8 degrees). All the lesions were treated by surgery (direct clipping 2, wrap-clipping 1), and severe atherosclerotic changes were observed at adjacent arterial walls in all cases. Ordinary wrap-clipping using a polytetrafluoroethylene membrane via the transsylvian approach was difficult because of the limited working space, requiring some special techniques such as usage of fenestrated clips, polyglycolic acid sheets, and combined approach with subtemporal craniotomy. Good clinical outcomes were achieved in 2 patients. CONCLUSION: BBAs at PCoA were predominantly occurred as the small bulges at the origins of wide-angled fetal-type PCoAs in elderly females. Hemodynamic stress and atherosclerosis would contribute to the aneurysmal formation. Wrap-clipping or direct clipping with additional techniques would be useful for this rare condition.

Neuronal dysfunction and hemodynamic disturbance due to venous congestion in dural arteriovenous fistula revealed by 123I-iomazenil SPECT.

OBJECTIVE: Retrograde leptomeningeal venous drainage (RLVD) of a dural arteriovenous fistula (dAVF) is associated with neurological morbidity and unfavorable outcomes. However, the direct damage to cortical neurons by dAVF with RLVD has not been elucidated. 123I-iomazenil (123I-IMZ) SPECT can reveal cerebral blood flow and cortical neuronal damage in early and late images, respectively. This study aimed to assess the cerebral venous congestive encephalopathy caused by dAVF using 123I-IMZ SPECT. METHODS: Based on the pre- and posttreatment MRI findings, patients were divided into three groups: a normal group, an edema group, and an infarction group. Radioactive counts in the early and late images of 123I-IMZ SPECT were investigated using the affected-to-contralateral side asymmetry ratio (ACR). RESULTS: None of the patients in the normal group showed any symptoms related to venous congestion. In contrast, all the patients in the edema and infarction groups developed neurological symptoms. The ACR in early images in the edema group was significantly lower than that in the normal group and significantly higher than that in the infarction group. The ACR in the late images of the infarction group was significantly lower than those of the normal and edema groups. After treatment, the neurological signs disappeared in the edema group, but only partial improvement was observed in the infarction group. The ACR in early images significantly improved after treatment in the edema group, but the ACR in late images did not change in any groups. CONCLUSIONS: 123I-IMZ SPECT is useful for evaluating hemodynamic disturbances and neuronal damage in dAVFs. The reduction in early images was correlated with the severity of venous congestive encephalopathy, and the significant reduction in late images is a reliable indicator of irreversible venous infarction caused by RLVD.

Recurring cervical internal carotid artery vasospasm elicited by head rotation: illustrative case.

BACKGROUND: Idiopathic extracranial internal carotid artery vasospasm (IEICAV) is a rare cerebrovascular disorder causing transient or permanent cerebral ischemia. The pathophysiology underlying this disorder is not well understood. Although various medical treatments have been tried, complete remission of vasospasm is difficult to achieve. The first case of bilateral IEICAV induced by head rotation, which was successfully treated by carotid artery stenting (CAS), was presented. OBSERVATIONS: A 40-year-old woman with bilateral IEICAV had been conservatively treated for 13 years. However, transient ischemic attacks (TIAs) were not suppressed. She eventually presented with a large brain infarction in the left hemisphere and was referred to our department. Digital subtraction angiography clearly demonstrated the triggering of internal carotid artery (ICA) vasospasm by head rotation. After CAS treatment, the TIAs disappeared completely. LESSONS: Clinicians should recognize that ordinary mechanical stimulation to the ICA by head rotation can induce vasospasm, and CAS should be performed for refractory IEICAV at the appropriate time to avoid cerebral infarction causing severe neurological deficits.

Neuroprotective effects of peroxisome proliferator-activated receptor γ agonist through activation of Akt and signal transducers and activators of transcription 3 in transient forebrain ischemia.

Peroxisome proliferator-activated receptor γ (PPARγ) belongs to the nuclear hormone receptor family and is a ligand-modulated transcriptional factor. Pioglitazone, a PPARγ ligand of the thiazolidinedione class, exerts several pleiotropic effects including neuroprotection in addition to reducing blood glucose and insulin resistance; however, its mechanism remains obscure. In this study, we examined the PPARγ expression and the protective effects of pioglitazone after transient forebrain ischemia. We focused on Akt and signal transducers and activators of transcription 3 (STAT3), key pathways of prosurvival signaling in ischemic neuronal injury as the mechanisms of pioglitazone's effects. Male Sprague-Dawley rats were given daily oral administration of pioglitazone (0.2, 2 and 20 mg/kg/d) or the vehicle, and transient forebrain ischemia was induced by 5-minute occlusion of bilateral common carotid arteries with hypotension. Western blot and immunohistochemistry revealed that PPARγ expression in the hippocampal CA1 subregion was upregulated 1-8 h after forebrain ischemia, which was observed mainly in pyramidal neurons. Most CA1 neurons were positive for TUNEL staining 5 days after ischemia, and pioglitazone administration reduced TUNEL-positive cells in a dose-dependent manner, with a significant difference in the 20 mg/kg/d group compared with the vehicle. Phosphorylation of Akt (Ser473) and its target, glycogen synthase kinase-3ß (Ser9), was increased after ischemia, and 20 mg/kg/d dose of pioglitazone significantly increased phosphorylation of these proteins. Furthermore, pioglitazone treatment enhanced phosphorylation of STAT3 (Tyr705) after ischemia. These results indicate that pioglitazone attenuates neuronal ischemic injury through the activation of Akt and STAT3 pathways.

Efficacy of Endoscopic Fluorescein Video Angiography in Aneurysm Surgery-Novel and Innovative Assessment of Vascular Blood Flow in the Dead Angles of the Microscope.

BACKGROUND: In aneurysm surgery, assessment of the blood flow around the aneurysm is crucial. Recently, intraoperative fluorescence video angiography has been widely adopted for this purpose. However, the observation field of this procedure is limited to the microscopic view, and it is difficult to visualize blood flow obscured by the skull base anatomy, parent arteries, and aneurysm. OBJECTIVE: To demonstrate the efficacy of a new small-caliber endoscopic fluorescence video angiography system employing sodium fluorescein in aneurysm surgery for the first time. METHODS: Eighteen patients with 18 cerebral aneurysms were enrolled in this study. Both microscopic fluorescence angiography and endoscopic fluorescein video angiography were performed before and after clip placement. RESULTS: Endoscopic fluorescein video angiography provided bright fluorescence imaging even with a 2.7-mm-diameter endoscope and clearly revealed blood flow within the vessels in the dead angle areas of the microscope in all 18 aneurysms. Consequently, it revealed information about aneurysmal occlusion and perforator patency in 15 aneurysms (83.3%) that was not obtainable with microscopic fluorescence video angiography. Furthermore, only endoscopic video angiography detected the incomplete clipping in 2 aneurysms and the occlusion of the perforating branches in 3 aneurysms, which led to the reapplication of clips in 2 aneurysms. CONCLUSION: The innovative endoscopic fluorescein video angiography system we developed features a small-caliber endoscope and bright fluorescence images. Because it reveals blood flow in the dead angle areas of the microscope, this novel system could contribute to the safety and long-term effectiveness of aneurysm surgery even in a narrow operative field.

Reversible Cerebral Metabolism Changes Using Proton Magnetic Resonance Spectroscopy in a Patient with Intracranial Dural Arteriovenous Fistula: A Case Report.

BACKGROUND: Cerebral metabolism can be disrupted by venous congestion in patients with intracranial dural arteriovenous fistula (DAVF), which may lead to adverse neurological outcomes. However, there are no clear indicators to guide cerebral evaluation and treatment selection in cases of DAVF. We describe a patient with a DAVF whose proton magnetic resonance spectroscopy ((1)H-MRS) findings were associated with improvements in clinical status. CASE DESCRIPTION: An elderly woman with a history of myocardial infarction presented with progressive dementia, aphasia, and a severe headache. We detected a transverse-sigmoid sinus DAVF, as well as abnormal levels of lactate and N-acetylaspartic acid (NAA) in the (1)H-MRS, and successfully treated the patient using surgical sinus skeletonization. However, follow-up (1)H-MRS revealed inconsistent reversals in the levels of lactate and NAA. In addition, we calculated the NAA/creatinine ratios from before and after surgery, which revealed postoperative increases in the ratios for the left temporal, right parietal, and left parietal regions. These increases occurred concurrently with improvements in the patient's cognitive function. CONCLUSIONS: (1)H-MRS may be useful for pretreatment detection of increased lactate levels, decreased NAA levels, and/or decreased NAA/creatinine ratios. These findings may indicate poorer cerebral metabolism, and show a need for more aggressive treatment. Furthermore, (1)H-MRS may be useful for evaluating the effect of conservative treatment and for indicating conversion to a more aggressive treatment.

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.

Hypoglossal canal dural arteriovenous fistula embolized under precise anatomical evaluation by selective intra-arterial injection computed tomography angiography.

Dural arteriovenous fistula (DAVF) involving the hypoglossal canal is rare but increasingly reported. To achieve complete obliteration without a procedure-related complication, understanding of the precise anatomy of this DAVF is essential. Here, we describe a 72-year-old man who underwent selective intra-arterial injection computed tomography angiography which allowed us to understand the detailed anatomy of the complex DAVF regarding access routes and the target regions for transvenous embolization (TVE). With the aid of this novel neuroimaging technique successful target TVE was achieved safely and completely.

Cerebral hemodynamic disturbance in dural arteriovenous fistula with retrograde leptomeningeal venous drainage: a prospective study using (123)I-iodoamphetamine single photon emission computed tomography.

OBJECT: The severity of cerebral hemodynamic disturbance caused by retrograde leptomeningeal venous drainage (RLVD) of a dural arteriovenous fistula (dAVF) is related to neurological morbidity and unfavorable outcome. However, the cerebral hemodynamics of this disorder have not been elucidated well. The aim of this study was to assess the relationship between the cerebral venous congestive encephalopathy represented as a high-intensity area (HIA) on T2-weighted MR images and the cerebral hemodynamics examined by (123)I-iodoamphetamine (IMP) single photon emission computed tomography (SPECT), as well as the predictive value of (123)I-IMP SPECT for the development and reversibility of venous congestion encephalopathy. METHODS: Based on the pre- and posttreatment T2 HIAs associated with venous congestion encephalopathy, patients were divided into 3 groups: a normal group, an edema group, and an infarction group. The regional cerebral blood flow (rCBF) at the region with RLVD was analyzed by (123)I-IMP SPECT, and the results were compared among the groups. RESULTS: There were 11, 6, and 3 patients in the normal, edema, and infarction groups, respectively. No patients in the normal group showed any symptoms related to venous congestion. In contrast, all patients in the edema and infarction groups developed neurological symptoms. The rCBF in the edema group was significantly lower than that in the normal group, and significantly higher than that in the infarction group. The cerebral vascular reactivity (CVR) of the infarction group was significantly lower than that of the normal and edema groups. After treatment, the neurological signs disappeared in the edema group, but only partial improvement was seen in the infarction group. The rCBF also significantly increased in the normal and edema groups, but not in the infarction group. CONCLUSIONS: Quantitative rCBF measurement is useful for evaluating hemodynamic disturbance in dAVF with RLVD. The reduction of rCBF was strongly correlated with the severity of venous congestive encephalopathy, and loss of CVR is a reliable indicator of irreversible venous infarction caused by RLVD.

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.

The role of PARL and HtrA2 in striatal neuronal injury after transient global cerebral ischemia.

The presenilin-associated rhomboid-like (PARL) protein and high temperature requirement factor A2 (HtrA2) are key regulators of mitochondrial integrity and play pivotal roles in apoptosis. However, their roles after cerebral ischemia have not been thoroughly elucidated. To clarify these roles, mice were subjected to transient global cerebral ischemia, and striatal neuronal injury was assessed. Western blot and coimmunoprecipitation analyses revealed that PARL and processed HtrA2 localized to mitochondria, and that PARL was bound to HtrA2 in sham animals. Expression of PARL and processed HtrA2 in mitochondria significantly decreased 6 to 72 hours after ischemia, and the binding of PARL to HtrA2 disappeared after ischemia. In contrast, expression of processed HtrA2 increased 24 hours after ischemia in the cytosol, where HtrA2 was bound to X chromosome-linked inhibitor-of-apoptosis protein (XIAP). Administration of PARL small interfering RNA inhibited HtrA2 processing and worsened ischemic neuronal injury. Our results show that downregulation of PARL after ischemia is a key step in ischemic neuronal injury, and that it decreases HtrA2 processing and increases neuronal vulnerability. In addition, processed HtrA2 released into the cytosol after ischemia contributes to neuronal injury via inhibition of XIAP.

Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice.

Transplantation of neural stem cells provides a promising therapy for stroke. Its efficacy, however, might be limited because of massive grafted-cell death after transplantation, and its insufficient capability for tissue repair. Interleukin 6 is a pro-inflammatory cytokine involved in the pathogenesis of various neurological disorders. Paradoxically, interleukin 6 promotes a pro-survival signalling pathway through activation of signal transducer and activator of transcription 3. In this study, we investigated whether cellular reprogramming of neural stem cells with interleukin 6 facilitates the effectiveness of cell transplantation therapy in ischaemic stroke. Neural stem cells harvested from the subventricular zone of foetal mice were preconditioned with interleukin 6 in vitro and transplanted into mouse brains 6 h or 7 days after transient middle cerebral artery occlusion. Interleukin 6 preconditioning protected the grafted neural stem cells from ischaemic reperfusion injury through signal transducer and activator of transcription 3-mediated upregulation of manganese superoxide dismutase, a primary mitochondrial antioxidant enzyme. In addition, interleukin 6 preconditioning induced secretion of vascular endothelial growth factor from the neural stem cells through activation of signal transducer and activator of transcription 3, resulting in promotion of angiogenesis in the ischaemic brain. Furthermore, transplantation of interleukin 6-preconditioned neural stem cells significantly attenuated infarct size and improved neurological performance compared with non-preconditioned neural stem cells. This interleukin 6-induced amelioration of ischaemic insults was abolished by transfecting the neural stem cells with signal transducer and activator of transcription 3 small interfering RNA before transplantation. These results indicate that preconditioning with interleukin 6, which reprograms neural stem cells to tolerate oxidative stress after ischaemic reperfusion injury and to induce angiogenesis through activation of signal transducer and activator of transcription 3, is a simple and beneficial approach for enhancing the effectiveness of cell transplantation therapy in ischaemic stroke.

Neural stem cells genetically modified to overexpress cu/zn-superoxide dismutase enhance amelioration of ischemic stroke in mice.

BACKGROUND AND PURPOSE: The harsh host brain microenvironment caused by production of reactive oxygen species after ischemic reperfusion injury offers a significant challenge to survival of transplanted neural stem cells (NSCs) after ischemic stroke. Copper/zinc-superoxide dismutase (SOD1) is a specific antioxidant enzyme that counteracts superoxide anions. We have investigated whether genetic manipulation to overexpress SOD1 enhances survival of grafted stem cells and accelerates amelioration of ischemic stroke. METHODS: NSCs genetically modified to overexpress or downexpress SOD1 were administered intracerebrally 2 days after transient middle cerebral artery occlusion. Histological and behavioral tests were examined from Days 0 to 28 after stroke. RESULTS: Overexpression of SOD1 suppressed production of superoxide anions after ischemic reperfusion injury and reduced NSC death after transplantation. In contrast, downexpression of SOD1 promoted superoxide generation and increased oxidative stress-mediated NSC death. Transplantation of SOD1-overexpressing NSCs enhanced angiogenesis in the ischemic border zone through upregulation of vascular endothelial growth factor. Moreover, grafted SOD1-overexpressing NSCs reduced infarct size and improved behavioral performance compared with NSCs that were not genetically modified. CONCLUSIONS: Our findings reveal a strong involvement of SOD1 expression in NSC survival after ischemic reperfusion injury. We propose that conferring antioxidant properties on NSCs by genetic manipulation of SOD1 is a potential approach for enhancing the effectiveness of cell transplantation therapy in ischemic stroke.

Activation of signal transducers and activators of transcription 3 in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning.

The signal transducers and activators of transcription 3 (STAT3) has been suggested to have neuroprotective roles. However, its role in ischemic preconditioning (PC) is still obscure. In this study, we examined the phosphorylation status of ser727-STAT3, which is necessary for activation of STAT3, and its roles in a rat global ischemia model with or without PC. PC was induced by 3 min of nonlethal ischemia 48 h before 5 min of lethal ischemia. Western blot analysis showed that phospho-ser727-STAT3 significantly increased from 8 to 48 h after nonlethal ischemia, while it increased only for 1h after lethal ischemia and returned to the baseline within 24h. In the preconditioned brains, phospho-ser727-STAT3 was induced at 1 to 4h after lethal ischemia, and decrease of its levels delayed compared to the nonconditioned brains. Immunohistochemistry revealed that phospho-ser727-STAT3 was expressed mainly in CA1 neurons after nonlethal ischemia. Additionally, STAT3 inhibitor peptide treatment prevented PC induced-neuroprotection. These results indicate that phosphorylation of ser727-STAT3 plays an important role in PC induced- neuroptotection.

Effects of valsartan on neuroprotection and neurogenesis after ischemia.

Experimental and clinical studies have revealed that angiotensin II type 1 receptor blocker has protective effects against ischemic brain injury, but the mechanism is still obscure. Angiotensin II type 1 receptor blocker may also have effects on neurogenesis through the activation of unblocked angiotensin II type 2 receptors. In this study, we showed that valsartan significantly suppressed superoxide production and cytochrome C release into the cytosol after transient forebrain ischemia and consequently attenuated ischemic neuronal damage without affecting the blood pressure in rats. However, valsartan has none of the expected effects on neurogenesis after ischemia. These results suggest that valsartan has neuroprotective effects on ischemic injury through the suppression of oxidative stress and mitochondrial injury.

Indocyanine green videoangiography to detect aneurysm and related vascular structures buried in subarachnoid clots.

This 44-year-old woman presented with a ruptured anterior communicating artery aneurysm. Intraoperative indocyanine green (ICG) videoangiography demonstrated the aneurysm neck and dome, which were buried in subarachnoid clots. Dissection and aspiration of the clots around the neck were safely performed without touching the ruptured points. The aneurysm was successfully clipped. The patient's postoperative course was excellent. This case illustrates the use of intraoperative ICG videoangiography to provide information about the anatomical location of the aneurysm neck and dome despite their being completely obscured by subarachnoid clots. Intraoperative ICG videoangiography allowed safer dissection of the ruptured aneurysm from the blood clots.