Author report 20 patients who have shown rapid clinical and/or radiographic deterioration among 168 patients (Pts) (48 children and 120 adults) who underwent an extracranial to intracranial bypass surgery for moyamoya disease (MMD).
They included 12 child-onset MMD and 8 adult-onset MMD patients with age ranging from 17 months to 37 years.
Results: 17 Pts (85%) of 20 Pts presented with cerebral ischemia or infarction related symptoms or signs. 18 Pts underwent combined direct/indirect or multiple indirect bypass surgery prior to their deterioration (unilateral in 17 Pts and bilateral in one Pt).
Two pediatric Pts (17-month-old and 24-month-old) showed a fulminant clinical course associated with bilateral radiographic progression despite they underwent bilateral bypass surgery.
16 Pts (80%) of 20 Pts progressed within 10 months after an initial study clinically or radiographically regardless of the site or the method of bypass surgery.
7 Pts (4 children and 3 adults) demonstrated clinical deterioration accompanied with the radiographic progression.
Conclusion: These findings indicate that MMD can be progressed rapidly clinically and/or radiographicaly in pediatric Pts as well as adult Pts, although their frequencies are much lower in adult Pts as compared with pediatric Pts.

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In this study we investigated the effect of postischemic hypothermia on ROS production following transient forebrain ischemia using an in vivo microdialysis technique. Forebrain ischemia was induced by bilateral carotid artery occlusion combined with hemorrhagic hypotension for 20 minutes in male Wistar rats. The body temperature was kept at 37°C during ischemia and controlled at either 32°C or 37°C after reperfusion. The amount of hydroxyl radical produced in striatum was evaluated by measurement of 2, 3-and 2, 5-dihydroxybenzoic acid (DHBA), which is generated by salicylate hydroxylation. We also measured the extracellular concentration of xanthine and striatal blood flow by the hydrogen clearance technique. In animals whose postischemic body temperature was maintained at 37°C, the levels of 2, 3-and 2, 5-DHBA significantly increased after reperfusion. The peak levels of 2, 3-and 2, 5-DHBA were 2.9-fold 2.7-fold increase above the corresponding baseline values, respectively. Postischemic hypothermia completely inhibited the hydroxyl radical formation. Likewise, xanthine formation was also inhibited by postischemic hypothermia. In contrast, striatal cerebral blood flow was not altered by temperature modulation during reperfusion. These results suggest that inhibition of ROS production accompanied with suppression of xanthine formation is implicated in the neuroprotection of postischemic hypothermia.

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The members of the mitogen-activated protein kinase (MAPK) which are characterized as prolinedirected serine-threonine-protein kinases have crucial roles in transducing stress-related signals in eukaryotic cells and regulate cell death and survival. Recent studies have demonstrated that the members of the MAPK family, in particular p38 are activated following ischemia/reperfusion and suggest that this kinase signaling pathway may be important and responsible for tissue injury after ischemia/reperfusion. We investigated the activation of p38 in various brain ischemic models to clarify the roles of this stress kinase during brain ischemia.
To clarify the role of p38 in ischemic tolerance, a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia, we used a gerbil model of 2-minute ischemia folio wed by 5-minute ischemia. After the 2-minute global ischemia, active p38 immunoreactivity was enhanced at 6 hours of reperfusion and continuously demonstrated 72 hours after ischemia in CA1 neurons. Pretreatment with SB203580, an inhibitor of active p38, reduced the ischemic tolerance effect in a dosedependent manner. Immunoblot analysis indicated that the phosphorylation pattern of p38 kinase in the hippocampus induced by lethal ischemia was altered by preceding sublethal ischemia (preconditioning). These findings indicate that p38 pathway may play important roles in neuronal death and survival during brain ischemia. Components of the p38 pathway are important target molecules for clarifying the mechanism of ischemic brain injury.

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Elucidation of molecular mechanisms underlying ischemic brain damage is crucial for developing novel strategy of brain protection against stroke. Glutamate toxicity, free radical and apoptosis have been believed important for ischemic neuronal vulnerability. Although morphological studies have not demonstrated the characteristics of apoptosis in vulnerable neurons, growing evidence show the involvement of apoptotic mechanism such as caspase activation and gene expression of Bcl-2 family protein in ischemic neuronal damage. Overexpression of BCL-2 by gene transfer and transgenic mice attenuates ischemic brain damage, suggesting the potential strategy to inhibit apoptotic mechanism. Several neuroprotective genes such as BCL-2 includes cAMP-response element in their 5'-promoter region. Phosphorylation of cyclic AMP-response element binding protein (CREB) and activation of CRE-mediated gene expression have been shown in surviving neurons after ischemia and believed important in acquisition of ischemic tolerance. Moreover, apoptosis may be involved in survival of newborn neurons. Recent evidences show activation of neural stem cells and neurogenesis in the hippocampus after ischemia. It is likely that enhancement of survival of newborn cells would lead to functional recovery after stroke. CREB phosphorylation is transiently unregulated in immature neurons after bromodeoxyuridine labeling, suggesting the role of CRE-mediated gene expression in survival of newborn cells.

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Topical application of GDNF greatly reduced the infarct size (48%) and brain edema (30%) at 24 hr of continuous MCAO in rats. The reduction of the infarct size was not related to a change of cerebral blood flow (CBF), but was accompanied by marked reduction of positive cells for TUNEL and caspases in the affected area. Thus, GDNF showed a direct protective effect against ischemic brain damage, but not secondary by improving CBF. Based on the strong protective effect of NTF protein against ischemic brain damage and the considerable transfer of a foreign gene into ischemic brain, an adenovirus vector containing the GDNF gene (Ad-GDNF) was prepared, and a possible protective effect of the Ad-GDNF transfer was examined after transient MCAO in rat. Pretreatment of animals with Ad-GDNF 24 hr before the subsequent 90 min of transient MCAO effectively reduced infract volume and area without affecting regional CBF compared to the vehicle or Ad-LacZ animal groups.

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Angiogenesis is an intricately regulated phenomenon. Its mechanisms in the ischemic brain have not been clearly elucidated. we investigated expression of angiogenesis-related genes using a cDNA array method as well as western blotting and immunohistochemistry, and compared these studies with a temporal profile of angigenesis in mouse brains after ischemia. The number of vessels significantly increased 3 days after injury, and proliferating endothelial cells increased as early as 1 day. This means angiogenesis occurs immediately after the injury. Ninety-six genes implicated in angiogenesis were investigated with a cDNA array study. We found that 42, 29, and 13 genes were increased at 1 hour, and 1 and 21 days, respectively. Most of the well-known angiogenic factors increased as early as 1 hour. Vessel stabilizing factors such as thrombospondins also increased. At 1 day, however, thrombospondins decreased to lower than in the control, indicating a shift from vascular protection to angiogenesis. At 21 days, many genes were decreased, but some involved in tissue repair were newly increased. Western blotting and immunohistochemistry revealed findings compatible with the cDNA array study. Many molecules act in an orchestrated fashion in the brain after ischemia, and should be taken into account for therapeutic angiogenesis for stroke.

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To study the predictive significance of neurochemical monitoring in malignant infarction, we investigated the correlation between perfusional disturbances and neurochemical substances in a transient ischemia model in cats.
METHODS : In 10 cats, the middle cerebral artery was occluded (MCAO) for 3 hours followed by 6 hours reperfusion. Microdialysis probes were inserted into the core and the perifocal site of the MCA territory. Concentrations of purine catabolites and amino acids were analyzed by HPLC. Adjacent to the microdialysis probes, laser Doppler probes measured regional CBF (LDF), strain-gauge MicroSensors measured intracranial pressure (ICP).
RESULTS : Later in the reperfusion period, five cats developed signs of malignant edema formation including drastic drop of CPP, and finally pupil dilation.
CONCLUSIONS : In the ischemic core, glutamate determinations during MCAO predict fatal outcome, not in the perifocal site. Secondary glutamate elevation during reperfusion is presumably caused by a drastic decrease of CPP to<50 mmHg in the final stage of malignant infarction. However, this drop of CPP does not elevate adenosine. We assume that after reperfusion, salvage pathways are able to resynthesize IMP but not AMP.

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The mature adult brain has long been regarded as non-regenerating organ. Recent research, however, has shown that endogenous neural progenitors exist within the adult brain, which continue to provide new neurons into the specialized neurogenic regions. Here, we provide evidence that the hippocampal pyramidal neurons can be successfully regenerated after ischemic neuronal death by recruitment of endogenous neural progenitors. This therapeutic approach would open a new avenue for treatment of stroke with wide therapeutic window.

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We investigated the role of protein kinase C (PKC) isoforms and tyrosine kinase in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). In the development of vasospasm, PKCδ plays a role, and PKDα in its maintenance. These evidence were confirmed by in-situ treatment study using "two-hemorrhage" canine model. Two weeks after the first hemorrhage, the activity of PKC was declined. On the other hand, the activity of tyrosine kinase was enhanced. In the mechanism of vasospasm, the main role to sustain the vasospasm would change from PKC to tyrosine kinase. We also investigated the roles of biomechanical and phenotypic changes of cerebral arteries in the mechanism of prolonged vasospasm after SAH. Using basilar arteries in "two-hemorrhage" canine model, we chronologically measured the maximal contraction capacity and arterial stiffness until day 28. We examined histological changes of vasospastic canine basilar arteries with hematoxylin-eosin staining, and also immunohistochemically investigated the expression of smooth muscle myosin heavy chain isoforms (SMemb, SM1, and SM2), markers of phenotypic changes. Chronological changes of collagen concentration in canine basilar arteries were also measured. Angiographic cerebral vasospasm continued until day 14, then gradually relived and returned control level on day 28. The maximal contraction capacity chronologically decreased until day 21, then it showed some relief on day 28. On the other hand, stiffness of arterial wall progressed until day 28. Histological findings showed medial thickening and increase connective tissue until day 21, then returned close to the control on day 28. Because of no change of collagen concentration, increased connective tissues did not consist of collagen, but some other proteins. Immunohistochemical study using anti-SMemb, SM1, and SM2 showed enhanced expression of SMemb from day 7 to day 21 and dispappearance of SM1 and SM2. These changes returned to the normal control artery on day 28. These results indicate that biomechanical changes of vascular smooth muscle cells and phenotypic changes occurred in vasospastic canine basilar arteries. These changes might play a pivotal role to sustain prolonged cerebral vasospasm longer than 2 weeks following SAH instead of active myogenic arterial tone.

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Objective : Vasospasm and development of a delayed ischemic neurologic deficit following subarachnoid hemorrhage (SAH) is still a major reason for poor outcome of patients with successful clipped or coiled intracerebral aneurysms. We report our preliminary results of a MR-imaging protocol in patients after SAH. Perfusion (PWI) and diffusion (DWI) weighted MR imaging was utilized to identify tissue at risk for developing infarction due to vasospasm. On the basis of the results patients were selected for ballon anigoplasty or aggressive triple-H therapy.
Methods : 25 patients were included in the protocol for MRI at the 1st, 3rd, and 8th day after SAH. MR imaging included PWI and DWI, MR-angiography (MRA) as well as axial T2, T2* and FLAIR sequences. To identify tissue at risk a protocol similar to that utilized in ischemic stroke was used : areas with a delay perfusion>6 sec and no elevation of signal intensity in DWI. MRA was screened for narrowing of intracranial arteries. On the basis of these findings patients were selected for aggressive triple H therapy, more invasive monitoring or-when tissue at risk was identified-for ballon angioplasty.
Results : In 3 patients tissue at risk could be identified due to vasospastic narrowing of intracranial arteries. PWI and DWI showed severe missmatch in different vascular territories. With DSA segmental proximal vasospasm could be confirmed and subsequent ballon angioplasty was performed. In all three patients progression into tissue infarction could be prevented. In follow up MR imaging impaired tissue perfusion was significantly reduced.
Conclusion : MR imaging utilizing perfusion and diffusion weighted imaging is a very promising noninvasive tool to detect tissue at risk for infarction in cerebral vasospasm after SAH. Appropriate measures can be taken to prevent infarction as indicated in our preliminary series.

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The progress of the magnetic resonance (MR) imaging in the cerebral stroke patients was remarkable, and it became possible to evaluate a brain perfusion or function. Here, we describe about the clinical application of the neuronal tracts and brain perfusion evaluation using 3.0 Tesla MR imaging. The subjects were patients with internal cerebral hemorrhage and major cerebral occlusive diseases. Three dimensional anisotropy contrast (3DAC) imaging and diffusion tensor imaging (DTI) were accepted to estimate the damages of neurnal tracts. Perfusion weighted images with the contrast medium were performed for a quantitative evaluation. The pyramidal tracts were depicted well with 3DAC imaging. Fractional anisotropy (FA) value generated from DTI can predict the outcome of the motor dysfunction in each patient at early stage. Cerebral blood volume calculated from PWI was correlated with and cerebral vascular reserve capacity. 3.0 Tesla MR imaging may develop in cerebral stroke patients in near future.

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Introduction of multislice CT (MSCT) has revolutionizing the diagnosis of cerebro-vascular disease. Newly developed 32/64-slice MSCT enabled us to acquire isotropic volumetric data of whole brain with the resolution of 0.5-mm. CT perfusion is one of the promising application for the diagnosis of early-staged cerebral ischemia. However, it can be hazardous in terms of ionic radiation because of multiplied exposure to the same level. A new quantum denoising filter was developed in order to solve this problem. It is possible to reduce more than 80% of dose using the filter in combination with lower kv/lower mA technique. This filter can also aids to improve the detection of early CT signs, which is important for the diagnosis of cerebral ischemia. Detection of the penumbra can be made by revealing the absence of early CT sign and low perfusion area in CT perfusion. Isotropic volumetric data provided by MSCT can also be an ideal source data for the highquality 3D-CT angiography. Improved temporal resolution of MSCT in obtaining volumetric data made it possible separated visualization of arteries and veins on single 3D-CTA image. The technique to visualize brain surface using isotropic data and volume rendering algorithm was also reported.

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MR angiography is a non-invasive technique which can provide important information about cerebral vascular diseases such as cerebral aneurysms or occlusive lesions. As recent progress in MR angiography, image quality has become excellent and acquisition time has become much shorter. After introduction of a new multidetector helical CT scanner, it has become possible to produce high-speed CT angiography of high quality with significantly shorter acquisition time for the intracranial and cervical vessels. The feasibility of 3D views of intracranial and cervical vessels computed from planar digital angiograms acquired with a rotational angiography system has been evaluated. In the cases with aneurysm, 3D angiography is superior to conventional DSA concerning visualization of the aneurysm architecture.

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Diffusion tensor imaging is a unique technique to visualize cerebral white matter tracts and also to evaluate them quantitatively using diffusion indices such as fractional anisotropy (FA). The orientation of white matter tracts can be analyzed and tracked by the methods named as diffusion tensor tractography (DTT) or fiber tracking. Three dimensional relationship between the white matter tracts (such as corticospinal tract, corticobulbar tract, optic radiation) and the lesions (such as infarcts, tumors, AVMs) was clearly visualized (by a freeware : dTV and VOLUME-ONE). This information was helpful to know the prognosis of infarction in the eary stage, and was useful in preoperative evaluation of tumors and AVMs. Segmentation of the white matter using DTT and its quantitative analysis by FA were useful to evaluate the degree of the white matter changes in degenerative changes such as Wallerian degeneration and ALS.

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During more than a century of observations and experiences by neuro-scientists, involving a broad spec-trum of neurosurgical procedures and diagnostic investigations, it became apparent very early that congenital malformations, degenerative, infectious, toxic, hypoxic, vascular and neoplastic lesions occur at specific predilection sites within certain compartments of the CNS. This postulate will be presented, discussed and illustrated with radiologic and clinical documentation.

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Perforators are best defined as the small penetrating vessels that terminate in the deep substances of the brain and have minimal ability to provide collateral circulation. Surgeons are well acquainted with the perforators exiting the anterior communicating artery complex, middle cerebral artery, top of the basilar artery, and trunk of the basilar artery. This presentation discusses the management of these perforators and strategies to minimize their injury during surgery.

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Background Despite being considerably frequent, the treatment of hematomas within the basal ganglia continues to be a matter of debate. Proponents of a surgical approach assert that reduction of the clot volume improves perfusion of compromised brain tissue, prevents intracranial hypertension, and also enhances the clearance of blood breakdown products thus preventing secondary brain edema and other potential neurotoxicity contributing to poor outcome, a conception that is strongly supported by experimental studies. Vice versa, referring to numerous clinical studies, advocates of a conservative management allege that open surgery with craniotomy and encephalotomy traumatizes the surrounding brain structures and might fix or even increase neurological deficits. Based on this concept particularly primarily non-comatose patients are often not intended to undergo an operative procedure. Contrary to these deep-seated antithetic perceptions we recently showed, however, that as well noncomatose patients harboring hematomas within the basal ganglia can profit from minimally invasive subacute stereotactic treatment, and our encouraging results using this multiple target aspiration technique are herewith presented.
Methods Following rigorous selection criteria, 84 consecutive non-comatose patients were treated by subacute stereotactic evacuation of the hematomas. GCS scores after initiation of treatment, occurrence of medical complications, length of in-patient stay before discharge for further rehabilitative treatment, mortality, and long-term outcome after one year were recorded for each patient and were compared with the results obtained in a comparable group of 39 patients treated purely medically in another hospital using a matched-pair analysis.
Results Mean degree of aspiration was 88.8%, and rebleeding occurred only once (1.6%). The level of consciousness improved markedly after stereotactic surgery, and GCS scores were significantly higher than those after pure medical treatment. In comparison with medical patients, complications were considerably fewer in the surgical group, and thus peri-ictal morbidity and mortality were significantly lower. Length of necessary treatment on the ICU as well as total in-patient stay in the acute care facility were significantly reduced. Employing four parameters commonly used to assess outcome, long-term outcome among survivors was significantly better in surgical patients compared to medical patients.
Conclusions The multilple target aspiration technique performed in the subacute stage is a rapid and safe method and combines a high success rate with very low risk of recurrent hemorrhage. Improving vigilance, the occurrence of medical complications in the course of hemorrhagic stroke is significantly decreased. Thus morbidity and mortality are reduced, recovery is accelerated, and patients are earlier suitable for further rehabilitative treatment. Since longterm outcome is better compared to pure medical treatment, primarily non-comatose patients with basal ganglia hematomas ultimately profit from this form of minimally invasive treatment.

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Diffusion tensor tractography is a newly developed method for tracing tracts in white matter using combination of diffusion tensor images. We evaluate the degree of impairment of optic tracts in the cases with visual field defect after temporal lobectomy using diffusion tensor tractography. We examined 8 cases after temporal lobectomy for temporal lobe epilepsy. Visual field defect in medial sector and lateral sector of upper 1/4 visual field were evaluated. Diffusion tensor tractography of optic radiation was made from 6 axes diffusion tensor images. We evaluated the correlation between the degree of visual field defect and visualization of Meyer's loop on tractographies. Medial sector field tends to be impaired after temporallobectomy. Diffusion tensor tractography showed incomplete to no visualization of Meyer's loop in the cases with severe visual field defect. While, visualization of optic radiation was almost complete in cases with mild visual field defect. Diffusion tensor tractography was useful in evaluating post surgical changes in optic radiation. Potential usefulness of tractography in surgical planning was also suggested.

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Functional imaging including perfusion study has been feasible in acute cerebral ischemia, which can provide the information of areas of pneumbra or tissue at risk even by MR examination. Pathophysiological significance or clinical usefulness of perfusion-diffusion MRI, however, has not been confirmed because of lack of comparison with experimental inspection or investigation of prediction for risk of thrombolysis. Some methodological drawbacks, i.e., tracer delay effect on dynamic susceptibility-contrast MRI, cause serious underestimation of CBF value in evaluating remediable area on perfusion MRI. Oxygen metabolic imaging by PET would be superior to MRI in detecting areas of evolving infarct in the hyperacute stage of cerebral infarction. Considering these unsolved problems, development of proper correction to improve accuracy of the method with the validation of physiological phenomenon would be needed in the functional MR imaging in the clinical state of the hyperacute stage of cerebral infarction.

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We sought to assess ischemic tissue reversibility by SPECT or diffusion/perfusion MRI in acute ischemic stroke patient who performed successful thrombolytic therapy. We had 546 consecutive cases of acute ischemic stroke in our hospital last year. Thrombolytic therapy was performed in 32 patients (22 in intraarterial thromblysis and 10 in intravenous t-PA) who had diffusion/perfusion mismatch within 6 hours from symptom onset. In patients who had successful vessel recanalization with treatment, relative ADC lesioncontralateral normal region ratios was obtains in the following regions : 1) infarct core with hyperintensity on DWI, abnormality on PWI and follow-up abnormality, 2) non-infarcted penumbra with abnormality on DWI and PWI, and normal follow-up and 3) hypoperfused tissue that remained viable with normal DWI, abnormal PWI and normalfollow-up. Fifteen patients with early vessel recanalization were studied. Mean time from symptom onset to recanalization was 5.1 hours. Within 4 hours from symptom onset, no regions of interest with an ADC ratio more than 0.8 infarcted. Between 4 hours and 7 hours, regions of interest with ADC of 0.8-0.9 showed viable or infacrtion. Evaluation of ischemic threshold measured by ADC ratio may provide important information for clinical decision making of thrombolytic therapy.

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Neuroprotective therapy is crucial to salvage the penumbra area surrounding the core of cerebral ischemia in the acute phase of ischemic stroke. Therefore various kinds of neuroprotective compounds have been developed.
In this symposium we introduced our experimental studies on several kinds of neuroprotective com-pounds and mild hypothermic therapy.
Effects of immunosuppressant, FK506, free radical scavenger, edaravone, poly (ADP-ribose) polymerase (PARP) inhibitor, CIA470 and super-apoptotic agent, PTD-FNK (Bcl-xL modified protein) on cerebral infarct volumes in transient focal ischemia in rats were studied, and also therapeutic time window of FK506 for neuroprotection was examined. Furthermore effect of mild hypothermic therapy (35°C) was investigated in FK506.
FK506 significantly reduced infarct volume, and the therapeutic time window was between 60 and 120 min in the dose (0.3mg/kg) in this model.
In the hypothermic studies, only combination treatment with FK506 and hypothermia significantly reduced infarct and edema volumes. Therefore mild hypothermic therapy could enhance the neuroprotective effect and prolong the therapeutic time window for the compound.
Edaravone significantly reduced infarct and edema volumes, and CIA470 also had significant effect on infarct and edema volumes in the low and high dose-treated groups.
Newly developed PTD-FNK, which is modified Bcl-xL protein combined with protein transduction domain (PTD) of HIV/Tat protein, significantly reduced infarct volume and ameliorated neurological symptoms. Protein therapeutics such as PTD-FNK may be a new therapeutic strategy for the acute ischemic stroke.
These present data show that these newly developed compounds and the combination treatment with mild hypothermia are effective for neuroprotection in acute cerebral ischemia. These therapies may be useful in clinical medical care for acute ischemic stroke.

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Treatment decisions are increasingly based on neuroimaging not only for differential diagnosis of cerebral ischemia, parenchymal hemorrhage, cerebral venous thrombosis, acute encephalitis or brain edema but mainly due to its impact for the indication of different therapeutic options and impact for prognosis. The neurological score of deficits and the time window are most important factors for therapeutic regimen. However, since stroke is a highly complex and inhomogenous disease rigid orientation along these two parameters alone is not decisive for stroke therapy, but requires additionally specific imaging patterns either of MRI or CT. Further, findings in functional imaging point to the probability that the degree of hyperperfusion may play a more important role compared to the volume of an ischemic damage. Therefore prior to treatment neuroimaging should evaluate the location of arterial occlusion, the location and extension of parenchymal hypoperfusion and the penumbra as treatable and thus salvageable tissue at risk, which is regarded as the most relevant strokefactor.
To achieve all data mandatory for a conclusive stroke therapy, the so called "imaging triage", has to be performed within a maximum of 30 minutes including evaluation of the image. Though many imaging tools are available for stroke diagnosis such as USdoppler, SPECT, PET, CT, MR or DSA multimodality investigation is not recommended in respect to time pressure. The rationals and algorithms for diagnostic procedures depend on the sensitivity of methods for defining the target of reperfusion therapy avoiding reperfusion of damaged brain tissue. Moreover, the imaging techniques chosen must give early and correct information about the prognosis of clinical outcome and the prediction of malignant infarction. These prerequisites are best fulfilled at the moment by MRI, if all modalities (DWI, PWI, ce MRA) are used. However, the sensitivity of currently developing more sophisticated CT-techniques (multi-row perfusion CT, CTA source images, 3-D-CTA) approachs close to that of MR.
The implications of a modern imaging in stroke will be exemplified.

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Acute local intra-arteriral fibrinolysis (LIF) should be neutrally evaluated at present. The efficacy of LIF has never been evaluated objectively, and standard pre-therapeutic evaluation and therapeutic technique has never been established. Regarding to the efficacy, PROACT II was performed and finished in USA, but final decision is still postponed. MELT Japan is now progressing in Japan. The subject of both studies is middle cerebral artery embolism, so no such study is still performed for basilar artery embolism. Standard pretherapeutic evaluation and therapeutic technique are established in MELT Japan. The patient in whom LIF can be started within 6 hours after onset, with the NIH stroke scale of 5 to 22, without ischemic lesion in cerebral cortex can be enrolled in MELT Japan. Midterm results were reported in February 2004. The total cases registered were 68 and the cases finishing follow-up period of 3 months were 52. The cases with modified Rankin Scale (mRS) 0 to 2 at 3 months were 12 in 26 LIF group, while 8 in control group. The study period of MELT Japan was postponed and MELT Japan is still in progress now.

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Treatment of acute ischemic stroke with alteplase, an intravenous recombinant tissue plasminogen activator (rt-PA) has been approved in 40 countries, but not yet in Japan. To assess the clinical applicability of this therapy in Japan, we conducted a single dose open label multicenter trial (Japan Alteplase Clinical Trial, J-ACT).
Inclusion and exclusion criteria in this study were almost the same as NINDS rt-PA Stroke Study, except that excluded were patients with early ischemic changes>1/3 of the MCA territory on the pretreatment CT, mild stroke defined as the pretreatment NIH Stroke Scale (NIHSS) score 4 or less, and patients with coma. Patients received alteplase at dose of 0.6 mg/kg. The dose was chosen because of the results of a study for patients with acute myocardial infarction and the duteplase study for embolic stroke patients both carried out earlier in Japan. The modified Rankin Scale (mRS), NIHSS, and Barthel Index scores at 3 months from stroke onset were evaluated for outcome measures. Adverse events and symptomatic intracranial hemorrhage (s-ICH) were assessed within the initial 3 months.
A total of 103 patients (78% for cardioembolic stroke) were enrolled. The baseline NIHSS scores were comparable to those in the NINDS trial. The incidence of s-ICH within 36 hours from treatment, and the ratio of good outcome (mRS 0-1) and mortality at 3 months were consistent with those in the NINDS trial. In con-clusion, the efficacy and safety of alteplase at 6.0 mg/kg in J-ACT was comparable to that at the 0.9 mg/kg in the NINDS trial.

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Fasudil (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1, 4-diazepine hydrochloride or AT877, HA1077, Eril) is a unique vasodilating and brain protecting drug. It has been used in Japan since 1995 in patients with aneurysmal subarachnoid hemorrhage (SAH) to prevent vasospasm. It showed more brain protective effect than vasodilating effect itself, which suggested its efficacy in the treatment of cerebral infarction. A recent double blind trial of fasudil (60mg, iv/60 min, bid for 14 days) on patients with acute cerebral infarction showed that it significantly improved both motor dysfunction (p=0.0013) on day 14 and ADL (P=0.0015) on 30 days. In experimental animal models of stroke, fasudil prevented decrease in number of hippocampal CA1 neurons, migration of white blood cells (WBCs) to the infarction area, inhibited free radical production by WBCs and normalized increased blood viscosity.
Mechanism of action of fasudil has gradually been elucidated, now inhibition of protein kinases, especially rho kinase (Ki=0.3 uM), and protein kinase C (Ki=3uM) are considered to be important. In both cerebral vasospasm and infarction, upregulation of Rho kinase is considered to be important in the pathogenesis of brain damage. Rho kinase inhibits myosin phosphatase, leading to increased phosphorylation of myosin light chain. Rho kinase also inhibits NO synthase in the vascular endothelium. Upregulated Rho and C kinases are considered to be involved in migration of WBCs, production of free radicals by NADPH oxidase in WBCs and decreased NO synthesis in the endothelium. Thus, inhibition of these protein kinases by fasudil can explain its clinical effects.
Hydroxylated metabolite of fasudil (M3) similarly inhibits both Rho and C kinases with longer biological half-life of about 5 hours compared with that of fasudil (45 min) after intravenous infusion. Effectiveness of fasudil by intermittent infusion (two or three times a day) may, at least partly, depend on its hydroxylated metabolite.

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Carotid atherosclerosis is resoponsible for atherothrombotic brain infarcts. Plaques with an ulcerated cap and overlying thrombus and those with a large lipid core may be more susceptible to distal embolisation and complication during carotid endarterectomy and angioplasty with stenting. Distal embolisation may lead to a variety of new ischemic brain lesions, including borderzone, arterial territorial, and lacunar infarcts. This diversity of the lesion appeared to be correlated with histologic features of the embolic materials (cholesterol crystal with or without other atheromatous components, fibrin, or platelets). This variation in the components of the emboli may determine the size and location of the lodged arteries and feasibility of re-opening and hemorrhagic transformation. Distal protection devices trap and divert many emboli seen with this procedure and therefore effectively prevent cerebral complication. Duplex and MRI of carotid artery may be useful for determining the risks of endovascular intervention within individual patients according to plaque morphology.

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Carotid ultrasonography (CUS) is essential for evaluating the carotid artery lesion in the following reasons. First, CUS is useful as a screening examination for patients with risk factors, because of its noninvasiveness and feasibility. Patients with hypertension, DM, hyperlipidemia or cardiovascular diseases have frequently progressive carotid artery lesions. CUS is recommended in patients with such risk factor who are symptom. Second, CUS is used to follow up carotid artery lesions, because of its non-invasiveness. Carotid artery stenosis often progresses increasing stroke risks, while the stenosis is retracted in some patients. Third, CUS can evaluate the nature of plaque not only morphologically but also pathologically. Plaques are classified into "echolucent", "echogenic" and "hyperechoic" from their echogenesity, and these classifications reflect atheroma/thrombus, fibrous tissue and calcification, respectively. Such tissue characterization is useful to evaluate the plaque vulnerability. Forth, CUS allows us to recognize the plaque mobility. Recently some plaques were found to strain with heartbeat, although the existence of floating thrombus attached to plaques has been known for many years. Strained plaques are considered reflect acute intra-plaque hemorrhage, and this finding is the serious sign of unstable plaque.

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Purpose : We started MR-angiography examination from 1992 in our brain health check-up opened at 1988 in Institute of Shimane Health Science. We studied natural history of intracranial artery stenosis in 2, 164 neurological normal subjects without any stroke history who received our brain health check-up.
Methods: We analyzed the influence of intracranial artery stenotic lesion for stroke onset during follow up including risk factors such as hypertension, silent brain infarction (SBI) and silent white matter lesion (PVH3-4).
Results : Intracranial artery stenosis was observed 4.7% including mild stenosis. The risk factors for arterial stenosis were aging and hypertension. Intracarnial artery stenosis significantly related to SBI and PVH3-4. Logistic analysis revealed that stenotic lesion is significant predictor for brain infarction (Odds ratio : 2.6). Severe stenosis related stroke onset.
Conclusion : Intracranial artery stenosis could be a predictor for brain infarction in normal subjects. Therefore, strict control of risk factors and intervention should be needed for these subjects.

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Percutaneous cerebral balloon angioplasty (PTCBA) has been developed. Procedural success and risks or long-term benefits must be anticipated before PTCBA for intracranial atherosclerotic lesions. To estimate them, you have to know angiographic lesions' characteristics appropriate to PTCBA.
1) Intracranial balloon angioplasty Forty-two clinically symptomatic patients with 42 hemodynamical1y significant intracranial lesions (% diameter stenosis>70) underwent initial and elective PTCBA between January 1992 and May 1996. Before the angioplasty treatment, the patients were classified into three groups according to the angiographic lesions' characteristics summarized as follows : type A, a short and concentric stenosis ; type B, a tubular lesion, or an extreme eccentric lesion ; and type C, a diffuse lesion. They were followed after PTCBA from one month to six years to compare between the three groups. Primary end points were death, stroke, or bypass surgery. The clinical success rates in type A, B and C groups were 92%, 86% and 33% (p = 0.0032), respectively. Cumulative risks of fatal or nonfatal ischemic stroke/ipsilateral bypass surgery in type A, B and C groups were 8%, 26% and 87% (p<0.0001), respectively. The cumulative risk of 8% in type A group patients appeared to be smaller than in historical studies. PTCBA for intracranial simple (type A) lesions produces a favorable clinical outcome for symptomatic patients.
2) Cerebral artery stenting
Between March 1998 and November 1998, 12 intracranial atherosclerotic lesions (type B or C) of the vertebrobasilar artery and the distal internal carotid artery in 10 patients were treated with stenting treatment using flexible balloon-expandable coronary stents. Ten lesions in 8 patients were sufficiently dilated with stents. No complications occurred during or after the procedure and no neurological ischemic events or restenosis have occurred during follow-up since successful CAS. Cerebral angioplasty and stenting may be a safe and effective means to resolve an intracranial atherosclerotic type B or C lesions and yield a favorable arteriographic and clinical outcome. Cerebral artery stenting can increase success rate and reduce risks for lesions inappropriate to balloon angioplasty.
3) PTCBA for chronic total occlusion
Chronic total occlusions younger than 3 months, shorter than 10 mm, are classified into type B lesions. They can be opened.
4) PTCBA and stenting for acute stroke patients
Clinical outcome of acute stroke patients presenting serious neurological symptoms due to total occlusions of the vertebro-basilar artery (VBA) is poor and direct percutaneous transluminal cerebral balloon angioplasty (PTCBA) and/or cerebral artery stenting (CAS) for recanalization of the VBA is promising.
In conclusion, PTCBA and stenting for ntracranial arteries is feasible and safe, and good clinical outcome following PTCBA and/or CAS for ntracranial arteries is expected.

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Endovascular treatment for stenosis of intracranial and skullbase cerebral arteries is promising but still investigational strategy. Recent development of balloon catheters and application of coronary stents to these arteries has enabled revascularization in selected cases. Indication of this treatment should be strictly limited to elderly/poor risk patients contraindicated to surgical treatment, patients with probable severe cerebral infarction by occlusion, patients with crescendo TIA/progressive stroke refractory to best medical treatment. Result of initial experiences, tips and pitfalls, and present status and future perspective of the treatment are presented. Accumulation of more experiences, development of devices, and technical improvement are needed for further refinement of this treatment in the future.

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The clinical effectiveness of neuroprotective therapy for acute stroke has not yet been proved definitively. Edaravone, was, however, exceptionally judged effective by the third phase clinical trial. The third phase trial of edaravone was unique from the viewpoint that the majority patients had small thrombotic infarction in the perforating artery territory and the time of drug administration was within 72 hours after stroke. Of all strokes in the perforating artery territory, 20-25% are known to show a progressive time course. Our diffusion-weighted MRI study indicated that ischemic lesions in the progressive type stroke were first located in a small area of corona radiata and later exstended towards the neighboring zones gradually. It is considered likely that edaravone exerted the protective action in such progressive type stroke. Neuroprotective drugs have never been succeeded in the treatment of embolic stroke, probably because they can inhibit only one of multiple pathways leading to ischemic neuronal death. Hypothermia inhibits all the pathways and may be more appropriate for the treatment of embolic stroke than neuroprotective drugs. In our recent clinical study, local hypothermia with a cooling helmet successfully reduced the brain temperature and ameliorated the clinical outcome of large embolic stroke. The local hypothermia is promising for the treatment of aged embolic stroke patients because of its feasibility, safety and non-invasiveness.

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