Koji Tokunaga

Determinants of Poor Outcome After Aneurysmal Subarachnoid Hemorrhage when both Clipping and Coiling Are Available: Prospective Registry of Subarachnoid Aneurysms Treatment (PRESAT) in Japan

OBJECTIVE To examine current determinants of poor outcome after aneurysmal subarachnoid hemorrhage (SAH) when ruptured aneurysms are treated with either microsurgery (clipping) or endovascular treatment (coiling) depending on each patients characteristics. METHODS Between March 2006 and February 2007, 534 patients with SAH were enrolled in the Prospective Registry of Subarachnoid Aneurysms Treatment (PRESAT) project. Patients were treated according to the preference of investigators who were experienced in performing both clipping and coiling. Factors influencing poor outcome (12-month modified Rankin Scale [mRS], 3-6) were determined using multivariate logistic regression analyses. RESULTS In this cohort, 32.4% of patients were World Federation of Neurosurgical Societies (WFNS) grade IV-V, and 28.1% had a poor outcome. Clipping was preferably performed for small aneurysms with a wide neck and for middle cerebral artery (MCA) aneurysms, whereas coiling was preferred for larger, internal carotid artery (ICA) and posterior circulation aneurysms. In addition to increasing age, admission WFNS grade IV-V, preadmission aneurysmal rerupture, vasospasm-induced cerebral infarct, pneumonia, sepsis, shunt-dependent hydrocephalus and seizure, postclipping hemorrhagic complications (odds ratio 4.8, 95% confidence interval 1.5-15.3, P < 0.01), and postcoiling ischemic complications (odds ratio 4.4, 95% confidence interval 1.3-15.2, P < 0.05) significantly caused poor outcomes, although the complications did not affect mortality. Type of treatment modality and size and location of aneurysms did not influence outcome. CONCLUSIONS Introducing an endovascular treatment option has made aneurysm characteristics less important to outcome, but procedural complications are problematic and should be reduced to improve outcome.

Prophylactic Thrombosis to Prevent New Bleeding and to Delay Aneurysm Surgery

Six aneurysms in five patients with acute aneurysmal subarachnoid hemorrhages were treated with direct thrombosis using cellulose acetate polymer within 4 hours of rupture. The aneurysms involved the internal carotid and posterior communicating arteries (two patients), the anterior choroidal artery (one patient), the bifurcation of the basilar artery (one patient), and the middle cerebral artery (two patients). Four patients underwent aggressive volume expansion after direct thrombosis with cellulose acetate polymer. The aneurysms remained thrombosed until operations on the necks were performed 2 to 7 weeks after the subarachnoid hemorrhages. Three patients were given intrathecal tissue plasminogen activator. One patient, who remained at neurological Grade V, was not treated surgically and died from cardiac failure. Five aneurysms in the remaining four patients were successfully clipped. These preliminary data suggest that immediate aneurysmal thrombosis, then aggressive preoperative prophylactic volume expansion and/or administration of intrathecal tissue plasminogen activator, can help prevent new bleeding and reduce delayed cerebral ischemia in patients after aneurysmal subarachnoid hemorrhages.

Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis

Parkinsons disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neuronal systems. Several therapeutic tools for PD include medication using L-DOPA and surgeries such as deep brain stimulation are established. However, the therapies are considered as symptomatic therapy, but not basic remedy for PD and a new regenerative therapy would be desired to explore. In this study, the neuroprotective/rescue effects of erythropoietin (EPO), a well known hematopoietic hormone, on dopaminergic neurons were explored with neurogeneic potencies of EPO. EPO (100 IU/day) was continuously administered with micro-osmotic pump for a week to PD model of rats induced by intrastriatal 6-hydroxydopamine (6-OHDA) injection with subsequent behavioral and immunohistochemical investigations. The number of amphetamine-induced rotations of EPO-treated rats significantly decreased, compared to the control rats. The preservation of dopaminergic neurons of EPO-treated rats were confirmed by tyrosine hydroxylase staining and Fluoro-Gold staining. The number of bromodeoxyuridine (BrdU)/polysialic acid-neural cell adhesion molecule (PSA-NCAM) double positive cells in the subventricular zone of EPO treated rats significantly increased with migratory potencies to the damaged striatum,compared to the control rats. Furthermore, TUNEL staining and phosphorylated Akt staining revealed that the neuroprotective/rescue effects of EPO might be mediated by anti-apoptotic effects through the increase of phosphorylated Akt. These results suggest that continuous low dose infusion of EPO exerts neuroprotective/rescue effects with neurogeneic potentials. EPO might be a strong tool for PD therapy, although the further experiments should be added.

Antivasospastic and antiinflammatory effects of caspase inhibitor in experimental subarachnoid hemorrhage

OBJECT Inflammation in the subarachnoid space and apoptosis of arterial endothelial cells have been implicated in the development of delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). The authors investigated mechanisms of possible antivasospastic effects of N-benzyl-oxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK), a caspase inhibitor that can inhibit both inflammatory and apoptotic systems, in animal models of SAH. METHODS Rabbits were assigned to three groups of eight animals each and were subjected to SAH by injection of blood into the cisterna magna. The experiments were performed in the following groups: SA only, SAH + vehicle, and SAH + Z-VAD-FMK. The Z-VAD-FMK (1 mg) or vehicle (5% dimethyl sulfoxide) was intrathecally administered before SAH induction. Diameters of the basilar artery (BA) were measured on angiograms obtained before and 2 days after SAH. The BA diameter on Day 2 was expressed as a percentage of that before SAH. Interleukin (IL)-1 in the cerebrospinal fluid (CSF) was examined using Western blotting, and brains were immunohistochemically examined for caspase-1 and IL-1beta. In a separate experiment, 20 rats were subjected to SAH and their brains were immunohistochemically assessed for caspase-1, IL-1beta, and macrophages. RESULTS. In rabbits, Z-VAD-FMK significantly attenuated cerebral vasospasm (the BA diameter on Day 2 in SAH-only, SAH + vehicle, and SAH + Z-VAD-FMK groups was 66.6 +/- 3.2%, 66.3 +/- 3.7%, and 82.6 +/- 4.9% of baseline, respectively), and suppressed IL-1beta release into the CSF and also suppressed immunoreactivities of caspase-1 and IL-1P in macrophages infiltrating into the subarachnoid space. Immunoreactivities for caspase-1 and IL-1P were observed in immunohistochemically proven infiltrating macrophages in rats. CONCLUSIONS These results indicate that caspase activation may be involved in the development of SAH-induced vasospasm through inflammatory reaction.

EFFECTS OF DEFEROXAMINE-ACTIVATED HYPOXIA-INDUCIBLE FACTOR-1 ON THE BRAINSTEM AFTER SUBARACHNOID HEMORRHAGE IN RATS

OBJECTIVEHypoxia-inducible factor (HIF)-1 is a transcription factor that regulates the expression of various neuroprotective genes. The goal of this study was to clarify the relationship between HIF-1 expression and subarachnoid hemorrhage (SAH) and to characterize the effects of deferoxamine (DFO)-induced increases in HIF-1 protein levels on the brainstem and the basilar artery (BA) after experimental SAH. METHODSRat single- and double-hemorrhage models (injected on Days 0 and 2) of SAH were used. We assessed the time courses for HIF-1 protein levels in the brainstems and the BA diameters within 10 minutes and 6 hours on Days 1 and 2 in the single-SAH model, and also on Day 7 in the double-SAH model. After induction of double hemorrhage in rats, DFO was injected intraperitoneally. We then evaluated HIF-1 protein expression and brainstem activity, BA diameter, and brainstem blood flow. RESULTSAfter the rats experienced SAH, HIF-1 protein expression was significantly greater at 10 minutes in the single-injection model and at 7 days in the double-injection model than at similar time points in the control group, and these increases correlated with degrees of cerebral vasospasm. DFO injection resulted in significant increases in HIF-1 protein expression and activity in the brainstems of rats with SAH, compared with the rats with SAH that were given placebos, and the rats without SAH in the double-hemorrhage model. Cerebral vasospasm and reduction of brainstem blood flow were significantly attenuated in the rats that were administered DFO. CONCLUSIONThese results show that a DFO-induced increase in HIF-1 protein level and activity exerts significant attenuation of BA vasospasm and reduction of brainstem blood flow in the rat model of SAH. DFO may be a promising agent for treating clinical SAH.

Endovascular treatment for bow hunter's syndrome: case report.

INTRODUCTION Bow hunters syndrome is a unique clinical entity caused by mechanical occlusion of the vertebral artery on head rotation. Although it is usually treated by direct surgical intervention, we report successful treatment using endovascular stent placement for contralateral vertebral artery stenosis. CASE DESCRIPTION A 56-year-old man presented with repeated vertigo and loss of consciousness caused by turning his head to the left. Right vertebral angiogram showed no abnormalities with the head in the neutral position. However, with the head rotated 60 degrees to the left, the right vertebral artery was completely occluded at the C1-2 level. A three-dimensional angiogram with bone window clearly demonstrated vertebral artery compression at the C1-2 level by the bony structure. The left subclavian angiogram revealed severe stenosis at the origin of the left vertebral artery. Left vertebral artery angioplasty followed by stent placement was successfully performed under local anesthesia. The patient showed an uneventful postoperative course and his preoperative symptoms disappeared. At 6 months postoperatively, a left subclavian angiogram showed good patency of the stented left vertebral artery and the patient showed no recurrent symptoms. CONCLUSION Vertebral artery stenting is a useful and less invasive option in the treatment of bow hunters syndrome in the setting of contralateral vertebral artery stenosis.

Assessment of the difference in posterior circulation involvement between pediatric and adult patients with moyamoya disease

OBJECT There is no description of the change in the posterior cerebral artery (PCA) in the diagnostic criteria of moyamoya disease (MMD). However, PCAs are often involved in the clinical setting, and an understanding of the significance of PCA lesions is therefore of great importance when evaluating the disease progression and predicting prognosis. The aim of this study was to assess the difference in posterior circulation involvement in pediatric and adult patients with MMD. METHODS The records of 120 consecutive patients with MMD were reviewed. The clinical manifestations at diagnosis were evaluated on the basis of symptoms and CT and MRI findings. The degree of steno-occlusive internal carotid artery (ICA) lesions and the existence of steno-occlusive PCA lesions were evaluated by observing a total of 240 ICAs and PCAs on angiography. Angiographic correlation between anterior and posterior circulation was assessed in pediatric and adult patients with MMD. RESULTS Seventeen (26%) of 66 pediatric patients and 18 (33%) of 54 adult patients exhibited steno-occlusive PCA lesions. There was no significant difference in the prevalence of PCA lesions between pediatric and adult patients with MMD (p = 0.36). The prevalence of infarction in pediatric and adult patients with PCA involvement was significantly higher than that in pediatric and adult patients without PCA involvement (p = 0.0003 and p = 0.003, respectively). There was no significant difference in the distribution of infarction areas between pediatric and adult patients with PCA involvement (p = 0.62). On the basis of the staging system used, steno-occlusive lesions in ICAs ipsilateral to PCAs with lesions were in significantly advanced stages compared with lesions in ICAs ipsilateral to PCAs without lesions in both pediatric and adult cases (p < 0.0001 and p = 0.0008, respectively). Pediatric patients had less advanced steno-occlusive lesions in ICAs ipsilateral to PCAs with lesions compared with adults (p < 0.05). CONCLUSIONS The clinical significance of posterior circulation involvement in MMD was similar between pediatric and adult patients. The only significant difference was that less advanced ICA lesions could complicate posterior circulation involvement in pediatric patients.

Mannitol enhances therapeutic effects of intra-arterial transplantation of mesenchymal stem cells into the brain after traumatic brain injury

Traumatic brain injury (TBI) sustained in a traffic accident or a fall is a major cause of death that affects a broad range of ages. The aim of this study was to investigate the therapeutic effects of intra-arterial transplantation of mesenchymal stem cells (MSCs) combined with hypertonic glycerol (25%) or mannitol (25%) in a TBI model of rats. TBI models were produced with a fluid percussion device. At 24h after TBI, MSCs (1×10(6)cells/100μl) with glycerol or mannitol were administered via the right internal carotid artery. Rats were evaluated behaviorally and immunohistochemically, and hyperpermeability of the blood-brain barrier (BBB) induced by hypertonic solutions was explored. Compared to PBS or glycerol, the administration of mannitol resulted in increased BBB disruption. The mannitol-treated rats showed significant improvement in motor function. Intra-arterial transplantation of MSCs caused no thromboembolic ischemia. Immunohistochemically, more MSCs were observed in the injured brain tissues of mannitol-treated rats than in glycerol or PBS-treated rats at 24h after transplantation. Intra-arterial transplantation of MSCs combined with mannitol is an effective treatment in a TBI model of rats. This technique might be used for patients with diseases of the central nervous system including TBI.

Effect of external stenting and systemic hypertension on intimal hyperplasia in rat vein grafts.

OBJECTIVE Overdistention of vein grafts in arterial circulation and systemic hypertension are thought to be influential risk factors contributing to vein graft failures. This study tested the effects of external stenting in preventing systemic hypertension and overdistention of the rat vein graft in the long term. METHODS Jugular vein grafts were interposed into the carotid artery of normotensive (n = 39) and two-kidney, one-clip hypertensive (n = 30) rats. Jugular vein grafts wrapped with 1.5-mm-diameter polyester stents were used in normotensive (n = 26) and hypertensive (n = 25) rats. The vein grafts were harvested at 1, 2, 4, 8, 12, and 24 weeks after the grafting procedure. The neointimal area and wall thickness were measured by computerized planimetry, and Ki-67 immunohistochemistry was used to detect replicative smooth muscle cells in the graft wall. RESULTS In each group, intimal hyperplasia was apparent at 1 week and increased gradually to 24 weeks. The number of Ki-67-positive cells was most increased at 2 weeks after the grafting procedure and gradually decreased thereafter. The numbers of Ki-67-positive cells and the extent of intimal hyperplasia were not significantly different between normotensive and hypertensive rats. Both neointima formation and cell proliferation in the graft wall were significantly reduced by external stenting as compared with the results with unstented grafts. CONCLUSION Systemic hypertension by itself is not a risk factor for intimal hyperplasia and experimental vein graft failure in the long term. External stenting is effective against intimal hyperplasia, and it is possible to reduce the subsequent atherosclerotic change of the vein graft wall and improve the long-term patency of the vein graft with external stenting.

Computational fluid dynamics of carotid arteries after carotid endarterectomy or carotid artery stenting based on postoperative patient-specific computed tomography angiography and ultrasound flow data.

BACKGROUND:There are significant differences in the postoperative morphological and hemodynamic conditions of the carotid arteries between carotid artery stenting (CAS) and endarterectomy (CEA). OBJECTIVE:To compare the postoperative rheological conditions after CAS with those after CEA with patch angioplasty (patch CEA) through the use of computational fluid dynamics (CFD) based on patient-specific data. METHODS:The rheological conditions in the carotid arteries were simulated in 2 patients after CAS and in 2 patients after patch CEA by CFD calculations. Three-dimensional reconstruction of the carotid arteries was performed with the images obtained with computed tomography angiography. The streamlines and wall shear stress (WSS) were calculated by a supercomputer. Adequate boundary conditions were determined by comparing the simulation results with ultrasound flow data. RESULTS:CFD was successfully calculated for all patients. The differences between the flow velocities of ultrasound data and those of the simulation results were limited. In the streamline analysis, the maximum flow velocities in the internal carotid artery after patch CEA were around two-thirds of those after CAS. Rotational slow flow was observed in the internal carotid artery bulb after patch CEA. WSS analysis found regional low WSS near the outer wall of the bulb. High WSS was observed at the distal end of the arteriotomy after patch CEA and at the residual stenosis after CAS. CONCLUSION:CFD of postoperative carotid arteries disclosed the differences in streamlines and WSS between CAS and patch CEA. CFD may allow us to obtain adequate rheological conditions conducive to achieving the best clinical results.